CN104356124A

CN104356124A - Oxazolidinone compound and composition containing same as well as application of oxazolidinone compound and composition

Info

Publication number: CN104356124A
Application number: CN201410603328.2A
Authority: CN
Inventors: 左应林; 郑金付; 张瑾; 吴守涛; 袁小凤; 林润锋; 王晓军; 文亮; 张英俊
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2014-10-30
Filing date: 2014-10-30
Publication date: 2015-02-18

Abstract

The invention relates to the field of blood coagulation, in particular to an oxazolidinone compound, or a stereoisomer, a tautomer, a nitrous oxide, a solvate, a metabolite, a salt or prodrug acceptable in pharmacy and a pharmaceutical composition containing the compound. The invention further relates to a preparation method for the compound and the pharmaceutical composition, and application of the compound and the pharmaceutical composition to the preparation of drugs for preventing, treating or relieving thromboembolic disease related to the factor Xa of a patient.

Description

Oxazolidinone compounds and composition thereof and purposes

Invention field

The invention belongs to pharmaceutical field, be specifically related to a class Xin oxazolidinone compounds, pharmaceutical composition, and for the preparation of the purposes of medicine.More particularly, compound of the present invention, composition may be used for the medicine preparing Xa factor inhibitor class medicine and treatment thrombotic disease.

Background technology

Short blood coagulation (hemostasis) and anticoagulation (anti-bolt) are the mechanism of two kinds of opposition in Hematological System of Professional Workers, each other contradiction keep relative equilibrium, and the process of this accurate harmony maintains the integrity of the recycle system.When in body, anti-freezing Fibrinolytic System reduces gradually, then there is blood coagulation when blood coagulation and anticoagulant functions overbalance in blood, thus cause thrombus or embolism, and then cause the thrombotic diseases such as such as myocardial infarction, apoplexy, DVT, pulmonary infarction.Thrombotic disease endangers the most serious disease in cardiovascular disorder, is the first killer of human health.

Along with illustrating further of Thrombosis Mechanism, for thrombotic feature and reason, researched and developed a lot of antithrombotic new drug, the medicine of existing inhibition thrombosis (anticoagulation) and anticoagulant, has again thrombolytic medicine.The former is mainly to the formation of thrombus with increase inhibited, and established thrombus mainly dissolves by the latter, thus eliminates the harm that thrombotic diseases causes the mankind.

Blood coagulation Xa factor is a kind of serine protease, can be zymoplasm by conversion of prothrombin, is an anticoagulation target spot having clinical value, is formed and have consequence in activation blood coagulation waterfall at control zymoplasm.Xa factor is positioned at the joint of inside and outside source property coagulation pathway, and the major catalytic II factor is factor converting to IIa, and the bio signal existed due to coagulation process amplifies, and a blood coagulation Xa factor inhibitor can suppress the physiologic effect of 138 thrombogen molecules.

Can know clearly from current result of study, the specific inhibitor of Xa factor as potential, valuable therapeutical agent, can be used for the treatment of thrombotic disease.The invention provides a kind of new Xa factor inhibitor---pyridine compounds, and pharmacy acceptable salt or its prodrug, this compounds effectively can treat thrombotic disease.

Abstract of invention

The invention provides a kind of compound or its pharmaceutical composition, effectively can prevent, alleviate or treat the thrombotic disease relevant to Xa factor.Compared with existing similar compound, compound of the present invention has better pharmacologically active, medicine for character, physico-chemical property and/or toxicological characteristics.Specifically, the compounds of this invention demonstrates good activity in FXa Inhibition test, demonstrate good absorption and higher bioavailability in pharmacokinetic studies in animal body, and the compounds of this invention solubleness is better, has more excellent druggability.

On the one hand, the present invention relates to a kind of compound, it is for such as formula the compound shown in (I), or the steric isomer tautomer of compound shown in formula (I), oxynitride, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

Wherein, A, R ¹, R ²with n, there is implication as described in the present invention.

In some embodiments, A is C _6-12aryl or-(C _1-4alkylidene group)-(C _6-12aryl), wherein, A is optionally by 1,2 or 3 R ³replaced;

R ¹for H, C _1-4alkyl, C _2-4thiazolinyl or C _2-4alkynyl;

Each R ²be H, D, F, Cl, Br, I, C independently _1-4alkyl, C _2-4thiazolinyl or C _2-4alkynyl;

Each R ³be H, D, F, Cl, Br, NO independently ₂, C _1-6alkyl, C _2-6thiazolinyl, C _2-6alkynyl ,-OR ^c,-NR ^ar ^b,-S (=O) ₂r ^c,-S (=O) ₂nR ^ar ^b,-C (=O) R ^c,-OC (=O) R ^c,-C (=O) OR ^c,-N (R ^a) C (=O) R ^c,-N (R ^a) S (=O) _tr ^cor-C (=O) NR ^ar ^b, wherein, each R ³independent optionally by 1,2 or 3 R ⁴group replaced;

Each R ⁴be H, D, F, Cl, Br, I, CN, NO independently ₂, N ₃, NH ₂, OH, C _1-4alkyl, C _2-4thiazolinyl, C _2-4alkynyl, C _1-4alkoxyl group, C _1-4alkylamino or C _1-4haloalkyl;

Each R ^a, R ^band R ^cbe separately H, C _1-4alkyl, C _2-4thiazolinyl, C _2-4alkynyl, C _3-6cycloalkyl, 5-6 former molecular heterocyclic radical, phenyl or 5-6 former molecular heteroaryl, wherein, each R ^a, R ^band R ^cindependently optionally independently be selected from D, F, Cl, Br, CN, N by 1,2 or 3 ₃, OH, NH ₂, C _1-4alkyl, C _1-4haloalkyl, C _1-4alkoxyl group or C _1-4the substituting group of alkylamino replaced; With

N is 0,1,2 or 3.

In other embodiments, A is phenyl, and described phenyl is optionally by 1,2 or 3 R ³replaced.

In some embodiments, R ¹be H, methyl, ethyl, propyl group or sec.-propyl independently.

In some embodiments, each R ³be H, D, F, Cl, Br, NO independently ₂, C _1-4alkyl, C _2-4thiazolinyl, C _2-6alkynyl ,-S (=O) ₂r ^c,-S (=O) ₂nR ^ar ^b,-C (=O) R ^c,-C (=O) OR ^cor-C (=O) NR ^ar ^b, wherein, each R ^a, R ^band R ^cbe separately H, methyl, ethyl, propyl group or sec.-propyl.

In other embodiments, each R ^a, R ^band R ^cbe separately H, methyl, ethyl, propyl group, sec.-propyl, C _3-6cycloalkyl, 5-6 former molecular heterocyclic radical, phenyl or 5-6 former molecular heteroaryl, wherein, each R ^a, R ^band R ^cindependently optionally independently be selected from D, F, Cl, Br, CN, N by 1,2 or 3 ₃, OH, NH ₂or CF ₃substituting group replaced.

In some embodiments, A is phenyl, optionally by 1 or 2 R ³replaced;

R ¹for H, methyl, ethyl, propyl group or sec.-propyl;

Each R ²be H, D, F, Cl or Br independently;

Each R ³be H, D, F, Cl, Br, NO independently ₂,-S (=O) ₂cH ₃or-S (=O) ₂nH ₂;

N is 1.

On the other hand, the present invention relates to a kind of pharmaceutical composition, comprise compound of the present invention, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.

On the other hand, the present invention relates to described compound or described pharmaceutical composition is preparing the purposes in medicine, described medicine is used for prevention, treats or alleviate thrombotic disease and disseminated inravascular coagulation (DIC).

In some embodiments, purposes of the present invention, wherein said thrombotic disease is myocardial infarction, stenocardia, to block and restenosis after revascularization or aorta Coronary artery bypass, apoplexy, the outbreak of of short duration local asphyxia, peripheral arterial occlusive disease, pulmonary infarction or venous thrombosis again.

Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will do more specifically complete description below.

Circumstantial letter of the present invention

Definition and general terms

Present detailed description certain embodiments of the present invention, the example is by the structural formula of enclosing and chemical formula explanation.The invention is intended to contain all to substitute, amendment and equivalent technical solutions, they include in the scope of the invention of such as claim definition.Those skilled in the art will appreciate that many or methods of being equal to similar with described herein and material can be used in putting into practice the present invention.The present invention is never limited to method as herein described and material.Combined document, patent and (include but not limited to defined term, term application, described technology, etc.) in one or more different from the application or conflicting situations of analogous material, be as the criterion with the application.

Should recognize further, some feature of the present invention, for clearly visible, be described in multiple independently embodiment, but also can provide in combination in single embodiment.Otherwise various feature of the present invention, for for purpose of brevity, is described in single embodiment, but also can provide separately or with the sub-portfolio be applicable to arbitrarily.

Unless otherwise indicated, all scientific and technical terminologies used in the present invention have the implication identical with the usual understanding of those skilled in the art of the invention.The all patents that the present invention relates to and public publication by reference entirety are incorporated to the present invention.

Unless otherwise indicated, following definition used herein should be applied.For purposes of the present invention, chemical element and periodic table of elements CAS version, and " chemistry and physics handbook ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can with reference to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley & Sons, description in New York:2007, its full content is incorporated to herein by reference.

