CA2396561C - Substituted oxazolidinones and their use in the field of blood coagulation - Google Patents
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- CA2396561C CA2396561C CA002396561A CA2396561A CA2396561C CA 2396561 C CA2396561 C CA 2396561C CA 002396561 A CA002396561 A CA 002396561A CA 2396561 A CA2396561 A CA 2396561A CA 2396561 C CA2396561 C CA 2396561C
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- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
The invention relates to the field of blood coagulation. Novel oxazolidinone derivatives of the general formula (I) (see formula I) processes for their preparation and their use as medicinally active compounds for the prophylaxis and/or treatment of disorders are described.
Description
-30725-107 (S) SUBSTITUTED OXAZOLINDINONES AND THEIR USE IN THE FIELD OF
BLOOD COAGULATION
The present invention relates to the field of blood coagulation. In particular, the present invention relates to novel oxazolidinone derivatives, to processes for their preparation and to their use as active compounds in medicaments.
Blood coagulation is a protective mechanism of the organism which helps to "seal"
defects in the wall of the blood vessels quickly and reliably. Thus, loss of blood can be avoided or kept to a minimum. Haemostasis after injury of the blood vessels is effected mainly by the coagulation system in which an enzymatic cascade of complex reactions of plasma proteins is triggered. Numerous blood coagulation factors are involved in this process, each of which factors converts, on activation, the respectively next inactive precursor into its active form. At the end of the cascade comes the conversion of soliible fiiarinogen into insoluble fibrin, resulting in the formation of a blood clot, Iri blood coagulation, traditionally the intrinsic and the extrinsic system, which end in a joint reaction path, are distinguished. Here factor Xa, which is formed from the proenzyme factor X, plays a key role, since it connects the two coagulation paths. The activated serine protease Xa cleaves prothrombin to thrombin. The resulting thrombin, in turn, cleaves fibrinogen to fibrin, a fibrous/gelatinous coagulant. In addition, thrombin is a potent effector of platelet aggregation which likewise contributes significantly to haemostasis.
Maintenance-of norrnal haemostasis - between bleeding and thrombosis - is subject to .
a complex regulatory mechanism. Uncontrolled activation of the coagulant system or defective inhibition of the activation processes may cause formation of local thrombi or embolisms in vessels (arteries, veins, lymph vessels) or in heart cavities.
This may lead to serious disorders, such as myocardial infarct, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive disorders, pulmonary embolisms or deep venous thromboses; hereinbelow, these disorders are collectively also referred to as thromboembolic disorders. In addition, in the case of consumption coagulopathy, hypercoagulability may - systemically - result in disseminated intravascular coagulation.
These thromboembolic disorders are the most frequent cause of morbidity and mortality in most industrialized countries (Pschyrembel, KIinisches Worterbuch Le A 34122-~oreis:n Countries
BLOOD COAGULATION
The present invention relates to the field of blood coagulation. In particular, the present invention relates to novel oxazolidinone derivatives, to processes for their preparation and to their use as active compounds in medicaments.
Blood coagulation is a protective mechanism of the organism which helps to "seal"
defects in the wall of the blood vessels quickly and reliably. Thus, loss of blood can be avoided or kept to a minimum. Haemostasis after injury of the blood vessels is effected mainly by the coagulation system in which an enzymatic cascade of complex reactions of plasma proteins is triggered. Numerous blood coagulation factors are involved in this process, each of which factors converts, on activation, the respectively next inactive precursor into its active form. At the end of the cascade comes the conversion of soliible fiiarinogen into insoluble fibrin, resulting in the formation of a blood clot, Iri blood coagulation, traditionally the intrinsic and the extrinsic system, which end in a joint reaction path, are distinguished. Here factor Xa, which is formed from the proenzyme factor X, plays a key role, since it connects the two coagulation paths. The activated serine protease Xa cleaves prothrombin to thrombin. The resulting thrombin, in turn, cleaves fibrinogen to fibrin, a fibrous/gelatinous coagulant. In addition, thrombin is a potent effector of platelet aggregation which likewise contributes significantly to haemostasis.
Maintenance-of norrnal haemostasis - between bleeding and thrombosis - is subject to .
a complex regulatory mechanism. Uncontrolled activation of the coagulant system or defective inhibition of the activation processes may cause formation of local thrombi or embolisms in vessels (arteries, veins, lymph vessels) or in heart cavities.
This may lead to serious disorders, such as myocardial infarct, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive disorders, pulmonary embolisms or deep venous thromboses; hereinbelow, these disorders are collectively also referred to as thromboembolic disorders. In addition, in the case of consumption coagulopathy, hypercoagulability may - systemically - result in disseminated intravascular coagulation.
These thromboembolic disorders are the most frequent cause of morbidity and mortality in most industrialized countries (Pschyrembel, KIinisches Worterbuch Le A 34122-~oreis:n Countries
-2-[clinical dictionary], 257s' edition, 1994, Walter de Gruyax Verlag, page 199 ff., entry "Blatgerinnung [blood eoagulationj; Rlfmpp Laxikon Chemmie, Version 1.5, 1998, Georg Thietne Veriag Stuttgart, entry "Blutgerinnung"; LubeR Strya, Biochemie [biochemistry), Spekntua der Wissenschaft Vertagagesellschaft mbH
S Heidelberg, 1990, page 259 ff.).
The anticoagulants, i e. substwcu for inlribiting or p:cventing blood ctmgnlation, which are known from the prior art have vatious, often grave disadvantages.
Accordingly, in practice, an efficient treahnent method or prophylaxis of d~mmbocmbolic disarders is very difficult and imsatisf'actory.
~. .
1n dtc therapy and prophylaaia of tl~mboetnbolic disorders, use is firstly made of hepaYin, which is administered parentesally or subcutaneoosly. Owing to moi+e favourable pharmacoldnetic pmperties, pr+efenencx is nowadays mame and moat given to low-molecular-weight hepmn; however, even with low-molecular-weight heparin, it is not possible to avoid the Irnown disadvantages described below, which aze involved in haparin therapy. Thus, heparin is ineffective when administered orally and has a relatively short half-life. Since heparin inhibits a plurality of factors of the blood coagulation cascade at the same tinie, the action is nonselective.
Mnroover, thera is a high risk of bleeding; in patticular, brain haenwrrhages and gastrointestinal bleeding may occur, which may result in thrnmbopenia, dng-inducxd alopecia or osteoporosis (Pschyirembel, Klinisches W&terbtich, 257' edition, 1994, Waiter de Gruyter Verlag, page 610, entry "Hepann"; Rompp Lexikon Chemie, Version 1.5, ~- 1998, Georg Thierne Verlag $tuttgart, entry "Heparin").
A secaond class of andcoagulants am the vitamin K antagonists. Meae include, for example, 1,3-indanediones, and especially compounds such as warfarin, phenprocaounAon, dicumarol and other coumarin derivatives which inhibit the = -,:...
synthesis of various products of caatain vitamin K-dependent eoagolotiori factors in the liver in a non-selective manner. Owing to the mechanism of action, however, the onset of de action is very slow (latency to the owet of action 36 to 48 hours). It is possible to administer the compounds orally; however, owing to the high risk of bleeding and the narrow therapeutic index, a time-mnsuming individual sdjustment and monitoring of the padent are required. Moraover, other adverae effeets, such as gastrointestinal disturbances, hair loss and skin necroses, have been described (Pschyrembel, Klinisches WBrterbuch, 257d' editiem,1994, Walcer de Gruyotr Verlag.
j~ A 34 122 FonagnCMWM
S Heidelberg, 1990, page 259 ff.).
The anticoagulants, i e. substwcu for inlribiting or p:cventing blood ctmgnlation, which are known from the prior art have vatious, often grave disadvantages.
Accordingly, in practice, an efficient treahnent method or prophylaxis of d~mmbocmbolic disarders is very difficult and imsatisf'actory.
~. .
1n dtc therapy and prophylaaia of tl~mboetnbolic disorders, use is firstly made of hepaYin, which is administered parentesally or subcutaneoosly. Owing to moi+e favourable pharmacoldnetic pmperties, pr+efenencx is nowadays mame and moat given to low-molecular-weight hepmn; however, even with low-molecular-weight heparin, it is not possible to avoid the Irnown disadvantages described below, which aze involved in haparin therapy. Thus, heparin is ineffective when administered orally and has a relatively short half-life. Since heparin inhibits a plurality of factors of the blood coagulation cascade at the same tinie, the action is nonselective.
Mnroover, thera is a high risk of bleeding; in patticular, brain haenwrrhages and gastrointestinal bleeding may occur, which may result in thrnmbopenia, dng-inducxd alopecia or osteoporosis (Pschyirembel, Klinisches W&terbtich, 257' edition, 1994, Waiter de Gruyter Verlag, page 610, entry "Hepann"; Rompp Lexikon Chemie, Version 1.5, ~- 1998, Georg Thierne Verlag $tuttgart, entry "Heparin").
A secaond class of andcoagulants am the vitamin K antagonists. Meae include, for example, 1,3-indanediones, and especially compounds such as warfarin, phenprocaounAon, dicumarol and other coumarin derivatives which inhibit the = -,:...
synthesis of various products of caatain vitamin K-dependent eoagolotiori factors in the liver in a non-selective manner. Owing to the mechanism of action, however, the onset of de action is very slow (latency to the owet of action 36 to 48 hours). It is possible to administer the compounds orally; however, owing to the high risk of bleeding and the narrow therapeutic index, a time-mnsuming individual sdjustment and monitoring of the padent are required. Moraover, other adverae effeets, such as gastrointestinal disturbances, hair loss and skin necroses, have been described (Pschyrembel, Klinisches WBrterbuch, 257d' editiem,1994, Walcer de Gruyotr Verlag.
j~ A 34 122 FonagnCMWM
-3-page 292 ff., entry "coiuaatin daivatives"; Illmann's Encyclopodia of Induuatrial Chemistry, 516 edition, VCH Verlagsgesellschaft, Weinheim, 1985 - 1996, entry "vitamin K").
Recently, a novel tlwerapeutic approach for the treatment andd prophyiaxis of throinboembolic diaotders has been described. This nowl dwapeutic approach aims to inhibit factor Xa (cf. WO-A-99/37304; WO-A-99/06371; J. Hattptrntum, J. Sttinebecher, Thrombosis Reseamh 1999, 93, 203; F. Al-Obeici, J. A. Ostrem, Factor Xa inhibitots by classical and combinatozial chemistry, DDT 1998, 3, 223;
F. Al-Obeidi, J. A. Ostrcm, Factor Xa inhibiton, Exp. Opin. Ther. Patents 1999, 9, 931; B. Kaiser,lltrornbin and factor Xa inhibitors, Drogs of the Future 1996, 23, 423; A. Uzan, Antithrombotic agmts, Emerging Drugs 1998, 3, 189; B.-Y. Zhu, R. M. Sce,rbarough, Curr. Opin. Card. Pulm. Ren. Inv. Drugs 1999,1(1), 63). It has been shown that, in animal models, various both peptidic and noopeptidic compounds are effective as factor Xa inhibitors.
Accordingly, it is an object of the present invention to provide novel substanees for controlling disorders, which substances have a wide therapeutic spearum.
In particular, they should be suitable for a nwre efficient prophylaxis and/or treatment of thromboembolic disorders, avoiding - at least to some extent -the disadvantages of the prior art described above, wheta the term "thmmboembolic disorders" in the context of the present invention is to be unde:atood as meaning, in ,.. particular, serious disarders, such as myocardial infanat, angina pectoris (including unstable angina), reocclusions and nsttenoses after angioplasty or aortocoronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive disorders, pulmonary embolisms or deep venous thromboses.
It is another object of the pnsent invention to provide novel anticoagt:lerns whichr'--inhibit the blood coagutation facw Xa with incneased selectiivity, avoiding -at least to sonie extent - the lx+oblems of the therapeutic methods for thmmboembolic disorders known from the prior art.
L& A 34122-Foaeigg Cougtdo
Recently, a novel tlwerapeutic approach for the treatment andd prophyiaxis of throinboembolic diaotders has been described. This nowl dwapeutic approach aims to inhibit factor Xa (cf. WO-A-99/37304; WO-A-99/06371; J. Hattptrntum, J. Sttinebecher, Thrombosis Reseamh 1999, 93, 203; F. Al-Obeici, J. A. Ostrem, Factor Xa inhibitots by classical and combinatozial chemistry, DDT 1998, 3, 223;
F. Al-Obeidi, J. A. Ostrcm, Factor Xa inhibiton, Exp. Opin. Ther. Patents 1999, 9, 931; B. Kaiser,lltrornbin and factor Xa inhibitors, Drogs of the Future 1996, 23, 423; A. Uzan, Antithrombotic agmts, Emerging Drugs 1998, 3, 189; B.-Y. Zhu, R. M. Sce,rbarough, Curr. Opin. Card. Pulm. Ren. Inv. Drugs 1999,1(1), 63). It has been shown that, in animal models, various both peptidic and noopeptidic compounds are effective as factor Xa inhibitors.
Accordingly, it is an object of the present invention to provide novel substanees for controlling disorders, which substances have a wide therapeutic spearum.
In particular, they should be suitable for a nwre efficient prophylaxis and/or treatment of thromboembolic disorders, avoiding - at least to some extent -the disadvantages of the prior art described above, wheta the term "thmmboembolic disorders" in the context of the present invention is to be unde:atood as meaning, in ,.. particular, serious disarders, such as myocardial infanat, angina pectoris (including unstable angina), reocclusions and nsttenoses after angioplasty or aortocoronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive disorders, pulmonary embolisms or deep venous thromboses.
It is another object of the pnsent invention to provide novel anticoagt:lerns whichr'--inhibit the blood coagutation facw Xa with incneased selectiivity, avoiding -at least to sonie extent - the lx+oblems of the therapeutic methods for thmmboembolic disorders known from the prior art.
L& A 34122-Foaeigg Cougtdo
-4-Accemdfngly, the pmsant invention provides substituted oxazolidinones of the pneral fonmula (1) R:
R R~
R"yR' (n, in which:
R' nTreswts optiona,uy benzo-fused thiophem (thienyl) which may optionally be mono- or polysubstituted;
R2 represents any orpinic radical;
R3, R", Rs, R6, R7 and Rg are identical or different and each represents hydrogen or rqxuents (C,-C6)-alkyl and their pharmaceutically acceptable saits, hydrates and prodrugs, except for compounds of the general formula (1) in which the radical R' is an unsubstituted 2-thiophrne radical and the radical R2 is simuitaneously a mono-or poiysubstituted phenyl radical and the radicals R3, R4, RS, R6, R7 and Rs ate each simultaneously hydrogen.
Prefenencx is given here to compounds of the geneisl formula (I), =...
in which R' repnesents optionally benzo-fused thiophene (thienyl) which may optionally be mono- or polysubstituted by a radieal from the group consisting of halogen; cyano; nitro; amino; aminomethyl; (CI-C')-alkyl which for its part may optionally be mono- or polysubstituted by halogen; (C3-C7)-cycloalkyl;
Le A 34122-FoWn QgagZig
R R~
R"yR' (n, in which:
R' nTreswts optiona,uy benzo-fused thiophem (thienyl) which may optionally be mono- or polysubstituted;
R2 represents any orpinic radical;
R3, R", Rs, R6, R7 and Rg are identical or different and each represents hydrogen or rqxuents (C,-C6)-alkyl and their pharmaceutically acceptable saits, hydrates and prodrugs, except for compounds of the general formula (1) in which the radical R' is an unsubstituted 2-thiophrne radical and the radical R2 is simuitaneously a mono-or poiysubstituted phenyl radical and the radicals R3, R4, RS, R6, R7 and Rs ate each simultaneously hydrogen.
Prefenencx is given here to compounds of the geneisl formula (I), =...
in which R' repnesents optionally benzo-fused thiophene (thienyl) which may optionally be mono- or polysubstituted by a radieal from the group consisting of halogen; cyano; nitro; amino; aminomethyl; (CI-C')-alkyl which for its part may optionally be mono- or polysubstituted by halogen; (C3-C7)-cycloalkyl;
Le A 34122-FoWn QgagZig
-5-(Ci-Ca)-aftxy; imidamlinyl; -C(=NH)NH2; carbamoyl; and mono- and di-(C,-C.)-atlcyl-Mninocarbonyl, R2 representa one of the groups below:
A-, AM-, D-M-A-, B-M-A-, B-, B-M-, r B-Ivt B-, D-M-B-, whete:
the radical "A" tepnsents (C',6-Cu}aryl, pnrfembly (C6-C,o)-aryl, in particular pbenyl or naphthyl, very puticulady pneferably phenyl;
the radical "B" repments a 5- or 6-aarmbered aromatic heterocycle which contains up to 3 heteroatoma and/or hetsxo chain members, in porticular up to 2 hetei+oatoms andlor heLe[o chain members, from the group consisting of S. N, NO (N-oxide) and 0;
the redical "D" mTreswts a saaurated or partially unsawr8ted, mono-or bicyclic, optionally benzo-fused 4- to 9-membered hetemcycle which containa up to tht+ee heteroatoms and/or hetero chain members frrom the group conaisdng of S, SO, SOZ, N, NO (N-oxide) and O;
the radical "M" repnuents NH-, -CHr, -C'H2CHr, -0-, -NIi-CHr, -CH2-NH-, -OCHr, -CH2O-, -CONH-, -NHCO-, -COO-, -OOC-, -S-, -SO=- or izpresents a covalent band;
where ,.... .
the gmups "A", "B" and "D" defined above may each optionally be morw- or polysubatituted by a radical from the group consisting of halogcn; tciftuoromethyl; oxo; cyano; nitro; cubunoyl; pyridyl; (Ci-C6)-alkanoyl; (C3-C,)-cycloalkkannoyl; (Cs-CI4)-"ca:bonyl; (Cs-C-a)-heteroarylcarbonyl; (Ci-C6)-alkanoyloxymethyloxy; (Cl-C4)-hydroxy-alkylcarbonyl; -COORr; -SO2Rn; -C(NRrR)=Ne; -CONRR";
-SO2NR19RM; -OR30; -NR"R31, (Ci-C6).allcyl and (C3-C7)_cycloalkyl, LeA34 122-Foneign Cotmcris,s
A-, AM-, D-M-A-, B-M-A-, B-, B-M-, r B-Ivt B-, D-M-B-, whete:
the radical "A" tepnsents (C',6-Cu}aryl, pnrfembly (C6-C,o)-aryl, in particular pbenyl or naphthyl, very puticulady pneferably phenyl;
the radical "B" repments a 5- or 6-aarmbered aromatic heterocycle which contains up to 3 heteroatoma and/or hetsxo chain members, in porticular up to 2 hetei+oatoms andlor heLe[o chain members, from the group consisting of S. N, NO (N-oxide) and 0;
the redical "D" mTreswts a saaurated or partially unsawr8ted, mono-or bicyclic, optionally benzo-fused 4- to 9-membered hetemcycle which containa up to tht+ee heteroatoms and/or hetero chain members frrom the group conaisdng of S, SO, SOZ, N, NO (N-oxide) and O;
the radical "M" repnuents NH-, -CHr, -C'H2CHr, -0-, -NIi-CHr, -CH2-NH-, -OCHr, -CH2O-, -CONH-, -NHCO-, -COO-, -OOC-, -S-, -SO=- or izpresents a covalent band;
where ,.... .
the gmups "A", "B" and "D" defined above may each optionally be morw- or polysubatituted by a radical from the group consisting of halogcn; tciftuoromethyl; oxo; cyano; nitro; cubunoyl; pyridyl; (Ci-C6)-alkanoyl; (C3-C,)-cycloalkkannoyl; (Cs-CI4)-"ca:bonyl; (Cs-C-a)-heteroarylcarbonyl; (Ci-C6)-alkanoyloxymethyloxy; (Cl-C4)-hydroxy-alkylcarbonyl; -COORr; -SO2Rn; -C(NRrR)=Ne; -CONRR";
-SO2NR19RM; -OR30; -NR"R31, (Ci-C6).allcyl and (C3-C7)_cycloalkyl, LeA34 122-Foneign Cotmcris,s
-6-whem (Ci-Cs}slkyl aad (C3-C?)-cycloalkyl for gheir pwtt may optionally be subsdtuted by a radical from the gmup consisting of cyatw; -0e; -NR2W9; -CO(NI~r(NRr0) aad -C(NRrO)=NR9, where:
v iseither0orl and Rr, 0 and R29 are idencical or differam and indepandently of one anothar each mpmmts hydcogen, (CI-C4)-alkyl, (C3-C7)-cycloaikyl, (Ci-Q)-alkanoyl, carbamoyl, trifluorotnethyl, phenyl or pyridyl, and/or Rr' and Oor Rr and e togetlrer with the nitrogcn atoin to wh"
they are attached fonn a saturated or partially unsaturated 5- to
v iseither0orl and Rr, 0 and R29 are idencical or differam and indepandently of one anothar each mpmmts hydcogen, (CI-C4)-alkyl, (C3-C7)-cycloaikyl, (Ci-Q)-alkanoyl, carbamoyl, trifluorotnethyl, phenyl or pyridyl, and/or Rr' and Oor Rr and e togetlrer with the nitrogcn atoin to wh"
they are attached fonn a saturated or partially unsaturated 5- to
7-mombeted hettnocycle having up to three, pnrfexably up to two, identical or different heteroatoms from the group conais4ng of N. 0 and S. and R30 and R31 are identical or differant and independently of one anothec each r+epresents hydrogcn, (CI-C.)-alkyl, (Ca-C7)-cycloalkyl, (C,-C4)-alkylsulphonyl, (Cj-C{}hydnoxyalkyl, (CI-C4)-aminoalkyi, di-(Ci-C4)-alkylarnino-(C,-C4)-aikyl, -CH2C(NRr'R28~ or -CORs3, = = . ~.._.
where represents (Ci-Ca)-alkoxy, (C1-C4)-alkoxy-(Ci-Ca)-alkyl, (Cj-C.)-alkoxycarbonyl-(Ci-Ca)-al1ry1, (Ci-Cs)-aminoalkyl, (CI-Cs)-alkoxycarbonyl, (CI-Ca)-alkanoyl-(Ci-Cs)-alkyl, (Ca-Cr)-cycloalkyl= (C,-Ca)-alkeayl, (CI-Cg)-alkyl, which may optionaUy be substituted by Le A 34 122Foreian Comtdm plx,nyl or acetyl= (Cs-CIs)-aryl, (CrCio)-}COMoaryl, trifluoromethyl, tetrahydmfuranyl or butyrolactone, R3, R4, Rs, R6 R7 aod Ra are ideaticg or 'dtffaent nd each rep~ents hyds,cgen or represeats (C,-C5}alkyl and their pharmaceutically accx.ptable salts, hydrues and prodrugs, except foer componnds of the pnaal focmula (1) in which dM radic.al R' is an unsubstituted 2-thiophene radical and the radical R2 is simultaneously a mono-or polysubstituted phesyl radicai and the radicals R3, e. Rs, R6, R7 and Rs m each simultaneously hydrogen.
Pcefenance is also given here to compounds of tlu gCnetW fomuila (1), in which R' represents thiophene (thienyl), in particular 2-thiophane, which may optionally be nxono- or polysubatituted by halopn, praferably chlorine or bromine, by amino, aminomethyl or (CI-Ca)-alkyl, preferably nzethyl, where the (CI-Ce)-alkyl radical for its part may optionaily be mono- or polysubstidited by halogen, preferably fluorine, ~~ R2 represents one of the groups below:
A-, A-M-, D-M-A-, B-M-A-, B-, B-M-, B-M-B-, D-M-B-, where:
jA A 34122-j~gMggCoamtnes - ~ -the radical "A" represams (C.s-C14)-aryl, Preferably (C,s-Clo}.arYl, in Pwdcular phenyl or naphthyl, verl' Puticulariy preferably Phatyl;
the radical "B" repTeaents a 5- or 6-membered atomatic hetnocycle which contains up to 3 hetetn toms and/or hetero cbain membtrs, in paracular up to 2 hetematoms and/or hetero chain members, from the gtoap coasisting of S. N. NO (N-oxide) and O;
the radical "D" represents a saturated or partially unsaurated 4- to 7-munbee+ed hetaocycle which contains up to three lommoatoms and/or herrx+o chain mcmbers from the group consisting of S, SO, SO2s N. NO
(N-oxide) and O;
the radical "M" repmsem -NH, -CHr, -CS2cijr, -0-, -NH-Cfi2-, -CH=-NH , -OCHs-, -CH2O-, -CONH , -NIiCO-. -COO-, -OOC-, -S-or represents a covalent bond;
wheie the groups "A", "B" and "D" defined above may in each case optionally be mono- or polysubstituted by a radical from the graip consisting of halogen; trifluoroniethyl; oxo; cyano; nitro; carbamoyl;
Pyndyl; (Ct-Cs)-allcanoyl; (C3-C7)-cycloslkatwyl; (C6 Cja)-arykarbonyl; (Cs-CIo)-heteroatylcarbonyl; (CI-C6)-alksnoyloxynxthyloxy; -COORY'; -S02Rr; -C(NRnRN)~;
-CONR=aV; -SO2NR~R"; -OR30; -NRft3l, (C,-C6)-alkyl and (C3-C7}-cyclo lkyl, whm (CI-C6),allcyl and (Cs-C7)-cY'cloalkyl for their put may optionalIy be substituted by a radical from the group consisting of cym-o; -ORr'; -NOe; -CO(NH),,(NRrR=) and -COirR26)-M", ti,....
whene:
v is eitha 0 or 1 and RP, 0 and e ara idantical or differeat and indepaadently of ona another each reMsents hydrogen, (Ci-Ca)-alkyl or (C3-C7)-cycloalkyl, je A 34122-Forei g~~'-ountries and/or Rr and R2B or e and R29 togetha with the nitrogm atom to which they are anadmd form a saturated or partially unsaturated 5- to 7-membered heterocycle having up to three, preferably up to two, identical or diffenent heternatom from the group consisting of N, 0 and S, and R30 and R31 a><,e identical or different aod 'uldependently of one anecher each ropresentg hydtngen, (CI-C4)-alkyl, (C3-C7)-cycloellryl, ,.~ (Cl-C4)-allrylsulphonyl. (CI-G)-hydroxyallryl, (CI-C4)-aminoalkyi, di-(CI-C4)-alkylamino-(CI-C4)-sikyl, (CI-C4)-alkanoyl, (C6-Cl4}arylcarbMYl, (Cs-Cjo)-heteroarylcarbonyl, (C 1-C4)-,alkylaminocarbonyl or -CH2C(NR270"e, R3, e, Rs, R6, R7 and Rs are identical or different and each zeptualts hydrogen or represents (C,-C6)-alkyl and their pharmaceutically acceptable salts, hydrates and prodtugs, except for compaunds of the general formula (I) in which the radical R' is an unsubstituted 2-thiophene radical and the radical R2 is simultaneously a mono-or polysubstituted phenyl radical and the radicals R3, R~, R', R6, R7 and Rs are each simultaneously hydrogen.
Particular preference is given here to compounds of the generai formula (1), in which : L.:._.
R' represents thiophene (thienyl), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, or by (CI-C=)-alkyl, preferably methyl, where the (Cl-CG)-alkyl radical for its part may optionally be mono- or polysubstituted by halogen, pneferably fluorine, R2 repnesents one of ihe groups below:
Le A 34 122-Poreian Countries A-, A-M-, D-lui A-, B-M-A-, B-, B-M-, B-M-B-, D-M-B-, where:
~.. the radical "A" represents phenyl or naphthyl, in particulas phenyl;
the radieal "B" represents a 5- or 6-membered aromatic hetarocycle which contains up to 2 heteroatoms from the group consisting of S. N, NO (N-oxide) and 0;
the radical "D" napresents a saturated or partially unsatiumted 5- or 6-membenod heterocycle which contains up to two heteroatoms mnd/or hetero chain members from the group consisting of S, SO, SOZ, N, NO
(N-oxide) and 0;
the radical "M" represents -NH-, -0-, -NH-CHr, -CH2-NH-, -OCHi-, -CHZO-, -CONH-, -NHCO- or repre,sents a covalent bond;
where the gmps "A", "B" and "D" defined above may in each case optionally be mono- or polysubstituted by a radical from the group consisting of halogen; trifluoramethyl; oxo; cyano; pyridyl; (Ci-C3)-alkanoyl; (C6-Cio)-arylcarbonyl; (Cs-C6)-heternarylcarbonyl; (CI-C3)-alkanoyloxymethyloxy; -C(NRnR23 )=NR29; -CONR28R29;
-SO2NR2gR29 ; -OH; -NR30R31; (CI-C<)-alkyl; and cyclopropyl~~
cyclopentyl or cyclohexyl, where (C I-C4)-alkyl and cyclopropyl, cyclopentyl or cyclohexyl for their part may optionally be substituted by a radical from the group consisting of cyano; -OH; -OCH3;
-NRft29; -CO(NH)õ(NRrR23) and -C(NRne)=NR29, where:
j{ A 34 1FonVism Countda v is eather 0 a 1, preferably 0, and Rn, e and e are ideatical or differa-t and indepeadattly of one another each tepiesants hydrogen, (Ci-Cs)-alkyl or else cyclopropyl, cyclopentyl or cycloiuxyl and/or RF and R2' or R27 and R" together with the nitrogen atom to which they are auacbed may form a saturated or partially unaturated 5- to ?-memberod heterocycle having up to two identical or different heteroatoms from the group consisting of N. 0 and S.
and R30 and R3' are identical or different and indepeadmly of one another each reptesents hydrogen, (CI-C4)-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (CI-C4)-alkylsulphonyl, (CI-C4)-hydroxyalkyl, (Ci-C4)-aminoalkyl, di-(Cj-C4)-alkylamino-(CI -C4)-alkyl, (Cl-C3)-alkanoyl or phenylcarbonyl, Rs, R6, R7 and Rs are identical or different and each rsgcrsents hydroen or rapresents (CI-C6)-alcyl and their phannacautically acceptable salts, hydrates and prodrugs, except for compotmds of the gmaal fonnula (1) in which the radical R' is an unsubstituted 2-thiophene radical and tha radical R2 is simultaneously a mono-or polysubstituted phenyl radical and the radicals R3, R'', Rs, R6, R7 and R are each.
simultaneously hydrogen.
Particular proference is given here to compounds of the gmoral formula (1), in which Le A 34122-Foneia Countries R' rep=ents 2-ftophene which may optionally be subatituned in the 5-position by a radical fi+om the goup consisdng of chlorine, bromfne, methyl or tdfluoroacssxhyl.
R2 rqpueou one of the gmwp below:
A-, AM, D-M-A-, B-M A-, B-, B-M, r-~
B-M-B-, D-M B-, where:
the radical "A" rapresents phenyl or naphthyl, in particular phenyl;
the radical 'B" mTmmts a 5- or 6-membered acomstic hetlerocycle which contains up to 2 heteroatoms from the group consisting of S, N, NO (N-oxide) and 0;
the radical "D" represents a saturated or partially iuisaturated 5- or 6-rnambeaed heterocyele which contains a nitrogen atom and optioeally a further txteroatom and/or hetero chain member from the group consisting of S. SO, SOZ and 0; or contains up to two heteroatoms andJor hetero chain members from the group consisting of S. SO, SO2 and O;
the radical "M" represents NH ,-0-, NH-CHZ-, -CH;I-NH-, -OCHr, -CH2O-, -CONH ,-NHCO- or rtpnesents a covalent bond;
whenc the grnups W. "B" and "Dõ defined above may in ewh case optionally be mono- or polysnbstituted by a radical fmm the gmwp consisting of halogen; triflnoron>ethyl; oxo; cyano; pyridyl; (Ci-Ca)-alkanoyl; (C6-Clo)-arylcarbonyl; (Cs-C6)-hetekoarylarbonyl; (CI-Cs)-alkanoyloxymathyloxy; -CONR23e; -SO2NRft29; -OH; -NR"Rsl;
(C,-C4)-alkyl; and cyclopropyl, cyclopentyl or cyalohexyl.
L&A 34 12Z-~Fc~'s, Commin wher+e (CrC4}a1ky1 and cyclopzopyl, cyclopentyl or cyclohexyl for their part may oWonally be substidnod by a radical from the group consisting of cyano; -0H; -OCH3;
-NR"R29; R28) and -C(NRrR2~=NR29, whene:
v is either 0 or l, lrncferably 0, suud R'", 0 and R?9 are identical or diffenmt and independenUy of one another each repmmt: hydrdgea, (CI-C4}alkyl or else cycloopropy), cyclopentyl or cyclohexyl and/or R27 and R~ or e and e Uopther with the nitrogen atom to which they are attached may form asawmted or partially unsawrated 5- to 7-membered heterocycle having up to two identical or different heteroatoms from the group consisting of N. 0 and S, and R30 and R3' ane identical or dift'aent and indr.pendpaly of one sawwer each repmsents hydrogen, (CI-C4)-alkyl, cyclopropyl, cyclopentyl, cyclohCXyf, (CI-Cs)-alkylsulphonyl- (CI-C4)-hydroxyalkyl, (CI-C4)-aminoalkyl, di-(CI-C4)-slkylamino-(CI-C4)-alkyl, (CI-C3)-alkanoyl or phenylcarbonyl, R3, R', Rs, Rs, R' and Ra are identical or different and each represents hydtoSen or represe: ts (Cl-C4)-alkY1 - _ t..., and their pharmaeeuticxlly aeceptable aalts, hydMes and procirugs, except for compounds of the ,general formula (1) in which the radical R' is an unsubstituted 2-thiophene radical and the radical R2 is simultaneously a mono-or polysubstituted phenyl radical and the radicals R3, R4, Rs, R6, R7 and Ra are each simultaneously hydrogen.
30725-107(S) - 13a -Exemplary also is a compound of formula (I) in which: R' is thienyl which is mono- or polysubstituted by a halogen radical, (C1-C$)-alkyl or trifluoromethyl, R2 is: A-, or D-M-A-, where: A is phenyl; D is a saturated or partially unsaturated, mono- or bicyclic 4- to 9-membered heterocycle which contains one, two or three heteroatoms and/or hetero chain members from the group consisting of S, SO, SO2, N, N-oxide and 0; and M is -CH2-, -SO2- or a covalent bond;
where A and D are each optionally mono- or polysubstituted by a halogen radical; trifluoromethyl; oxo; cyano; nitro;
carbamoyl; pyridyl; (C1-C6) -alkanoyl; (C1-C4) -hydroxy-alkylcarbonyl; -COOR27; -CONRZ$R29; -S02NR28R29; -OR30; -NR30R31;
(C3-C7) -cycloalkyl; or (C1-C6) -alkyl, which is optionally substituted by cyano, -OR27, -NRzSR29 or -C (NRz7R28) =NR29, where: R27, RzB and R29 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, (C3-C7) -cycloalkyl, (C1-C4) -alkanoyl, carbamoyl, trifluoromethyl, phenyl or pyridyl, and/or R27 and R 28 or R27 and R29 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- to 7-membered heterocycle having one, two or three identical or different heteroatoms from the group consisting of N, 0 and S, and R30 and R31 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, (C3-C7) -cycloalkyl, (Ci-C4) -hydroxyalkyl or -COR33, where R33 is (C1-C6) -alkoxy; (C1-C4) -alkoxy- (C1-C4) -alkyl;
(C1-C4) -alkoxycarbonyl- (C1-C4) -alkyl; (C1-C4) -aminoalkyl;
(C1-C4) -alkoxycarbonyl; (C1-C4) -alkanoyl- (C1.-C4) -alkyl;
(C3-C7) -cycloalkyl; (C2-C6) -alkenyl; (C1-C8) -alkyl, which is optionally substituted by phenyl or acetyl; (C6-C14)-aryl;
(C5-C10)-heteroaryl; trifluoromethyl; tetrahydrofuranyl; or butyrolactone, and each of R3, R4, R5, R6, R' and R8 is hydrogen, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound.
A 34122-Egmin Very particular prefercna is given hene to compounds of the general fonmula (I), in which R' repre=ents 2-thiopheae which is snbuituted in the 5-poastion by a radical from the group coosisting of chloiine, brarune, tuethyl and trifluo~yl, R2 represents D-A-:
where:
the radical "A" repn'aents phmyletu;
the radical "D" n:prosoats a sadua<ed 5- or b-membered feueocycle, which is atlached to "A" via a nitrogea atom, which has a carbonyl gctwp ditectly adjacent to ft linking nitrogen atom and in which ona cuban riag member may be replaced by ahatmatom from the group consiacing of S, N and 0;
when the gmup "A" defined above may optionally be taono- or disubstituted in the meta position with respect to the point of attachment to the oxazolidinone, by a radical frnm the group consisting of fluorine, chlorine, nitro, amino, trifluoromethyl, methyl and cyano, RS, R6, R' and Ra each repment hydrogen and their phartnsceutically acceptable aalts, hydrates and prodrugs.
- ~.
Very paRicular pifeeence is also givm heoa to the compound having the following formula Le A 34122-FomigQ~~+ies O '. q HN
and to its pharrmaceudcally acceptable sahs, hydrates and prodrugs.
In the compounds of the genecsl fvrmula (I) above, the radical R' may in particular mpseunt optionally benzo-fused thiopherue (thienyl) which may optionally be mono- or polysubstituted by a radical from the group consisting of halogen; cyano; nitro; (C,-Cs)-alkyl, which for its part may optionally be mono- or polysubstituted by halogen; (C3-Cj)-cycloalkyl;
(CI-Cs)-alkoxy; imidazolinyl; -C(=NH)NH2; carbamoyl; and mono- and di-(CI-C4)-alkylaminocarbonyl.
In the compounds of the general formula (I), the radical R' may preferably represent thiophene (thienyt), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorite or bromine, or by (Cl-Cs)-alkyl, preferabiy methyl, where the (CI-Cs)-alkyl radical, preferably the methyl cadical, may for its part optionally be mono-or polysubstituted by halogen, preferably fluorine.
In the compounds of the general formula (1), the radicals - .+:.._ R3, R4, Rs, R6, RT and Rg may be idantical or different and nsay repreatnt, in particualr, hydrogen or (CI-C6)-alkyl, preferably hydrogen or (Cl-Ca)-alkyl, very paracularly pteferably hydrogen.
?he radical R2, i.e. the organic radical, can in psnticular be selected from the substituent groups listed below:
In the compoiuids of the general formula (I), the tadica]
I.e A 34122-Faneign Countries R= may, in pattic.ular, represent a gmup of the foUowing formula:
Y-X' -(CI12)~-X-(CO)a{Cl"l -(CRgR14)m-(CH2)'2-where:
m is an iategtr from 0 to 6, preferably fnom 1 to 3, n is eitber 0or 1, p is an integer fr+om 0 to 3, prefiaably either 0 or 1, 01 is an integer 0 or l, 02 is an integer 0 or l.
R9 and R1 are identical or different and each nepmsents hydrogen; (Cl-Cs)-a11cyl, pceferably nxthyl; (C--Ca).alkoxy, prefeaably methoxy-, (C3-C7)-cycloalkyl; hydroxyl or fluorine, X and X' ate identical or different and each ropmasts 0; N R" or a covalent bond, .--wham R" t+epmesents H; (CrC4)-aikyl, prefCrably mwthyl, or (C3-C7)-cycloalkyl, Y repeadnts i 3- to 7-membomd sourated or partially unsauumod cxclic,-, hydrocarbon radical which optionally contains 1" to 3" ic3enticat or diffemat hetaca toms and/ar hetero chain members from the groap consisting of N, 0, S, SO and SO2, whcra:
this radica! Y may optionally be sulmtiteftd by a 5- or 6-membened aromatic or a 3- to 7-manbet+ed saturated or partially unsat<ttated j& B1Z j: I'"artian Caunne.s . = -17-cyclic hydrocffibon radical which optionally contaias up to 3 identical or differcnt hctst+oatoms from the group consisting of N, 0 and S and wfiere this radical may for its part optionapy be substituted by a S radical from the group cmsisting of cyano; hydroxyl; ha)opn;
(C!-C4)-alkyl; -C(=NR12)NRi3RIs'; and -NR'4R1s, whm:
R12 mpsr.seats hych+ogen, (CI-Ca)-alkyl or (C3-C+cycloalkyl;
R13 and R13* are identical or diffarent and independently of one anothez each nepreants hydrogen, (CI-C4)-sllcyl or (C3-C+
cycloalkyl and/or R" and R13= togedw with the N atom to which they ae attached form a 5- to 7-mraabeied hete.mc.ycle which may optionaAy, oontain up to 2 further heteroatoms from the group consisting of N, 0 and S;
R'4 and Rls are identical or different and indqmdkntly of one anotticr each nepresents hydrogen, (Ci-C4)-alkyl, (C3-C7)-cycloalkyl or (Cl-Cs)-alkanoyl;
andfor -::,...
this tadical Y may funthernaTe optionally be . .subsTituted by a radical from the group consfsting of oxo; cyano; thiono;
halogen; -ORIS; ~is; -NRIsRr; õC(=:M'h1VRft19' and (CI-C4)-alkyl, in which (CI-Ca)-atkyl for its part may optionally be substituLed by a radical from the group consisting of hydmyi;
CyBflo; -NR16R17 Md _C(=NR19)NR19R19,, La A 341224Foa+eian CQuutda whene:
R16 and R" are identical or diffennt md indepeadently of one anothec each repmsents hydt+ngen, (Cl-C4)-alkyl, (C3-C7)-cycloslkyl oc (CI-C3)-alkmx)Y1;
R'E represents hydrogen, (CI-C4)-alkyf or (C3-C7)-c)"cloaikyl:
R'9 and R'9* ae+e idaWcal or different and independently of one aeother each npeatts hydiogee, (C,-Cs)-alkyl or (Cr C7)-cycloallryl and/or R'9 and R19* together with the N atom, to which they are attached focm a 5- to 7-membawd heterocycle which may optionally contain up to 2 further heteroatoms from the group consisting of N, 0 and S.
Particular pceference is given to compounds of the gawral fosmnla (1) in which the radical R~ iepmsenrs a group of the following formuia Y-X'-(CfI2)rX-(CO)p-(CH2J,,-(CR9R'0)W(CH)"2-where - -.,.,....
m is an'imeger from 0 to 3, n is an integec 0 or 1, p is an integer 0 or 1, 01 is an integar 0 or 1.
It A 34122 Foreian Coamtries = -19-o= is an integer 0 or 1, R9 and Rl0 att identical or different and each sapnzenta hydrogen; mcthyl;
methoxy; hydcoxyl or flomine, X and X' ara idauical or different and each nepmoaits 0; N-Rl 1 or a covalent bond where Rt 1 r+ept=ents H or mexhyl, Y repruents a 5- to 7-membaed saunated cyclic hydrocarbon mdical which optionally contains I or 2 identical or different hataroatoms and/or hatero ehain members from the group consisting of N, 0, S. SO
aed SO=, in particular cyclohexyl, pipecazinyl, rnorpholinyl, .15 thiornorpholinyl, diazepinyl, pyrrolidinyl and pipGridinyl, where:
this radical Y may optionally be substitteead by a 5- or 6-membered aromatic or a 5- to 7-membered saturated or partially unsaturated cyclic hydmcarbon radical which optionally contains up to 2 identical or diffemt hettroatoms from the group consisting of N, 0 and S and #40~ wheac this radical for its patt may be substitutod by a radical 5am the group consisting of cyano; hydroxyl; 8uorine; chlorine; (CI-Cs)-alkyl;
-Q=W~NR i3Ria= . . u and NRi'R , where: - ~:...
~i R iepnsents hydt+ogen, niethyl, ethY1, cyclopiroPY1, cYc1opmtyl or cyclohexyl;
R'3 and R13= are identical or different and independently of one anadver each ncpsemts hydc+ogen, methyl, ethyl, cyclopropyl, cyclopentyl or cyclohexyl andlor Le A H 122,-Fam= Countrtes R13 and R13' together with the N azom to which they sre attached farm a S- to 7 nsrmbered heterocycle which may optionally contsnn up to 2 further heteroatosns from the group consisting of N, O
and S. in pwdculw piparidinyl, piperaz.inyl, maspholinyl and thiomapholinyl;
R'4 and R13 are idtetical or different and indapmdently of one another each rqmsents hydt+ogen, methyl, ethyl, cycloprapyl, .10 cyclopentyl or cyclohexyl or ebn sextyl;
.-~
and/or this radical Y may fuitherniore optionally be substidwed by a radical frotn the group consiating of oxo; cyano; thiono;
fluorine; chlorine; -OH; -OCH3; =NR16; -NH2: N(CH3)2;
-C(-NR'sMft'r and medhyl, in which methyl for its past may optionally be substituud by a radical from the group co sisting of hydroxyl; cyano; -NR16R"
and -C(-NR1a)mi9Rt9'.
wheiz:
R'6 and R" are identical or different and indepeodentiy of one another each repmaeMS hydrogen, methyl, (C3-C7)-cycloalkyl or acetyl;
R1 rePrsents hydc'ogen, neshyl or (C3-C7)-cycio ]ky1:
R'9 and Rt9' are identical or different and indepaWently of one another each repcesents hydrogen, methyl or (C3-C7)-cycloalkyl and/or Le A 34 122-gorggn Countrics . = -21-R'9 and Rl"" togcther with the N atmn to which they are attached form a S- to 7-mmbered heterocycle which may optionally contain up to 2 furtlter hetomtoms from the group consisting of N, 0 and S. in patcicuZar piperidinyl, piperazinyl, modpholbyl and thio-morpholinyl.
Likewise, in the compounds of the Seneral formula (1), the tadical R2 may represent a group of the fonnuta below:
r-- Z{CO)r(CR70R2'),-where:
l5 s is an intm fzotn 1 to 6, t is either 0 or 1, R2D and R21 are identical or diffenmt and each nogresents hydrogae, (CI-Cs)-alkyl, (C,-Cs)-alkoxy, (C3-C7)-cyctoalkyl, hydroxyl or flnarine, Z represaxs a rxlical which is selectod from the gmup eonwisting of cyano; -CWR2~=NR24; -CO(NFWR22 R23; and NR2Rl*, where:
u ia either 0 or l, preferably 0, and -., R21, R?3 and Rx are idCntical or diffa+ent and 'nA ependently of one another each repmsents hydrogm, (CI-Cs)-allryl or (C3-C7)-cycloalkyl, pneferably hydrogen or methyl, andJor R' and R23 topdw with the N atom to which they are attached form a 5- to 7-membered hetexocycle which may optionally contain L& A 34 in -FANeigB CqMUries , = -22-up to, 2 furthcr hetenoatows and/or hetero chain membecs fcom the group consiating of N. O, S, SO and SO2;
Oand R26 ara identiptl or diffar.nt and independently of one anot}ter each represents hydt+ogen, (CI-C4)-aDcyl or (C3-C7)-cycloaluyi, preferably hydrogen, methyl or ethyl, whet+e (CI-C4)-alky! and (C3-C7)-cycloalkyl for their part may optionally be substituted by hydroxyl ar (CI-Cs)-alkoxy.
Fwtlmrmone, in the compounds of the geuaal formula (I), the redical R2 may represent one of the foilowing groups:
A-, A-M-, 1S D-M-A-, B-M-A-, B-, B-M-, B-M-B-, D-M-B-, where:
.~- the tsdical "A" represents (C,o-C,4)-uyl, prefmbly (C6-Cto)-ao~ in patic.ular phenyl or naphthyl, vay patticularly preferably phenyl;
the radical "B" ropre,sents a 5- or 6-membemd aromatic heterocyck which contains up to 3 hetematoms and/or hetero chain members, in particular up to 2 hetea+oatoms an,d/or hetero chain members, from the group consiating of.S, N. NO (N-oxide) and 0;
the radical "LY' npz+esents a aatunued or partially unsauuated 4- to 7-rnembered heterocycle which contains up to three heteroaototns and/er hetero chain members from the group consisting of S, SO, SOZ, N, NO (N-oxide) and O;
the radical "M" represents -NH-, -CHr, -CH2CHr, -0-, -NH-CH2-, -CH2-NH-, -OCl"Ir, -CHZO-, -CONH-, -NHCO-, -COO-, -OOC-, -S- or represents a covalent bond;
Le A 34122-Foeai gn _Countries = -23-where ahe groups "A", "B" and "D" defined above may in each case opaonally be mono- or polysubstituted by a nadical from the gronp consisting of halogen;
trifluoromethyl; oxo; cyano; nitro; carbamoyl; pyridyl; (Ci-C6)-alkanoyl; (C3-C+cycloalkanoyl; (C6-Cja)-arylcerbonyl; (Cs-Clo)-heteroatyicarbonyl; (Cl-Ca)-alkaioyloxymethyloxy; -COORn; -SO2Rr; -C(NRnR'~=NR~;
-CONR'"Rp; -SO2,NRftp; -0R30; -NRsoR31, (Cl-C6}-alkyl and (Cj-CT)-cycloalkyl, whera- (CI-C6)-alkyl and (Cs-C+cycloalkyl for their part may optionally be r---substituted by a mdical from the group consisting of cyano; -ORn; NRft 29;
-CO(NH)õ(NRrR~) and -C(NRrR2~=NR", where:
v is either 0 or 1 and Rr, Rn and R" are identical or differcnt and independtntly of one another each represents hydrogen, (Ci-C4)-alkyl or (C3-C7)-cycloalkyl andlor R27 and e or R 27 and e toget>w with the nitrogen atom to which they are ~-- attached form a saturated or partially nnsaturated 5- to 7-membened heterocycle having up to three, preferably up to two, identical or different heteroatoms from the group consisting of N, 0 and S, and R30 and R3' are identical or diffe.rent and indepexrdendy of one another eseh . .: L.--..
represents hydrogen, (CI-Ca)-alkyl, (C3-CO-cy'cloalkyl, (CI-C4)-alkyl-sulphonyl, (CI-C4)-hydroxyalkyl, (Ct-C4)-atninoalkyl, di-(Ci-C4)-alkylamino-(Ci-C4)-alkyl, (CI-Ca)-alkanoyl, (C6-C14)-arylcarbonyl, (Cs-Cio)-heteroaryicarbonyl, (CI-Ca)-alkylaminocarbonyl or -CHZC(NRrR'2)=Ne.
Prefercncx is also given to compounds of the general fo:mula (1) in which the radical Le A 34122-Foneiin Countries R2 nepnmts one of the gmups below:
A-, A-M-, D-M-A-, B-M-A-, B-, B-M, B-M-B-, the radical "A" npnsents phenyl or naphthyl, in particular ptmyl;
the radical 'B" nqxuem a 5- or 6-nnembend aromatic heterncyck whicb contains up to 2 heteroatoms from the group consisting of S, N, NO (N-oxido) and O;
thc radical "D" rcpzesents a satuaated or partially unsaturated S- or 6-mpnberad heterocycle which contains up to two heteroatoms andlor hetero chain members from the group consisting of S, SO, SO2, N, NO (N-oxide) and O;
the radical "1vP' represents -NH-, -0-, -NH-CFIz-, -CH2-NH , -OCH2-, -CH2O-. -CONH , -NHCO- or repmsents a crnralent bond;
where the groups "A", "B" and "D" defined above may in each case optionally be mono- or polysubstituted by a radical from the group consisting of halogen;
tritluoromethyl; oxo; cyano; pyridyl; (Ci-C;)-alkanoyl; (C6-Cio)-arylcarbonyl;
(Cs-CG)-heteroarylcarbonyl; (CI-C3)-alkaroyloxymethyloxy, -C0RrR2s)=NR"; -CONRft29; -SO2NRMR29; -OH; -NR30R31; (C1-Q)-~ _ atkyl; and cyclopiopyl, cyclopattyl or cyclohexyl, whece (Ci-Ca)-alkyl and cycloprc4r-1, cyclopentyl or cycloheacyl for tlieir part may optionally be substihrted by a radical from the group cot4sisting of cyano;
-OH; -OCH3; -NRft29; -CO(Nfi)õ(NRr'e) and -C{NR7Ra*W, where:
A 34 122 Fomei Cotmtcim . = -25-v is either 0 or 1, preferably 0, and Rr, e mtd e ara idanical or differa+t and indepaadmtly of one aiothar each represents hydrogen, (C,-C4)-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl and/or Rr and or R27 and Rr togethar with the nitrogen atom to which they are anached may feam a saturated or partially unsaturaoed 5- to 7-nKmbered hederocycle having up to two identical or diPkrent ~ hetttoatoms from the group consisting of N, 0 and S, and R30 and R31 am identical or differeat and independently of one another each tepments hydc+ogen. (CI-Ca)-alkyl, cyclop'opyl, cyclopentyl.
cyclohexyl, (CI-Ca)-alkYlsulphonYl, (CI-Ca)-hYdroxYalkYl, (CI-Ca)-aminoalkyl, di-(CG-Cs)-alkylamino-(CI-C4)-a1ky1, (CI-C3)-alkanoyl or phcnYksrbonYl=
Likewise, in the compounds of the gcneral formula (I), the radieal R2 may represr.nt a group of the following formula R
I O~ /
where -.z .._ R32 represents hydrngen or (C,-C~alkyl, preferably hydivgen or methyl, and W represenas S. NH or O, prefexably S.
Moreover, in the compamda of the general formula (1), the radical RI may be a graup of the formula below -- ..~
Le A 3412Z-EgWa C'.amtifes = -26-/
=
Finally, in the compounds of the general foamula (I), the radicW
R2 may be a group of dte fomwla below ~ N ' ~ N \
O
To date, oxazolidinones have essentiaUy only been described as antibiodcs, and in individual cases also as MAO inhibitors and fibrinogen antagonists (review:
Riedl, B., F.ndennaan, R.. Exp. Opin. Tt et Patents 19l9, 9(5), 625), where a small 5-[acyi-aminomethyl] group (preferably 5-[acetylaminonuKhyl)) appears to be essentiat for the antibacterial activity.
Substituted aryl- and haeroarylphenyloxazolidinones in which a mono- or polysubstituted phenyl radical may be attached to the N atom of the oxazolidinone dng and which may have an unsimwsed N nethyl-2 thiophenecarboxamide radical in the 5-position of the oxazolidinone ring, and their use as antibactarial substances.
aoe known fronn U.S. Patents US-A-S 929 248, US-A-5 801246, US-A-5 756 732, US-A-5 654 435, US-A-5 654 428 and US-A-5 565 571. =-.U_ 1n addidon, benzamidine-containing oxazolidinones are known as synthetic intermediates in the synthesis of factor Xa inhibitors and/or fibrinogen antagonists (WO-A-99131092, EP-A-623615).
Depending on the substitution patcan, the compounds of the genaal fomula (I) acrording to the invention may exist in soet+eoison~eeic fomu whidt we either Iiloa image and mirror image (enantiomas) or not like image and minnr imap I.e A 341Z2 FoWT
= ' -27-(diasoe~wmcts). T'he inveation relatea both to the enmstiomas or diestenonoess and to their respective mixdues. The iaoanac fanns, like the diutmeoaners, can be sepwated in a lanown maaner into the stereoismmcally uniform components.
