Patent ID: 6479519
Filing Date: 2002-11-12
Classification: A61P,C07C,C07D

Abstract:
A compound of formula (I): wherein:R1 is hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy; X1, X2 and X6 independently represent N or CR10; and one of X3, X4 and X5 represents CR11 and the others independently represents N or CR10; R10 is hydrogen, amino, halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, nitro or trifluoromethyl; R11 represents a group â€”L1â€”Ar1â€”L2â€”Y; L1 represents a â€”R2â€”R3â€” linkage; R2 is a straight or branched C1-6alkylene chain, a straight or branched C2-6alkenylene chain or a straight or branched C2-6alkynylene chain; R3 is a direct bond, cycloalkylene, heterocycloalkylene, arylene, heteroaryldiyl, â€”C(&boxH;Z)â€”NR4â€”, â€”NR4â€”C(&boxH;Z)â€”, â€”Z1â€”, â€”C(&boxH;O)â€”, â€”C(&boxH;NOR4)â€”, â€”NR4â€”C(&boxH;Z)â€”NR4â€”, â€”SO2â€”NR4â€”, â€”NR4â€”SO2â€”, â€”Oâ€”C(&boxH;O)â€”, â€”C(&boxH;O)â€”Oâ€”, â€”NR4â€”C(&boxH;O)â€”Oâ€” or â€”Oâ€”C(&boxH;O)â€”NR4â€”; R4 is a hydrogen atom or a lower alkyl group; Z is O or S; Z1 is O, S(O)n or NR4; n is zero or an integer 1 or 2; provided that an oxygen, nitrogen or sulphur atom in R3 is not attached directly to a carbon carbon multiple bond in R2; Ar1 is arylene or heteroaryldiyl; L2 represents: (i) a direct bond; (ii) an alkylene, alkenylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene linkage each optionally substituted by (a) carboxy, R5, â€”ZH, â€”ZR5, â€”C(&boxH;O)â€”R5, â€”N(R12)â€”C(&boxH;O)â€”R13, â€”N(R12)â€”C(&boxH;O)â€”OR13, â€”N(R12)â€”SO2â€”R13, â€”NY1Y2, or â€”[C(&boxH;O)â€”N(R6)â€”C(R4)(R7)]pâ€”C(&boxH;O)â€”NY1Y2, or by (b) alkyl substituted by carboxy, imidazolyl, â€”ZH, â€”ZR5, â€”C(&boxH;O)â€”NY1Y2 or â€”NY1Y2; (iii) a â€”[C(&boxH;O)â€”N(R6)â€”C(R4)(R7)]pâ€” linkage; (iv) a â€”Z2â€”R9â€” linkage; (v) a â€”C(&boxH;O)â€”CH2â€”C(&boxH;O)â€” linkage; (vi) a â€”R9â€”Z2â€”R9â€” linkage; or (vii) a â€”C(R4)(R8)â€”[C(&boxH;O)â€”N(R6)â€”C(R4)(R7)]pâ€” linkage; R5 is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl, or heterocycloalkylalkyl; R6 is hydrogen, R5 or alkyl substituted with alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or â€”NY1Y2; R7 and R8 are each independently selected from hydrogen or a group consisting amino acid side chains and corresponding protected derivatives, carboxy, R5, â€”ZH, â€”ZR5, â€”C(&boxH;O)â€”R5, or â€”C(&boxH;O)â€”NY1Y2, or alkyl substituted by carboxy, â€”ZH, â€”ZR5, â€”NY1Y2, â€”NHâ€”C(&boxH;O)â€”R5, â€”C(&boxH;O)â€”R2â€”NH2, â€”C(&boxH;O)â€”Ar1â€”NH2, â€”C(&boxH;O)â€”R2â€”CO2H, or â€”C(&boxH;O)â€”NY1Y2; or R6 and R7 or R6 and R8 together with the atoms to which they attached form a 3- to 6-membered heterocycloalkyl ring; R9 is C1-6alkylene, optionally substituted by R5; R12 is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R13 is alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, or alkyl substituted by aryl, carboxy, cycloalkyl, heteroaryl, heterocycloalkyl, â€”ZH, â€”ZR5, â€”C(&boxH;O)â€”NY1Y2 or â€”NY1Y2; Y1 and Y2 are independently hydrogen, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkyl substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, â€”NY1Y2, or one or more â€”CO2R12 or â€”C(&boxH;O)â€”NY1Y2 