Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-10-29
1998-05-05
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544249, A61K 31505, C07D40304
Patent
active
057474990
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel anti-cancer agents and more particularly it relates to cyclopentaquinazoline derivatives which possess anti-cancer activity.
One group of anti-cancer agents comprises antimetabolites having anti-folate activity, such as aminopterin and methotrexate. A newer compound of this type which showed considerable promise in clinical trials is known as CB3717 and is described and claimed in United Kingdom Patent No. 2 065 653B. Despite its promising activity against human breast, ovarian and liver cancer, however, CB3717 shows symptoms of toxicity in humans, particularly in relation to the liver and kidneys (Cancer Treatment Reports, 1986, 70, 1335). Such adverse side effects are reduced in compounds in which the 2-amino substituent of CB3717 is either missing or is replaced by one of various alternative substituents as described and claimed respectively in United Kingdom Patents Nos. 2 175 903 and 2 188 319.
Compounds of this type are believed to act as anti-cancer agents by inhibiting the enzyme thymidylate synthase which catalyses the methylation of deoxyuridine monophosphate to produce thymidine monophosphate which is required for DNA synthesis. The anti-cancer activity of CB3717 and like compounds may be assessed in vitro by determining their inhibitory effect on that enzyme, and in cell cultures by their inhibitory effect on cancer cell lines such as the mouse leukaemia cell line L1210, the mouse lymphoma cell line L5178Y TK-/- and the human breast cancer cell line MCF-7.
Antimetabolites such as aminopterin and methotrexate which are inhibitors of enzymes which utilise folic acid derivatives have also shown promise in the treatment of various allergic diseases such as allergic rhinitis, atopic dermatitis and psoriasis.
Antimetabolites such as methotrexate have also shown promise in the treatment of various inflammatory diseases such as inflammation of the joints, especially rheumatoid arthritis, osteoarthritis and gout, and inflammation of the gastrointestinal tract, especially inflammatory bowel disease, ulcerative colitis and gastritis (New England J. Med., 1985, 312, 818).
We have now found that certain cyclopentaquinazoline derivatives show a good level of activity both as regards their ability to inhibit thymidylate synthase and also as regards their anti-cancer activity against various cell lines.
Accordingly the present invention comprises a cyclopentaquinazoline of formula (I): ##STR2## wherein R.sup.1 is hydrogen, amino, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 hydroxyalkyl or C.sub.1-4 fluoroalkyl; alkynyl, C.sub.2-4 hydroxyalkyl, C.sub.2-4 halogenoalkyl or C.sub.1-4 cyanoalkyl; pyrimidinediyl which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, C.sub.1-4 alkyl and C.sub.1-4 alkoxy; and --CONHCH(CO.sub.2 H)-- and Ar.sup.2 or is a C.sub.1-2 alkylene group; pyridinediyl or pyrimidinediyl which in the case of phenylene may optionally bear one or two substituents on the ring selected from halogeno, nitro, C.sub.1-4 alkyl and C.sub.1-4 alkoxy; N-(phenylsulphonyl)carbamoyl which may optionally bear one or two substituents on the phenyl ring selected from the group consisting of halogeno, nitro, C.sub.1-4 alkyl and C.sub.1-4 alkoxy, tetrazol-5-ylthio, tetrazol-5-ylsulphinyl or tetrazol-5-ylsulphonyl; or alkynyl; N-(phenylsulphonyl)carbamoyl which may optionally bear one or two substituents on the phenyl ring selected from the group consisting of halogeno, nitro, C.sub.1-4 alkyl and C.sub.1-4 alkoxy, tetrazol-5-ylthio, tetrazol-5-ylsulphinyl or tetrazol-5-ylsulphonyl; and CH(CO.sub.2 H)Y.sup.3 ; or N-(phenylsulphonyl)carbamoyl which may optionally bear one or two substituents on the phenyl ring selected from the group consisting of halogeno, nitro, C.sub.1-4 alkyl and C.sub.1-4 alkoxy, tetrazol-5-ylthio, tetrazol-5-ylsulphinyl or tetrazol-5-ylsulphonyl; and CH(CO.sub.2 H)Y.sup.5 provided that when R is hydrogen and Y.sup.4 is carboxy it is not the residue of glutamic acid; or --A.sup.5 --CON(R)CH(Y.sup.4)-
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Bavetsias Vassilios
Boyle Francis Thomas
Hennequin Laurent Francois Andre
Marriott Jonathan Hugh
British Technology Group Limited
Grumbling Matthew V.
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