Patent EA-004676-B1 (EA)
Title: Novel heterocyclic derivatives, preparation method and pharmaceutical compositions containing same
Inventor: LESIEUR DANIEL
IPC: C07D471/04
Filed: 2001-02-01
Abstract: 1. Compounds of formula (I) : wherein: X represents an oxygen or sulphur atom or a CH2 or group (wherein R'<2> together with R<2> forms an additional bond), R' and R<2>, which may be identical or different, each represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety may be linear or branched, an aryloxy group, an aryl-(C1-C6)alkoxy group in which the alkoxy moiety may be linear or branched, a linear or branched (C1-C6)alkoxy group, a hydroxy group, an ammo group, a linear or branched (C1-C6)alkylamino group or a dialkylamino group in which the alkyl moieties are linear or branched C1-C6, or R' and R<2> together form an oxo, thioxo or imino group, it being possible furthermore for R<2> to form with R'<2> an additional bond, A represents a (C1-C6)alkylene chain in which a CH2 group may be replaced by a hetero atom selected from oxygen and sulphur, by an NRa group (wherein Ra represents a hydrogen atom or a linear or branched (C1-C6)alkyl group), or by a phenylene or naphthylene group, B represents a linear or branched (C1-C6)alkyl group or a linear or branched (C2-C6)alkenyl group, those groups being substituted by a R<5> group, by a group of formula (II): or by a group of formula (III) in which groups: - the representation ---denotes that the bond is single or double, - R<5> represents a group wherein Z represents a sulphur atom or an oxygen atom and Z' represents an OR or NRR' group, - and R<6> represents a group , wherein Z" represents a Z' or R group, (wherein R and R', which may be identical or different, each represents a R" or -C(Me)2COOR" group wherein R" represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety may be linear or branched, an aryl-(C2-C6)alkenyl group in which the alkenyl moiety may be linear or branched, an aryl-(C2-C6)alkynyl group in which the alkynyl moiety may be linear or branched, a heteroaryl group, a heteroaryl-(C1-C6)alkyl group in which the alkyl moiety may be linear or branched, a heteroaryl-(C2-C6)alkenyl group in which the alkenyl moiety may be linear or branched, a heteroaryl-(C2-C6)alkynyl group in which the alkynyl moiety may be linear or branched, a (C3-C8)cycloalkyl group, a (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety may be linear or branched, or a linear or branched (C1-C6)polyhaloalkyl group), R<3> and R<4>, which may be identical or different, each represents a hydrogen atom, a halogen atom or a R, OR or NRR' group (wherein R and R' are as defined hereinbefore), or R<3> and R<4> together with the carbon atoms carrying them, when they are carried by two adjacent carbon atoms, form a ring that has 5 or 6 ring members and that may contain a hetero atom selected from oxygen, sulphur and nitrogen, D represents: a benzene nucleus, in which case X cannot represent a group as defined hereinbefore, or D represents a pyridine, pyrazine, pyrimidine or pyridazine nucleus, those nuclei being unsubstituted or substituted by from 1 to 3 identical or different groups selected from R, OR, S(O)nR, C(Z)R, C(Z)OR, NRR', C(Z)OR, C(Z)NRR', , (in which groups R, R" and Z are as defined hereinbefore and n is 0,1 or 2), cyano, nitro and halogen atoms, wherein: when A represents a CH2 group, B cannot represent a linear or branched (C1-C6)alky1 group substituted by a group when the groups A and B are in the ortho position in relation to one another on the benzene nucleus carrying them, B cannot represent a linear or branched (C2-C6)alkenylene group substituted by a group when A represents a group , B cannot represent a -CH2-COOH group, aryl is to be understood as a phenyl, naphthyl or biphenyl group, which groups may be partially hydrogenated, heteroaryl is to be understood as any mono- or bi-cyclic aromatic group containing from 5 to 10 ring members, which may be partially hydrogenated on one of the rings in the case of bicyclic heteroaryls, and which contains from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur, wherein the aryl and heteroaryl groups so defined may be substituted by from 1 to 3 groups selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, carboxy, formyl, NRbRc (wherein Rb and Rc, which may be identical or different, each represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group or a heteroaryl group), ester, amido, nitro, cyano, O-C(Me)2COOR" (wherein R" is as defined hereinbefore) and