WO2003024946A2 - Oxamate derivatives containing a variously substituted nitrogen heterocycle - Google Patents

Oxamate derivatives containing a variously substituted nitrogen heterocycle Download PDF

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Publication number
WO2003024946A2
WO2003024946A2 PCT/EP2002/009435 EP0209435W WO03024946A2 WO 2003024946 A2 WO2003024946 A2 WO 2003024946A2 EP 0209435 W EP0209435 W EP 0209435W WO 03024946 A2 WO03024946 A2 WO 03024946A2
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radical
optionally substituted
hydrogen atom
aryl
alkyl
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PCT/EP2002/009435
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French (fr)
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WO2003024946A3 (en
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Gérard Moinet
Caroline Leriche
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Merck Patent Gmbh
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Priority to AU2002337009A priority Critical patent/AU2002337009A1/en
Publication of WO2003024946A2 publication Critical patent/WO2003024946A2/en
Publication of WO2003024946A3 publication Critical patent/WO2003024946A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to oxamate derivatives containing a vari- ously substituted nitrogen heterocycle, which are useful in the treatment of pathologies associated with insulin resistance syndrome.
  • Patent application WO 99/46237 from Novo Nordisk describes compounds containing a group of the oxamate type which can be used in the treatment of diabetes.
  • the present invention is directed towards novel compounds having improved properties.
  • R represents a hydrogen atom or a (C1-C3) alkyl radical, and X represents an O or S atom or a radical -CR5R5'- or -NR6- ;
  • R1 , R2, R3 and R4 possibly being, independently, a hydrogen atom or a (C1-C3) alkyl radical
  • R5 and R5' independently of each other, represent: a hydrogen atom, a hydroxyl radical, a (C1-C5) alkyl radical, a radical of the formula -CO-R7 or an optionally substituted (C6-C14) aryl group;
  • R6 possibly being chosen from: a hydrogen atom; an optionally substituted (C1- C10) alkyl radical or an optionally substituted (C2-C10) alkene radical; a radical of the formula:
  • R8 m and n being as defined below; an optionally substituted (C6-C14) aryl radical; a 5- to 8-membered heterocyclic radical comprising one or more hetero atoms (O, N or S) and optionally substituted; a sulfonyl radical optionally substituted by at least one group chosen from: an optionally substituted (C1-C20) alkyl radical, an optionally substituted perfluoroalkyl radical, an optionally substituted (C6-C14) aryl radical, an optionally substituted 5- to 8-membered cycloalkyl radical or an optionally substituted 5- to 8-membered heterocyclic radical comprising one or more O, N or S hetero atoms, and an optionally substituted styryl radical,
  • n and n which may be identical or different, represent 0 or 1 ;
  • R7 represents a hydroxyl radical or a (C1-C5) alkyl, (C1-C5) alkoxy, (C6-C14) aryl or (C6-C14) aryloxy radical;
  • R8 possibly being a hydrogen atom, a hydroxyl radical, a (C1-C5) alkoxy radical, a (C1-C5) alkyl radical, an optionally substituted (C2-C5) alkene radical, an optionally substituted 5- to 8-membered cycloalkyl or cycloalkoxy radical, an optionally substituted (C6-C14) aryl or (C6-C14) aryloxy radical, an optionally substituted 5- to 8-membered heterocyclic or heteroaryloxy radical containing one or more hetero atoms chosen from O, N and S, or a radical -NR9R'9, R9 and R'9, which may be identical or different, may be a hydrogen atom, an optionally substituted (C1 -C5) alkyl radical, an optionally substituted (C6-C14) aryl radical or a radical -COR7, R9 and R9' possibly constituting a 3- to 10- membered ring optionally containing one or
  • R1 and R6 can together form a 3- to 10-membered ring optionally containing one or more O, N or S hetero atoms; with the exclusion of the compounds of the formula (I) in which:
  • X is NR6, in which R6 represents a phenyl radical substituted in the para position with a methyl radical and in the meta position with a halogen atom,
  • X is NR6, in which R6 represents a benzyl or ⁇ -phenethyl radical,
  • X is O and R1 , R2, R3 and R4 represent a hydrogen atom
  • X is CR5R'5 and R1 , R2, R3, R4, R5 and R * 5 represent a hydrogen atom
  • aryl, aryloxy or heterocyclic radicals When the aryl, aryloxy or heterocyclic radicals are substituted, they may be substituted by at least one group chosen from a hydroxyl radical, a halogen atom, a (01 -05) alkoxy radical, an optionally substituted (01 -05) alkyl radical, a cyano radical, a (01 -05) perfluoroalkyl radical, a (01 -05) perfluoroalkoxy radical, a (01 -05) acyl radical, a nitro group, a radical -NR9R'9 or a (C6-C14) aryl radical, R9 and R'9 being as defined above.
  • the (C6-C14)aryl(C1-C10)alkyl radicals, alkylaryl radicals or heterocyclic radicals substituted by an aryl radical may be interrupted with a sulfonamide or sulfone group.
