Anti-cancer cyclopenta[G]quinazoline compounds

A cyclopenta[g]quinazoline of the formula (I):

• wherein:
• A is a group OR0 or NR0R1 wherein R0 and R1 are each independently hydrogen C1-4 akyl, C3-4 alkenyl, C3-4 alkynyl, C2-4 hydroxyalkyl, C2-4 halogenoalkyl or C1-4 cyanoalkyl, or R0 and R1 together with the intermediate N form a five- or six-membered heterocyclic ring;
• p is an integer in the range 1 to 4;
• R2is hydrogen, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, C2-4 hydroxyalkyl, C2-4 halogenoalkyl or C1-4 cyanoalkyl;
• Ar1 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
• R3 is a group of the formula:
• -A1Ar2A2-Y1
• in which A1 is a bond between the α-carbon atom of the group —CO—NH—CH(CO2H)—and Ar2 or is a C1-2 alkylene group;
• Ar2 is phenylene, tetrazolediyl, thiophenediyl, thiazolediyl, pyridinediyl 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;
• A2 is a C1-3 alkylene or C2-3 alkenylene group;
• and
• Y1 is carboxyl, tetrazol-5-yl, N-(1-4 alkylsulfonyl)carbamoyl, N-(phenyl-sulfonyl)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-ylsulfinyl or tetrazol-5-ylsulfonyl;
• or
• Y1 is a group of the formula:
• —CON(R)CH(Y2)Y3
• in which R is hydrogen, C1-4 alkyl, C3-4 alkenyl or C3-4 alkynyl;
• Y2is carboxy, tetrazol-5-yl, N-(C1-4 alkylsulfonyl)carbamoyl, N-(phenyl-sulfonyl)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-ylsulfinyl or tetrazol-5-ylsulfonyl;
• and
• Y3 is the residue of a naturally occurring amino acid NH2CH(CO2H)Y3;
• or
• Y3 is a group of the formula:
• -A4-CO2H
• in which A4 is a C2-6 alkylene group;
• R3 is a group of the formula:
• -A5-CON(R)CH(Y4)Y5
• in which A5 is a C1-6 alkylene group and R is as defined above;
• Y4 is carboxy, tetrazol-5-yl, N-(C-4 alkylsulfonyl)carbamoyl, N-(phenyl-sulfonyl)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-ylsulfinyl or tetrazol-5-ylsulfonyl;
• and
• Y5 is the residue of a naturally occurring amino acid NH2CH(CO2H)Y5;
• or
• Y5 is a group of the formula:
• -A4-CO2H
• in which A4 is as defined above;
• or
• Y5 is a group of the formula:
• -A6-Ar3-A7-Y6
• in which A6 is a bond between the a-carbon atom of the group
• -A5-CON(R)CH(Y4)- and Ar3 or is a C1-2 alkylene group;
• Ar3 is phenylene, tetrazolediyl, thiophenediyl, thiazolediyl, pyridinediyl 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;
• A7 is a C1-3 alkylene or C2-3 alkenylene group;
• and
• Y6 is carboxy, tetrazol-5-yl, N-(C1-4 alkylsulfonyl)carbamoyl, N-(phenyl-sulfonyl)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-ylsulfinyl or tetrazol-5-ylsulfonyl;
• or
• R3 is a group of the formula:
• -A8-X-Ar4
• in which A8 is a C1-4 alkylene group;
• X is sulfinyl, sulfonyl or methylene;
• and
• Ar4 is 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl or, except when X is methylene, tetrazol-5-yl;
• the compound (I) optionally being in the form of a pharmaceutically acceptable salt or ester.