Fwdwmom, catain couqxmids of the general fasnnila (1) am be pessart in tauto eric fomQs. This is known to the pman skiDed in the art, aad such compounds an likewise within the scope of the invention.
Physiologically acceptable, ie. phanasceutically compatible, salts can be salts of the compotmds according to the invention with inorganic or argmiic acids.
Preference is given to salts with inorganic acids, such as, for example, hydrochioric scid, hydrobronric acid, phosphoric acid or sulphuric acid, or to salts with org~mic cafboxylic or sulphonic .acids, such as, for example, acetic acid, trifluonoacetic acid, propionic acid, nuteic acid, fumsric acid, malic acid, citric acid, ttttaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, . benxenesalphonic acid, toiuanesulphonic acid or naphdialeaed~ilphonic acid.
Other pharmaceutically compatible salts which may be mentioned are salts with custonwy bases, such as, for exxople, atlcali me<al salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, dasived from anuaonia or organic amines, such as, for example, dietfiylarnine, triethylamine, ethyldnsoprnpylamine, ptoaine, dibeazylatnine, N-methylmotphotine, dihydroabietylamine or methylpipersdine.
According to the invention, n3dagf ase fotin4 of the eompounds of the gdnaal forrcuula (1) above which form a molecule compound (solvate) in the solid or liquid state by hydration with water. jn the hydmes, the waoer molecules att attached thnough secondary valkncies by internoiecular foraes, in particular hydrvgen biidges.
Solid ,..
hydrates contain water as so-called crystal water in stoichiometric ratios, where the water molecules do not have to be equivalant with rapect to their binding star-Exampks of hydrates am sesquihydrates, monohydrates, dihydnsm or trihyd:aoes.
Equally suitable are the hydrates of salts of the compounds acoording to the invention.
According to the invention, nMRftge an fomns of the compoimds of the genecal formula (I) above which for their pazt can be biologically aetive or inactive, but which Is A 34122-FoeeioColmtries can be convettod into the costr~pondin$ biologically active form (for acaa~k metabolically, solvolytiaIly or in another way).
EWom repnmft fluorine, chlorine, bmmrine md iodine. Prafrx+ena is given to chlorine or fluorine.
(C&~' rcpsr,sents a straight-chain or brwwhed alkyl radical having I to 8 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isoprupyl, n-butyl, isobutyl, tat-butyl, n-pentyl and nfiexyl. The cocre:ponding all)l gronps with fewer carbon atoms, such as, for exampk, (CI-Cs)-alkyl and (Cl-C4)-alkyl, ait derived ,,.. analogously from this defmition. In geneaal, preference is given to (CI-C4)-allcyl.
The meating of the cxnzesponding component of other monr complex substituents, such as, fOr exampk, ghbulphwnyl, hydcvxygll4A hydroxygkyjcatbonyl, alkoxy-g~}c , alkoxyearbonyl-" alkenoyl 1 1 aminoal___y(k or alkylamino kg~ is likewise daived from this definition.
(CrQ)-Cv~c__ loalkvl >tpments a cyclic alkyl radical having 3 to 7 carbon atoms.
Exanples whieh may be nlonioned are: cyclopropyl, cyclobutyl, eycloptntyl, cyclohexyl or cycloheptyi. The corruponding cycloalkyl groups having fewer carbon atoms, such as. for example, (Cs-Cs)-cycloalkyl, are daivea analogously from this definition. Piefercnoe is given to cyclopropyl, cyclapentyl and cyclohexyl.
The areanaing of the canrsponding component of ottier mom complex substituents, such as, for example, Mcloallcanovl, is likewise derived ftan this defiirition.
In the context of the invaltion, (C2-C
~Ml represents a straight-chain or brolched alkenyl nsdical having 2 to 6 carbon atoms. Preference is given to a straight-chain ot . ,,....
brmhed alkmyl radical having 2 to 4 carbon atoms. Eaamptes which may be mentioned are: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.
(C~,~1-Alka~cv nepraeirts a straight-chain or bsomW alkoxy radical having I to
where represents (Ci-Ca)-alkoxy, (C1-C4)-alkoxy-(Ci-Ca)-alkyl, (Cj-C.)-alkoxycarbonyl-(Ci-Ca)-al1ry1, (Ci-Cs)-aminoalkyl, (CI-Cs)-alkoxycarbonyl, (CI-Ca)-alkanoyl-(Ci-Cs)-alkyl, (Ca-Cr)-cycloalkyl= (C,-Ca)-alkeayl, (CI-Cg)-alkyl, which may optionaUy be substituted by Le A 34 122Foreian Comtdm plx,nyl or acetyl= (Cs-CIs)-aryl, (CrCio)-}COMoaryl, trifluoromethyl, tetrahydmfuranyl or butyrolactone, R3, R4, Rs, R6 R7 aod Ra are ideaticg or 'dtffaent nd each rep~ents hyds,cgen or represeats (C,-C5}alkyl and their pharmaceutically accx.ptable salts, hydrues and prodrugs, except foer componnds of the pnaal focmula (1) in which dM radic.al R' is an unsubstituted 2-thiophene radical and the radical R2 is simultaneously a mono-or polysubstituted phesyl radicai and the radicals R3, e. Rs, R6, R7 and Rs m each simultaneously hydrogen.
Pcefenance is also given here to compounds of tlu gCnetW fomuila (1), in which R' represents thiophene (thienyl), in particular 2-thiophane, which may optionally be nxono- or polysubatituted by halopn, praferably chlorine or bromine, by amino, aminomethyl or (CI-Ca)-alkyl, preferably nzethyl, where the (CI-Ce)-alkyl radical for its part may optionaily be mono- or polysubstidited by halogen, preferably fluorine, ~~ R2 represents one of the groups below:
A-, A-M-, D-M-A-, B-M-A-, B-, B-M-, B-M-B-, D-M-B-, where:
jA A 34122-j~gMggCoamtnes - ~ -the radical "A" represams (C.s-C14)-aryl, Preferably (C,s-Clo}.arYl, in Pwdcular phenyl or naphthyl, verl' Puticulariy preferably Phatyl;
the radical "B" repTeaents a 5- or 6-membered atomatic hetnocycle which contains up to 3 hetetn toms and/or hetero cbain membtrs, in paracular up to 2 hetematoms and/or hetero chain members, from the gtoap coasisting of S. N. NO (N-oxide) and O;
the radical "D" represents a saturated or partially unsaurated 4- to 7-munbee+ed hetaocycle which contains up to three lommoatoms and/or herrx+o chain mcmbers from the group consisting of S, SO, SO2s N. NO
(N-oxide) and O;
the radical "M" repmsem -NH, -CHr, -CS2cijr, -0-, -NH-Cfi2-, -CH=-NH , -OCHs-, -CH2O-, -CONH , -NIiCO-. -COO-, -OOC-, -S-or represents a covalent bond;
wheie the groups "A", "B" and "D" defined above may in each case optionally be mono- or polysubstituted by a radical from the graip consisting of halogen; trifluoroniethyl; oxo; cyano; nitro; carbamoyl;
Pyndyl; (Ct-Cs)-allcanoyl; (C3-C7)-cycloslkatwyl; (C6 Cja)-arykarbonyl; (Cs-CIo)-heteroatylcarbonyl; (CI-C6)-alksnoyloxynxthyloxy; -COORY'; -S02Rr; -C(NRnRN)~;
-CONR=aV; -SO2NR~R"; -OR30; -NRft3l, (C,-C6)-alkyl and (C3-C7}-cyclo lkyl, whm (CI-C6),allcyl and (Cs-C7)-cY'cloalkyl for their put may optionalIy be substituted by a radical from the group consisting of cym-o; -ORr'; -NOe; -CO(NH),,(NRrR=) and -COirR26)-M", ti,....
whene:
v is eitha 0 or 1 and RP, 0 and e ara idantical or differeat and indepaadently of ona another each reMsents hydrogen, (Ci-Ca)-alkyl or (C3-C7)-cycloalkyl, je A 34122-Forei g~~'-ountries and/or Rr and R2B or e and R29 togetha with the nitrogm atom to which they are anadmd form a saturated or partially unsaturated 5- to 7-membered heterocycle having up to three, preferably up to two, identical or diffenent heternatom from the group consisting of N, 0 and S, and R30 and R31 a><,e identical or different aod 'uldependently of one anecher each ropresentg hydtngen, (CI-C4)-alkyl, (C3-C7)-cycloellryl, ,.~ (Cl-C4)-allrylsulphonyl. (CI-G)-hydroxyallryl, (CI-C4)-aminoalkyi, di-(CI-C4)-alkylamino-(CI-C4)-sikyl, (CI-C4)-alkanoyl, (C6-Cl4}arylcarbMYl, (Cs-Cjo)-heteroarylcarbonyl, (C 1-C4)-,alkylaminocarbonyl or -CH2C(NR270"e, R3, e, Rs, R6, R7 and Rs are identical or different and each zeptualts hydrogen or represents (C,-C6)-alkyl and their pharmaceutically acceptable salts, hydrates and prodtugs, except for compaunds of the general formula (I) in which the radical R' is an unsubstituted 2-thiophene radical and the radical R2 is simultaneously a mono-or polysubstituted phenyl radical and the radicals R3, R~, R', R6, R7 and Rs are each simultaneously hydrogen.
Particular preference is given here to compounds of the generai formula (1), in which : L.:._.
R' represents thiophene (thienyl), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, or by (CI-C=)-alkyl, preferably methyl, where the (Cl-CG)-alkyl radical for its part may optionally be mono- or polysubstituted by halogen, pneferably fluorine, R2 repnesents one of ihe groups below:
Le A 34 122-Poreian Countries A-, A-M-, D-lui A-, B-M-A-, B-, B-M-, B-M-B-, D-M-B-, where:
~.. the radical "A" represents phenyl or naphthyl, in particulas phenyl;
the radieal "B" represents a 5- or 6-membered aromatic hetarocycle which contains up to 2 heteroatoms from the group consisting of S. N, NO (N-oxide) and 0;
the radical "D" napresents a saturated or partially unsatiumted 5- or 6-membenod heterocycle which contains up to two heteroatoms mnd/or hetero chain members from the group consisting of S, SO, SOZ, N, NO
(N-oxide) and 0;
the radical "M" represents -NH-, -0-, -NH-CHr, -CH2-NH-, -OCHi-, -CHZO-, -CONH-, -NHCO- or repre,sents a covalent bond;
where the gmps "A", "B" and "D" defined above may in each case optionally be mono- or polysubstituted by a radical from the group consisting of halogen; trifluoramethyl; oxo; cyano; pyridyl; (Ci-C3)-alkanoyl; (C6-Cio)-arylcarbonyl; (Cs-C6)-heternarylcarbonyl; (CI-C3)-alkanoyloxymethyloxy; -C(NRnR23 )=NR29; -CONR28R29;
-SO2NR2gR29 ; -OH; -NR30R31; (CI-C<)-alkyl; and cyclopropyl~~
cyclopentyl or cyclohexyl, where (C I-C4)-alkyl and cyclopropyl, cyclopentyl or cyclohexyl for their part may optionally be substituted by a radical from the group consisting of cyano; -OH; -OCH3;
-NRft29; -CO(NH)õ(NRrR23) and -C(NRne)=NR29, where:
j{ A 34 1FonVism Countda v is eather 0 a 1, preferably 0, and Rn, e and e are ideatical or differa-t and indepeadattly of one another each tepiesants hydrogen, (Ci-Cs)-alkyl or else cyclopropyl, cyclopentyl or cycloiuxyl and/or RF and R2' or R27 and R" together with the nitrogen atom to which they are auacbed may form a saturated or partially unaturated 5- to ?-memberod heterocycle having up to two identical or different heteroatoms from the group consisting of N. 0 and S.
and R30 and R3' are identical or different and indepeadmly of one another each reptesents hydrogen, (CI-C4)-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (CI-C4)-alkylsulphonyl, (CI-C4)-hydroxyalkyl, (Ci-C4)-aminoalkyl, di-(Cj-C4)-alkylamino-(CI -C4)-alkyl, (Cl-C3)-alkanoyl or phenylcarbonyl, Rs, R6, R7 and Rs are identical or different and each rsgcrsents hydroen or rapresents (CI-C6)-alcyl and their phannacautically acceptable salts, hydrates and prodrugs, except for compotmds of the gmaal fonnula (1) in which the radical R' is an unsubstituted 2-thiophene radical and tha radical R2 is simultaneously a mono-or polysubstituted phenyl radical and the radicals R3, R'', Rs, R6, R7 and R are each.
simultaneously hydrogen.
Particular proference is given here to compounds of the gmoral formula (1), in which Le A 34122-Foneia Countries R' rep=ents 2-ftophene which may optionally be subatituned in the 5-position by a radical fi+om the goup consisdng of chlorine, bromfne, methyl or tdfluoroacssxhyl.
R2 rqpueou one of the gmwp below:
A-, AM, D-M-A-, B-M A-, B-, B-M, r-~
B-M-B-, D-M B-, where:
the radical "A" rapresents phenyl or naphthyl, in particular phenyl;
the radical 'B" mTmmts a 5- or 6-membered acomstic hetlerocycle which contains up to 2 heteroatoms from the group consisting of S, N, NO (N-oxide) and 0;
the radical "D" represents a saturated or partially iuisaturated 5- or 6-rnambeaed heterocyele which contains a nitrogen atom and optioeally a further txteroatom and/or hetero chain member from the group consisting of S. SO, SOZ and 0; or contains up to two heteroatoms andJor hetero chain members from the group consisting of S. SO, SO2 and O;
the radical "M" represents NH ,-0-, NH-CHZ-, -CH;I-NH-, -OCHr, -CH2O-, -CONH ,-NHCO- or rtpnesents a covalent bond;
whenc the grnups W. "B" and "Dõ defined above may in ewh case optionally be mono- or polysnbstituted by a radical fmm the gmwp consisting of halogen; triflnoron>ethyl; oxo; cyano; pyridyl; (Ci-Ca)-alkanoyl; (C6-Clo)-arylcarbonyl; (Cs-C6)-hetekoarylarbonyl; (CI-Cs)-alkanoyloxymathyloxy; -CONR23e; -SO2NRft29; -OH; -NR"Rsl;
(C,-C4)-alkyl; and cyclopropyl, cyclopentyl or cyalohexyl.
L&A 34 12Z-~Fc~'s, Commin wher+e (CrC4}a1ky1 and cyclopzopyl, cyclopentyl or cyclohexyl for their part may oWonally be substidnod by a radical from the group consisting of cyano; -0H; -OCH3;
-NR"R29; R28) and -C(NRrR2~=NR29, whene:
v is either 0 or l, lrncferably 0, suud R'", 0 and R?9 are identical or diffenmt and independenUy of one another each repmmt: hydrdgea, (CI-C4}alkyl or else cycloopropy), cyclopentyl or cyclohexyl and/or R27 and R~ or e and e Uopther with the nitrogen atom to which they are attached may form asawmted or partially unsawrated 5- to 7-membered heterocycle having up to two identical or different heteroatoms from the group consisting of N. 0 and S, and R30 and R3' ane identical or dift'aent and indr.pendpaly of one sawwer each repmsents hydrogen, (CI-C4)-alkyl, cyclopropyl, cyclopentyl, cyclohCXyf, (CI-Cs)-alkylsulphonyl- (CI-C4)-hydroxyalkyl, (CI-C4)-aminoalkyl, di-(CI-C4)-slkylamino-(CI-C4)-alkyl, (CI-C3)-alkanoyl or phenylcarbonyl, R3, R', Rs, Rs, R' and Ra are identical or different and each represents hydtoSen or represe: ts (Cl-C4)-alkY1 - _ t..., and their pharmaeeuticxlly aeceptable aalts, hydMes and procirugs, except for compounds of the ,general formula (1) in which the radical R' is an unsubstituted 2-thiophene radical and the radical R2 is simultaneously a mono-or polysubstituted phenyl radical and the radicals R3, R4, Rs, R6, R7 and Ra are each simultaneously hydrogen.
30725-107(S) - 13a -Exemplary also is a compound of formula (I) in which: R' is thienyl which is mono- or polysubstituted by a halogen radical, (C1-C$)-alkyl or trifluoromethyl, R2 is: A-, or D-M-A-, where: A is phenyl; D is a saturated or partially unsaturated, mono- or bicyclic 4- to 9-membered heterocycle which contains one, two or three heteroatoms and/or hetero chain members from the group consisting of S, SO, SO2, N, N-oxide and 0; and M is -CH2-, -SO2- or a covalent bond;
where A and D are each optionally mono- or polysubstituted by a halogen radical; trifluoromethyl; oxo; cyano; nitro;
carbamoyl; pyridyl; (C1-C6) -alkanoyl; (C1-C4) -hydroxy-alkylcarbonyl; -COOR27; -CONRZ$R29; -S02NR28R29; -OR30; -NR30R31;
(C3-C7) -cycloalkyl; or (C1-C6) -alkyl, which is optionally substituted by cyano, -OR27, -NRzSR29 or -C (NRz7R28) =NR29, where: R27, RzB and R29 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, (C3-C7) -cycloalkyl, (C1-C4) -alkanoyl, carbamoyl, trifluoromethyl, phenyl or pyridyl, and/or R27 and R 28 or R27 and R29 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- to 7-membered heterocycle having one, two or three identical or different heteroatoms from the group consisting of N, 0 and S, and R30 and R31 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, (C3-C7) -cycloalkyl, (Ci-C4) -hydroxyalkyl or -COR33, where R33 is (C1-C6) -alkoxy; (C1-C4) -alkoxy- (C1-C4) -alkyl;
(C1-C4) -alkoxycarbonyl- (C1-C4) -alkyl; (C1-C4) -aminoalkyl;
(C1-C4) -alkoxycarbonyl; (C1-C4) -alkanoyl- (C1.-C4) -alkyl;
(C3-C7) -cycloalkyl; (C2-C6) -alkenyl; (C1-C8) -alkyl, which is optionally substituted by phenyl or acetyl; (C6-C14)-aryl;
(C5-C10)-heteroaryl; trifluoromethyl; tetrahydrofuranyl; or butyrolactone, and each of R3, R4, R5, R6, R' and R8 is hydrogen, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound.
A 34122-Egmin Very particular prefercna is given hene to compounds of the general fonmula (I), in which R' repre=ents 2-thiopheae which is snbuituted in the 5-poastion by a radical from the group coosisting of chloiine, brarune, tuethyl and trifluo~yl, R2 represents D-A-:
where:
the radical "A" repn'aents phmyletu;
the radical "D" n:prosoats a sadua<ed 5- or b-membered feueocycle, which is atlached to "A" via a nitrogea atom, which has a carbonyl gctwp ditectly adjacent to ft linking nitrogen atom and in which ona cuban riag member may be replaced by ahatmatom from the group consiacing of S, N and 0;
when the gmup "A" defined above may optionally be taono- or disubstituted in the meta position with respect to the point of attachment to the oxazolidinone, by a radical frnm the group consisting of fluorine, chlorine, nitro, amino, trifluoromethyl, methyl and cyano, RS, R6, R' and Ra each repment hydrogen and their phartnsceutically acceptable aalts, hydrates and prodrugs.
- ~.
Very paRicular pifeeence is also givm heoa to the compound having the following formula Le A 34122-FomigQ~~+ies O '. q HN
and to its pharrmaceudcally acceptable sahs, hydrates and prodrugs.
In the compounds of the genecsl fvrmula (I) above, the radical R' may in particular mpseunt optionally benzo-fused thiopherue (thienyl) which may optionally be mono- or polysubstituted by a radical from the group consisting of halogen; cyano; nitro; (C,-Cs)-alkyl, which for its part may optionally be mono- or polysubstituted by halogen; (C3-Cj)-cycloalkyl;
(CI-Cs)-alkoxy; imidazolinyl; -C(=NH)NH2; carbamoyl; and mono- and di-(CI-C4)-alkylaminocarbonyl.
In the compounds of the general formula (I), the radical R' may preferably represent thiophene (thienyt), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorite or bromine, or by (Cl-Cs)-alkyl, preferabiy methyl, where the (CI-Cs)-alkyl radical, preferably the methyl cadical, may for its part optionally be mono-or polysubstituted by halogen, preferably fluorine.
In the compounds of the general formula (1), the radicals - .+:.._ R3, R4, Rs, R6, RT and Rg may be idantical or different and nsay repreatnt, in particualr, hydrogen or (CI-C6)-alkyl, preferably hydrogen or (Cl-Ca)-alkyl, very paracularly pteferably hydrogen.
?he radical R2, i.e. the organic radical, can in psnticular be selected from the substituent groups listed below:
In the compoiuids of the general formula (I), the tadica]
I.e A 34122-Faneign Countries R= may, in pattic.ular, represent a gmup of the foUowing formula:
Y-X' -(CI12)~-X-(CO)a{Cl"l -(CRgR14)m-(CH2)'2-where:
m is an iategtr from 0 to 6, preferably fnom 1 to 3, n is eitber 0or 1, p is an integer fr+om 0 to 3, prefiaably either 0 or 1, 01 is an integer 0 or l, 02 is an integer 0 or l.
R9 and R1 are identical or different and each nepmsents hydrogen; (Cl-Cs)-a11cyl, pceferably nxthyl; (C--Ca).alkoxy, prefeaably methoxy-, (C3-C7)-cycloalkyl; hydroxyl or fluorine, X and X' ate identical or different and each ropmasts 0; N R" or a covalent bond, .--wham R" t+epmesents H; (CrC4)-aikyl, prefCrably mwthyl, or (C3-C7)-cycloalkyl, Y repeadnts i 3- to 7-membomd sourated or partially unsauumod cxclic,-, hydrocarbon radical which optionally contains 1" to 3" ic3enticat or diffemat hetaca toms and/ar hetero chain members from the groap consisting of N, 0, S, SO and SO2, whcra:
this radica! Y may optionally be sulmtiteftd by a 5- or 6-membened aromatic or a 3- to 7-manbet+ed saturated or partially unsat<ttated j& B1Z j: I'"artian Caunne.s . = -17-cyclic hydrocffibon radical which optionally contaias up to 3 identical or differcnt hctst+oatoms from the group consisting of N, 0 and S and wfiere this radical may for its part optionapy be substituted by a S radical from the group cmsisting of cyano; hydroxyl; ha)opn;
(C!-C4)-alkyl; -C(=NR12)NRi3RIs'; and -NR'4R1s, whm:
R12 mpsr.seats hych+ogen, (CI-Ca)-alkyl or (C3-C+cycloalkyl;
R13 and R13* are identical or diffarent and independently of one anothez each nepreants hydrogen, (CI-C4)-sllcyl or (C3-C+
cycloalkyl and/or R" and R13= togedw with the N atom to which they ae attached form a 5- to 7-mraabeied hete.mc.ycle which may optionaAy, oontain up to 2 further heteroatoms from the group consisting of N, 0 and S;
R'4 and Rls are identical or different and indqmdkntly of one anotticr each nepresents hydrogen, (Ci-C4)-alkyl, (C3-C7)-cycloalkyl or (Cl-Cs)-alkanoyl;
andfor -::,...
this tadical Y may funthernaTe optionally be . .subsTituted by a radical from the group consfsting of oxo; cyano; thiono;
halogen; -ORIS; ~is; -NRIsRr; õC(=:M'h1VRft19' and (CI-C4)-alkyl, in which (CI-Ca)-atkyl for its part may optionally be substituLed by a radical from the group consisting of hydmyi;
CyBflo; -NR16R17 Md _C(=NR19)NR19R19,, La A 341224Foa+eian CQuutda whene:
R16 and R" are identical or diffennt md indepeadently of one anothec each repmsents hydt+ngen, (Cl-C4)-alkyl, (C3-C7)-cycloslkyl oc (CI-C3)-alkmx)Y1;
R'E represents hydrogen, (CI-C4)-alkyf or (C3-C7)-c)"cloaikyl:
R'9 and R'9* ae+e idaWcal or different and independently of one aeother each npeatts hydiogee, (C,-Cs)-alkyl or (Cr C7)-cycloallryl and/or R'9 and R19* together with the N atom, to which they are attached focm a 5- to 7-membawd heterocycle which may optionally contain up to 2 further heteroatoms from the group consisting of N, 0 and S.
Particular pceference is given to compounds of the gawral fosmnla (1) in which the radical R~ iepmsenrs a group of the following formuia Y-X'-(CfI2)rX-(CO)p-(CH2J,,-(CR9R'0)W(CH)"2-where - -.,.,....
m is an'imeger from 0 to 3, n is an integec 0 or 1, p is an integer 0 or 1, 01 is an integar 0 or 1.
It A 34122 Foreian Coamtries = -19-o= is an integer 0 or 1, R9 and Rl0 att identical or different and each sapnzenta hydrogen; mcthyl;
methoxy; hydcoxyl or flomine, X and X' ara idauical or different and each nepmoaits 0; N-Rl 1 or a covalent bond where Rt 1 r+ept=ents H or mexhyl, Y repruents a 5- to 7-membaed saunated cyclic hydrocarbon mdical which optionally contains I or 2 identical or different hataroatoms and/or hatero ehain members from the group consisting of N, 0, S. SO
aed SO=, in particular cyclohexyl, pipecazinyl, rnorpholinyl, .15 thiornorpholinyl, diazepinyl, pyrrolidinyl and pipGridinyl, where:
this radical Y may optionally be substitteead by a 5- or 6-membered aromatic or a 5- to 7-membered saturated or partially unsaturated cyclic hydmcarbon radical which optionally contains up to 2 identical or diffemt hettroatoms from the group consisting of N, 0 and S and #40~ wheac this radical for its patt may be substitutod by a radical 5am the group consisting of cyano; hydroxyl; 8uorine; chlorine; (CI-Cs)-alkyl;
-Q=W~NR i3Ria= . . u and NRi'R , where: - ~:...
~i R iepnsents hydt+ogen, niethyl, ethY1, cyclopiroPY1, cYc1opmtyl or cyclohexyl;
R'3 and R13= are identical or different and independently of one anadver each ncpsemts hydc+ogen, methyl, ethyl, cyclopropyl, cyclopentyl or cyclohexyl andlor Le A H 122,-Fam= Countrtes R13 and R13' together with the N azom to which they sre attached farm a S- to 7 nsrmbered heterocycle which may optionally contsnn up to 2 further heteroatosns from the group consisting of N, O
and S. in pwdculw piparidinyl, piperaz.inyl, maspholinyl and thiomapholinyl;
R'4 and R13 are idtetical or different and indapmdently of one another each rqmsents hydt+ogen, methyl, ethyl, cycloprapyl, .10 cyclopentyl or cyclohexyl or ebn sextyl;
.-~
and/or this radical Y may fuitherniore optionally be substidwed by a radical frotn the group consiating of oxo; cyano; thiono;
fluorine; chlorine; -OH; -OCH3; =NR16; -NH2: N(CH3)2;
-C(-NR'sMft'r and medhyl, in which methyl for its past may optionally be substituud by a radical from the group co sisting of hydroxyl; cyano; -NR16R"
and -C(-NR1a)mi9Rt9'.
wheiz:
R'6 and R" are identical or different and indepeodentiy of one another each repmaeMS hydrogen, methyl, (C3-C7)-cycloalkyl or acetyl;
R1 rePrsents hydc'ogen, neshyl or (C3-C7)-cycio ]ky1:
R'9 and Rt9' are identical or different and indepaWently of one another each repcesents hydrogen, methyl or (C3-C7)-cycloalkyl and/or Le A 34 122-gorggn Countrics . = -21-R'9 and Rl"" togcther with the N atmn to which they are attached form a S- to 7-mmbered heterocycle which may optionally contain up to 2 furtlter hetomtoms from the group consisting of N, 0 and S. in patcicuZar piperidinyl, piperazinyl, modpholbyl and thio-morpholinyl.
Likewise, in the compounds of the Seneral formula (1), the tadical R2 may represent a group of the fonnuta below:
r-- Z{CO)r(CR70R2'),-where:
l5 s is an intm fzotn 1 to 6, t is either 0 or 1, R2D and R21 are identical or diffenmt and each nogresents hydrogae, (CI-Cs)-alkyl, (C,-Cs)-alkoxy, (C3-C7)-cyctoalkyl, hydroxyl or flnarine, Z represaxs a rxlical which is selectod from the gmup eonwisting of cyano; -CWR2~=NR24; -CO(NFWR22 R23; and NR2Rl*, where:
u ia either 0 or l, preferably 0, and -., R21, R?3 and Rx are idCntical or diffa+ent and 'nA ependently of one another each repmsents hydrogm, (CI-Cs)-allryl or (C3-C7)-cycloalkyl, pneferably hydrogen or methyl, andJor R' and R23 topdw with the N atom to which they are attached form a 5- to 7-membered hetexocycle which may optionally contain L& A 34 in -FANeigB CqMUries , = -22-up to, 2 furthcr hetenoatows and/or hetero chain membecs fcom the group consiating of N. O, S, SO and SO2;
Oand R26 ara identiptl or diffar.nt and independently of one anot}ter each represents hydt+ogen, (CI-C4)-aDcyl or (C3-C7)-cycloaluyi, preferably hydrogen, methyl or ethyl, whet+e (CI-C4)-alky! and (C3-C7)-cycloalkyl for their part may optionally be substituted by hydroxyl ar (CI-Cs)-alkoxy.
Fwtlmrmone, in the compounds of the geuaal formula (I), the redical R2 may represent one of the foilowing groups:
A-, A-M-, 1S D-M-A-, B-M-A-, B-, B-M-, B-M-B-, D-M-B-, where:
.~- the tsdical "A" represents (C,o-C,4)-uyl, prefmbly (C6-Cto)-ao~ in patic.ular phenyl or naphthyl, vay patticularly preferably phenyl;
the radical "B" ropre,sents a 5- or 6-membemd aromatic heterocyck which contains up to 3 hetematoms and/or hetero chain members, in particular up to 2 hetea+oatoms an,d/or hetero chain members, from the group consiating of.S, N. NO (N-oxide) and 0;
the radical "LY' npz+esents a aatunued or partially unsauuated 4- to 7-rnembered heterocycle which contains up to three heteroaototns and/er hetero chain members from the group consisting of S, SO, SOZ, N, NO (N-oxide) and O;
the radical "M" represents -NH-, -CHr, -CH2CHr, -0-, -NH-CH2-, -CH2-NH-, -OCl"Ir, -CHZO-, -CONH-, -NHCO-, -COO-, -OOC-, -S- or represents a covalent bond;
Le A 34122-Foeai gn _Countries = -23-where ahe groups "A", "B" and "D" defined above may in each case opaonally be mono- or polysubstituted by a nadical from the gronp consisting of halogen;
trifluoromethyl; oxo; cyano; nitro; carbamoyl; pyridyl; (Ci-C6)-alkanoyl; (C3-C+cycloalkanoyl; (C6-Cja)-arylcerbonyl; (Cs-Clo)-heteroatyicarbonyl; (Cl-Ca)-alkaioyloxymethyloxy; -COORn; -SO2Rr; -C(NRnR'~=NR~;
-CONR'"Rp; -SO2,NRftp; -0R30; -NRsoR31, (Cl-C6}-alkyl and (Cj-CT)-cycloalkyl, whera- (CI-C6)-alkyl and (Cs-C+cycloalkyl for their part may optionally be r---substituted by a mdical from the group consisting of cyano; -ORn; NRft 29;
-CO(NH)õ(NRrR~) and -C(NRrR2~=NR", where:
v is either 0 or 1 and Rr, Rn and R" are identical or differcnt and independtntly of one another each represents hydrogen, (Ci-C4)-alkyl or (C3-C7)-cycloalkyl andlor R27 and e or R 27 and e toget>w with the nitrogen atom to which they are ~-- attached form a saturated or partially nnsaturated 5- to 7-membened heterocycle having up to three, preferably up to two, identical or different heteroatoms from the group consisting of N, 0 and S, and R30 and R3' are identical or diffe.rent and indepexrdendy of one another eseh . .: L.--..
represents hydrogen, (CI-Ca)-alkyl, (C3-CO-cy'cloalkyl, (CI-C4)-alkyl-sulphonyl, (CI-C4)-hydroxyalkyl, (Ct-C4)-atninoalkyl, di-(Ci-C4)-alkylamino-(Ci-C4)-alkyl, (CI-Ca)-alkanoyl, (C6-C14)-arylcarbonyl, (Cs-Cio)-heteroaryicarbonyl, (CI-Ca)-alkylaminocarbonyl or -CHZC(NRrR'2)=Ne.
Prefercncx is also given to compounds of the general fo:mula (1) in which the radical Le A 34122-Foneiin Countries R2 nepnmts one of the gmups below:
A-, A-M-, D-M-A-, B-M-A-, B-, B-M, B-M-B-, the radical "A" npnsents phenyl or naphthyl, in particular ptmyl;
the radical 'B" nqxuem a 5- or 6-nnembend aromatic heterncyck whicb contains up to 2 heteroatoms from the group consisting of S, N, NO (N-oxido) and O;
thc radical "D" rcpzesents a satuaated or partially unsaturated S- or 6-mpnberad heterocycle which contains up to two heteroatoms andlor hetero chain members from the group consisting of S, SO, SO2, N, NO (N-oxide) and O;
the radical "1vP' represents -NH-, -0-, -NH-CFIz-, -CH2-NH , -OCH2-, -CH2O-. -CONH , -NHCO- or repmsents a crnralent bond;
where the groups "A", "B" and "D" defined above may in each case optionally be mono- or polysubstituted by a radical from the group consisting of halogen;
tritluoromethyl; oxo; cyano; pyridyl; (Ci-C;)-alkanoyl; (C6-Cio)-arylcarbonyl;
(Cs-CG)-heteroarylcarbonyl; (CI-C3)-alkaroyloxymethyloxy, -C0RrR2s)=NR"; -CONRft29; -SO2NRMR29; -OH; -NR30R31; (C1-Q)-~ _ atkyl; and cyclopiopyl, cyclopattyl or cyclohexyl, whece (Ci-Ca)-alkyl and cycloprc4r-1, cyclopentyl or cycloheacyl for tlieir part may optionally be substihrted by a radical from the group cot4sisting of cyano;
-OH; -OCH3; -NRft29; -CO(Nfi)õ(NRr'e) and -C{NR7Ra*W, where:
A 34 122 Fomei Cotmtcim . = -25-v is either 0 or 1, preferably 0, and Rr, e mtd e ara idanical or differa+t and indepaadmtly of one aiothar each represents hydrogen, (C,-C4)-alkyl or else cyclopropyl, cyclopentyl or cyclohexyl and/or Rr and or R27 and Rr togethar with the nitrogen atom to which they are anached may feam a saturated or partially unsaturaoed 5- to 7-nKmbered hederocycle having up to two identical or diPkrent ~ hetttoatoms from the group consisting of N, 0 and S, and R30 and R31 am identical or differeat and independently of one another each tepments hydc+ogen. (CI-Ca)-alkyl, cyclop'opyl, cyclopentyl.
cyclohexyl, (CI-Ca)-alkYlsulphonYl, (CI-Ca)-hYdroxYalkYl, (CI-Ca)-aminoalkyl, di-(CG-Cs)-alkylamino-(CI-C4)-a1ky1, (CI-C3)-alkanoyl or phcnYksrbonYl=
Likewise, in the compounds of the gcneral formula (I), the radieal R2 may represr.nt a group of the following formula R
I O~ /
where -.z .._ R32 represents hydrngen or (C,-C~alkyl, preferably hydivgen or methyl, and W represenas S. NH or O, prefexably S.
Moreover, in the compamda of the general formula (1), the radical RI may be a graup of the formula below -- ..~
Le A 3412Z-EgWa C'.amtifes = -26-/
=
Finally, in the compounds of the general foamula (I), the radicW
R2 may be a group of dte fomwla below ~ N ' ~ N \
O
To date, oxazolidinones have essentiaUy only been described as antibiodcs, and in individual cases also as MAO inhibitors and fibrinogen antagonists (review:
Riedl, B., F.ndennaan, R.. Exp. Opin. Tt et Patents 19l9, 9(5), 625), where a small 5-[acyi-aminomethyl] group (preferably 5-[acetylaminonuKhyl)) appears to be essentiat for the antibacterial activity.
Substituted aryl- and haeroarylphenyloxazolidinones in which a mono- or polysubstituted phenyl radical may be attached to the N atom of the oxazolidinone dng and which may have an unsimwsed N nethyl-2 thiophenecarboxamide radical in the 5-position of the oxazolidinone ring, and their use as antibactarial substances.
aoe known fronn U.S. Patents US-A-S 929 248, US-A-5 801246, US-A-5 756 732, US-A-5 654 435, US-A-5 654 428 and US-A-5 565 571. =-.U_ 1n addidon, benzamidine-containing oxazolidinones are known as synthetic intermediates in the synthesis of factor Xa inhibitors and/or fibrinogen antagonists (WO-A-99131092, EP-A-623615).
Depending on the substitution patcan, the compounds of the genaal fomula (I) acrording to the invention may exist in soet+eoison~eeic fomu whidt we either Iiloa image and mirror image (enantiomas) or not like image and minnr imap I.e A 341Z2 FoWT
= ' -27-(diasoe~wmcts). T'he inveation relatea both to the enmstiomas or diestenonoess and to their respective mixdues. The iaoanac fanns, like the diutmeoaners, can be sepwated in a lanown maaner into the stereoismmcally uniform components.
Fwdwmom, catain couqxmids of the general fasnnila (1) am be pessart in tauto eric fomQs. This is known to the pman skiDed in the art, aad such compounds an likewise within the scope of the invention.
Physiologically acceptable, ie. phanasceutically compatible, salts can be salts of the compotmds according to the invention with inorganic or argmiic acids.
Preference is given to salts with inorganic acids, such as, for example, hydrochioric scid, hydrobronric acid, phosphoric acid or sulphuric acid, or to salts with org~mic cafboxylic or sulphonic .acids, such as, for example, acetic acid, trifluonoacetic acid, propionic acid, nuteic acid, fumsric acid, malic acid, citric acid, ttttaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, . benxenesalphonic acid, toiuanesulphonic acid or naphdialeaed~ilphonic acid.
Other pharmaceutically compatible salts which may be mentioned are salts with custonwy bases, such as, for exxople, atlcali me<al salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, dasived from anuaonia or organic amines, such as, for example, dietfiylarnine, triethylamine, ethyldnsoprnpylamine, ptoaine, dibeazylatnine, N-methylmotphotine, dihydroabietylamine or methylpipersdine.
According to the invention, n3dagf ase fotin4 of the eompounds of the gdnaal forrcuula (1) above which form a molecule compound (solvate) in the solid or liquid state by hydration with water. jn the hydmes, the waoer molecules att attached thnough secondary valkncies by internoiecular foraes, in particular hydrvgen biidges.
Solid ,..
hydrates contain water as so-called crystal water in stoichiometric ratios, where the water molecules do not have to be equivalant with rapect to their binding star-Exampks of hydrates am sesquihydrates, monohydrates, dihydnsm or trihyd:aoes.
Equally suitable are the hydrates of salts of the compounds acoording to the invention.
According to the invention, nMRftge an fomns of the compoimds of the genecal formula (I) above which for their pazt can be biologically aetive or inactive, but which Is A 34122-FoeeioColmtries can be convettod into the costr~pondin$ biologically active form (for acaa~k metabolically, solvolytiaIly or in another way).
EWom repnmft fluorine, chlorine, bmmrine md iodine. Prafrx+ena is given to chlorine or fluorine.
(C&~' rcpsr,sents a straight-chain or brwwhed alkyl radical having I to 8 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isoprupyl, n-butyl, isobutyl, tat-butyl, n-pentyl and nfiexyl. The cocre:ponding all)l gronps with fewer carbon atoms, such as, for exampk, (CI-Cs)-alkyl and (Cl-C4)-alkyl, ait derived ,,.. analogously from this defmition. In geneaal, preference is given to (CI-C4)-allcyl.
The meating of the cxnzesponding component of other monr complex substituents, such as, fOr exampk, ghbulphwnyl, hydcvxygll4A hydroxygkyjcatbonyl, alkoxy-g~}c , alkoxyearbonyl-" alkenoyl 1 1 aminoal___y(k or alkylamino kg~ is likewise daived from this definition.
(CrQ)-Cv~c__ loalkvl >tpments a cyclic alkyl radical having 3 to 7 carbon atoms.
Exanples whieh may be nlonioned are: cyclopropyl, cyclobutyl, eycloptntyl, cyclohexyl or cycloheptyi. The corruponding cycloalkyl groups having fewer carbon atoms, such as. for example, (Cs-Cs)-cycloalkyl, are daivea analogously from this definition. Piefercnoe is given to cyclopropyl, cyclapentyl and cyclohexyl.
The areanaing of the canrsponding component of ottier mom complex substituents, such as, for example, Mcloallcanovl, is likewise derived ftan this defiirition.
In the context of the invaltion, (C2-C
~Ml represents a straight-chain or brolched alkenyl nsdical having 2 to 6 carbon atoms. Preference is given to a straight-chain ot . ,,....
brmhed alkmyl radical having 2 to 4 carbon atoms. Eaamptes which may be mentioned are: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.
(C~,~1-Alka~cv nepraeirts a straight-chain or bsomW alkoxy radical having I to
8 carbon atoms. Examples which may be rnentioned are: methoxy, ethoxy, n-propoxy, isopsvpoxy, n-butDxy. isobutoxy, tett-butoxy, n-pentoxy, n-hexoxy, n-heptoxy and n-octoxy. The conesponding alkoxy groups having fewer carbon atoms, such as, for Le A 34122-Foneimn Coaruies = -Z9-exmt>pk, (Ct-Cs)-alkoxy sad (Cj-C.s)-Alkoxy, ane derived analogously from this definition. In general, prefetaiux is given to (Cl-Ca}alk,oxy.
Me mesning of the %; ~ gap 1 Ai g cosnponaat of other mom complex subuiweats, such as, for example gjkcy-aikyl, g%2gxcarbonyl alkyl and ft&ycacbonyl, is likewise derived from tlus definrritition.
Mono- or di-lCy-Q1~alkvlaminocadarvl nept+esents an atnino groap which is attached via a carbonyl gmup aad which has a straigR-t-duin or bra~nched or two ideatiul or diffenut straight-chain or branchod alkyl substitudtaits having in each case 1 to 4 carbon ,.- atoms. Baaospks which may be mmHened am methylamino, ditylamuno, n-propylamino, isopnopyiamino, t-butylamino, N.N-dimethytamino, N,N-diethylamino, N-athy11V methylwnino, Nanet1vyllV n-pz+opylamino, IV isopr"1V n-propylanrino and N-t-butyl N-methylamino.
(Ct;Q)-Allcnwvl tepcasents a straight-clain or branwbed alkyl radical having I
to 6 carbon atoms which canies a doubly attached oxygen atom. in the 1-position and is attached via the 1-position. Examples which may be mentioned att: formyl, asxtyl, propionyl, n-butyryl, i-butyryl, pivaloyl, n-hexanoyl. The eocraponding atkanoyl groups with fewer carbon atoms, such as, for example, (C,-Cs)-alkanoyl, (Ci-Ca)-alkanoyl and (Ci-Cs)-alkanoyl, an daived analogously from this definition.
In genesal, pneferaxe is given to (Ci-C3)-atkanoyl.
The mming of the cotreaporrding componeat of otha mn cxxnpkx subatituents, such as, for example, cyclog&WA and ;lkNoWkyl, is likawise deiived from this definition.
(C,-CZkCvcloalkaewl ieprmnts a cycloalkyl radical having 3 to 7 carbon atoms.as, defined above, whid- is attached via a carbonyl group.
(Cy~~,~Yl~~ mpamts a straight-chain or branclmed dkanoyloxymethyloxy nvdcai having 1 to 6 carbon atoms. FxaRrples which nuy be mentioned are: acxtoxynxthyloxy, propionoxymethyloxy, n-butyroxymethyloxy, i-butyroxymethyloxy, pivaloyloxymethyloxy, n-hexanoyloxymethyloxy. Tf>e correspcmding alkanoyloxymethyloxy groups having fewer carbon atoms, such as, for I,e A34122 Forci ~g~ica example, (Ci-C3)-aticaaoyloxymethyloxy, are deriVed analogonsly from tbis dCftltiOll. In $GDet'Sl, Ptefelellce iS $[VEIl t0 (Ci-C3)'w[I.A+YlO7CymC&ylQZy QC rep:cs=ta an aromatic nidical having 6 to 14 carbon abozme. Faramptes which msy be mendooed are: PhenYL nqpbihYl, P~ md aiftwaayL The comesponding aryl gronpe wiffi fewa carbon atoms, soch as, for exsmple, (C6-Clo)-aryl are aerivea aoatoSously from this aefinitiom In gAraal, prtf eoce is givea to (C6-CIC)-WA-The meaning of the coc~+eapo~ding eoapx= of odier more caoaeVlex substituants, swch as, for eranmPle, -an&uboayl, is lOmwise derived fi~oea this defiddm lCS:Qlp}:HdmWd or a, 5- to 10-maubared at+onadc haaoc.vele hsvft ug to 3 hatumtoms and/or hot= chain meaibem fi+otn ttre gM cons(stima of S. O. N aod NO
~l a; 1 1 1 1 1 11 a mono- or bicyclic hetmvin m mstic which is attacihad via a oarbon ring atom of the hctwaWAS-An'"c or, if approPriate, via a nitrogm ring atom of the heD~oscomabic. Examples which may be mmtioned are: pyridyl, pyridyl N-oxide, PYTiMidA PYAkziqA. PYrzin3'l. thieayl, fiuyl, PYrroIYI. PYxMIYI, imidazolyl, thiazolyl, oxazolyl or isoamlyl, indolizinyl, iadoiyl, benzo[b]thienyl, beozo[b]furyl, intlaaolyl, quiaolyl, isoqainolyl, naphthyridinyl, quinazolinyl. The correspaod'mg hcta+ocyclas haviag a smaller ring aize, snch as, for ocample, 5- or 6 membered aromatic hdaroayeles, az+e detived malogonsly from thia de$vam In gencral, prefarence is given to 5- or 6-membeted mnmatic hdemcycles, such as, for example, PYddyL PYi'id)-1 N-oaride, Pyrimadyi, Pyridazinyl, fiayl and thieayl.
The, meamng of to onareapomding co ponent of ot6er mm eovoes snbstkuaots, such as, for example, is likewise derived fmm this defmition.
A3-- to 9-6end saturated or pmjbft unsamaed. mo.o- or bi..vchc, o~A!hi benzo-fueed hetesoavocle bavina nn t,L3 baaaMUms and/or h,atero c' mambecs fim the ggm cgmdafmg of S. SO,$Q,Z. NM (N-oaidel mdO represents a hetecocycle which may oontain one or m-sn+e double bonds, whieh may be mono-or bicyctic, to whieh a beazene ring may be fnsed to two adjacant carbon ring atoms and w]>ich is attached via a ca:bon ring atom or a nitrogen ring atom. Exampks wbich may be mentioned are: teuahydinfiwA pyrrolidinyl, PyrmItrA PiPesidinyi, 1,2-Le A 3412Z-Fa+zigU Camaaiea dihydtopyridiny1,1,4-dihydtoQyridinyl= piperazinyl, n"holinyl, motplwlinyl N-oxide, thiomorpholinyl, amepinyl, 1A-diaaaepinyl smd cyalohoxyl. Pnefeaaicx is given oD
PiPmidinyl, motphotinyl and pyrrolidinyl.
The eoVtOMPOnM'ng cycles having a snwlkr ring sizu, sndh as, for exmmple, 5-tio 7-memberod cycles, are darived analogously from this definition.
The ptesent invemon also pnnvides a process for pnepering the conipounds of the genea=al formula (1) according to the invention where either, according to one process altesnative [A] compounds of the general formula (II) R:
'N
R' Rs Re , R, FMI"*%Ra in which the radieals R2, R3, R4, Rs, R6 and R' are each as defined above, are reacted with carboxylic acids of the genera[ formula (lII) HO R' (II[), ~ _ = - . {,:....
in which the radcal R' is as defined above.
Le A 341Z2-E98da QMjpgg or else with the corresponding catbonyl halides, peferably cwbonyl chlorides, or else with the eornesponding symmettic or mixed caboxyiic anhydrides of the carboxylic acids of the general formula (III) defined above S in inert solvents, if appropriate in the p.msencx of an activating or coupling agent and/or a base, to give compounds of the general formula (I) R.:, .1 Rs Rs r" =
R s R=' yR' (I}.
in which the mdicals R', R2, R3, R~, RS, R6, R7 and Rs are each as defined above, or else according to a procxss alternative [B] conzpounds of the general formula (IV) Ra R' s ~s .z._ in which the radicals R. R. R4, Rs, R6, R7 and Ra are each as deined above, are converted, using a suitable selecave oxidizing agant in an inert solvent, into the corresponding epoxide of the general formula (V) Le l~341224%zilm CamUits = ' -33-Rs Rs ~
R' ~. , N R
Rs Rs in which the radicals R', R3, R4, Rs, R6, R7 and R are rach as defined above, and, by neaction in an inwt solvent, if appt+opziate in the pnesenee of a catalyst, with an amine of the general formula (VI).
R2 - NHz (VD, in which the radical R2 is as detined above, the compounds of the general formula (VII) . ! s 6 s N ,00L R, (VU)-H ~ =
in which the radicals R', R2, R3, R', R. R6, R7 and Ri ara each~ as defiried' _ above, are initially pnopared and subsequendy, in an iaert solvent in the pnesence of phosgene or phosgene equivalents, such as, for example, earbonykliimidazole (CDI), cyclized to give the compounds of the pneral formula (I) Le. A 34122-Forr~ffi Caemtrxs = = - 34, .
_ry R' R Rs . ' R'- R' (I) in which the radicals R', RI, R3, R4, Rs, R6, RC and R are each as defined above, whem - both far proceas aharna6ve [A] and for process altarnative [B] - in the case where R2 contains a 3- to 7-membec+ed saturated or partially unsavxated cyclic hydrocarbon radical having one or morc identical or different heteroatoms from the group consisting of N and S, an oxidation with a selective oxidizing agent to afford the cosesponding sulphane, suiphoocide or N-oxide niay follow and/or whene - both for process alternative (A] and for process alternative [B] - in the case where the compound prepared in this manner has a cyano group in the molecule, an amidinadon of this cyano group by customwy methods may follow and/or ,,...
whec+e - both for process alternative [A] and for process alternadve [B] - in the case where the componnd prepared in this manner has a BOC aniino protective gmup in the molecule, removal of this, BOC amino protective group by cusoomary methods may follow and/or Le A 34 122Faneamn Camtries = ' -35-whw+e - both for process alternative [A] and for process altemative [B] - in the case whaze the compound prepared in this mmmcr has an aniline or benzyiamine radical in the molecule, a reaction of this amino group with various reagentt such as carbozylic acids, cwboxylic anhydrides, carbonyl chlorides, isocynnates, suiphonyl chlorides or alkyl halides to give the corresponding derivmtives may follow and/or where - both fw' pd+ocxss altetnative [A] and for prrocxss alternative [8] -in the ~.. cese where the compound pu ey - p ri in this mwner has a phenyl iing in .t6e molecule, a neaction with chlomsulphonic ecid and subaequent rsaction with amines to give the cornesponding sulphonamrides may follow.
The proeesses according to the invention can be illustrated in an euemplary manner by the equs-tions below:
[A]
~
HO ~ ~
q o-b-b+
a (iw'P~I~EtI'~
FN
p F
M!!ft t NHt ~ . _.
IA A 34 122-Foceian Cotmtries = -36-[B]
MMa --------aa ~ -- /
HN
,-- The oxidaiion step dsscccibed above, which is optional, can be illustrated in an exemplary manner by the equation below:
F F
NAAOJOs0. 0 ~
d p'' p F
O- ~ d Suitable solvents for the processes daacribed above are organic solvents which at+e inert under the reaction conditions. These include halogenated hydrocarbons, such as dichloromethane, trichlonomethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, tetraehioroethane, 1,2-dichloroethylone or trichlaroethylene, ethers, _ such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ethi=c or diethylene glycol dimethyl ether. alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons, such as benzene. xylene, toluene, hexane or cyclohexane, dimethylformamide, dimethyl sulphoxide, acetonitrile, pyridine, hexa-methylphosphoric trianride or water.
It is also possible to use solvent mixtures of the solvents mentioned above.
Le A 34122 rvadgq Coamtries Ssdtable acdvating or coupling agents for the processes described above ane the neapnts which are customarily used for this purpose, for example N'-(34msethylaminopropyl)-N-ethylcarbodiimide - $Ct, N,N'-dicyclohexytca:bo-damide,1-hy~idroxy-lH-benzotciazole - H20 and the like.
Saitable bates are the customary inorganic or organic bases. These pi+eferably include alkali metal hydraxides, such as, for example, sodium hydroxide or potassium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or sodium methoxide or potassium inetlwxide or sodium ethoxide or pataasium ethoxide or potassium tert-butoxide, or amides, such as sodium amfde, ~.. lithium bis-(triraethylsilyl)amide or lithium diisopmpylamide, or amines, such as triethyiamine, diisoprnpylethylamine, diisopropylamine, 4N,IV-dimethylamino-pyridine or pyridine.
The base can be employed hei+e in an amount of from 1 to 5 mol, preferably from i to 2 mol, based on 1 mol of the compounds of the genenW formula (11).
The reactions are generally carried out in a tamperature range of from 78 C to reflux te:mperatuce, preferably in the range from 0 C to teflux temperatwe.
The nõacfions can be cairied out at atmospheric, elevated or reduced pres:m (for example in the range from 0.5 to 5 bar). In general, the reactions are carried out at aomosphcric pnuure.
Suitable sekctive oxidizing agents, both for the preparation of the epoocides and for the optional oxidation to give the sulphone, sulphoxide or N-oxide, are m-chlorroperbenzoic acid (MCPBA), sodium metaperiodate, N-methylmorpholine N-oxide (NMO), monoperoxyphthalic acid or osndum tetroxide.
.30 With respect to the pmparation of the epoxides, the prtparation conditiana which are customary for this purpose are employed.
With reapext to more detailed procas conditions for the optional oxidation to give the sulphone, saiphoxide or N-oxide, reference is made to the following liunture:
M. R. Barbachyn et al., J. Med Chem.1996, 39, 580 and WO-A 97I10223.
IAA 341ZLEft sio ~' tries Fattlornw+e, reference is made to Examples 14 to 16 given in the experimental part.
The optional amidation is catried out under antommy conditions. For more details, nefercnce is made to Examples 31 to 35 and 140 to 147.
The compounds of the grneral formulae (II), (III), (IV) and (VI) are known per se to the person skilled in the wt or can be prepated by customsty methods. For oxazolidinones, in patticular the 5-(atninomethyl)-2-oxooxarto}idines required, cf.