Except as otherwise noted or in context, have obvious conflict, article used herein " ", " one (kind) " and " described " are intended to comprise " at least one " or " one or more ".Therefore, these articles used herein refer to the article of one or more than one (i.e. at least one) object.Such as, " component " refers to one or more component, more than one component namely may be had to be taken into account in the embodiment of described embodiment and adopt or use.

Term used in the present invention " study subject " refers to animal.Typically described animal is Mammals.Study subject, such as, also refer to primate (the such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc.In certain embodiments, described study subject is primate.In other embodiments, described study subject is people.

Term used in the present invention " patient " refers to people's (comprising adult and children) or other animals.In some embodiments, " patient " refers to people.

Term " comprises " for open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.

" steric isomer " refers to have identical chemical constitution, but atom or the group compound that spatially arrangement mode is different.Steric isomer comprises enantiomer, diastereomer, conformer (rotational isomer), geometrical isomer (cis/trans) isomer, atropisomer, etc.

" chirality " is that have can not the molecule of overlapping character with its mirror image; And " achirality " refer to can be overlapping with its mirror image molecule.

" enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror.

" diastereomer " refers to two or more chiral centre and the steric isomer of its molecule not mirror image each other.Diastereomer has different physical propertiess, as fusing point, boiling point, spectral quality and reactivity.Non-enantiomer mixture is by high resolution analysis operation as electrophoresis and chromatogram, and such as HPLC is separated.

Stereochemical definitions Sum fanction used in the present invention generally follows S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley & Sons, Inc., New York, 1994.

Many organic compound exist with optical active forms, and namely they have the ability that the plane of plane polarized light is rotated.When describing optically active compound, prefix D and L or R and S is used to represent the absolute configuration of molecule about one or more chiral centre.Prefix d and l or (+) and (-) are the symbols being used to specify plane polarized light rotation caused by compound, and wherein (-) or l represent that compound is left-handed.Prefix is the compound of (+) or d is dextrorotation.Concrete steric isomer is an enantiomer, and the mixture of this isomer is called enantiomeric mixture.The 50:50 mixture of enantiomer is called racemic mixture or racemic modification, when not having stereoselectivity or stereospecificity in chemical reaction or process, can occur this situation.

Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can exist with the form of racemize or enantiomorph enrichment, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in (R)-or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

According to the selection of starting material and method, the compounds of this invention can with in possible isomer or their mixture, and the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of unsymmetrical carbon) exists.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent preparation, or use routine techniques to split.If compound contains a double bond, substituting group may be E or Z configuration; If containing dibasic cycloalkyl in compound, the substituting group of cycloalkyl may have cis or transconfiguration.

The mixture of any steric isomer of gained can be separated into pure or substantially pure geometrical isomer according to the difference in component physicochemical property, enantiomer, diastereomer, such as, by chromatography and/or Steppecd crystallization.

By known method, the method that the racemic modification of any gained end product or intermediate is familiar with by those skilled in the art can be split into optical antipode, e.g., by being separated its diastereoisomeric salt obtained.Racemic product also can be separated by chiral chromatography, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, enantiomer can be prepared by asymmetric synthesis, such as, can with reference to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ^nded.Robert E.Gawley, Jeffrey Aub é, Elsevier, Oxford, UK, 2012); Eliel, E.L.Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H.Tables of Resolving Agents and Optical Resolutions p.268 (E.L.Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques:A Practical Approach (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim, Germany, 2007).

Term " tautomer " or " tautomeric form " refer to the constitutional isomer transformed mutually by low energy barrier (low energy barrier) with different-energy.If tautomerism is possible (as in the solution), then can reach the chemical equilibrium of tautomer.Such as, proton tautomer (protontautomer) (also referred to as Prototropic tautomers (prototropic tautomer)) comprises the mutual conversion undertaken by proton shifting, as keto-enol isomerization and imine-enamine isomerizations.Valence tautomerism body (valence tautomer) comprises the mutual conversion undertaken by the restructuring of some bonding electronss.The specific examples of keto-enol tautomerism is the change of pentane-2,4-diketone and 4-hydroxyl penta-3-alkene-2-keto tautomer.Another example tautomeric is phenol-keto tautomerism.A specific examples of phenol-keto tautomerism is the change of pyridine-4-alcohol and pyridine-4 (1H)-one tautomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention all within the scope of the present invention.

As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or special example inside picture embodiment, subclass, and the compounds that the present invention comprises.

Should be appreciated that " optional replacement " this term can exchange use with " substituted or non-substituted " this term.Generally speaking, term " replacement " represent give the one or more hydrogen atoms in structure replace by concrete substituting group.Unless other aspects show, an optional substituted radical can replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.

Term " unsubstituted ", represents and specifies group without substituting group.

Term " optionally by ... replaced ", can " not replace or quilt ... replaced " to exchange with term and use, namely described structure is unsubstituted or is replaced by one or more substituting group of the present invention, and substituting group of the present invention includes, but are not limited to D, F, Cl, Br, I, N ₃, CN, NO ₂, OH, SH, NH ₂, alkyl, haloalkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-S (=O) ₂-alkyl ,-S (=O) ₂nH ₂,-C (=O)-alkyl ,-OC (=O)-alkyl or-C (=O) O-alkyl.

In addition, it should be noted that, unless otherwise explicitly pointed out, adopted in the present invention describing mode " each ... be independently " and " ... be independently of one another " and " ... be independently " can exchange, all should be interpreted broadly, it both can refer in different group, did not affect mutually between concrete option expressed between same-sign, also can represent in identical group, not affect mutually between concrete option expressed between same-sign.

At each several part of this specification sheets, the come into the open substituting group of compound of the present invention is open according to radical species or scope.Particularly point out, each the independently sub-combinations thereof that the present invention includes each member of these radical species and scope.Such as, term " C ₁-C ₆alkyl " refer in particular to independent disclosed methyl, ethyl, C ₃alkyl, C ₄alkyl, C ₅alkyl and C ₆alkyl.

At each several part of the present invention, describe connection substituting group.When this structure clearly needs linking group, be interpreted as linking group for the Ma Kushi variable cited by this group.Such as, if this structure needs linking group and Ma Kushi group definition for this variable lists " alkyl " or " aryl ", then should be appreciated that, " alkyl " or " aryl " alkylidene group or the arylene group of connection should be represented respectively.

The term " alkyl " that the present invention uses or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight or branched univalent hydrocarbyl group, wherein, the substituting group that described alkyl group can optionally be described by one or more the present invention replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 carbon atom; In another embodiment, alkyl group contains 1-6 carbon atom; In yet another embodiment, alkyl group contains 1-4 carbon atom; Also in one embodiment, alkyl group contains 1-3 carbon atom.

The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH ₃), ethyl (Et ,-CH ₂cH ₃), n-propyl (n-Pr ,-CH ₂cH ₂cH ₃), sec.-propyl (i-Pr ,-CH (CH ₃) ₂), normal-butyl (n-Bu ,-CH ₂cH ₂cH ₂cH ₃), isobutyl-(i-Bu ,-CH ₂cH (CH ₃) ₂), sec-butyl (s-Bu ,-CH (CH ₃) CH ₂cH ₃), the tertiary butyl (t-Bu ,-C (CH ₃) ₃), n-pentyl (-CH ₂cH ₂cH ₂cH ₂cH ₃), 2-amyl group (-CH (CH ₃) CH ₂cH ₂cH ₃), 3-amyl group (-CH (CH ₂cH ₃) ₂), 2-methyl-2-butyl (-C (CH ₃) ₂cH ₂cH ₃), 3-methyl-2-butyl (-CH (CH ₃) CH (CH ₃) ₂), 3-methyl isophthalic acid-butyl (-CH ₂cH ₂cH (CH ₃) ₂), 2-methyl-1-butene base (-CH ₂cH (CH ₃) CH ₂cH ₃), n-hexyl (-CH ₂cH ₂cH ₂cH ₂cH ₂cH ₃), 2-hexyl (-CH (CH ₃) CH ₂cH ₂cH ₂cH ₃), 3-hexyl (-CH (CH ₂cH ₃) (CH ₂cH ₂cH ₃)), 2-methyl-2-amyl group (-C (CH ₃) ₂cH ₂cH ₂cH ₃), 3-methyl-2-amyl group (-CH (CH ₃) CH (CH ₃) CH ₂cH ₃), 4-methyl-2-amyl group (-CH (CH ₃) CH ₂cH (CH ₃) ₂), 3-methyl-3-amyl group (-C (CH ₃) (CH ₂cH ₃) ₂), 2-methyl-3-amyl group (-CH (CH ₂cH ₃) CH (CH ₃) ₂), 2,3-dimethyl-2-butyl (-C (CH ₃) ₂cH (CH ₃) ₂), 3,3-dimethyl-2-butyl (-CH (CH ₃) C (CH ₃) ₃), n-heptyl, n-octyl, etc.