  • alkyl and alkene radicals When the alkyl and alkene radicals are substituted, they may be substituted by one or more of the following groups: (01 -05) alkyl group, a halogen atom, a radical -NR9R'9, R9 and R'9 being as defined above, hydroxyl, (01 -05) alkoxy, cyano, a radical of the formula -CO-R7.R7 being as defined above, optionally substituted (C6-C14) aryl, optionally substituted aryloxy, 5- to 8-membered heterocycle including one or more O, N or S hetero atoms, 5- to 8- membered cycloalkyl optionally containing one or more O, N or S hetero atoms, a sulfonyl radical.
  • the substituted cycloalkyl radicals are preferably substituted by at least one (C1 -C5) alkyl radical.
  • aryl radicals that may be mentioned as homocarbon-based structures are the phenyl, ⁇ -naphthyl, ⁇ -naphthyl, anthrax- cenyl and fluorenyl radicals.
  • aryl radicals that are preferred are the phenyl and naphthyl radicals.
  • heterocycles are optionally aromatic (hetero- aryl).
  • heterocyclic radicals that may be mentioned are the thienyl, benzothiazole, benzimidazole, 1 ,2-diazine, imidazolyl, pyrazolyl, pyrazinyl, benzothienyl, morpholinyl, furyl, 2H-furyl, pyrrolyl, pyridyl, piperidyl, pyrrolidinyl, quinolyl and carbazolyl radicals.
  • heterocyclic radicals that are preferred are the quinolyl, furyl, benzothienyl, morpholinyl and thienyl radicals.
  • linear or branched alkyl groups in particular containing from 1 to
  • alkene groups that may mentioned in particular are ethenyl, propenyl, 2-propenyl, 2-methylpropenyl and 2-methylpropen-2-yl.
  • alkoxy groups containing from 1 to 6 carbon atoms mention may be made in particular of the methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy radicals.
  • the (hetero)aryloxy radicals are aromatic (heterocyclic) radicals linked to the rest of the compound via an oxygen atom.
  • cycloalkyl radicals that may mentioned in particular are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, at least one of the carbons of the ring possibly being replaced with an O, N or S hetero atom.
  • the cycloalkyl radicals may be substituted by a (01 -05) alkyl or (01 -05) alkoxy radical or a ketone function.
  • the cycloalkoxy radicals are cycloalkyl radicals linked to the rest of the compound via an oxygen atom.
  • halogen groups that may mentioned in particular are fluorine, chlorine, bromine and iodine.
  • 3- to 10-membered rings optionally containing one or more O, N or S hetero atoms mention may be made in particular of the benzimidazole ring.
  • the invention also relates to the tautomeric forms and to the enantiomers, diastereoisomers and epimers of the compounds of the general formula (I).
  • the compounds of the general formula (I) contain nitrogen atoms and carboxylic functions and may be monosalified or disalified with mineral or organic acids.
  • the compounds of the general formula (I) also comprise the pharmaceutically acceptable solvates and salts.
  • the compounds of the formula (I) according to the invention as defined above containing a sufficiently acidic function or a sufficiently basic function, or both, may include the pharmaceutically acceptable corresponding salts of an organic or mineral acid or of an organic or mineral base.
  • salts such as the hydrochloride, acetate, benzoate, citrate, fumarate, embonate, chlorophenoxyacetate, glycolate, palm- oate, aspartate, methanesulfonate, maleate, para-chlorophenoxyisobutyrate, formate, lactate, succinate, sulfate, tartrate, cyclohexanecarboxylate, hexanoate, octanoate, decanoate, hexadecanoate, octadecanoate, benzenesulfonate, trimethoxybenzoate, para-toluenesulfonate, adamantinecarboxylate, glycoxylate, glutamate, pyrrolidonecarboxylate, naphthalenesulfonate, glucose-1 -phosphate, nitrate, sulfite, dithionate, phosphate, dobesilate
  • the salts of the compounds of the general formula (I) are advantageously alkali metal salts, and preferably sodium salts, or alkaline-earth metal salts.
  • Examples of salts of the compounds of the general formula (I) include pharmacologically acceptable salts, such as the sodium salts, potassium salts, magnesium salts, calcium salts, amine salts and other salts of the same type (aluminium, iron, bismuth, etc.).
  • the amine salts that are not pharmacologically acceptable may serve as a means of identification, purification or racemisation.
  • the compounds of the general formula (I) may be prepared in particular by two synthetic routes:
  • the present invention also relates to a process for preparing compounds of the formula (I) as defined above, comprising the following steps: (i) coupling of an amino ring with an oxalyl chloride in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C, followed by (ii) a saponification in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C.
  • the invention relates to another process for preparing compounds of the formula (I) as defined above, comprising the following steps: (i) coupling of piperazine with an oxalyl chloride in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C, followed by (ii) coupling with an acid chloride in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C, and finally (iii) a saponification in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C.
  • R8, m and n being as defined above.
