Patent EA-002818-B1 (EA)
Title: New cyclic compounds having a cycloalkylene chain, a process for their preparation and pharmaceutical compositions containing them
Inventor: LANGLOIS MICHRL
IPC: C07C233/23
Filed: 1999-10-11
Abstract: 1. Compound of formula (I):   wherein A represents a ring system of formula (II):   wherein R can be substituent in any position of the ring system II, or A represents a ring system of formula (III):   wherein Z represents an oxygen atom, a sulphur atom, a NR<1> group (wherein R<1> represents a hydrogen atom, or a linear or branched (C1-C6)alkyl group, D' represents a benzene ring or a pyridine ring, wherein R substitutes the D' ring and G1 substitutes the other ring, it being understood that the ring systems of formula (II) or (III) may be substituted, in addition to the R and G1 groups, by from one to three identical or different groups selected from linear or branched (C1-C6)alkoxy group, an aryl group, an aryl-(C1-C6)alkyl in which the alkyl moiety is linear or branched; R represents Ra, ORa or SRa group wherein Ra is a linear or branched (C1-C6)alkyl group; or forms, with the carbon atom carrying it and with an adjacent carbon atom, a ring of formula (IV):   wherein E represents an oxygen atom or sulfur, wherein the resulting ring contains from 5 to 7 atoms, G1 and G2, which may be identical or different, represent a single bond or an alkylene chain -(CH2)t- (wherein t is 1, 2, 3 or 4), p is 0, 1, 2, 3 or 4, q is 0, 1, 2, 3 or 4, with 1<=p+q<=4; B represents an -NR<1>aC(Q)R<2>a, -NR<1>aC(Q)NR<2>aNR<3>a or C(Q)NR<1>aNR<2>a, group wherein Q represents an oxygen or sulfur atom, R<1>a is hydrogen, R<2>a is a group, selected from linear or branched (C2-C6)alkenyl, (C3-C8)cycloalkyl and from linear or branched (C1-C6)alkyl, which can be optionally with halogen atom, and R<3>a is hydrogen, it being understood that: - "aryl" is understood to mean the groups phenyl, naphthyl or biphenyl, it being possible for those groups to be substituted by one or more identical or different radicals selected from hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, linear or branched polyhalo-(C1-C6)alkyl, cyano, carboxy, linear or branched (C1-C6)alkoxycarbonyl, nitro, amino and halogen atoms, - "heteroaryl" is understood to mean any mono- or poly-cyclic aromatic group containing from 5 to 10 atoms and containing from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur, it being possible for those groups to be substituted by one or more radicals selected from hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, linear or branched polyhalo-(C1-C6)alkyl, cyano, carboxy, linear or branched (C1-C6)alkoxycarbonyl, nitro, amino and halogen atoms, with the proviso that: - when A represents a naphthalene group unsubstituted or substituted by one methoxy or one methyl group, G1 and G2 simultaneously represent a single bond, and B represents   or NHCOMe group, it is not possible to have (q = 0 and p = 4) or (q = 4 and p = 0), - when A represents an indole group substituted in the 2-position by the group   B cannot represent a urea group, 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 p is 1, 2, 3 or 4 and q is 0 (or p is 0 and q is 1, 2, 3 or 4), 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 p is 1 and q is 0 (or p is 0 and q is 1), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 4. Compounds of formula (I) according to Claim 3 characterised in that R-A-G1 and G2-B groups are in the trans configuration, 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 R represents an ORa, SRa or Ra 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 R represents an ORa 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 R forms, with the carbon atom carrying it and with an adjacent carbon atom, a ring of formula (IV), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 8. Compounds of fomlula (I) according to Claim 1 wherein A represents a ring system of formula (II) substituted in the 7-position by R and in the 1- or 2-position by -G1, A being unsubstituted or substituted (as well as by the substituents R and G1) in the 2- or 3-position, 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 A represents a ring system of formula (III) substituted in the 