Term " alkylidene group " represents the saturated bivalent hydrocarbon radical group removing two hydrogen atoms and obtain from saturated straight or branched alkyl.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In one embodiment, alkylidene group contains 1-6 carbon atom; In another embodiment, alkylidene group contains 1-4 carbon atom; In yet another embodiment, alkylidene group contains 1-3 carbon atom; Also in one embodiment, alkylidene group contains 1-2 carbon atom.Such example comprises methylene radical (-CH ₂-), ethylidene (-CH ₂cH ₂-), isopropylidene (-CH (CH ₃) CH ₂-) etc.

Term " thiazolinyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has a unsaturated site at least, namely has a carbon-to-carbon sp ²double bond, wherein, described alkenyl group can optionally replace by one or more substituting group described in the invention, it comprises " cis " and the location of " tans ", or the location of " E " and " Z ".In one embodiment, alkenyl group comprises 2-8 carbon atom; In another embodiment, alkenyl group comprises 2-6 carbon atom; In yet another embodiment, alkenyl group comprises 2-4 carbon atom.The example of alkenyl group comprises, but is not limited to, vinyl (-CH=CH ₂), allyl group (-CH ₂cH=CH ₂) etc.

Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has a unsaturated site at least, namely have a carbon-to-carbon sp triple bond, wherein, described alkynyl group can optionally replace by one or more substituting group described in the invention.In one embodiment, alkynyl group comprises 2-8 carbon atom; In another embodiment, alkynyl group comprises 2-6 carbon atom; In yet another embodiment, alkynyl group comprises 2-4 carbon atom.The example of alkynyl group comprises, but is not limited to, ethynyl (-C ≡ CH), propargyl (-CH ₂c ≡ CH), 1-proyl (-C ≡ C-CH ₃) etc.

Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.In one embodiment, alkoxy base contains 1-6 carbon atom; In another embodiment, alkoxy base contains 1-4 carbon atom; In yet another embodiment, alkoxy base contains 1-3 carbon atom.The substituting group that described alkoxy base can optionally be described by one or more the present invention replace.

The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH ₃), oxyethyl group (EtO ,-OCH ₂cH ₃), 1-propoxy-(n-PrO, n-propoxy-,-OCH ₂cH ₂cH ₃), 2-propoxy-(i-PrO, i-propoxy-,-OCH (CH ₃) ₂), 1-butoxy (n-BuO, n-butoxy ,-OCH ₂cH ₂cH ₂cH ₃), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH ₂cH (CH ₃) ₂), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH ₃) CH ₂cH ₃), 2-methyl-2-propoxy-(t-BuO, t-butoxy ,-OC (CH ₃) ₃), 1-pentyloxy (n-pentyloxy ,-OCH ₂cH ₂cH ₂cH ₂cH ₃), 2-pentyloxy (-OCH (CH ₃) CH ₂cH ₂cH ₃), 3-pentyloxy (-OCH (CH ₂cH ₃) ₂), 2-methyl-2-butoxy (-OC (CH ₃) ₂cH ₂cH ₃), 3-methyl-2-butoxy (-OCH (CH ₃) CH (CH ₃) ₂), 3-methyl-l-butoxy (-OCH ₂cH ₂cH (CH ₃) ₂), 2-methyl-l-butoxy (-OCH ₂cH (CH ₃) CH ₂cH ₃), etc.

Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents alkyl, thiazolinyl or alkoxy base replace by one or more halogen atom, such example comprises, but is not limited to, trifluoromethyl (-CF ₃), trifluoromethoxy (-OCF ₃) etc.

Term " carbocylic radical " or " carbocyclic ring " expression contain 3-12 carbon atom, nonaromatic saturated or the unsaturated monocycle of part, dicyclo or the three-ring system of unit price or multivalence.Carbon bicyclic group comprises spiral shell carbon bicyclic group, condenses carbon bicyclic group and bridge carbon bicyclic group, and suitable carbocylic radical group comprises, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of carbocylic radical group comprises further, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, etc.

Term " cycloalkyl " expression contains 3-12 carbon atom, nonaromatic saturated or the unsaturated monocycle of part, dicyclo or the three-ring system of unit price or multivalence.In one embodiment, cycloalkyl comprises 3-12 carbon atom; In another embodiment, cycloalkyl comprises 3-8 carbon atom; In yet another embodiment, cycloalkyl comprises 3-6 carbon atom.The example of group of naphthene base comprises, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.The substituting group that described group of naphthene base can optionally be described by one or more the present invention replace.

Term " heterocyclic radical " and " heterocycle " commutative use herein, all refer to and comprise the saturated of 3-12 annular atoms or the undersaturated monocycle of part, dicyclo or three rings, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, heterocyclic radical can be carbon back or nitrogen base, and-CH ₂-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of heterocyclic radical comprises, but be not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1, 3-dioxy cyclopentyl, two sulphur cyclopentyl, THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, alkyl dioxin, dithiane base, thioxane base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia suberane base, oxygen azepine base, diaza base, sulphur azepine base, indoline base, 1,2,3,4-tetrahydro isoquinolyl, 1,3-Ben Bing bis-Evil cyclopentadienyl, 2-oxa--5-azabicyclo [2.2.1]-5-in heptan base.-CH in heterocyclic radical ₂-group is comprised by the example of-C (=O)-replacement, but be not limited to, 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl, 2-piperidone base, 3-morpholine ketone group, 3-thiomorpholine ketone group, pyriconyl, 3,5-dioxopiperidine bases and pyrimidine dione base.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to tetramethylene sulfone base, 1,1-dioxothiomorpholinyl.Described heterocyclyl groups can not be substituted independently or replace by one or more substituting group described in the invention.

In one embodiment, heterocyclic radical is 3-6 former molecular heterocyclic radical, and refer to and comprise the saturated of 3-6 annular atoms or the undersaturated monocycle of part, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 3-6 former molecular heterocyclic radical can be carbon back or nitrogen base, and-CH ₂-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of 3-6 former molecular heterocyclic radical comprises, but be not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1, 3-dioxy cyclopentyl, two sulphur cyclopentyl, THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, alkyl dioxin, dithiane base, thioxane base.-CH in heterocyclic radical ₂-group is comprised by the example of-C (=O)-replacement, but be not limited to, 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl, 2-piperidone base, 3-morpholine ketone group, 3-thiomorpholine ketone group, pyriconyl, 3,5-dioxopiperidine bases and pyrimidine dione base.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to tetramethylene sulfone base, 1,1-dioxothiomorpholinyl.Described 3-6 former molecular heterocyclyl groups can not be substituted independently or replace by one or more substituting group described in the invention.

In another embodiment, heterocyclic radical is 5 former molecular heterocyclic radicals, and refer to and comprise the saturated of 5 annular atomses or the undersaturated monocycle of part, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 5 former molecular heterocyclic radicals can be carbon back or nitrogen base, and-CH ₂-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of 5 former molecular heterocyclic radicals includes, but are not limited to: pyrrolidyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3-dioxy cyclopentyl, two sulphur cyclopentyl.-CH in heterocyclic radical ₂-group is included, but not limited to 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl by the example of-C (=O)-replacement.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to tetramethylene sulfone base.Described 5 former molecular heterocyclyl groups can not be substituted independently or replace by one or more substituting group described in the invention.

In another embodiment, heterocyclic radical is 6 former molecular heterocyclic radicals, and refer to and comprise the saturated of 6 annular atomses or the undersaturated monocycle of part, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 6 former molecular heterocyclic radicals can be carbon back or nitrogen base, and-CH ₂-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of 6 former molecular heterocyclic radicals includes, but are not limited to: THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, alkyl dioxin, dithiane base, thioxane base.-CH in heterocyclic radical ₂-group is included, but not limited to 2-piperidone base, 3-morpholine ketone group, 3-thiomorpholine ketone group, pyriconyl, 3,5-dioxopiperidine bases and pyrimidine dione base by the example of-C (=O)-replacement.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to 1,1-dioxothiomorpholinyl.Described 6 former molecular heterocyclyl groups can not be substituted independently or replace by one or more substituting group described in the invention.

Term " n former molecular ", wherein n is integer, typically describes the number of ring member nitrogen atoms in molecule, and in described molecule, the number of ring member nitrogen atoms is n.Such as, piperidyl is 6 former molecular Heterocyclylalkyls, and 1,2,3,4-naphthane is 10 former molecular carbocylic radical groups.

Term " undersaturated " used in the present invention represents in group containing one or more degree of unsaturation.

Term " heteroatoms " refers to O, S, N, P and Si, comprises the form of any oxidation state of N, S and P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, such as, N (N as in 3,4-dihydro-2 h-pyrrole base), NH (NH as in pyrrolidyl) or NR (NR as in the pyrrolidyl that N-replaces).

Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Term " aryl " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the carbocyclic ring system of the monocycle of 6-10 annular atoms, dicyclo and three rings, wherein, at least one member ring systems is aromatic, wherein each member ring systems comprises 3-7 former molecular ring, and has one or more attachment point to be connected with the rest part of molecule.Term " aryl " can exchange with term " aromatic nucleus " and use.The example of aromatic yl group can comprise phenyl, naphthyl and anthryl.Described aromatic yl group can not be substituted independently or replace by one or more substituting group described in the invention.

