Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-09-20
1995-08-22
Tsang, Cecilia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514260, 544285, 544287, A61K 31505, C07D23972
Patent
active
054440610
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB92/00476 filed Mar. 18, 1992.
This invention relates to novel anti-cancer agents: and more particularly it relates to quinazoline 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 Specification 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. 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 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.
We have now found that certain quinazoline derivatives not only show a good level of activity, in particular in respect of their ability to inhibit thymidylate synthase, but also have a different mode of action from CB3717 and other related quinazoline derivatives which have been described. Thus it is believed that CB3717 and more particularly its 2-methyl analogue, which is described and claimed in UK Patent No. 2 188 319, owe anti-tumour activity to an intracellular polyglutamate form but that the compounds of the present invention act directly without being gamma-glutamylated. This alternative mode of action of the compounds of the present invention provides the potential for more precise control in the administration of the compounds to cancer patients, deriving especially from a shorter period of intracellular retention following the completion of administration and a lack of dependence on polyglutamylation which may vary in degree from one patient to another. Moreover, the replacement of the L-glutamic acid residue of CB3717 by an alternative group in the compounds of the present invention will confer different physical properties thereby influencing the overall characteristics of the compounds.
Accordingly the present invention comprises a quinazoline of formula (I): ##STR2## wherein R.sup.1 is hydrogen or amino; or R.sup.1 is alkyl, alkoxy or alkylthio each of up to 6 carbon atoms; substituents selected from halogeno, hydroxy and alkanoylamino each of up to 6 carbon atoms; substituents selected from hydroxy and alkoxy of up to 6 carbon atoms; alkoxyalkyl, mercaptoalkyl, alkylthioalkyl, halogenoalkyl, cyanoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkanol, alkanoylalkyl, carboxyalkyl, carbamoylalkyl or alkanoyl each of up to 6 carbon atoms; bears one or more substituents selected from halogeno, cyano, nitro, hydroxy, amino and carbamoyl and alkyl, alkoxy, halogenoalkyl, alkanoylamino and alkoxycarbonyl each of up to 6 carbon atoms; N-terminal amino acid residue thereof attached to the carbonyl group of COR.sup.3 is an L- or D-amino acid residue --NHCH(CO.sub.2 H)--A--CO-- in which A is an alkylene group of up to 6 carbon atoms and the second amino acid residue is of an .alpha.-amino acid which has the D-configuration at its asymmetric .alpha.-carbon atom; each of up
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Bisset Graham M. F.
Jackman Ann L.
Jodrell Duncan I.
British Technology Group Limited
Tsang Cecilia
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