WQ-A-98/01446; WO-A-93123384; WO-A=97I030r'J2; J. A. Tuclca= et al., J. Med.
Chera. 1998, 41, 3727; S. J. Brickner et al., J. Med. Chem. 1"6, 39, 673;
W. A. Gregory et al., J.1Ned. Chem.1"4, 32, 1673.
The compounds of the genaW formula (I) according to the invention have an unfoneseeable useful pharmacological activity spectrum and a=e thec+efore particularly suitable for the prophylaxis and/or rnament of disordera.
The compounds of the genaral formula (1) according to the ivnention -including the compounds which are excluded by disclaimer from the ehemical product protection - act in particular as anticoagulants and can therefore pieferably be employed in nxdicaments for the prophylaxis snd/or therapy of thromboembolic disorders. For the purpose of the present invention, "t}Tomboeinbolic disorders"
include, in particular, serious disorders such as myocardial infaret, angina pectoris (including unstable angina), mocciusions and restenoses after angioplasty or arntoeoronary bypass, stnnlce, transitory ischaemic attacks, penpla-al atusial occlusion disorders, pulmmmy embolisms or deep venous ttuomboses.
Fxthermore, the coznpouads of the general formnla (1) according to the invention - including the componnds which are excluded by disclaimtr froom=
tiw;, chemical product protection - are also suitable for tnating disseminated intravascular coagulation (DIC).
Finally, the compounds of the ganeral formula (1) according to the invention - including the compounds which are excluded by disclaimer from the chemical product piotection - am also suitabte for the praphylaxis aad/or meatrnent of atherosclerosis and arthritis, and additionally also for the prophylaxis and/or treammt of Alzheimer's disease and cancer.
LgA341224%Wm Candfies The compounds of the @eneral foimula (I) according to the invention -including the compounds excluded by disclaimer frozn the chemical product protection - act in particular as selective inhuNtots of the blood coagulation factorr Xa and do not inhibit, or only inhibit at considerably higher concentrations, other serine proteases as well, such as thrombin, plasrnin or trypsin.
In the context of the pt+eseat inventioa, inhibitors of the blood coagWation factor Xa in which the ICso vaiues for the facWr Xa inhibltion atc lower by a factor of 100, preferably by a factor of 500, in particular by a factor of 1000, than the ICM
values ~., for the inhibition of otha serine proteases, in patticular thrombin, plasmin and trypsin, are refelred to as being õselective", whena with a view to the test metbods for selectivity, reference is made to the test methods of Examples A-1) a1) and a.2) described below.
The eompoumd: of the generai formula (1) according to the invention -including the compounds which are excluded by disclaimer fran the cheniical product protection -can fiwthamoce be used for pneventing coagulation ex vivo, for example for bmked blood or biological samples which contain factor Xa.
The present invention thus provides oxazolidinones of the formula (1) effecting in pamticular an unexpected, strong and selective inhibition of factor Xa, and this also applies to the comWmds excluded by disclaimer from the chemical pmduct protection.
The presm invention finther provides medicaments and phatmaoeutical campositions comptfsing at least one conVOnnd of the ganeral formula (1) according to the invention together with one or more phannacoiogically acceptable auxiliari~es.
or excipients, which nitxdicaments and pharmaceutical compositions can be used for the indications mentioned above.
Furthermmore, the present invention relates to a method for the prophylaxis and/or tneabnent of disordexs of the human or animal body; in paticular of the abovementioned disorders, using the compounds of the general formula (I) acconding to the invention - including the compounds excluded by disclaimer from the chemical product protection.
Le A 34122-Forethm Comtries Furthmmorc, the preunt invwtion also includes a method for prevendng blood eosguladon in vitro, in particular in banked blood or biologieal samples which contain faccw Xa, which method ia chuadaixed in that coMounds of the geneanl fommla (I) - including the eon-pounds excluded by disclaimer from the chemical product protection - are added.
AI] customary administration fonans are suitable for administration of the compounds according to the invention. Admiiriscmtion is pzeEerably caaied out orally, lingually, 10- sublingually, buccally, roctally or parentarally (i.e. bypaasing the intestinal uwet, that ,=. is intravendusly, intraas=oerially, fnt:acarWally, intracutaneously, subcutaneoualy, ttansdcnnally, intraperitoneally or intramuscularly). Particulariy suitable are oral aad intravenous administration. Very particular preference is given to oral adminisrrstion, this being a further advantage with respect to the prior-art therapy of thromboernbolic disonders.
The novel active cxunpoimds of the general formula (1) csin be converted in a known manner into the customary formulations, such aa tablets, augar-eosod tablets, pills, gcanutes, aerosols, syrups, emulsions, suspensions and solutions, using inert non-toxic pharmaceatically suitable excipients or solvents. Herc, the therapeutically active compound should in each case be present in a concentration of from about 0.1 to 95% by weight, preferably fi+om 0.5 to 90% by weight, in particular from i to 85%
by weight. of the total mixtum i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
In spite of this, if appropriate, it may be necessary to depart from the amounts mentioned, namely depanding on the body weight or on the type of administration route, on the individual response to the medicament, on the mtnner of its formulatigm L
and the time or interval at which administration takes place. Thus, in sonie cases it may be adeQuate to manage with less than the abovementioned minimum amount, while in other cases the upper linrit mentioned must be exceeded. In the case of the administration of relatively lage amounts, it may be advisable to divide these into several individual administrations over the course of the day:
The formula6ons are pnspared, for example, by extending the active cotrqxxnds with solvents and/or excipients, if appmpriate using emulsifiers and/or dispersants, it I&A 34 122 Faeian Conntriel = -41-being pasible, for example if dse diluent used is water, optionally to use organic solvents as auxilistry solvents.
In getteral it has pioved advantageous in the case of intravenout adminisoation to administer amounts from appzoximately 0.001 to 10 mg/kg, prdersbly aploximaWy 0.01 to 10 mg/kg, in pacticxda approxinmtely 0.1 to 8 mWkg, of body weight to achieve effective results.
In general, it has proved advtmtagoous in the case of oral admWismWon to administer amounta fram appTOximately 0.01 to 50 mg/kg, preferably approxitnately 0.1 to ~ 10 mg/kg, in particular ~PPaftly 0.5 to 8 mg/lcg, of body weight to achieve effective results.
In spite of this, if appropriate, it may be necessary in the case of intravenous or oral administration to deparc from the atnamts mentioned, namely depending on the body weight or on the type of administration route, on the individual tespornse to the medicament, on the tnannerr of its formulation and the time or interval at which adminigmon takres placx. Thus, in some cases it may be adequate to manage with less than the abovemendoned mininum amount, while in other cases the upper limit mentioned must be exceeded. In the case of the admitistratfon of relatively large amounts, it may be advisable to divide these over the course of the day, namely into several individual doses or as a continuous infusion.
!~ Compared to the evnveational preparatiorA for treaitin= throanboanbolic diiordas, the compomds of the generat formula (1) sccorcling to the invention -includieg the compounds excluded by disclaimer from the chemical product proteetion - are distinguished in paaticular by the fact that a grieaterr therapeutic range is achieved by the selective inhibition of factor Xa. For the patient, this rneans a. lower risk- oL-. .
bleeding, and for the trcating physician, this means that the patient is easier to adjust Moieovec - owing to the mechanism - the onset of action is more rapid. Above all, however, the oompotpzds accoeding to the invendou pe=mit an oral admirastration forat, which is a further advantage of the therapy with the compounds according to the invention.
The present invention is illusuued by the examples below; however, these examples an not nxant to restrict the invention in any way.
34122 Foratn CwnVia EumWO
A Enhmdm,of the nhvslobadcal activltv 1. Giseral test etbods The particulerly advantaWous biological properties of the compounds according to the invention can be detetrnined by the foIIowing methods.
A) Tem lmriotion (in vitru) ~. .
a.1) Det~ermioadon of the factor Xa Ldibition The enzymatic aqivity of human factor Xa (FXa) was measured using the eonvmion of a chromogenic substrate specific for FXa. Factor Xa cleaves p-nitroaniline from the chromogenic substrate. The determinations were carried out in microtitre plates as follows.
The test substances, in various concentcations, were dissolved in DMSO and incubated at 25 C with human PXa (0.5 nmoVl dissolved in 50 mmol/l of tris buffer [C,C,C-tris(hydroxymethyl)-aminomethane], 150 mmol/1 of NaCI, 0.1% BSA
(bovine serum albumin), pH = 8.3) for 10 minutes. Pure DMSO was used as control.
The chromogenic substrate (150 mol/1 of Pefachrome FXa from Pentapharm) was then addod. After an incubation time of 20 ririnutes at 25 C, the extinction at 405 nm was determined. The extinctions of the test mixtures containing test substarnx were compared with the control mixtures without test substance, and die ICm values were calculated from these data.
a.2) De,terminntbn of the selectlvity To assess selective FXa inhibition, the test substances were examined for their inhibition of other hunm serine proteases such as thrombin, trypsin and plasmin_ To detecmine the enzymatic activity of thrombin (75 mUhnl), trypsin (500 mUtml) and piasmin (3.2 nmol/1), these enzymes were dissolved in tris buffer (100 mmol/!, 20 mmol/l CaC12, pH = 8.0) and incubated with test substance or solvent for 10 minutes. The enzysnstic reac.-tion was then sterted by adding the corresponding Le A 34122-T!oneim, Countries specific cMromogaiic substtatea (Chromozyna Thranbin fr+osn Boetninger Mannheim, Chromozym Trypsin from Boehringer Mannheim, Chromozym Plasmin from Boetningrer Mannheim) and the extinction at 405 nm was deLernained after 20 minutes. All dewrjninautions were carried out at 37 C. The extinctions of the test arixtune,s containing test substance were compared with the control samples without test substance, and the ICso values were calculated from these data.
a.3) Determioatbn d t6e ~t adion The anticosgulant action of the ust substances was determined in vitro in human ,=. plasma. To this end, human blood was drawn off in a mixing ratio of sodium citrate/blood of 1/9 using a 0.11 molar sodium citrate solution as receiver.
Immediately after the blood had been drawn off, it was mixed thoroughly and cxntrifuged at about 2000 g for 10 minutes. The supernatant was pipetted off.
The prothrombin time (PT, synonyms: thromboplastin time, quick test) was decernrined in the presence of varying coacenaations of test subctancx or the cxmtsponding solvent using a commercial test kit (Neoplastin from Boehringer Mannheim). The test compounds wcre incubated with the plasma at 37 C for 10 minutss. Cflaigulacion was then started by addition of thromboplastin, and the time when coagulation occurred was deoerrnined. The concentration of test anbstance which effected a doubling of the prothrombin tinu was detetmined.
b) Dets.rminatioa Qftheantithrombotic actlvkv (in vivo) b.1) Arteriovenous shunt modd (rat) Fasting male rats (strain: HSD CPB:WU) having a weight of 200-250 g wera anaesthecized using a RompunlKetavet solution (12 mglkg! 50 ing/kg). Thrombus ,_ formation was initiated in an arteriovenous shunt in accordance with the method described by Christopher N. Berry et al., Br. J. Pharmacol. (1994), 113, 1209-1214.
To this end, the left jugular vein and the right carotid artery were exposcd.
The two vessels wem connected by an extracorporeal shunt using a polyethylene tube (PE
60) of a lengtb of 10 cm. In the middle, this polyethykne tube was anschad to a further polyethylene tube (PE 160) of a length of 3 cm which contained a roughened nylon thread which had been aamged to form a loop, to form a thrombogenic surface.
The extracorponaal circulation was maintained for 15 minutes. The shunt was then A 34 122-FbreilM CgUMgL
= = -44-ranoved and the nylon tlmead with the thrombus was weighed immediately. The weight of the nylon thread on its own had been detemiined before the experineat was starued. Befos+c the exuacorporeal circulation was sei up, the test substmces were administered to the amrnals while awake either intravenously via the tail vein or ozaUy using a pharyngeal tube.
~- .
:,~..
1 A A 34122-Pon:in Ca~
'i'ho results are shown in Tabk 1:
Table 1: AntittZgMbotic acdYjlyin du Werioyenous ahunt model /rat) after or,l or intravenous adtninistration Lv.
!" 114 3 b.2) Arterial tluoobods modd (rat) Male faeting rats (strain: HSD CPB: WU) were anaesthetized as described above.
On average, the rats had a w+sight of about 200 S. The left carotid artery was exposed (about 2 cm). The formation of an arterial thrombus was induced by mechanical injury to the blood vessel in accordance with the method described by K. Meng et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. To this end, the exposed carotid artery was clamped from the blood flow, cooled to -12 C in a metal trough for 2 manutes and, to standardize the size of the throu-bi, simultaneously compressed using a weight of 200 g. The blood flow was then additionally reduced by a clip which was placed around the carotid artery distally from the injueed, section of the vessel. The proxinul clamp was removed, and the wound was closed and re-opened after 4 houra to remove the injured section of the vessel. Ttmsoction of -tha =-=
vessel was opened longitudinally and the thrombus was mnoved from the injured section of the vessel. The moist weight of the thrombi was detamined immediately.
The test substatwes wene administered to the animals while awake at the beginning of the experiment, either intravenously via the tail vein or orally using a pharyngeal tube.
Ie A 34122 FMeia Camtries = -46-b3) Venmu tbrombosis modd (rat) Mok fasting rats (strain: HSD CPB: WU) wei+e anaesthetized as described above.
On average, the rats had a weight of about 200 g. The left jugular vein was exposed (about 2 cm). The fonaation of a venoas tlirombus was induced by mechanical injury to the blood vessel in accordance with the method describad by K Meag et a1., Naunyn-Schmiedeberg's Aroh. P'harmacol. (1977), 301, 115-119. To this end, the jugular vein was clamped from the blood flow, cooled to -12 C in a melal trough for 2 minutes and, to standardize the size of the thrombi, simnltaneausly compmssed using a weight of 200 S. The blood flow was re-opened and the wound was closed.
After 4 hours, the wound was se-opened to nnnove the thmmbi from the injured scctions of the vessel. The moist weight of the thzombi was demmned immediataly.
The test substances wem adininisteried to the animals while awake at the beginning of the experiment, either intravenously via the tail vein or orally using a pharyngeal tube.
I.e A 34 1224kadSo Casntries = -47-B ftMG"FWwwJw startlnt mateiiala The preparation of 3-aioipholinone is deacribed in US 5 349 045.
The preparation of N-(2,3-epoxypropyl)phdzalimide is described in J.-W. Chem et W.
Tetraludr+on I.ett.1l98,39,8483.
Thc subttituted anilines can be obtainod by racting, for exalapk, 4tluotonitro-benzene, 2,4-difluouronittnbenzene or 4-chloionin~obenzene with the appropriate amines or amides in the presenrx of a base. This can also be carried out using Pd catalysts, such -as Pd(OAc)j/DPPFINaOt Bu (Tetrahedron Lett. 1999,40,2035) or copper (Renger, Synthesis 1985,856; Aabischer et al.. Iieteancycles 1998,48.2225).
Likowise, it is possible to initially convert halogensted atomatics without nitro group into the cornesponding amides, followed by nitratfon in the 4-position (US3279880).
L~42~ahul~-3atvlloitrols~mene NOz NO
O 2 NMP, NaH
C~ +
N O
'O
2 mol (202 g) of motpholin-3-oee (E. Pfeil, U. Harder, Angew. Chem.
79,1967,188) are dissolved in 21 of N-methylpynrolidone (NMP). Over a period of 2 h, 88 g (2.2 mol) of sodium hydride (60% in pasaffin) ate thca added a littie at.a, time. AfieT..--the evolution of hydrogen has ceased, 282 g (2 mol) of 4fluoronitirobenzene am added dropwise with c:ooTing at room temperutw e, over a period of 1 h. md the reaction mixture is then stin~ed ovemight. At 12 mbor and 76 C, 1.71 of the liquid volume m+e then distilled off, the ns;idut is poured into 21 of water and this radxture is extracted twice with in each case 1 1 of ethyl aoaate. After washing of the conibined organic phases with water, the nwcme is dried over sodium sulphate and the solvent is distilled off under reduced pressure. Purification is carried out by silica gel chromatography using hexanelethyl acetate (1:1) end subsequent crystallization I& A 34122-F=*n Couetriea = -48-from ethyl acetate. This gives 78 g of product as a colourless to brownish solid, in a yield of 17.696 of gheary.
IH NMR (300 MHz, CI)C13): 3.86 (m, 2 H, CH2CH=), 4.08 (m, 2 H, CHzCHz), 4.49 (s, 2 H, CH2CO), 7.61 (d, 2 H, 3.-8.95 Hz, CHCfI), 8.28 (d, 2 H, 31=8.95 Hz, CHCH) MS 0196) = 222 (74, M"), 193 (100), 164 (28), 150 (21), 13.6 (61), 117 (22), (24).90 (37),76 (38),63 (32),50 (25) T1m following compounds were synthesiud atudogonsly:
. 3-tluoro=4-(4-motpholin-3-ony1)nihobanzene 4-(N-piperidonyl)Wtrtobe~Ie 3-fluoio4-(N-piperidonyl)nionobeozene 4-(N-pynolidonyl)nitrobenzene 3-fluozo-4-(N-pyrroiidonyl)nitrobenzene II. 4(4-Meraho~õ3onv ~
H2, Pd/C ( .~
N O N
(0:r co In an autoclave, 63 g(0.275 mol) of 4-(4morpholin-3-onyl)nittobenzenc are dissolved in 200 tnl of teuahydruffiuan, admixed with 3.1 g of Pd/C (596ig) and hydcogenatad at 70 C and a hydrogen pressura of 50 bar for 8 h. The eatalyst is filtered off, the solvent is then distilled off under reduced pressure and the product is purified by crystallization from ethyl acetate. 20 g of product are obtained as : a:.....
colourless to bluish solid, in a yield of 37.6% of theory.
Purification can also be carried out by silica gel chtomatogtaphy using hexane%thyl acetate. -'H-NMR (300 MHz, CDC13): 3.67 (m, 2 H, ClY2CH2), 3.99 (m, 2 H, CH2CH2), 4.27 (s, 2 H, CH2CO), 6.68 (d, 2 H, 3l=8.71 Hz, CHCH), 7.03 (d, 2 H, 31=8.71 Hz, CHCH) _..., ,,._ } 30725-107 (S) MS (r.L%) = 192 (100, M+), 163 (48), 133 (26), 119 (76), 106 (49), 92 (38), 67 (27), 65 (45), 52 (22), 78 (22) The following compounds were synthesized analogously:
3-fluoro-4-(4-morpholin-3-onyl)aniline 4-(N-piperidonyl)aniline 3-fluoro-4-(N-piperidonyl)aniline 4-(N-pyrroli donyl)aniline 3-fluoro-4-(N=pyrrolidonyl)aniline General method for preparing 4-substituted anilinies by reacting 1-fluoro-4-nitrobenzenes and 1-chloro-4-nitrobenzenes with primary or secondary amines, followed bv reduction x R=\N,R== R.\N,R..
R
I j + R'.N.R'" R _ (\
H
X=F,CI
where:
R is fluorine, chlorine, nitro, amino, trifluroromethyl, methyl or cyano; and R' and R" together with the nitrogen atom to which they are bonded form a saturated ) - or 6-membered heterocycle.
Equirnolar amounts of the fluoronitrobenzene or chloronitrobenzene and the amine are dissolved in dimethyl sulphoxide or acetonitrile (0.1 M to 1 M solution), and the mixture is stirred at 100 C overnight. After cooling to RT, the reaction mixture is diluted with ether and washed with water. The organic phase is dried over MaSO4, filtered and concentrated. If a precipitate forms in the reaction mixture, the precipitate is filtered off and washed with ether or acetonitrile. If the mother liquor also contains product, it is worked up as described using ether and water. The crude products can be purified by silica gel chromatography (dichloromethane/cyclohexanelr:-and dichloromethane/ethanol mixtures).
'30725-107 (S) - 49a -For the subsequent reduction, the nitro compound is dissolved in methanol, ethanol or ethanol/dichloromethane mixtures (0.01 M to 0.5 M solution) admixed with palladium on carbon (10%) and stirred under an atmospheric hydrogen pressure overniaht_ The mixture is then filtered and concentrated. The crude product can be purified by silica gel chromatojraphy (dichloromethane/ethanol mixtures) or preparative reversed-phase HPLC (acetonitrile/water mixtures).
Le A 34 122 Foreign Coueaies Altetaatively, ttw redadng agent used cm also be iron powder. To this end, the nitro compound is dissolved in aaaic acid (0.1 M to 0.5 M solution) and, at 90 C, six equivalents of iron powder and water (0.3 to 0.5 times the volume of the acetic acid) am added a littie at a time over a period of 10-15 min. After a fiuther 30 min at 90 C, the mixture is filtered and the fihiate is concentrated. The residue is worked up by extraction with ethyl acetate and 2N aqueous sodium hydroxide solution. Ttie organic phase is dried over nmgnesium sulphate, filtered and concentrated. The crude product can be ptnified by silica gel chroinatogcaphy (dichl(x omethanelethanol mixtures) or preparative reversed-phase HPI:C (acetonitrileJ'water mixnu+es).
The foAowing starting materiah werc praparod in an analogous manner:
III-1. tert-buh-1=1=(4aminQnhao~ll~L-oroWis~e MS (ESI): nVz (%) = 304 (M+H+MeCN,100), 263 (M+H, 20);
HPLC (method 4): rt = 2.79 min.
rn- 1A~Udn2oheuvll-3-WarMttmaarboxamlde MS (ESI): m/z (%) = 220 (M+H, 100);
HPLC (method 4): rt = 0.59 min.
M-3s 1-(_ 4_amino~. h_envll ,-4-_ !
MS (ESI): m/z (%) = 220 (IvI+H,100);
HPLC (method 4): rt = 0.57 min.
T -4. 144-RMkQDbenvl14; Diwridinene MS (ESn: m/z (%) =191(M+H,100);
HPLC (method 4): rt = 0.64 min. -,y III 5. ~.-(~luaYl~-L-~olinamide MS (ESn: m/z (96) _ 206 (M+H,100);
IiPLC (method 4): rt = 0.72 min.
DI-6. fl44-udnopbooyll-3-ainerldinvlln~nol MS (ESl): nVz (96) = 207 (M+H,100);
HPLC (method 4): rt = 0.60 min.
Le A 34 122-Fbnei Countries III-7. f~-(4-a~minonhenvl>-~-ntnerid~v~ol MS (ESI): m!z (%) = 207 (M+H,100);
APLC (ttwe,ttwd 4): rt = 0.59 min.
III-8. ethvll-(4-~minonheavl)-MS (ESI): m/z (96) = 249 (M+H, 35),175 (100);
HPI.C (saethod 4): rt = 2.43 min.
III-9. 1l-44-4 ai*ovl)-2-v1'lPi''o dnvilmgthenol ~.. MS (ESI): m/z (%) =193 (M+H, 45);
HPLC (method 4): rt = 0.79 niin.
III-10. 4(Z-methvlbxearaLydrn-SH-nvrrabt3.4.dli~nx~ol-S-vl~hmvlamine starting from 2-methylhexahydro-2H-pyrrolo[3,4-d]isoxazole (Ziegler, Carl B., et al.;
J. Heterocycl. Chem.; 25; 2; 1988; 719-723) MS (ESI): mlz (%) = 220 (M+H, 50),171 (100);
BPLC (method 4): rt = 0.54 min.
III-11. 4(l-nvctoWm-1)-3-(trifluoro ethv~
MS (ESI): ni/z (96) = 231 (M+H, 100);
HPLC (method 7): rt = 3.40 niin.
'~ III-12.3-cWor9-4-(i-s isvl~
MS (ESI): m!z (46) =197 (M+Ii,100);
HPLC (method 4): rt = 0.78 min.
IIL-13.5-amino-2=(4 n --t..
MS (ESI): mlz (96) = 222 (M+H, 100);
HPL.C (methcxi 4): rt = 0.77 min.
III-14. 3-methoxv444-mornbo ievlNeiiiw MS (ESI): m/z (96) = 209 (M+H.100);
HPLC (mexhod 4): rt = 0.67 min.
III-15.1-f5-andna244 vl)nlhenvlktlaaone 30725-107(S) MS (ESI): rrilz (%) = 221 (M+H, 100);
HPLC (method 4): rt = 0.77 min.
General method for preparing 4-substituted anilines by reacting 1-fluoro-4-nitrobenzenes with amides, followed by reduction R... R...
F R'"" R==~NO R.,\N0 R R TR + R \N11~O -~ \ R RR H
00 0 -N=0 NH2 where:
R and R' each independently are fluorine, chlorine, nitro, amino, trifluoromethyl, methyl or cyano; and R" and R"' together with the nitrogen atom to which they are bonded from a saturated 5- or 6-membered heterocycle having a carbonyl group directly adjacent to the linking nitrogen atom.
The amide is dissolved in DMF and admixed with 1.5 equivalents of potassium tert-butoxide. The mixture is stirred at RT for 1 h, and 1.2 equivalents of the 1-fluoro-4-nitrobenzene are then added a little at a time. The reaction mixture is stirred at RT
overnight, diluted with ether or ethyl acetate and washed with sat. aqu.
sodium bicarbonate solution. The organic phase is dried over magnesium sulphate, filtered and concentrated. The crude product can be purified by silica gel chromatography (dichloromethane/ethanol mixtures).
For the subsequent reduction, the nitro compound is dissolved in ethanol (0.01 M to 0.5 M solution), admixed with palladium on carbon (10%) and stirred under atmospheric hydrogen pressure overnight. The mixture is then filtered and concentrated. The crude product can be purified by silica gel chromatography (dichloromethane/ethanol mixtures) or preparative reversed-phase BPLC
(acetonitrile/water mixtures).
30725-107 (S) - 52a -Alternatively, the reducing agent used can also be iron powder. To this end, the nitro compound is dissolved in acetic acid (0.1 M to 0.5 M solution) and, at 90 C;
sik-equivalents of iron powder and water (0.3 to 0.5 times the volume of the acetic acid) are added a little at a time over a period of 10-15 min. After a further 30 min at 90 C, the mixture is filtered and the filtrate is concentrated. The residue is worked up by extraction with ethyl acetate and 2N aqueous sodium hydroxide solution. The organic phase is dried over magnesium sulphate, filtered and concentrated. The crude product can be purified by silica gel chromatography (dichloromethane/ethanol mixtures) or preparative reversed-phase HPLC (acetonitrile/water mixtures).
A 34 1 FqW,gp Countriss The following :tarcing matetials werc pmpared in an analogous manner:
MS (ESI): miz (%) = 245 (M+H, 100);
HPI.C (nn;thod 4): rt = 2.98 min MS (ESI): m/z (96) = 261(M+Ii,100);
HPLC (method 4): rt = 2.54 min.
=-. IV-3. 4d4-aminft2dtoronhemrU-MS (E,SI): miz (96) = 227 (M+H, 100);
HPi,C (method 4): rt = =1.96 ntin.
jV-4. 4444ndao- 1)-3-~~
MS (ESD: m/z (96) = 207 (M+H,100);
HPLC (method 4): rt = 0.71 rnin.
IV-5. 5-amina2-(3-oaco-4-wobanDbumuftrik MS (ESD: tb/z (96) ffi 218 (M+H, 100);
HPLC (method 4): rt =1.85 niin.
tV-6- 1-(~pg-lrchloro~}'-~ ovriolidinone MS (ESI): m/z (96) = 211(M+H,100);
HPI,C (method 4): rt = 2.27 min.
1 V-7. 444-Amla9-Z.b&imMthvlnbenvlk3-mQmhdbM
starting frwm 2-tluoro-1,3-dimethyl-5-nitrobenzene (Bartoli at al., J. Org.
Chea%_ 1975, 40, 872):
MS (ESD: m/z (96) = 221(M+H,100);
HPLC (method 4): rt= 0.77 ntin.
I V-S. 4-,~~~dismiaot~h~avll-3-mmnholinone starting from 1-fluoro-2,4diniorobenzene:
MS (ESD: nVz (96) = 208 (M+H,100);
HPLC (method 4): rt = 0.60 mfn.
La A 34 122--Facin Camtriea -$4-IY-9. ~-~~I-~AO-I~C~OlO~VD-~lC~1Vl-}IL~A~
starting from 2-methyl-3-morpholinone (Pfeil, E.; Aander, U.; Angew. Chem.
1967, 79,188):
MS (ESi): m/z (96) = 241(M+H,100);
HPLC (mechoa 4): rt = 2.27 min.
Iy-19. 4-(44mino-2-ddoronbn.-D.6=methvl-3-mornhollnone statting fi+om 6-medhyl-3-morpilolinone (EP 350 002):
MS (FSI): m/z ('96) = 241 (M+H, 100);
FiPLC (method 4): rt = 2.43 min.
:., __ Le A 34 12?-ZRMj~en Camtries 'The Facamples 1 to 13,17 to 19 and 36 to 57 below refer to process variant [A].
Frepamtion of S-chbro-N-{[(SS).3-(3-Quoro-4-moiphollnopbenyl).lrozo.1,3.
wcaxolldin=5-yl]nmethyl}.Z-thiopheaecarboxaoWde F
H
(5S)-5-(Amirromethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolidin-2-ono (preparation see S. J. Briclcncr et al., J. Med. C.'heui. 19%, 39, 673) (0.45 g, 1.52 mmol), 5-chlorothiophene-2-carboxylic acid (0.25 g, 1.52 mmol) and 1 hydroxy-lH-benzotriazole hydrate (HOBT) (0.3 g, 1.3 equivalents) are dissolved in
Me mesning of the %; ~ gap 1 Ai g cosnponaat of other mom complex subuiweats, such as, for example gjkcy-aikyl, g%2gxcarbonyl alkyl and ft&ycacbonyl, is likewise derived from tlus definrritition.
Mono- or di-lCy-Q1~alkvlaminocadarvl nept+esents an atnino groap which is attached via a carbonyl gmup aad which has a straigR-t-duin or bra~nched or two ideatiul or diffenut straight-chain or branchod alkyl substitudtaits having in each case 1 to 4 carbon ,.- atoms. Baaospks which may be mmHened am methylamino, ditylamuno, n-propylamino, isopnopyiamino, t-butylamino, N.N-dimethytamino, N,N-diethylamino, N-athy11V methylwnino, Nanet1vyllV n-pz+opylamino, IV isopr"1V n-propylanrino and N-t-butyl N-methylamino.
(Ct;Q)-Allcnwvl tepcasents a straight-clain or branwbed alkyl radical having I
to 6 carbon atoms which canies a doubly attached oxygen atom. in the 1-position and is attached via the 1-position. Examples which may be mentioned att: formyl, asxtyl, propionyl, n-butyryl, i-butyryl, pivaloyl, n-hexanoyl. The eocraponding atkanoyl groups with fewer carbon atoms, such as, for example, (C,-Cs)-alkanoyl, (Ci-Ca)-alkanoyl and (Ci-Cs)-alkanoyl, an daived analogously from this definition.
In genesal, pneferaxe is given to (Ci-C3)-atkanoyl.
The mming of the cotreaporrding componeat of otha mn cxxnpkx subatituents, such as, for example, cyclog&WA and ;lkNoWkyl, is likawise deiived from this definition.
(C,-CZkCvcloalkaewl ieprmnts a cycloalkyl radical having 3 to 7 carbon atoms.as, defined above, whid- is attached via a carbonyl group.
(Cy~~,~Yl~~ mpamts a straight-chain or branclmed dkanoyloxymethyloxy nvdcai having 1 to 6 carbon atoms. FxaRrples which nuy be mentioned are: acxtoxynxthyloxy, propionoxymethyloxy, n-butyroxymethyloxy, i-butyroxymethyloxy, pivaloyloxymethyloxy, n-hexanoyloxymethyloxy. Tf>e correspcmding alkanoyloxymethyloxy groups having fewer carbon atoms, such as, for I,e A34122 Forci ~g~ica example, (Ci-C3)-aticaaoyloxymethyloxy, are deriVed analogonsly from tbis dCftltiOll. In $GDet'Sl, Ptefelellce iS $[VEIl t0 (Ci-C3)'w[I.A+YlO7CymC&ylQZy QC rep:cs=ta an aromatic nidical having 6 to 14 carbon abozme. Faramptes which msy be mendooed are: PhenYL nqpbihYl, P~ md aiftwaayL The comesponding aryl gronpe wiffi fewa carbon atoms, soch as, for exsmple, (C6-Clo)-aryl are aerivea aoatoSously from this aefinitiom In gAraal, prtf eoce is givea to (C6-CIC)-WA-The meaning of the coc~+eapo~ding eoapx= of odier more caoaeVlex substituants, swch as, for eranmPle, -an&uboayl, is lOmwise derived fi~oea this defiddm lCS:Qlp}:HdmWd or a, 5- to 10-maubared at+onadc haaoc.vele hsvft ug to 3 hatumtoms and/or hot= chain meaibem fi+otn ttre gM cons(stima of S. O. N aod NO
~l a; 1 1 1 1 1 11 a mono- or bicyclic hetmvin m mstic which is attacihad via a oarbon ring atom of the hctwaWAS-An'"c or, if approPriate, via a nitrogm ring atom of the heD~oscomabic. Examples which may be mmtioned are: pyridyl, pyridyl N-oxide, PYTiMidA PYAkziqA. PYrzin3'l. thieayl, fiuyl, PYrroIYI. PYxMIYI, imidazolyl, thiazolyl, oxazolyl or isoamlyl, indolizinyl, iadoiyl, benzo[b]thienyl, beozo[b]furyl, intlaaolyl, quiaolyl, isoqainolyl, naphthyridinyl, quinazolinyl. The correspaod'mg hcta+ocyclas haviag a smaller ring aize, snch as, for ocample, 5- or 6 membered aromatic hdaroayeles, az+e detived malogonsly from thia de$vam In gencral, prefarence is given to 5- or 6-membeted mnmatic hdemcycles, such as, for example, PYddyL PYi'id)-1 N-oaride, Pyrimadyi, Pyridazinyl, fiayl and thieayl.
The, meamng of to onareapomding co ponent of ot6er mm eovoes snbstkuaots, such as, for example, is likewise derived fmm this defmition.
A3-- to 9-6end saturated or pmjbft unsamaed. mo.o- or bi..vchc, o~A!hi benzo-fueed hetesoavocle bavina nn t,L3 baaaMUms and/or h,atero c' mambecs fim the ggm cgmdafmg of S. SO,$Q,Z. NM (N-oaidel mdO represents a hetecocycle which may oontain one or m-sn+e double bonds, whieh may be mono-or bicyctic, to whieh a beazene ring may be fnsed to two adjacant carbon ring atoms and w]>ich is attached via a ca:bon ring atom or a nitrogen ring atom. Exampks wbich may be mentioned are: teuahydinfiwA pyrrolidinyl, PyrmItrA PiPesidinyi, 1,2-Le A 3412Z-Fa+zigU Camaaiea dihydtopyridiny1,1,4-dihydtoQyridinyl= piperazinyl, n"holinyl, motplwlinyl N-oxide, thiomorpholinyl, amepinyl, 1A-diaaaepinyl smd cyalohoxyl. Pnefeaaicx is given oD
PiPmidinyl, motphotinyl and pyrrolidinyl.
The eoVtOMPOnM'ng cycles having a snwlkr ring sizu, sndh as, for exmmple, 5-tio 7-memberod cycles, are darived analogously from this definition.
The ptesent invemon also pnnvides a process for pnepering the conipounds of the genea=al formula (1) according to the invention where either, according to one process altesnative [A] compounds of the general formula (II) R:
'N
R' Rs Re , R, FMI"*%Ra in which the radieals R2, R3, R4, Rs, R6 and R' are each as defined above, are reacted with carboxylic acids of the genera[ formula (lII) HO R' (II[), ~ _ = - . {,:....
in which the radcal R' is as defined above.
Le A 341Z2-E98da QMjpgg or else with the corresponding catbonyl halides, peferably cwbonyl chlorides, or else with the eornesponding symmettic or mixed caboxyiic anhydrides of the carboxylic acids of the general formula (III) defined above S in inert solvents, if appropriate in the p.msencx of an activating or coupling agent and/or a base, to give compounds of the general formula (I) R.:, .1 Rs Rs r" =
R s R=' yR' (I}.
in which the mdicals R', R2, R3, R~, RS, R6, R7 and Rs are each as defined above, or else according to a procxss alternative [B] conzpounds of the general formula (IV) Ra R' s ~s .z._ in which the radicals R. R. R4, Rs, R6, R7 and Ra are each as deined above, are converted, using a suitable selecave oxidizing agant in an inert solvent, into the corresponding epoxide of the general formula (V) Le l~341224%zilm CamUits = ' -33-Rs Rs ~
R' ~. , N R
Rs Rs in which the radicals R', R3, R4, Rs, R6, R7 and R are rach as defined above, and, by neaction in an inwt solvent, if appt+opziate in the pnesenee of a catalyst, with an amine of the general formula (VI).
R2 - NHz (VD, in which the radical R2 is as detined above, the compounds of the general formula (VII) . ! s 6 s N ,00L R, (VU)-H ~ =
in which the radicals R', R2, R3, R', R. R6, R7 and Ri ara each~ as defiried' _ above, are initially pnopared and subsequendy, in an iaert solvent in the pnesence of phosgene or phosgene equivalents, such as, for example, earbonykliimidazole (CDI), cyclized to give the compounds of the pneral formula (I) Le. A 34122-Forr~ffi Caemtrxs = = - 34, .
_ry R' R Rs . ' R'- R' (I) in which the radicals R', RI, R3, R4, Rs, R6, RC and R are each as defined above, whem - both far proceas aharna6ve [A] and for process altarnative [B] - in the case where R2 contains a 3- to 7-membec+ed saturated or partially unsavxated cyclic hydrocarbon radical having one or morc identical or different heteroatoms from the group consisting of N and S, an oxidation with a selective oxidizing agent to afford the cosesponding sulphane, suiphoocide or N-oxide niay follow and/or whene - both for process alternative (A] and for process alternative [B] - in the case where the compound prepared in this manner has a cyano group in the molecule, an amidinadon of this cyano group by customwy methods may follow and/or ,,...
whec+e - both for process alternative [A] and for process alternadve [B] - in the case where the componnd prepared in this manner has a BOC aniino protective gmup in the molecule, removal of this, BOC amino protective group by cusoomary methods may follow and/or Le A 34 122Faneamn Camtries = ' -35-whw+e - both for process alternative [A] and for process altemative [B] - in the case whaze the compound prepared in this mmmcr has an aniline or benzyiamine radical in the molecule, a reaction of this amino group with various reagentt such as carbozylic acids, cwboxylic anhydrides, carbonyl chlorides, isocynnates, suiphonyl chlorides or alkyl halides to give the corresponding derivmtives may follow and/or where - both fw' pd+ocxss altetnative [A] and for prrocxss alternative [8] -in the ~.. cese where the compound pu ey - p ri in this mwner has a phenyl iing in .t6e molecule, a neaction with chlomsulphonic ecid and subaequent rsaction with amines to give the cornesponding sulphonamrides may follow.
The proeesses according to the invention can be illustrated in an euemplary manner by the equs-tions below:
[A]
~
HO ~ ~
q o-b-b+
a (iw'P~I~EtI'~
FN
p F
M!!ft t NHt ~ . _.
IA A 34 122-Foceian Cotmtries = -36-[B]
MMa --------aa ~ -- /
HN
,-- The oxidaiion step dsscccibed above, which is optional, can be illustrated in an exemplary manner by the equation below:
F F
NAAOJOs0. 0 ~
d p'' p F
O- ~ d Suitable solvents for the processes daacribed above are organic solvents which at+e inert under the reaction conditions. These include halogenated hydrocarbons, such as dichloromethane, trichlonomethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, tetraehioroethane, 1,2-dichloroethylone or trichlaroethylene, ethers, _ such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ethi=c or diethylene glycol dimethyl ether. alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons, such as benzene. xylene, toluene, hexane or cyclohexane, dimethylformamide, dimethyl sulphoxide, acetonitrile, pyridine, hexa-methylphosphoric trianride or water.
It is also possible to use solvent mixtures of the solvents mentioned above.
Le A 34122 rvadgq Coamtries Ssdtable acdvating or coupling agents for the processes described above ane the neapnts which are customarily used for this purpose, for example N'-(34msethylaminopropyl)-N-ethylcarbodiimide - $Ct, N,N'-dicyclohexytca:bo-damide,1-hy~idroxy-lH-benzotciazole - H20 and the like.
Saitable bates are the customary inorganic or organic bases. These pi+eferably include alkali metal hydraxides, such as, for example, sodium hydroxide or potassium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or sodium methoxide or potassium inetlwxide or sodium ethoxide or pataasium ethoxide or potassium tert-butoxide, or amides, such as sodium amfde, ~.. lithium bis-(triraethylsilyl)amide or lithium diisopmpylamide, or amines, such as triethyiamine, diisoprnpylethylamine, diisopropylamine, 4N,IV-dimethylamino-pyridine or pyridine.
The base can be employed hei+e in an amount of from 1 to 5 mol, preferably from i to 2 mol, based on 1 mol of the compounds of the genenW formula (11).
The reactions are generally carried out in a tamperature range of from 78 C to reflux te:mperatuce, preferably in the range from 0 C to teflux temperatwe.
The nõacfions can be cairied out at atmospheric, elevated or reduced pres:m (for example in the range from 0.5 to 5 bar). In general, the reactions are carried out at aomosphcric pnuure.
Suitable sekctive oxidizing agents, both for the preparation of the epoocides and for the optional oxidation to give the sulphone, sulphoxide or N-oxide, are m-chlorroperbenzoic acid (MCPBA), sodium metaperiodate, N-methylmorpholine N-oxide (NMO), monoperoxyphthalic acid or osndum tetroxide.
.30 With respect to the pmparation of the epoxides, the prtparation conditiana which are customary for this purpose are employed.
With reapext to more detailed procas conditions for the optional oxidation to give the sulphone, saiphoxide or N-oxide, reference is made to the following liunture:
M. R. Barbachyn et al., J. Med Chem.1996, 39, 580 and WO-A 97I10223.
IAA 341ZLEft sio ~' tries Fattlornw+e, reference is made to Examples 14 to 16 given in the experimental part.
The optional amidation is catried out under antommy conditions. For more details, nefercnce is made to Examples 31 to 35 and 140 to 147.
The compounds of the grneral formulae (II), (III), (IV) and (VI) are known per se to the person skilled in the wt or can be prepated by customsty methods. For oxazolidinones, in patticular the 5-(atninomethyl)-2-oxooxarto}idines required, cf.
WQ-A-98/01446; WO-A-93123384; WO-A=97I030r'J2; J. A. Tuclca= et al., J. Med.
Chera. 1998, 41, 3727; S. J. Brickner et al., J. Med. Chem. 1"6, 39, 673;
W. A. Gregory et al., J.1Ned. Chem.1"4, 32, 1673.
The compounds of the genaW formula (I) according to the invention have an unfoneseeable useful pharmacological activity spectrum and a=e thec+efore particularly suitable for the prophylaxis and/or rnament of disordera.
The compounds of the genaral formula (1) according to the ivnention -including the compounds which are excluded by disclaimer from the ehemical product protection - act in particular as anticoagulants and can therefore pieferably be employed in nxdicaments for the prophylaxis snd/or therapy of thromboembolic disorders. For the purpose of the present invention, "t}Tomboeinbolic disorders"
include, in particular, serious disorders such as myocardial infaret, angina pectoris (including unstable angina), mocciusions and restenoses after angioplasty or arntoeoronary bypass, stnnlce, transitory ischaemic attacks, penpla-al atusial occlusion disorders, pulmmmy embolisms or deep venous ttuomboses.
Fxthermore, the coznpouads of the general formnla (1) according to the invention - including the componnds which are excluded by disclaimtr froom=
tiw;, chemical product protection - are also suitable for tnating disseminated intravascular coagulation (DIC).
Finally, the compounds of the ganeral formula (1) according to the invention - including the compounds which are excluded by disclaimer from the chemical product piotection - am also suitabte for the praphylaxis aad/or meatrnent of atherosclerosis and arthritis, and additionally also for the prophylaxis and/or treammt of Alzheimer's disease and cancer.
LgA341224%Wm Candfies The compounds of the @eneral foimula (I) according to the invention -including the compounds excluded by disclaimer frozn the chemical product protection - act in particular as selective inhuNtots of the blood coagulation factorr Xa and do not inhibit, or only inhibit at considerably higher concentrations, other serine proteases as well, such as thrombin, plasrnin or trypsin.
In the context of the pt+eseat inventioa, inhibitors of the blood coagWation factor Xa in which the ICso vaiues for the facWr Xa inhibltion atc lower by a factor of 100, preferably by a factor of 500, in particular by a factor of 1000, than the ICM
values ~., for the inhibition of otha serine proteases, in patticular thrombin, plasmin and trypsin, are refelred to as being õselective", whena with a view to the test metbods for selectivity, reference is made to the test methods of Examples A-1) a1) and a.2) described below.
The eompoumd: of the generai formula (1) according to the invention -including the compounds which are excluded by disclaimer fran the cheniical product protection -can fiwthamoce be used for pneventing coagulation ex vivo, for example for bmked blood or biological samples which contain factor Xa.
The present invention thus provides oxazolidinones of the formula (1) effecting in pamticular an unexpected, strong and selective inhibition of factor Xa, and this also applies to the comWmds excluded by disclaimer from the chemical pmduct protection.
The presm invention finther provides medicaments and phatmaoeutical campositions comptfsing at least one conVOnnd of the ganeral formula (1) according to the invention together with one or more phannacoiogically acceptable auxiliari~es.
or excipients, which nitxdicaments and pharmaceutical compositions can be used for the indications mentioned above.
Furthermmore, the present invention relates to a method for the prophylaxis and/or tneabnent of disordexs of the human or animal body; in paticular of the abovementioned disorders, using the compounds of the general formula (I) acconding to the invention - including the compounds excluded by disclaimer from the chemical product protection.
Le A 34122-Forethm Comtries Furthmmorc, the preunt invwtion also includes a method for prevendng blood eosguladon in vitro, in particular in banked blood or biologieal samples which contain faccw Xa, which method ia chuadaixed in that coMounds of the geneanl fommla (I) - including the eon-pounds excluded by disclaimer from the chemical product protection - are added.
AI] customary administration fonans are suitable for administration of the compounds according to the invention. Admiiriscmtion is pzeEerably caaied out orally, lingually, 10- sublingually, buccally, roctally or parentarally (i.e. bypaasing the intestinal uwet, that ,=. is intravendusly, intraas=oerially, fnt:acarWally, intracutaneously, subcutaneoualy, ttansdcnnally, intraperitoneally or intramuscularly). Particulariy suitable are oral aad intravenous administration. Very particular preference is given to oral adminisrrstion, this being a further advantage with respect to the prior-art therapy of thromboernbolic disonders.
The novel active cxunpoimds of the general formula (1) csin be converted in a known manner into the customary formulations, such aa tablets, augar-eosod tablets, pills, gcanutes, aerosols, syrups, emulsions, suspensions and solutions, using inert non-toxic pharmaceatically suitable excipients or solvents. Herc, the therapeutically active compound should in each case be present in a concentration of from about 0.1 to 95% by weight, preferably fi+om 0.5 to 90% by weight, in particular from i to 85%
by weight. of the total mixtum i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
In spite of this, if appropriate, it may be necessary to depart from the amounts mentioned, namely depanding on the body weight or on the type of administration route, on the individual response to the medicament, on the mtnner of its formulatigm L
and the time or interval at which administration takes place. Thus, in sonie cases it may be adeQuate to manage with less than the abovementioned minimum amount, while in other cases the upper linrit mentioned must be exceeded. In the case of the administration of relatively lage amounts, it may be advisable to divide these into several individual administrations over the course of the day:
The formula6ons are pnspared, for example, by extending the active cotrqxxnds with solvents and/or excipients, if appmpriate using emulsifiers and/or dispersants, it I&A 34 122 Faeian Conntriel = -41-being pasible, for example if dse diluent used is water, optionally to use organic solvents as auxilistry solvents.
In getteral it has pioved advantageous in the case of intravenout adminisoation to administer amounts from appzoximately 0.001 to 10 mg/kg, prdersbly aploximaWy 0.01 to 10 mg/kg, in pacticxda approxinmtely 0.1 to 8 mWkg, of body weight to achieve effective results.
In general, it has proved advtmtagoous in the case of oral admWismWon to administer amounta fram appTOximately 0.01 to 50 mg/kg, preferably approxitnately 0.1 to ~ 10 mg/kg, in particular ~PPaftly 0.5 to 8 mg/lcg, of body weight to achieve effective results.
In spite of this, if appropriate, it may be necessary in the case of intravenous or oral administration to deparc from the atnamts mentioned, namely depending on the body weight or on the type of administration route, on the individual tespornse to the medicament, on the tnannerr of its formulation and the time or interval at which adminigmon takres placx. Thus, in some cases it may be adequate to manage with less than the abovemendoned mininum amount, while in other cases the upper limit mentioned must be exceeded. In the case of the admitistratfon of relatively large amounts, it may be advisable to divide these over the course of the day, namely into several individual doses or as a continuous infusion.
!~ Compared to the evnveational preparatiorA for treaitin= throanboanbolic diiordas, the compomds of the generat formula (1) sccorcling to the invention -includieg the compounds excluded by disclaimer from the chemical product proteetion - are distinguished in paaticular by the fact that a grieaterr therapeutic range is achieved by the selective inhibition of factor Xa. For the patient, this rneans a. lower risk- oL-. .
bleeding, and for the trcating physician, this means that the patient is easier to adjust Moieovec - owing to the mechanism - the onset of action is more rapid. Above all, however, the oompotpzds accoeding to the invendou pe=mit an oral admirastration forat, which is a further advantage of the therapy with the compounds according to the invention.
The present invention is illusuued by the examples below; however, these examples an not nxant to restrict the invention in any way.
34122 Foratn CwnVia EumWO
A Enhmdm,of the nhvslobadcal activltv 1. Giseral test etbods The particulerly advantaWous biological properties of the compounds according to the invention can be detetrnined by the foIIowing methods.
A) Tem lmriotion (in vitru) ~. .
a.1) Det~ermioadon of the factor Xa Ldibition The enzymatic aqivity of human factor Xa (FXa) was measured using the eonvmion of a chromogenic substrate specific for FXa. Factor Xa cleaves p-nitroaniline from the chromogenic substrate. The determinations were carried out in microtitre plates as follows.
The test substances, in various concentcations, were dissolved in DMSO and incubated at 25 C with human PXa (0.5 nmoVl dissolved in 50 mmol/l of tris buffer [C,C,C-tris(hydroxymethyl)-aminomethane], 150 mmol/1 of NaCI, 0.1% BSA
(bovine serum albumin), pH = 8.3) for 10 minutes. Pure DMSO was used as control.
The chromogenic substrate (150 mol/1 of Pefachrome FXa from Pentapharm) was then addod. After an incubation time of 20 ririnutes at 25 C, the extinction at 405 nm was determined. The extinctions of the test mixtures containing test substarnx were compared with the control mixtures without test substance, and die ICm values were calculated from these data.
a.2) De,terminntbn of the selectlvity To assess selective FXa inhibition, the test substances were examined for their inhibition of other hunm serine proteases such as thrombin, trypsin and plasmin_ To detecmine the enzymatic activity of thrombin (75 mUhnl), trypsin (500 mUtml) and piasmin (3.2 nmol/1), these enzymes were dissolved in tris buffer (100 mmol/!, 20 mmol/l CaC12, pH = 8.0) and incubated with test substance or solvent for 10 minutes. The enzysnstic reac.-tion was then sterted by adding the corresponding Le A 34122-T!oneim, Countries specific cMromogaiic substtatea (Chromozyna Thranbin fr+osn Boetninger Mannheim, Chromozym Trypsin from Boehringer Mannheim, Chromozym Plasmin from Boetningrer Mannheim) and the extinction at 405 nm was deLernained after 20 minutes. All dewrjninautions were carried out at 37 C. The extinctions of the test arixtune,s containing test substance were compared with the control samples without test substance, and the ICso values were calculated from these data.
a.3) Determioatbn d t6e ~t adion The anticosgulant action of the ust substances was determined in vitro in human ,=. plasma. To this end, human blood was drawn off in a mixing ratio of sodium citrate/blood of 1/9 using a 0.11 molar sodium citrate solution as receiver.
Immediately after the blood had been drawn off, it was mixed thoroughly and cxntrifuged at about 2000 g for 10 minutes. The supernatant was pipetted off.
The prothrombin time (PT, synonyms: thromboplastin time, quick test) was decernrined in the presence of varying coacenaations of test subctancx or the cxmtsponding solvent using a commercial test kit (Neoplastin from Boehringer Mannheim). The test compounds wcre incubated with the plasma at 37 C for 10 minutss. Cflaigulacion was then started by addition of thromboplastin, and the time when coagulation occurred was deoerrnined. The concentration of test anbstance which effected a doubling of the prothrombin tinu was detetmined.
b) Dets.rminatioa Qftheantithrombotic actlvkv (in vivo) b.1) Arteriovenous shunt modd (rat) Fasting male rats (strain: HSD CPB:WU) having a weight of 200-250 g wera anaesthecized using a RompunlKetavet solution (12 mglkg! 50 ing/kg). Thrombus ,_ formation was initiated in an arteriovenous shunt in accordance with the method described by Christopher N. Berry et al., Br. J. Pharmacol. (1994), 113, 1209-1214.
To this end, the left jugular vein and the right carotid artery were exposcd.
The two vessels wem connected by an extracorporeal shunt using a polyethylene tube (PE
60) of a lengtb of 10 cm. In the middle, this polyethykne tube was anschad to a further polyethylene tube (PE 160) of a length of 3 cm which contained a roughened nylon thread which had been aamged to form a loop, to form a thrombogenic surface.
The extracorponaal circulation was maintained for 15 minutes. The shunt was then A 34 122-FbreilM CgUMgL
= = -44-ranoved and the nylon tlmead with the thrombus was weighed immediately. The weight of the nylon thread on its own had been detemiined before the experineat was starued. Befos+c the exuacorporeal circulation was sei up, the test substmces were administered to the amrnals while awake either intravenously via the tail vein or ozaUy using a pharyngeal tube.
~- .
:,~..
1 A A 34122-Pon:in Ca~
'i'ho results are shown in Tabk 1:
Table 1: AntittZgMbotic acdYjlyin du Werioyenous ahunt model /rat) after or,l or intravenous adtninistration Lv.
!" 114 3 b.2) Arterial tluoobods modd (rat) Male faeting rats (strain: HSD CPB: WU) were anaesthetized as described above.
