Patent ID: 6417161
Filing Date: 2002-07-09
Classification: A61K,A61P,C07D,C07K

Abstract:
A compound having the Formula I, including stereoisomers: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:A1 represents a structural fragment of Formula IIa, IIb, IIc, IId, IIe, IIf or IIg: â€ƒwherein: k is an integer 0, 1, 2, 3 or 4; j is an integer 1, 2, 3 or 4; q is an integer 0, 1, 2 or 3; R1 represents H, C1-4 alkyl, or R11OOCâ€”(C1-4)alkyl-, optionally substituted in the position which is alpha to the carbonyl group, with a group R14â€”(CH2)pâ€”, wherein p is 0, 1 or 2 and R14 is methyl, phenyl, OH, COOR12, CONHR12, where R12 is H or C1-4 alkyl group, and R11 is H, C1-6 alkyl, or benzyl substituted in the 4-position by COOR12, where R12 is as defined above, or R1 represents R13â€”NHâ€”COâ€”(C1-4)alkyl-, optionally substituted alpha to the carbonyl with C1-4 alkyl and where R13 is H, C1-4 alkyl or â€”CH2COOR12, where R12 is as defined above, or R1 represents R12OOCâ€”CH2â€”OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is optionally substituted alpha to the carbonyl with C1-4 alkyl and where R12 is as defined above, or R1 represents C1-4 alkylsulfonyl, Ph(4-COOR12)â€”SO2â€”, Ph(3-COOR12)â€”SO2â€”, Ph(2-COOR12)â€”SO2â€”, where R12 is as defined above, or R1 represents C1-4 alkylcarbonyl, or R1 represents C1-4 alkoxycarbonyl, or R1 represents â€”COâ€”(CH2)pâ€”COOR12, where R12 is as defined above and p is an integer 0, 1 or 2, or R1 represents â€”CH2PO(OR15)2, â€”CH2SO3H or â€”CH2â€”(5-(1H)-tetrazolyl), where R15 is, individually at each occurrence, H, methyl or ethyl; R2 represents H or C1-4 alkyl, carboxy(C1-4)alkyl or C1-4 alkoxycarbonyl(C1-4)alkyl; R3 represents C1-4 alkyl, optionally having one or more fluorine atoms, or R3 represents cyclopentyl, cyclohexyl or phenyl, any of which may be optionally substituted with C1-4 alkyl, or R3 represents fluoren-9-yl, or 9-hydroxyfluoren-9-yl, or R3 represents a phenyl group substituted with one to three OR16, where R16 is independently H or C1-4 alkyl and k is 0, 1, or R3 represents a 1-naphthyl or 2-naphthyl group and k is 0, 1, or R3 represents a cis- or trans-decalin group and k is 0, 1, or R3 represents 4-pyridyl, 3-pyrrolidyl or 3-indolyl, any of which is optionally substituted with OR16, where R16 is as defined above and k is 0, 1, or R3 represents Si(Me)3 or CH(R17)2, wherein R17 is independently C1-4 alkyl, cyclopentyl, cyclohexyl, benzyl or phenyl, or, in Formula IIa, where one R17 is cyclopentyl, cyclohexyl or phenyl, and the other R17 forms an ethylene bridge together with R1 and k is 0, 1, or 2; R5 represents C1-4 alkyl, phenyl, or benzyl; R21 represents H, C(O)R41, SiR42R43R44 or C1-6 alkyl which latter group is optionally substituted or terminated by one or more substituents selected from OR45 or (CH2)tR46; R42, R43 and R44 independently represent H, phenyl or C1-6 alkyl; R46 represents C1-4 alkyl, phenyl, OH, C(O)OR47 or C(O)N(H)R48; R8 represents H, C1-4 alkyl or CH2C(O)OR49; R45 and R47 independently represent H, C1-4 alkyl or C7-9 alkylphenyl; R41 and R49 independently represent H or C1-4 alkyl; and t represents 0, 1 or 2; R22 and R23 independently represent H, C1-4 alkyl, cyclohexyl or phenyl; R24 represents a structural fragment of Formula IVa, IVb or IVc, â€ƒwherein v, w and u independently represent 0, 1, 2, 3 or 4; R34 and R35 independently represent