Term " heteroaryl " represents containing 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, dicyclo and three-ring system, wherein at least one member ring systems is aromatic, and at least one aromatic ring system comprises one or more heteroatoms, wherein each member ring systems comprises 5-7 former molecular ring, and has one or more attachment point to be connected with molecule rest part.Term " heteroaryl " can exchange with term " hetero-aromatic ring " or " heteroaromatics " and use.In one embodiment, heteroaryl is comprise heteroatomic 5-6 the former molecular heteroaryl that 1,2,3 or 4 is independently selected from O, S and N.Described heteroaryl groups can not be substituted independently or replace by one or more substituting group described in the invention.

The example of heteroaryl groups comprises, but be not limited to, 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, pyrazinyl, 1, 3, 5-triazinyl, also following dicyclo is comprised, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl is (as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl is (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), imidazo [1, 2-a] pyridyl, pyrazolo [1, 5-a] pyridyl, pyrazolo [1, 5-a] pyrimidyl, imidazo [1, 2-b] pyridazinyl, [1, 2, 4] triazolo [4, 3-b] pyridazinyl, [1, 2, 4] triazolo [1, 5-a] pyrimidyl, [1, 2, 4] triazolo [1, 5-a] pyridyl, etc..

Term " alkylamino " comprises " N-alkylamino " and " N, N-dialkyl amido ", wherein amino group separately replace by one or two alkyl group.Some of them embodiment is, alkylamino is one or two C _1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is, alkylamino is C _1-4more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to, N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.

Term " aryloxy " or " aryloxy " comprise the optional aryl replaced, as defined herein, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein aromatic yl group has implication as described in the present invention, and such example comprises, but is not limited to phenoxy group, tolyloxy, second phenoxy group etc.

Term " aminoalkyl group " comprise the C that replaces by one or more amino _1-10straight or branched alkyl group.Some of them embodiment is, aminoalkyl group the C that replaces by one or more amino group _1-6" more rudimentary aminoalkyl group ", such example comprises, but is not limited to, aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.

As described in the invention, substituting group is drawn a key and is connected to the member ring systems (shown in a) that the ring at center is formed and represents substituting group any commutable position in this member ring systems and can replace.Such as, formula a represent substituting group can on A ring any position that may be substituted, shown in b ~ formula d.

Time term " blocking group " or " PG " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC; Boc), carbobenzoxy-(Cbz) (CBZ, Cbz) and the sub-methoxycarbonyl (Fmoc) of 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH ₂cH ₂sO ₂ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can reference for the general description of blocking group: T W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug _1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al., Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.

" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, described in 1977,66:1-19..The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N ⁺(C _1-4alkyl) ₄salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C _1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid and monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.

Term as used in the present invention " treatment " any disease or illness, some embodiment middle fingers improve disease or illness (namely slow down or stop or palliate a disease or the development of its at least one clinical symptom) wherein.In other embodiments, " treatment " refers to relax or improve at least one body parameter, comprises the body parameter may not discovered for patient.In other embodiments, " treatment " refer to from health (such as stablizing perceptible symptom) or physiology (such as stablizing the parameter of health) or above-mentioned two aspects regulate disease or illnesss.In other embodiments, " treatment " refer to prevent or postpone the outbreak of disease or illness, generation or deterioration.

" thrombotic disease " used in the present invention refers to the disease of being drawn by thrombosis and thromboembolism two kinds of pathologic processes, also known as thrombotic diseases.Thrombosis refers under certain condition, and shaped components in blood is partially formed embolus at Ink vessel transfusing or cardiac intima, causes vasculature part or blocks completely, the pathologic process of corresponding site blood supply obstacle.Thromboembolism is that thrombus is come off by forming part, and with in blood flow process, part or all of artery-clogging, causes the pathologic process of blood vessel or global ischemia, anoxic, necrosis, extravasated blood and oedema.The example of thrombotic disease includes but not limited to arterial cardiovascular thromboembolic disorders, intravenous cardio thromboembolic disorders and the thromboembolic disorders in the chamber of heart.This type of disease more specifically example comprises, but be not limited to, myocardial infarction, stenocardia (comprising unstable angina), acute coronary syndrome, to block and restenosis after revascularization or aorta Coronary artery bypass, apoplexy, the outbreak of of short duration local asphyxia, peripheral arterial occlusive disease, arterial thrombus, Coronary thrombosis, cerebral artery thrombosis formation, cerebral embolism, renal infarction, pulmonary infarction, thrombophlebitis, venous thrombosis or venous thrombosis again, etc.

" disseminated inravascular coagulation (DIC) " used in the present invention refers to the coagulation system activation occurred on various diseases basis, cause extensive microthrombusis in thin vessels, consume a large amount of thrombin and secondary hyperfibrinolysis, and then cause the clinical syndrome of general hemorrhage and microcirculation failure.The formation of microthrombus widely can cause multiple organ dysfunction syndrome, activates fibrinolytic system and thrombin is exhausted, thus secondary hemorrhage.Therefore disseminated inravascular coagulation is a kind of blood coagulation and hemorrhage concurrent syndromes.At present, main methods for the treatment of be on the basis actively controlling protopathy, carry out anti-freezing, substitute, platelet aggregation-against and supportive treatment etc. of suiting the medicine to the illness.Therefore, compounds for treating disseminated inravascular coagulation disclosed by the invention can be used.

Pharmaceutically useful acid salt can be formed with mineral acid and organic acid, such as acetate, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, hydrosulfate/vitriol, camsilate, muriate/hydrochloride, chloro theophylline salt, Citrate trianion, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydriodate/iodide, isethionate, lactic acid salt, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, poly-semi-lactosi hydrochlorate, propionic salt, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.

Such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. can be comprised by its derivative mineral acid obtaining salt.

Such as acetic acid, propionic acid, oxyacetic acid, oxalic acid, toxilic acid, propanedioic acid, succsinic acid, fumaric acid, tartrate, citric acid, phenylformic acid, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, sulphosalicylic acid etc. can be comprised by its derivative organic acid obtaining salt.

Pharmaceutically acceptable base addition salt can be formed with mineral alkali and organic bases.

Can be comprised by its derivative mineral alkali obtaining salt, the metal of I race to the XII race of such as ammonium salt and periodictable.In certain embodiments, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; Particularly suitable salt comprises ammonium, potassium, sodium, calcium and magnesium salts.

Can comprise primary amine, secondary amine and tertiary amine by its derivative organic bases obtaining salt, the amine of replacement comprises the amine, cyclic amine, deacidite etc. of naturally occurring replacement.Some organic amine comprises, such as, and Isopropylamine, dibenzylethylenediamine dipenicillin G (benzathine), choline salt (cholinate), diethanolamine, diethylamine, Methionin, meglumine (meglumine), piperazine and Trometamol.

Pharmacologically acceptable salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes.Generally speaking, such salt can react by making the suitable alkali of the free acid form of these compounds and stoichiometry (oxyhydroxide, carbonate, supercarbonate etc. as Na, Ca, Mg or K), or by making the suitable acid-respons of the free alkali form of these compounds and stoichiometry be prepared.Such reaction is carried out usually in water or organic solvent or the mixture of the two.Usually, when suitable, need to use non-aqueous media as ether, ethyl acetate, ethanol, Virahol or acetonitrile.At such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985); " pharmaceutical salts handbook: character, choice and application (Handbook of Pharmaceutical Salts:Properties; Selection; and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) other can be found to be suitable for the list of salt in.

In addition, compound disclosed by the invention, comprise their salt, also can obtain, for their crystallization with their hydrate forms or the form comprising its solvent (such as ethanol, DMSO, etc.).Compound is come into the open in the present invention can with pharmaceutically acceptable solvent (comprising water) inherently or by design forming solvate; Therefore, the present invention be intended to comprise solvation and the form of non-solvation.

Any structural formula that the present invention provides is also intended to represent these compounds not by the form of the form of isotopic enrichment and isotopic enrichment.The compound of isotopic enrichment has the structure of the general formula description that the present invention provides, except one or more atom is replaced by the atom with selected nucleidic mass or total mass number.The Exemplary isotopes can introduced in the compounds of this invention comprises the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, as ²h, ³h, ¹¹c, ¹³c, ¹⁴c, ¹⁵n, ¹⁷o, ¹⁸o, ¹⁸f, ³¹p, ³²p, ³⁵s, ³⁶cl and ¹²⁵i.

On the other hand, such as, wherein there is radio isotope in the compound that the present invention that compound of the present invention comprises isotopic enrichment defines, as ³h, ¹⁴c and ¹⁸those compounds of F, or wherein there is non radioactive isotope, as ²h and ¹³c.The compound of such isotopic enrichment can be used for metabolism research and (uses ¹⁴c), reaction kinetics research (uses such as ²h or ³h), detect or imaging technique, as positron emission tomography (PET) or the SPECT (single photon emission computed tomography) (SPECT) comprising medicine or substrate tissue measure of spread, or can be used in the radiotherapy of patient. ¹⁸the compound of F enrichment is desirable especially for PET or SPECT research.Use suitable isotope labeling reagent to substitute original used unmarked reagent described by embodiment in the routine techniques that shown in the formula (I) of isotopic enrichment, compound can be familiar with by those skilled in the art or the present invention and preparation process to prepare.