On average, the rats had a w+sight of about 200 S. The left carotid artery was exposed (about 2 cm). The formation of an arterial thrombus was induced by mechanical injury to the blood vessel in accordance with the method described by K. Meng et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. To this end, the exposed carotid artery was clamped from the blood flow, cooled to -12 C in a metal trough for 2 manutes and, to standardize the size of the throu-bi, simultaneously compressed using a weight of 200 g. The blood flow was then additionally reduced by a clip which was placed around the carotid artery distally from the injueed, section of the vessel. The proxinul clamp was removed, and the wound was closed and re-opened after 4 houra to remove the injured section of the vessel. Ttmsoction of -tha =-=
vessel was opened longitudinally and the thrombus was mnoved from the injured section of the vessel. The moist weight of the thrombi was detamined immediately.
The test substatwes wene administered to the animals while awake at the beginning of the experiment, either intravenously via the tail vein or orally using a pharyngeal tube.
Ie A 34122 FMeia Camtries = -46-b3) Venmu tbrombosis modd (rat) Mok fasting rats (strain: HSD CPB: WU) wei+e anaesthetized as described above.
On average, the rats had a weight of about 200 g. The left jugular vein was exposed (about 2 cm). The fonaation of a venoas tlirombus was induced by mechanical injury to the blood vessel in accordance with the method describad by K Meag et a1., Naunyn-Schmiedeberg's Aroh. P'harmacol. (1977), 301, 115-119. To this end, the jugular vein was clamped from the blood flow, cooled to -12 C in a melal trough for 2 minutes and, to standardize the size of the thrombi, simnltaneausly compmssed using a weight of 200 S. The blood flow was re-opened and the wound was closed.
After 4 hours, the wound was se-opened to nnnove the thmmbi from the injured scctions of the vessel. The moist weight of the thzombi was demmned immediataly.
The test substances wem adininisteried to the animals while awake at the beginning of the experiment, either intravenously via the tail vein or orally using a pharyngeal tube.
I.e A 34 1224kadSo Casntries = -47-B ftMG"FWwwJw startlnt mateiiala The preparation of 3-aioipholinone is deacribed in US 5 349 045.
The preparation of N-(2,3-epoxypropyl)phdzalimide is described in J.-W. Chem et W.
Tetraludr+on I.ett.1l98,39,8483.
Thc subttituted anilines can be obtainod by racting, for exalapk, 4tluotonitro-benzene, 2,4-difluouronittnbenzene or 4-chloionin~obenzene with the appropriate amines or amides in the presenrx of a base. This can also be carried out using Pd catalysts, such -as Pd(OAc)j/DPPFINaOt Bu (Tetrahedron Lett. 1999,40,2035) or copper (Renger, Synthesis 1985,856; Aabischer et al.. Iieteancycles 1998,48.2225).
Likowise, it is possible to initially convert halogensted atomatics without nitro group into the cornesponding amides, followed by nitratfon in the 4-position (US3279880).
L~42~ahul~-3atvlloitrols~mene NOz NO
O 2 NMP, NaH
C~ +
N O
'O
2 mol (202 g) of motpholin-3-oee (E. Pfeil, U. Harder, Angew. Chem.
79,1967,188) are dissolved in 21 of N-methylpynrolidone (NMP). Over a period of 2 h, 88 g (2.2 mol) of sodium hydride (60% in pasaffin) ate thca added a littie at.a, time. AfieT..--the evolution of hydrogen has ceased, 282 g (2 mol) of 4fluoronitirobenzene am added dropwise with c:ooTing at room temperutw e, over a period of 1 h. md the reaction mixture is then stin~ed ovemight. At 12 mbor and 76 C, 1.71 of the liquid volume m+e then distilled off, the ns;idut is poured into 21 of water and this radxture is extracted twice with in each case 1 1 of ethyl aoaate. After washing of the conibined organic phases with water, the nwcme is dried over sodium sulphate and the solvent is distilled off under reduced pressure. Purification is carried out by silica gel chromatography using hexanelethyl acetate (1:1) end subsequent crystallization I& A 34122-F=*n Couetriea = -48-from ethyl acetate. This gives 78 g of product as a colourless to brownish solid, in a yield of 17.696 of gheary.
IH NMR (300 MHz, CI)C13): 3.86 (m, 2 H, CH2CH=), 4.08 (m, 2 H, CHzCHz), 4.49 (s, 2 H, CH2CO), 7.61 (d, 2 H, 3.-8.95 Hz, CHCfI), 8.28 (d, 2 H, 31=8.95 Hz, CHCH) MS 0196) = 222 (74, M"), 193 (100), 164 (28), 150 (21), 13.6 (61), 117 (22), (24).90 (37),76 (38),63 (32),50 (25) T1m following compounds were synthesiud atudogonsly:
. 3-tluoro=4-(4-motpholin-3-ony1)nihobanzene 4-(N-piperidonyl)Wtrtobe~Ie 3-fluoio4-(N-piperidonyl)nionobeozene 4-(N-pynolidonyl)nitrobenzene 3-fluozo-4-(N-pyrroiidonyl)nitrobenzene II. 4(4-Meraho~õ3onv ~
H2, Pd/C ( .~
N O N
(0:r co In an autoclave, 63 g(0.275 mol) of 4-(4morpholin-3-onyl)nittobenzenc are dissolved in 200 tnl of teuahydruffiuan, admixed with 3.1 g of Pd/C (596ig) and hydcogenatad at 70 C and a hydrogen pressura of 50 bar for 8 h. The eatalyst is filtered off, the solvent is then distilled off under reduced pressure and the product is purified by crystallization from ethyl acetate. 20 g of product are obtained as : a:.....
colourless to bluish solid, in a yield of 37.6% of theory.
Purification can also be carried out by silica gel chtomatogtaphy using hexane%thyl acetate. -'H-NMR (300 MHz, CDC13): 3.67 (m, 2 H, ClY2CH2), 3.99 (m, 2 H, CH2CH2), 4.27 (s, 2 H, CH2CO), 6.68 (d, 2 H, 3l=8.71 Hz, CHCH), 7.03 (d, 2 H, 31=8.71 Hz, CHCH) _..., ,,._ } 30725-107 (S) MS (r.L%) = 192 (100, M+), 163 (48), 133 (26), 119 (76), 106 (49), 92 (38), 67 (27), 65 (45), 52 (22), 78 (22) The following compounds were synthesized analogously:
3-fluoro-4-(4-morpholin-3-onyl)aniline 4-(N-piperidonyl)aniline 3-fluoro-4-(N-piperidonyl)aniline 4-(N-pyrroli donyl)aniline 3-fluoro-4-(N=pyrrolidonyl)aniline General method for preparing 4-substituted anilinies by reacting 1-fluoro-4-nitrobenzenes and 1-chloro-4-nitrobenzenes with primary or secondary amines, followed bv reduction x R=\N,R== R.\N,R..
R
I j + R'.N.R'" R _ (\
H
X=F,CI
where:
R is fluorine, chlorine, nitro, amino, trifluroromethyl, methyl or cyano; and R' and R" together with the nitrogen atom to which they are bonded form a saturated ) - or 6-membered heterocycle.
Equirnolar amounts of the fluoronitrobenzene or chloronitrobenzene and the amine are dissolved in dimethyl sulphoxide or acetonitrile (0.1 M to 1 M solution), and the mixture is stirred at 100 C overnight. After cooling to RT, the reaction mixture is diluted with ether and washed with water. The organic phase is dried over MaSO4, filtered and concentrated. If a precipitate forms in the reaction mixture, the precipitate is filtered off and washed with ether or acetonitrile. If the mother liquor also contains product, it is worked up as described using ether and water. The crude products can be purified by silica gel chromatography (dichloromethane/cyclohexanelr:-and dichloromethane/ethanol mixtures).
'30725-107 (S) - 49a -For the subsequent reduction, the nitro compound is dissolved in methanol, ethanol or ethanol/dichloromethane mixtures (0.01 M to 0.5 M solution) admixed with palladium on carbon (10%) and stirred under an atmospheric hydrogen pressure overniaht_ The mixture is then filtered and concentrated. The crude product can be purified by silica gel chromatojraphy (dichloromethane/ethanol mixtures) or preparative reversed-phase HPLC (acetonitrile/water mixtures).
Le A 34 122 Foreign Coueaies Altetaatively, ttw redadng agent used cm also be iron powder. To this end, the nitro compound is dissolved in aaaic acid (0.1 M to 0.5 M solution) and, at 90 C, six equivalents of iron powder and water (0.3 to 0.5 times the volume of the acetic acid) am added a littie at a time over a period of 10-15 min. After a fiuther 30 min at 90 C, the mixture is filtered and the fihiate is concentrated. The residue is worked up by extraction with ethyl acetate and 2N aqueous sodium hydroxide solution. Ttie organic phase is dried over nmgnesium sulphate, filtered and concentrated. The crude product can be ptnified by silica gel chroinatogcaphy (dichl(x omethanelethanol mixtures) or preparative reversed-phase HPI:C (acetonitrileJ'water mixnu+es).
The foAowing starting materiah werc praparod in an analogous manner:
III-1. tert-buh-1=1=(4aminQnhao~ll~L-oroWis~e MS (ESI): nVz (%) = 304 (M+H+MeCN,100), 263 (M+H, 20);
HPLC (method 4): rt = 2.79 min.
rn- 1A~Udn2oheuvll-3-WarMttmaarboxamlde MS (ESI): m/z (%) = 220 (M+H, 100);
HPLC (method 4): rt = 0.59 min.
M-3s 1-(_ 4_amino~. h_envll ,-4-_ !
MS (ESI): m/z (%) = 220 (IvI+H,100);
HPLC (method 4): rt = 0.57 min.
T -4. 144-RMkQDbenvl14; Diwridinene MS (ESn: m/z (%) =191(M+H,100);
HPLC (method 4): rt = 0.64 min. -,y III 5. ~.-(~luaYl~-L-~olinamide MS (ESn: m/z (96) _ 206 (M+H,100);
IiPLC (method 4): rt = 0.72 min.
DI-6. fl44-udnopbooyll-3-ainerldinvlln~nol MS (ESl): nVz (96) = 207 (M+H,100);
HPLC (method 4): rt = 0.60 min.
Le A 34 122-Fbnei Countries III-7. f~-(4-a~minonhenvl>-~-ntnerid~v~ol MS (ESI): m!z (%) = 207 (M+H,100);
APLC (ttwe,ttwd 4): rt = 0.59 min.
III-8. ethvll-(4-~minonheavl)-MS (ESI): m/z (96) = 249 (M+H, 35),175 (100);
HPI.C (saethod 4): rt = 2.43 min.
III-9. 1l-44-4 ai*ovl)-2-v1'lPi''o dnvilmgthenol ~.. MS (ESI): m/z (%) =193 (M+H, 45);
HPLC (method 4): rt = 0.79 niin.
III-10. 4(Z-methvlbxearaLydrn-SH-nvrrabt3.4.dli~nx~ol-S-vl~hmvlamine starting from 2-methylhexahydro-2H-pyrrolo[3,4-d]isoxazole (Ziegler, Carl B., et al.;
J. Heterocycl. Chem.; 25; 2; 1988; 719-723) MS (ESI): mlz (%) = 220 (M+H, 50),171 (100);
BPLC (method 4): rt = 0.54 min.
III-11. 4(l-nvctoWm-1)-3-(trifluoro ethv~
MS (ESI): ni/z (96) = 231 (M+H, 100);
HPLC (method 7): rt = 3.40 niin.
'~ III-12.3-cWor9-4-(i-s isvl~
MS (ESI): m!z (46) =197 (M+Ii,100);
HPLC (method 4): rt = 0.78 min.
IIL-13.5-amino-2=(4 n --t..
MS (ESI): mlz (96) = 222 (M+H, 100);
HPL.C (methcxi 4): rt = 0.77 min.
III-14. 3-methoxv444-mornbo ievlNeiiiw MS (ESI): m/z (96) = 209 (M+H.100);
HPLC (mexhod 4): rt = 0.67 min.
III-15.1-f5-andna244 vl)nlhenvlktlaaone 30725-107(S) MS (ESI): rrilz (%) = 221 (M+H, 100);
HPLC (method 4): rt = 0.77 min.
General method for preparing 4-substituted anilines by reacting 1-fluoro-4-nitrobenzenes with amides, followed by reduction R... R...
F R'"" R==~NO R.,\N0 R R TR + R \N11~O -~ \ R RR H
00 0 -N=0 NH2 where:
R and R' each independently are fluorine, chlorine, nitro, amino, trifluoromethyl, methyl or cyano; and R" and R"' together with the nitrogen atom to which they are bonded from a saturated 5- or 6-membered heterocycle having a carbonyl group directly adjacent to the linking nitrogen atom.
The amide is dissolved in DMF and admixed with 1.5 equivalents of potassium tert-butoxide. The mixture is stirred at RT for 1 h, and 1.2 equivalents of the 1-fluoro-4-nitrobenzene are then added a little at a time. The reaction mixture is stirred at RT
overnight, diluted with ether or ethyl acetate and washed with sat. aqu.
sodium bicarbonate solution. The organic phase is dried over magnesium sulphate, filtered and concentrated. The crude product can be purified by silica gel chromatography (dichloromethane/ethanol mixtures).
For the subsequent reduction, the nitro compound is dissolved in ethanol (0.01 M to 0.5 M solution), admixed with palladium on carbon (10%) and stirred under atmospheric hydrogen pressure overnight. The mixture is then filtered and concentrated. The crude product can be purified by silica gel chromatography (dichloromethane/ethanol mixtures) or preparative reversed-phase BPLC
(acetonitrile/water mixtures).
30725-107 (S) - 52a -Alternatively, the reducing agent used can also be iron powder. To this end, the nitro compound is dissolved in acetic acid (0.1 M to 0.5 M solution) and, at 90 C;
sik-equivalents of iron powder and water (0.3 to 0.5 times the volume of the acetic acid) are added a little at a time over a period of 10-15 min. After a further 30 min at 90 C, the mixture is filtered and the filtrate is concentrated. The residue is worked up by extraction with ethyl acetate and 2N aqueous sodium hydroxide solution. The organic phase is dried over magnesium sulphate, filtered and concentrated. The crude product can be purified by silica gel chromatography (dichloromethane/ethanol mixtures) or preparative reversed-phase HPLC (acetonitrile/water mixtures).
A 34 1 FqW,gp Countriss The following :tarcing matetials werc pmpared in an analogous manner:
MS (ESI): miz (%) = 245 (M+H, 100);
HPI.C (nn;thod 4): rt = 2.98 min MS (ESI): m/z (96) = 261(M+Ii,100);
HPLC (method 4): rt = 2.54 min.
=-. IV-3. 4d4-aminft2dtoronhemrU-MS (E,SI): miz (96) = 227 (M+H, 100);
HPi,C (method 4): rt = =1.96 ntin.
jV-4. 4444ndao- 1)-3-~~
MS (ESD: m/z (96) = 207 (M+H,100);
HPLC (method 4): rt = 0.71 rnin.
IV-5. 5-amina2-(3-oaco-4-wobanDbumuftrik MS (ESD: tb/z (96) ffi 218 (M+H, 100);
HPLC (method 4): rt =1.85 niin.
tV-6- 1-(~pg-lrchloro~}'-~ ovriolidinone MS (ESI): m/z (96) = 211(M+H,100);
HPI,C (method 4): rt = 2.27 min.
1 V-7. 444-Amla9-Z.b&imMthvlnbenvlk3-mQmhdbM
starting frwm 2-tluoro-1,3-dimethyl-5-nitrobenzene (Bartoli at al., J. Org.
Chea%_ 1975, 40, 872):
MS (ESD: m/z (96) = 221(M+H,100);
HPLC (method 4): rt= 0.77 ntin.
I V-S. 4-,~~~dismiaot~h~avll-3-mmnholinone starting from 1-fluoro-2,4diniorobenzene:
MS (ESD: nVz (96) = 208 (M+H,100);
HPLC (method 4): rt = 0.60 mfn.
La A 34 122--Facin Camtriea -$4-IY-9. ~-~~I-~AO-I~C~OlO~VD-~lC~1Vl-}IL~A~
starting from 2-methyl-3-morpholinone (Pfeil, E.; Aander, U.; Angew. Chem.
1967, 79,188):
MS (ESi): m/z (96) = 241(M+H,100);
HPLC (mechoa 4): rt = 2.27 min.
Iy-19. 4-(44mino-2-ddoronbn.-D.6=methvl-3-mornhollnone statting fi+om 6-medhyl-3-morpilolinone (EP 350 002):
MS (FSI): m/z ('96) = 241 (M+H, 100);
FiPLC (method 4): rt = 2.43 min.
:., __ Le A 34 12?-ZRMj~en Camtries 'The Facamples 1 to 13,17 to 19 and 36 to 57 below refer to process variant [A].
Frepamtion of S-chbro-N-{[(SS).3-(3-Quoro-4-moiphollnopbenyl).lrozo.1,3.
wcaxolldin=5-yl]nmethyl}.Z-thiopheaecarboxaoWde F
H
(5S)-5-(Amirromethyl)-3-(3-fluoro-4-morpholinophenyl)-1,3-oxazolidin-2-ono (preparation see S. J. Briclcncr et al., J. Med. C.'heui. 19%, 39, 673) (0.45 g, 1.52 mmol), 5-chlorothiophene-2-carboxylic acid (0.25 g, 1.52 mmol) and 1 hydroxy-lH-benzotriazole hydrate (HOBT) (0.3 g, 1.3 equivalents) are dissolved in
9.9 nil of DMF. 0.31 g (1.98 mmol, 1.3 equivalents) of N'-(3-disnethylaminopropyl)-N-ethylcaubodiimide (EDCI) aro added, and 0.39 g(0.53 ml, 3.05 mmol, 2 equivakats) of diisopropylethylamine (D1FA) are added dmpwisc at room temperature. The mixtune is stirred at rovm temperature overnight. 2 g of silica gel aee added, and the mixwre is evaporated to dryness under reduced pmssme. The residue is chrotnatographed on silica gel using a tolueneJethyl acetate gradient. This gives 0.412 g (61S96 of theory) of the targiet compound of melting point (m.p.) 197 C. ,._ Rf (SiOs, toluenelethyl acetate 1:1) = 0.29 (statting materiai = 0.0);
MS (DCI) 440.2 (M+H). Cl pattem;
'H NMIIt (d6-DMSO, 300 NlJiz) 2.95 (m, 4Yi). 3.6 (t, 2H); 3.72 (m, 4H), 3.8 (dd, 1H), 4.12 (t, 1H), 4.75-4.85 (m, 1H), 7.05 (t, 1H), 7.15-7.2 (m, 311), 7.45 (dd, IH), 7.68 (d,1H), 8.95 (t,1H).
U A 34 122 -Fot+etQn Countrua = -56-Exwnpb 2 5-Chbro-N-{I(SS)-3-(4-aarpholioop6myl)-7roiou-1,3-oxaaolidfn-5-yl]mctbyl}-2-thiophenecarboxam3de CI
HN I
is obtained analogously from benryi 4morpholinophenylcarbamate via the (5S)-5-(aminmaethyl)-3-(3 tluoro-4-morpholinophenyl)-1,3-oxazolidin-2-one intarmediate (see Example 1).
M.p.: 198 C;
ICso value = 43 nM;
Rt (SiO2, toluene%ihyl acetate 1:1) = 0.24.
Ezampk3 5-Chloro-N-({(SS)-3-[3-Anoro-4-(1,4thiuinan-4-yt)pbasyl]-2-oao-l,3-oxaaoH-din-5-yl }miethyl}2-ttuep F
p m is obtained analogously from (5S)-5-(aminomathyl)-3-(3-fluoio-4-(1,4-thiazinan-yl)phenylj-1,3-oxazolidin-2-one (preparadon see M. R. Barbachyn et al-, J. Med Chem. 1996,39,680).
M.p.: 193 C;
Yield: 82%;
Rf (Si0=, toluene/ethyl acetate 1:1) = 0.47 (starting material = 0.0).
I.e A 34 122 For+ci~n Counnies ,.._.
Examb 4 5-Bromo-N-(((S.S}3-[3-llnoro-4-(1,4tbis>~a~-4-y!)pbenyl]-Z-oaw-1,3-oxnzolidin-5-yl} methyl}.Z-tbiuplmecarboacamide F
~
r HN
is obtained analogously from 5-bromothiopto-e-2-carboxylic acid.
M.p.: 200 C.
Exampk 5 N-({(SS)-3-[3-Flaoro-4(1,r1-thlasalaan-4yl)pbmyn-2-oxo-1,3-o==lidin-5-yl}methyl}3-nuthyl-2-tltiophmecarboxsmide HN re\
is obtained analogously from 5-methylthiophene-2-carboxylic acid.
M.p.: 167 C.
IA A 34122-Faceign Countries Emumple6 5-C6bro-N-{j{SS)-3-(6-medzyhbkoo[Z,3-b]pyrld~ 2-yl)-?roaoo-1,3-oXNXnlidin-5-y1]rt>eZhyl}-2-t6fop6e.necACboxwadde H
p is obtained analogously from (5S)-5{aminomethyl)-3-(b-mcthyhhieno[2,3-b]pyridin-2-yl}1,3-oxazolidin-2-one (pnparation see EP-A-785 200).
M.p.: 247 C.
Exumok 7 5-Chloro-N-{ [(5S)-3-(3-methyl-2-oxo-2,3dihydro-1,3-be=ot6imol-6-yl)-2-oxo-1,3-oxszolidin-S-yl]tnetbyl}-2-thiopbenecuboxamtde N
o~s o H
= ,,.,._..
~
q is obtained analo,paisly from 6-[(5S)-54aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-nxxt-yl-1,3-benzoshiazol-2(3H}one (prcparation see EP-A-738 726).
M.p.: 217 C.
Le A 34 M-FomiS'fi CQllfttl les E=mple :5-Cbtlwo-N {((SS}3.{3=fl110l0-+~{{4-(4-ppl~di>ipl)pip~Ojp~yl}-2roz0-1,3-oxazoltdin-5=3'1)m~Yjl-24hbpheaearboxamide F
\ ~ .
S a is obtained analogoualy from (SS)-5-(aminomahyl0-{3-fluono-4-j4-(4 pyridinyl)piperazinojphenyl1-1,3-oxazolidin-2-one (preparation analogously to J. A.
Tucker et al., J. Mad. Chern. 1998, 41, 3727).
MS (ESI) 516 (M+M,Cl pattarn.
Exumple9 5-Chloro-N-({(SS)-3-[3-fluoro-4-(4mot6ylpipeudm)plnmylj-2-oxo-1,3-o=noWi-din-S-yl}aretltyl}2-thiopbenecarboxamide \N F
N
S G
is obtained anelogously frvm (5S)-5-(aminomethyl)-3-j3-fluoro-4(4-methylpiperazino)phenylj-1,3-oxazolidin-2-one.
r A 34-122. oreilM CouDtr;es = -b0-5-Adoro-N-((('~vS}3-[3-flnoro-4-( 1-yl~P>~3'Il-~
oxo-1,3-oxaxolldin-5-yl}mt6yp-Z-tWoP6a-scuboxamide S
'N, F
is oMained analogously from (SS)-S-(ami:wmethyl)-3-[3-fluoro-4-(4-tcit-butooty-carbonylpiperazin-l-yl)phenylj-l,3-oxazolidin-2-one (pi+eparadon see WO-A-93123384, which has already been cited).
M.p.:184 C;
Rr (Si02, toiuenelethyl acetate 1:1) = 0.42.
Exano1e11 s-Chloro-N-(((bS)-3-[3-ttaoro-4-(piperazio-1-yi)phsoy~2roxo-1,3~iidio-5-yl?meftW
HN- F
V ~ _..
\
~ Qa is obtained by macting Example 12 with trifluorawcetic acid in methylene chloride.
ICso value = 140 nM;
Le A 34122-Foreia Countries lIi NMR [c!s-DMSO]: 3.01-3.25 (m, 8H), 3.5-3.65 (m, 2H), 3.7-3.9 (m,1H), 4.054.2 (m,1H), 4.75-4.9 (nn, 1I3), 7.05-7.25 (m, 3H), 7.5 (dd,1H), 7.7 (d,1H), 8.4 (broad s, lli), 9.0 (L,1$).
5-C61oro-N-[((SS)-3-CS,t-bipytidLsyl-S-yl)-2-oxo-l,3-oxasolidin-S-yl)mwbyl]-2-thbopheaecarboxamide N~
ra"', N
O
a /\
S C, is obtained analogously from (5S)-5-anrinoniethyl-3-(2,4'-bipyridinyl-5-yl)-2-oxo-1,3-oxazolidin-2-one (pnparation see EP-A-789 026).
Rf (Si02, ethyl ecetaoe%thanol 1:2) = 0.6;
MS (ESI) 515 (M+H), Cl pattern.
Exxmle 13 5-Chloro-N-{ [(SS)-2-ozo-3-(4pipecidinophenyl)-1rl-oxazolidin-5-yl]methyl}-2-thiop6maarboxamide ,.._, HN
' \ CI
S
T
IA A 34 I 22-FaM ___._-_ti___.~dea is obtained frotn 5-(hydroxymethyl)-3-(4-piperidi~yl)-1,3-oxezolidin-2-one (preparation see DE 2708236) after mesyladon, reaction with potaasium phthalimide, hydrazinolysis and reaction with 5-chlocothioplr,nG-2rcarboxylic acid.
it.r (Si02, ethyl aeetateltolnene 1:1) = 0.31;
m.p.205 C.
&no* 17 5-Chloro-N-({(SS)-2-aw-3-I4-(2-amo-1 PynvBdo71)1Pben711-1,3~u1idio 3-yl}methyl)-2-thlophenecarhuxumide .0-, Anaiogously to the lrnown symheBis adbeme (see SJ. Briclnor et al., J. Med.
Clem.
1996, 39, 673), 1-(4-aninophenyi)pyrrolidin-2-one (pneparation see Reppe et al., Justus Liebigs Ann. Chem.; 596; 1955; 209) gives, after neaction with benzyloxyr.wbonyl chlaride, followed by nsaction with R glycidyl butyrate, mesylation, reaction with potassium phthalimide, hydrazinolysis in methanol and reaction with 5-chlorothiophene-2-carboxylic acid, finally 5-chloro-N-(t(5S)-2-oxo-3-[4(2-oxo-l-pyffolidinyl)phonyl]-1,3-oxazolidin-5-yl )methyl)-2-thio-phenecarboxamide. The 5-chloro-N-(( (5S)-2-oxo-3-[4-(2-oxo-l-pyirolid'myl)-phenyij-1,3-oxazolidin-5-yl }methyl)-2-thioPhenxatbOxamide obtained in this manner has an ICso valne of 4 nM (test method for the ICyo value aec:ording to Example A-l.al described above) "detennination of the inhibition of factor Xa").
M-p-- 229'C:
Rf value (Si02, toluene%thyl acetate 1:1) = 0.05 (starting material: = 0.0);
MS (ESI): 442.0 (2196, M+Na, Cl pattern), 420.0 (72%, M+H, CI pattern), 302.3 (1296), 215(5296),145 (10096);
'H-NMR (d6-DMSO, 300 MHz): 2.05 (m,2H), 2.45 (m,2H), 3.6 (t,2H), 3.77-3.85 (m,3H), 4.15(t,1H), 4.75-4.85 (m,1H), 7.2 (d,1H), 7.5 (d,2H), 7.65 (d,2H), 7.69 (d,1H), 8.96 (t,1H).
Le A 34122-Fomi gn Cauntries The individual stepa of the synthesis of Example 17 described above with die respective precursors ane as follows:
At -20 C, 4 g (22.7 mmol) of 1-(4-aminophenyl)pynolidin-2-one and 3.6 ml (28.4 maal) of N,N-dimethylaniline in 107 ml of tetrahydrofuran ate admixed slowly with 4.27 g (25.03 mmoI) of benzyl chloroformate. The mixture is stinrod at -for 30 minutes and then allowed to warm to room temperature. 0.51 of ethyl acetate are added, and the organic phase is washed with 0.51 of saturated NaCI
solution. The organic phase is sepusted off and dried with MgSO4, and the solvent is evaporated under.reduced pressure. The residue is triturated with diethyl ether and filtered off ,== with suction. This gives 5.2 g (73.8% of thcory) of benzyl 4(2-oxo-1-pyirolidinyl)phenylcarbamaoe as light-beigc crystals of melting point 174 C.
At -10 C and under argon, 1.47 g(16.66 mmol) of isoamyl alcohol in 200 nil of tetrahydrofuran are admixerl dropwise with 7.27 ml of a 2.5 M solution of n-butyllithium (BuLi) in hexane, a further 8 nd of BuLi solution being rnquired for the added indicator N-benzylidenebenzylamine to change colour. The mixture is stirned at -10 C for 10 niinutes and cooled to -78 C, and a solution of 4.7 g (15.14 mmol) of benzyl 4-(2-oxo-l-pyrrolidinyl)phenylcarbamate is added slowly.
Another 4 ml of n-BuLi solution are then added until the colour of the indicator changes to pink. The mixture is stitred at -78 C for 10 minutes, 2.62 g(18.17 mmol) of R-glycidyl butyrate are added and the nrixture is stirred at -78 C for another minutes.
25 Overnight, the nrixtun; is allowed to wanm to room temperaturz, 200 rnl of water ate added and the Tfff fraction is evaporated under reduced pressure. The aqueous residue is extracted with ethyl acetate and the organic phase is dried with MgSO4 and evaporated under reduced piessure. The msidue is tritutated with 500 ml of diethy(,,.,, ether and the precipitated crystals are filtered off with suction under redneed 30 pnessm.
This gives 3.76 g (90% of theory) of (5R)-5-(hydroxymethyl).3-[4-(2-oxo-l-pytroli-dinyl)phenyl]-1,3-oxazolidin-2-one of melting point 148 C, with an Rf value (SiO2, toluene%thyl acetate 1:1) of 0.04 (starting matetial= 0.3).
Le A 34 122Foreisa Couimries At 0 C, 3.6 g (13.03 mmol) of (5R)-5-(hydc+oxymethyl)-3-[4-(2-oxo-1-pyrnolidinyl)phenyl]-1,3-oxazolidin-2-one and 2.9 g (28.67 mmol) of triethylamine are inidally charged with stirring in 160 ml of dichloronxWme. 1.79 g (15.64 mmol) of nwthanesulphonyl chloride are added with stirring, and the mixtriu+e is stirred at 0 C for 1.5 hours and then at room umVeromre for 3 h.
The reaction niixture is washed with water and the squoaus phase is reextracted with methylene chloride. The combined organic extcacts are dried with MgSOa and concentrated. The nesidue (1.67 g) is then dissolved in 70 ml of acxtonitrile, admixed with 2.62 g (14.16 mmol) of pocassium phthalimide and stiffed in a closed vessel at ~-- 180 C in a niicrowave oven for 45 minutes.
The nuxtune is filtered -off from insoluble residues, the fihrate is evaporated under reduced pressure and the residue (1.9 g) is dissolved in medmol and admixed with 0.47 g(9.37 mmol) of hydrazine hydrate. The mixture is boiled for 2 hours, cooled, adnrixed with satucated sodium bicarbonate solution and exhacted six times with a total of 21 of inethykne chloride. The combined organic extracts of the crude (5S)-5-(aminomethyl)-3-[4-(2-oxo-l-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one are dried with MgSOa and concentrated under reduced pressure.
The end product, 5-chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-l-pyrrolidinyl)phenylj-1,3-oxazolidin-5-yl)methyl)-2-thiophenecarboxamide, is prepared by dissolving 0.32 g (1.16 mmol) of the (5S)-5-(aminomethyl)-3-[4(2-oxo-l-pyrrolidinyl)phenyl]-1,3-oxazotidin-2-one prepared above, 5-chlorothiophene-2-carboxylic acid (0.19 g;
1.16 nunol) and 1-hydroxy-IH-benzotriazole hydtate (HOBT) (0.23 g, 1.51 nunol) in 7.6 nd of DMF. 0.29 g (1.51 mmol) of N-(3-dimethylaminopropyl}N-ethylcarbodiimide (EDCI) are added, and 0.3 g (0.4 ml; 2.32 mmol, 2 equivalents) of diisopropylethylamine (DIEA) are added dropwise at room temperature. The mixturn..._..
is sqn+cd at room temperature ovemight.
The nrixtune is evaporated to dryness under neduced pmssurc and the residue is dissolved in 3 ml of DMSO and chromatographed on an RP-MPL.C using an acaonitrile/water/0.596 TFA gradient. From the appropriate fractions, the aoetonitrile fraction is evaporated and the pmcipitated compound is filtered off with suction. This gives 0.19 g(3996 of theory) of the target compound.
Lie A 34122-Foceign Coantrim TW following compounds wane prepared in an anslogous snanner:
In=* 3$
S-Chbro-N-({(5S)-2-oxo-3-[4(1-pyrrolidloyl)phmy!]-1,3-oaazoUdjn-S-y1}nuethyl}2-tbiop6eaaatrboxumide Analogously to Example 17, 4pycmlidin-1-yl-aniline (Reppe et al., Justus Liebigs Ann. Chem.; 596; 1955; 151) gives the compound 5-chlav-N-({(5S)-2-oxo-3-[4(1-pymolidinyl)ptwnyi]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide.
~-- ICSO=40 nM;
m.p.: 216 C;
Rr value (SiOI, toluendethyl acetate 1:1) = 0.31 [starting maoaial: = 0.0j.
Lwmje19 5-Cbloro-N-({(SS)-2-oaro-3-[4(dietbyhmino)pheny1]-1,3-oxasrolldin-5-yl }mothyl)-2-thlopi~eneearboxamide Analogously, N,N-diethylphenyl-1,4di8mine (US-A-2 811555; 1955) gives the compound 5-chloro-N-({(5S)-2-oxo-3-[4(diethylamino)phenyl]-1,3-oxazolidin-5-yl }methyl}2-thiophenecaaboxanaida ICO--270 nM;
m.p.: 181 C;
Rf value (Si(h, tolumelethyl acetate 1:1) = 0.25 [starting cnaterial: = 0.0].
~ample = ,, _.
S-CWoiro-N-({(SS).3-[Z-methyl4-(4morp6ollnyl)phenyl]-2-oxo-l,3-oxxazolidin-5-y!}mcthyl)-24biophenearboacanWe starting from 2-methyl-4-(4-morpholinyl)aniline (J.E.LuValle et al.
JAnLChim.Soe.
1948, 70, 2223):
MS (ESI): mh (%) = 436 ([M+Hr', 100), Cl pattern;
HPLC (method 1): rt (96) = 3.77 (98).
ICso: 1.26 M
Le A 34 IZZ-Fot+eian Camuies . =
Fxuwk 37 5dbloroo-N-{[(SS)-3-(3-chbso-4-mwp6olinop4eayl)-2-ozo-l,3roaeolidin-6-yllamethyl}-2-t6ioP
starting from 3-chloro4-(4morpholinyl)eniline (H.RSnyder et aL J.Pharni.Sci.
1977, 66,1204):
MS (ESI): m/z (%) = 456 ([M+Hj',100), C12 psttarn;
HPLC (amhod 2): rt (%) = 431(100).
ICw 33 nM
=~-~ Frii~~:~$ .
S-GbIoo-N-(( (SS')-3-[4(4-naorphoHnyl4alp6onyl)p6enyl]-Z-aaoo-1,.~~
5-yl }metbyt}2-thiop6enecarboxandde staRing from 4{4morpholinylsulphonyl)aniline (Adams et al. J.Am.Chem.Soc 1939, 61, 2342):
MS (ESI): mtz (%) = 486 ([M+H]', 100), Cl pattern;
HPI.C (method 3): rt (96) = 4.07 (100).
Eaaemnle 3~9 S-Chloro-N-(( (SS)-3.[4-(1-axeHdlnylsalphonyqphenyl].2.ox,o-1,3-omuolidin-S-7Qmet6yl)-Z-thbp e starting ft+om 4-(1-azetidinylsulphonyl)sniiine:
MS (DCI, NH3): nVz (96) = 473 ([M+NH4]',100), Cl pattern;
HPLC (method 3): rt (~o) = 4.10 (100).
ICW 0.84 M ,,.
Exmole. gQ
S-Chioro N-I((SS)-3-{4-I(dboetbylamioo)atip6onyl)Piomyl)-?roxo-1,3-oxazolidin-S-yl)methyl]-2-t6iopl~renrboacemide starting finm 4-amino-N,N-dimethylbenzemulphonarnide (I.KKhmma et aL
J.MedChern.199?, 40, 1619):
MS (F.SI): m/z (96) = 444 ([M+H]+, 100), Cl P ttern;
I.e A. 34122-Forei su Camtties HPLC (method 3): rt (96) = 4.22 (100).
ICso: 90 nM
General methad for the ecybOon of 5-(aminomethyl)-3-[4(2rozo-l-pyrro-lidlayl)phenyl]-1,3-oxnWidin-2-ow with carbonyl chlorides.
NFLi + cl YR _._.y ~ = Q ' Under argon and at room temperature, an about 0.1 molar solution of 5-(aminonuthyl)-3-[4-(2-oxo-l-pyrrolidinyl)phenyI]-1,3-oxazolidin-2-one (from Example 45) (1.0 eq.) and absolute pyridine (about 6 eq.) in absolute dichiorornethane is added dropwise to the appropriate acid chloride (2.5 eq.).
The mixture is stinred at rnom temperature for about 4 h, and about 5.5 eq of PS-trisamine (Argonaut Technologies) are then added. The suspension is stin;ed gently for 2 h, diluted with dichloromethane/DMF (3:1) and then filtesed (the resin is washed with dichloromethane/DMF) and the ftltrate is concentrated. If appropriate, the product that is obtained is purified by preparative RP-HPLC.
The following compounds were prepared in an analogous manner.
Exssmle 41 ,. _ N-((2-oxo-3-[4-(2-ouo-l-pyn'olidinyt)pbnyl]-1,3-oxazolidln-5-yl}methyl)-2-thiophene-carboxamlde LC-MS (method 6): m/a (%) = 386 (M+Ii, 100);
LC-MS: rt (%) = 3.04 (100).
ICW. 1.3 M
Le A 34122 Famign Countdo Geaeral metbOd for pceparing acyi detivaeiva stacliog from S-(u~oe~6j1)'3.
snd earbuylk acids + H018 'R
-O
R
Qeo The appropriate carboxylic acid (about 2 eq.) and a mixture of abaolute dichloromethane/DMF (about 9:1) are added to 2.9 eq. of resin-bonded carbodiimide (PS-carbodiimide, Argonaut Terhnologies)_ The mixtune is shaken gently at rooxn teinperanme for about 15 min, 5-(aminomethyl)-3-[4(2-oxo-l-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one (from Example 45) (1.0 eq.) is then added and the mixture is shaken ovenmght, after which the sesin is fihr.red off (and washed with dichloronuthane), and the filtrate is concentrated. If apprapriate, the nesulting product is parified by pieparative RP-HPLC.
The following cxympounds were prepared in an analogous manner:
Exassim1*42 5-Metbyl-N-({2-oaro 3-[4-(2-oxo-l-pyre'ulidinyl)p6eny1I-1,3-oanmltdln-S-y1 }methyl}.2-tltlophenecarboxamide I.C-MS: m/z (96) = 400 (M+H,100);
LC-MS (method 6): it (%) = 3.23 (100).
ICso: 0.16 M
Exenmk 43 5-Bromo-N-(12-omo-3{4-(2-oxo-l-p3'rraNdba3'1)pbm71I-i 71}nnthYl)-2-tbiop LC-MS : nVz (%) = 466 (M+H, 100);
LC-MS (nxthod 5): rt (96) = 3.48 (78)=
Le A 34 122Foreinn Counttia IC~e 0.014 M
F3i01Q1f~4$
S-Cbloro-N-(((SS)-2-mco-3-[4(3-oxo-4umpholinyl)PbmyU=1,3-auaollMiin=5-yl}mdhyn-2-Q
O / .. _~H=
1-~N v .-..,- O
O
O
O
O ----~
N
C~
O
~NN
3~1 O ,...
O a) 2-((?R)-2-Hydr+o34'-3-([4-(3-oxo-4-avorp6olinyl)PdmyUamino}PruPyl)-1X-ieo' indok-1,3(2f3)-dione:
A suspension of 2-[(2S)-2-oxirmyhnethyl]-ltl-isoindole-1,3(2f1)-dione (A.
Crutcait et al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mituol) and 4-(4aminophenyt)-3-morpholinone (5.37 g, 27.9 mmol) in ethanoUwaLec (9:1, 140 n-J) is refluxed for I& A 34 1Foreian Countries 14 h (the precipitate dissolves, after some time again fomation of a precipitate). The precipitate (desinad product) is filtered off, washed three times with diethyl ether and dried. The combined mother liquors are eoncentrated under reduced pn:ssure and, after addition of a second portion of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)4one (2.84 g, 14.0 mmol), suspended in ethanoUwater (9:1, 70 ml) and refluxed for 13 h (the precipitate dissolves, after some time again fornoation of a prccipitate). The precipitate (desired product) is filtered off, washed three tinies with diethyl ether and dried. Total yield: 10.14 g, 92% of theory.
MS (ESI): m/z (%) = 418 ([M+Na]+, 84), 396 ([M+H]+, 93);
HPLC (method 3): rt (96) = 3.34 (100).
b) 2-({(5S)-Z-Oxo-3-[4(--oxo-4-mocplwl3nyl)p6eayll-l,3-ozaar-lidin--5-y1}nL-thyt}Lfl-tadndole-1,3(Z!'I)-dione:
Under argon and at room lcmperature, N,N'-carbonyldiimidazole (2.94 g, 18.1 mtnol) and dimethylaminopyridine (a catalytic anwunt) are added to a suspension of the amino alcohol (3.58 g, 9.05 nunol) in tetrahydrofuran (90 ml). The reaction suspension is stirned at 60 C for 12 h(the precipitate dissolves, after sonn tinie again fonnation of a precipitate), adniixed with a second portion of N,N'-catbonyldiimidazole (2.94 g, 18.1 nunol) and stirred at 60 C for another 12 h.
The precipitate (desired product) is filtered off, washed with tetzahydrofuran and dried The filtrate is coneentnued unekr reduced pressure and further product is purified by flash chromatography (dichloromethanelmethanol niixturzs). Total yield: 3.32 g, 87%
of theory.
MS (ESI): m!z (%) = 422 ([M+M',100);
HPLC (method 4): rt (%) = 3.37 (100).
c) 5-Ciiloro-N{{(5S)-2-oxo-3-[4(3-oxo-4-morpltolinyl)phmyl]-l,3-oxazolWlti-.S,.-_ yl}nmtfiyl}-2-thlophenaorboxamide:
At room temperature, nuthylamine (40% strength in water, 10.2 ml, 0.142 mol) is added dropwise to a suspension of the oxazolidinone (4.45 g, 10.6 mmol) in ethanol (102 nil). The reaction mixture is refluxed for I h and concentraoed under reduced pressure. The crude product is used without further purification for the' next reaction.
Le A 34 122Fot+eist Coun_tries Under argon and at 0 C, 5-chlotothiophene-2-carbonyl chloride (2.29 g, 12.7 mmol) is added dropwise to a solution of dn; amine in pyridine (90 ml). Ice-cooting is removed and the reaction mixdn=e is stirred at room temperat:u=e for 1 h and admixed with water. Dichloromethane is added and the phases are separated, and the aqueous phase is then extracud with dichloromahane. The combined organic phases an dried (sodium sulphate), fihend and concentrated under reduced pressure. TU desired product is purified by flash chromatography (dichiocrnmethaneJmetbanol mixwres).
Total yield: 3.92 g, 86% of theory.
M.p: 232-233 C;
'H 1VMR (DMSO-d6, 200 MHz): 9.05-8.90 (t, J= 5.8 Hz, 1H), 7.70 (d. J= 4.1 Hz, 1H). 7.56 (d, J = 9.0 Hz, 2H}, 7.41 (d, J= 9.0 Hz, 2Ii), 7.20 (d, J= 4.1 Hz, 1H), 4.93-4.75 (in, 1H), 4.27-4.12 (m, 3H), 4.02-3.91 (m, 2H), 3.91-3.79 (dd, J =
6.1 Hz, 9.2 Hz,1H), 3.76-3.66 (m, 2H), 3.66-3.54 (nz, 2H);
MS (ESI): m/z (%) = 436 ([M+Hj',100, Cl pattern);
HPLC (method 2): rt (%) = 3.60 (100);
[a)21D = -38 (c 0.2985, DMSO); ee: 99%.
ICso: 0.7 nM
The following compounds were prepaned in an analogous manner.
EUpEtote 45 5-Methyl-N-(t (5S)-2-ozo-3-[4(3-oxa4-morpholfnmyl)pheayl]-1,3-oxaaolkUn-5-yl}methyl}2-thiophenecarboxamide MS (FSI): m/z (%) = 831 ([2M+HJ', 100), 416 ([M+H]', 66);
IPI.C (method 3): rt (%) = 3.65 (100).
ICSO: 4.2 nM
,....
Ezmple 46 5-Broaw-N-({(SS).2-oxo-3-[4-(3-ozo-4-morpholinyl)Pbmyll-ir3-ozmw1dln-5-yl}methyl}2-tb[opbeaecsrboxa~ide MS (ESI): m/z (%) = 480 ([M+H]',100, Br paturn);
HPLC (method 3): it (%) = 3.87 (100).
ICio: 03 nM
j& A 34 122-Fort}lm Countries Ezaawk 5-Chloro-N-{[(SS)-3-(3-i oProPI'l-?roxo-2,3-diLydro-1,3-beamxanl-6-yl)-2-oza 1,3-oxaxolidln-5-yl]methyl)-2-tbiophenesarboxamide O Cl Ha CH3 CH QN
"p-C s ~ 0 ~
O
~.
/
O~ C
O~
q 200 mg (0.61 mmol) of 6-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-iso-propyl-1,3-benzoxazol-2(3H)-one hydtvchloride (EP 738726) are suspended in 5 ml of tetrahydrofwan and admixed with 0.26 ml (1.83 mmol) of triethylamine and 132 mg (0.73 mmol) of 5-chlorothiophene-2-carbonyl chloride. The reac6on mixture is stirred at room temperature ovemight and then concentrated The product is isolated by column chromatography (silica gel, methylene chloridelethaiol =
50/1 to 20/1). This gives 115 mg (43% of theory) of the desired compound.
MS (ESI): ni/z (96) = 436 (M+H, 100);
FP'I.C (method 4): rt = 3.78 niin.
The following corapounds were prepared in an analogous manner.
Le A 34122-Fareign Countries Example No. uucwm P. I Cl ZCso LuK
48 O~~'' 10 0.12 ~
~ N
F
,=-, Oo~
49 ~ J..~. 0 cuo ~ 0.074 14~-o 50 195 1.15 a 51 12 1.19 52 160 0.19 53 (ESI): 0.74 3 M/z ('b) +Al+. . .....
100), Cl attern Iz A 34 122-Foreign Ccxm 'es ' ' - -74-Example No. tructure M.P. [ C) ICSD [ M]
54 cam 221 0.13 Ofl-k N
m 5-amino-2-pytrolidino-~trile (Grell, W., Hnmans, .; Griss, G., Sauter, R;
upprixht, E. et al.;
.Med.Chem.1998, 41; 5219) 55 56 0.04 from 3-(4-amino-phenyl)-xazolidin-2-one (Artico, M. et ; Farmaco Ed.Sci. 1969,24;
179) 56 18 0.004 57 ~ ~ 126 0.58 o ,....
n . : RJ
Le A34 122-Fcreigp Camtries Examples 20 to 30 and 58 to 139 below ncfer to pnocess variant [B], and Examples 20 and 21 describe the pmpmdon of pt+ectusois.
E=mmk Prepuatioa of N-agyl-5-chbro-2r \'~NNs + C,l CI ..._._...,. H
An ice-cookd solution of 2.63 nil (35 nmmol) of allylamine in 14.2 ml of absdute pyridine and 14.2 ml of absolute'IZ>F is admixed dropwisc with 5-chlvro-thioplkno-2-catbonyl chloride (7.61 g, 42 nnnol). ke-cooling is removed and the mixture is stimed at toom temperuure for 3 h and then concentrated under teduced ptessam The residue is admixod with water and the solid is filtded off. The crnde pcoduct is purified by flaah chramatography over silica gel (dichloromethane).
Yield: 7.20 g(9996 of theory);
MS (DCI, M4).- m/z (%) = 219 (M+NH4, 100), 202 (M+H, 32);
HPI.C (method 1): rt (%) = 3.96 uiin (98.9).
le 21 ,-. AvpwstlOn of 5-cizloro-N-(2-oxirsnylmethyl)-2-dtlaphmecirboxamide \~H (~..._ .
An ice-cooled sohWon of 2.0 g (9.92 maal) of N-allyl-5-chlflro-2-thiopltenecactioxanride in 10 ml of dichloromethane is sdmixed with mda-chlaraperbenzoic acid (3.83 g, about 60% str+ength). The mixture is stirred overnight, during which it is allowed to watm to rmom tempdature, and is then wsatmd with
MS (DCI) 440.2 (M+H). Cl pattem;
'H NMIIt (d6-DMSO, 300 NlJiz) 2.95 (m, 4Yi). 3.6 (t, 2H); 3.72 (m, 4H), 3.8 (dd, 1H), 4.12 (t, 1H), 4.75-4.85 (m, 1H), 7.05 (t, 1H), 7.15-7.2 (m, 311), 7.45 (dd, IH), 7.68 (d,1H), 8.95 (t,1H).
U A 34 122 -Fot+etQn Countrua = -56-Exwnpb 2 5-Chbro-N-{I(SS)-3-(4-aarpholioop6myl)-7roiou-1,3-oxaaolidfn-5-yl]mctbyl}-2-thiophenecarboxam3de CI
HN I
is obtained analogously from benryi 4morpholinophenylcarbamate via the (5S)-5-(aminmaethyl)-3-(3 tluoro-4-morpholinophenyl)-1,3-oxazolidin-2-one intarmediate (see Example 1).
M.p.: 198 C;
ICso value = 43 nM;
Rt (SiO2, toluene%ihyl acetate 1:1) = 0.24.
Ezampk3 5-Chloro-N-({(SS)-3-[3-Anoro-4-(1,4thiuinan-4-yt)pbasyl]-2-oao-l,3-oxaaoH-din-5-yl }miethyl}2-ttuep F
p m is obtained analogously from (5S)-5-(aminomathyl)-3-(3-fluoio-4-(1,4-thiazinan-yl)phenylj-1,3-oxazolidin-2-one (preparadon see M. R. Barbachyn et al-, J. Med Chem. 1996,39,680).
M.p.: 193 C;
Yield: 82%;
Rf (Si0=, toluene/ethyl acetate 1:1) = 0.47 (starting material = 0.0).
I.e A 34 122 For+ci~n Counnies ,.._.
Examb 4 5-Bromo-N-(((S.S}3-[3-llnoro-4-(1,4tbis>~a~-4-y!)pbenyl]-Z-oaw-1,3-oxnzolidin-5-yl} methyl}.Z-tbiuplmecarboacamide F
~
r HN
is obtained analogously from 5-bromothiopto-e-2-carboxylic acid.
M.p.: 200 C.
Exampk 5 N-({(SS)-3-[3-Flaoro-4(1,r1-thlasalaan-4yl)pbmyn-2-oxo-1,3-o==lidin-5-yl}methyl}3-nuthyl-2-tltiophmecarboxsmide HN re\
is obtained analogously from 5-methylthiophene-2-carboxylic acid.
M.p.: 167 C.
IA A 34122-Faceign Countries Emumple6 5-C6bro-N-{j{SS)-3-(6-medzyhbkoo[Z,3-b]pyrld~ 2-yl)-?roaoo-1,3-oXNXnlidin-5-y1]rt>eZhyl}-2-t6fop6e.necACboxwadde H
p is obtained analogously from (5S)-5{aminomethyl)-3-(b-mcthyhhieno[2,3-b]pyridin-2-yl}1,3-oxazolidin-2-one (pnparation see EP-A-785 200).
M.p.: 247 C.
Exumok 7 5-Chloro-N-{ [(5S)-3-(3-methyl-2-oxo-2,3dihydro-1,3-be=ot6imol-6-yl)-2-oxo-1,3-oxszolidin-S-yl]tnetbyl}-2-thiopbenecuboxamtde N
o~s o H
= ,,.,._..
~
q is obtained analo,paisly from 6-[(5S)-54aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-nxxt-yl-1,3-benzoshiazol-2(3H}one (prcparation see EP-A-738 726).
M.p.: 217 C.
Le A 34 M-FomiS'fi CQllfttl les E=mple :5-Cbtlwo-N {((SS}3.{3=fl110l0-+~{{4-(4-ppl~di>ipl)pip~Ojp~yl}-2roz0-1,3-oxazoltdin-5=3'1)m~Yjl-24hbpheaearboxamide F
\ ~ .
S a is obtained analogoualy from (SS)-5-(aminomahyl0-{3-fluono-4-j4-(4 pyridinyl)piperazinojphenyl1-1,3-oxazolidin-2-one (preparation analogously to J. A.
Tucker et al., J. Mad. Chern. 1998, 41, 3727).
MS (ESI) 516 (M+M,Cl pattarn.
Exumple9 5-Chloro-N-({(SS)-3-[3-fluoro-4-(4mot6ylpipeudm)plnmylj-2-oxo-1,3-o=noWi-din-S-yl}aretltyl}2-thiopbenecarboxamide \N F
N
S G
is obtained anelogously frvm (5S)-5-(aminomethyl)-3-j3-fluoro-4(4-methylpiperazino)phenylj-1,3-oxazolidin-2-one.
r A 34-122. oreilM CouDtr;es = -b0-5-Adoro-N-((('~vS}3-[3-flnoro-4-( 1-yl~P>~3'Il-~
oxo-1,3-oxaxolldin-5-yl}mt6yp-Z-tWoP6a-scuboxamide S
'N, F
is oMained analogously from (SS)-S-(ami:wmethyl)-3-[3-fluoro-4-(4-tcit-butooty-carbonylpiperazin-l-yl)phenylj-l,3-oxazolidin-2-one (pi+eparadon see WO-A-93123384, which has already been cited).
M.p.:184 C;
Rr (Si02, toiuenelethyl acetate 1:1) = 0.42.
Exano1e11 s-Chloro-N-(((bS)-3-[3-ttaoro-4-(piperazio-1-yi)phsoy~2roxo-1,3~iidio-5-yl?meftW
HN- F
V ~ _..
\
~ Qa is obtained by macting Example 12 with trifluorawcetic acid in methylene chloride.
ICso value = 140 nM;
Le A 34122-Foreia Countries lIi NMR [c!s-DMSO]: 3.01-3.25 (m, 8H), 3.5-3.65 (m, 2H), 3.7-3.9 (m,1H), 4.054.2 (m,1H), 4.75-4.9 (nn, 1I3), 7.05-7.25 (m, 3H), 7.5 (dd,1H), 7.7 (d,1H), 8.4 (broad s, lli), 9.0 (L,1$).