  • Another particular group of compounds of the formula (I) is that in which X represents -NR6 in which R6 represents an optionally substituted sulfonyl radical as defined above.
  • the insulin resistance is characterised by a reduction in the action of insulin (cf. Presse Medicale, 1997, 26 (No. 14), 671-677) and is involved in a large number of pathological conditions, such as diabetes and more particularly non- insulin-dependent diabetes (type II diabetes or NIDDM), dyslipidaemia, obesity and arterial hypertension, and also certain microvascular and macrovascular complications, for instance atherosclerosis, retinopathies and neuropathies.
  • diabetes cf. Presse Medicale, 1997, 26 (No. 14), 671-677
  • NIDDM non- insulin-dependent diabetes
  • dyslipidaemia e.g., obesity and arterial hypertension
  • microvascular and macrovascular complications for instance atherosclerosis, retinopathies and neuropathies.
  • the compounds of the formula (I) are thus useful in the treatment of pathologies associated with hyperglycaemia.
  • the compounds of the formula (I) are those described above, including therein those previously excluded by (i), (ii), (iii) and (iv).
  • the present invention thus also relates to pharmaceutical compositions comprising, as active principle, at least one compound according to the invention, including therein those previously excluded by (i), (ii), (iii) and (iv), in a pharmacologically acceptable support.
  • compositions are intended for treating pathologies associated with hyperglycaemia, in particular such as diabetes, dyslipidaemia, obesity, arterial hypertension, neuropathies, nephropathies or atherosclerosis. More specifically, these compositions are intended for treating diabetes.
  • the present invention also relates to the use of at least one compound according to the invention, including therein those previously excluded by (i), (ii), (iii) and (iv), for the preparation of a pharmaceutical composition intended for treating pathologies associated with hyperglycaemia and more specifically diabetes.
  • compositions according to the invention may be presented in forms intended for parenteral, oral, rectal, permucous or percutaneous administration. They will thus be presented in the form of injectable solutions or suspensions or multi-dose bottles, in the form of plain or coated tablets, sugar-coated tablets, wafer capsules, gel capsules, pills, cachets, powders, suppositories or rectal capsules, solutions or suspensions, for percutaneous use in a polar solvent, or for permucous use.
  • the excipients that are suitable for such administrations are cellulose derivatives or microcrystalline cellulose derivatives, alkaline-earth metal carbonates, magnesium phosphate or potassium phosphate, starches, modified starches, lactose or glucose for the solid forms.
  • the preferred excipients for rectal use are cocoa butter or polyethylene glycol stearates.
  • the vehicles that are most convenient for parenteral use are water, aqueous solutions, physiological saline and isotonic solutions.
  • the dosage may vary within a wide range as a function of the therapeutic indication and the route of administration, and also the age and weight of the individual.
  • the daily dose can range from 0.5 mg to 1000 mg/kg, preferably from 0.5 mg to 500 mg/kg, more preferably from 0.05 mg to 100 mg/kg and advantageously from 0.01 mg to 20 mg/kg of body weight.
  • the antidiabetic activity of the compounds of the formula (I) orally was determined on an experimental model of non-insulin-dependent diabetes, induced in rats with steptozotocin.
  • the model of non-insulin-dependent diabetes is obtained in rats by means of a neonatal injection of steptozotocin.
  • the diabetic rats used are eight weeks old.
  • the animals are housed, from the day of birth to the day of the experiment, in an animal house at a regulated temperature of 21 to 22°C and are subjected to a fixed cycle of light (from 7 a.m. to 7 p.m.) and of darkness (from 7 p.m. to 7 a.m.).
  • Their feed consisted of a maintenance diet, and water and feed were supplied "ad libitum", with the exception of fasting for the two hours preceding the tests, during which time the feed was removed (post-absorptive state).
  • the rats are treated orally for one (D1 ) or four (D4) days with the test product.
  • the results obtained are collated in Table B by way of example. These results show the efficacy of the compounds of the formula (I) for reducing gly- caemia in the diabetic animals. These results are expressed as a percentage change in the glycaemia at D1 and D4 (number of days of treatment) relative to DO (before the treatment).

Abstract

The invention relates to compounds of the general formula (I), in which R, R1, R2, R3, R4 and X are as defined in claim 1. These compounds may be used in the treatment of pathologies associated with insulin resistance syndrome.

Description

Oxamate derivatives containing a variously substituted nitrogen heterocycle
The present invention relates to oxamate derivatives containing a vari- ously substituted nitrogen heterocycle, which are useful in the treatment of pathologies associated with insulin resistance syndrome.
Patent application WO 99/46237 from Novo Nordisk describes compounds containing a group of the oxamate type which can be used in the treatment of diabetes. The present invention is directed towards novel compounds having improved properties.