5-position by R and in the 3-position by G1, A being unsubstituted or substituted (in addition to the substituents R and G1) in the 2-position, 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 G1 represents a single bond and G2 represents a single bond or a CH2 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 B represents an -NHCOR<2>a or -CONHRa group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 12. Compounds of formula (I) according to Claim 1 substituted:  by a group of formula (V):   wherein n is 0 or 1 and B' represents -NHCOR2a or -CONHR<2>a group, -ORa, SRa, or Ra group, and - optionally by an alkoxy, aryl or arylalkyl 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 A represents a naphthalene, a chroman or a benzochroman, substituted in the 1- or 2-position (formula II) by a group of formula (V):   wherein n is 0 or 1 and B' represents an -NHCOR2a or -CONHR<2>a group, substituted - in the 7-position (formula II) by an ORa, SRa or Ra group, and - optionally substituted in the 3-position (formula II) by an aryl or arylalkyl group, or in the 2-position (formula II) by an alkoxy group, 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 A represents a benzothiophene, a benzomran, an indole or an azaindole, - substituted in the 3-position (formula III) by a group of formula (V):   wherein n is 0 or 1 and B' represents an -NHCOR2a or -CONHR<2>a group, - substituted in the 5-position (formula III) by an ORa, SRa or Ra group, and - optionally substituted in the 2-position (formula III) by an aryl or arylalkyl group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 15. Compounds of formula (I) according to Claim 1 wherein A represents a naphthalene, - substituted in the 1-position by a group of formula (V):   wherein n is 0 or 1 and B' represents an -NHCOR2a or -CONHR<2>a group, - substituted in the 7-position by an ORa group, and - optionally substituted in the 3-position by an aryl or arylalkyl group, or in the 2-position by an ORa group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 16. Compounds of formula (I) according to Claim 1, which are: N-[2-(7-methoxy-1-naphthyl)-l-cyclopropyl]acetamide, N-[2-(7-methoxy-1-naphthyl)-1-cyclopropyl]propanamide, N-[2-(7-methoxy-1-naphthyl)-1-cyclopropyl]butanamide, N-[2-(7-methoxy-1-naphthyl)-1-cyclopropyl]cyclopropanecarboxamide, N-[2-(2,7-dimethoxy-1-naphthyl)-1-cyclopropyl]acetamide, N-[2-(2,7-dimethoxy-1-naphthyl)-1-cyclopropyl]propanamide, N-[2-(2,7-dimethoxy-1-naphthyl)-1-cyclopropyl]butanamide, N-[2-(2-methoxy-1-naphthyl)-1-cyclopropyl]acetamide, N-[2-(2-methoxy-1-naphthyl)-1-cyclopropyl]propanamide, N-[2-(2-methoxy-1-naphthyl)-1-cyclopropyl]butanamide, N-[2-(2-methoxy-1-naphthyl)-1-cyclopropylmethyl]acetamide, N-[2-(2-methoxy-1-naphthyl)-1-cyclopropylmethyl]propanamide, N-[2-(2-methoxy-1-naphthyl)-1-cyclopropylmethyl]butanamide, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 17. Compounds of formula (I) according to Claim 15 characterised in that -(CH2)n-B and R-A-G1- are in the trans configuration, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 18. Process for the preparation of compounds of formula (I) according to Claim 1 characterised in that there is used as starting material a compound of formula (VI) :   wherein R, A, G1, G2, p and q are as defined hereinabove, which is subjected, after activation to the acid chloranhydride or in the presence of a coupling agent, to the action of an amine HNR<1>aR<2>a, wherein R<1>a and R<2>a are as defined hereinabove to yield a compound of formula (I/a), a particular case of the compounds of formula (I):   wherein R, A, G1, G2, R<1>a, R<2>a, p and q are as defined hereinabove, which may be subjected to the action of a thionisation agent to obtain a compound of formula (I/b), a particular case of the compounds of formula (I),   wherein R, A, G1, G2, R<1>a, R<2>a, p and q are as defined hereinabove, or subjected, after conversion to the corresponding azide, to a Curtius rearrangement to yield, after hydrolysis, an amine of formula (VII):   wherein R, A, G1, G2, p and q are as defined hereinabove, which is either: - reacted with an acyl chloride ClCOR<2>a, or the corresponding mixed or symmetric anhydride wherein R<2>a, is as defined hereinabove to yiel