5-C61oro-N-[((SS)-3-CS,t-bipytidLsyl-S-yl)-2-oxo-l,3-oxasolidin-S-yl)mwbyl]-2-thbopheaecarboxamide N~
ra"', N
O
a /\
S C, is obtained analogously from (5S)-5-anrinoniethyl-3-(2,4'-bipyridinyl-5-yl)-2-oxo-1,3-oxazolidin-2-one (pnparation see EP-A-789 026).
Rf (Si02, ethyl ecetaoe%thanol 1:2) = 0.6;
MS (ESI) 515 (M+H), Cl pattern.
Exxmle 13 5-Chloro-N-{ [(SS)-2-ozo-3-(4pipecidinophenyl)-1rl-oxazolidin-5-yl]methyl}-2-thiop6maarboxamide ,.._, HN
' \ CI
S
T
IA A 34 I 22-FaM ___._-_ti___.~dea is obtained frotn 5-(hydroxymethyl)-3-(4-piperidi~yl)-1,3-oxezolidin-2-one (preparation see DE 2708236) after mesyladon, reaction with potaasium phthalimide, hydrazinolysis and reaction with 5-chlocothioplr,nG-2rcarboxylic acid.
it.r (Si02, ethyl aeetateltolnene 1:1) = 0.31;
m.p.205 C.
&no* 17 5-Chloro-N-({(SS)-2-aw-3-I4-(2-amo-1 PynvBdo71)1Pben711-1,3~u1idio 3-yl}methyl)-2-thlophenecarhuxumide .0-, Anaiogously to the lrnown symheBis adbeme (see SJ. Briclnor et al., J. Med.
Clem.
1996, 39, 673), 1-(4-aninophenyi)pyrrolidin-2-one (pneparation see Reppe et al., Justus Liebigs Ann. Chem.; 596; 1955; 209) gives, after neaction with benzyloxyr.wbonyl chlaride, followed by nsaction with R glycidyl butyrate, mesylation, reaction with potassium phthalimide, hydrazinolysis in methanol and reaction with 5-chlorothiophene-2-carboxylic acid, finally 5-chloro-N-(t(5S)-2-oxo-3-[4(2-oxo-l-pyffolidinyl)phonyl]-1,3-oxazolidin-5-yl )methyl)-2-thio-phenecarboxamide. The 5-chloro-N-(( (5S)-2-oxo-3-[4-(2-oxo-l-pyirolid'myl)-phenyij-1,3-oxazolidin-5-yl }methyl)-2-thioPhenxatbOxamide obtained in this manner has an ICso valne of 4 nM (test method for the ICyo value aec:ording to Example A-l.al described above) "detennination of the inhibition of factor Xa").
M-p-- 229'C:
Rf value (Si02, toluene%thyl acetate 1:1) = 0.05 (starting material: = 0.0);
MS (ESI): 442.0 (2196, M+Na, Cl pattern), 420.0 (72%, M+H, CI pattern), 302.3 (1296), 215(5296),145 (10096);
'H-NMR (d6-DMSO, 300 MHz): 2.05 (m,2H), 2.45 (m,2H), 3.6 (t,2H), 3.77-3.85 (m,3H), 4.15(t,1H), 4.75-4.85 (m,1H), 7.2 (d,1H), 7.5 (d,2H), 7.65 (d,2H), 7.69 (d,1H), 8.96 (t,1H).
Le A 34122-Fomi gn Cauntries The individual stepa of the synthesis of Example 17 described above with die respective precursors ane as follows:
At -20 C, 4 g (22.7 mmol) of 1-(4-aminophenyl)pynolidin-2-one and 3.6 ml (28.4 maal) of N,N-dimethylaniline in 107 ml of tetrahydrofuran ate admixed slowly with 4.27 g (25.03 mmoI) of benzyl chloroformate. The mixture is stinrod at -for 30 minutes and then allowed to warm to room temperature. 0.51 of ethyl acetate are added, and the organic phase is washed with 0.51 of saturated NaCI
solution. The organic phase is sepusted off and dried with MgSO4, and the solvent is evaporated under.reduced pressure. The residue is triturated with diethyl ether and filtered off ,== with suction. This gives 5.2 g (73.8% of thcory) of benzyl 4(2-oxo-1-pyirolidinyl)phenylcarbamaoe as light-beigc crystals of melting point 174 C.
At -10 C and under argon, 1.47 g(16.66 mmol) of isoamyl alcohol in 200 nil of tetrahydrofuran are admixerl dropwise with 7.27 ml of a 2.5 M solution of n-butyllithium (BuLi) in hexane, a further 8 nd of BuLi solution being rnquired for the added indicator N-benzylidenebenzylamine to change colour. The mixture is stirned at -10 C for 10 niinutes and cooled to -78 C, and a solution of 4.7 g (15.14 mmol) of benzyl 4-(2-oxo-l-pyrrolidinyl)phenylcarbamate is added slowly.
Another 4 ml of n-BuLi solution are then added until the colour of the indicator changes to pink. The mixture is stitred at -78 C for 10 minutes, 2.62 g(18.17 mmol) of R-glycidyl butyrate are added and the nrixture is stirred at -78 C for another minutes.
25 Overnight, the nrixtun; is allowed to wanm to room temperaturz, 200 rnl of water ate added and the Tfff fraction is evaporated under reduced pressure. The aqueous residue is extracted with ethyl acetate and the organic phase is dried with MgSO4 and evaporated under reduced piessure. The msidue is tritutated with 500 ml of diethy(,,.,, ether and the precipitated crystals are filtered off with suction under redneed 30 pnessm.
This gives 3.76 g (90% of theory) of (5R)-5-(hydroxymethyl).3-[4-(2-oxo-l-pytroli-dinyl)phenyl]-1,3-oxazolidin-2-one of melting point 148 C, with an Rf value (SiO2, toluene%thyl acetate 1:1) of 0.04 (starting matetial= 0.3).
Le A 34 122Foreisa Couimries At 0 C, 3.6 g (13.03 mmol) of (5R)-5-(hydc+oxymethyl)-3-[4-(2-oxo-1-pyrnolidinyl)phenyl]-1,3-oxazolidin-2-one and 2.9 g (28.67 mmol) of triethylamine are inidally charged with stirring in 160 ml of dichloronxWme. 1.79 g (15.64 mmol) of nwthanesulphonyl chloride are added with stirring, and the mixtriu+e is stirred at 0 C for 1.5 hours and then at room umVeromre for 3 h.
The reaction niixture is washed with water and the squoaus phase is reextracted with methylene chloride. The combined organic extcacts are dried with MgSOa and concentrated. The nesidue (1.67 g) is then dissolved in 70 ml of acxtonitrile, admixed with 2.62 g (14.16 mmol) of pocassium phthalimide and stiffed in a closed vessel at ~-- 180 C in a niicrowave oven for 45 minutes.
The nuxtune is filtered -off from insoluble residues, the fihrate is evaporated under reduced pressure and the residue (1.9 g) is dissolved in medmol and admixed with 0.47 g(9.37 mmol) of hydrazine hydrate. The mixture is boiled for 2 hours, cooled, adnrixed with satucated sodium bicarbonate solution and exhacted six times with a total of 21 of inethykne chloride. The combined organic extracts of the crude (5S)-5-(aminomethyl)-3-[4-(2-oxo-l-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one are dried with MgSOa and concentrated under reduced pressure.
The end product, 5-chloro-N-({(5S)-2-oxo-3-[4-(2-oxo-l-pyrrolidinyl)phenylj-1,3-oxazolidin-5-yl)methyl)-2-thiophenecarboxamide, is prepared by dissolving 0.32 g (1.16 mmol) of the (5S)-5-(aminomethyl)-3-[4(2-oxo-l-pyrrolidinyl)phenyl]-1,3-oxazotidin-2-one prepared above, 5-chlorothiophene-2-carboxylic acid (0.19 g;
1.16 nunol) and 1-hydroxy-IH-benzotriazole hydtate (HOBT) (0.23 g, 1.51 nunol) in 7.6 nd of DMF. 0.29 g (1.51 mmol) of N-(3-dimethylaminopropyl}N-ethylcarbodiimide (EDCI) are added, and 0.3 g (0.4 ml; 2.32 mmol, 2 equivalents) of diisopropylethylamine (DIEA) are added dropwise at room temperature. The mixturn..._..
is sqn+cd at room temperature ovemight.
The nrixtune is evaporated to dryness under neduced pmssurc and the residue is dissolved in 3 ml of DMSO and chromatographed on an RP-MPL.C using an acaonitrile/water/0.596 TFA gradient. From the appropriate fractions, the aoetonitrile fraction is evaporated and the pmcipitated compound is filtered off with suction. This gives 0.19 g(3996 of theory) of the target compound.
Lie A 34122-Foceign Coantrim TW following compounds wane prepared in an anslogous snanner:
In=* 3$
S-Chbro-N-({(5S)-2-oxo-3-[4(1-pyrrolidloyl)phmy!]-1,3-oaazoUdjn-S-y1}nuethyl}2-tbiop6eaaatrboxumide Analogously to Example 17, 4pycmlidin-1-yl-aniline (Reppe et al., Justus Liebigs Ann. Chem.; 596; 1955; 151) gives the compound 5-chlav-N-({(5S)-2-oxo-3-[4(1-pymolidinyl)ptwnyi]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide.
~-- ICSO=40 nM;
m.p.: 216 C;
Rr value (SiOI, toluendethyl acetate 1:1) = 0.31 [starting maoaial: = 0.0j.
Lwmje19 5-Cbloro-N-({(SS)-2-oaro-3-[4(dietbyhmino)pheny1]-1,3-oxasrolldin-5-yl }mothyl)-2-thlopi~eneearboxamide Analogously, N,N-diethylphenyl-1,4di8mine (US-A-2 811555; 1955) gives the compound 5-chloro-N-({(5S)-2-oxo-3-[4(diethylamino)phenyl]-1,3-oxazolidin-5-yl }methyl}2-thiophenecaaboxanaida ICO--270 nM;
m.p.: 181 C;
Rf value (Si(h, tolumelethyl acetate 1:1) = 0.25 [starting cnaterial: = 0.0].
~ample = ,, _.
S-CWoiro-N-({(SS).3-[Z-methyl4-(4morp6ollnyl)phenyl]-2-oxo-l,3-oxxazolidin-5-y!}mcthyl)-24biophenearboacanWe starting from 2-methyl-4-(4-morpholinyl)aniline (J.E.LuValle et al.
JAnLChim.Soe.
1948, 70, 2223):
MS (ESI): mh (%) = 436 ([M+Hr', 100), Cl pattern;
HPLC (method 1): rt (96) = 3.77 (98).
ICso: 1.26 M
Le A 34 IZZ-Fot+eian Camuies . =
Fxuwk 37 5dbloroo-N-{[(SS)-3-(3-chbso-4-mwp6olinop4eayl)-2-ozo-l,3roaeolidin-6-yllamethyl}-2-t6ioP
starting from 3-chloro4-(4morpholinyl)eniline (H.RSnyder et aL J.Pharni.Sci.
1977, 66,1204):
MS (ESI): m/z (%) = 456 ([M+Hj',100), C12 psttarn;
HPLC (amhod 2): rt (%) = 431(100).
ICw 33 nM
=~-~ Frii~~:~$ .
S-GbIoo-N-(( (SS')-3-[4(4-naorphoHnyl4alp6onyl)p6enyl]-Z-aaoo-1,.~~
5-yl }metbyt}2-thiop6enecarboxandde staRing from 4{4morpholinylsulphonyl)aniline (Adams et al. J.Am.Chem.Soc 1939, 61, 2342):
MS (ESI): mtz (%) = 486 ([M+H]', 100), Cl pattern;
HPI.C (method 3): rt (96) = 4.07 (100).
Eaaemnle 3~9 S-Chloro-N-(( (SS)-3.[4-(1-axeHdlnylsalphonyqphenyl].2.ox,o-1,3-omuolidin-S-7Qmet6yl)-Z-thbp e starting ft+om 4-(1-azetidinylsulphonyl)sniiine:
MS (DCI, NH3): nVz (96) = 473 ([M+NH4]',100), Cl pattern;
HPLC (method 3): rt (~o) = 4.10 (100).
ICW 0.84 M ,,.
Exmole. gQ
S-Chioro N-I((SS)-3-{4-I(dboetbylamioo)atip6onyl)Piomyl)-?roxo-1,3-oxazolidin-S-yl)methyl]-2-t6iopl~renrboacemide starting finm 4-amino-N,N-dimethylbenzemulphonarnide (I.KKhmma et aL
J.MedChern.199?, 40, 1619):
MS (F.SI): m/z (96) = 444 ([M+H]+, 100), Cl P ttern;
I.e A. 34122-Forei su Camtties HPLC (method 3): rt (96) = 4.22 (100).
ICso: 90 nM
General methad for the ecybOon of 5-(aminomethyl)-3-[4(2rozo-l-pyrro-lidlayl)phenyl]-1,3-oxnWidin-2-ow with carbonyl chlorides.
NFLi + cl YR _._.y ~ = Q ' Under argon and at room temperature, an about 0.1 molar solution of 5-(aminonuthyl)-3-[4-(2-oxo-l-pyrrolidinyl)phenyI]-1,3-oxazolidin-2-one (from Example 45) (1.0 eq.) and absolute pyridine (about 6 eq.) in absolute dichiorornethane is added dropwise to the appropriate acid chloride (2.5 eq.).
The mixture is stinred at rnom temperature for about 4 h, and about 5.5 eq of PS-trisamine (Argonaut Technologies) are then added. The suspension is stin;ed gently for 2 h, diluted with dichloromethane/DMF (3:1) and then filtesed (the resin is washed with dichloromethane/DMF) and the ftltrate is concentrated. If appropriate, the product that is obtained is purified by preparative RP-HPLC.
The following compounds were prepared in an analogous manner.
Exssmle 41 ,. _ N-((2-oxo-3-[4-(2-ouo-l-pyn'olidinyt)pbnyl]-1,3-oxazolidln-5-yl}methyl)-2-thiophene-carboxamlde LC-MS (method 6): m/a (%) = 386 (M+Ii, 100);
LC-MS: rt (%) = 3.04 (100).
ICW. 1.3 M
Le A 34122 Famign Countdo Geaeral metbOd for pceparing acyi detivaeiva stacliog from S-(u~oe~6j1)'3.
snd earbuylk acids + H018 'R
-O
R
Qeo The appropriate carboxylic acid (about 2 eq.) and a mixture of abaolute dichloromethane/DMF (about 9:1) are added to 2.9 eq. of resin-bonded carbodiimide (PS-carbodiimide, Argonaut Terhnologies)_ The mixtune is shaken gently at rooxn teinperanme for about 15 min, 5-(aminomethyl)-3-[4(2-oxo-l-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one (from Example 45) (1.0 eq.) is then added and the mixture is shaken ovenmght, after which the sesin is fihr.red off (and washed with dichloronuthane), and the filtrate is concentrated. If apprapriate, the nesulting product is parified by pieparative RP-HPLC.
The following cxympounds were prepared in an analogous manner:
Exassim1*42 5-Metbyl-N-({2-oaro 3-[4-(2-oxo-l-pyre'ulidinyl)p6eny1I-1,3-oanmltdln-S-y1 }methyl}.2-tltlophenecarboxamide I.C-MS: m/z (96) = 400 (M+H,100);
LC-MS (method 6): it (%) = 3.23 (100).
ICso: 0.16 M
Exenmk 43 5-Bromo-N-(12-omo-3{4-(2-oxo-l-p3'rraNdba3'1)pbm71I-i 71}nnthYl)-2-tbiop LC-MS : nVz (%) = 466 (M+H, 100);
LC-MS (nxthod 5): rt (96) = 3.48 (78)=
Le A 34 122Foreinn Counttia IC~e 0.014 M
F3i01Q1f~4$
S-Cbloro-N-(((SS)-2-mco-3-[4(3-oxo-4umpholinyl)PbmyU=1,3-auaollMiin=5-yl}mdhyn-2-Q
O / .. _~H=
1-~N v .-..,- O
O
O
O
O ----~
N
C~
O
~NN
3~1 O ,...
O a) 2-((?R)-2-Hydr+o34'-3-([4-(3-oxo-4-avorp6olinyl)PdmyUamino}PruPyl)-1X-ieo' indok-1,3(2f3)-dione:
A suspension of 2-[(2S)-2-oxirmyhnethyl]-ltl-isoindole-1,3(2f1)-dione (A.
Crutcait et al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mituol) and 4-(4aminophenyt)-3-morpholinone (5.37 g, 27.9 mmol) in ethanoUwaLec (9:1, 140 n-J) is refluxed for I& A 34 1Foreian Countries 14 h (the precipitate dissolves, after some time again fomation of a precipitate). The precipitate (desinad product) is filtered off, washed three times with diethyl ether and dried. The combined mother liquors are eoncentrated under reduced pn:ssure and, after addition of a second portion of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)4one (2.84 g, 14.0 mmol), suspended in ethanoUwater (9:1, 70 ml) and refluxed for 13 h (the precipitate dissolves, after some time again fornoation of a prccipitate). The precipitate (desired product) is filtered off, washed three tinies with diethyl ether and dried. Total yield: 10.14 g, 92% of theory.
MS (ESI): m/z (%) = 418 ([M+Na]+, 84), 396 ([M+H]+, 93);
HPLC (method 3): rt (96) = 3.34 (100).
b) 2-({(5S)-Z-Oxo-3-[4(--oxo-4-mocplwl3nyl)p6eayll-l,3-ozaar-lidin--5-y1}nL-thyt}Lfl-tadndole-1,3(Z!'I)-dione:
Under argon and at room lcmperature, N,N'-carbonyldiimidazole (2.94 g, 18.1 mtnol) and dimethylaminopyridine (a catalytic anwunt) are added to a suspension of the amino alcohol (3.58 g, 9.05 nunol) in tetrahydrofuran (90 ml). The reaction suspension is stirned at 60 C for 12 h(the precipitate dissolves, after sonn tinie again fonnation of a precipitate), adniixed with a second portion of N,N'-catbonyldiimidazole (2.94 g, 18.1 nunol) and stirred at 60 C for another 12 h.
The precipitate (desired product) is filtered off, washed with tetzahydrofuran and dried The filtrate is coneentnued unekr reduced pressure and further product is purified by flash chromatography (dichloromethanelmethanol niixturzs). Total yield: 3.32 g, 87%
of theory.
MS (ESI): m!z (%) = 422 ([M+M',100);
HPLC (method 4): rt (%) = 3.37 (100).
c) 5-Ciiloro-N{{(5S)-2-oxo-3-[4(3-oxo-4-morpltolinyl)phmyl]-l,3-oxazolWlti-.S,.-_ yl}nmtfiyl}-2-thlophenaorboxamide:
At room temperature, nuthylamine (40% strength in water, 10.2 ml, 0.142 mol) is added dropwise to a suspension of the oxazolidinone (4.45 g, 10.6 mmol) in ethanol (102 nil). The reaction mixture is refluxed for I h and concentraoed under reduced pressure. The crude product is used without further purification for the' next reaction.
Le A 34 122Fot+eist Coun_tries Under argon and at 0 C, 5-chlotothiophene-2-carbonyl chloride (2.29 g, 12.7 mmol) is added dropwise to a solution of dn; amine in pyridine (90 ml). Ice-cooting is removed and the reaction mixdn=e is stirred at room temperat:u=e for 1 h and admixed with water. Dichloromethane is added and the phases are separated, and the aqueous phase is then extracud with dichloromahane. The combined organic phases an dried (sodium sulphate), fihend and concentrated under reduced pressure. TU desired product is purified by flash chromatography (dichiocrnmethaneJmetbanol mixwres).
Total yield: 3.92 g, 86% of theory.
M.p: 232-233 C;
'H 1VMR (DMSO-d6, 200 MHz): 9.05-8.90 (t, J= 5.8 Hz, 1H), 7.70 (d. J= 4.1 Hz, 1H). 7.56 (d, J = 9.0 Hz, 2H}, 7.41 (d, J= 9.0 Hz, 2Ii), 7.20 (d, J= 4.1 Hz, 1H), 4.93-4.75 (in, 1H), 4.27-4.12 (m, 3H), 4.02-3.91 (m, 2H), 3.91-3.79 (dd, J =
6.1 Hz, 9.2 Hz,1H), 3.76-3.66 (m, 2H), 3.66-3.54 (nz, 2H);
MS (ESI): m/z (%) = 436 ([M+Hj',100, Cl pattern);
HPLC (method 2): rt (%) = 3.60 (100);
[a)21D = -38 (c 0.2985, DMSO); ee: 99%.
ICso: 0.7 nM
The following compounds were prepaned in an analogous manner.
EUpEtote 45 5-Methyl-N-(t (5S)-2-ozo-3-[4(3-oxa4-morpholfnmyl)pheayl]-1,3-oxaaolkUn-5-yl}methyl}2-thiophenecarboxamide MS (FSI): m/z (%) = 831 ([2M+HJ', 100), 416 ([M+H]', 66);
IPI.C (method 3): rt (%) = 3.65 (100).
ICSO: 4.2 nM
,....
Ezmple 46 5-Broaw-N-({(SS).2-oxo-3-[4-(3-ozo-4-morpholinyl)Pbmyll-ir3-ozmw1dln-5-yl}methyl}2-tb[opbeaecsrboxa~ide MS (ESI): m/z (%) = 480 ([M+H]',100, Br paturn);
HPLC (method 3): it (%) = 3.87 (100).
ICio: 03 nM
j& A 34 122-Fort}lm Countries Ezaawk 5-Chloro-N-{[(SS)-3-(3-i oProPI'l-?roxo-2,3-diLydro-1,3-beamxanl-6-yl)-2-oza 1,3-oxaxolidln-5-yl]methyl)-2-tbiophenesarboxamide O Cl Ha CH3 CH QN
"p-C s ~ 0 ~
O
~.
/
O~ C
O~
q 200 mg (0.61 mmol) of 6-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-iso-propyl-1,3-benzoxazol-2(3H)-one hydtvchloride (EP 738726) are suspended in 5 ml of tetrahydrofwan and admixed with 0.26 ml (1.83 mmol) of triethylamine and 132 mg (0.73 mmol) of 5-chlorothiophene-2-carbonyl chloride. The reac6on mixture is stirred at room temperature ovemight and then concentrated The product is isolated by column chromatography (silica gel, methylene chloridelethaiol =
50/1 to 20/1). This gives 115 mg (43% of theory) of the desired compound.
MS (ESI): ni/z (96) = 436 (M+H, 100);
FP'I.C (method 4): rt = 3.78 niin.
The following corapounds were prepared in an analogous manner.
Le A 34122-Fareign Countries Example No. uucwm P. I Cl ZCso LuK
48 O~~'' 10 0.12 ~
~ N
F
,=-, Oo~
49 ~ J..~. 0 cuo ~ 0.074 14~-o 50 195 1.15 a 51 12 1.19 52 160 0.19 53 (ESI): 0.74 3 M/z ('b) +Al+. . .....
100), Cl attern Iz A 34 122-Foreign Ccxm 'es ' ' - -74-Example No. tructure M.P. [ C) ICSD [ M]
54 cam 221 0.13 Ofl-k N
m 5-amino-2-pytrolidino-~trile (Grell, W., Hnmans, .; Griss, G., Sauter, R;
upprixht, E. et al.;
.Med.Chem.1998, 41; 5219) 55 56 0.04 from 3-(4-amino-phenyl)-xazolidin-2-one (Artico, M. et ; Farmaco Ed.Sci. 1969,24;
179) 56 18 0.004 57 ~ ~ 126 0.58 o ,....
n . : RJ
Le A34 122-Fcreigp Camtries Examples 20 to 30 and 58 to 139 below ncfer to pnocess variant [B], and Examples 20 and 21 describe the pmpmdon of pt+ectusois.
E=mmk Prepuatioa of N-agyl-5-chbro-2r \'~NNs + C,l CI ..._._...,. H
An ice-cookd solution of 2.63 nil (35 nmmol) of allylamine in 14.2 ml of absdute pyridine and 14.2 ml of absolute'IZ>F is admixed dropwisc with 5-chlvro-thioplkno-2-catbonyl chloride (7.61 g, 42 nnnol). ke-cooling is removed and the mixture is stimed at toom temperuure for 3 h and then concentrated under teduced ptessam The residue is admixod with water and the solid is filtded off. The crnde pcoduct is purified by flaah chramatography over silica gel (dichloromethane).
Yield: 7.20 g(9996 of theory);
MS (DCI, M4).- m/z (%) = 219 (M+NH4, 100), 202 (M+H, 32);
HPI.C (method 1): rt (%) = 3.96 uiin (98.9).
le 21 ,-. AvpwstlOn of 5-cizloro-N-(2-oxirsnylmethyl)-2-dtlaphmecirboxamide \~H (~..._ .
An ice-cooled sohWon of 2.0 g (9.92 maal) of N-allyl-5-chlflro-2-thiopltenecactioxanride in 10 ml of dichloromethane is sdmixed with mda-chlaraperbenzoic acid (3.83 g, about 60% str+ength). The mixture is stirred overnight, during which it is allowed to watm to rmom tempdature, and is then wsatmd with
10% sodium hydrogen sulphate solution (three times). The orMic phsse is washed with savurated sodium bicarbonate solution (twice) and with sanuatea sodiurn 34122- d Cggooig chloride soluticm, dsied over aagwumn sulphate and concenbued. The prodncc is ptnifiea by silica gel ctu~omatog~sphy (cyclohexane/ethyl acetate 1:1).
Yield: 837 mg (39% of tbwty);
MS (DCT, NH4): zMz (%) =253 (M+1VH4,100), 218 (M+H, 80);
HP'LC (method 1): rt (%) = 3.69 min (about 80).
Gmeral method for prep.ring u6stbuted N-(3-amino-2-h,ydro:ypropyl}4-chloro-~thiop deerlvattves xbwdog fcom S-ddo%N-(2-o:iranylmethyl)-2r R-N
~" . H+ h/~N S CI R.
% H
At room teimperatnue or at umpmom up to W C, 5-chloro-N-(2=oxiranytmethyl}
2-thiophaiecarboxamide (1.0 eq.) is added a little at a time to a solution of the primary amine or sadline clei{ivadve (1.5 to 2.5 eq.) in 1,4-dioxane, l,4dioxaawvvater mixtares or ethanol, ethanol/wader tnixtares (about 0.3 to 1.0 molfl). The mixture is stirred for 2 to 6 hours and then concentrated. From the neaction mixture, the product can be isolated by silica gel clu+omato8raphy (cyclohexane/ethyl acetate mixtures, dichl anol mixw:es or dichl(xomethanNmethanol/triethylamine mixtUMs).
=, , The following compounds wem prepa+ed in an analogous manner:
UNWk 22 N-[3-(iansylamino)-2~bydro:,ypcopYl]-5-chloro-2-t6iop6eoecarbozsndde MS (F.SI): rn/z (%) = 325 (M+H,100);
HPLC (method 1): rt (96) = 3.87 min (97.9).
Examnle 23 5-Chloro-N-[3~(3~cyaneadl~o)=7r-ltydroxyi~p7-!]'?rthiop~an~ecacboxanadtk MS (ESI): m/z (96) = 336 (M+H, 100);
HP'LC (tnethod 2): rt (96) = 4.04 min (100).
Le A 3412'l-Fot+eiaM Coimtries ~ = -77-E=ml):LBa4 5-Cl~oro-N-[3-(4-cysu~oeoUiav}2-hrileoxypropyq-Z=thieP6m~arbo~a=ide MS (FS1): m/z (96) ~ 336 (M+H,100);
HPLC (method 1): rt (96) = 4.12 min (100).
Emumb 25 s-cbaoro-N-{3-[4-(cyanometly-1)asgno]-2-hyarwq-prapyl}-2-t61op MS (ESI): m/z (96) = 350 (M+H,100);
H'LC (mcthod 4): rt ( ~) = 3.60 inin (95.4).
S-Chloro-N-{3-[3-(cyswomethyl)noilino}.2-bydroxppropyl}-2-thMphenecarboacamide MS (ESI): mlz (96) = 350 (M+H,100);
HPLC (method 4): rt(96) = 3.76 min (94.2).
Ex =-@k 58 tart-Butyl 4-[(3-{[(5-chloro-2-thtmyl)carbonyllamino}-2-hydroxypropyl)sminol-benzylcarbent~ate starting from tert-butyl (Bioorg. Med. Chem. Len.; 1997;
1921-1926):
MS (FS-pos): m/z (%) = 440 (M+4L 100), (ES-neg): m/z (96) = 438 (M H.100);
HPLC (mcchod 1): rt (96) = 4.08 (100).
. ,.....
Fxumnie S9 tant lintit 4[(3-([(5-c61oro-?r46imylkarbonyl]eadno}-2-hydroxypropyt)eminol-starting from N-tert-twtyloxycarbonyl-1,4phenylenediamine:
MS (ESI): m!z (96) = 426 (M+H. 45).370 (100);
Le A 34 M;Fonzisn Coemties H'PLC (method 1): rt (96) = 4.06 (100).
ymmko tat-Bntyl 2-bydn"-34[442-ozo-l-Pl'n*WiD71)PbaYlAmdw}PinPYi-earb-smate stating from 1-(4-aminophenyt)-2-pyctolidinono (lustus Liebigs Ann. Chem.;
1955;
5% 204):
MS (DCI, NH3): mPz (%) = 350 (M+H,100);
FlP'LC (medW 1): rt (96) = 3.57 (97).
5-Cbbco-N-(3-{[3-tluuro-4-(3-om)Amorpholiayt)phdayl]nndno)-Z-hydrosypro-P7l)-2-thiopbeneemboa=ide 800 mg (3.8 auaol) of 4(4-amino-2-fluorophenyl)-3-mozpholinone and 700 mg (3.22 aunol) of 5-chlav-N{2-oxiran*wthyi)-2-thiaplaunecarboxamide in 15 ail of ethanol and 1 ml of watar ai+e heated under nflux for 6 hours. '17o mixture is concentrated under reduced p:mure and troated with ethyl acetate, precipitated crystals are filtered off with suction and the mother liquor is cin n,,wgcephed giving 276 mg (17% of thcory) of the target compound.
Rf (ethyl acetate): 0.25.
LUMQk. 62 (N-C3-AiOiliuo-2-hydroxyp~opy!}S-cbioro-Z- .:...
statting fiom aniline:
MS (DCI, NH3): ndz (96) : 311([M+H]+,100), C'a pattern;
HPLC (mediod 3): rt (96) = 3.79 (100).
Examic 63 5-(hloro-N-(2-6rdroaq--3-1[4-(3-oaw-4-mo )propyt}2-thiophenecarboautmide "
j,g A 34 122 Foi+eigg a tria , -79-stasting irom 4-(4aminophenyl)-3-morpholinane:
MS (ESI): m/z (%) = 410 ([INI+H]+, 50), Cl pattWrn;
IMC (mahod 3): rt (96) = 3.58 (100).
S Fmmmk N434{4-[Aatyl(c3rcloProP7l)~minoJP~YI}~iao}2~hlydca~qpropyl]-S~chiaen-2=thiophmacrboYamlde starting from N{4-aminaQheayl)-N-cyclqropylacetsmide:
MS (F.SI): m!z (%) = 408 ([M+H]+,100), Cl pnuern;
IiP'i.C (method 3): it (%) = 3.77 (100).
.-,-~1~~ .
N-I3-({4-IA~~3~l~~p~Yl}amino}2-hY~7p~1~I~-rblo~-2-t6lophet~carboxamide starting from N-(4-arrtinophenyl)-N-mcihylacetamida:
MS (ESI): mlz (96) = 382 (M+H,100);
BPLC (mathod 4): rt= 3.31 min.
EXNMDIC"
5436bro-N-(2-1#Ydro:y-3-{I4-(iH-i,Z,34riazul-1-7-lkgmypwdm)proP71}~
,-. thiop6eae- srboxaoside starting from 4-(1H 1,2,3-triazol-l-yl)aniline (Bouchet et al.;
J.Chem.Soc.Perkin Trans.2; 1974; 449):
MS (ESI): mVz (%) = 378 (M+H,100);
H'i,C (metbod 4): st = 3.55 min.
,.,,.
tat batyl 1-{4-[(34[(S-c6loro-2-tbimyl)carbonyl]amiao)-2-hydroxppropyl}
amino]ph~ayl}Irprullnae MS (ESI): mm/z (96) = 480 (M+H,100);
HPLC (method 4): it = 3.40 min.
Le A 3}1 ' :QWIB Countries Eumpb 6$
1-{4-[(3-([(5-Cibre-2. )-2o-hldroxypropyQem3noh*e-Qyl}-apip=dleenrboxamiae MS (FSn: m/z (96) = 437 (M+H,100);
I1pLC (method 4): rt = 2.39 min.
fan* 69 1-t4-((3-(E(3-Chiuro-2rt6ienyi)crbonyOmmko}-7.-b7do7Propy1YandmJpbe-nyl}- e MS (ESI): ndz (%) = 437 (M+H, 100);
HPI.C (method 4): rt= 2.43 min.
E+r nk 7Q
5-C61oro-N-(2-6ydroxY 3-{E4-t4-0zo-l-Pjpe<'ldlnyi~heaYl~miao}ProPyr)-2-tl~iop~ouu~de MS (FSI): rnlz (96) = 408 (M+H, 100);
HPLC (nxthod 4): rt= 2.43 min.
fMM* 71 E(s-cldoro-2-thienyl~arbo~yl]smino}?.6ydroxypropyl).minolt~-1-44-[(34 nA-L-prOtinamide MS (ESI): nVz (%) = 423 (M+H, 100);
HI'LC (mahod 4): R= 2.51 n3in.
- . ,.__ .
Examnk 72 ~
5-Chioro-N-[2rhydrozy-3-({4-(3.(hydroxynnthyl)-1-piperidinlrllphenyl)-amino)pcopyl]-2-thiop6eneP-1- rbo3unmide MS (ESI): m/z (%) = 424 (M+H, 100);
HPLC (method 4): rt = 2.43 niin.
l.e A 34õ121-1?oreeIM CggMgiu FnmipbZ3 S-Cbbro-N42r6ydenxy-3-(1441-(hydeom7nnih7i)-1-p*wkVn7U~}-amino)propyl]- e MS (ESI): m!z (96) = 424 (M+H,100);
HPLC (method 4): rt = 2.49 min.
Ezairob 74 Ethyl 1-{4-I(3-{[(5-cbbro-2-tbbn-Yl)arbonyllambo)-24ydroac7prop7l)-emino]Phenyl}-2'PiP~rldln~caii~oxyletc ,.:
MS (ESA: mh (96) = 466 (M+H.100);
HPLC (method 4): rt = 3.02 min.
ARMAN
S-Chbro-N-[?rhydroxy-3-({4[2{hYdroarynn6y)-l.-pyrroMin7UphoW1}hudnO)-prop71]-2-MS (ESI): m/z (96) = 410 (M+H,100);
1P'I.C (method 4): rt = 2.48 niin.
~= 5-ChbraN-(Z-hydroxy-3-{[4(2-meth}-lhhexshYdra-SIi pyrrob[3A-d]kowazot-5-il)pm1l]amiuo}proW)=2-tbWphenecarboxamide MS (ESI): ndz (96) = 437 (M+H,100).
HPLC (method 5): rt = 1.74 min.
S-Chbro-N-(2-hydroary-3-([4(1-pytr)lldinYl)}3-{triAaoromethyl)phea7l]-aaRiino}pr*pYl)-2-tbbp MS (ESI): ni/z (96) = 448 (M+H, 100);
HPLC (tnahod 4): tt = 3.30 nain.
34 122 Fomign Comajia Sd7~loro-N-(Z6~ydroxy~3-{[4.(?~o~au-l-pyrtoUdiny!)-3-(trlfl~a~+o~thyl~ylJ=
wino}propyt}2-thiopbena"rboxaaaide MS (ESI): nVz (96) = 462 (M+H.100);
HPLC (method 4): rt = 3.50 min.
Ezaawk 79 S-Chloro-N-(3-{[3.chloro-4-(3-oxu-4-moi'pholiayl)p-lualllsmim}-2-6ydnxy-propYl}Z-MS (ESI): nm/z (96) = 444 (M+H,100);
HPI.C (method 4): rt = 3.26 min.
EBMRksQ
S-Chioro-N-(2-hydroxy3-{[4(3-ozo-4-morpbolinyl)-3-(~nmetbyl)pbmyl]-aminolp:Opyl)-Z-mbpbmecacboacandde MS (ESI): m!z (96) = 478 (M+H,100);
HPLC (method 4): rt = 3.37 mi1i.
Elll! e 81 5-Cbloro-N{2-hydromq-3-([3.mathyl-4(3-oxo-4.morpbolioyl)pbenyljaoodno}-propyl)-2-t6iophenecsrbw=mide MS (ESI): m/z (%) = 424 (M+H,100);
HPLC (method 4): rt = 2.86 min.
: :,....
Fa3ll~.~c 5-C3lcro-N-(3-([3-ryaao-4(3-oxo-4-ma'p6dlayl)phmyl]aoaino}-2-iq+droxypro-p)'1}2-thloP e MS (ESI): m/z (%) = 435 (M+H,100);
HPLC (metthod 4): rt= 3.10 niin.
La A 341 j%m;,p Coantries FiiinllB~~
5-Cbloro-N-(3-([3-chbro-4-(1-pyrrolldiuyl)pMenybunino)-2-hydcoxyprop3'l)-Z-thlophena:arbos~mide MS (ESI): m/z (qb) = 414 (M+fI,100);
HPLC (method 4): rt = 2.49 min.
Farat~k &1 5-CWoro-N-(3-{[3-cbloro-4-(Z=oaw-l-pyrrolMiinyl)phenyl]smb-o)-2-hydrotypro-pyl)-I- .
MS (ESI): m/z (96) = 428 (M+H,100);
HPILC (method 4): rt = 3.39 min.
3-Chloro-N-(3-([3rS-dimethyl-4-(3-mao-4-morpbolinyl}phmyl)saaiao)-2-bydro-xyprqpyl)-2-thiopheaecsrboxwide MS (ESI): m/z (%) = 438 (M+Ii.100);
HPLC (method 4): rt = 2.84 nrin.
~-- N-(3-{134Amiwcwbonyl}4-(4-mocp6olinypplunyl]omino)-2-Lydre"pr"Yi)-5-chloro-2-thiopbmemboxamide MS (ESI): m/z (%) = 439 (M+H,100);
HP'LC (method 4): rt = 2.32 min.
Exumvk 87 5-Cldoro-N.(2=hydroxy-3-{t3-amoho"-a-(4-a"rpboqnYl)ibmyrl=dm}lmPyl)-2-thiopheaemrboxamide MS (F.SI): m/z (96) = 426 (M+H,100);
HP1rC (metbod 4): rt = 2.32 min.
I.e A 34122-Fonign Countries Exomic 88 N-(3-([3-Aoetyl-4-c4-=orphoRayrndkenY1]amim}-~7drox7Prop7n-s-adoro-Z-thlop6aIFsrboxendde MS (ESI): m/z (96) = 438 (M+H, 100);
HPLC (method 4): rt = 2.46 min.
ExaoMk 89 N-(3-{[3-Amino4-(3-oxo-4-morpbolinyl)pheayljambo}-2-hydroxypropyl}S-dhloro-2.
-MS (F-SI): m/z (96) - 425 (M+H,100);
HPLC (method 4): rt = 2.45 min.
Emuupk90 5-Chlora-N-(3-4 [3-c61ora-4(2-met6yl-3-ozo4-awrpboftyl)pbmyUawhw}-Z-hydroxypropyl}2-thiopheneorboxamide MS (ESI): m!z (%) = 458 (M+H, 100);
HPI.C (method 4): rt = 3.44 min.
Exgaok 91 ,,.. 5-Chloro-N-(3-{ y1-5-oxo-4-nwrphoUnyl)pheny!]amino}-2-hydroxypropyl}2-thlophenearbosamide MS (ESI): ni/z (%) = 458 (M+H.100);
HPL.C (medlod 4): rt= 3.48 min.
- : .
E:anmk 91a 5-G'hsuro-N-[2-hydr'nap=3-({4-[ i)oe3thyUphm74}smiuo)-pmpylJ-2-t6lophenecarboxamkie starting from * 4-(4-amino-benzyl)-3-mwrpholinone (Swrey et a1.; J. Amer.
Chem.
Soc.; 77; 1955; 633):
MS (ESI): m/z (%) = 424 (M+H, 100);
Le A 34122-Fom-0 Cmoics HPLC (method 4): rt = 2.66 mia GmaW md6od foar prspaft 34ub~d S46ioco-N-[(2roioo-I,3~om~olWin-5-yl)methyl]-2- derivatlves starting frnm snbstitoted N-(34wino-2=hydraarypropyl}5-chbro- dtciva>ives R, 0 N , S I cl ~
F( At room Lempenuaxe, cnbodumichzole (1.2 to 1.8 eq.) or a similar phosgene eqtiivalentt are added to a solution of the subatituted N{3-aYaino-2-hydroxypropy!}5..
chloro-2 thiophenecathoxamide derivative (1.0 eq.) in abaolute 'lHff (about 0.1 mol/l). At room Lempaaame or, if apptqoriate, at elevated tempaatm (up to 70 C), the mixtnre is stirred for 2 to 18 h and then conoentratod under reduoad pcossure. The product can be puified by silics gel chrortaatognphy i5 (dich mixtum or cyclohexane/ethyl aRxtate mixtures).
The following eompoueds vve.re pnrparod in an analogous mmusei:
Examnk 27 1V [(3-Beozyl2-oxo-1,3-a:aaolidin-S-yl)mathyq-S-+chloro-2-thiophaxcsrboacamide MS (DCI, NH4): m/z (9b) = 372 (M+Na,100), 351(M+H. 45);
FiPLC (method 1): tt (96) = 4.33 min (100).
~._ Examrile 28 S-Chjoro-N-{[3d'.l-cyanopbenyl)-2-oxo-1,3-oxaaolidtn-S-yllmthyl}-2-thiophenecarboYandde MS (DCI, NIW: m/z (96) = 362 (M+H, 42), 145 (100);
HPLC (method 2): rt (96) = 4.13 min (100).
AH 13 U-qmdjz Sountries L~~Z
S-C6loe+o-N-({3-[4(cyen=mah7l)pLmy1]-?roxo-1,3-ox=lidin-5-yl}methlrl)-2-thiophenecarboacemide MS (ESI): nm/z (96) = 376 (M+H.100);
APLC (method 4): rt = 4.12 min Emawk IV
5dhloro-N-((3-[3-(cl-moawb-yl)p6eayl]-2-oxo-1,3-amamolidin-5-yl)udbyn.2-t6iopheoecarba~mide =
MS (ESI): m/z (98) = 376 (M+H,100);
HPLC (mediod 4): rt = 4.17 min ~ ~Qjl~.s tert-Buty1 4-[5-({[(S-chioro-2-ihkayl)cerbon711mioo}mahyq-?romo-1,3-oa mlidio-3-yl]beuzylcacbamate starting from Example 58:
MS (ESI): m/z (96) = 488 (M+Na, 23),349 (100);
IIPLC (method 1): it (96) = 4.51 (99.5).
r-~
tsrt-Butyl4-[S-({[(S-chloro-2-t6tenyqcarboa-yljsuino}met6yl}.2-oxo-l,34xamoll-din-3.yl]pbneaylcar>amte starting fmm Example 59:
MS (FSl): m/z (%) = 493 (M+Na, 70).452 (M+H,10), 395 (100);
.. . ....
HP'I.C (method 1): tt (9b) = 4.41 (100).
E=mk Aent-Butyl 2-ozo-3-[4-(2-oxo-1-pyrrolidiqyl)plaayl]-1,3-ox=lidiu-5-yl}methyl-cacbsuate staiting from Example 60:
MS (DCT, NH3): adz (96) = 393 (M+Nli4,100);
Le A 341 -Fmcjgn C.amtries I3PLC (medwd 3): it (96) = 3.97 (100).
FacsmQie 95 3'1)P6m711-2-0~-1,3-0~-5-yl)methyl)-2-thiop6m~ocarboxamide F ~
260 mg (0.608 nsmol) of 5-chioco-N-(3-{ [3-fluoro-4-(3-oxo-4-matptwlinyl)phenyl]-amino)-2-hydroxypropyl)-2_thiopheaecacbaxamide (from Example 61), 197 mg (1.22 mmol) of carbonylirnidazole and 7 mg of dimethylaminopyridine in 20 nd of dioxane are boiled mWer reflux for 5 hours. 20 nd of acetonitrile are thc.u added and the mixduz is sdrned in a closed vessel in a microwave oven at 180 C for 30 minutes.
1S The soludon is coneentrated using a rotoy evaporatUor and chionvLographed on an RP-HPLC column. This gives 53 mg (19% of thomy) of the tuget compowd.
NMR (300 1i[Hz ds DMSO): &= 3.6-3.7 (m.4H), 3.85 (dd.1H), 3.95 (m,2H), 4.2 (m,1H), 4.21 (s,2H), 4.85 (m,1H), 4.18 (s,?.li), 7.19 (d,18,thiophene), 7.35 (dd1H), 7.45 (t,1H), 7.55 (dd,lIi), 7.67 (d,llH,thiophCne), 8.95 (t,1H.CONH).
Exumak %
. : : ,.....
5-C61ore-N-[(2oxo-3-plkayl-1,3on~5-yl~nethyl]-~
tbiep starting from Example 62:
MS (ESI): m/z (96) = 359 ([M+Na]'', 71), 337 ([M+H]',100), Cl pattera;
IiFi.C (method 3): rt (96) = 4.39 (100).
ICso: 2 M
I.e A 34 122-Fg,ei,gn ColJlltlaies Famuk 97 S-C61oro-Nd{?~-oa~o-3-[4-(3-0~o-4-morphollanylh+hmylj-l,3-n:azolidin-S-yl}-mWhyl)-2-thiophenecarbo=mide starting from Exanple 63:
MS (gSI): m/z (%) = 458 ([M+Naj;, 66).436 ([M+H]+.100), Cl porn;
HPLC (methad 3): rt (96) = 3.89 (100).
ICA,: 1.4 nM
N-[(3-{4[Acetyl(cydopropyljaodnolpLtayl)-2-oxo-l,3-oxwolldln-S-yl)methyl]-5-ehken-starting from Facmr4tle 64:
MS (ESI): m/z (%) = 456 ([M+Naj+, 55),434 ([M+Hj+,100), Cl pattern;
HI'LC (method 3): it (96) = 4.05 (100).
ICso: 50 nM
EXBmItk N-[C3-[4-[Acql(mdhyl)audmjplmyl}-2-eoro-l3-oxaeolldin-S-yl)met6ylj-S-chloro-2-t6iop MS (ESI): m/z (96) = 408 (M+H, 30),449 (M+H+MeCN, 100);
000. HPLC (rnedod 4): rt = 3.66 min.
Examok 100 S-(;~loro-1W({?ro~[4(lIi-1,?,3-trlszol-i-y!)plusyll-1,3~oiidin-5-yl}- .: ,:
methyl}Z-thiophenecnrboxamide MS (FSI): m/z (%) = 404 (M+H, 45), 445 (M+H+MeCN,100);
I3PI;C (nethod 4): tt = 3.77 min.
Egunvle 101 Twt-butyl 1-{4[S-({[(S.cbbro..2_thienyl)carbo yl]~mbo}a~et6y1}?roxe.l,3-oxazolfdln-3-yl]pheayl}-Lr-prolioat+e T. A 34 1 Zf Fnaigil _nnnW
Nrs (ESi): rarz (~) =450 (M+H-56, 25), 506 (M+H,100):
HiYLC (metlW 4): rt= 5.13 min.
Fianmk 1C
1-{4-[s-a [(s.chbro-a.mimyr)carbonynamiw}mdbyn-z-oxo--1,Uxm=Bft-3-ynp,,lllA}-4-~re~a--rboxn=ae MS (FSn: miz M = 463 (M+H,100r HPLC (nuthod 4): rt = 2.51 niin.
Enuunk 103 r-~
1-{4-I5d{[(5-ChOro-Z-thea71)krbonyllamdw)nmdYl)-?.uo-1,3=oxasoiidin-3-YllPbml'i}-3-PiPerjdjnaerboxaaide MS (ESI): mli (96) = 463 (M+H,100);
H'pLC (mcthod 4): rt = 2.67 min.
Exomak 104 S-Chloro-N-((2-oao-3-[4(4-oaw-l-Pipaidinyl)phenyl]-1,3-oxuolidia-5-pl)met6pl}?4Mop e MS (ESI): mJz ('96) = 434 (M+H, 40), 452 (M+H+H20, 100), 475 (M+H+MeCN, 60);
HPLC (methfld 4): rt = 3.44 ntin.
Exwnde 105 1-{4-[S-({[(S-Chloro-2-tbienyl)arbonyiNwiw}methy!)-2-oze-1,3-oxazolidtn-3- -,: .
3QPbwy1}-L.Piroln=de MS (ESI): rr/z (%) = 449 (M+H.100);
HP'LC (method 4): rt= 3.54 min.
j~ A 341Z2 FgW Counttie.s -90_ E:d-k m 5-C~oro-N-[(3-[4-[3-{Ip'dro~q-met6yl)-1-piperidiny1~ay1}-?romo-l,3-a~o~-din-S-y1*wthylj-2- e MS (ESI): mJz (96) = 450 (M+H,100);
HpLC (method 5): rt = 2.53 mia.
Examele 107 S-cbloro-N [(3-{ 1-piperidiuyl]~)-2-ozo-1,3-oxamoli-din-S-yl)uwMyi}Z-tldopbenecarboacamdde MS (ESI): m!z (96) = 450 (M+H,100);
HpI:C (me,thod 5): rt= 2.32 min.
ramp*
F.tlp-1 1-{4-[S-({[(S~cWoro-?.thi~oyl)carbonyt]~o}mbhyl)-?.-o~ao-l,3-oa~oli-din-3-yl]pleenyl)-2-piperidieasrbuxylate MS (F.SI): m/z (96) = 492 (M+H, 100);
HP LC (nmthod 5): rt = 4.35 min.
&ua ~-. 5-(bioro-N4044-"ydmqnud7-1)'1-pyrrobdinyUPbmyl}-2-ozo-l,3*xmoi-din-S-y1)methyl]-2-t6bp x-mide MS (ESI): m/z (96) = 436 (M+H,100);
HPLC (aiethod 4): rt = 2.98 nsin.
- .~._.
E,~x~l~e 110 S-C6bro-N-({?,-ozo-3-[4(1-pyrroiWbryn-3-( yl}1,3-oz~oli-din-5-yi}metbyl)-2.t<siophmecaclqxanafde MS (F.SI): m/z (%) = 474 (M+H, 100);
HP1.C (method 4): tt = 4.63 min.
A 34122 Fonin C~untnes KumQ#e lil 5.C61oro-N-({3-[ SH 5-yl~ayl]-2-oxo-1,3-aarasolidin-5-yl}met6yl}2-miop MS (ESn: m/z (96) = 463 (M+E,100);
H'LC (method 4): rt= 2.56 niin.
~* in 5-Chloro-N-({2-o:ko-3-[4(Z-oxo-l-pyre+olWinyl)-3-(ttitluonumetLyl)pheftyll-1,3-oauzolidin-5-yl)md6y1)-2-tWoplknccarboxumlde MS (ESI): mh (96) = 488 (M+H,100);
HPLC (method 4): rt= 3.64 min.
E:amole J13 5-Chioiro-Nd(3-[ morpbOftyl)pbenyq-2-oz0-1,3-oaeolldin-5-yl)mdhyl)-2-thiophenecuboxanaide MS (ESn: m/z (%) = 470 (M+H,100);
HpLC (method 4): it = 3.41 min.
EmgglQle 114 ~=, 5-C61oro-N-({2roaco-3-[4-(3-oaoo-4-~rorPholinyl}3-(trt~lnoromethyf)Phen71}-1,3-wmolidln=5-yl)methyl}2-MS (F.SI): nVz (96) = 504 (M+H,100);
1PLC (method 4): rt == 3.55 niin.
,.._.
Ezmnpk 115 5-Chloro-N-({3-[3-methyl-4-(3-oxo-4-morpboftyl)Pbes7'II-?rozo-1,3-o=Lulidin-5-yl}nLethyl).2-thiopbcnecarboxamide MS (ESn: mlz (%) = 450 (M+H, 100);
HPLC (method 4): rt = 3.23 min.
Le A 34 122~Fo~ei go Qgumwea 5-Chloro-N-({3-[3-~'e~-~-C~-~P~~yl)~Y11~~~~idJn-5-yl}methyl}Z.
MS (ESI): m!z (%) = 461(M+H,100);
HPLC (method 4): rt = 3.27 min.
E 1e117 S-Chbc+o-N-({3(3-chbro-4-(1-Py~Minyl)pbenyll-Z-+omo-1,3-oxmoUdid-'S-yl}md]tyl)-2-tbiapbenecarboaovffide MS (ESI): m/z (%) = 440 (M+H,100);
HpI,C (method 4): rt = 3.72 min.
Esaa~k IL8_ 5-(:hWwN-({3-[34daAro-4(2-0mo-l-pyrrolidi*nyl)~3-2-oxzo-l,3-oxamolitUn-5-11}methyl)-?rthiophmecerboxamide MS (FSI): m/z (96) = 454 (M+H, 100);
HPLC (method 4): rt = 3.49 rain.
,-. S43lloro.N-((3-[3,S-dimeth744-(3~Om-4-mocPhdin3'1)Pl~lll-?roaco-1,3~0~-zolidin-S-yl}methyl}Z-MS (ESI): m/z (%) = 464 (M+4L 100);
BP1.C (mdhod 4): rt = 3.39 min.
:_...
Eiample 120 N-({3-P.l4Amjaocmrbonyl}4-(4-morp6olio7fipbenJ41-2-oxo-l,34awzdiain-5.
yl}methyi)-S-cltbro-2-t2jop>~csrboxsniide MS (ESI): mFz (%) = 465 (M+H,100);
HPLC (method 4): rt= 3.07 min.
ja A 34_122-Fameim Can,nries . -93-T1oii~I~E.~1 S-C~-Ia~ o-N-(t3-[3-o~hoaq-4-(4-~a~orpboliuyl)Pl~rl]-2roooo-l,3-oz~olidiu-S-yl}methyl)-Z-tonadde MS (BSI): m/z (96) = 452 (M+H,100);
HpLC (aAdod 4): rt= 2.86 smn.
'Examob N-({3.[3.Acetyl-4(4morpho~nyl~he0yl)-?roio-1,~o~olWin-6-yl}methlrl}S.
chloro-Z-t>dophme=bozuide MS (ESI): m!z (9b) = 464 (M+H,100);
HPLC (method 4): rt = 3.52 min.