Thus, the present invention relates to compounds of the general formula (I):
Figure imgf000002_0001
(I)
in which:
R represents a hydrogen atom or a (C1-C3) alkyl radical, and X represents an O or S atom or a radical -CR5R5'- or -NR6- ;
R1 , R2, R3 and R4 possibly being, independently, a hydrogen atom or a (C1-C3) alkyl radical; R5 and R5', independently of each other, represent: a hydrogen atom, a hydroxyl radical, a (C1-C5) alkyl radical, a radical of the formula -CO-R7 or an optionally substituted (C6-C14) aryl group;
R6 possibly being chosen from: a hydrogen atom; an optionally substituted (C1- C10) alkyl radical or an optionally substituted (C2-C10) alkene radical; a radical of the formula:
Figure imgf000003_0001
R8, m and n being as defined below; an optionally substituted (C6-C14) aryl radical; a 5- to 8-membered heterocyclic radical comprising one or more hetero atoms (O, N or S) and optionally substituted; a sulfonyl radical optionally substituted by at least one group chosen from: an optionally substituted (C1-C20) alkyl radical, an optionally substituted perfluoroalkyl radical, an optionally substituted (C6-C14) aryl radical, an optionally substituted 5- to 8-membered cycloalkyl radical or an optionally substituted 5- to 8-membered heterocyclic radical comprising one or more O, N or S hetero atoms, and an optionally substituted styryl radical,
m and n, which may be identical or different, represent 0 or 1 ;
R7 represents a hydroxyl radical or a (C1-C5) alkyl, (C1-C5) alkoxy, (C6-C14) aryl or (C6-C14) aryloxy radical;
R8 possibly being a hydrogen atom, a hydroxyl radical, a (C1-C5) alkoxy radical, a (C1-C5) alkyl radical, an optionally substituted (C2-C5) alkene radical, an optionally substituted 5- to 8-membered cycloalkyl or cycloalkoxy radical, an optionally substituted (C6-C14) aryl or (C6-C14) aryloxy radical, an optionally substituted 5- to 8-membered heterocyclic or heteroaryloxy radical containing one or more hetero atoms chosen from O, N and S, or a radical -NR9R'9, R9 and R'9, which may be identical or different, may be a hydrogen atom, an optionally substituted (C1 -C5) alkyl radical, an optionally substituted (C6-C14) aryl radical or a radical -COR7, R9 and R9' possibly constituting a 3- to 10- membered ring optionally containing one or more O, N or S hetero atoms;
when X represents -NR6, R1 and R6 can together form a 3- to 10-membered ring optionally containing one or more O, N or S hetero atoms; with the exclusion of the compounds of the formula (I) in which:
- (i) X is NR6, in which R6 represents a phenyl radical substituted in the para position with a methyl radical and in the meta position with a halogen atom,
- (ii) X is NR6, in which R6 represents a benzyl or β-phenethyl radical,
- (iii) X is O and R1 , R2, R3 and R4 represent a hydrogen atom,
- (iv) X is CR5R'5 and R1 , R2, R3, R4, R5 and R*5 represent a hydrogen atom,
and also the tautomeric forms, enantiomers, diastereoisomers and epimers thereof, and the pharmaceutically acceptable salts thereof.
When the aryl, aryloxy or heterocyclic radicals are substituted, they may be substituted by at least one group chosen from a hydroxyl radical, a halogen atom, a (01 -05) alkoxy radical, an optionally substituted (01 -05) alkyl radical, a cyano radical, a (01 -05) perfluoroalkyl radical, a (01 -05) perfluoroalkoxy radical, a (01 -05) acyl radical, a nitro group, a radical -NR9R'9 or a (C6-C14) aryl radical, R9 and R'9 being as defined above.
The (C6-C14)aryl(C1-C10)alkyl radicals, alkylaryl radicals or heterocyclic radicals substituted by an aryl radical may be interrupted with a sulfonamide or sulfone group.
When the alkyl and alkene radicals are substituted, they may be substituted by one or more of the following groups: (01 -05) alkyl group, a halogen atom, a radical -NR9R'9, R9 and R'9 being as defined above, hydroxyl, (01 -05) alkoxy, cyano, a radical of the formula -CO-R7.R7 being as defined above, optionally substituted (C6-C14) aryl, optionally substituted aryloxy, 5- to 8-membered heterocycle including one or more O, N or S hetero atoms, 5- to 8- membered cycloalkyl optionally containing one or more O, N or S hetero atoms, a sulfonyl radical.
The substituted cycloalkyl radicals are preferably substituted by at least one (C1 -C5) alkyl radical. In the text hereinabove, among the aryl radicals that may be mentioned as homocarbon-based structures are the phenyl, α-naphthyl, β-naphthyl, anthrax- cenyl and fluorenyl radicals. Among the aryl radicals that are preferred are the phenyl and naphthyl radicals.
In the present invention, the heterocycles are optionally aromatic (hetero- aryl).
Among the heterocyclic radicals that may be mentioned are the thienyl, benzothiazole, benzimidazole, 1 ,2-diazine, imidazolyl, pyrazolyl, pyrazinyl, benzothienyl, morpholinyl, furyl, 2H-furyl, pyrrolyl, pyridyl, piperidyl, pyrrolidinyl, quinolyl and carbazolyl radicals. Among the heterocyclic radicals that are preferred are the quinolyl, furyl, benzothienyl, morpholinyl and thienyl radicals.