In addition, particularly deuterium is (that is, for higher isotope ²h or D) replacement can provide some treatment advantage, these advantages are brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index improves brings.Should be appreciated that the deuterium in the present invention is seen as the substituting group of formula (I) compound.The concentration of such higher isotope particularly deuterium can be defined by the isotopic enrichment factor.Term used in the present invention " the isotopic enrichment factor " refers to specified ratio between isotopic isotopic abundance and natural abundance.If the substituting group of the compounds of this invention is designated as deuterium, this compound has at least 3500 (each deuterium at D atom place 52.5% of specifying mixes) to each D atom of specifying, at least 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (deuterium of 75% mixes), at least 5500 (deuterium of 82.5% mixes), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7 (deuterium of 97% mixes), the isotopic enrichment factor of at least 6600 (deuterium of 99% mixes) or at least 6633.3 (deuterium of 99.5% mixes).It can be the such as D that isotropic substance replaces that the pharmaceutically useful solvate of the present invention comprises wherein recrystallisation solvent ₂o, acetone-d ₆, DMSO-d ₆those solvates.

Unless other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.

The description of compound of the present invention

The invention provides a kind of compound, or its pharmaceutical composition, can effectively treat the thrombotic disease relevant to Xa factor.

On the one hand, the present invention relates to a kind of compound, it is for such as formula the compound shown in (I), or the steric isomer of compound shown in formula (I), tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

Wherein: A, R ¹, R ²with n, there is implication as described in the present invention.

R ¹for H, C _1-4alkyl, C _2-4thiazolinyl or C _2-4alkynyl;

N is 0,1,2 or 3.

In some embodiments, A is phenyl, optionally by 1 or 2 R ³replaced;

R ¹for H, methyl, ethyl, propyl group or sec.-propyl;

Each R ²be H, D, F, Cl or Br independently;

N is 1.

Also in some embodiments, the present invention relates to following one of them compound or its steric isomer, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or its prodrug, but be never limited to these compounds:

On the other hand, the present invention relates to described compound or described pharmaceutical composition is preparing the purposes in medicine, described medicine is for suppressing Xa factor.

The present invention comprises the application of the compounds of this invention and pharmacy acceptable salt thereof, for the production of pharmaceutical prod treatment patient thrombotic disease, comprises the disease that those are described in the invention.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound representated by formula (I) and the pharmaceutically acceptable carrier of at least one, vehicle, thinner, assistant agent, the effective therapeutic dose needed for vectorial combination.

The present invention comprises treatment equally or alleviates patient's thrombotic disease, or the method to this illness sensitivity, and the treatment significant quantity that the method comprises the representative compound of use formula (I) is treated patient.

Thrombotic disease of the present invention is myocardial infarction, stenocardia, to block and restenosis after revascularization or aorta Coronary artery bypass, apoplexy, the outbreak of of short duration local asphyxia, peripheral arterial occlusive disease, pulmonary infarction or venous thrombosis again.

Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.

Specifically, salt is pharmacy acceptable salt.It must be applicable to chemistry or toxicologically that term " pharmaceutically acceptable " comprises material or composition, relevant with other components of composition preparation and the Mammals that is used for the treatment of.

The salt of compound of the present invention also comprise for the preparation of or purifying formula (I) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I), but not necessarily pharmacy acceptable salt.

If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.

If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, from the organic salt that amino acid obtains, as glycine and arginine, and ammonia, as uncle ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.

The pharmaceutical composition of the compounds of this invention, preparation, administration and purposes

The invention provides a kind of pharmaceutical composition, it comprises compound disclosed by the invention, or compound listed in embodiment, and pharmaceutically acceptable vehicle, carrier, adjuvant, solvent or their combination.In composition of the present invention, patient's thrombotic disease can be treated or be alleviated to the amount of compound or effectively as Xa factor inhibitor.

There is free form in compound of the present invention, or suitable, as pharmaceutically acceptable derivates.According to the present invention, pharmaceutically acceptable derivates comprises, but be not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of ester class, or can directly or indirectly according to other any adducts or derivatives of needing administration of patient, the compound described by other aspects of the present invention, its meta-bolites or its residue.

As described in the invention, the pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier, assistant agent further, or vehicle, these are applied as the present invention, comprise any solvent, thinner, or other liquid excipients, dispersion agent or suspension agent, tensio-active agent, isotonic agent, thickening material, emulsifying agent, sanitas, solid binder or lubricant, etc., be suitable for distinctive target formulation.As with described by Publication about Document: In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, show that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Except carrier medium and the inconsistent scope of compound of the present invention of any routine, such as produced any bad biological effect or the interaction produced in harmful mode with any other component of pharmaceutically acceptable composition, their purposes is also the scope that the present invention considers.

The material that can be used as pharmaceutically acceptable carrier comprises, but be not limited to, ion-exchanger, aluminium, aluminum stearate, Yelkin TTS, serum protein, as human serum protein, buffer substance is as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloidal silicon, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanolin, sugar, as lactose, dextrose plus saccharose, starch is as W-Gum and potato starch, Mierocrystalline cellulose and its derivative as Xylo-Mucine, ethyl cellulose and rhodia, natural gum powder, Fructus Hordei Germinatus, gelatin, talcum powder, auxiliary material is as cocoa butter and suppository wax, oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil, glycol compound, as propylene glycol and polyoxyethylene glycol, ester class is as ethyl oleate and Ethyl Lauroyl acid esters, agar, buffer reagent is as magnesium hydroxide and aluminium hydroxide, Lalgine, pyrogen-free water, isotonic salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, coating agents, sweeting agent, seasonings and spices, sanitas and antioxidant.

The compounds of this invention can be applied with the form of oral preparation, as tablet, and capsule (wherein each comprises the formula of sustained release or time controlled released), pill, pulvis, granula, elixir, tincture, suspension agent, syrup, and emulsifying agent.They also can with intravenously (bolus or transfusion), intraperitoneal, and subcutaneous or intramuscular form is used, and the dosage form of all uses is all known by the those of ordinary skill of pharmaceutical field.They can be used separately, but generally select to use together with a kind of pharmaceutical carriers by based on selected method of application and the pharmacy practice of standard.

The dosage regimen of the compounds of this invention by different with known various factors, as the characteristics of pharmacokinetics of particular agent and pattern thereof and route of administration; The race of recipient, age, sex, healthy state, medical conditions and body weight; The nature and extent of symptom; The kind of parallel treatment; The frequency for the treatment of; The approach of dispenser, the kidney of patient and liver function, and the effect that hope reaches.A doctor or animal doctor can make decision and the medicine being with effective amount prevents, offsets or stop the development of thromboembolic disorders.

According to general governing principle, in order to reach the effect of specifying, each activeconstituents used day oral dosage scope be about 0.001 between 1000mg/kg body weight, preferably, between about 0.01 to 100mg/kg body weight.And, most preferably, between about 1.0 to 20mg/kg body weight/day.Use for intravenous, in the infusion process of conventional rate most preferred dosage range be about 1 to about 10mg/kg body weight/minute.The compounds of this invention can to use once a day, or can with every day at twice, use for three times or four times.

Compound of the present invention can use through the local of suitable nasal carrier and use with intranasal form, or uses with cutaneous routes through the subsides of skin medicine by using.When using with the form of transdermal delivery system, the dosage used during whole medication is continuous print instead of interval.

Typically, this compound and the suitable pharmaceutical diluents selected according to the form used and conventional pharmacy practice, vehicle, or carrier (referring to pharmaceutical carriers at this) is mixed to be used, and method of application can be oral tablet, capsule, elixir, syrup etc.

Such as, use for tablet or capsules per os, active medicine component can combine, as lactose with a kind of oral, atoxic, pharmaceutically acceptable inert carrier, starch, sucrose, glucose, methylcellulose gum, Magnesium Stearate, Si Liaodengji dicalcium phosphate feed grade, calcium sulfate, N.F,USP MANNITOL, sorbyl alcohol etc.; For Orally administered in liquid form, oral drug components can with any oral, atoxic, pharmaceutically acceptable inert carrier combine, as ethanol, glycerine, water etc.And, when needs or required time, suitable tackiness agent, slipping agent, decomposing agents and tinting material also can join in mixture.Suitable tackiness agent comprises starch, gelatin, natural sugar as glucose or beta lactose, corn sweetener, natural gum that is natural and synthesis as gum arabic, tragacanth, or sodiun alginate, carboxymethyl cellulose, polyethylene glycol, wax etc.The lubricant applied in these formulations comprises sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium acetate, sodium-chlor etc.Decomposition agent includes, but not limited to starch, methylcellulose gum, agar, wilkinite, xanthan gum, etc.

The compounds of this invention also can be used with the form of liposomal delivery system, as the vesica of little individual layer, and the vesica of large individual layer and multilamellar vesicle.Liposome can be formed by different phosphatide, as cholesterol, and stearylamine, or phosphatidylcholine.