Fsamde 123 N.((3-[3-Amino-4-(3-axo-4-morpholnl'1)PbosYl}?roxo-1,3-ox=ulidin-S-yl)-metbyl)-S-c6loro-2, tl-loplrenecarboxamide MS (F-4n: m/z (%) = 451 (M+H, 100);
HpI,C (authod 6): rt = 3.16 niin.
EUMRle 124 ,.- 5-Chloro-N-((3-[3-ebloro-4-(Z-uadhYl-3-oxo-4-morpboiiaryl)pbmyl]=2-0mo-1,3-oxazolidin-5-yl)met6yl)-2-tbiophena~t boacamide MS (ESI): nVz (%) = 484 (M+H, 100);
HPLC (me&od 4): it = 3.59 tain.
.,...
JM=k 125 S-(~bro-N-({3-C3-eibro-4-CL~a~etdyi-3-ouo-4-oaoepbolt~yl)p6~71]-?.ozo-1,3-oxazolidln-&yl}meAyn-2=l5iophemmar6oaomide MS (ESI): m/z (%) = 484 (M+H,100);
HPLC (method 4): rt = 3.63 min.
Le w34122FozianCoMaim = -94-Eamole iZSa S-CWoro-N-[(~~.ozu,3-{4-[f3-ow-4-mmp6o~Yi~y1]pbeqy1}-1,3exsaol8dta-s.yQmewyq-2-MS (ESI): ra/z (96) = 450 (M+H,100):
SpI.C (method 4): rt = 3.25 nin.
Via epoxide opaM with an amine and subsequent cy+ciizatioa to give the ca~nespcmding oxazolidinooe, it was also pomhle to prepare the following compounds:
le No. M.P. snucum [ C] Cso [ M]
126 " .013 -127 F _, o p 159 .0007 0~'!!~'ti.~, ~'~ j..~ 198 .002 ~o 129 Q~~ Q w 196 .001 ~õ~.N ar r-~ 0 o 130 F .0033 ~~ s a 130a o j=.~ . 194 ~''1..,/'- ~ ~[~-p = , ~._...
oY~
131 195 .8S
132 06 .12 I& A 34122-Foneinn QgMdu ample No. uucduae p. ( C] rlm (EtMj 33 o f 17 ).062 134 ~.., F~. .48 1-(4-amino-phenyl)-'pe:idin-3-ol (Tong, L.KJ. et al.;
.Anor.Chem.Soc 1960; 82, 1988).
135 Q 02 L.1 ~' 7~
136 5c 39 1.2 s .~
O
137 f 19 .044 Ff o~o 38 95 .42 139 17 1.7 .y.:. _.
Le A 34 122nFoodgaCanstries Exwnpks 14 to 16 below ane wocking exampka for the opticeai oxidation stap..
LUEgIg 14 5-thloro-N-({(5S)-3-[3-flaoro4l-(1-oaoolilambda14,4-HWdnso4.y1)Pwa3'lJ-2, oxo-1,3-oxazHdin-S-yl)mabyn- e F
Ci HN
At 0 C, 5-chloro-N-({(5S)-3-[3-flwso-4-(1,4-thiazSnan-4-yi)phenylJ-2-oxo-1,3-oxazolidin-5-yl }methyl).2-thiophenacarboxamide (0.1 g, 0.22 mmol) fram Faxample 3 in mc.thanol (0.77 ml) is added to a solution of sodium ptciodate (0.05 g, 0.23 mmol) in water (0.54 rril), and the mixture is stirred at 0 C for 3 h. 1 ml of DMF
is then added, and the mixture is stirred at RT for 8 h. After addition of a further 50 mg of sodium pesiodate, the mixtum is once more stirred at RT overnight.
The niixture is then admixed with 50 ml of watar, and the insoluble product is filtered off with saction. Washing with water and drying gives 60 mg (5896 of theory) of crystals.
M.p.: 257 C;
Rt (silica gel, toluenelethyl acxtaoe 1:1) = 0.54 (starting matecial = 0.46);
ICso value =1.1 M;
MS (DCI) 489 (M+NHA), Cl pauern.
. , ~ A 34 l22 Foneign Coun'es = -97-Pe+epasatiioa af Sc6lsro-N-({(8,S).3{4-(1,1-diozo-1[Lmbda]s,4thkr3nan-4yi),3-fluot,uplmiyl]-2.-oaoo-1,3-oacaxolidin-5-yl)moNtyl)-2-mlop F
O
N p . ~. .
5-Chloro-N ({(5S)-3-[3-fluoro-4-(1,4-thiazin=-4y1Mmy1]-2-oxo-1,3-oxazolidin-yl}methyl}2-thioghenecarboxamide frmm Example 3(0.1 g, 0.22 mmol) in 332 mi of a mixture of 1 part of water and 3 patts of aoetone is adniixed with 80 mg (0.66 mmol) of N methylmorpholine N-oxide (NMO) and 0.1 ml of a 2.5% strength solution of osmium tatroxide in 2-methyl-2-pTopanol. The mixtute is stirred at room temperature overnight, and another 40 mg of NMO are added. The mixture is stinvd for a finther night and then potn+ed into 50 ml of water and exttacted tM+ee times with ethyl acetate. The organic phase gives, after drying and concentrating, 23 mg and the aqueous phase, after removal of the insoluble solid by filtration with suction, 19 mg (in tota13996 of thecxy) of the target compound.
M.p.: 238 C;
ltt (tolueneJethyl ac:etate 1:1) = 0.14 (starting matelial ffi 0.46);
ICso vaiue = 210 nM;
MS (DCI): 505 (M+NH4), Cl pauein-. .. ~ ,.._.
ExapPk16 S-Chlviro-N={[(SS)- Unoplenyl}2-oxo-1,3-ozuoUdin-S-yl]methyl}-2-thiophe~rboxanodde N-oxde is obtained by tc+eating 5-chloro-N {[(SS)-3-(3-fluoTO-4-morpholinophenyl}2-oxo-1,3-oxaZolidin-5-yllmethyl }-2-thiopl'renecarboxamide from F.xample 1 with the magnesium salt of monopemxyphthalic acid MS (ESI): 456 (M+H, 21%, C) pattern), 439 (10096).
Le A 341 ,Z-Zgoian Count:ies = -98-The Exampks 31 to 35 and 140 to 147 below refer to the optional smidinetion step.
General nwdiod for preparing addfines and amidlne derivsdves starti,ttg hom cyanomothyWhmy!-Bnbstlbioed S~laro-N-[(2-aso-l,3oe,solidio-5-yl)memyl}-2-thlophenaarboxsmide deti vatives The cyanomethylphenyl-subRtituted 5-chloro-N [(2-oxo-1,3-oxazzolidm- 5-yi)naethylj-2-thiophenecarboxamide derivative in question (1.0 eq.) is, together with triethylamine (8.0 eq.), stirred at RT in a sattuated solution of hydnogan sulphide in pyridine (about 0.05 - 0.1 mol/l) for one to two days. The reaction mixtune is diluted with ethyl acetate (EtOAc) and washed with 2 N hydrochloiic acid. The organic phase is dried with MgSOa, filtered and eoncentrate,d under reduced pressure.
The crude product is dissolved in acxtone (0.01-0.1 mol/l) and admixed with methyl iodide (40 eq.). The reaction mixture is stirne:d at room temperature (RT) for 2 to 5 h and then concentrated under reduced psessiue.
The residue is dissolved in inethanol (0.01-0.1 mo)/1) and, to prepu+e the unsttbstitnted amidines, admixed with anunanium acetate (3 eq.) and arnrnoniom chloride (2 eq.). To lx+epare the substituted nmidine derivatives, primary or secondary amines (1.5 eq.) and acetic acid (2 eq.) are added to the methanolic solution.
After 5-h, the solvent is removed under reduced pressure and the residue is purified by ,-- chramatography over an RP8 silica gel column (wat,er/aeetonitrile 911-1/1 + 0.1%
25 trifluoroecxtic acid).
The following compounrda were prepared in an analogous rmmner:
-~--Examnle 31:
N-({3-[4-(2-Amino-Z-iminoethyl)p6enylJ-2-oxo-1,3-oxswlidin-5-yl }metbyl)-S-chloro- 2-thiophenearboxamide MS (ESI): ns/z (96) = 393 (M+H, 100);
I3PLC (method 4): rt = 2.63 min ~CA 34 1Z2-EOWs'1 CoW1t[In irUS* 32., 5-A~loro-N-{{3.[3.(4y.S.dilrydro-iH-bdd.ml-Zryi~etryl~rl)=2-o~ou-1,3-o:azo4din-5-yi}methyl}2-dtiop6mecarboxamide MS (ESA: m/z (96) = 419 (M+H.100);
HIPLC (method 4): rt= 2.61 aun Exaiannle 33:
5-Cbloro-N-[(3-(3-[Z-inino-Z-(4-narphoftyl)etbyllp6enyl}-2-oxo-l,-~oti-din-S-yl)tnethyl]-2, MS (ESI): mlz (%) = 463 (1VI+1L 100);
H'P'LC (method 4): rt = 2.70 min E34:
S-(~cv-N-Lp-;3-CL-fm~o-2-(1-P1rrolldin7lktLyl]phenyl}-?-oxo-l,3-oxaso8-dSn-S-yl)mdhyn-Z-t6lophenearboxamlde MS (ESI): m/z (96) = 447 (M+H, 100);
F;P'X (metlwd 4): rt = 2.82 min Examph 35:
N-({3-[3dZ -A-mino-?+4minoatbyl)P6anyll ?-oae)--1,3-oxamolidLa-S-yl}met6yq-5-ehloro-2-t61ophenecarbox,amide MS (ESI): m/z (%) = 393 (M+H,100);
HPLC (method 4): rt= 2.60 min . .....
Eacar140 S-(hLoro-N-({3-[4-(4,5-di6ydro-1H=imidezol-2-ylam*yl)phmyp-2-oaco-1,3-oxa-zoGdln-S-yl}mdhyl}-2-thiop6anecarboxamide MS (ESI): mfz (%) = 419 (IvI+H, 100);
HPLC (med xied 4): ct = 2.65 min Le,& 34 122-Fbrain QURWU
Eza~k 141 5-(biono-N-E(344-[Z-~-Z-( }-Z~oaoo-l,3-oa~mol[=
din-S-TDmethyi]' S MS (ESI): rnla (96) = 463 (M+H,100);
H?LC (method 4): rt= 2.65 min IMOok 142 5-Ch=+o-N-{(3-{4[2-in*w-2-(1-pipm"ayl)d6y]UPbmyl)-2-oaro-l,3-oxmHdin-S.yl)methyl]-2- e MS (ESI): m/z (96) ~ 461(M+H,100);
HpLC (method 4): it = 2.83 min 1s gum* 143 5-CLlaro-N-[(3-(4-[?4miao-?+-(1-pyrnN&n)l)dmyl]P6eM1} -?.-o3w1.3-ozmoli-din-5-yl)methll]-?4biophe,nenrbozmmide MS {ESI): m!z (%) = 447 (M+H,100);
Hp'LC (method 4): rt = 2.76 min E~~k: 144 ~-. 54MIWO-N-[(3-{'I-[2-(cyckPontYbmdm)-2-indnoetbyl]pbenyl)-2-oaw-l,3-oxazo-lldin-S-yI*ethylj-2-*iopbenecarboxudde MS (F.SI): m/z (%) = 461(M+4L 100);
HPLC (method 4): rt= 2.89 min Fine*.?.~'~..
543doro-N-([3-04 2-led~o-Z-[4Z~~71)~kmyl)P~nyi)-2-o 0-1,3-oac~~oolklin-6-yl]methyl}-Ms (ESI): m/z (96) = 475 (M+H,100);
ffi'LC (method 4): rt = 2.79 min L& A 34 122:FQLTI.s! Sc4111itries Fmple146 N-({3-[4-(2-Anilino-2-lminodbpl)phenyl]-2-oxo-1,3-o==lldin-5-1l)=S3-1)-S-chloro-Z-MS (FSI): rnlz (96) = 469 (M+H,100);
H'PLC (metbod 4): rt = 2.83 min Exampk 147 S-Chbro-N-[(3-{4[2-Wmino-2-(2-pyridinyhuaino)dhyl]phml}-?.-0m0-1,3-ooe-zollalin-5-yl)snetayf]-2-thiopbmtorboztmide MS (ESI): m/z (%) = 470 (M+H, 100);
HPLC (method 4): rt = 2.84 min Examptes 148 to 151 below refer to the nernoval of BOC amino protoctive groups:
Genaal method for removing Boc protect[ve groups (tart-butyloxycarbonyl)=
R-H lok --"' R-NH2 N
Aqueous trifluoroacedc acid (TFA, about 90%) is added dropwisz to an ice-cooled solution of a tert-butyloxycarbonyl-(Boc) protected compound .in chloroform or dichloromethane (about 0.1 to 0.3 mol/1). After about 15 min, ice-cooling is temoved and the mixture is stirred at roorn temperature for appc+nxinuuely 2-3 h, and the solution is then concentrated and dried under high vacuuni. The residue is taken up in dichlonomethane or dichloromethaneJmethanol and washed with sauuated sodiuw bicarbonate or iN sodium hydmroxide solution. The organic phase is, washed witfw--sanusted sodium chloride solution, drfed over a little magnesium sulphate and concentrated. If appropriate, purification is carried out by crystallization from et'her or ether/dichloromethane mixtuns.
The following compounds were prepared in an analogous manner from the cornesponding Boc-pnot,acted precursora:
LtA3412e?:F4tttl11 C.,a~ntries Exas~ i~ 148 N-((3-[4-(AnsbomemYl)phenyl]-7-0SC0-3-oocaaolidin-S-yl}metb7l)4-cislw*-2-tLiapheme-carboxamide starting from Eaunple 92:
MS (ESI): m/z (%) = 349 (M NI6 25), 305 (100);
RPI.C (method 1): rt (96) = 3.68 (98).
ICio: 2.2 M
$~gple, 149 N-{C3-(4-AndnOpbm71)-2-oxo-1,3-oxsxOlldin-3-yi]melhyl}-S-cbloro-2-tl~opbenocarbozs~ide staroing fromEx"le 93:
MS (ESI): m/z (%) = 352 (M+H, 25);
HP'i,C (method 1): rt (96) = 3.50 (100).
IC--~: 2 M
An alternstive auaMiomtricallY pare syntthesis of this coznpound is shown in the scheme below (cf. also Delalande S.A., DE 2836305,1979; Chem.Abstr. 90, 186926):
1. BuU
2. lyddyl butyra~ O
~ ' 1/~ OH
O NH4C"%O
1.) phtlWftds, DEADPPl+, 2.) NH,NFL,.H=O ln s~henol ' + H
3.) 5-chloro-2 O S
acid. EDC.IFiOgT
Zn44CL- HN / H
S
Le A 34122-PoWQn Countries = 103 -~
5-(;6loro1V-({3-[4-(a1ye7bnkO)pbnnyil-2-oxo-l,3-oxaeolidin-5-yl}nwbyl}2-thiopbenecarboxsuaide starting ffom Example 152:
MS (ES-pos): m!z (%) = 408 (100);
HPLC (method 3): rt (%) = 3.56 (97).
ICw 2 M
Eunwh1'S1 5-(Aniaomethyl)-3-j4-(2-ozo-l-pyrroldiq,i'1)plhaU'1]-1A-oxaaolidfw2-oae staRing from Exampk 60:
MS (FSO: m/z (%) = 276 (M+H,100);
HPLC (method 3): rt (%) = 2.99 (100).
IC50: 2 M
The Examples 152 to 166 below refer to the amino group derivatization of aniline- or benzylamine-substituted oxazolidiaones using various reagents:
Exa 5-Chloro-N-((3-[4-(N-,tsrt-butybxyearbonyl-glycylamino)pbenyl]-2-ouo-1,3-,.. oxazolidin-5-yl)nmthyl).2-thliophenecarboxamtde 10~
4j,,YO-,Cr - ~ ,......
O p At 0 C, 754 mg (2.1 mmol) of 1V {[3-(4-aminophenyi).2-oxo-1,3-oxazolidin-5-yljmethyl)-5-chloro-2-thiophenecarboxamide (from Example 149) are added to a solution of 751 mg (4.3 mmol) of Boc-glycine. 870 mg (6.4 mmol) of HOBT
(1-hydroxy-IH-benzotriazole x H20), 1790 mg (4.7 mmol) of HBTU
[O-(benzotriazol-l-yi)-N,N,N',N' tetramethyluronium hexafluorophosphaLe] and 1.41 inl (12.9 mmol) of N-methylmorpholine in 15 ml of DMF/CH2C12 (1:1). The LeA 341 Fccet,gn Canttrkn mixture is stirned at roam temperatune overnight and then diluted with waa.
The precipitated solid is filtered off and dried. Y'zeld: 894 mg (79.7% of theory);
MS (DCI, NH3): mlz (96) = 526 (M+1VH4,100);
HPI.rC (method 3): it (%) o 4.17 (97).
JMMRb153 N-[C3-{4-I(A+c,elybmbo)metby1)Phenyl}-Z-ooo-l4-m~ia-S-yl)methyi}S-cbloro-Z-thiop }t~ S
O
O
At 0 C, a mixture of 30 mg (0.082 mmol) of N-({3-[4-(aminomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}snethyl)-5-chloro-2-thiophene-cacboxamide (from Example 148) in 1.5 ml of absolute THF and 1.0 ml of absolute clichloramethane, and 0.02 ml of absolute pyridine is mixed with acetic anhydride (0.015 m), 0.164 mmol). The mixtim is stirned at rootn tempcratuee overnight. Addition of ethex and crystaUization affords the product. Yield: 30 mg (87% of thomy), MS (ESI): m/z (%) = 408 (M+I3,18), 305 (85);
HPLC (method 1): rt (4b) = 3-78 (97).
ICW 0.6 M
Esunole 154 1V {C3-(4-{[(AmWoau'bonyl)eaa~oltne<6y1}Pl~nyl}?rozo-l,3-oarmlidin-5-yl}
methyl).29-cbloro-2-tLiop61 ecsirboxsmide O~
o '1( Le A 34122-Foeeion ComRWe At room tempaaaue, 0.19 mi (0.82 mmol) of uimxdiylsilylisocyanoe we added dropwise to a mixtm of 30 mg (0.082 mmol) of N-({ 3-[4(aminomethyi)pheayl}-2-oxo-l,3-oxazolidin-5-yl jsietbyl)-5-chloro-2-thiophene-cwboxamide (from Example 148) in 1.0 ml of dichloromedme. The mixture is stimed ovemight and, after addition of ether, the product is then obtained by filtnadon. Yie1d: 21.1 mg (52% of dleory).
MS (SSI): tdz (96) = 449 (M+H, 5), 305 (12);
HP'LC (method 1): rt (~b) = 3.67 (83).
ICso:1.3 EcM
Gea" memod for ae,yhtlog N-{[3-(4-oobnop6enyl}2-oxo-lA-o==iidio-5-yqmethyl}4-cbloro- with csrbonyl chbridkm ---~ s Under argon, an approximately 0.1 motar solution of N-{ [3-(4-anrinqphenyl)-2-oxo-1,3-oxaaolidin-5-yl)methyl)-5-chloso-2 thiopiKnecaftxamide (from Example 149) (1.0 eq.) in absolute dichlot cdanelpytidine (19:1) is added dropwise to the appropriate acid chloride (2.5 eq.). The mixture is stirnd overnight and then admixed with about 5 eq. of PS trisamine (Argonaat Technologies) and 2 nil of absolute dichloronnethane. The mixture is stined gently for 1 h and then fihered off, and the filtrate is concentrated. If appropniate, the paeducts m purifiod by prcparadve RP
KPLC. : ~...
The following compounds were prepared in an analogous nwmer.
Fjosumale HMS
N-({3.j4.(AatyLimino)piayt}2-oxo-1,3-oxozoBtin-5-yl)metbyI}.S.chloro-2-tWbphme-csrboxamdde I.C-MS: mJz (96) - 394 (M+I;, 100);
I t A 34 122-Fnned:n C_ es LC-MS (metirod 6): it (96) = 3.23 (100).
ICso= 1.2 M
F_" Mf 5-Chloro-N-[(2-oaro-3-{4[(2-thiesykacbonyl)uainolpbonyl}-1,3-o~io-.~',-y1*eltyU-2-LC-MS: m/z (96) a 462 (M+H,100);
LC-MS (matwd 6): it (96) = 3.87 (100).
ICso: 1.3 M
Finnimb 157 SACWbro-N-[(3-{4I(amt6ozyacetyl*mioo]p6my1}-?rozo-l,3-ozmol[din S-yA-methyQ-2-t6iop6awcarboacsmide LC-MS: mh (%) = 424 (M+H,100);
LC-MS (method 6): rt (qb) = 3.39 (100).
ICyo: 0.73 pM
Examlk 158 N-{4-[S-({[(S-Chbro-2 t6ionyl)carboayl]am:iTMw}methyl)-2-oxo-l,3-oxamuliiin-3-y0pbany1}-3 e LC-MS: m/z (96) = 475 (M+H, 100).
ICso: 0.46 M
~~-S-Chloro,~V-{C3-(~[(3-cLloropropyq~onyl~a~ioo}pl,myi)-2~'xo-I,3-ozazolidln-S-yl]tnwthyl}-Z-thlophmecsirboxamide )"O 4,r 1N ~, ~ O
~ ~
q LeA3dllZFae+ei~n~
An ice-cooled solution of 26.4 mg (0.15 mmol) of 3-chloro-l-ptaQ~ulphaz-yl chlonide and 0.03 ml (0.2 mmol) of ttiethylamine in 3.5 ml of absolute dichloro-methane is admixed with 35 mg (0.1 mmol) of N-{ [3-(4aminopfienyl)-2-oxo-l,3-oxazolidin 5-yl]-metbyl } S-ch~2-thiophene-carboxamide (from Example 149).
After 30 min, ice-cooling is removed and the niixture is stirred at room temperatun oveaz-ight, and 150 mg (about 5S eq.) of PS-trisamine (Argonaut Technologies) and 0.5 ml of dichloromethane aoe den addod. T9x wapension is sdnred Scntly for 2 h and filtered (the resin is washed with dichloromethanehaethanol),/ad the filtrate is concentrated The product is purified by pizpmadve RP-ilWW. Yield: 19.6 mg (40%
of theory).
LC-M5: m/2 (96) = 492 (M+H,100);
LC-MS (method 5): it (%) = 3.82 (91).
IC$O: 1.7 M
$am* 1_6A
5-C61oro-N-((3.[4{1,1-dbxido-2-lsothi oUdinyl)phmyl]-2-ooou-l,3-oxa,sol4idio-5-yl}metbyl)-2-thiophenecarboxamiide -~ O,s C1 fS~
~ O
A mixtm+e of 13.5 mg (0.027 mmol) of 5=chloro-N-{ [3-(4-{ [(3-chloropropyl)sul-phcmyl]amino}phenyl).2-0xo-1,3-oxazolidin-5-yllmethyl }-2-thiophaae-carboxamide (from Example 159) and 7.6 mg (0.055 mmol) of potassium csrbonsoe in 0.2 ml of DMF is heated at 100 C for 2 h. After cooling, the mixtum is diluted witb, ..
dichloromethane and waahed with water. The organic phase is dried and concentrated. 7he residue is purified by preparative thin-layer chromatography (silica gel, dichlcx+onothaneJmethomol, 95:5). Yield: 1.8 mg (14.4% of thoory), MS (ESI): m/z (%) = 456 (M+Ii,15), 412 (100);
LC MS (rruthod 4): rt (96) = 3.81(90).
ICSO: 0.14 M
jA A 34122-Forei CcWrries B,na~~1 S-Oioro-N-[((SS)a-{4I(S{hlot'pPmtaaayi)awJnolPb=yl}-2-oxo-l,3Ouaxog-din-5-yl)saet6yl]-2-thiopheneoarboxamide S
ct- CI
0.5 g (1.29 mmol) of N-{[(5S)-3-(4-aminaomyl).2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-24iopmacazboxamide (from Example 149) is dissolved in 27 ml of tstaahydrofia'a~i and admixed with 0.2 g (1.29 aunol) of 5-chlorovaleryl chloride and 0395 ml (2.83 mmol) of triethylamine. The niixture is concentrated under reduced pressure and cM+omatogtaphed over silica gel using a toloeae%thyl acetate=l:1-> ethyl aeetate gradient. This gives 315 mg (52% of theory) of a solid.
M.p.: 211 C.
Exgnwk 162 S-C'hlora-N-({(5S).2-oxo-3-[4.(2-oxo-l-pipee3dinyr~}-1,3-ozanUidin-S-y!}-methyl}.2-thiophmeatrlwxaadde O
C,N
S p Under inert conditions, 5 nil of DMSO are admixed with 30 mg of NaH (60% in paraffin oil), and the mixture is heated at 75 C for 30 min, untii the evolution of gas has ceased. A solution of 290 mg (0.617 nnmol) of 5-chloro-N-[((SS)-3-{4-[(5-chloropentanoyl)amino)phenyl )-2-oxo-1,3-oxazolidin-5-ylrnethy13-2-thiophau-carboxamide (from Example 161) in 5 ml of rntthylene chloride is then added dropwise, and the mixture is stirnd at roozn tennperaume ovemight. The reaction is terminated and the mixtare is poured into 100 ml of water and extated with ethyl Le A 34122-Fatelan Cmmain = .-109-satste. The evapmted ocgnic Pha.qe is - -o~na~ogophed on an RP-8 ooluam and the product is eluted with acdtanitrikJwater. This gives 20 mg (7.5% of theory) of the target compamd.
M.p.: 20S C;
NMR (300 MHz do-DMSO): b= 1.85 (m,4H), 235 (m,2H), 3.5$ (m,4H), 3.85 (m,1H), 4.2 (t,1H), 4.82 (m,1H), 7.18 (d,1H,thiophene), 7.26 (d,?.Il), 7.5 (d,2H), 2.68 (d,1H,thiophene), 9.0 (t,1H,CONH).
ICw- 2.8 nM
&BEft 163 S-C6bro-N-[((SS)4-{4-[C3-bromopopioa7l)saaina]p6eapl)-2-oaoo-1,3wnxoN-din=5-yl)wd7U-Y(S
is obtained in an analogous manner from Example 149.
Eguwle 164 S-Chbro-N-({(SS)-2-oxo-3-[4-(2romo-l-axdidiayt)pheay[}1,3-oxuWdio-5-yt)-methql)-2-tidophenwar6oarunide is obtained in an oaaalogpx mwm by cyclization of the opea-chein btamopropionyl compasnd from Example 163 using Na11/DMSO.
MS (ESI): m/z (%) = 406 ([M+HJ'.100), Cl p ttern.
ICso: 380 nM
IA A 34122-&g Counuies AUMRk 165 tat-Butyl 4-{4-[S-({ [(S-c6loro-2-thkoyl)carbonyl]amino}me"}2-oxo-l,3-oxs-zolidin-3-yf jphenyl}-3,S-dloxo-l-paperazinecarboxylate O
A solution of 199 mg (0.85 mmol) of Boc-iminodiacxtic acid, 300 mg (2.2 mmol) of HOBT, 0.66 ml (6 mmol) of N-methylmorpholine and 647 mg (1.7 mmol) of HBTU
is admixed with 300 mg (0.85 mmol) of N-{[3-(4-anninophenyl)-2-oxo-1,3-oxazolidin-5-yl]-methyl }-5-chloro-2-thiophene-carboxanzide in 6 ml of a mixture of DMF and dichloromethane (1:1). The nzixture is stined overnight, diluted with dichloromethme and then washed with water, satuiatzd ammonium chloride solution, saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The organic phase is dried over magnr,sium sulphate and concentrated. The crude product is purified by silica gel chrotnatogrraphy (dichlosomethane/methanol 98:2). Yield: 134 mg (29% of theory);
MS (ESI): m/z (%) = 571(M+Na, 82), 493 (100);
HPLC (method 3): rt (9b) = 4.39 (90).
ICW 2 kM
Examok 166 N-[((5S)-3-{4-[(3R)-3-Amina-7..oxal-Pyrn&Unyl]Pbm7l}-2-oxo-YA.oaaaolidio-5-yl)cnathylI-S-chioro-24biopheaecarboxstmide tritluoroaataft BOCNH COOH
+ HOBT
'~f S CI EDC, DIEA
~~a 30725=107 (S) H3C'C O~ O O O
1V N p ~ Me3S1, K2CO3 CI
O
'-CH3 TFA
BOCNH N ~ N N
S CI
O
O O
_O
_~N
N~N ~ 1 CI
O
N2-(tert-Butoxycarbonyl)-NI-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}
methyl)-2-oxo-1,3-oxazolidin-3-yl)phenyl}-D-methionineamide 429 mg (1.72 mmol) of N-BOC-D-methionine, 605 mg (1.72 mmol) of N-{[(5S)-3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl }-5-chloro-2-thiophenecarbox-amide, and 527 ma (3.44 mmol) of HOBT hydrate are dissolved in 35 ml of DMF
and admixed with 660 mg (3.441 mmol) of EDCI hydrochloride and then dropwise with 689 rng (5.334 mmol) of N-ethyl-diisopropylamine. The mixture is stirred at room temperature for two days. The resulting suspension is filtered off with suction and the residue is washed with DMF. The combined filtrates are admixed with a little silica gel, concentrated under reduced pressure and chromatographed over silica gel using a toluene -> T10EA7 gradient. This gives 170 mg (17% of theory) of the target compound of melting point 183 C. (T10EA7 means toluene to ethyl acetate =
ratio 10 to 7.) Rf (SiOZ, toluene/ethyl acetate=l:1):0.2.
'H-NMR (300 MHz, d6-DMSO): 8=1.4 (s,IH,BOC), 1.88-1.95 (m,2H), 2.08 (s,3H,SMe), 2.4-2.5 (m,2H, partially obscurbed by DMSO), 3.6 (m,2H), 3.8 (m,1H), 4.15 (m,2H), 4.8 (m,1H), 7.2 (1H, thiophene), 7.42 (d, part of an AB system, 2H), 7.6 (d, part of an AB system, 2H), 7.7 (d, IH, thiophene), 8.95 (t,1H, CH2NHCO), 9.93 (bs,1H,NH).
l.e A 34122-Favigg Countria tert Butl-1 (3R)-I-{4-[(S3)-S-({[(Schloro-2-thimyl)'arbonyl]ssnino}methyi}2-oxo-1,3-ozs=Udin-3-yljpbenyl}-2-oxo-3-pyrroiidlnyMs#rboniate 170 mg (0.292 mmol) of N2-(tert-butox)carbonyl)-Nl-{4[(SS)-5-(([(5-chloro-2-thienyl)arbonyl]amino}methyl)-2-oxa-1,3-oxazolidin-3-yl]phenyl}-D-methioirine-amide are dissolved in 2 ml of DMSO and admixed with 178.5 mg (0.875 mmal) of tsimethylsulphonium iodide and 60.4 mg (0.437 nmmol) of potsssium carbonate, and the mixtune is stirned at 80 C for 3.5 hours. The mixture is then concentrated under high vacuum and the naaidue is waahed with ethanoL 99 mg of the target compound 10, nmain.
'H-NMR (300 MHz do-DMSO): a=1.4 (s,1H.BOC), 1.88-2.05 (m,IH), 2.3-2.4 (nn,1H), 3.7-3.8 (m,3H), 3.8-3.9 (m,1H), 4.1-4.25 (m,1H), 4.25-4.45 (m,1H), 4.75-4.95 (m,lIi), 7.15 (1FI, thiooheee), 7.25 (d,110, 7.52 (d, part of an AB
systoa, 2H), 7.65 (d, part of an AB system, 2Fi), 7.65 (d,1H, thiophene), 9.0 (broad s,1H).
N-[((55)-3-{4-[(3R)-3-Amino-Z-ozo-l-pprrolidinyl]phenyl}-2-oxo-l,3-oxnolidin-5-Ylhnethyll-5-chloco-2-tldop>kaec.rbonmlde tzith.oroaoetate 97 mg (0.181 mmol) of tert-butyl (3R)-1-(4-[(5S)-5-{([(5-chloro-2-thienyl)carbonyljamino?methyl)-2-oxo-1,3-oxazolidin-3-yllphenyl }-2-oxo-3-pyrroli-dinylcarbatnato are suspended in 4 ml of methylene chloride, 1.5 ml of trifluotoacedc acid are added and the mixture is stirred at roorn temperature for 1 hour. The niixture is then concentrated under reduced pressure and the residue is pmified on an RP-HPLC (scctomtrileJwater10.1% TFA gradient). Evaporation of the appropriate fraction gives 29 mg (37% of theory) of the target compound of melting point (decomp.).
Rf (SiO20EtOH/LEA=17:1) 0.19.
'H-NMR (300 MHz da DMSO): 8=1.92-2.2 (m,1H), 2.4-2.55 (m,1H, pArtiallyobscured by DMSO peak), 3.55-3.65 (m,2H), 3.75-3.95 (m,314), 4.1-4.3 (m.ZH), 4.75-4.9 (m,1H), 7.2 (1H, thiophene), 7.58 (d, part of an AB system, 2H), 7.7 (d, part of an AB system, 2H), 7.68 (d, IH, thiophene), 8.4 (broad 011. NH3), 8.9 (t,1H,NHCO).
Le A 34 122-Foneien Coantrie.s ' 113 -The Examples 167 to 170 below refer to the introduction of sutphonamide gwups in phenyl-substimd oxazolidinone.s:
Generai method for preparbng sebatituted snlphommtides startlng from S-chloro-N-[(?roxo 3-pbmyl-1,3-oacs=)ltdin-S-ylhmetbyll-2-tbiop6m~aearboxao~de C
4 q_, p R' __..r.. R'SN- C
Under argon and at 5 C, 5-chloro-N-[(2-oxo-3-phenyl-1,3-oxazolidin-5-yl)methyl)-2-thiophenecarboxamide (from Example 96) is added to chlomsulphonic acid (12 eq.).
The reaction niixtiue is stined at room temperature for 2 h and then poured into ice-water. The resulting psecipitate is filtered off, washed with water and dried.
Under argan and at room temperawre, the pnx.~ipitate is then dissolved in tetrahydivfuran (0.1 nzoUl) and admixed with the appropriate amine (3 eq.), triethylamine (1.1 eq.) and dimethylaminopyridine (0.1 eq.). The reaction niixture is sdmed for 1-2 h and thea concentrated under reduced pressure. The desired product is purified by flash chronutography (dichlorornethanehnethanol mixturts)...
The following compounds were prepared in an analogous manner.
Exataole 167 5-Chloro-N-({2-oxo-3-[4-(1-pyrevMnybulphonyt)plmyq-1,3-oaramlidin-S-yl}-methyi)-2-thbphenecarboxam3de MS (ESI): nVz (96) = 492 ((M+Na]+,100), 470 ([N+i+H]', 68), Cl pattern;
Le A 34122-Foreia Camtries HPLC (method 3): tt (96) = 4.34 (100).
ICW. 0.5 M
&amok 168 SdCblaro-N-[(3-{4-[(4-met6yl-l-piperazinyl)mohonylkahmyl}-2-oxo-1,3-oxa-zolidia-S-yl)nnethyq4-thiophenecarboxawAde MS (ESI): rn/z (%) = 499 ([M+H]'',100), Cl patoern;
HPLC (method 2): rt (96) = 33 (100).
,--5-Chloro-N-((2-cia4o-3-W1-p1PWMWylwlpbonyl)P6my!]-1,34xumiidin-S-yl)-methyl)-Z-tbbpheneesrbozwaide MS (ESI): m/z (%) = 484 ([M+H]+,100), Cl patiern;
BPI.C (method 2): rt (96) = 4.4 (100).
EXMok 170 S-Cldoro N=[(3-(4-[(4-hydroxy-l-PiPMinyl)#Wpbmy]lpbonyl}-2-oxo-l,3-oaca-zolidia-S-yl)methyl]-2-thiOP e MS (ESI): nm/z (%) = 500 ([M+H]'',100), Cl pattern;
HPLC (mediod 3): rt (96) = 3.9 (100).
Eimmale 171 5-Chbro-N-({Z-oxo-3-[4-(1-pyrmOdbmyQphmyl]~1j-oxwolidia-S-pi}nehyi)-2-thioph~rboxamide -:,.._.
o ---' a 30725=107(S) 780 mg (1.54 mmol) of tert-butyl 1-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}-methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}prolinate are dissolved in 6 ml of dichloromethane and 9 ml of trifluoroacetic acid, and the mixture is stirred at 40 C
for two days. The reaction mixture is then concentrated and stirred with ether and 2N
aqueous sodium hydroxide solution. The aqueous phase is concentrated and stirred with ether and 2N hydrochloric acid. The organic phase of this extraction is dried over MgSO4, filtered and concentrated. The crude product is chromatographed over silica gel (CHZCIz/EtOH/conc. aqu. NH3 sol. = 100/1/0.1 to 20/110.1).
This gives 280 mg (40% of theory) of the product.
MS (ESI): m/z (%) = 406 (M+H, 100);
HPLC (method 4): rt = 3.81 min.
HPLC parameter and LC-MS parameter for the HPLC and LC-MS data Qiven in the examples above (the unit of the retention time (rt) is minutes):
TM
[1] Column: Kromasil C18, L-R temperature: 30 C, flow rate = 0.75 ml min-i, eluent: A = 0.01 M HC1O4, B = CH3CN, gradient: -> 0.5 min 98%A -> 4.5 min 10%A ->6.5 min 10%A
TM
[2] Column: Kromasil C18 60*2, L-R temperature: 30 C, flow rate = 0.75 ml min"', eluent: A = 0.01 M H3PO4, B = CH3CN, gradient: -> 0.5 min 90%A -> 4.5 min 10%A ->6.5 min 10%A
TM
[3] Column: Kromasil C18 60*2, L-R temperature: 30 C, flow rate = 0.75 ml min-1, eluent: A = 0.005 M HC1O4, B CH3CN, gradient: -> 0.5 min 98%A -> 4.5 min 10%A ->6.5 min 10%A
[4] Column: Syznmetry TM C18 2.1x150 mm, column oven: 50 C; flow rate -0.6 ml min-', eluent: A = 0.6 g 30% strength HCl/ 1 of water, B = CH3CN, gradient:
0.0 min 90%A -> 4.0 min 10%A ->9 min 10%A
30725=107 (S) [5] MHZ-2Q, Instrument Micromass Quattro LCZ
TM
Column Symmetry C18, 50 mm x 2.1 mm, 3.5 m, temperature: 40 C, flow rate =
0.5 ml min-', eluent A = CH3CN + 0.1% formic acid, eluent B = water + 0.1%
formic .5 acid, gradient: 0.0 min 10% A -> 4 min 90% A -> 6 min 90% A
[6] MHZ-2P, Instrument Micromass Platform LCZ
TM
Column Symmetry C18, 50 mm x 2.1 mm, 3.5 m, temperature: 40 C, flow rate =
0.5 ml miri', eluent A = CH3CN + 0.1% formic acid, eluent B = water + 0.1%
formic acid, gradient: 0.0 min 10% A -> 4 min 90% A -> 6 min 90% A
[7] MHZ-7Q, Instrument Micromass Quattro LCZ
TM
Column Symmetry C18, 50 mm x 2.1 mm, 3.5 m, temperature: 40 C, flow rate =
0.5 ml min-', eluent A = CH3CN + 0.1% formic acid, eluent B = water + 0.1%
formic acid, gradient: 0.0 min 5% A -> 1 min 5% A -> 5 min 90% A -> 6 min 90% A
General method for preparing oxazolidinones of the general formula B by solid-phase-supported synthesis Reactions with different resin-bonded products were carTied out in a set of separated reaction vessels.
5-(Bromomethyl)-3-(4-fluoro-3-nitrophenyl)-1,3-oxazolidin-2-one A (prepared from epibromohydrin and 4-fluoro-3-nitrophenyl isocyanate usina LiBr/Bu3PO in xylene analogously to US 4128654, Ex.2) (1.20 g, 3.75 mmol) and ethyldiisopropylamine (DIEA, 1.91 ml, 4.13 mmol) were dissolved in DMSO (70 ml), admixed with a secondary amine (1.1 eq., amine component 1) and reacted at 55 C for 5 h.
TentaGel SAM resin (5.00 g, 0.25 mmol/g) was added to this solution, and the mixture was reacted at 75 C for 48 h. The resin was filtered, washed repeatedly with methanol (MeOH), dimethylformamide (DMF), MeOH, dichloromethane (DCM) and diethyl ether and dried. The resin (5.00 g) was suspended in dichloromethane (80 ml), admixed with DIEA (10 eq.) and 5-chlorothiophene-2-carbonyl chloride [prepared by reactinc, 5-chlorothiophene-2-carboxylic acid (5 eq.) and 1-chloro-l-dimethylamino-2-methylpropene (5 eq.) in DCM (20 ml) at room temperature for 15 minutes] and the mixture was reacted at room temperature for 5 h. The resulting resin was filtered, washed repeatedly with MeOH, DCM and diethyl ether and dried. The resin was then 30725-107 (S) suspended in DMF/water (v/v 9:2, 80 ml), admixed with SnC12*2HZ0 (5 eq.) and reacted at room temperture for 18 h. The resin was washed repeatedly with MeOH, DMF, water, MeOH, DCM and diethyl ether and dried. This resin was suspended in DCM, admixed with DIEA (10 eq.) and, at 0 C, with an acid chloride (5 eq. of acid derivative 1), and the mixture was reacted at room temperature overnight.
Prior to the reaction, carboxylic acids were converted into the corresponding acid chlorides by reaction with 1-dimethylamino-l-chloro-2-methylpropene (1 eq., based on the carboxylic acid) in DCM at room temperature for 15 min. The resin was washed repeatedly with DMF, water, DMF, MeOH, DCM and diethyl ether and dried. If the acid derivative 1 used was an Fmoc-protected amino acid, the Fmoc protective group was removed in the last reaction step by reaction with piperidine/DMF (v/v, 1/4) at room temperature for 15 minutes, and the resin was washed with DMF, MeOH, DCM and diethyl ether and dried. The products were then removed from the solid phase using trifluoroacetic acid (TFA)/DCM (v/v, 1/1), the resin was filtered off and the reaction solutions were concentrated. The crude products were filtered over silica gel (DCM/MeOH, 9:1) and evaporated, giving a set of products B.
02N 0 R:N.R2 1 OzN O
~ H R - J~
F N O -_.-~ N N
Br R Br A
TentaGeISAMNH2 R ~ 2 - ~
am, N N O
TM
RZ L-~N
~TentaGeISAM
CI
S ci 02N O
O
\ / N N O O S C!
Rz ~TGSAM
30725-107(S) R, HzN 0 CI
SnClz N LN '' 0 5C1 O N
5Eq TGSAM
>=O
HN 0 TFA/DCM, R' _ 1 /1 N ~~ N 0 S CI
RZ
N
TGSAM
>=D
HN O
, RN - N O O S Ci R~Z ~ l Y-I ~/
NH
B
Compounds which were prepared by solid-phase-supported synthesis:
Example 172 N-({ 3-[3-Amino-4-(1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide ' ~ CI
C~-O N YN~'~N S
Analogously to the general procedure for preparing the derivatives B, 5 a TM
(1.25 mmol) of TentaGel SAM resin were reacted with pyrrolidine as amine derivative 1. The aniline obtained after reduction with SnC1Z*2HZ0 was, without any further acylation step, removed from the solid phase and concentrated. The crude product was partitioned between ethyl acetate and NaHCO3 solution and the organic phase was salted out using NaCl, decanted and evaporated to dryness. This crude 30725-107(S) product was purified by vacuum flash chromatooraphy over silica gel (dichloro-methane/ethyl acetate, 3:1 - 1:2).
1H-NMR (300 MHz, CDC]3): 1.95 - 2.08, br, 4 H; 3.15-3.30, br, 4 H; 3.65-3.81, m, 2 H; 3.89, ddd, 1H; 4.05, dd, 1 H; 4.81, dddd, 1 H; 6.46, dd, 1 H; 6.72, dd, 1 H; 6.90, dd, 1 H; 6.99, dd,.1 H; 7.03, dd, 1 H; 7.29, d, 1 H.
Example 173 N-[(3-{3-(i3-Alanylamino)-4-[(3-hydroxypropyl)amino]phenyl}-2-oxo-1,3-oxa-zolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamide HzN
O
HO O
' \ CI
~-N :b-NN O N S
H ~
O
An alogously to the Deneral procedure for preparing the derivatives B, 5 g TM
(1.25 mmol) of TentaGel SAM resin were reacted with azetidine as amine derivative 1 and Fmoc-B-alanine as acid derivative 1. The crude product obtained after the removal was stirred in methanol at room temperature for 48 h and evaporated to dryness. This crude product was purified by reversed phase BPLC using a water/TFA/acetonitrile gradient.
'H-NMR (400 MHz, CD3OD): 2.31, tt, 2 H; 3.36, t, 2 H; 3.54, t, 2 H; 3.62, t, 2 H;
3.72, dd, 1 H; 3.79, dd, I H; 4.01, dd, 1 H; 4.29, dd, 2 H; 4.43, t, 2 H; 4.85-4.95, m, 1H;7.01,d,1H;4.48-7.55,m,2H;7.61,d,1H;7.84,d,1H.
Example 174 N-({3-[4-(3-Amino-l-pyrrolidinyl)-3-nitrophenyl]-2-oxo-1,3-oxazolidin-5-y1}-methyl)-5-chloro-2-thiophenecarboxamide 30725-107(S) Cl H N NOz O S
2 ~_O O
N N
NH
Analogously to the general procedure for preparing the derivatives B, 130 mg TM
(32.5 mol) of TentaGel SAM resin were reacted with tert-butyl 3-pyrrolidinylcarbamate as amine derivative 1. The nitrobenzene derivative obtained after the acylation with 5-chlorothiophenecarboxylic acid was removed from the solid phase and concentrated. This crude product was purified by reversed phase HPLC using a water/TFAlacetonitrile gradient.
'H-NMR (400 MHz, CD3OH): 2.07-2.17, m, 1 H; 2.39-2.49, m, 1 H; 3.21-3.40, m, 2 H; 3.45, dd, 1 H; 3.50-3.60, m, I H; 3.67, dd, 1 H; 3.76, dd, 1 H; 3.88-4.00, m, 2 H;
4.14-4.21,t,1H;4.85-4.95,m,1H;7.01,d,1H;7.11,d,1H;7.52,d,1H;7.66, dd, 1 H; 7.93, d, 1 H.
Example 175 N-({3-[3-Amino-4-(1-piperidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-y1}methyl)-5-chloro-2-thiophenecarboxamide HZN O
~ 1 \ CI
CN N N S
O
Analogously to the general procedure for preparing the derivatives B, 130 mg TM
(32.5 mol) of TentaGel SAM resin were reacted with piperidine as arnrne:
derivative 1. The aniline obtained after the reduction was, without any further acylation step, removed from the solid phase and concentrated. This crude product was purified by reversed phase HPLC using a water/TFA/acetonitrile gradient.
'H-NMR (400 MHz, CD3OH): 1.65-1.75, m, 2 H; 1.84-1.95, m, 4 H; 3.20-3.28, m, 4 H; 3.68, dd, 1 H; 3.73, dd, 1H; 3.90, dd, 1 H; 4.17, dd, 1 H; 4.80-4.90, m, 1 H;
7.00, d, 1 H; 7.05, dd, 1 H; 7.30-7.38, m, 2H; 7.50, d, 1 H.
30725-107 (S) Example 176 N-({3-[3-(Acetylamino)-4-(1-pyrrolidinyl)phenyl]-2-oxo-1;3-oxazolidin-S-yl}-methyl)-5-chloro-2-thiophenecarboxamide I,== O
HN O
CI
CN N a S
O
Analogously to the aeneral procedure for preparing the derivatives B, 130 mg TM
(32.5 mol) of TentaGel SAM resin were reacted pyrrolidine as amine derivative I
and acetyl chloride as acid derivative 1. The crude product was partitioned between ethyl acetate NaHCO3 solution and the organic phase was salted out using NaC1, decanted and evaporated to dryness. This crude product was purified by vacuum flash chromatography over silica gel (dichioromethane/ethyl acetate, 1: 1-0: 1).
iH-NMR (400 MHz, CD3OH): 1.93 -.2.03, br, 4 H; 2.16, s, 3 H; 3.20-3.30, br, 4 H;
3.70, d, 2 H; 3.86, dd, IH; 4.10, dd, 1 H; 4.14, dd, 1 H; 4.80-4.90, m, 1 H;
7.00, d, 1 H; 7.07, d, 1 H; 7.31, dd, 1 H; 7.51, d, 1 H; 7.60, d, 1 H.
The followina compounds were prepared analogously to the aeneral procedure.
xample Structure et. PLC
ime lo ]
177 N .62 19.7 O O
CI S
~ I/ N-)--\N
O
178 O 00 O~ 49 3.7 N N
N
CIe\
N
Le A 34 122-Fomlgn C_ounaies k trucaure 79 J .63 6.7 p~0 O N O~o ~N
180 1.37 44.8 O p N O O
04 181 N .16 83 ~N N
O p 182 ~ 31 3 O
S N
Q O
~-- 183 r 100 O~
N ~N
q ,....
184 .9l 1 o~,, ,J N
. ~.o P
Le A 34122-Foeeign CnmmWo LlruCt1m ~
185 O-\ 1--p .72 5.2 Nl~ N
JJ--~~N~"' ~10 O q 86 0~ .17 46 N
O
187 O 1.61 50.2 s ~lo (D
88 O N~ ~O. p /'1 .89 6 - N
q Nl~
189 No O p,,r .37 2.9 .p- - ~-N
q 190 3.6 3.9 _ =
O
q S N
'/~
Le A 34 1,~.2-"grciSj Co=ries . -124-Exumpk ftucbure C
%
191 .52 70.1 O
S N
p N~
O
192 Orp-o O 4O .52 46.6 S
,r+ q N
193 --fO .87 .1 O N ~
p N N
194 O-f O p_' 11 .25 1.1 ~Or N
LD
195 .66 7 O - : . =h.....
-t -, p CI
N
U A34 j22rForciaa Camuias xRmple &Uctum C
196 ~p Or .4 2.1 N~N ~N/
S
N
N
197 3.13 8.9 S I-N O
~T O
N
198 0 Oo o .67 75.5 '~..f CI
N
199 0 0.f 0 0 ~'"1 72 5S.7 CI =- N
00 .71 7.3 ~ 0**f 0 0 t==N
q Le A 3412Z-Forei~n Countrie.a = -126 -tructnre C
%
1 .22 00 O
2 p p_ .89 5.7 q ND
203 O p-f 0 pp .19 9.6 S
q N
204 o.f o p~ .ss .2 N T D
N
N
p N
205 ~ 44 69.6 i--{p p O 0 Np N :....
.86 11.8 '*f p O
p 1A A 34 122-Fom1s1 COBBti]C&
c 207 O O-f p O .8 .6 p p______ N
08 O .41 77 O=~
N
p N
09 2.56 7.9 O
N
~
~ N
p p--f 0 p 3.67 8.4 a
Yield: 837 mg (39% of tbwty);
MS (DCT, NH4): zMz (%) =253 (M+1VH4,100), 218 (M+H, 80);
HP'LC (method 1): rt (%) = 3.69 min (about 80).
Gmeral method for prep.ring u6stbuted N-(3-amino-2-h,ydro:ypropyl}4-chloro-~thiop deerlvattves xbwdog fcom S-ddo%N-(2-o:iranylmethyl)-2r R-N
~" . H+ h/~N S CI R.
% H
At room teimperatnue or at umpmom up to W C, 5-chloro-N-(2=oxiranytmethyl}
2-thiophaiecarboxamide (1.0 eq.) is added a little at a time to a solution of the primary amine or sadline clei{ivadve (1.5 to 2.5 eq.) in 1,4-dioxane, l,4dioxaawvvater mixtares or ethanol, ethanol/wader tnixtares (about 0.3 to 1.0 molfl). The mixture is stirred for 2 to 6 hours and then concentrated. From the neaction mixture, the product can be isolated by silica gel clu+omato8raphy (cyclohexane/ethyl acetate mixtures, dichl anol mixw:es or dichl(xomethanNmethanol/triethylamine mixtUMs).
=, , The following compounds wem prepa+ed in an analogous manner:
UNWk 22 N-[3-(iansylamino)-2~bydro:,ypcopYl]-5-chloro-2-t6iop6eoecarbozsndde MS (F.SI): rn/z (%) = 325 (M+H,100);
HPLC (method 1): rt (96) = 3.87 min (97.9).
Examnle 23 5-Chloro-N-[3~(3~cyaneadl~o)=7r-ltydroxyi~p7-!]'?rthiop~an~ecacboxanadtk MS (ESI): m/z (96) = 336 (M+H, 100);
HP'LC (tnethod 2): rt (96) = 4.04 min (100).
Le A 3412'l-Fot+eiaM Coimtries ~ = -77-E=ml):LBa4 5-Cl~oro-N-[3-(4-cysu~oeoUiav}2-hrileoxypropyq-Z=thieP6m~arbo~a=ide MS (FS1): m/z (96) ~ 336 (M+H,100);
HPLC (method 1): rt (96) = 4.12 min (100).
Emumb 25 s-cbaoro-N-{3-[4-(cyanometly-1)asgno]-2-hyarwq-prapyl}-2-t61op MS (ESI): m/z (96) = 350 (M+H,100);
H'LC (mcthod 4): rt ( ~) = 3.60 inin (95.4).
S-Chloro-N-{3-[3-(cyswomethyl)noilino}.2-bydroxppropyl}-2-thMphenecarboacamide MS (ESI): mlz (96) = 350 (M+H,100);
HPLC (method 4): rt(96) = 3.76 min (94.2).
Ex =-@k 58 tart-Butyl 4-[(3-{[(5-chloro-2-thtmyl)carbonyllamino}-2-hydroxypropyl)sminol-benzylcarbent~ate starting from tert-butyl (Bioorg. Med. Chem. Len.; 1997;
1921-1926):
MS (FS-pos): m/z (%) = 440 (M+4L 100), (ES-neg): m/z (96) = 438 (M H.100);
HPLC (mcchod 1): rt (96) = 4.08 (100).
. ,.....
Fxumnie S9 tant lintit 4[(3-([(5-c61oro-?r46imylkarbonyl]eadno}-2-hydroxypropyt)eminol-starting from N-tert-twtyloxycarbonyl-1,4phenylenediamine:
MS (ESI): m!z (96) = 426 (M+H. 45).370 (100);
Le A 34 M;Fonzisn Coemties H'PLC (method 1): rt (96) = 4.06 (100).
ymmko tat-Bntyl 2-bydn"-34[442-ozo-l-Pl'n*WiD71)PbaYlAmdw}PinPYi-earb-smate stating from 1-(4-aminophenyt)-2-pyctolidinono (lustus Liebigs Ann. Chem.;
1955;
5% 204):
MS (DCI, NH3): mPz (%) = 350 (M+H,100);
FlP'LC (medW 1): rt (96) = 3.57 (97).