Among the linear or branched alkyl groups in particular containing from 1 to
20 carbon atoms, mention may be made in particular of the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, pentadecyl, hexadecyl, 2-ethylhexyl, 2-methylbutyl, 2-methylpentyl, 1-methyl- hexyl and 3-methylheptyl radicals.
Among the alkene groups that may mentioned in particular are ethenyl, propenyl, 2-propenyl, 2-methylpropenyl and 2-methylpropen-2-yl.
Among the alkoxy groups containing from 1 to 6 carbon atoms, mention may be made in particular of the methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy radicals.
The (hetero)aryloxy radicals are aromatic (heterocyclic) radicals linked to the rest of the compound via an oxygen atom.
Among the cycloalkyl radicals that may mentioned in particular are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, at least one of the carbons of the ring possibly being replaced with an O, N or S hetero atom.
When they are substituted, the cycloalkyl radicals may be substituted by a (01 -05) alkyl or (01 -05) alkoxy radical or a ketone function. The cycloalkoxy radicals are cycloalkyl radicals linked to the rest of the compound via an oxygen atom.
Among the halogen groups that may mentioned in particular are fluorine, chlorine, bromine and iodine. Among the 3- to 10-membered rings optionally containing one or more O, N or S hetero atoms, mention may be made in particular of the benzimidazole ring.
The compounds that are excluded from the present invention are described in patent US 2 875 205 as antiparasitic agents, in publication Acta Pol. Pharma. 28 (1971) 267-270 and in patent application JP 62-209 051 filed by Sumitomo Kagaku Kogyo K. K.
The invention also relates to the tautomeric forms and to the enantiomers, diastereoisomers and epimers of the compounds of the general formula (I).
The compounds of the general formula (I) contain nitrogen atoms and carboxylic functions and may be monosalified or disalified with mineral or organic acids.
The compounds of the general formula (I) also comprise the pharmaceutically acceptable solvates and salts. The compounds of the formula (I) according to the invention as defined above containing a sufficiently acidic function or a sufficiently basic function, or both, may include the pharmaceutically acceptable corresponding salts of an organic or mineral acid or of an organic or mineral base.
They may be, for example, salts such as the hydrochloride, acetate, benzoate, citrate, fumarate, embonate, chlorophenoxyacetate, glycolate, palm- oate, aspartate, methanesulfonate, maleate, para-chlorophenoxyisobutyrate, formate, lactate, succinate, sulfate, tartrate, cyclohexanecarboxylate, hexanoate, octanoate, decanoate, hexadecanoate, octadecanoate, benzenesulfonate, trimethoxybenzoate, para-toluenesulfonate, adamantinecarboxylate, glycoxylate, glutamate, pyrrolidonecarboxylate, naphthalenesulfonate, glucose-1 -phosphate, nitrate, sulfite, dithionate, phosphate, dobesilate, thioctate, hippurate, 3-benz- amidopropanoate, glucuronate, L-pyrrolidone-5-carboxylate, cholate, α-glucose- 1 -phosphate, alginate, 4-aminobenzoate or chondroitin sulfate.
The salts of the compounds of the general formula (I) are advantageously alkali metal salts, and preferably sodium salts, or alkaline-earth metal salts. Examples of salts of the compounds of the general formula (I) include pharmacologically acceptable salts, such as the sodium salts, potassium salts, magnesium salts, calcium salts, amine salts and other salts of the same type (aluminium, iron, bismuth, etc.). The amine salts that are not pharmacologically acceptable may serve as a means of identification, purification or racemisation. The compounds of the general formula (I) may be prepared in particular by two synthetic routes:
1- coupling of an amino ring with an oxalyl chloride in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C, followed by a saponification in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C,
2- coupling of piperazine with an oxalyl chloride in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C, followed by coupling with an acid chloride in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C, and finally a saponification in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C. Thus, the present invention also relates to a process for preparing compounds of the formula (I) as defined above, comprising the following steps: (i) coupling of an amino ring with an oxalyl chloride in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C, followed by (ii) a saponification in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C.
The invention relates to another process for preparing compounds of the formula (I) as defined above, comprising the following steps: (i) coupling of piperazine with an oxalyl chloride in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C, followed by (ii) coupling with an acid chloride in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C, and finally (iii) a saponification in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C.
The method for introducing an oxalyl chloride onto an amino compound is described in particular by Kubo, Akinori et al. in J. Org. Chem.; EN; 53; 18; 1988; 4295-4310. The saponification step has been described in particular by Naumov, Yu. A. et al. in J. Org. Chem. USSR (Engl. Transl.);EN; 12; 1976; 2428-2432; Zh. Org. Khim.; RU; 12; 1976; 2507-2511.
One particular group of compounds of the formula (I) is that in which X represents -NR6 in which R6 represents a radical of the formula:
Figure imgf000008_0001
R8, m and n being as defined above.