groups; or the group â€”NY1Y2 may form a 5- to 7-membered cyclic amine which (i) may be optionally substituted with one or more substituents selected from alkoxy, carboxamido, carboxy, hydroxy, oxo (or a 5-, 6- or 7-membered cyclic acetal derivative thereof), R13; (ii) may also contain a further heteroatom selected from O, S, SO2, or NY3; and (iii) may also be fused to additional aryl, heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system; Y3 is hydrogen, alkyl, aryl, arylalkyl, â€”C(&boxH;O)â€”R14, â€”C(&boxH;O)â€”OR14 or â€”SO2R14 (in which R14 is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; Z2 is O, S(O)n, NR4, SONR4, C(&boxH;O)NR4 or C(&boxH;O); and p is zero or an integer 1 to 4; and Y is carboxy, an acid bioisostere, or â€”C(&boxH;O)â€”NY1Y2; and the corresponding N-oxides, and their ester prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and ester prodrugs; but excluding the compounds (2-{2-[4-(3-(2-methylphenyl)ureido)-phenyl]-acetylamino}-thiazol-4-yl)-acetic acid, 2-phenylacetylamino-3-{4-[4-(3-(2-methylphenyl)ureido)-benzyloxy]-phenyl}-propionic acid, 2-phenylacetylamino-3-(4{2-[4-(3-(2-methylphenyl)ureido)-phenyl]-ethoxy}-phenyl)-propionic acid, 2-benzylsulphonylamino-3-{4-[4-(3-(2-methylphenyl)ureido)-benzyloxy]-phenyl}-propionic acid, (butane-1-sulphonylamino)-{2-[4-(3-(2-methylphenyl)-ureido)-benzyl]-benzofuran-6-yl}-acetic acid, 3-(benzylaminocarbonyl)-(4{2-[4-(3-(2-methylphenyl)ureido)-phenyl]-ethoxy}-benzyl)-propionic acid and 2-benzyloxycarbonylamino-3-(5-{3-[4-(3-(2-methylphenyl)ureido)-phenyl]-propyl}-thiophene-2-yl)-propionic acid; and with the proviso that L1 cannot represent C1-6alkylene-C(&boxH;O)â€”NHâ€” or C1-6alkylene when Ar1 represents optionally substituted phenylene, Y represents â€”CO2H, â€”SO3H, â€”PO4H2 or tetrazole, and L2 represents (i) a direct bond, (ii) an alkylene or alkenylene linkage each optionally substituted by (a) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl, or by (b) alkyl substituted by alkoxy, hydroxy, arylalkyoxy, heteroarylalkyloxy, alkylthio, carboxy, alkoxycarbonyl, or â€”C(&boxH;O)â€”NH2, (iii) a â€”[C(&boxH;O)â€”N(R6)â€”C(R4)(R7)]pâ€” linkage in which R4 is hydrogen or lower alkyl, R6 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl or alkyl substituted by alkoxy, hydroxy or alkylthio, R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl or alkyl substituted by alkenyl, alkynyl, alkoxy, hydroxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, carboxy, alkoxycarbonyl or carboxamide, and p is one, (iv) a â€”Z2â€”R9â€” linkage in which Z2 is O, S, NR4, SO2NR4 or C(&boxH;O)NR4 and R9 is C1-4alkylene, optionally substituted by alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl, or (v) a â€”CH2â€”Z2â€”R9â€” linkage in which Z2 is O, NR4 or C(&boxH;O)NR4 and R9 is C1-4alkylene, optionally substituted by alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;wherein said acid bioisostere is selected from the group consisting of â€”C(&boxH;O)â€”NHOH, â€”C(&boxH;O)â€”CH2OH, â€”C(&boxH;O)â€”CH2SH, â€”C(&boxH;O)â€”NHâ€”CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, heteroarylsulphonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl and heterocyclic phenols.