5-Cbbco-N-(3-{[3-tluuro-4-(3-om)Amorpholiayt)phdayl]nndno)-Z-hydrosypro-P7l)-2-thiopbeneemboa=ide 800 mg (3.8 auaol) of 4(4-amino-2-fluorophenyl)-3-mozpholinone and 700 mg (3.22 aunol) of 5-chlav-N{2-oxiran*wthyi)-2-thiaplaunecarboxamide in 15 ail of ethanol and 1 ml of watar ai+e heated under nflux for 6 hours. '17o mixture is concentrated under reduced p:mure and troated with ethyl acetate, precipitated crystals are filtered off with suction and the mother liquor is cin n,,wgcephed giving 276 mg (17% of thcory) of the target compound.
Rf (ethyl acetate): 0.25.
LUMQk. 62 (N-C3-AiOiliuo-2-hydroxyp~opy!}S-cbioro-Z- .:...
statting fiom aniline:
MS (DCI, NH3): ndz (96) : 311([M+H]+,100), C'a pattern;
HPLC (mediod 3): rt (96) = 3.79 (100).
Examic 63 5-(hloro-N-(2-6rdroaq--3-1[4-(3-oaw-4-mo )propyt}2-thiophenecarboautmide "
j,g A 34 122 Foi+eigg a tria , -79-stasting irom 4-(4aminophenyl)-3-morpholinane:
MS (ESI): m/z (%) = 410 ([INI+H]+, 50), Cl pattWrn;
IMC (mahod 3): rt (96) = 3.58 (100).
S Fmmmk N434{4-[Aatyl(c3rcloProP7l)~minoJP~YI}~iao}2~hlydca~qpropyl]-S~chiaen-2=thiophmacrboYamlde starting from N{4-aminaQheayl)-N-cyclqropylacetsmide:
MS (F.SI): m!z (%) = 408 ([M+H]+,100), Cl pnuern;
IiP'i.C (method 3): it (%) = 3.77 (100).
.-,-~1~~ .
N-I3-({4-IA~~3~l~~p~Yl}amino}2-hY~7p~1~I~-rblo~-2-t6lophet~carboxamide starting from N-(4-arrtinophenyl)-N-mcihylacetamida:
MS (ESI): mlz (96) = 382 (M+H,100);
BPLC (mathod 4): rt= 3.31 min.
EXNMDIC"
5436bro-N-(2-1#Ydro:y-3-{I4-(iH-i,Z,34riazul-1-7-lkgmypwdm)proP71}~
,-. thiop6eae- srboxaoside starting from 4-(1H 1,2,3-triazol-l-yl)aniline (Bouchet et al.;
J.Chem.Soc.Perkin Trans.2; 1974; 449):
MS (ESI): mVz (%) = 378 (M+H,100);
H'i,C (metbod 4): st = 3.55 min.
,.,,.
tat batyl 1-{4-[(34[(S-c6loro-2-tbimyl)carbonyl]amiao)-2-hydroxppropyl}
amino]ph~ayl}Irprullnae MS (ESI): mm/z (96) = 480 (M+H,100);
HPLC (method 4): it = 3.40 min.
Le A 3}1 ' :QWIB Countries Eumpb 6$
1-{4-[(3-([(5-Cibre-2. )-2o-hldroxypropyQem3noh*e-Qyl}-apip=dleenrboxamiae MS (FSn: m/z (96) = 437 (M+H,100);
I1pLC (method 4): rt = 2.39 min.
fan* 69 1-t4-((3-(E(3-Chiuro-2rt6ienyi)crbonyOmmko}-7.-b7do7Propy1YandmJpbe-nyl}- e MS (ESI): ndz (%) = 437 (M+H, 100);
HPI.C (method 4): rt= 2.43 min.
E+r nk 7Q
5-C61oro-N-(2-6ydroxY 3-{E4-t4-0zo-l-Pjpe<'ldlnyi~heaYl~miao}ProPyr)-2-tl~iop~ouu~de MS (FSI): rnlz (96) = 408 (M+H, 100);
HPLC (nxthod 4): rt= 2.43 min.
fMM* 71 E(s-cldoro-2-thienyl~arbo~yl]smino}?.6ydroxypropyl).minolt~-1-44-[(34 nA-L-prOtinamide MS (ESI): nVz (%) = 423 (M+H, 100);
HI'LC (mahod 4): R= 2.51 n3in.
- . ,.__ .
Examnk 72 ~
5-Chioro-N-[2rhydrozy-3-({4-(3.(hydroxynnthyl)-1-piperidinlrllphenyl)-amino)pcopyl]-2-thiop6eneP-1- rbo3unmide MS (ESI): m/z (%) = 424 (M+H, 100);
HPLC (method 4): rt = 2.43 niin.
l.e A 34õ121-1?oreeIM CggMgiu FnmipbZ3 S-Cbbro-N42r6ydenxy-3-(1441-(hydeom7nnih7i)-1-p*wkVn7U~}-amino)propyl]- e MS (ESI): m!z (96) = 424 (M+H,100);
HPLC (method 4): rt = 2.49 min.
Ezairob 74 Ethyl 1-{4-I(3-{[(5-cbbro-2-tbbn-Yl)arbonyllambo)-24ydroac7prop7l)-emino]Phenyl}-2'PiP~rldln~caii~oxyletc ,.:
MS (ESA: mh (96) = 466 (M+H.100);
HPLC (method 4): rt = 3.02 min.
ARMAN
S-Chbro-N-[?rhydroxy-3-({4[2{hYdroarynn6y)-l.-pyrroMin7UphoW1}hudnO)-prop71]-2-MS (ESI): m/z (96) = 410 (M+H,100);
1P'I.C (method 4): rt = 2.48 niin.
~= 5-ChbraN-(Z-hydroxy-3-{[4(2-meth}-lhhexshYdra-SIi pyrrob[3A-d]kowazot-5-il)pm1l]amiuo}proW)=2-tbWphenecarboxamide MS (ESI): ndz (96) = 437 (M+H,100).
HPLC (method 5): rt = 1.74 min.
S-Chbro-N-(2-hydroary-3-([4(1-pytr)lldinYl)}3-{triAaoromethyl)phea7l]-aaRiino}pr*pYl)-2-tbbp MS (ESI): ni/z (96) = 448 (M+H, 100);
HPLC (tnahod 4): tt = 3.30 nain.
34 122 Fomign Comajia Sd7~loro-N-(Z6~ydroxy~3-{[4.(?~o~au-l-pyrtoUdiny!)-3-(trlfl~a~+o~thyl~ylJ=
wino}propyt}2-thiopbena"rboxaaaide MS (ESI): nVz (96) = 462 (M+H.100);
HPLC (method 4): rt = 3.50 min.
Ezaawk 79 S-Chloro-N-(3-{[3.chloro-4-(3-oxu-4-moi'pholiayl)p-lualllsmim}-2-6ydnxy-propYl}Z-MS (ESI): nm/z (96) = 444 (M+H,100);
HPI.C (method 4): rt = 3.26 min.
EBMRksQ
S-Chioro-N-(2-hydroxy3-{[4(3-ozo-4-morpbolinyl)-3-(~nmetbyl)pbmyl]-aminolp:Opyl)-Z-mbpbmecacboacandde MS (ESI): m!z (96) = 478 (M+H,100);
HPLC (method 4): rt = 3.37 mi1i.
Elll! e 81 5-Cbloro-N{2-hydromq-3-([3.mathyl-4(3-oxo-4.morpbolioyl)pbenyljaoodno}-propyl)-2-t6iophenecsrbw=mide MS (ESI): m/z (%) = 424 (M+H,100);
HPLC (method 4): rt = 2.86 min.
: :,....
Fa3ll~.~c 5-C3lcro-N-(3-([3-ryaao-4(3-oxo-4-ma'p6dlayl)phmyl]aoaino}-2-iq+droxypro-p)'1}2-thloP e MS (ESI): m/z (%) = 435 (M+H,100);
HPLC (metthod 4): rt= 3.10 niin.
La A 341 j%m;,p Coantries FiiinllB~~
5-Cbloro-N-(3-([3-chbro-4-(1-pyrrolldiuyl)pMenybunino)-2-hydcoxyprop3'l)-Z-thlophena:arbos~mide MS (ESI): m/z (qb) = 414 (M+fI,100);
HPLC (method 4): rt = 2.49 min.
Farat~k &1 5-CWoro-N-(3-{[3-cbloro-4-(Z=oaw-l-pyrrolMiinyl)phenyl]smb-o)-2-hydrotypro-pyl)-I- .
MS (ESI): m/z (96) = 428 (M+H,100);
HPILC (method 4): rt = 3.39 min.
3-Chloro-N-(3-([3rS-dimethyl-4-(3-mao-4-morpbolinyl}phmyl)saaiao)-2-bydro-xyprqpyl)-2-thiopheaecsrboxwide MS (ESI): m/z (%) = 438 (M+Ii.100);
HPLC (method 4): rt = 2.84 nrin.
~-- N-(3-{134Amiwcwbonyl}4-(4-mocp6olinypplunyl]omino)-2-Lydre"pr"Yi)-5-chloro-2-thiopbmemboxamide MS (ESI): m/z (%) = 439 (M+H,100);
HP'LC (method 4): rt = 2.32 min.
Exumvk 87 5-Cldoro-N.(2=hydroxy-3-{t3-amoho"-a-(4-a"rpboqnYl)ibmyrl=dm}lmPyl)-2-thiopheaemrboxamide MS (F.SI): m/z (96) = 426 (M+H,100);
HP1rC (metbod 4): rt = 2.32 min.
I.e A 34122-Fonign Countries Exomic 88 N-(3-([3-Aoetyl-4-c4-=orphoRayrndkenY1]amim}-~7drox7Prop7n-s-adoro-Z-thlop6aIFsrboxendde MS (ESI): m/z (96) = 438 (M+H, 100);
HPLC (method 4): rt = 2.46 min.
ExaoMk 89 N-(3-{[3-Amino4-(3-oxo-4-morpbolinyl)pheayljambo}-2-hydroxypropyl}S-dhloro-2.
-MS (F-SI): m/z (96) - 425 (M+H,100);
HPLC (method 4): rt = 2.45 min.
Emuupk90 5-Chlora-N-(3-4 [3-c61ora-4(2-met6yl-3-ozo4-awrpboftyl)pbmyUawhw}-Z-hydroxypropyl}2-thiopheneorboxamide MS (ESI): m!z (%) = 458 (M+H, 100);
HPI.C (method 4): rt = 3.44 min.
Exgaok 91 ,,.. 5-Chloro-N-(3-{ y1-5-oxo-4-nwrphoUnyl)pheny!]amino}-2-hydroxypropyl}2-thlophenearbosamide MS (ESI): ni/z (%) = 458 (M+H.100);
HPL.C (medlod 4): rt= 3.48 min.
- : .
E:anmk 91a 5-G'hsuro-N-[2-hydr'nap=3-({4-[ i)oe3thyUphm74}smiuo)-pmpylJ-2-t6lophenecarboxamkie starting from * 4-(4-amino-benzyl)-3-mwrpholinone (Swrey et a1.; J. Amer.
Chem.
Soc.; 77; 1955; 633):
MS (ESI): m/z (%) = 424 (M+H, 100);
Le A 34122-Fom-0 Cmoics HPLC (method 4): rt = 2.66 mia GmaW md6od foar prspaft 34ub~d S46ioco-N-[(2roioo-I,3~om~olWin-5-yl)methyl]-2- derivatlves starting frnm snbstitoted N-(34wino-2=hydraarypropyl}5-chbro- dtciva>ives R, 0 N , S I cl ~
F( At room Lempenuaxe, cnbodumichzole (1.2 to 1.8 eq.) or a similar phosgene eqtiivalentt are added to a solution of the subatituted N{3-aYaino-2-hydroxypropy!}5..
chloro-2 thiophenecathoxamide derivative (1.0 eq.) in abaolute 'lHff (about 0.1 mol/l). At room Lempaaame or, if apptqoriate, at elevated tempaatm (up to 70 C), the mixtnre is stirred for 2 to 18 h and then conoentratod under reduoad pcossure. The product can be puified by silics gel chrortaatognphy i5 (dich mixtum or cyclohexane/ethyl aRxtate mixtures).
The following eompoueds vve.re pnrparod in an analogous mmusei:
Examnk 27 1V [(3-Beozyl2-oxo-1,3-a:aaolidin-S-yl)mathyq-S-+chloro-2-thiophaxcsrboacamide MS (DCI, NH4): m/z (9b) = 372 (M+Na,100), 351(M+H. 45);
FiPLC (method 1): tt (96) = 4.33 min (100).
~._ Examrile 28 S-Chjoro-N-{[3d'.l-cyanopbenyl)-2-oxo-1,3-oxaaolidtn-S-yllmthyl}-2-thiophenecarboYandde MS (DCI, NIW: m/z (96) = 362 (M+H, 42), 145 (100);
HPLC (method 2): rt (96) = 4.13 min (100).
AH 13 U-qmdjz Sountries L~~Z
S-C6loe+o-N-({3-[4(cyen=mah7l)pLmy1]-?roxo-1,3-ox=lidin-5-yl}methlrl)-2-thiophenecarboacemide MS (ESI): nm/z (96) = 376 (M+H.100);
APLC (method 4): rt = 4.12 min Emawk IV
5dhloro-N-((3-[3-(cl-moawb-yl)p6eayl]-2-oxo-1,3-amamolidin-5-yl)udbyn.2-t6iopheoecarba~mide =
MS (ESI): m/z (98) = 376 (M+H,100);
HPLC (mediod 4): rt = 4.17 min ~ ~Qjl~.s tert-Buty1 4-[5-({[(S-chioro-2-ihkayl)cerbon711mioo}mahyq-?romo-1,3-oa mlidio-3-yl]beuzylcacbamate starting from Example 58:
MS (ESI): m/z (96) = 488 (M+Na, 23),349 (100);
IIPLC (method 1): it (96) = 4.51 (99.5).
r-~
tsrt-Butyl4-[S-({[(S-chloro-2-t6tenyqcarboa-yljsuino}met6yl}.2-oxo-l,34xamoll-din-3.yl]pbneaylcar>amte starting fmm Example 59:
MS (FSl): m/z (%) = 493 (M+Na, 70).452 (M+H,10), 395 (100);
.. . ....
HP'I.C (method 1): tt (9b) = 4.41 (100).
E=mk Aent-Butyl 2-ozo-3-[4-(2-oxo-1-pyrrolidiqyl)plaayl]-1,3-ox=lidiu-5-yl}methyl-cacbsuate staiting from Example 60:
MS (DCT, NH3): adz (96) = 393 (M+Nli4,100);
Le A 341 -Fmcjgn C.amtries I3PLC (medwd 3): it (96) = 3.97 (100).
FacsmQie 95 3'1)P6m711-2-0~-1,3-0~-5-yl)methyl)-2-thiop6m~ocarboxamide F ~
260 mg (0.608 nsmol) of 5-chioco-N-(3-{ [3-fluoro-4-(3-oxo-4-matptwlinyl)phenyl]-amino)-2-hydroxypropyl)-2_thiopheaecacbaxamide (from Example 61), 197 mg (1.22 mmol) of carbonylirnidazole and 7 mg of dimethylaminopyridine in 20 nd of dioxane are boiled mWer reflux for 5 hours. 20 nd of acetonitrile are thc.u added and the mixduz is sdrned in a closed vessel in a microwave oven at 180 C for 30 minutes.
1S The soludon is coneentrated using a rotoy evaporatUor and chionvLographed on an RP-HPLC column. This gives 53 mg (19% of thomy) of the tuget compowd.
NMR (300 1i[Hz ds DMSO): &= 3.6-3.7 (m.4H), 3.85 (dd.1H), 3.95 (m,2H), 4.2 (m,1H), 4.21 (s,2H), 4.85 (m,1H), 4.18 (s,?.li), 7.19 (d,18,thiophene), 7.35 (dd1H), 7.45 (t,1H), 7.55 (dd,lIi), 7.67 (d,llH,thiophCne), 8.95 (t,1H.CONH).
Exumak %
. : : ,.....
5-C61ore-N-[(2oxo-3-plkayl-1,3on~5-yl~nethyl]-~
tbiep starting from Example 62:
MS (ESI): m/z (96) = 359 ([M+Na]'', 71), 337 ([M+H]',100), Cl pattera;
IiFi.C (method 3): rt (96) = 4.39 (100).
ICso: 2 M
I.e A 34 122-Fg,ei,gn ColJlltlaies Famuk 97 S-C61oro-Nd{?~-oa~o-3-[4-(3-0~o-4-morphollanylh+hmylj-l,3-n:azolidin-S-yl}-mWhyl)-2-thiophenecarbo=mide starting from Exanple 63:
MS (gSI): m/z (%) = 458 ([M+Naj;, 66).436 ([M+H]+.100), Cl porn;
HPLC (methad 3): rt (96) = 3.89 (100).
ICA,: 1.4 nM
N-[(3-{4[Acetyl(cydopropyljaodnolpLtayl)-2-oxo-l,3-oxwolldln-S-yl)methyl]-5-ehken-starting from Facmr4tle 64:
MS (ESI): m/z (%) = 456 ([M+Naj+, 55),434 ([M+Hj+,100), Cl pattern;
HI'LC (method 3): it (96) = 4.05 (100).
ICso: 50 nM
EXBmItk N-[C3-[4-[Acql(mdhyl)audmjplmyl}-2-eoro-l3-oxaeolldin-S-yl)met6ylj-S-chloro-2-t6iop MS (ESI): m/z (96) = 408 (M+H, 30),449 (M+H+MeCN, 100);
000. HPLC (rnedod 4): rt = 3.66 min.
Examok 100 S-(;~loro-1W({?ro~[4(lIi-1,?,3-trlszol-i-y!)plusyll-1,3~oiidin-5-yl}- .: ,:
methyl}Z-thiophenecnrboxamide MS (FSI): m/z (%) = 404 (M+H, 45), 445 (M+H+MeCN,100);
I3PI;C (nethod 4): tt = 3.77 min.
Egunvle 101 Twt-butyl 1-{4[S-({[(S.cbbro..2_thienyl)carbo yl]~mbo}a~et6y1}?roxe.l,3-oxazolfdln-3-yl]pheayl}-Lr-prolioat+e T. A 34 1 Zf Fnaigil _nnnW
Nrs (ESi): rarz (~) =450 (M+H-56, 25), 506 (M+H,100):
HiYLC (metlW 4): rt= 5.13 min.
Fianmk 1C
1-{4-[s-a [(s.chbro-a.mimyr)carbonynamiw}mdbyn-z-oxo--1,Uxm=Bft-3-ynp,,lllA}-4-~re~a--rboxn=ae MS (FSn: miz M = 463 (M+H,100r HPLC (nuthod 4): rt = 2.51 niin.
Enuunk 103 r-~
1-{4-I5d{[(5-ChOro-Z-thea71)krbonyllamdw)nmdYl)-?.uo-1,3=oxasoiidin-3-YllPbml'i}-3-PiPerjdjnaerboxaaide MS (ESI): mli (96) = 463 (M+H,100);
H'pLC (mcthod 4): rt = 2.67 min.
Exomak 104 S-Chloro-N-((2-oao-3-[4(4-oaw-l-Pipaidinyl)phenyl]-1,3-oxuolidia-5-pl)met6pl}?4Mop e MS (ESI): mJz ('96) = 434 (M+H, 40), 452 (M+H+H20, 100), 475 (M+H+MeCN, 60);
HPLC (methfld 4): rt = 3.44 ntin.
Exwnde 105 1-{4-[S-({[(S-Chloro-2-tbienyl)arbonyiNwiw}methy!)-2-oze-1,3-oxazolidtn-3- -,: .
3QPbwy1}-L.Piroln=de MS (ESI): rr/z (%) = 449 (M+H.100);
HP'LC (method 4): rt= 3.54 min.
j~ A 341Z2 FgW Counttie.s -90_ E:d-k m 5-C~oro-N-[(3-[4-[3-{Ip'dro~q-met6yl)-1-piperidiny1~ay1}-?romo-l,3-a~o~-din-S-y1*wthylj-2- e MS (ESI): mJz (96) = 450 (M+H,100);
HpLC (method 5): rt = 2.53 mia.
Examele 107 S-cbloro-N [(3-{ 1-piperidiuyl]~)-2-ozo-1,3-oxamoli-din-S-yl)uwMyi}Z-tldopbenecarboacamdde MS (ESI): m!z (96) = 450 (M+H,100);
HpI:C (me,thod 5): rt= 2.32 min.
ramp*
F.tlp-1 1-{4-[S-({[(S~cWoro-?.thi~oyl)carbonyt]~o}mbhyl)-?.-o~ao-l,3-oa~oli-din-3-yl]pleenyl)-2-piperidieasrbuxylate MS (F.SI): m/z (96) = 492 (M+H, 100);
HP LC (nmthod 5): rt = 4.35 min.
&ua ~-. 5-(bioro-N4044-"ydmqnud7-1)'1-pyrrobdinyUPbmyl}-2-ozo-l,3*xmoi-din-S-y1)methyl]-2-t6bp x-mide MS (ESI): m/z (96) = 436 (M+H,100);
HPLC (aiethod 4): rt = 2.98 nsin.
- .~._.
E,~x~l~e 110 S-C6bro-N-({?,-ozo-3-[4(1-pyrroiWbryn-3-( yl}1,3-oz~oli-din-5-yi}metbyl)-2.t<siophmecaclqxanafde MS (F.SI): m/z (%) = 474 (M+H, 100);
HP1.C (method 4): tt = 4.63 min.
A 34122 Fonin C~untnes KumQ#e lil 5.C61oro-N-({3-[ SH 5-yl~ayl]-2-oxo-1,3-aarasolidin-5-yl}met6yl}2-miop MS (ESn: m/z (96) = 463 (M+E,100);
H'LC (method 4): rt= 2.56 niin.
~* in 5-Chloro-N-({2-o:ko-3-[4(Z-oxo-l-pyre+olWinyl)-3-(ttitluonumetLyl)pheftyll-1,3-oauzolidin-5-yl)md6y1)-2-tWoplknccarboxumlde MS (ESI): mh (96) = 488 (M+H,100);
HPLC (method 4): rt= 3.64 min.
E:amole J13 5-Chioiro-Nd(3-[ morpbOftyl)pbenyq-2-oz0-1,3-oaeolldin-5-yl)mdhyl)-2-thiophenecuboxanaide MS (ESn: m/z (%) = 470 (M+H,100);
HpLC (method 4): it = 3.41 min.
EmgglQle 114 ~=, 5-C61oro-N-({2roaco-3-[4-(3-oaoo-4-~rorPholinyl}3-(trt~lnoromethyf)Phen71}-1,3-wmolidln=5-yl)methyl}2-MS (F.SI): nVz (96) = 504 (M+H,100);
1PLC (method 4): rt == 3.55 niin.
,.._.
Ezmnpk 115 5-Chloro-N-({3-[3-methyl-4-(3-oxo-4-morpboftyl)Pbes7'II-?rozo-1,3-o=Lulidin-5-yl}nLethyl).2-thiopbcnecarboxamide MS (ESn: mlz (%) = 450 (M+H, 100);
HPLC (method 4): rt = 3.23 min.
Le A 34 122~Fo~ei go Qgumwea 5-Chloro-N-({3-[3-~'e~-~-C~-~P~~yl)~Y11~~~~idJn-5-yl}methyl}Z.
MS (ESI): m!z (%) = 461(M+H,100);
HPLC (method 4): rt = 3.27 min.
E 1e117 S-Chbc+o-N-({3(3-chbro-4-(1-Py~Minyl)pbenyll-Z-+omo-1,3-oxmoUdid-'S-yl}md]tyl)-2-tbiapbenecarboaovffide MS (ESI): m/z (%) = 440 (M+H,100);
HpI,C (method 4): rt = 3.72 min.
Esaa~k IL8_ 5-(:hWwN-({3-[34daAro-4(2-0mo-l-pyrrolidi*nyl)~3-2-oxzo-l,3-oxamolitUn-5-11}methyl)-?rthiophmecerboxamide MS (FSI): m/z (96) = 454 (M+H, 100);
HPLC (method 4): rt = 3.49 rain.
,-. S43lloro.N-((3-[3,S-dimeth744-(3~Om-4-mocPhdin3'1)Pl~lll-?roaco-1,3~0~-zolidin-S-yl}methyl}Z-MS (ESI): m/z (%) = 464 (M+4L 100);
BP1.C (mdhod 4): rt = 3.39 min.
:_...
Eiample 120 N-({3-P.l4Amjaocmrbonyl}4-(4-morp6olio7fipbenJ41-2-oxo-l,34awzdiain-5.
yl}methyi)-S-cltbro-2-t2jop>~csrboxsniide MS (ESI): mFz (%) = 465 (M+H,100);
HPLC (method 4): rt= 3.07 min.
ja A 34_122-Fameim Can,nries . -93-T1oii~I~E.~1 S-C~-Ia~ o-N-(t3-[3-o~hoaq-4-(4-~a~orpboliuyl)Pl~rl]-2roooo-l,3-oz~olidiu-S-yl}methyl)-Z-tonadde MS (BSI): m/z (96) = 452 (M+H,100);
HpLC (aAdod 4): rt= 2.86 smn.
'Examob N-({3.[3.Acetyl-4(4morpho~nyl~he0yl)-?roio-1,~o~olWin-6-yl}methlrl}S.
chloro-Z-t>dophme=bozuide MS (ESI): m!z (9b) = 464 (M+H,100);
HPLC (method 4): rt = 3.52 min.
Fsamde 123 N.((3-[3-Amino-4-(3-axo-4-morpholnl'1)PbosYl}?roxo-1,3-ox=ulidin-S-yl)-metbyl)-S-c6loro-2, tl-loplrenecarboxamide MS (F-4n: m/z (%) = 451 (M+H, 100);
HpI,C (authod 6): rt = 3.16 niin.
EUMRle 124 ,.- 5-Chloro-N-((3-[3-ebloro-4-(Z-uadhYl-3-oxo-4-morpboiiaryl)pbmyl]=2-0mo-1,3-oxazolidin-5-yl)met6yl)-2-tbiophena~t boacamide MS (ESI): nVz (%) = 484 (M+H, 100);
HPLC (me&od 4): it = 3.59 tain.
.,...
JM=k 125 S-(~bro-N-({3-C3-eibro-4-CL~a~etdyi-3-ouo-4-oaoepbolt~yl)p6~71]-?.ozo-1,3-oxazolidln-&yl}meAyn-2=l5iophemmar6oaomide MS (ESI): m/z (%) = 484 (M+H,100);
HPLC (method 4): rt = 3.63 min.
Le w34122FozianCoMaim = -94-Eamole iZSa S-CWoro-N-[(~~.ozu,3-{4-[f3-ow-4-mmp6o~Yi~y1]pbeqy1}-1,3exsaol8dta-s.yQmewyq-2-MS (ESI): ra/z (96) = 450 (M+H,100):
SpI.C (method 4): rt = 3.25 nin.
Via epoxide opaM with an amine and subsequent cy+ciizatioa to give the ca~nespcmding oxazolidinooe, it was also pomhle to prepare the following compounds:
le No. M.P. snucum [ C] Cso [ M]
126 " .013 -127 F _, o p 159 .0007 0~'!!~'ti.~, ~'~ j..~ 198 .002 ~o 129 Q~~ Q w 196 .001 ~õ~.N ar r-~ 0 o 130 F .0033 ~~ s a 130a o j=.~ . 194 ~''1..,/'- ~ ~[~-p = , ~._...
oY~
131 195 .8S
132 06 .12 I& A 34122-Foneinn QgMdu ample No. uucduae p. ( C] rlm (EtMj 33 o f 17 ).062 134 ~.., F~. .48 1-(4-amino-phenyl)-'pe:idin-3-ol (Tong, L.KJ. et al.;
.Anor.Chem.Soc 1960; 82, 1988).
135 Q 02 L.1 ~' 7~
136 5c 39 1.2 s .~
O
137 f 19 .044 Ff o~o 38 95 .42 139 17 1.7 .y.:. _.
Le A 34 122nFoodgaCanstries Exwnpks 14 to 16 below ane wocking exampka for the opticeai oxidation stap..
LUEgIg 14 5-thloro-N-({(5S)-3-[3-flaoro4l-(1-oaoolilambda14,4-HWdnso4.y1)Pwa3'lJ-2, oxo-1,3-oxazHdin-S-yl)mabyn- e F
Ci HN
At 0 C, 5-chloro-N-({(5S)-3-[3-flwso-4-(1,4-thiazSnan-4-yi)phenylJ-2-oxo-1,3-oxazolidin-5-yl }methyl).2-thiophenacarboxamide (0.1 g, 0.22 mmol) fram Faxample 3 in mc.thanol (0.77 ml) is added to a solution of sodium ptciodate (0.05 g, 0.23 mmol) in water (0.54 rril), and the mixture is stirred at 0 C for 3 h. 1 ml of DMF
is then added, and the mixture is stirred at RT for 8 h. After addition of a further 50 mg of sodium pesiodate, the mixtum is once more stirred at RT overnight.
The niixture is then admixed with 50 ml of watar, and the insoluble product is filtered off with saction. Washing with water and drying gives 60 mg (5896 of theory) of crystals.
M.p.: 257 C;
Rt (silica gel, toluenelethyl acxtaoe 1:1) = 0.54 (starting matecial = 0.46);
ICso value =1.1 M;
MS (DCI) 489 (M+NHA), Cl pauern.
. , ~ A 34 l22 Foneign Coun'es = -97-Pe+epasatiioa af Sc6lsro-N-({(8,S).3{4-(1,1-diozo-1[Lmbda]s,4thkr3nan-4yi),3-fluot,uplmiyl]-2.-oaoo-1,3-oacaxolidin-5-yl)moNtyl)-2-mlop F
O
N p . ~. .
5-Chloro-N ({(5S)-3-[3-fluoro-4-(1,4-thiazin=-4y1Mmy1]-2-oxo-1,3-oxazolidin-yl}methyl}2-thioghenecarboxamide frmm Example 3(0.1 g, 0.22 mmol) in 332 mi of a mixture of 1 part of water and 3 patts of aoetone is adniixed with 80 mg (0.66 mmol) of N methylmorpholine N-oxide (NMO) and 0.1 ml of a 2.5% strength solution of osmium tatroxide in 2-methyl-2-pTopanol. The mixtute is stirred at room temperature overnight, and another 40 mg of NMO are added. The mixture is stinvd for a finther night and then potn+ed into 50 ml of water and exttacted tM+ee times with ethyl acetate. The organic phase gives, after drying and concentrating, 23 mg and the aqueous phase, after removal of the insoluble solid by filtration with suction, 19 mg (in tota13996 of thecxy) of the target compound.
M.p.: 238 C;
ltt (tolueneJethyl ac:etate 1:1) = 0.14 (starting matelial ffi 0.46);
ICso vaiue = 210 nM;
MS (DCI): 505 (M+NH4), Cl pauein-. .. ~ ,.._.
ExapPk16 S-Chlviro-N={[(SS)- Unoplenyl}2-oxo-1,3-ozuoUdin-S-yl]methyl}-2-thiophe~rboxanodde N-oxde is obtained by tc+eating 5-chloro-N {[(SS)-3-(3-fluoTO-4-morpholinophenyl}2-oxo-1,3-oxaZolidin-5-yllmethyl }-2-thiopl'renecarboxamide from F.xample 1 with the magnesium salt of monopemxyphthalic acid MS (ESI): 456 (M+H, 21%, C) pattern), 439 (10096).
Le A 341 ,Z-Zgoian Count:ies = -98-The Exampks 31 to 35 and 140 to 147 below refer to the optional smidinetion step.
General nwdiod for preparing addfines and amidlne derivsdves starti,ttg hom cyanomothyWhmy!-Bnbstlbioed S~laro-N-[(2-aso-l,3oe,solidio-5-yl)memyl}-2-thlophenaarboxsmide deti vatives The cyanomethylphenyl-subRtituted 5-chloro-N [(2-oxo-1,3-oxazzolidm- 5-yi)naethylj-2-thiophenecarboxamide derivative in question (1.0 eq.) is, together with triethylamine (8.0 eq.), stirred at RT in a sattuated solution of hydnogan sulphide in pyridine (about 0.05 - 0.1 mol/l) for one to two days. The reaction mixtune is diluted with ethyl acetate (EtOAc) and washed with 2 N hydrochloiic acid. The organic phase is dried with MgSOa, filtered and eoncentrate,d under reduced pressure.
The crude product is dissolved in acxtone (0.01-0.1 mol/l) and admixed with methyl iodide (40 eq.). The reaction mixture is stirne:d at room temperature (RT) for 2 to 5 h and then concentrated under reduced psessiue.
The residue is dissolved in inethanol (0.01-0.1 mo)/1) and, to prepu+e the unsttbstitnted amidines, admixed with anunanium acetate (3 eq.) and arnrnoniom chloride (2 eq.). To lx+epare the substituted nmidine derivatives, primary or secondary amines (1.5 eq.) and acetic acid (2 eq.) are added to the methanolic solution.
After 5-h, the solvent is removed under reduced pressure and the residue is purified by ,-- chramatography over an RP8 silica gel column (wat,er/aeetonitrile 911-1/1 + 0.1%
25 trifluoroecxtic acid).
The following compounrda were prepared in an analogous rmmner:
-~--Examnle 31:
N-({3-[4-(2-Amino-Z-iminoethyl)p6enylJ-2-oxo-1,3-oxswlidin-5-yl }metbyl)-S-chloro- 2-thiophenearboxamide MS (ESI): ns/z (96) = 393 (M+H, 100);
I3PLC (method 4): rt = 2.63 min ~CA 34 1Z2-EOWs'1 CoW1t[In irUS* 32., 5-A~loro-N-{{3.[3.(4y.S.dilrydro-iH-bdd.ml-Zryi~etryl~rl)=2-o~ou-1,3-o:azo4din-5-yi}methyl}2-dtiop6mecarboxamide MS (ESA: m/z (96) = 419 (M+H.100);
HIPLC (method 4): rt= 2.61 aun Exaiannle 33:
5-Cbloro-N-[(3-(3-[Z-inino-Z-(4-narphoftyl)etbyllp6enyl}-2-oxo-l,-~oti-din-S-yl)tnethyl]-2, MS (ESI): mlz (%) = 463 (1VI+1L 100);
H'P'LC (method 4): rt = 2.70 min E34:
S-(~cv-N-Lp-;3-CL-fm~o-2-(1-P1rrolldin7lktLyl]phenyl}-?-oxo-l,3-oxaso8-dSn-S-yl)mdhyn-Z-t6lophenearboxamlde MS (ESI): m/z (96) = 447 (M+H, 100);
F;P'X (metlwd 4): rt = 2.82 min Examph 35:
N-({3-[3dZ -A-mino-?+4minoatbyl)P6anyll ?-oae)--1,3-oxamolidLa-S-yl}met6yq-5-ehloro-2-t61ophenecarbox,amide MS (ESI): m/z (%) = 393 (M+H,100);
HPLC (method 4): rt= 2.60 min . .....
Eacar140 S-(hLoro-N-({3-[4-(4,5-di6ydro-1H=imidezol-2-ylam*yl)phmyp-2-oaco-1,3-oxa-zoGdln-S-yl}mdhyl}-2-thiop6anecarboxamide MS (ESI): mfz (%) = 419 (IvI+H, 100);
HPLC (med xied 4): ct = 2.65 min Le,& 34 122-Fbrain QURWU
Eza~k 141 5-(biono-N-E(344-[Z-~-Z-( }-Z~oaoo-l,3-oa~mol[=
din-S-TDmethyi]' S MS (ESI): rnla (96) = 463 (M+H,100);
H?LC (method 4): rt= 2.65 min IMOok 142 5-Ch=+o-N-{(3-{4[2-in*w-2-(1-pipm"ayl)d6y]UPbmyl)-2-oaro-l,3-oxmHdin-S.yl)methyl]-2- e MS (ESI): m/z (96) ~ 461(M+H,100);
HpLC (method 4): it = 2.83 min 1s gum* 143 5-CLlaro-N-[(3-(4-[?4miao-?+-(1-pyrnN&n)l)dmyl]P6eM1} -?.-o3w1.3-ozmoli-din-5-yl)methll]-?4biophe,nenrbozmmide MS {ESI): m!z (%) = 447 (M+H,100);
Hp'LC (method 4): rt = 2.76 min E~~k: 144 ~-. 54MIWO-N-[(3-{'I-[2-(cyckPontYbmdm)-2-indnoetbyl]pbenyl)-2-oaw-l,3-oxazo-lldin-S-yI*ethylj-2-*iopbenecarboxudde MS (F.SI): m/z (%) = 461(M+4L 100);
HPLC (method 4): rt= 2.89 min Fine*.?.~'~..
543doro-N-([3-04 2-led~o-Z-[4Z~~71)~kmyl)P~nyi)-2-o 0-1,3-oac~~oolklin-6-yl]methyl}-Ms (ESI): m/z (96) = 475 (M+H,100);
ffi'LC (method 4): rt = 2.79 min L& A 34 122:FQLTI.s! Sc4111itries Fmple146 N-({3-[4-(2-Anilino-2-lminodbpl)phenyl]-2-oxo-1,3-o==lldin-5-1l)=S3-1)-S-chloro-Z-MS (FSI): rnlz (96) = 469 (M+H,100);
H'PLC (metbod 4): rt = 2.83 min Exampk 147 S-Chbro-N-[(3-{4[2-Wmino-2-(2-pyridinyhuaino)dhyl]phml}-?.-0m0-1,3-ooe-zollalin-5-yl)snetayf]-2-thiopbmtorboztmide MS (ESI): m/z (%) = 470 (M+H, 100);
HPLC (method 4): rt = 2.84 min Examptes 148 to 151 below refer to the nernoval of BOC amino protoctive groups:
Genaal method for removing Boc protect[ve groups (tart-butyloxycarbonyl)=
R-H lok --"' R-NH2 N
Aqueous trifluoroacedc acid (TFA, about 90%) is added dropwisz to an ice-cooled solution of a tert-butyloxycarbonyl-(Boc) protected compound .in chloroform or dichloromethane (about 0.1 to 0.3 mol/1). After about 15 min, ice-cooling is temoved and the mixture is stirred at roorn temperature for appc+nxinuuely 2-3 h, and the solution is then concentrated and dried under high vacuuni. The residue is taken up in dichlonomethane or dichloromethaneJmethanol and washed with sauuated sodiuw bicarbonate or iN sodium hydmroxide solution. The organic phase is, washed witfw--sanusted sodium chloride solution, drfed over a little magnesium sulphate and concentrated. If appropriate, purification is carried out by crystallization from et'her or ether/dichloromethane mixtuns.
The following compounds were prepared in an analogous manner from the cornesponding Boc-pnot,acted precursora:
LtA3412e?:F4tttl11 C.,a~ntries Exas~ i~ 148 N-((3-[4-(AnsbomemYl)phenyl]-7-0SC0-3-oocaaolidin-S-yl}metb7l)4-cislw*-2-tLiapheme-carboxamide starting from Eaunple 92:
MS (ESI): m/z (%) = 349 (M NI6 25), 305 (100);
RPI.C (method 1): rt (96) = 3.68 (98).
ICio: 2.2 M
$~gple, 149 N-{C3-(4-AndnOpbm71)-2-oxo-1,3-oxsxOlldin-3-yi]melhyl}-S-cbloro-2-tl~opbenocarbozs~ide staroing fromEx"le 93:
MS (ESI): m/z (%) = 352 (M+H, 25);
HP'i,C (method 1): rt (96) = 3.50 (100).
IC--~: 2 M
An alternstive auaMiomtricallY pare syntthesis of this coznpound is shown in the scheme below (cf. also Delalande S.A., DE 2836305,1979; Chem.Abstr. 90, 186926):
1. BuU
2. lyddyl butyra~ O
~ ' 1/~ OH
O NH4C"%O
1.) phtlWftds, DEADPPl+, 2.) NH,NFL,.H=O ln s~henol ' + H
3.) 5-chloro-2 O S
acid. EDC.IFiOgT
Zn44CL- HN / H
S
Le A 34122-PoWQn Countries = 103 -~
5-(;6loro1V-({3-[4-(a1ye7bnkO)pbnnyil-2-oxo-l,3-oxaeolidin-5-yl}nwbyl}2-thiopbenecarboxsuaide starting ffom Example 152:
MS (ES-pos): m!z (%) = 408 (100);
HPLC (method 3): rt (%) = 3.56 (97).
ICw 2 M
Eunwh1'S1 5-(Aniaomethyl)-3-j4-(2-ozo-l-pyrroldiq,i'1)plhaU'1]-1A-oxaaolidfw2-oae staRing from Exampk 60:
MS (FSO: m/z (%) = 276 (M+H,100);
HPLC (method 3): rt (%) = 2.99 (100).
IC50: 2 M
The Examples 152 to 166 below refer to the amino group derivatization of aniline- or benzylamine-substituted oxazolidiaones using various reagents:
Exa 5-Chloro-N-((3-[4-(N-,tsrt-butybxyearbonyl-glycylamino)pbenyl]-2-ouo-1,3-,.. oxazolidin-5-yl)nmthyl).2-thliophenecarboxamtde 10~
4j,,YO-,Cr - ~ ,......
O p At 0 C, 754 mg (2.1 mmol) of 1V {[3-(4-aminophenyi).2-oxo-1,3-oxazolidin-5-yljmethyl)-5-chloro-2-thiophenecarboxamide (from Example 149) are added to a solution of 751 mg (4.3 mmol) of Boc-glycine. 870 mg (6.4 mmol) of HOBT
(1-hydroxy-IH-benzotriazole x H20), 1790 mg (4.7 mmol) of HBTU
[O-(benzotriazol-l-yi)-N,N,N',N' tetramethyluronium hexafluorophosphaLe] and 1.41 inl (12.9 mmol) of N-methylmorpholine in 15 ml of DMF/CH2C12 (1:1). The LeA 341 Fccet,gn Canttrkn mixture is stirned at roam temperatune overnight and then diluted with waa.
The precipitated solid is filtered off and dried. Y'zeld: 894 mg (79.7% of theory);
MS (DCI, NH3): mlz (96) = 526 (M+1VH4,100);
HPI.rC (method 3): it (%) o 4.17 (97).
JMMRb153 N-[C3-{4-I(A+c,elybmbo)metby1)Phenyl}-Z-ooo-l4-m~ia-S-yl)methyi}S-cbloro-Z-thiop }t~ S
O
O
At 0 C, a mixture of 30 mg (0.082 mmol) of N-({3-[4-(aminomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}snethyl)-5-chloro-2-thiophene-cacboxamide (from Example 148) in 1.5 ml of absolute THF and 1.0 ml of absolute clichloramethane, and 0.02 ml of absolute pyridine is mixed with acetic anhydride (0.015 m), 0.164 mmol). The mixtim is stirned at rootn tempcratuee overnight. Addition of ethex and crystaUization affords the product. Yield: 30 mg (87% of thomy), MS (ESI): m/z (%) = 408 (M+I3,18), 305 (85);
HPLC (method 1): rt (4b) = 3-78 (97).
ICW 0.6 M
Esunole 154 1V {C3-(4-{[(AmWoau'bonyl)eaa~oltne<6y1}Pl~nyl}?rozo-l,3-oarmlidin-5-yl}
methyl).29-cbloro-2-tLiop61 ecsirboxsmide O~
o '1( Le A 34122-Foeeion ComRWe At room tempaaaue, 0.19 mi (0.82 mmol) of uimxdiylsilylisocyanoe we added dropwise to a mixtm of 30 mg (0.082 mmol) of N-({ 3-[4(aminomethyi)pheayl}-2-oxo-l,3-oxazolidin-5-yl jsietbyl)-5-chloro-2-thiophene-cwboxamide (from Example 148) in 1.0 ml of dichloromedme. The mixture is stimed ovemight and, after addition of ether, the product is then obtained by filtnadon. Yie1d: 21.1 mg (52% of dleory).
MS (SSI): tdz (96) = 449 (M+H, 5), 305 (12);
HP'LC (method 1): rt (~b) = 3.67 (83).
ICso:1.3 EcM
Gea" memod for ae,yhtlog N-{[3-(4-oobnop6enyl}2-oxo-lA-o==iidio-5-yqmethyl}4-cbloro- with csrbonyl chbridkm ---~ s Under argon, an approximately 0.1 motar solution of N-{ [3-(4-anrinqphenyl)-2-oxo-1,3-oxaaolidin-5-yl)methyl)-5-chloso-2 thiopiKnecaftxamide (from Example 149) (1.0 eq.) in absolute dichlot cdanelpytidine (19:1) is added dropwise to the appropriate acid chloride (2.5 eq.). The mixture is stirnd overnight and then admixed with about 5 eq. of PS trisamine (Argonaat Technologies) and 2 nil of absolute dichloronnethane. The mixture is stined gently for 1 h and then fihered off, and the filtrate is concentrated. If appropniate, the paeducts m purifiod by prcparadve RP
KPLC. : ~...
The following compounds were prepared in an analogous nwmer.
Fjosumale HMS
N-({3.j4.(AatyLimino)piayt}2-oxo-1,3-oxozoBtin-5-yl)metbyI}.S.chloro-2-tWbphme-csrboxamdde I.C-MS: mJz (96) - 394 (M+I;, 100);
I t A 34 122-Fnned:n C_ es LC-MS (metirod 6): it (96) = 3.23 (100).
ICso= 1.2 M
F_" Mf 5-Chloro-N-[(2-oaro-3-{4[(2-thiesykacbonyl)uainolpbonyl}-1,3-o~io-.~',-y1*eltyU-2-LC-MS: m/z (96) a 462 (M+H,100);
LC-MS (matwd 6): it (96) = 3.87 (100).
ICso: 1.3 M
Finnimb 157 SACWbro-N-[(3-{4I(amt6ozyacetyl*mioo]p6my1}-?rozo-l,3-ozmol[din S-yA-methyQ-2-t6iop6awcarboacsmide LC-MS: mh (%) = 424 (M+H,100);
LC-MS (method 6): rt (qb) = 3.39 (100).
ICyo: 0.73 pM
Examlk 158 N-{4-[S-({[(S-Chbro-2 t6ionyl)carboayl]am:iTMw}methyl)-2-oxo-l,3-oxamuliiin-3-y0pbany1}-3 e LC-MS: m/z (96) = 475 (M+H, 100).
ICso: 0.46 M
~~-S-Chloro,~V-{C3-(~[(3-cLloropropyq~onyl~a~ioo}pl,myi)-2~'xo-I,3-ozazolidln-S-yl]tnwthyl}-Z-thlophmecsirboxamide )"O 4,r 1N ~, ~ O
~ ~
q LeA3dllZFae+ei~n~
An ice-cooled solution of 26.4 mg (0.15 mmol) of 3-chloro-l-ptaQ~ulphaz-yl chlonide and 0.03 ml (0.2 mmol) of ttiethylamine in 3.5 ml of absolute dichloro-methane is admixed with 35 mg (0.1 mmol) of N-{ [3-(4aminopfienyl)-2-oxo-l,3-oxazolidin 5-yl]-metbyl } S-ch~2-thiophene-carboxamide (from Example 149).
After 30 min, ice-cooling is removed and the niixture is stirred at room temperatun oveaz-ight, and 150 mg (about 5S eq.) of PS-trisamine (Argonaut Technologies) and 0.5 ml of dichloromethane aoe den addod. T9x wapension is sdnred Scntly for 2 h and filtered (the resin is washed with dichloromethanehaethanol),/ad the filtrate is concentrated The product is purified by pizpmadve RP-ilWW. Yield: 19.6 mg (40%
of theory).
LC-M5: m/2 (96) = 492 (M+H,100);
LC-MS (method 5): it (%) = 3.82 (91).
IC$O: 1.7 M
$am* 1_6A
5-C61oro-N-((3.[4{1,1-dbxido-2-lsothi oUdinyl)phmyl]-2-ooou-l,3-oxa,sol4idio-5-yl}metbyl)-2-thiophenecarboxamiide -~ O,s C1 fS~
~ O
A mixtm+e of 13.5 mg (0.027 mmol) of 5=chloro-N-{ [3-(4-{ [(3-chloropropyl)sul-phcmyl]amino}phenyl).2-0xo-1,3-oxazolidin-5-yllmethyl }-2-thiophaae-carboxamide (from Example 159) and 7.6 mg (0.055 mmol) of potassium csrbonsoe in 0.2 ml of DMF is heated at 100 C for 2 h. After cooling, the mixtum is diluted witb, ..
dichloromethane and waahed with water. The organic phase is dried and concentrated. 7he residue is purified by preparative thin-layer chromatography (silica gel, dichlcx+onothaneJmethomol, 95:5). Yield: 1.8 mg (14.4% of thoory), MS (ESI): m/z (%) = 456 (M+Ii,15), 412 (100);
LC MS (rruthod 4): rt (96) = 3.81(90).
ICSO: 0.14 M
jA A 34122-Forei CcWrries B,na~~1 S-Oioro-N-[((SS)a-{4I(S{hlot'pPmtaaayi)awJnolPb=yl}-2-oxo-l,3Ouaxog-din-5-yl)saet6yl]-2-thiopheneoarboxamide S
ct- CI
0.5 g (1.29 mmol) of N-{[(5S)-3-(4-aminaomyl).2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-24iopmacazboxamide (from Example 149) is dissolved in 27 ml of tstaahydrofia'a~i and admixed with 0.2 g (1.29 aunol) of 5-chlorovaleryl chloride and 0395 ml (2.83 mmol) of triethylamine. The niixture is concentrated under reduced pressure and cM+omatogtaphed over silica gel using a toloeae%thyl acetate=l:1-> ethyl aeetate gradient. This gives 315 mg (52% of theory) of a solid.
M.p.: 211 C.
Exgnwk 162 S-C'hlora-N-({(5S).2-oxo-3-[4.(2-oxo-l-pipee3dinyr~}-1,3-ozanUidin-S-y!}-methyl}.2-thiophmeatrlwxaadde O
C,N
S p Under inert conditions, 5 nil of DMSO are admixed with 30 mg of NaH (60% in paraffin oil), and the mixture is heated at 75 C for 30 min, untii the evolution of gas has ceased. A solution of 290 mg (0.617 nnmol) of 5-chloro-N-[((SS)-3-{4-[(5-chloropentanoyl)amino)phenyl )-2-oxo-1,3-oxazolidin-5-ylrnethy13-2-thiophau-carboxamide (from Example 161) in 5 ml of rntthylene chloride is then added dropwise, and the mixture is stirnd at roozn tennperaume ovemight. The reaction is terminated and the mixtare is poured into 100 ml of water and extated with ethyl Le A 34122-Fatelan Cmmain = .-109-satste. The evapmted ocgnic Pha.qe is - -o~na~ogophed on an RP-8 ooluam and the product is eluted with acdtanitrikJwater. This gives 20 mg (7.5% of theory) of the target compamd.
M.p.: 20S C;
NMR (300 MHz do-DMSO): b= 1.85 (m,4H), 235 (m,2H), 3.5$ (m,4H), 3.85 (m,1H), 4.2 (t,1H), 4.82 (m,1H), 7.18 (d,1H,thiophene), 7.26 (d,?.Il), 7.5 (d,2H), 2.68 (d,1H,thiophene), 9.0 (t,1H,CONH).
ICw- 2.8 nM
&BEft 163 S-C6bro-N-[((SS)4-{4-[C3-bromopopioa7l)saaina]p6eapl)-2-oaoo-1,3wnxoN-din=5-yl)wd7U-Y(S
is obtained in an analogous manner from Example 149.
Eguwle 164 S-Chbro-N-({(SS)-2-oxo-3-[4-(2romo-l-axdidiayt)pheay[}1,3-oxuWdio-5-yt)-methql)-2-tidophenwar6oarunide is obtained in an oaaalogpx mwm by cyclization of the opea-chein btamopropionyl compasnd from Example 163 using Na11/DMSO.
MS (ESI): m/z (%) = 406 ([M+HJ'.100), Cl p ttern.
ICso: 380 nM
IA A 34122-&g Counuies AUMRk 165 tat-Butyl 4-{4-[S-({ [(S-c6loro-2-thkoyl)carbonyl]amino}me"}2-oxo-l,3-oxs-zolidin-3-yf jphenyl}-3,S-dloxo-l-paperazinecarboxylate O
A solution of 199 mg (0.85 mmol) of Boc-iminodiacxtic acid, 300 mg (2.2 mmol) of HOBT, 0.66 ml (6 mmol) of N-methylmorpholine and 647 mg (1.7 mmol) of HBTU
is admixed with 300 mg (0.85 mmol) of N-{[3-(4-anninophenyl)-2-oxo-1,3-oxazolidin-5-yl]-methyl }-5-chloro-2-thiophene-carboxanzide in 6 ml of a mixture of DMF and dichloromethane (1:1). The nzixture is stined overnight, diluted with dichloromethme and then washed with water, satuiatzd ammonium chloride solution, saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The organic phase is dried over magnr,sium sulphate and concentrated. The crude product is purified by silica gel chrotnatogrraphy (dichlosomethane/methanol 98:2). Yield: 134 mg (29% of theory);
MS (ESI): m/z (%) = 571(M+Na, 82), 493 (100);
HPLC (method 3): rt (9b) = 4.39 (90).
ICW 2 kM
Examok 166 N-[((5S)-3-{4-[(3R)-3-Amina-7..oxal-Pyrn&Unyl]Pbm7l}-2-oxo-YA.oaaaolidio-5-yl)cnathylI-S-chioro-24biopheaecarboxstmide tritluoroaataft BOCNH COOH
+ HOBT
'~f S CI EDC, DIEA
~~a 30725=107 (S) H3C'C O~ O O O
1V N p ~ Me3S1, K2CO3 CI
O
'-CH3 TFA
BOCNH N ~ N N
S CI
O
O O
_O
_~N
N~N ~ 1 CI
O
N2-(tert-Butoxycarbonyl)-NI-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}
methyl)-2-oxo-1,3-oxazolidin-3-yl)phenyl}-D-methionineamide 429 mg (1.72 mmol) of N-BOC-D-methionine, 605 mg (1.72 mmol) of N-{[(5S)-3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl }-5-chloro-2-thiophenecarbox-amide, and 527 ma (3.44 mmol) of HOBT hydrate are dissolved in 35 ml of DMF
and admixed with 660 mg (3.441 mmol) of EDCI hydrochloride and then dropwise with 689 rng (5.334 mmol) of N-ethyl-diisopropylamine. The mixture is stirred at room temperature for two days. The resulting suspension is filtered off with suction and the residue is washed with DMF. The combined filtrates are admixed with a little silica gel, concentrated under reduced pressure and chromatographed over silica gel using a toluene -> T10EA7 gradient. This gives 170 mg (17% of theory) of the target compound of melting point 183 C. (T10EA7 means toluene to ethyl acetate =
ratio 10 to 7.) Rf (SiOZ, toluene/ethyl acetate=l:1):0.2.
