Cyclopentaquinazoline compounds

摘要

Cyclopentaquniazoline of the formula (I): wherein R<1> is hydrogen, amino C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl or C1-4 fluoroalkyl; wherein R<2> is hydrogen, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, C2-4 hydroxyalkyl, C2-4 halogenalkyl or C1-4 cyanoalkyl; Ar<1> is phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, C1-4 alkyl and C1-4 alkoxy; and wherein R<3> is a group of the formula: -A<1>-Ar<2>-A<2>-Y<1> in which A<1> is a bond between the alpha -carbon atom of the group -CONHCH(CO2H)- and A- or is a C1-2 alkylene group; Ar<2> is phenylene, tetrazoldiyl, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which in the case of phenylene may optionally bear one to two substituents on the ring selected from halogeno, nitro, C1-4 alkyl and C1-4 alkoxy; A<2> is a C1-3 alkylene or C2-3 alkylene group; and Y<1> is baroxy, tetrazol 5-yl, N-(C1-4 alkylsulphonyl)carbamoyl, N-(phenylsulphonyl)carbamoyl which may optionally bear one or two substituents on the phenyl ring selected from the group consisting of halogeno, nitro, C1-4 alkyl and C1-4 alkoxy, tetrazol-5-ylthio, tetrazol-5-ylsulphinyl or tetrazol-5-ylsulphonyl; or Y<1> is a group of the formula: -CON(R)CH(Y<2>)Y<3> in which R is hydrogen C1-4 alkyl, C3-4 alkenyl or C3-4 alkynyl; Y<2> is carboxy, tetrazol-5-yl, N-(C1-4 alkylsulphonyl)carbamoyl, N-(phenylsulphonyl)carbamoyl which may optionally bear one or two substituents on the phenyl ring selected from the group consisting of halogeno, nitro, C1-4 alkyl and C1-4 alkoxy, tetrazol-5-ylthio, tetrazol-5-ylsulphinyl or tetrazol-5-ylsulphonyl; and Y<3> is the residue of a naturally occurring amino acid NH2CH(CO2H)Y<3>; or Y<3> is a group of the formula:- -A<4>-CO2H in which A<4> is a C2-6 alkylene group other than ethylene; wherein R<3> is a group of the formula:- -A<5>-CON(R)CH(Y<4>)Y<5> in which A<5> is a C1-6 alkylene group and R is as defined above; Y<4> is carboxy, tetrazol-5-yl, N-(C1-4 alkylsulphonyl)carbamoyl, N-(phenylsulphonyl(carbamoyl which may optionally bear one or two substituents on the phenyl ring selected from the group consisting of halogeno, nitro, C1-4 alkyl and C1-4 alkoxy, tetrazol-5-ylthio, tetrazol-5-ylsulphinyl or tetrazol-5-ylsulphonyl; and Y<5> is the residue of a naturally occurring amino acid NH2CH(CO2H)Y<5> provided that when R is hydrogen and Y<4> is carboxy it is not the residue of glutamic acid; or Y<5> is a group of the formula:- -A<4>CO2H in which A<4> is as defined above; or Y<5> is a group of the formula:- -A<6>-Ar<3>-A<7>-Y<6> in which A<6> is a bond between the alpha -carbon atom of the group -A<5>-CON(R)CH(Y<4>)- and Ar<3> or is a C1-2 alkylene group; Ar<3> is phenylene, tetrazolidyl, thiophenediyl, thiazolediyl, pryidinediyl or pyrimidinediyl which in the case of phenylene may optionally bear one or two substituents on the ring selected from halogeno, nitro, C1-4 alkyl and C1-4 alkoxy; A<7> is a C1-3 alkylene or C2-3 alkenylene group; and Y<6> is carboxy, tetrazol-5-yl, N-(C1-4 alkylsulphonyl)carbamoyl, N-(phenylsulphonyl)carbamoyl which may optionally bear one or two substituents on the phenyl ring selected from the group consisting of halogeno, nitro, C1-4 alkyl and C1-4 alkoxy, tetrazol-5-ylthio, tetrazol-5-ylsulphinyl or tetrazol-5-ylsulphonyl; or wherein R<3> is a group of the formula:- -A<8>-X-Ar<4> in which A<8> is a C1-4 alkylene group; X is sulphinyl, sulphonyl or methylene; and Ar<4> is 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl or, except when X is methylene, tetrazol-5-yl; or a pharmaceutically acceptable salt or ester thereof are of therapeutic value particularly in the treatment of cancer. Precursors of the above formula (IIIA):- wherein R<4> is hydrogen or a protecting group.