H, Si(Me)3, 1- or 2-naphthyl, a polycyclic hydrocarbyl group, CHR31R32 or C1-4 alkyl (which latter group is optionally substituted by one or more fluorine atoms), or C3-8 cycloalkyl, phenyl, methylenedioxyphenyl, benzodioxanyl, benzofuranyl, dihydrobenzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, coumaranonyl, coumarinyl or dihydrocoumarinyl (which latter twelve groups are optionally substituted by one or more of C1-4 alkyl (which latter group is optionally substituted by one or more halo substituent), C1-4 alkoxy, halo, hydroxy, cyano, nitro, SO2NH2, C(O)OH or N(H)R33); R31 and R32 independently represent cyclohexyl or phenyl; R36 and R37 independently represent H, C1-4 alkyl, C3-8 cycloalkyl, phenyl (which latter group is optionally substituted by one or more of C1-4 alkyl (which latter group is optionally substituted by one or more halo substituent), C1-4 alkoxy, halo, hydroxy, cyano, nitro, SO2NH2, C(O)OH or N(H)R38) or together with the carbon atom to which they are attached form a C3-8 cycloalkyl ring; R33 and R38 independently represent H or C(O)R39; and R39 represents H, C1-4 alkyl or C1-4 alkoxy; A2 represents a structural fragment of Formula IIIa, IIIb or IIIc: â€ƒwherein: d is 0, 1 or 2; e is 1, 2, 3 or 4; Y represents a methylene group, or Y represents an ethylene group and the resulting 5-membered ring may optionally carry one or two fluorine atoms, a hydroxy group or an oxo group in position 4, or may or may not be unsaturated, or Y represents â€”CH2â€”Oâ€”, â€”CH2â€”Sâ€”, â€”CH2â€”SOâ€”, with the heteroatom functionality in position 4, or Y represents a n-propylene group and the resulting 6-membered ring may optionally carry in position 5 one fluorine atom, a hydroxy group or an oxo group, carry two fluorine atoms in one of positions 4 or 5 or be unsaturated in position 4 and 5, or carry in position 4 a C1-4 alkyl group, or Y represents â€”CH2â€”CH2â€”, CH2â€”Sâ€”CH2â€”, â€”CH2â€”SOâ€”CH2â€”, or Y represents â€”CH2H2â€”CH2â€”CH2â€”; R3 is as defined as for R4 above; R6 represents H or C1-4 alkyl, carboxy, C1-4 alkoxycarbonyl, carboxy(C1-4)alkyl or C1-4 alkoxycarbonyl(C1-4)alkyl; provided that when A1 is a fragment of Formula IIb, and A2 is a fragment of Formula IIIb, then R4 is not 1-naphthyl or 2-naphthyl; R7 is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di-alkylamino, provided that n is other than zero when R7 is hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di-alkylamino; R8, R9 and R10 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxyalkyl; or R7 and R8 are taken together to form â€”(CH2)iâ€”, where i is zero (a bond), 1 or 2, while R9 and R10 are defined as above; or R7 and R10 are taken together to form â€”(CH2)jâ€”, where j is zero (a bond), or 1 to 8, while R8 and R9 are defined as above; or R9 and R10 are taken together to form â€”(CH2)hâ€”, where h is 2-8, while R7 and R8 are defined as above; R18 is one of hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl, or alternatively, R18 and R10 taken together to form â€”(CH2)wâ€”, where w is 1-5; X is oxygen; Ra, Rb and Rc are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or â€”CO2Rw; Rw is alkyl, cycloalkyl, phenyl, benzyl, â€ƒwhere Rd and Rc are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, R8 is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl; n is from zero to 8; and m is from zero to 4.