Another particular group of compounds of the formula (I) is that in which X represents -NR6 in which R6 represents an optionally substituted sulfonyl radical as defined above.
The insulin resistance is characterised by a reduction in the action of insulin (cf. Presse Medicale, 1997, 26 (No. 14), 671-677) and is involved in a large number of pathological conditions, such as diabetes and more particularly non- insulin-dependent diabetes (type II diabetes or NIDDM), dyslipidaemia, obesity and arterial hypertension, and also certain microvascular and macrovascular complications, for instance atherosclerosis, retinopathies and neuropathies.
In this respect, reference will be made, for example, to Diabetes, vol. 37, 1988, 1595-1607 ; Journal of Diabetes and its complications, 1998, 12, 110-119 or Horm. Res., 1992, 38, 28-32. The compounds of the invention have high hypoglycaemiant activity.
The compounds of the formula (I) are thus useful in the treatment of pathologies associated with hyperglycaemia. In this case, the compounds of the formula (I) are those described above, including therein those previously excluded by (i), (ii), (iii) and (iv). The present invention thus also relates to pharmaceutical compositions comprising, as active principle, at least one compound according to the invention, including therein those previously excluded by (i), (ii), (iii) and (iv), in a pharmacologically acceptable support.
More particularly, these compositions are intended for treating pathologies associated with hyperglycaemia, in particular such as diabetes, dyslipidaemia, obesity, arterial hypertension, neuropathies, nephropathies or atherosclerosis. More specifically, these compositions are intended for treating diabetes.
The present invention also relates to the use of at least one compound according to the invention, including therein those previously excluded by (i), (ii), (iii) and (iv), for the preparation of a pharmaceutical composition intended for treating pathologies associated with hyperglycaemia and more specifically diabetes.
The pharmaceutical compositions according to the invention may be presented in forms intended for parenteral, oral, rectal, permucous or percutaneous administration. They will thus be presented in the form of injectable solutions or suspensions or multi-dose bottles, in the form of plain or coated tablets, sugar-coated tablets, wafer capsules, gel capsules, pills, cachets, powders, suppositories or rectal capsules, solutions or suspensions, for percutaneous use in a polar solvent, or for permucous use. The excipients that are suitable for such administrations are cellulose derivatives or microcrystalline cellulose derivatives, alkaline-earth metal carbonates, magnesium phosphate or potassium phosphate, starches, modified starches, lactose or glucose for the solid forms.
The preferred excipients for rectal use are cocoa butter or polyethylene glycol stearates.
The vehicles that are most convenient for parenteral use are water, aqueous solutions, physiological saline and isotonic solutions.
On the basis of his general knowledge, a person skilled in the art can readily determine the adjuvants that are suitable for the desired formulation of the composition according to the invention so as to prepare a pharmacologically acceptable support.
The dosage may vary within a wide range as a function of the therapeutic indication and the route of administration, and also the age and weight of the individual. Thus, on average, for a patient weighing about 75 kg, the daily dose can range from 0.5 mg to 1000 mg/kg, preferably from 0.5 mg to 500 mg/kg, more preferably from 0.05 mg to 100 mg/kg and advantageously from 0.01 mg to 20 mg/kg of body weight.
The examples that follow illustrate the invention, but without limiting it. A- Example of the preparation of a compound of the formula (I)
Route 1 - Preparation of [4-(3-methoxyphenyl)piperazin-1-yl]oxoacetic acid
8.62 g of potassium carbonate (1.2 eq.) and 7.07 g of ethoxalyl chloride in 30 ml of toluene are added to 10 g (0.052 mol) of 1 -(3-methoxyphenyl)piperazine in 125 ml of THF at 0°C. The mixture is stirred for 3 hours at room temperature. After hydrolysis (100 ml, H20), the product is extracted three times with dichloro- methane. The combined organic phases are dried over magnesium sulfate and then concentrated under vacuum to give 6.7 g of an orange-coloured oil (0.023 mol, 44%).
1.89 g (1 eq.) of NaOH are added to 6.6 g (0.023 mol) of ethyl [4-(3- methoxyphenyl)piperazin-1-yl]oxoacetate in 28 ml of methanol, and the mixture is stirred at room temperature for 10 hours. The product is filtered off and dried to give 6.1 g (0.021 mol, 93%) of [4-(3-methoxyphenyl)piperazin-1-yl]oxoacetic acid in the form of a white powder, which is a product of the formula (I).
Route 2 - Preparation of ethyl 2-oxo-[4-(4-toluenesulfonyl)piperazin-1-yl]- acetate
75 ml of a solution of ethoxalyl chloride in acetic acid (0.667 mol) are added to 86.14 g (1 mol) of piperazine in 800 ml of acetic acid. The mixture is stirred for 10 hours at room temperature. After filtering off the precipitate, the filtrate is concentrated under vacuum and the product is then purified on a chromatography column (silica, eluent: dichloromethane/10% MeOH) to give 94 g of ethyl 2-oxo-2-piperazin-1-ylacetate. 90.0 g (0.483 mol, 61%) of the hydrochloride salt are obtained after adding a 7N solution of HCI in ethanol.
