Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-06-28
1998-08-04
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544249, C07D23970, A61K 31495
Patent
active
057894175
DESCRIPTION:
BRIEF SUMMARY
This is a .sctn.371 National Phase Application of PCT/GB93/02281 filed Nov. 4, 1993.
This invention relates to tricyclic compounds, or pharmaceutically-acceptable salts or esters thereof, which possess anti-cancer activity. The invention includes tricyclic compounds, processes for their manufacture, pharmaceutical compositions containing them and their use in the manufacture of medicaments for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
One group of anti-tumour compounds comprises the antimetabolites, such as aminopterin and methotrexate, which are inhibitors of enzymes which utilise folic acid derivatives. 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 Specification No. 2065653B. 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 kidney (Cancer Treatment Reports, 1986, 70, 1335).
Compounds of the CB3717-type are believed to act as anti-tumour agents by inhibiting the enzyme thymidylate synthase, which enzyme catalyses the methylation of deoxyuridine monophosphate to produce thymidine monophosphate which is required for DNA synthesis. The anti-cancer activity of CB3717 may be assessed in vitro by determining its inhibitory effect on that enzyme, and in cell cultures by its 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.
Other compounds of the CB3717-type have been described and claimed in European Patent Application Nos. 0 239 362, 0 284 338, 0 339 976, 0 373 891, 0 459 730 and 0 509 643. These compounds and the new compounds of the present invention may have their anti-cancer activity assessed by their activity against, for example, thymidylate synthase and the L1210, L5178Y TK-/- and MCF-7 cell lines.
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. The tricyclic compounds of the present invention, being antimetabolites, are thus of value as therapeutic agents in the treatment of, for example, allergic conditions such as 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 312, 818!. The tricyclic compounds of the present invention are thus of value as therapeutic agents in the treatment of, for example, inflammatory disease such as rheumatoid arthritis.
We have now found that the tricyclic compounds of the present invention possess potent inhibitory activity against thymidylate synthase and also potent anti-cancer activity as demonstrated by inhibition of the growth of the L1210, L5178Y TK-/- and MCF-7 cell lines.
According to the invention there is provided a tricyclic compound of the formula I: ##STR2## wherein R.sup.1 is hydrogen, amino, (1-4C)alkyl, (1-4C)alkoxy, hydroxy-(1-4C)alkyl or fluoro-(1-4C)alkyl; hydroxy-(2-4C)alkyl, halogeno-(2-4C)alkyl or cyano-(1-4C)alkyl; pyrimidinediyl which may optionally bear one or two substituents selected from the group consisting of halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy; and tetrazol-5-ylthio, tetrazol-5-ylsulphinyl or tetrazol-5-ylsulphonyl, or Y.sup.1 is a group of the formula is (1-6C)alkylene and Y.sup.2 is carboxy or tetrazol-5-yl, and wherein said N-(phenylsulphonyl)carbamoyl group may optionally bear one or two substituents on the phenyl ring selected from the group consisting of halogeno, nitro, (1-4C)alkyl and (1-4C)alkoxy, group consisting of L-alanine, L-leucine, L-isoleucine, L
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Boyle Francis Thomas
Crook James William
Matusiak Zbigniew Stanley
British Technology Group Ltd.
Ford John M.
Zeneca Limited
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