Patent EA-002442-B1 (EA)
Title: New hydrazide compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: MONGE VEGA A
IPC: A61K31/4406
Filed: 1999-12-16
Abstract: 1. Compounds of formula (I): R-NH-A-CO-NH-NH-(W)n-Z                       (I) wherein: -  n is 0 or 1, - W represents a -CO- group or an S(O)r group wherein r is 0,1 or 2, - Z represents a group selected from optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, - R represents a group selected from : Zi-T-CO-Zi-O-T-CO-Zi-T-0-CO-Zi-T-S(O)q- wherein: - Zi represents an optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group, - T represents a ( bond or an alkylene, alkenylene or alkynylene group, - q represents an integer 0, 1 or 2, - A represents a linear or branched alkylene group having from 3 to 8 carbon atoms, a linear or branched alkenylene group having from 3 to 8 carbon atoms, a linear or branched alkynylene group having from 3 to 8 carbon atoms, an alkylenecycloalkylene group, a cycloalkylenealkylene group, an alkylenecycloalkylenealkylene group, an alkylenearylene group, an arylenealkylene group, an alkylenearylenealkylene group, a grouping   wherein B1 represents an optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyi group, or A forms with the nitrogen atom a grouping   wherein B2 represents a saturated or unsaturated mono- or bi-cyclic system having from 5 to 11 ring members, optionally containing from 1 to 3 additional hetero atoms selected from nitrogen, oxygen and sulphur, with the proviso that when simultaneously n is 0, A represents a grouping   B1 being a benzyl group, and Z represents an optionally substituted phenyl group, then R is other than a benzoyl group, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that: the term "alkyl" denotes a linear or branched group having from 1 to 6 carbon atoms, the term "alkylene" denotes a linear or branched bivalent radical containing from 1 to 6 carbon atoms, unless indicated otherwise, the term "alkenylene" denotes a linear or branched bivalent radical containing from 2 to 6 carbon atoms and from 1 to 3 double bonds, unless indicated otherwise, the term "alkynylene" denotes a linear or branched bivalent radical containing from 2 to 6 carbon atoms and from 1 to 3 triple bonds, unless indicated otherwise, the term "aryl" denotes a phenyl, naphthyl, dihydronaphthyl or tetrahydronaphthyl group, and the term "arylene" denotes a bivalent radical of the same type, the term "heteroaryl" denotes an unsaturated or partially unsaturated mono- or bi-cyclic group having from 5 to 11 ring members, containing from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulphur, the term "alkylenecycloalkylene" represents a grouping -A1-A2-, the term "cycloalkylene-alkylene" represents a grouping -A2-A1, and the term "alkylenecycloalkylenealkylene" represents a grouping -A1-A2-A1, the term "alkylenearylene" represents a grouping -A1-A3-, the term "arylenealkylene" represents a grouping -A3-A1-, the term "alkylenearylenealkylene" represents a grouping -A1-A3-A1-, wherein A1 is an alkylene group as defined hereinbefore, A2 is a (C4-C8)cycloalkylene group, and A3 is an arylene group as defined hereinbefore, the expression "optionally substituted" applied to the terms "aryl", "arylalkyl", "heteroaryl" and "heteroarylalkyl" indicates that those groups are substituted on their cyclic moiety by from 1 to 5 identical or different substituents selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, halogen, hydroxy, perhalo-( C1-C6)alkyl in which the alkyl moiety is linear or branched, nitro, linear or branched (C1-C6)acyl, linear or branched (C1-C6)alkylsulphonyl, and amino (amino optionally being substituted by one or two linear or branched (C1-C6)alkyl and/or linear or branched (C1-C6)acyl groups). 2. Compounds of formula (I) according to claim 1 wherein W represents a -CO- group, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 3. Compounds of formula (I) according to claim 1 wherein W represents a -SO2- group, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 4. Compounds of formula (I) according to claim 1 wherein R represents a grouping Z1-T-CO, T being an alkylene group or a bond, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 5. Compounds of formula (I) according to claim 1 wherein R represents a grouping Z1-O-T-CO, T being an alkylene group or a bond, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 6. Compounds of formula (I) according to claim 1 wherein R represents a grouping Z1-T-O-CO, T being an alkylene group or a bond, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 7. Compounds of formula (I) according to claim 1 wherein R represents a grouping Z1-T-S(O)q-, T being an alkylene group or a bond, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 8. Compounds of formula (I) according to claim 1 wherein Z represents an optionally substituted aryl or optionally substituted heteroaryl group, their enantiomers, 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 grouping  wherein B1 is an optionally substituted arylalkyi group, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 10. Compounds of formula (I) according to claim 1 wherein A represents an alkylenecycloalkylene group, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 11. Compounds of formula (I) according to claim 1 wherein A represents an alkylenearylene group, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 12. Compounds of formula (I) according to claim 1 wherein A represents a grouping    their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 13. Compound of formula (I) according to claim 1 wherein W represents a -CO- group, Z represents a group selected from optionally substituted aryl and optionally substituted heteroaryl, R represents a grouping selected from Z1-T-CO-, Z1-O-T-CO-, Z1-T-O-CO-and Z1-T-S(O)q- wherein Z1 is an optionally substituted aryl or optionally substituted heteroaryl group, T represents an alkylene group, and q is 2, and A represents an alkylenecycloalkylene group, a grouping   wherein B1 is an optionally substituted arylalkyl group, or A forms with the adjacent nitrogen atom a pyrrolidine, perhydroindole or piperidine group, and its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 14. Compound of formula (I) according to claim 1 which is N2-({4-[(2-benzoylhydrazino)-carbonyl]cyclohexyl}methyl)-2-naphthalenesulphonamide, and its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 15. Compound of formula (I) according to claim 1 which is Nl-({4-[(2-benzoylhydrazino)-carbonyl]cyclohexyl}methyl)-l-(2-nitrobenzene)sulphonamide, and its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 16. Compound of formula (I) according to claim 1 which is Nl-[l-benzyl-2-oxo-2-(2-phenylhydrazino)ethyl]-l-(4-chlorobenzene)sulphonamide, and addition salts thereof with a pharmaceutically acceptable acid or base. 17. Process for the preparation of compounds of formula (I) characterized in that there is used as starting material a compound of formula (II): H2N-A-COOH                       (II) wherein A is as defined for formula (I), which is condensed in a basic medium with a halogen compound of formula (III): R-C1                                     (III) wherein R is as defined for formula (I), to yield a compound of formula (IV): R-NH-ACOOH                   (IV) wherein R and A are as defined hereinbefore, which compound (IV) is condensed, in the presence of a coupling agent, with a monosubstituted hydrazine of formula (V), H2N-NH-(W)n-Z                 (V) wherein n, W and Z are as defined for formula (I), to yield compounds of formula (I): R-NH-A-CO-NH-NH-(W)n-Z                   (I)  wherein R, A, n, W and Z are as defined hereinbefore, which compound of formula (I): - may be purified, if necessary, according to a conventional purification technique, - is separated, where appropriate, into its isomers according to a conventional separation technique, - is converted, if desired, into an addition salt thereof with a pharmaceutically acceptable acid or base. 18. Pharmaceutical compositions comprising as active ingredient at least one compound according to any one of claims 1 to 16, on its own or in combination with one or more inert, non-toxic pharmaceutically acceptable excipients or carriers. 19. Pharmaceutical compositions according to claim 18 comprising at least one active ingredient according to any one of claims 1 to 16 for use as a neuropeptide Y receptor ligand in the treatment of pathologies associated with eating behaviour disorders or energy balance disorders, selected from diabetes, obesity, bulimia.