The compounds of this invention also with the polymkeric substance coupling of solubility, this polymer is as the pharmaceutical carriers of target.Such polymer comprises polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyl methacrylate amine-phenol, poly-hydroxyethyl l-asparagine phenol, or with polyethylene oxide-polylysine that palmitoyl residues replaces.And, the compounds of this invention can with a class Biodegradable polymeric coupling, for completing controllable drug release, such as, poly(lactic acid), polyglycolic acid, the multipolymer of poly(lactic acid) and polyglycolic acid, poly- _εcaprolactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydropyrane, polybutylcyanoacrylate, and the crosslinked or amphipathic blocking-up multipolymer of hydrogel.

Be suitable for the per unit dosage of the formulation (pharmaceutical composition) used, the activeconstituents of about 1mg to about 100mg can be contained.In these pharmaceutical compositions, the weight of activeconstituents generally will account for about 0.5-95% of the gross weight of composition.

Gelatine capsule can contain activeconstituents and powder carrier, as lactose, and starch, derivatived cellulose, Magnesium Stearate, stearic acid, etc.Similar thinner can be used to make compressed tablets.The product of Tablet and Capsula as sustainable release can be manufactured to be provided in the medicine of continuous release in for some time.The tablet of compression can add sugar-coat or wrap thin film to cover any offending taste and to make tablet and air exclusion, or adds that the bag of enteric solubility is optionally decomposed by gastrointestinal disturbances road.

Orally administered liquid dosage form can containing tinting material and food flavouring to improve the acceptance of patient.

Usually, water, a kind of suitable oil, salt solution, the dextrose (glucose) of hydration, and relevant sugar soln and glycol (as propylene glycol or polyoxyethylene glycol) are the Suitable carriers of parenteral solution.Without the water-soluble salt of solution preferably containing activeconstituents that enteron aisle is used, suitable stablizer, and buffer substances that may be necessary.Antioxidant is suitable stablizer, and as sodium bisulfite, S-WAT, or vitamins C, both also can combinationally use separately and also can use citric acid and its salt and EDETATE SODIUM salt.In addition, parenteral solution also contains sanitas, as geramine, and methyl-or propyl group-p-Hydroxybenzoate, and chlorobutanol.

Wherein compound of the present invention and other anti-freezing agent combination, such as, for every kg patient body weight, a kind of per daily dose can be the compound of the formula (I) of about 0.1 to 100mg and second antithrombotics of about 1 to 7.5mg.For a kind of Tabules, compound of the present invention can be generally that each dose unit has about 5 to 10mg, and the amount of the second anti-agglutinant is that each dose unit has approximately from 1 to 5mg.Wherein, other anti-freezing reagent specifically comprises, but be not limited to, Eliquis, razaxaban, Yi Dushaban, shellfish Qu Shaban, dabigatran, bemiparin, Enoxaparin Sodium, Tinzaparin sodium, Danaparoid sodium, piperylene sodium, nadroparin calcium, Ardeparin Sodium, Parnaparin Sodium etc.

According to general governing principle, the compounds of this invention and a kind of antiplatelet agent combination are used, general per daily dose can be that per kilogram patient body weight about 0.01 arrives the compound of the formula (I) of 25mg and the antiplatelet reagent of about 50 to 150mg, and preferably approximately 0.1 arrives the compound of the formula (I) of 1mg and the antiplatelet reagent of about 1 to 3mg.

When compound and the thrombolytics combined administration of formula (I), general per daily dose can be the compound of per kilogram patient body weight about 0.1 to the formula (I) of 1mg, and under thrombolytics existent condition, compared with general dosage when using separately with thrombolytics, when thrombolytics is used together with the compound of formula (I), the dosage of thrombolytics can reduce about 70-80%.

When two or more aforesaid second therapeutical agents are used together with the compound of formula (I), usually, additional or the collaborative effect of therapeutical agent when considering co-administered, the amount of each component in typical per daily dose and typical formulation, relative to usual dosage when using separately, can decline to some extent.

Especially, when providing as a single dose unit, between the activeconstituents that there is combination, there is the possibility of chemical reaction.Due to this reason, when the compound of formula (I) and the second therapeutical agent are in a single dose unit during united, their compound method will make the minimize physical contact between activeconstituents (namely be, reduce), although active ingredient combinations is in a single dose unit.Such as, a kind of activeconstituents can be enteric coating bag quilt.By enteric coating bag by a kind of activeconstituents, likely not only make the contact between the activeconstituents of associating minimize, but also a kind of release in the gastrointestinal tract likely controlled in these compositions is not so that the one of these components discharge and discharge in small intestine under one's belt.It is further that activeconstituents a kind of also can superscribe the material affecting its sustained release in the gastrointestinal tract and can be used for the physical contact reduced between the activeconstituents of associating, the component of sustained release also can extraly with enteric coating bag by so that this composition only discharges in enteron aisle.Another method is also had to relate to the formula of associating product, a kind of polymer coating of lasting and/or enteric release of one of them component, and another component also uses polymer as a kind of HYDROXY PROPYL METHYLCELLULOSE (HPMC) of low viscosity rank or other suitable material bag quilt known in the field, to reach the object of further separate active ingredients.The reaction of polymer coating pair and other component defines a kind of obstruction additionally.

Once understanding present disclosure, these and other make the minimized method of contact between the component of associating product of the present invention be clearly for those skilled in the art, no matter they are used with single formulation or use with the form be separated, but be in the identical time or use in an identical manner.

The compound that the present invention relates to or its pharmaceutical salts or its hydrate can be effective to prevent, process, treat or alleviate patient's thrombotic disease, particularly effectively can treat myocardial infarction, stenocardia, block and restenosis after revascularization or aorta Coronary artery bypass, apoplexy, the outbreak of of short duration local asphyxia, peripheral arterial occlusive disease, pulmonary infarction or venous thrombosis.

General building-up process

Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I).Reaction scheme below and embodiment are used for illustrating content of the present invention further.

Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.

The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.

Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.

Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all through dry.

Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1 ₃, d ₆-DMSO, CD ₃oD or d ₆-acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, two triplet), ddd (doublet of doublet of doublets, doublet in pairs), ddt (doublet of doublet of triplets, triplet in pairs), dddd (doublet of doublet of doublet of doublets, double doublet in pairs).Coupling constant, represents with hertz (Hz).

Algorithm (MS) data are measured by the spectrograph of the serial LC-MS of Agilent 6320 being equipped with G1312A binary pump and a G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315B DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.

Algorithm (MS) data are measured by the spectrograph of the serial LC-MS of Agilent 6120 being equipped with G1311A quaternary pump and G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315D DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.

Above two kinds of spectrographs are provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Volume injected is determined by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC records reading by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is the formic acid acetonitrile solution (phase A) of 0.1% and the formic acid ultrapure water solution (phase B) of 0.1%.Condition of gradient elution is as shown in table 1:

Table 1

Compound purifying is evaluated by Agilent 1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature remains on 40 DEG C.

The use of brief word below runs through the present invention:

NH ₄c1 ammonia chloride

CBZ, Cbz benzyloxycarbonyl

TBDMS, TBS t-Butyldimethylsilyl

Ms methylsulfonyl

HATU 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester

DIEA, DIPEA DIPEA

CHCl ₃chloroform

CDI N, N-carbonyl dimidazoles

CDC1 ₃deuterochloroform

CuI cuprous iodide

KI potassiumiodide

DMF DMF

DMAP DMAP

DMSO dimethyl sulfoxide (DMSO)

EA, EtOAc ethyl acetate

G gram

Mg milligram

Mol mole

Mmol mmole

H hour

Min minute

HCl hydrochloric acid

H ₂hydrogen

MeOH, CH ₃oH methyl alcohol

EtOH, CH ₃cH ₂oH ethanol

CH ₂cl ₂, DCM methylene dichloride

ML milliliter

μ L microlitre

N ₂nitrogen

Pd/C palladium/carbon

PE sherwood oil (60-90 DEG C)

K ₂cO ₃salt of wormwood

RT, rt room temperature

NaHCO ₃sodium bicarbonate

NaCl sodium-chlor

NaOH sodium hydroxide

Na ₂sO ₄sodium sulfate

NaN ₃sodiumazide

THF tetrahydrofuran (THF)

TBHP tertbutanol peroxide

Et ₃n, TEA triethylamine

H ₂o water

N-BuLi n-Butyl Lithium

N-Bu ₄nF tetra-n-butyl Neutral ammonium fluoride

DIBAH, DIBAL-H diisobutyl aluminium hydride

Ti (Oi-Pr) ₄titanium isopropylate

L-(+)-DET L-(+)-diethyl tartrate

Ph ₃p triphenylphosphine

FXa factor Xa

Tris Tutofusin tris

Preparation the present invention comes into the open the typical synthesis step of compound as shown in synthetic schemes 1 ~ 2 below.Unless otherwise indicated, each R ², R ³have definition as described in the present invention with n, m is 1,2 or 3.

