Patent EA-005155-B1 (EA)
Title: Vitronectin receptor antagonist bicyclic compounds, preparation method and compositions containing same
Inventor: CASARA PATRICK
IPC: A61K31/44
Filed: 2001-03-06
Abstract: 1. A compound selected from those of formula (I): wherein: G represents a phenyl group, G1 and G2 represent a carbon, -T1- represents a group selected from -CH2-CH2-, -CH(CH- and -CH-CH2- and -T2- represents a bond, R5 represents a -(CH2)m-COOR6, R6 and R6' independently represent hydrogen, alkyl, optionally substituted aryl, or optionally substituted arylalkyl, -W- represents -CH-, (C- or (C- and -A- represents -CH2- or (CH-, -X- represents a group selected from -CO-X1-, -CO-NR6-X1-, -NR6-CO-X1-, -O-X1-, -SO2-NR6-X1- and -S(O)n-X1-, wherein n is from 0 to 2 inclusive and X1 represents an alkylene, -Y- represents a group selected from -Y1-, -Y2-Y1-, and -Y1-Y2-Y1-, wherein Y1 represents alkylene, alkenylene, or alkynylene, and Y2 represents arylene, heteroarylene, cycloalkylene, or heterocycloalkylene, Z- represents a group selected from Z1-, Z10-NR6- and Z10-NR6-CO- wherein Z10 represents an alkyl or Z1, and Z1 represents a group selected from Z2-, Z20-NR6- and Z20-NR6-CO-, wherein Z20 represents alkyl, heteroalkyl, Z2, and Z2 represents an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, an optionally substituted heteroarylalkyl, an optionally substituted heterocycloalkylalkyl, an optionally substituted fused arylheteroaryl, an optionally substituted fused arylheterocycloalkyl, an optionally substituted fused heteroarylheterocycloalkyl, an optionally substituted fused heterocycloalkylheteroaryl, an optionally substituted fused heteroarylheteroaryl or a fused cycloalkylheterocycloalkyl, m is an integer of from 1 to 6 inclusive, wherein: "alkyl" is a linear or branched, 1 to 6 carbon alkyl group, "heteroalkyl" is an alkyl in which a carbon atom has been replaced by a hetero atom selected from nitrogen, oxygen and sulphur, "alkylene" is a linear or branched divalent 1 to 6 carbon group, "alkenylene" is a linear or branched divalent 2 to 6 carbon group with 1 to 3 double bonds, "alkynylene" is a linear or branched divalent 2 to 6 carbon group with 1 to 3 triple bonds, "cycloalkyl" is a saturated 3 to 8 carbon cyclic group, "cycloalkylene" is a saturated 3 to 8 carbon cyclic divalent group, "heterocycloalkyl" is a saturated cyclic 5 to 7 ring membered group with 1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur, "aryl" is a phenyl or naphthyl, "heteroaryl" is an unsaturated or partially unsaturated mono- or bi-cyclic 5 to 11 membered group with 1 to 5 hetero atoms selected from nitrogen, oxygen and sulphur, "fused arylheteroaryl" is a polycyclic group formed by an aryl and a heteroaryl, each as defined hereinabove, and conjoined by means of any one of their bonds, "fused arylheterocycloalkyl" is a bi- or tri-cyclic group formed by an aryl and a heterocycloalkyl, each as defined hereinabove, and conjoined by means of any one of their bonds, "fused heteroarylheterocycloalkyl" is a bi- or tri-cyclic group formed by a heteroaryl and a heterocycloalkyl, each as defined hereinabove, and conjoined by means of any one of their bonds, "fused heterocycloalkylheteroaryl" is a bi- or tri-cyclic group formed by a heteroaryl and a heterocycloalkyl, each as defined hereinabove, and conjoined by means of any one of their bonds, "fused heteroarylheteroaryl" is a polycyclic group formed by two heteroaryl groups, as defined hereinabove, and conjoined by means of any one of their bonds, "fused cycloalkylheterocycloalkyl" is a bicyclic group formed by a cycloalkyl and a heterocycloalkyl, each as defined hereinabove, and conjoined by means of any one of their bonds, the ending "-ene" is that the group in question is a divalent radical having the same meanings as the base radical, the expression "optionally substituted" in connection with the groups heterocycloalkyl, aryl, arylalkyl, heteroaryl, fused arylheteroaryl, fused heteroarylheterocycloalkyl, fused heteroarylheteroaryl and fused arylheterocycloalkyl is that those groups are unsubstituted or substituted by one or more atoms or groups selected from alkyl, alkoxy, hydroxy, mercapto, cyano, amino (optionally substituted by one or two alkyl), nitro, carboxy, alkoxycarbonyl, aminocarbonyl (optionally substituted by one or two alkyl), wherein the heteroaryl and heterocycloalkyl groups may also be substituted by an oxo, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 2. A compound of formula (I) of claim 1, wherein R5 represents a -CH2-COOR6 group, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 3. A compound of formula (I) of claim 1, wherein X is selected from -CO-NR6-X1, -NR6-CO-X1 and -O-X1, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 4. A compound of formula (I) of claim 1, wherein Y represents Y1 or the group Y1-Y2-Y1, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 5. A compound of formula (I) of claim 1, wherein Z represents a heteroaryl, heterocycloalkyl, fused arylheteroaryl or fused heterocycloalkylheteroaryl. 