30 μl of triethylamine (2 eq.) and 1.1 eq. of toluene sulfonyl [lacuna] are added to 50 mg (0.224 mmol) of ethyl 2-oxo-2-piperazin-1-ylacetate in 5 ml of dichloromethane. The reaction mixture is stirred for 10 hours. The mixture is filtered through silica (ethyl acetate) and the solvent is evaporated off to give 675 mg (0.198 mmol, 88.5%) of ethyl 2-oxo-[4-(4-toluenesulfonyl)piperazin-1-yl]- acetate.
The formulae and characteristics of the compounds of the formula (I) are collated in Table A.
Table A
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
The results of the pharmacological studies will be given hereinbelow.
STUDY OF THE ANTIDIABETIC ACTIVITY IN NOSTZ RATS
The antidiabetic activity of the compounds of the formula (I) orally was determined on an experimental model of non-insulin-dependent diabetes, induced in rats with steptozotocin.
The model of non-insulin-dependent diabetes is obtained in rats by means of a neonatal injection of steptozotocin.
The diabetic rats used are eight weeks old. The animals are housed, from the day of birth to the day of the experiment, in an animal house at a regulated temperature of 21 to 22°C and are subjected to a fixed cycle of light (from 7 a.m. to 7 p.m.) and of darkness (from 7 p.m. to 7 a.m.). Their feed consisted of a maintenance diet, and water and feed were supplied "ad libitum", with the exception of fasting for the two hours preceding the tests, during which time the feed was removed (post-absorptive state).
The rats are treated orally for one (D1 ) or four (D4) days with the test product. Two hours after the final administration of the product and 30 minutes after the animals have been anaesthetised with pentobarbital sodium (Nembutal®), a 300 μl blood sample is taken from the end of the tail. The results obtained are collated in Table B by way of example. These results show the efficacy of the compounds of the formula (I) for reducing gly- caemia in the diabetic animals. These results are expressed as a percentage change in the glycaemia at D1 and D4 (number of days of treatment) relative to DO (before the treatment). Table B
Figure imgf000019_0001
Other compounds were synthesised and then analysed; they are presented in the table (C) below.
Figure imgf000019_0002
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Table (C): Hewlett Packard LC/MSD (Simple Quad)- Orthogonal Spray - Source APCI and API-EC, HP Series 1100 Line with diode array, nf: not found

Claims

1- Compounds of the general formula (I)
Figure imgf000032_0001
(I)
in which:
R represents a hydrogen atom or a (C1-C3) alkyl radical, and X represents an O or S atom or a radical -CR5R5'- or -NR6- ;
R1 , R2, R3 and R4 possibly being, independently, a hydrogen atom or a (C1 -C3) alkyl radical;
R5 and R5', independently of each other, represent: a hydrogen atom, a hydroxyl radical, a (C1-C5) alkyl radical, a radical of the formula -CO-R7 or an optionally substituted (C6-C14) aryl group;
R6 possibly being chosen from: a hydrogen atom; an optionally substituted (C1 - C10) alkyl radical or an optionally substituted (C2-C10) alkene radical; a radical of the formula:
Figure imgf000032_0002
R8, m and n being as defined below; an optionally substituted (C6-C14) aryl radical; a 5- to 8-membered heterocyclic radical comprising one or more hetero atoms (O, N or S) and optionally substituted; a sulfonyl radical optionally substituted by at least one group chosen from: an optionally substituted (C1-C20) alkyl radical, an optionally substituted perfluoroalkyl radical, an optionally substituted (C6-C14) aryl radical, an optionally substituted 5- to 8-membered cycloalkyl radical or an optionally substituted 5- to 8-membered heterocyclic radical comprising one or more O, N or S hetero atoms, and an optionally substituted styryl radical,
m and n, which may be identical or different, represent 0 or 1 ;
R7 represents a hydroxyl radical or a (C1-C5) alkyl, (C1-C5) alkoxy, (C6-C14) aryl or (C6-C14) aryloxy radical;
R8 possibly being a hydrogen atom, a hydroxyl radical, a (C1-C5) alkoxy radical, a (C1-C5) alkyl radical, an optionally substituted (C2-C5) alkene radical, an optionally substituted 5- to 8-membered cycloalkyl or cycloalkoxy radical, an optionally substituted (C6-C14) aryl or (C6-C14) aryloxy radical, an optionally substituted 5- to 8-membered heterocyclic or heteroaryloxy radical containing one or more hetero atoms chosen from O, N and S, or a radical -NR9R'9,
R9 and R'9, which may be identical or different, may be a hydrogen atom, an optionally substituted (C1-C5) alkyl radical, an optionally substituted (C6-C14) aryl radical or a radical -COR7, R9 and R9' possibly constituting a 3- to 10- membered ring optionally containing one or more O, N or S hetero atoms;
when X represents -NR6, R1 and R6 can together form a 3- to 10-membered ring optionally containing one or more O, N or S hetero atoms; with the exclusion of the compounds of the formula (I) in which:
- (i) X is NR6, in which R6 represents a phenyl radical substituted in the para position with a methyl radical and in the meta position with a halogen atom, - (ii) X is NR6, in which R6 represents a benzyl or β-phenethyl radical,
- (iii) X is O and R1 , R2, R3 and R4 represent a hydrogen atom,
- (iv) X is CR5R'5 and R1 , R2, R3, R4, R5 and R'5 represent a hydrogen atom,
and also the tautomeric forms, enantiomers, diastereoisomers and epimers thereof, and the pharmaceutically acceptable salts thereof.