Synthetic schemes 1:

Have such as formula (10)shown the present invention general synthetic method that compound can be described by synthetic schemes 1 that comes into the open prepares, and concrete steps can reference example.In synthetic schemes 1, paraiodoaniline ( 1) and compound ( 2) in suitable solvent, as second alcohol and water, be obtained by reacting compound ( 3).Compound ( 3) under the katalysis of DMAP, in a heated condition with CDI reacting generating compound ( 4).Compound ( 4) and methylamine under Elevated Temperature Conditions, occur hydrolysis reaction obtain compound ( 5).Compound ( 5) with replace thiophenic acid ( 6) under the effect of HATU and DMAP condensation obtain compound ( 7).Compound ( 7) with replace phenylo boric acid compound ( 8), in the basic conditions, in ethers (as glycol dimethyl ether) solvent, under the condition of heating, at palladium catalyst (as Pd (dppf) Cl ₂) there is linked reaction under catalysis, obtain compound ( 9).Compound ( 9) in acid condition (as trifluoroacetic acid, the ethyl acetate solution of hydrogenchloride) slough Boc protecting group obtain compound ( 10).

Synthetic schemes 2:

Have such as formula (10)shown the present invention general synthetic method that compound can be described by synthetic schemes 2 that comes into the open prepares, and concrete steps can reference example.In synthetic schemes 2, compound ( 7) with replace phenylboronic acid compound ( 11) in the basic conditions, in ethers (as glycol dimethyl ether) solvent, under the condition of heating, at palladium catalyst (as Pd (dppf) Cl ₂) there is linked reaction under catalysis, obtain compound ( 12).

The following examples can the present invention will be further described, but these embodiments should as the restriction to scope of the present invention.

Embodiment

the chloro-N-of embodiment 15-((5S)-2-oxo-3-[the amino methylsulfonyl phenyl of 4-)-phenyl]-1,3-oxazolidine-5-base } methyl)-thiophene-2-carboxamide derivatives

step 1) 2-((2R)-2-hydroxyl-3-[4-iodophenyl-amino] propyl group-1H-isoindoline-1,3 (2H)-diketone

By (S)-N-Racemic glycidol phthalic imidine (2.0g, 10.0mmol) with paraiodoaniline (2.2g, 10.0mmol) be dissolved in the mixing solutions of ethanol/water (9/1 (v/v), 100mL), be heated to return stirring 12 hours.There is solid to separate out in reaction system, suction filtration, filter cake washed with diethylether, dry.Filtrate decompression boils off solvent, adds (S)-N-Racemic glycidol phthalic imidine (1.0g, 5.0mmol) and is heated to return stirring 12 hours.Have solid to separate out, suction filtration, filter cake washed with diethylether, dry, obtaining title compound is white solid (3.6g, 87%).

¹H NMR(CDCl ₃,400MHz):7.85-7.88(m,2H),7.38-7.77(m,2H),7.41(d,J＝8.8Hz,2H),6.48(d,J＝8.8Hz,2H),4.11-4.16(m,1H),3.90(d,J＝5.0Hz,2H),3.13-3.27(m,2H).

step 2) 2-({ (5S)-2-oxo-3-[4-iodophenyl]-1,3-oxazolidine-5-base } methyl)-1H-isoindoline-1,3 (2H)-diketone

By N, N '-carbonyl dimidazoles (2.6g, 16.1mmol) add 2-((2R)-2-hydroxyl-3-[4-iodophenyl-amino] propyl group-1H-isoindoline-1 with DMAP (catalytic amount), 3 (2H)-diketone (3.4g, 8.1mmol) be dissolved in tetrahydrofuran (THF) (90mL), gained reaction system is heated to 60 DEG C and stirs 12 hours, and then N is added in reaction mixture, N '-carbonyl dimidazoles (2.6g, 16.1mmol), after adding, continue to stir 12 hours at 60 DEG C.Suction filtration, filter cake tetrahydrofuran (THF) washs, and dries.Obtaining title compound is white solid (3.0g, 83%).

¹H NMR(CDCl ₃,400MHz):7.87-7.89(m,2H),7.52-7.77(m,2H),7.66(d,J＝8.8Hz,2H),7.30(d,J＝8.8Hz,2H),4.96-5.00(m,1H),4.07-4.17(m,2H),3.87-4.00(m,2H).

step 3) 4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-base] iodobenzene

By methylamine (40% aqueous solution, 3.5mL) join 2-({ (5S)-2-oxo-3-[4-iodophenyl]-1,3-oxazolidine-5-base } methyl)-1H-isoindoline-1, in ethanol (80mL) solution of 3 (2H)-diketone (1.6g, 5.0mmol).Gained reaction mixture is heated to return stirring 1 hour, and be cooled to pressure reducing and steaming solvent after room temperature, thick product directly casts single step reaction without purifying.

step 4) the chloro-N-of 5-({ (5S)-2-oxo-3-[4-iodobenzene]-1,3-oxazolidine-5-base } methyl)-thiophene-2-carboxamide derivatives

2-chlorothiophene-5-formic acid (0.8g is added successively in two mouthfuls of round-bottomed flasks of 50mL, 5.0mmol), N, N-diisopropylethylamine (1.7mL, 10.0mmol), DMF (20mL), HATU (2.9g, 7.5mmol) and (S)-((5-(5-(amino methyl)-2-Yang Dai oxazolidine-3-base)-2-chlorothiophene-3-base) methyl) (methyl) t-butyl carbamate (thick product).Gained reaction mixture at room temperature stirs 2 hours, extracts by ethyl acetate (30mL × 2).The organic phase merged, uses water (20mL × 2), saturated aqueous common salt (20mL) to wash, anhydrous sodium sulfate drying successively.Filter, pressure reducing and steaming solvent, the thick product of gained is through purification by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1), and obtaining title compound is white solid (1.5g, two step total recoverys: 64%).

¹H NMR(CDCl ₃,400MHz):8.02(s,1H),7.66(d,J＝8.8Hz,2H),7.30(d,J＝4.0Hz,1H),7.28(d,J＝8.8Hz,2H),6.90(d,J＝4.0Hz,1H),6.60(t,J＝6.0Hz,1H),4.82-4.89(m,1H),4.08(t,J＝8.8Hz,1H),3.71-3.92(m,3H).

step 5) the chloro-N-of 5-({ (5S)-2-oxo-3-[4-(2-tert-butyl aminosulfonvlphenyl)-phenyl]-1,3-oxazolidine-5-base } methyl)-thiophene-2-carboxamide derivatives

By chloro-for 5-N-({ (5S)-2-oxo-3-[4-iodobenzene]-1,3-oxazolidine-5-base } methyl)-thiophene-2-carboxamide derivatives (231mg, 0.5mmol), N-(tertiary butyl)-2-(4,4,5,5-tetramethyl--1,3,2-dioxaborinate-2-base) benzsulfamide (154mg, 0.6mmol) and Pd (dppf) Cl ₂(73mg, 0.1mmol) is dissolved in glycol dimethyl ether (16mL), adds the aqueous solution (4mL) of sodium carbonate (106mg, 1.0mmol), is heated to 85 DEG C under nitrogen protection and stirs 2 hours.Be chilled to room temperature, add water (10mL), extract by ethyl acetate (30mL × 3).Merge organic phase, use water (20mL × 2), saturated aqueous common salt (40mL) to wash successively, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product is through column chromatography purification (petrol ether/ethyl acetate (v/v)=2/1), and obtaining title compound is white solid (263mg, 96%).

¹H NMR(CDCl ₃,400MHz):8.02(dd,J＝1.2Hz&J＝8.0Hz,1H),7.61(d,J＝8.8Hz,2H),7.53(td,J＝7.6Hz&J＝1.2Hz,1H),7.51(d,J＝8.8Hz,2H),7.48(td,J＝7.6Hz&J＝1.2Hz,1H),7.33(d,J＝4.0Hz,1H),7.28(d,J＝1.2Hz,1H),6.91(d,J＝4.0Hz,1H),6.60(brs,1H),4.89-4.91(m,1H),4.18(t,J＝8.8Hz,1H),3.75-3.94(m,3H),3.63(s,1H),2.01(s,9H).

step 6) the chloro-N-of 5-((5S)-2-oxo-3-[the amino methylsulfonyl phenyl of 4-)-phenyl]-1,3-oxazolidine-5-base } methyl)-thiophene-2-carboxamide derivatives

At the chloro-N-of 5-({ (5S)-2-oxo-3-[4-(2-tert-butyl aminosulfonvlphenyl)-phenyl]-1; 3-oxazolidine-5-base } methyl)-thiophene-2-carboxamide derivatives (219mg, 0.4mmol) methylene dichloride (10mL) solution in add trifluoroacetic acid (3mL).Be heated to return stirring 16 hours.Be chilled to room temperature, add the sodium hydrogen carbonate solution (20mL) of 2M, extract by ethyl acetate (20mL × 3).Merge organic phase, use water (20mL × 2), saturated aqueous common salt (20mL) to wash successively, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product is through column chromatography purification (sherwood oil/methylene dichloride (v/v)=1/1), and obtaining title compound is white solid (148mg, 75%).