'H-NMR (300 MHz, d6-DMSO): 8=1.4 (s,IH,BOC), 1.88-1.95 (m,2H), 2.08 (s,3H,SMe), 2.4-2.5 (m,2H, partially obscurbed by DMSO), 3.6 (m,2H), 3.8 (m,1H), 4.15 (m,2H), 4.8 (m,1H), 7.2 (1H, thiophene), 7.42 (d, part of an AB system, 2H), 7.6 (d, part of an AB system, 2H), 7.7 (d, IH, thiophene), 8.95 (t,1H, CH2NHCO), 9.93 (bs,1H,NH).
l.e A 34122-Favigg Countria tert Butl-1 (3R)-I-{4-[(S3)-S-({[(Schloro-2-thimyl)'arbonyl]ssnino}methyi}2-oxo-1,3-ozs=Udin-3-yljpbenyl}-2-oxo-3-pyrroiidlnyMs#rboniate 170 mg (0.292 mmol) of N2-(tert-butox)carbonyl)-Nl-{4[(SS)-5-(([(5-chloro-2-thienyl)arbonyl]amino}methyl)-2-oxa-1,3-oxazolidin-3-yl]phenyl}-D-methioirine-amide are dissolved in 2 ml of DMSO and admixed with 178.5 mg (0.875 mmal) of tsimethylsulphonium iodide and 60.4 mg (0.437 nmmol) of potsssium carbonate, and the mixtune is stirned at 80 C for 3.5 hours. The mixture is then concentrated under high vacuum and the naaidue is waahed with ethanoL 99 mg of the target compound 10, nmain.
'H-NMR (300 MHz do-DMSO): a=1.4 (s,1H.BOC), 1.88-2.05 (m,IH), 2.3-2.4 (nn,1H), 3.7-3.8 (m,3H), 3.8-3.9 (m,1H), 4.1-4.25 (m,1H), 4.25-4.45 (m,1H), 4.75-4.95 (m,lIi), 7.15 (1FI, thiooheee), 7.25 (d,110, 7.52 (d, part of an AB
systoa, 2H), 7.65 (d, part of an AB system, 2Fi), 7.65 (d,1H, thiophene), 9.0 (broad s,1H).
N-[((55)-3-{4-[(3R)-3-Amino-Z-ozo-l-pprrolidinyl]phenyl}-2-oxo-l,3-oxnolidin-5-Ylhnethyll-5-chloco-2-tldop>kaec.rbonmlde tzith.oroaoetate 97 mg (0.181 mmol) of tert-butyl (3R)-1-(4-[(5S)-5-{([(5-chloro-2-thienyl)carbonyljamino?methyl)-2-oxo-1,3-oxazolidin-3-yllphenyl }-2-oxo-3-pyrroli-dinylcarbatnato are suspended in 4 ml of methylene chloride, 1.5 ml of trifluotoacedc acid are added and the mixture is stirred at roorn temperature for 1 hour. The niixture is then concentrated under reduced pressure and the residue is pmified on an RP-HPLC (scctomtrileJwater10.1% TFA gradient). Evaporation of the appropriate fraction gives 29 mg (37% of theory) of the target compound of melting point (decomp.).
Rf (SiO20EtOH/LEA=17:1) 0.19.
'H-NMR (300 MHz da DMSO): 8=1.92-2.2 (m,1H), 2.4-2.55 (m,1H, pArtiallyobscured by DMSO peak), 3.55-3.65 (m,2H), 3.75-3.95 (m,314), 4.1-4.3 (m.ZH), 4.75-4.9 (m,1H), 7.2 (1H, thiophene), 7.58 (d, part of an AB system, 2H), 7.7 (d, part of an AB system, 2H), 7.68 (d, IH, thiophene), 8.4 (broad 011. NH3), 8.9 (t,1H,NHCO).
Le A 34 122-Foneien Coantrie.s ' 113 -The Examples 167 to 170 below refer to the introduction of sutphonamide gwups in phenyl-substimd oxazolidinone.s:
Generai method for preparbng sebatituted snlphommtides startlng from S-chloro-N-[(?roxo 3-pbmyl-1,3-oacs=)ltdin-S-ylhmetbyll-2-tbiop6m~aearboxao~de C
4 q_, p R' __..r.. R'SN- C
Under argon and at 5 C, 5-chloro-N-[(2-oxo-3-phenyl-1,3-oxazolidin-5-yl)methyl)-2-thiophenecarboxamide (from Example 96) is added to chlomsulphonic acid (12 eq.).
The reaction niixtiue is stined at room temperature for 2 h and then poured into ice-water. The resulting psecipitate is filtered off, washed with water and dried.
Under argan and at room temperawre, the pnx.~ipitate is then dissolved in tetrahydivfuran (0.1 nzoUl) and admixed with the appropriate amine (3 eq.), triethylamine (1.1 eq.) and dimethylaminopyridine (0.1 eq.). The reaction niixture is sdmed for 1-2 h and thea concentrated under reduced pressure. The desired product is purified by flash chronutography (dichlorornethanehnethanol mixturts)...
The following compounds were prepared in an analogous manner.
Exataole 167 5-Chloro-N-({2-oxo-3-[4-(1-pyrevMnybulphonyt)plmyq-1,3-oaramlidin-S-yl}-methyi)-2-thbphenecarboxam3de MS (ESI): nVz (96) = 492 ((M+Na]+,100), 470 ([N+i+H]', 68), Cl pattern;
Le A 34122-Foreia Camtries HPLC (method 3): tt (96) = 4.34 (100).
ICW. 0.5 M
&amok 168 SdCblaro-N-[(3-{4-[(4-met6yl-l-piperazinyl)mohonylkahmyl}-2-oxo-1,3-oxa-zolidia-S-yl)nnethyq4-thiophenecarboxawAde MS (ESI): rn/z (%) = 499 ([M+H]'',100), Cl patoern;
HPLC (method 2): rt (96) = 33 (100).
,--5-Chloro-N-((2-cia4o-3-W1-p1PWMWylwlpbonyl)P6my!]-1,34xumiidin-S-yl)-methyl)-Z-tbbpheneesrbozwaide MS (ESI): m/z (%) = 484 ([M+H]+,100), Cl patiern;
BPI.C (method 2): rt (96) = 4.4 (100).
EXMok 170 S-Cldoro N=[(3-(4-[(4-hydroxy-l-PiPMinyl)#Wpbmy]lpbonyl}-2-oxo-l,3-oaca-zolidia-S-yl)methyl]-2-thiOP e MS (ESI): nm/z (%) = 500 ([M+H]'',100), Cl pattern;
HPLC (mediod 3): rt (96) = 3.9 (100).
Eimmale 171 5-Chbro-N-({Z-oxo-3-[4-(1-pyrmOdbmyQphmyl]~1j-oxwolidia-S-pi}nehyi)-2-thioph~rboxamide -:,.._.
o ---' a 30725=107(S) 780 mg (1.54 mmol) of tert-butyl 1-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}-methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}prolinate are dissolved in 6 ml of dichloromethane and 9 ml of trifluoroacetic acid, and the mixture is stirred at 40 C
for two days. The reaction mixture is then concentrated and stirred with ether and 2N
aqueous sodium hydroxide solution. The aqueous phase is concentrated and stirred with ether and 2N hydrochloric acid. The organic phase of this extraction is dried over MgSO4, filtered and concentrated. The crude product is chromatographed over silica gel (CHZCIz/EtOH/conc. aqu. NH3 sol. = 100/1/0.1 to 20/110.1).
This gives 280 mg (40% of theory) of the product.
MS (ESI): m/z (%) = 406 (M+H, 100);
HPLC (method 4): rt = 3.81 min.
HPLC parameter and LC-MS parameter for the HPLC and LC-MS data Qiven in the examples above (the unit of the retention time (rt) is minutes):
TM
[1] Column: Kromasil C18, L-R temperature: 30 C, flow rate = 0.75 ml min-i, eluent: A = 0.01 M HC1O4, B = CH3CN, gradient: -> 0.5 min 98%A -> 4.5 min 10%A ->6.5 min 10%A
TM
[2] Column: Kromasil C18 60*2, L-R temperature: 30 C, flow rate = 0.75 ml min"', eluent: A = 0.01 M H3PO4, B = CH3CN, gradient: -> 0.5 min 90%A -> 4.5 min 10%A ->6.5 min 10%A
TM
[3] Column: Kromasil C18 60*2, L-R temperature: 30 C, flow rate = 0.75 ml min-1, eluent: A = 0.005 M HC1O4, B CH3CN, gradient: -> 0.5 min 98%A -> 4.5 min 10%A ->6.5 min 10%A
[4] Column: Syznmetry TM C18 2.1x150 mm, column oven: 50 C; flow rate -0.6 ml min-', eluent: A = 0.6 g 30% strength HCl/ 1 of water, B = CH3CN, gradient:
0.0 min 90%A -> 4.0 min 10%A ->9 min 10%A
30725=107 (S) [5] MHZ-2Q, Instrument Micromass Quattro LCZ
TM
Column Symmetry C18, 50 mm x 2.1 mm, 3.5 m, temperature: 40 C, flow rate =
0.5 ml min-', eluent A = CH3CN + 0.1% formic acid, eluent B = water + 0.1%
formic .5 acid, gradient: 0.0 min 10% A -> 4 min 90% A -> 6 min 90% A
[6] MHZ-2P, Instrument Micromass Platform LCZ
TM
Column Symmetry C18, 50 mm x 2.1 mm, 3.5 m, temperature: 40 C, flow rate =
0.5 ml miri', eluent A = CH3CN + 0.1% formic acid, eluent B = water + 0.1%
formic acid, gradient: 0.0 min 10% A -> 4 min 90% A -> 6 min 90% A
[7] MHZ-7Q, Instrument Micromass Quattro LCZ
TM
Column Symmetry C18, 50 mm x 2.1 mm, 3.5 m, temperature: 40 C, flow rate =
0.5 ml min-', eluent A = CH3CN + 0.1% formic acid, eluent B = water + 0.1%
formic acid, gradient: 0.0 min 5% A -> 1 min 5% A -> 5 min 90% A -> 6 min 90% A
General method for preparing oxazolidinones of the general formula B by solid-phase-supported synthesis Reactions with different resin-bonded products were carTied out in a set of separated reaction vessels.
5-(Bromomethyl)-3-(4-fluoro-3-nitrophenyl)-1,3-oxazolidin-2-one A (prepared from epibromohydrin and 4-fluoro-3-nitrophenyl isocyanate usina LiBr/Bu3PO in xylene analogously to US 4128654, Ex.2) (1.20 g, 3.75 mmol) and ethyldiisopropylamine (DIEA, 1.91 ml, 4.13 mmol) were dissolved in DMSO (70 ml), admixed with a secondary amine (1.1 eq., amine component 1) and reacted at 55 C for 5 h.
TentaGel SAM resin (5.00 g, 0.25 mmol/g) was added to this solution, and the mixture was reacted at 75 C for 48 h. The resin was filtered, washed repeatedly with methanol (MeOH), dimethylformamide (DMF), MeOH, dichloromethane (DCM) and diethyl ether and dried. The resin (5.00 g) was suspended in dichloromethane (80 ml), admixed with DIEA (10 eq.) and 5-chlorothiophene-2-carbonyl chloride [prepared by reactinc, 5-chlorothiophene-2-carboxylic acid (5 eq.) and 1-chloro-l-dimethylamino-2-methylpropene (5 eq.) in DCM (20 ml) at room temperature for 15 minutes] and the mixture was reacted at room temperature for 5 h. The resulting resin was filtered, washed repeatedly with MeOH, DCM and diethyl ether and dried. The resin was then 30725-107 (S) suspended in DMF/water (v/v 9:2, 80 ml), admixed with SnC12*2HZ0 (5 eq.) and reacted at room temperture for 18 h. The resin was washed repeatedly with MeOH, DMF, water, MeOH, DCM and diethyl ether and dried. This resin was suspended in DCM, admixed with DIEA (10 eq.) and, at 0 C, with an acid chloride (5 eq. of acid derivative 1), and the mixture was reacted at room temperature overnight.
Prior to the reaction, carboxylic acids were converted into the corresponding acid chlorides by reaction with 1-dimethylamino-l-chloro-2-methylpropene (1 eq., based on the carboxylic acid) in DCM at room temperature for 15 min. The resin was washed repeatedly with DMF, water, DMF, MeOH, DCM and diethyl ether and dried. If the acid derivative 1 used was an Fmoc-protected amino acid, the Fmoc protective group was removed in the last reaction step by reaction with piperidine/DMF (v/v, 1/4) at room temperature for 15 minutes, and the resin was washed with DMF, MeOH, DCM and diethyl ether and dried. The products were then removed from the solid phase using trifluoroacetic acid (TFA)/DCM (v/v, 1/1), the resin was filtered off and the reaction solutions were concentrated. The crude products were filtered over silica gel (DCM/MeOH, 9:1) and evaporated, giving a set of products B.
02N 0 R:N.R2 1 OzN O
~ H R - J~
F N O -_.-~ N N
Br R Br A
TentaGeISAMNH2 R ~ 2 - ~
am, N N O
TM
RZ L-~N
~TentaGeISAM
CI
S ci 02N O
O
\ / N N O O S C!
Rz ~TGSAM
30725-107(S) R, HzN 0 CI
SnClz N LN '' 0 5C1 O N
5Eq TGSAM
>=O
HN 0 TFA/DCM, R' _ 1 /1 N ~~ N 0 S CI
RZ
N
TGSAM
>=D
HN O
, RN - N O O S Ci R~Z ~ l Y-I ~/
NH
B
Compounds which were prepared by solid-phase-supported synthesis:
Example 172 N-({ 3-[3-Amino-4-(1-pyrrolidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophenecarboxamide ' ~ CI
C~-O N YN~'~N S
Analogously to the general procedure for preparing the derivatives B, 5 a TM
(1.25 mmol) of TentaGel SAM resin were reacted with pyrrolidine as amine derivative 1. The aniline obtained after reduction with SnC1Z*2HZ0 was, without any further acylation step, removed from the solid phase and concentrated. The crude product was partitioned between ethyl acetate and NaHCO3 solution and the organic phase was salted out using NaCl, decanted and evaporated to dryness. This crude 30725-107(S) product was purified by vacuum flash chromatooraphy over silica gel (dichloro-methane/ethyl acetate, 3:1 - 1:2).
1H-NMR (300 MHz, CDC]3): 1.95 - 2.08, br, 4 H; 3.15-3.30, br, 4 H; 3.65-3.81, m, 2 H; 3.89, ddd, 1H; 4.05, dd, 1 H; 4.81, dddd, 1 H; 6.46, dd, 1 H; 6.72, dd, 1 H; 6.90, dd, 1 H; 6.99, dd,.1 H; 7.03, dd, 1 H; 7.29, d, 1 H.
Example 173 N-[(3-{3-(i3-Alanylamino)-4-[(3-hydroxypropyl)amino]phenyl}-2-oxo-1,3-oxa-zolidin-5-yl)methyl]-5-chloro-2-thiophenecarboxamide HzN
O
HO O
' \ CI
~-N :b-NN O N S
H ~
O
An alogously to the Deneral procedure for preparing the derivatives B, 5 g TM
(1.25 mmol) of TentaGel SAM resin were reacted with azetidine as amine derivative 1 and Fmoc-B-alanine as acid derivative 1. The crude product obtained after the removal was stirred in methanol at room temperature for 48 h and evaporated to dryness. This crude product was purified by reversed phase BPLC using a water/TFA/acetonitrile gradient.
'H-NMR (400 MHz, CD3OD): 2.31, tt, 2 H; 3.36, t, 2 H; 3.54, t, 2 H; 3.62, t, 2 H;
3.72, dd, 1 H; 3.79, dd, I H; 4.01, dd, 1 H; 4.29, dd, 2 H; 4.43, t, 2 H; 4.85-4.95, m, 1H;7.01,d,1H;4.48-7.55,m,2H;7.61,d,1H;7.84,d,1H.
Example 174 N-({3-[4-(3-Amino-l-pyrrolidinyl)-3-nitrophenyl]-2-oxo-1,3-oxazolidin-5-y1}-methyl)-5-chloro-2-thiophenecarboxamide 30725-107(S) Cl H N NOz O S
2 ~_O O
N N
NH
Analogously to the general procedure for preparing the derivatives B, 130 mg TM
(32.5 mol) of TentaGel SAM resin were reacted with tert-butyl 3-pyrrolidinylcarbamate as amine derivative 1. The nitrobenzene derivative obtained after the acylation with 5-chlorothiophenecarboxylic acid was removed from the solid phase and concentrated. This crude product was purified by reversed phase HPLC using a water/TFAlacetonitrile gradient.
'H-NMR (400 MHz, CD3OH): 2.07-2.17, m, 1 H; 2.39-2.49, m, 1 H; 3.21-3.40, m, 2 H; 3.45, dd, 1 H; 3.50-3.60, m, I H; 3.67, dd, 1 H; 3.76, dd, 1 H; 3.88-4.00, m, 2 H;
4.14-4.21,t,1H;4.85-4.95,m,1H;7.01,d,1H;7.11,d,1H;7.52,d,1H;7.66, dd, 1 H; 7.93, d, 1 H.
Example 175 N-({3-[3-Amino-4-(1-piperidinyl)phenyl]-2-oxo-1,3-oxazolidin-5-y1}methyl)-5-chloro-2-thiophenecarboxamide HZN O
~ 1 \ CI
CN N N S
O
Analogously to the general procedure for preparing the derivatives B, 130 mg TM
(32.5 mol) of TentaGel SAM resin were reacted with piperidine as arnrne:
derivative 1. The aniline obtained after the reduction was, without any further acylation step, removed from the solid phase and concentrated. This crude product was purified by reversed phase HPLC using a water/TFA/acetonitrile gradient.
'H-NMR (400 MHz, CD3OH): 1.65-1.75, m, 2 H; 1.84-1.95, m, 4 H; 3.20-3.28, m, 4 H; 3.68, dd, 1 H; 3.73, dd, 1H; 3.90, dd, 1 H; 4.17, dd, 1 H; 4.80-4.90, m, 1 H;
7.00, d, 1 H; 7.05, dd, 1 H; 7.30-7.38, m, 2H; 7.50, d, 1 H.
30725-107 (S) Example 176 N-({3-[3-(Acetylamino)-4-(1-pyrrolidinyl)phenyl]-2-oxo-1;3-oxazolidin-S-yl}-methyl)-5-chloro-2-thiophenecarboxamide I,== O
HN O
CI
CN N a S
O
Analogously to the aeneral procedure for preparing the derivatives B, 130 mg TM
(32.5 mol) of TentaGel SAM resin were reacted pyrrolidine as amine derivative I
and acetyl chloride as acid derivative 1. The crude product was partitioned between ethyl acetate NaHCO3 solution and the organic phase was salted out using NaC1, decanted and evaporated to dryness. This crude product was purified by vacuum flash chromatography over silica gel (dichioromethane/ethyl acetate, 1: 1-0: 1).
iH-NMR (400 MHz, CD3OH): 1.93 -.2.03, br, 4 H; 2.16, s, 3 H; 3.20-3.30, br, 4 H;
3.70, d, 2 H; 3.86, dd, IH; 4.10, dd, 1 H; 4.14, dd, 1 H; 4.80-4.90, m, 1 H;
7.00, d, 1 H; 7.07, d, 1 H; 7.31, dd, 1 H; 7.51, d, 1 H; 7.60, d, 1 H.
The followina compounds were prepared analogously to the aeneral procedure.
xample Structure et. PLC
ime lo ]
177 N .62 19.7 O O
CI S
~ I/ N-)--\N
O
178 O 00 O~ 49 3.7 N N
N
CIe\
N
Le A 34 122-Fomlgn C_ounaies k trucaure 79 J .63 6.7 p~0 O N O~o ~N
180 1.37 44.8 O p N O O
04 181 N .16 83 ~N N
O p 182 ~ 31 3 O
S N
Q O
~-- 183 r 100 O~
N ~N
q ,....
184 .9l 1 o~,, ,J N
. ~.o P
Le A 34122-Foeeign CnmmWo LlruCt1m ~
185 O-\ 1--p .72 5.2 Nl~ N
JJ--~~N~"' ~10 O q 86 0~ .17 46 N
O
187 O 1.61 50.2 s ~lo (D
88 O N~ ~O. p /'1 .89 6 - N
q Nl~
189 No O p,,r .37 2.9 .p- - ~-N
q 190 3.6 3.9 _ =
O
q S N
'/~
Le A 34 1,~.2-"grciSj Co=ries . -124-Exumpk ftucbure C
%
191 .52 70.1 O
S N
p N~
O
192 Orp-o O 4O .52 46.6 S
,r+ q N
193 --fO .87 .1 O N ~
p N N
194 O-f O p_' 11 .25 1.1 ~Or N
LD
195 .66 7 O - : . =h.....
-t -, p CI
N
U A34 j22rForciaa Camuias xRmple &Uctum C
196 ~p Or .4 2.1 N~N ~N/
S
N
N
197 3.13 8.9 S I-N O
~T O
N
198 0 Oo o .67 75.5 '~..f CI
N
199 0 0.f 0 0 ~'"1 72 5S.7 CI =- N
00 .71 7.3 ~ 0**f 0 0 t==N
q Le A 3412Z-Forei~n Countrie.a = -126 -tructnre C
%
1 .22 00 O
2 p p_ .89 5.7 q ND
203 O p-f 0 pp .19 9.6 S
q N
204 o.f o p~ .ss .2 N T D
N
N
p N
205 ~ 44 69.6 i--{p p O 0 Np N :....
.86 11.8 '*f p O
p 1A A 34 122-Fom1s1 COBBti]C&
c 207 O O-f p O .8 .6 p p______ N
08 O .41 77 O=~
N
p N
09 2.56 7.9 O
N
~
~ N
p p--f 0 p 3.67 8.4 a
11 iS N .54 69.8 N
1~
O
la O-to O~ .84 9.2 N~N
a N'1 La A 34322 Fa+eian Camtries = -128 -C
13 p0.~0 Ojf"'~O .41 7.8 N N'~
p "a N
14 'oyop q*rj Al 5.4 N '"N N
q N
15 0 0 O .Ol 13 S N ~-rl NZD
16 0 o-f 0 O,,r 3.46 19.5 N
C{
!7 .4 60.2 T
~ O
a . .._.
18 1.79 70.9 S N
N~N~~
~
LaA34122=Faeilm Coggdg ~n~re 19 0 S7 1.5 O ~
N N
N
220 O-rO O .68 00 .~- <
N
. f q N
221 O O.t O p 0 53 63.5 %oN
22 O 0-t0 .66 92 N N
~-- "*oc q Nq N
223 O O~f 0 Oro .76 93 q N
2124A O=~ 3.45 77A
CI N~~ ~
Le A 34122- C_r___,.Qantnes T3. 25 3.
0 p~ .94 l.a N
,~- ZD
227 -f p p .15 66.3 1-y- 'a CI N
8 ~~~,,,,JJJ
~O'P"O O .~41 55.1 N
~3( N
229 0- .83 1.1 S N~ = ....
O
230 p p~,0 p~ 7 3 N N
S ric.
Le A 34 122-FomeiBp Couniria = -131-xsmpk tructur+e 0 O .39 .2 N q ~
~
Nr--c ~O p~ .85 4.9 NT N
ZD
3 O O O .17 1 0~
S N~N
CI ~Dr N
N
234 .21 1.8 N
N_6 , 35 0 p o .75 100 ~ ~..N ~
1~y,.N
Np .,..-.
N
36 .94 50 p o S ~N O O
~
Ie A 34 1Foreign ountries = -132-tracture 7 .65 1S .8 O '~ O
N ~0 ~ 4.475.3 S
N-~,~ _ 0 O
39 .24 2.2 F F N
40 0 .76 15.1 N
Cf lo~
241 0 1OrO O~ .17 2.5 . - N
~ ric N
242 O O-f O p //~ .6 4.$
1 O~
ZD
Le A 34 122-Forejgn Countries tMdure C
243 .12 1.6 O
.71 66.2 1-,CM 0 O
S
4S .86 2 Orp 6N,crN,-l -' 246 0 .23 83 N~N O O
CI ~
.-~ N--~
47 N O~O O 4.17 2.4 N
~ Nr~
~/
L& A 34 I22-Foreisn Cauntirie,s Sbudure C
;9. 35 p~p O
G NQ
O={
49 p pNYI--- .41 60.3 '..' O N
CI N
O-( 250 \ 3.31 5.2 O p O N
N
O~( N ND, N .86 36.5 p p*~-.69 .8 : . ,<.. .
52 p p-f 0 pr-O 2 89 cl cc N
N
Le A 34122-Fotrasm Camtnes tivcd:re 3 O O~O O ~ 81 .. 7.4 Nj a ~
'~
~
N
254 py 0 ON .19 5.4 p ~
N
D
All products of the solid-phase-supported synthesis were clwacterized by LC-MS.
As standud, the following sepaistion system was used: HP 1100 with UV detector (208 - 400 nm), oven tempeature 40 C, Waters-Symmetry C I8 column (50 mm x 2.1 mm, 3.5 m), mobile phase A: 99.9% scetonitri1d0.1% fomoic acid, mobile phase B: 99.9% water/ 0.19b formic acid; gradient:
una A:% B:% flow rate D.00 10.0 90.0 .50 .00 90.0' 10.0 .50 6.00 90.0 10.0 .50 5.10 10.0 90.0 1.00 7.50 10.0 90.0 0.50 37ie subsmnoes wese dewcted using a Midoauas QnKOro LCZ MS, ioeiitarion: ES"C"
positivdnegative.
In tfie snucom listed above which comprise the radical(s) or -0, 0.00 what is meant is in each case a H ~ or -OH function.
1~
O
la O-to O~ .84 9.2 N~N
a N'1 La A 34322 Fa+eian Camtries = -128 -C
13 p0.~0 Ojf"'~O .41 7.8 N N'~
p "a N
14 'oyop q*rj Al 5.4 N '"N N
q N
15 0 0 O .Ol 13 S N ~-rl NZD
16 0 o-f 0 O,,r 3.46 19.5 N
C{
!7 .4 60.2 T
~ O
a . .._.
18 1.79 70.9 S N
N~N~~
~
LaA34122=Faeilm Coggdg ~n~re 19 0 S7 1.5 O ~
N N
N
220 O-rO O .68 00 .~- <
N
. f q N
221 O O.t O p 0 53 63.5 %oN
22 O 0-t0 .66 92 N N
~-- "*oc q Nq N
223 O O~f 0 Oro .76 93 q N
2124A O=~ 3.45 77A
CI N~~ ~
Le A 34122- C_r___,.Qantnes T3. 25 3.
0 p~ .94 l.a N
,~- ZD
227 -f p p .15 66.3 1-y- 'a CI N
8 ~~~,,,,JJJ
~O'P"O O .~41 55.1 N
~3( N
229 0- .83 1.1 S N~ = ....
O
230 p p~,0 p~ 7 3 N N
S ric.
Le A 34 122-FomeiBp Couniria = -131-xsmpk tructur+e 0 O .39 .2 N q ~
~
Nr--c ~O p~ .85 4.9 NT N
ZD
3 O O O .17 1 0~
S N~N
CI ~Dr N
N
234 .21 1.8 N
N_6 , 35 0 p o .75 100 ~ ~..N ~
1~y,.N
Np .,..-.
N
36 .94 50 p o S ~N O O
~
Ie A 34 1Foreign ountries = -132-tracture 7 .65 1S .8 O '~ O
N ~0 ~ 4.475.3 S
N-~,~ _ 0 O
39 .24 2.2 F F N
40 0 .76 15.1 N
Cf lo~
241 0 1OrO O~ .17 2.5 . - N
~ ric N
242 O O-f O p //~ .6 4.$
1 O~
ZD
Le A 34 122-Forejgn Countries tMdure C
243 .12 1.6 O
.71 66.2 1-,CM 0 O
S
4S .86 2 Orp 6N,crN,-l -' 246 0 .23 83 N~N O O
CI ~
.-~ N--~
47 N O~O O 4.17 2.4 N
~ Nr~
~/
L& A 34 I22-Foreisn Cauntirie,s Sbudure C
;9. 35 p~p O
G NQ
O={
49 p pNYI--- .41 60.3 '..' O N
CI N
O-( 250 \ 3.31 5.2 O p O N
N
O~( N ND, N .86 36.5 p p*~-.69 .8 : . ,<.. .
52 p p-f 0 pr-O 2 89 cl cc N
N
Le A 34122-Fotrasm Camtnes tivcd:re 3 O O~O O ~ 81 .. 7.4 Nj a ~
'~
~
N
254 py 0 ON .19 5.4 p ~
N
D
All products of the solid-phase-supported synthesis were clwacterized by LC-MS.
As standud, the following sepaistion system was used: HP 1100 with UV detector (208 - 400 nm), oven tempeature 40 C, Waters-Symmetry C I8 column (50 mm x 2.1 mm, 3.5 m), mobile phase A: 99.9% scetonitri1d0.1% fomoic acid, mobile phase B: 99.9% water/ 0.19b formic acid; gradient:
una A:% B:% flow rate D.00 10.0 90.0 .50 .00 90.0' 10.0 .50 6.00 90.0 10.0 .50 5.10 10.0 90.0 1.00 7.50 10.0 90.0 0.50 37ie subsmnoes wese dewcted using a Midoauas QnKOro LCZ MS, ioeiitarion: ES"C"
positivdnegative.
In tfie snucom listed above which comprise the radical(s) or -0, 0.00 what is meant is in each case a H ~ or -OH function.
Claims (70)
1. A compound of formula (I):
in which:
R1 is thienyl which is mono- or polysubstituted by a halogen radical, (C1-C8)-alkyl or trifluoromethyl, R2 is:
A-, or D-M-A-, where:
A is phenyl;
D is a saturated or partially unsaturated, mono-or bicyclic 4- to 9-membered heterocycle which contains one, two or three heteroatoms and/or hetero chain members from the group consisting of S, SO, SO2, N, N-oxide and O; and M is -CH2-, -SO2- or a covalent bond;
where A and D are each optionally mono- or polysubstituted by a halogen radical; trifluoromethyl; oxo;
cyano; nitro; carbamoyl; pyridyl; (C1-C6)-alkanoyl;
(C1-C4)-hydroxy-alkylcarbonyl; -COOR27; -CONR28R29; -SO2NR28R29;
-OR30; -NR30R31; (C3-C7)-cycloalkyl; or (C1-C6)-alkyl, which is optionally substituted by cyano, -OR27, -NR28R29 or -C(NR27R28)=NR29, where:
R27, R28 and R29 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C1-C4)-alkanoyl, carbamoyl, trifluoromethyl, phenyl or pyridyl, and/or R27 and R28 or R27 and R29 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- to 7-membered heterocycle having one, two or three identical or different heteroatoms from the group consisting of N, O and S, and R30 and R31 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C1-C4)-hydroxyalkyl or -COR33, where R33 is (C1-C6)-alkoxy; (C1-C4)-alkoxy- (C1-C4)-alkyl;
(C1-C4)-alkoxycarbonyl-(C1-C4)-alkyl; (C1-C4)-aminoalkyl;
(C1-C4)-alkoxycarbonyl; (C1-C4)-alkanoyl-(C1-C4)-alkyl;
(C3-C7)-cycloalkyl; (C2-C6)-alkenyl; (C1-C8)-alkyl, which is optionally substituted by phenyl or acetyl; (C6-C14)-aryl;
(C5-C10)-heteroaryl; trifluoromethyl; tetrahydrofuranyl; or butyrolactone, and each of R3, R4, R5, R6, R7 and R8 is hydrogen, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound.
in which:
R1 is thienyl which is mono- or polysubstituted by a halogen radical, (C1-C8)-alkyl or trifluoromethyl, R2 is:
A-, or D-M-A-, where:
A is phenyl;
D is a saturated or partially unsaturated, mono-or bicyclic 4- to 9-membered heterocycle which contains one, two or three heteroatoms and/or hetero chain members from the group consisting of S, SO, SO2, N, N-oxide and O; and M is -CH2-, -SO2- or a covalent bond;
where A and D are each optionally mono- or polysubstituted by a halogen radical; trifluoromethyl; oxo;
cyano; nitro; carbamoyl; pyridyl; (C1-C6)-alkanoyl;
(C1-C4)-hydroxy-alkylcarbonyl; -COOR27; -CONR28R29; -SO2NR28R29;
-OR30; -NR30R31; (C3-C7)-cycloalkyl; or (C1-C6)-alkyl, which is optionally substituted by cyano, -OR27, -NR28R29 or -C(NR27R28)=NR29, where:
R27, R28 and R29 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C1-C4)-alkanoyl, carbamoyl, trifluoromethyl, phenyl or pyridyl, and/or R27 and R28 or R27 and R29 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- to 7-membered heterocycle having one, two or three identical or different heteroatoms from the group consisting of N, O and S, and R30 and R31 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C1-C4)-hydroxyalkyl or -COR33, where R33 is (C1-C6)-alkoxy; (C1-C4)-alkoxy- (C1-C4)-alkyl;
(C1-C4)-alkoxycarbonyl-(C1-C4)-alkyl; (C1-C4)-aminoalkyl;
(C1-C4)-alkoxycarbonyl; (C1-C4)-alkanoyl-(C1-C4)-alkyl;
(C3-C7)-cycloalkyl; (C2-C6)-alkenyl; (C1-C8)-alkyl, which is optionally substituted by phenyl or acetyl; (C6-C14)-aryl;
(C5-C10)-heteroaryl; trifluoromethyl; tetrahydrofuranyl; or butyrolactone, and each of R3, R4, R5, R6, R7 and R8 is hydrogen, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound.
2. The compound according to claim 1, wherein R2 is A-, or D-M-A-, where:
A is phenyl;
D is a saturated or partially unsaturated 4- to 7-membered heterocycle which contains one, two or three heteroatoms and/or hetero chain members from the group consisting of S, SO, SO2, N, N-oxide and O;
M is -CH2- or a covalent bond;
where A and D are each optionally mono- or polysubstituted by a halogen radical; trifluoromethyl; oxo;
cyano; nitro; carbamoyl; pyridyl; (C1-C6)-alkanoyl; -COOR27;
-CONR28R29; -SO2NR28R29; -OR30; -NR30R31; (C3-C7)-cycloalkyl; or (C1-C6)-alkyl, which is optionally substituted by cyano, -OR27, -NR28R29 or -C(NR17R28)=NR29, where:
R27, R28 and R29 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl or (C3-C7)-cycloalkyl, and/or R27 and R28 or R27 and R29 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- to 7-membered heterocycle having one, two or three, identical or different heteroatoms from the group consisting of N, O and S, and R30 and R31 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C1-C4)-hydroxyalkyl, (C1-C4)-alkanoyl, (C6-C14)-arylcarbonyl or (C5-C10)-heteroarylcarbonyl, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound.
A is phenyl;
D is a saturated or partially unsaturated 4- to 7-membered heterocycle which contains one, two or three heteroatoms and/or hetero chain members from the group consisting of S, SO, SO2, N, N-oxide and O;
M is -CH2- or a covalent bond;
where A and D are each optionally mono- or polysubstituted by a halogen radical; trifluoromethyl; oxo;
cyano; nitro; carbamoyl; pyridyl; (C1-C6)-alkanoyl; -COOR27;
-CONR28R29; -SO2NR28R29; -OR30; -NR30R31; (C3-C7)-cycloalkyl; or (C1-C6)-alkyl, which is optionally substituted by cyano, -OR27, -NR28R29 or -C(NR17R28)=NR29, where:
R27, R28 and R29 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl or (C3-C7)-cycloalkyl, and/or R27 and R28 or R27 and R29 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- to 7-membered heterocycle having one, two or three, identical or different heteroatoms from the group consisting of N, O and S, and R30 and R31 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C1-C4)-hydroxyalkyl, (C1-C4)-alkanoyl, (C6-C14)-arylcarbonyl or (C5-C10)-heteroarylcarbonyl, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound.
3. The compound according to claim 1, wherein R2 is:
A-, or D-M-A-, where:
A is phenyl;
D is a saturated or partially unsaturated 5- or 6-membered heterocycle which contains one or two heteroatoms and/or hetero chain members from the group consisting of S, SO, SO2, N, N-oxide and O;
M is a covalent bond;
where A and D are each optionally mono- or polysubstituted by a halogen radical; trifluoromethyl; oxo;
cyano; pyridyl; (C1-C3)-alkanoyl; -CONR28R29; -SO2NR28R29; -OH;
-NR30R31; cyclopropyl; cyclopentyl; cyclohexyl; or (C1-C4)-alkyl, which is optionally substituted by cyano, -OH, -OCH3, -NR28R29 or -C(NR27R28)=NR29, where:
R27, R28 and R29 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, cyclopropyl, cyclopentyl or cyclohexyl, and/or R27 and R28 or R27 and R29 together with the nitrogen atom to which they are attached may form a saturated or partially unsaturated 5- to 7-membered heterocycle having one or two identical or different heteroatoms from the group consisting of N, O and S, and R30 and R31 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C1-C4)-hydroxyalkyl, (C1-C3)-alkanoyl or phenyl carbonyl, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound.
A-, or D-M-A-, where:
A is phenyl;
D is a saturated or partially unsaturated 5- or 6-membered heterocycle which contains one or two heteroatoms and/or hetero chain members from the group consisting of S, SO, SO2, N, N-oxide and O;
M is a covalent bond;
where A and D are each optionally mono- or polysubstituted by a halogen radical; trifluoromethyl; oxo;
cyano; pyridyl; (C1-C3)-alkanoyl; -CONR28R29; -SO2NR28R29; -OH;
-NR30R31; cyclopropyl; cyclopentyl; cyclohexyl; or (C1-C4)-alkyl, which is optionally substituted by cyano, -OH, -OCH3, -NR28R29 or -C(NR27R28)=NR29, where:
R27, R28 and R29 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, cyclopropyl, cyclopentyl or cyclohexyl, and/or R27 and R28 or R27 and R29 together with the nitrogen atom to which they are attached may form a saturated or partially unsaturated 5- to 7-membered heterocycle having one or two identical or different heteroatoms from the group consisting of N, O and S, and R30 and R31 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C1-C4)-hydroxyalkyl, (C1-C3)-alkanoyl or phenyl carbonyl, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound.
4. The compound according to claim 1, wherein R1 is 2-thienyl which is substituted in the 5-position by a chlorine radical, bromine radical, methyl or trifluoromethyl, R2 is:
A-, or D-M-A-, where:
A is phenyl;
D is a saturated or partially unsaturated 5- or 6-membered heterocycle which contains a nitrogen atom and optionally a further heteroatom and/or hetero chain member from the group consisting of S, SO, SO2 and O; or contains one or two heteroatoms and/or hetero chain members from the group consisting of S, SO, SO2 and O;
M is a covalent bond;
where A and D are each optionally mono- or polysubstituted by a halogen radical; trifluoromethyl; oxo;
cyano; pyridyl; (C1-C3) -alkanoyl; -CONR28R29; -SO2NR28R29; -OH;
-NR30R31; cyclopropyl; cyclopentyl; cyclohexyl; or (C1-C4)-alkyl, which is optionally substituted by cyano, -OH, -OCH3, -NR28R29 or -C(NR27R28)=NR29, where:
R27, R28 and R29 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, cyclopropyl, cyclopentyl or cyclohexyl, and/or R27 and R28 or R27 and R29 together with the nitrogen atom to which they are attached may form a saturated or partially unsaturated 5- to 7-membered heterocycle having one or two identical or different heteroatoms from the group consisting of N, O and S, and R30 and R31 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C1-C4)-hydroxyalkyl, (C1-C3)-alkanoyl or phenylcarbonyl, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or a prodrug of the compound.
A-, or D-M-A-, where:
A is phenyl;
D is a saturated or partially unsaturated 5- or 6-membered heterocycle which contains a nitrogen atom and optionally a further heteroatom and/or hetero chain member from the group consisting of S, SO, SO2 and O; or contains one or two heteroatoms and/or hetero chain members from the group consisting of S, SO, SO2 and O;
M is a covalent bond;
where A and D are each optionally mono- or polysubstituted by a halogen radical; trifluoromethyl; oxo;
cyano; pyridyl; (C1-C3) -alkanoyl; -CONR28R29; -SO2NR28R29; -OH;
-NR30R31; cyclopropyl; cyclopentyl; cyclohexyl; or (C1-C4)-alkyl, which is optionally substituted by cyano, -OH, -OCH3, -NR28R29 or -C(NR27R28)=NR29, where:
R27, R28 and R29 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, cyclopropyl, cyclopentyl or cyclohexyl, and/or R27 and R28 or R27 and R29 together with the nitrogen atom to which they are attached may form a saturated or partially unsaturated 5- to 7-membered heterocycle having one or two identical or different heteroatoms from the group consisting of N, O and S, and R30 and R31 are identical or different and independently of one another each is hydrogen, (C1-C4)-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C1-C4)-hydroxyalkyl, (C1-C3)-alkanoyl or phenylcarbonyl, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or a prodrug of the compound.
5. A compound of the formula wherein R1 is 2-thienyl which is substituted in the 5-position by chlorine, bromine, methyl or trifluoromethyl, R2 is D-A-:
where:
A is phenylene;
D is a saturated 5- or 6-membered heterocycle, which is attached to A via a nitrogen atom, which has a carbonyl group directly adjacent to the linking nitrogen atom and in which one carbon ring member may be replaced by a S, N or O heteroatom;
where A is optionally mono- or disubstituted in the meta position with respect to the point of attachment to the oxazolidinone, by a fluorine radical, chlorine radical, nitro, amino, trifluoromethyl, methyl or cyano, and each of R3, R4, R5, R6, R7 and R8 is hydrogen, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or a prodrug of the compound.
where:
A is phenylene;
D is a saturated 5- or 6-membered heterocycle, which is attached to A via a nitrogen atom, which has a carbonyl group directly adjacent to the linking nitrogen atom and in which one carbon ring member may be replaced by a S, N or O heteroatom;
where A is optionally mono- or disubstituted in the meta position with respect to the point of attachment to the oxazolidinone, by a fluorine radical, chlorine radical, nitro, amino, trifluoromethyl, methyl or cyano, and each of R3, R4, R5, R6, R7 and R8 is hydrogen, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or a prodrug of the compound.
6. The compound or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound.
7. The compound according to claim 6, which is the hydrate.
8. The compound
9. Process for preparing a compound as defined in any one of claims 1 to 8, comprising, according to a process alternative [A] or [B]:
[A] reacting a compound of formula (II) in which R2, R3, R4, R5, R6, R7 and R8 are each as defined in claim 1 with a carboxylic acid of the formula (III) in which R1 is as defined in claim 1, or with the corresponding carbonyl halide, or with the corresponding symmetric or mixed carboxylic anhydride of the carboxylic acid of the formula (III) defined above in an inert solvent, if appropriate in the presence of an activating or coupling agent and/or a base, to give a compound of the formula in which R1, R2, R3, R4, R5, R6, R7 and R8 are each as defined in claim 1, or [B] converting a compound of the formula (IV) in which R1, R3, R4, R5, R6, R7 and R8 are each as defined in claim 1, using a suitable selective oxidizing agent in an inert solvent, into the corresponding epoxide of the formula (V) in which R1, R3, R4, R5, R6, R7 and R8 are each as defined in claim 1, and, reacting in an inert solvent, if appropriate in the presence of a catalyst, the epoxide of formula (V) with an amine of the formula (VI) R2-NH2 (VI) in which R2 is as defined in claim 1, to obtain a compound of the formula (VII) in which R1, R2, R3, R4, R5, R6, R7 and R8 are each as defined in claim 1, and, subsequently, in an inert solvent in the presence of phosgene or phosgene equivalents, cyclizing the compound of formula (VII) to give a compound of the formula in which R1, R2, R3, R4, R5, R6, R7 and R8 are each as defined in claim 1, where - both for process alternative [A] and for process alternative [B] - in the case where R2 contains a 3- to 7-membered saturated or partially unsaturated cyclic hydrocarbon radical having one or more identical or different heteroatoms from the group consisting of N and S, an oxidation with a selective oxidizing agent to afford the corresponding sulphone, sulphoxide or N-oxide may follow and/or where - both for process alternative [A] and for process alternative [B] - in the case where the compound prepared in this manner has a cyano group in the compound, an amidination of this cyano group may follow and/or where - both for process alternative [A] and for process alternative [B] - in the case where the compound prepared in this manner has a BOC amino protective group in the compound, removal of this BOC amino protective group may follow and/or where - both for process alternative [A] and for process alternative [B] - in the case where the compound prepared in this manner has an aniline or benzylamine radical in the compound, a reaction of this amino group with various reagents to give the corresponding derivatives may follow and/or where - both for process alternative [A] and for process alternative [B] - in the case where the compound prepared in this manner has a phenyl ring in the compound, a reaction with chlorosulphonic acid and subsequent reaction with an amine to give the corresponding sulphonamides may follow.
[A] reacting a compound of formula (II) in which R2, R3, R4, R5, R6, R7 and R8 are each as defined in claim 1 with a carboxylic acid of the formula (III) in which R1 is as defined in claim 1, or with the corresponding carbonyl halide, or with the corresponding symmetric or mixed carboxylic anhydride of the carboxylic acid of the formula (III) defined above in an inert solvent, if appropriate in the presence of an activating or coupling agent and/or a base, to give a compound of the formula in which R1, R2, R3, R4, R5, R6, R7 and R8 are each as defined in claim 1, or [B] converting a compound of the formula (IV) in which R1, R3, R4, R5, R6, R7 and R8 are each as defined in claim 1, using a suitable selective oxidizing agent in an inert solvent, into the corresponding epoxide of the formula (V) in which R1, R3, R4, R5, R6, R7 and R8 are each as defined in claim 1, and, reacting in an inert solvent, if appropriate in the presence of a catalyst, the epoxide of formula (V) with an amine of the formula (VI) R2-NH2 (VI) in which R2 is as defined in claim 1, to obtain a compound of the formula (VII) in which R1, R2, R3, R4, R5, R6, R7 and R8 are each as defined in claim 1, and, subsequently, in an inert solvent in the presence of phosgene or phosgene equivalents, cyclizing the compound of formula (VII) to give a compound of the formula in which R1, R2, R3, R4, R5, R6, R7 and R8 are each as defined in claim 1, where - both for process alternative [A] and for process alternative [B] - in the case where R2 contains a 3- to 7-membered saturated or partially unsaturated cyclic hydrocarbon radical having one or more identical or different heteroatoms from the group consisting of N and S, an oxidation with a selective oxidizing agent to afford the corresponding sulphone, sulphoxide or N-oxide may follow and/or where - both for process alternative [A] and for process alternative [B] - in the case where the compound prepared in this manner has a cyano group in the compound, an amidination of this cyano group may follow and/or where - both for process alternative [A] and for process alternative [B] - in the case where the compound prepared in this manner has a BOC amino protective group in the compound, removal of this BOC amino protective group may follow and/or where - both for process alternative [A] and for process alternative [B] - in the case where the compound prepared in this manner has an aniline or benzylamine radical in the compound, a reaction of this amino group with various reagents to give the corresponding derivatives may follow and/or where - both for process alternative [A] and for process alternative [B] - in the case where the compound prepared in this manner has a phenyl ring in the compound, a reaction with chlorosulphonic acid and subsequent reaction with an amine to give the corresponding sulphonamides may follow.
10. A medicament comprising at least one compound as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, and one or more pharmacologically acceptable auxiliaries or excipients.
11. A medicament comprising the compound as defined in claim 8, and one or more pharmacologically acceptable auxiliaries or excipients.
12. Use of a compound as defined in claim 1, 2, 3, 4, or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, for preparing a medicament or a pharmaceutical composition for the prophylaxis and/or treatment of a thromboembolic disorder.
13. The use according to claim 12, wherein the thromboembolic disorder is myocardial infarct.
14. The use according to claim 12, wherein the thromboembolic disorder is angina pectoris.
15. The use according to claim 12, wherein the thromboembolic disorder is a reocclusion or restenosis after angioplasty or aorto-coronary bypass.
16. The use according to claim 12, wherein the thromboembolic disorder is stroke.
17. The use according to claim 12, wherein the thromboembolic disorder is a transitory ischaemic attack.
18. The use according to claim 12, wherein the thromboembolic disorder is a peripheral arterial occlusive disease.
19. The use according to claim 12, wherein the thromboembolic disorder is a pulmonary embolism.
20. The use according to claim 12, wherein the thromboembolic disorder is a deep venous thrombosis.
21. The use according to claim 12, wherein the thromboembolic disorder is unstable angina.
22. Use of a compound as defined in claim 1, 2, 3, 4, or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, for preparing a medicament or a pharmaceutical composition for the prophylaxis and/or treatment of a disorder which is influenced positively by inhibition of factor Xa.
23. Use of a compound as defined in claim 1, 2, 3, 4, or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, for preparing a medicament or a pharmaceutical composition for the prophylaxis and/or treatment of atherosclerosis.
24. The use according to claim 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23, wherein the medicament or pharmaceutical composition is for prophylaxis.
25. The use according to claim 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23, wherein the medicament or pharmaceutical composition is for treatment.
26. Use of a compound as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, for preparing a medicament or a pharmaceutical composition for the treatment of disseminated intravascular coagulation (DIC).
27. Use of a compound as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, for preparing a medicament or a pharmaceutical composition for the inhibition of factor Xa.
28. The use according to claim 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27, wherein the compound is as defined in claim 8.
29. Method for preventing the coagulation of blood in vitro by adding a compound as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8 to the blood.
30. The method according to claim 29, wherein the blood is banked blood or a biological sample containing factor Xa.
31. Use of a compound as defined in claim 1, 2, 3, 4, or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, for preventing the coagulation of blood ex vivo.
32. Use of a compound as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, for preventing coagulation ex vivo for a biological sample which contains factor Xa.
33. Use of a compound as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, for the prophylaxis and/or treatment of a thromboembolic disorder.
34. The use according to claim 33, wherein the thromboembolic disorder is myocardial infarct.
35. The use according to claim 33, wherein the thromboembolic disorder is angina pectoris.
36. The use according to claim 33, wherein the thromboembolic disorder is a reocclusion or restenosis after angioplasty or aorto-coronary bypass.
37. The use according to claim 33, wherein the thromboembolic disorder is stroke.
38. The use according to claim 33, wherein the thromboembolic disorder is a transitory ischaemic attack.
39. The use according to claim 33, wherein the thromboembolic disorder is a peripheral arterial occlusive disease.
40. The use according to claim 33, wherein the thromboembolic disorder is pulmonary embolism.
41. The use according to claim 33, wherein the thromboembolic disorder is deep venous thrombosis.
42. The use according to claim 33, wherein the thromboembolic disorder is unstable angina.
43. Use of a compound as defined in claim 1, 2, 3, 4, or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, for the prophylaxis and/or treatment of a disorder which is positively influenced by factor Xa.
44. Use of a compound as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, for the prophylaxis and/or treatment of atherosclerosis.
45. The use according to claim 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 or 44, which is for prophylaxis.
46. The use according to claim 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 or 44, which is for treatment.
47. Use of a compound as defined in claim 1, 2, 3, 4, or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, for the treatment of disseminated intravascular coagulation (DIC).
48. Use of a compound as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, for the inhibition of factor Xa.
49. The use according to claim 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 or 48, wherein the compound is as defined in claim 8.
50. The use according to claim 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49, which is oral.
51. A pharmaceutical formulation comprising a compound as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, and a solvent and/or excipient, for use in the prophylaxis and/or treatment of a thromboembolic disorder.
52. The pharmaceutical formulation of claim 51, wherein the thromboembolic disorder is myocardial infarct.
53. The pharmaceutical formulation of claim 51, wherein the thromboembolic disorder is angina pectoris.
54. The pharmaceutical formulation of claim 51, wherein the thromboembolic disorder is a reocclusion or restenosis after angioplasty or aorto-coronary bypass.
55. The pharmaceutical formulation of claim 51, wherein the thromboembolic disorder is stroke.
56. The pharmaceutical formulation of claim 51, wherein the thromboembolic disorder is a transitory ischaemic attack.
57. The pharmaceutical formulation of claim 51, wherein the thromboembolic disorder is a peripheral arterial occlusive disease.
58. The pharmaceutical formulation of claim 51, wherein the thromboembolic disorder is a pulmonary embolism.
59. The pharmaceutical formulation of claim 51, wherein the thromboembolic disorder is a deep venous thrombosis.
60. The pharmaceutical formulation of claim 51, wherein the thromboembolic disorder is unstable angina.
61. A pharmaceutical formulation comprising a compound as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, and a solvent and/or excipient, for use in the prophylaxis and/or treatment of atherosclerosis.
62. A pharmaceutical formulation comprising a compound as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, and a solvent and/or excipient, for use in the prophylaxis and/or treatment of a disorder which is influenced by inhibition of factor Xa.
63. The pharmaceutical formulation of claim 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 or 62, which is for prophylaxis.
64. The pharmaceutical formulation of claim 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 or 62, which is for treatment.
65. A pharmaceutical formulation comprising a compound as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, and a solvent and/or excipient, for use in the treatment of disseminated intravascular coagulation (DIC).
66. A pharmaceutical formulation comprising a compound as defined in claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or prodrug of the compound, or the compound as defined in claim 8, and a solvent and/or excipient, for use in the inhibition of factor Xa.
67. The pharmaceutical formulation of claim 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 or 66, wherein the compound is as defined in claim 8.
68. A pharmaceutical formulation as defined in claim 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 or 67, which is in the form of a tablet.
69. The compound for use orally as an antithrombotic.
70. The compound for use orally in the inhibition of factor Xa.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19962924A DE19962924A1 (en) | 1999-12-24 | 1999-12-24 | Substituted oxazolidinones and their use |
| DE19962924.2 | 1999-12-24 | ||
| PCT/EP2000/012492 WO2001047919A1 (en) | 1999-12-24 | 2000-12-11 | Substituted oxazolidinones and their use in the field of blood coagulation |
Publications (2)
| Publication Number | Publication Date |
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| CA2396561A1 CA2396561A1 (en) | 2001-07-05 |
| CA2396561C true CA2396561C (en) | 2008-10-14 |
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| CA002396561A Expired - Lifetime CA2396561C (en) | 1999-12-24 | 2000-12-11 | Substituted oxazolidinones and their use in the field of blood coagulation |
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