2- Compounds according to Claim 1 , characterised in that they are of the general formula (I) in which X represents -NR6 in which R6 represents a radical of the formula:
Figure imgf000034_0001
R8, m and n being as defined in Claim 1.
3- Compounds according to Claim 1 , characterised in that they are of the general formula (I) in which X represents -NR6 in which R6 represents an optionally substituted sulfonyl radical as defined in Claim 1.
4- Process for preparing compounds of the formula (I) as defined according to one of the preceding claims, comprising the following steps: (i) coupling of an amino ring with an oxalyl chloride in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C, followed by (ii) a saponification in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C.
5- Process for preparing compounds of the formula (I) as defined according to one of the preceding claims, comprising the following steps: (i) coupling of piperazine with an oxalyl chloride in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C, followed by (ii) coupling with an acid chloride in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C, and finally (iii) a saponification in a polar solvent at a temperature of from -20 to 50°C, more particularly 0-20°C. 6- Pharmaceutical composition comprising, as active principle, at least one compound of the general formula (I)
Figure imgf000035_0001
(I)
in which:
R represents a hydrogen atom or a (C1-C3) alkyl radical, and X represents an O or S atom or a radical -CR5R5'- or -NR6- ;
R1 , R2, R3 and R4 possibly being, independently, a hydrogen atom or a (C1-C3) alkyl radical;
R5 and R5', independently of each other, represent: a hydrogen atom, a hydroxyl radical, a (C1-C5) alkyl radical, a radical of the formula -CO-R7 or an optionally substituted (C6-C14) aryl group;
R6 possibly being chosen from: a hydrogen atom; an optionally substituted (C1 - C10) alkyl radical or an optionally substituted (C2-C10) alkene radical; a radical of the formula:
Figure imgf000035_0002
R8, m and n being as defined below; an optionally substituted (C6-C14) aryl radical; a 5- to 8-membered heterocyclic radical comprising one or more hetero atoms
(O, N or S) and optionally substituted; a sulfonyl radical optionally substituted by at least one group chosen from: a (C1-C20) alkyl radical, a perfluoroalkyl radical, an optionally substituted (C6- C14) aryl radical, an optionally substituted 5- to 8-membered cycloalkyl radical or an optionally substituted 5- to 8-membered heterocyclic radical comprising one or more O, N or S hetero atoms, and an optionally substituted styryl radical,
m and n, which may be identical or different, represent 0 or 1 ;
R7 represents a hydroxyl radical or a (C1-C5) alkyl, (C1-C5) alkoxy, (C6-C14) aryl or (C6-C14) aryloxy radical;
R8 possibly being a hydrogen atom, a hydroxyl radical, a (C1-C5) alkoxy radical, a (C1-C5) alkyl radical, an optionally substituted (C2-C5) alkene radical, an optionally substituted 5- to 8-membered cycloalkyl or cycloalkoxy radical, an optionally substituted (C6-C14) aryl or (C6-C14) aryloxy radical, an optionally substituted 5- to 8-membered heterocyclic or heteroaryloxy radical containing one or more hetero atoms chosen from O, N and S, or a radical -NR9R'9,
R9 and R'9, which may be identical or different, may be a hydrogen atom, an optionally substituted (C1-C5) alkyl radical, an optionally substituted (C6-C14) aryl radical or a radical -COR7, R9 and R9' possibly constituting a 3- to 10- membered ring optionally containing one or more O, N or S hetero atoms;
when X represents -NR6, R1 and R6 can together form a 3- to 10-membered ring optionally containing one or more O, N or S hetero atoms;
and also the tautomeric forms, enantiomers, diastereoisomers and epimers thereof, and the pharmaceutically acceptable salts thereof.
7- Composition according to Claim 6, intended for treating pathologies associated with hyperglycaemia. 8- Composition according to Claim 6, intended for treating diabetes, dyslipidaemia, obesity, arterial hypertension, neuropathies, nephropathies or atherosclerosis.
9- Composition according to Claim 6, intended for treating diabetes.
10- Use of at least one compound as defined in Claim 6, for the preparation of a pharmaceutical composition intended for treating pathologies associated with hyperglycaemia and more specifically diabetes.
PCT/EP2002/009435 2001-09-14 2002-08-23 Oxamate derivatives containing a variously substituted nitrogen heterocycle WO2003024946A2 (en)

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