6. A compound of formula (I) of claim 1, wherein Z represents Z10-NR6, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 7. A compound of formula (I) of claim 1, wherein G represents phenyl, G1 and G2 each represent a carbon, R5 represents a -CH2-COOR6, R6 is selected from hydrogen and alkyl, T2 represents a bond, T1 represents a group selected from -CH(CH- and (CH-CH2-, A represents -CH2- or (CH- and W represents a -CH- or -C(, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 8. A compound of formula (I) of claim 7, wherein X is selected from -CO-NR6-X1-, -NR6-CO-X1- and -O-X1-, X1 is methylene, Y represents -Y1- or the group -Y1-Y2-Y1 in which Y1 is alkylene and Y2 represents arylene, and Z represents heteroaryl, heterocycloalkyl, fused arylheteroaryl or fused heterocycloalkylheteroaryl or Z10-NR6 wherein Z10 represents a group selected from heteroaryl, heterocycloalkyl, fused arylheteroaryl and fused heterocycloalkylheteroaryl, and R6 is hydrogen, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 9. A compound of formula (I), which is [7-({[4-(2-pyridylamino)butanoyl]amino}methyl)-6,9-dihydro-5H-benzo[a]cyclohepten-5-yl]acetic acid. 10. A compound of formula (I), which is [7-({[5-(2-pyridylamino)pentanoyl]amino}methyl)-6,9-dihydro-5H-benzo[a]cyclohepten-5-yl]acetic acid hydrochloride. 11. A compound of formula (I), which is [7-(2-oxo-2-{[3-(2-pyridylamino)propyl]amino}ethyl)-5H-benzo[a]cyclohepten-5-yl]acetic acid. 12. A compound of formula (I), which is [7-({[4-(4,5-dihydro-IH-imidazol-2-ylamino)-butanoyl]amino}methyl)-6,9-dihydro-5H-benzo[a]cyclohepten-5-yl]acetic acid hydrochloride. 13. A compound of formula (I), which is [7-({[4-(2-pyridylamino)butanoyl]amino}methyl)-5H-benzo[a]cyclohepten-5-yl]acetic acid. 14. A compound of formula (I), which is [7-({[4-(1H-benzimidazol-2-ylamino)butanoyl]-amino}methyl)-5H-benzo[a]cyclohepten-5-yl]acetic acid. 15. A compound of formula (I), which is [7-({[4-(1H-benzimidazol-2-ylamino)butanoyl]-amino}methyl)-6,9-dihydro-5H-benzo[a]cyclohepten-5-yl]acetic acid. 16. A compound of formula (I), which is [7-({[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)-butanoyl]amino}methyl)-6,9-dihydro-5H-benzo[a]cyclohepten-5-yl]acetic acid hydrochloride. 17. A compound of formula (I), which is [7-({[4-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-butanoyl]amino}methyl)-6,9-dihydro-5H-benzo[a]cyclohepten-5-yl]acetic acid hydrochloride. 18. Process for the preparation of the compounds of formula (I) according to claim 1, characterised in that the starting material used is a compound of formula (II/a): wherein G, G1, G2 T1, T2 and R5 are as defined for formula (I), W and A are as defined hereinabove, and R represents a CHO, CN or AlkOOC-CH= group, which, when R represents a formyl group, is subjected to a Wittig or Homer Emons reaction so as to homologise the chain carrying the aldehyde function, by using the appropriate reagent, to yield a compound of formula (III/a): wherein G, G1, G2 T1, T2, R5 A and W are as defined hereinabove, X'1 represents an alkylene or alkenylene group having from two to six carbon atoms and Ra represents a cyano, formyl or alkoxycarbonyl group according to the reagent chosen, which compound (III/a), with the compounds of formula (III/b): a particular case of the compounds of formula (II/a) wherein G, G1, G2 T1, T2, R5 W and A are as defined hereinabove and Alk represents an alkyl group, the broken lines indicating the optional presence of a double bond, constitute the entirety of the compounds of formula (III-l): - the Ra group of which compound (III) is either reduced in alcohol, or deprotected when it represents a masked hydroxy group, to yield a compound of formula (IV): wherein G, G1, G2 T1, T2, R5 A W and X1 are as defined for formula (I), which is subjected to a halogenation reaction to yield a compound of formula (V): wherein G, G1, G2 T1, T2, R5 A W and X1 are as defined hereinabove and Hal represents a halogen atom, which is treated, in basic medium, with a compound of formula Z-Y-OH wherein Z and Y are as defined for formula (I), to yield a compound of formula (I/a): a particular case of the compounds of formula (I) wherein G, G1, G2 T1, T2, R5, X1, W, A, Y and Z are as defined for formula (I), or which is treated, in basic medium, with a compound of formula Z-Y-SH wherein Z and Y are as defined for formula (I), to yield a compound of formula (I/b): a particular case of the compounds of formula (I) wherein G, G1, G2 T1, T2, R5, X1, W, A, Y and Z are as defined for formula (I), the sulphur atom of which may be oxidised to yield a compound of formula (I/c): a particular case of the compounds of formula (I) wherein G, G1, G2 T1, T2, R5, X1, W, A