halogen atoms, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 2. Compounds of formula (I) according to claim 1, wherein R<1> and R<2> form an oxo group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 3. Compounds of formula (I) according to claim 1, wherein R<3> and R<4> simultaneously represent a hydrogen atom, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 4. Compounds of formula (I) according to claim 1, wherein A represents an alkylene group in which a CH2 group may be replaced by a hetero atom, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 5. Compounds of formula (I) according to claim 1, wherein A represents an ethyleneoxy group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 6. Compounds of formula (I) according to claim 1, wherein A represents an alkylene group in which a CH2 group may be replaced by a phenylene or naphthylene group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 7. Compounds of formula (I) according to claim 1, wherein X represents an oxygen atom or a sulphur atom, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 8. Compounds of formula (I) according to claim 1, wherein X represents a CHR'<2> group and D represents a pyridine nucleus, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 9. Compounds of formula (I) according to claim 1, wherein B represents an alkyl or alkenyl group, those groups being substituted by a group of formula (II), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 10. Compounds of formula (I) according to claim 1, wherein B represents an alkyl or alkenyl group, those groups being substituted by a R<5> group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 11. Compounds of formula (I) according to claim 1, wherein D represents an unsubstituted benzene nucleus, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 12. Compounds of formula (I) according to claim 1, wherein D represents a benzene nucleus substituted by an arylcarbonyl group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 13. Compounds of formula (I) according to claim 1, wherein D represents a pyridine nucleus, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 14. Compounds of formula (I) according to claim 1, wherein D represents a pyrazine, pyrimidine or pyridazine nucleus, their enantiomers and diastereoisomers. and addition salts thereof with a pharmaceutically acceptable acid or base. 15. Compounds of formula (I) according to claim 1, which are diethyl 2-{4-[2-(2-oxo-1,3-benzoxazol-3(2H)-yl)ethoxy]benzylidene}malonate, diethyl 2-{4-[2-(2-oxo-1,3-benzothiazol-3(2H)-yl)ethoxy]benzylidene}malonate and diethyl 2-{4-[3-(2-oxo-1,3-benzothiazol-3(2H)-yl)propoxy]benzylidene}malonate, and addition salts thereof with a pharmaceutically acceptable acid or base. 16. Compounds of formula (I) according to claim 1, which are diethyl 2-{4-[2-(2-oxo-1,3-benzoxazol-3(2H)-yl)ethoxy]benzyl}malonate, 3-ethoxy-3-oxo-2-{4-[2-(2-oxo-1,3-benzoxazol-3(2H)-yl)ethoxy]benzyl}propanoic acid, 2-{4-[2-(2-oxo-1,3-benzoxazol-3(2H)-yl)ethoxy]benzyl}malonic acid, diethyl 2-{4-[2-(2-oxo-1,3-benzothiazol-3(2H)-yl)ethoxy]benzyl}malonate, dimethyl 2-{4-[2-(2-oxo-1,3-benzothiazol-3(2H)-yl)-ethoxy]benzyl}malonate, 3-methoxy-3-oxo-2-{4-[2-(2-oxo-1,3-benzothiazol-3(2H)-yl)ethoxy]benzyl}propanoic acid, 3-ethoxy-3-oxo-2-{4-[2-(2-oxo-1,3-benzothiazol-3(2H)-yl)ethoxy]benzyl}propanoic acid and 2-{4-[2-(2-oxo-1,3-benzothiazol-3(2H)-yl)ethoxy]benzyl}malonic acid, and addition salts thereof with a pharmaceutically acceptable acid or base. 17. Compounds of formula (I) according to claim 1, which are dimethyl 2-{4-[2-(6-benzoyl-2-oxo-1,3-benzothiazol-3(2H)-yl)ethoxy]benzyl}malonate, dimethyl 2-{4-[2-(6-benzoyl-2-oxo-1,3-benzoxazol-3(2H)-yl)ethoxy]benzyl}malonate, dimethyl 2-{4-[2-(6-(2-chlorobenzoyl)-2-oxo-1,3-benzothiazol-3(2H)-yl)ethoxy]benzyl}malonate, dimethyl 2-{4-[2-(6-([1,1'-biphenyl]-4-ylcarbonyl)-2-oxo-1,3-benzomiazol-3(2H)-yl)ethoxy]-benzyl} malonate, dimethyl 2-{4-[2-(6-(1-naphthoyl)-2-oxo-1,3-benzothiazol-3(2H)-yl)ethoxy]benzyl}malonate, dimethyl 2-{4-[2-(6-(3-chlorobenzoyl)-2-oxo-1,3-benzo-thiazol-3(2H)-yl)ethoxy]benzyl}malonate, dimethyl 2-{4-[2-(2-oxo-6-(3-pyridyl-carbonyl)-1,3-benzothiazol-3(2H)-yl)ethoxy]benzyl}malonate, dimethyl 2-{4-[2-(6-(4-chlorobenzoyl)-2-oxo-1,3-benzothiazol-3(2H)-yl)ethoxy]benzyl}malonate, 2-{4-[2-(6-benzoyl-2-oxo-1,3-benzothiazol-3(2H)-yl)ethoxy]benzyl}malonic acid, dimethyl 2-{4-[2-(6-(2-naphthoyl)-2-oxo-1,3-benzothiazol-3(2H)-yl)ethoxy]benzyl}malonate, dimethyl 2-{4-[2-(6-(4-methoxybenzoyl)-2-ox