MS(ESI,pos.ion)m/z:491.9[M+1] ⁺；

¹H NMR(DMSO-d ₆,400MHz):8.99(t,J＝2.0Hz,1H),8.03(dd,J＝1.2Hz&J＝8.0Hz,1H),7.69(d,J＝4.0Hz,1H),7.60(td,J＝7.2Hz&J＝1.6Hz,1H),7.55-7.58(m,3H),7.41(d,J＝8.8Hz,1H),7.31(dd,J＝1.2Hz&J＝7.6Hz,1H),7.21(s,2H),7.20(d,J＝4.0Hz,1H),4.84-4.88(m,1H),4.23(t,J＝8.8Hz,1H),3.87-3.91(m,1H),3.61-3.64(m,2H).

the chloro-N-of embodiment 25-((5S)-2-oxo-3-[4-(2-methylsulfonyl phenyl)-phenyl]-1,3-oxazolidine-5-yl} methyl)-thiophene-2-carboxamide derivatives

step 1) and the chloro-N-of 5-((5S)-2-oxo-3-[4-(2-methylsulfonyl phenyl)-phenyl]-1,3-oxazolidine-5-yl} methyl)-thiophene-2-carboxamide derivatives

By chloro-for 5-N-({ (5S)-2-oxo-3-[4-iodobenzene]-1,3-oxazolidine-5-base } methyl)-thiophene-2-carboxamide derivatives (138mg, 0.3mmol), 2-methylsulfonyl phenylo boric acid (80mg, 0.4mmol) and Pd (dppf) Cl ₂(37mg, 0.05mmol) be dissolved in glycol dimethyl ether (16mL), add the aqueous solution (4mL) of sodium carbonate (64mg, 20.6mmol) wherein, gained reaction system is warming up to 85 DEG C under nitrogen atmosphere, stirs 4 hours.After gained reaction mixture is cooled to room temperature, add water (10mL) wherein, then use ethyl acetate (20mL × 2) to extract.Merge organic phase, use water (20mL), saturated aqueous common salt (20mL) to wash successively, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, the thick product of gained is through purification by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), and obtaining title compound is white solid (118mg, 80%).

MS(ESI,pos.ion)m/z:491.1[M+1] ⁺；

¹H NMR(CDCl ₃,400MHz):8.02(dd,J＝1.2Hz&J＝8.0Hz,1H),7.65(td,J＝7.6Hz&J＝1.2Hz,1H),7.61(d,J＝8.8Hz,2H),7.56(td,J＝7.6Hz&J＝1.2Hz,1H),7.47(d,J＝8.8Hz,2H),7.32-7.35(m,2H),6.90(d,J＝4.0Hz,1H),6.60(t,J＝6.0Hz,1H),4.89-4.91(m,1H),4.18(t,J＝8.8Hz,1H),3.75-3.94(m,3H),2.65(s,3H).

Biological activity test

a. mankind FXa enzyme level experiment

test method

The enzymic activity of mankind's factor Xa (FXa) is by the transformation assay for the specific chromogenic substrate of FXa.To this, p-Nitraniline is fallen in factor Xa cracking from chromogenic substrate.This is determined as follows to state and carries out on microwell plate.

Tester is dissolved in the methyl-sulphoxide of 10% by different concns, (10nM is dissolved in 50mM Tris to get compound 5 μ L and mankind FXa, 150mM NaCl, pH=8.3) 10 μ L mix, 15min is hatched in 25 DEG C of constant incubators, FXa chromophoric substrate (800 μMs, sigma) 5 μ L is added, in 25 DEG C of 405nm place kinetic test absorbances after hatching.

data analysis

By the test mixing thing containing test substances and not containing test substances control mixture relatively and calculate IC by these data ₅₀value.Result see table 2, the experimental result of the compound that table 2 provides for the embodiment of the present invention in the experiment of FXa enzyme level.

The experimental result of the compound that table 2 embodiment of the present invention provides in the experiment of FXa enzyme level

Experimentally result is known, and the compounds of this invention has good factor Xa inhibit activities

b. anticoagulation effect in vitro test

Test compounds extends the clotting time of rabbit plasma, the anticoagulation effect in vitro of assessment compound

experimental technique

1. the preparation of each concentration compound

Get each compound working fluid (100mM) of 4 μ L, be diluted to the working fluid of each concentration with methyl-sulphoxide liquid.

2. the preparation of plasma sample

Get some rabbits, auricular vein injects 3% pentobarbital solution (30mg/kg) anesthesia, with the vacuum test tube aorta abdominalis blood sampling containing 3.8% Sodium Citrate 0.2mL to 2mL, collect multitube, turn upside down mixing for several times, leave standstill 10min, in the centrifugal 10min of 3000rpm, draw each pipe blood plasma, all blood plasma is mixed to same centrifuge tube, 1.6mL often pipe packing, it is for subsequent use to insert rapidly-80 DEG C of Refrigerator stores.

3. application of sample and mensuration clotting time PT and APTT

Get out 1.5mL EP manage, often pipe adds 180 μ L plasma specimens; In each pipe blood specimen, add the medicine of 4 μ L respective concentration respectively, control group adds 4 μ L dimethyl sulfoxide solutions, and concussion mixing, hatches 5min for 37 DEG C; PT and APTT is measured with Sysmex CA1500 Automatic coagulometer.

data analysis

Draw amount effect curve, matching is carried out to curve, calculate the concentration (CT of the test compounds that the clotting time of sening as an envoy to doubles thus ₂).Result see table 3, the experimental result of the compound that table 3 provides for the embodiment of the present invention in vitro in anticoagulation test.

The Compound ira vitro anticoagulation experimental result that table 3 embodiment of the present invention provides

Experimentally result is known, and the compounds of this invention has the significant effect extending the clotting time.

Physico-chemical property is tested

a. the solubleness test of compound

experimental technique

In 15mL tapered tube, add water (10mL), vibration limit, limit adds sample, until sample stops dissolving, and 37 DEG C of water bath with thermostatic control jolting 24h, jolting speed 40rpm.After jolting terminates, sample is filtered through water system millipore filtration (0.45 μm, Φ 13mm), discard just filtrate, precision pipettes subsequent filtrate (500 μ L), adds diluent acetonitrile-water (500 μ L, v/v=60/40), the two mixing, obtains need testing solution.

Get need testing solution (40 μ L), adopt HPLC to detect, by one point external standard method calculation sample concentration, experimental result is in table 4.The experimental result of compound in solubleness test experiments that table 4 provides for the embodiment of the present invention.

The experimental result of the compound that table 4 embodiment of the present invention provides in solubleness test experiments

Experimentally result is known, and the compounds of this invention has good solvability.

In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this specification sheets or example and different embodiment or example can carry out combining and combining by those skilled in the art.

Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.

Claims

1. a compound, it is for such as formula the compound shown in (I), or the steric isomer of compound shown in formula (I), tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

Wherein:

A is C _6-12aryl or-(C _1-4alkylidene group)-(C _6-12aryl), wherein, A is optionally by 1,2 or 3 R ³replaced;

R ¹for H, C _1-4alkyl, C _2-4thiazolinyl or C _2-4alkynyl;

N is 0,1,2 or 3.

2. compound according to claim 1, wherein, A is phenyl, and described phenyl is optionally by 1,2 or 3 R ³replaced.

3. compound according to claim 1, wherein, R ¹be H, methyl, ethyl, propyl group or sec.-propyl independently.

4. compound according to claim 1, wherein, each R ³be H, D, F, Cl, Br, NO independently ₂, C _1-4alkyl, C _2-4thiazolinyl, C _2-6alkynyl ,-S (=O) ₂r ^c,-S (=O) ₂nR ^ar ^b,-C (=O) R ^c,-C (=O) OR ^cor-C (=O) NR ^ar ^b, wherein, each R ^a, R ^band R ^cbe separately H, methyl, ethyl, propyl group or sec.-propyl.

5. compound according to claim 1, wherein, each R ^a, R ^band R ^cbe separately H, methyl, ethyl, propyl group, sec.-propyl, C _3-6cycloalkyl, 5-6 former molecular heterocyclic radical, phenyl or 5-6 former molecular heteroaryl, wherein, each R ^a, R ^band R ^cindependently optionally independently be selected from D, F, Cl, Br, CN, N by 1,2 or 3 ₃, OH, NH ₂or CF ₃substituting group replaced.

6. compound according to claim 1, wherein, A is phenyl, optionally by 1 or 2 R ³replaced;

R ¹for H, methyl, ethyl, propyl group or sec.-propyl;

Each R ²be H, D, F, Cl or Br independently;

Each R ³be H, D, F, Cl, Br, NO independently ₂,-S (=O) ₂cH ₃or-S (=O) ₂nH ₂; With

N is 1.

7. compound according to claim 1, has one of them structure following:

Or the steric isomer of said structure, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, metabolic precursor thereof, pharmacy acceptable salt or prodrug.

8. a pharmaceutical composition, comprises the arbitrary described compound of claim 1-7, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.

9. the compound described in any one of claim 1-7 or pharmaceutical composition according to claim 8 are preparing the purposes in medicine, and described medicine is used for prevention, treats or alleviate thrombotic disease and disseminated inravascular coagulation (DIC).

10. purposes according to claim 9, wherein said thrombotic disease is myocardial infarction, stenocardia, to block and restenosis after revascularization or aorta Coronary artery bypass, apoplexy, the outbreak of of short duration local asphyxia, peripheral arterial occlusive disease, pulmonary infarction or venous thrombosis again.