Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-05-02
1998-12-01
Dees, Jose G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514256, 536 285, 536 2855, 536 2852, 536 2854, 544316, 544336, A61K 3170, C07H 1910, C07D23902
Patent
active
058439170
DESCRIPTION:
BRIEF SUMMARY
This application is filed pursuant to 35 U.S.C. .sctn. 371 as a United States National Phase Application of International Application No. PCT/GB94/02428 filed Nov. 4, 1994 which claims priority from GB9322795.7 filed Nov. 5, 1993.
The present invention relates to compounds which comprise certain enzyme inactivators which are useful in medicine, particularly cancer chemotherapy, covalently linked to antineoplastic agents, particulary 5-fluorouracil (5-FU).
5-Fluorouracil has been used in cancer chemotherapy since 1957. Sensitive tumours include breast cancer, gastrointestinal malignancies, and cancers of the head and neck; 5-fluorouracil is also used as a radiation sensitiser. 5-Fluorouracil is metabolised rapidly in the liver (half-life between 8 and 20 minutes) by the enzyme dihydrothymidine dehydrogenase (uracil reductase). It has been reported (Cancer Research 46, 1094, 1986) that 5-(2-bromovinyl)-uracil (BVU) is an inhibitor of dihydrothymidine dehydrogenase which both retards the metabolism of 5-fluorouracil and enhances its antitumour activity. It has been reported that 5-(2-bromovinyl)-2'-deoxyuridine (which is metabolised in vivo to BVU) enhances the antitumour activity of 5-fluorouracil and 5-deoxy-5-fluorouridine, a prodrug of 5-fluorouracil (Biochemical Pharmacology 38; 2885, 1989).
W092/04901 discloses 5-substituted uracil derivatives which are useful as inactivators of uracil reductase; they increase the level and half-life of 5-fluorouracil in plasma and enhance the activity of 5-fluorouracil. These derivatives also reduce the normally encountered variations of 5-fluorouracil plasma levels between subjects. 5-ethynyluracil is 100-fold more potent than BVU as an inactivator of uracil reductase.
It has now been found that useful compounds can be produced by covalently linking a uracil reductase inactivator moiety with a 5-fluorouracil moiety or a prodrug thereof.
Therefore a first aspect the present invention provides a compound of the formula: represents 5-fluorouracil or a prodrug thereof, and L is a linking group covalently linked to both X and Y. Preferably X is a 5-substituted or 5,6-dihydro-5-substituted uracil derivative, the 5-substituent being bromo, iodo, cyano, halo-substituted C.sub.1-4 alkyl, C.sub.2-6 alkenyl, halo substituted C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, halo substituted C.sub.2-6 alkynyl group.
These compounds when administered to a subject, for example a mammal such as a human, provide both a uracil reductase inactivator as well as the 5-fluorouracil antineoplastic agent itself. Thus, only a single active agent need be administered to a subject.
In addition, these compounds have the advantage that they can be administered orally. 5-Fluorouracil cannot normally be administered orally, as it is destroyed by uracil reductase in the gastrointestinal tract. A single agent, which provides 5-FU and which can be administered orally, is now provided.
By a C.sub.2-6 alkenyl or C.sub.2-6 alkynyl group is meant a straight or branched chain alkenyl or alkynyl group, the latter including an alkenyl or alkynyl group substituted by a C.sub.2-6 cycloalkyl group.
The halogen substituent on the alkenyl or alkynyl group is preferably bromo, chloro or iodo. Halo-substituted ethenyl and ethynyl groups are particularly preferred. Usually only one halo substituent will be present. Preferred halo-substituted alkenyl groups are substituted in the 1-position.
The uracil derivative moiety is preferably one wherein the 5-substituent is a C.sub.2-6 alkynyl group (optionally halo-substituted), conveniently a C.sub.2-4 alkynyl group and preferably an ethynyl or propynyl group. In preferred 1-halo-alkenyl and alkynyl derivatives the multiple bond is in the 1-position. Particularly preferred uracil derivatives which form part of the compounds as hereinbefore defined are 5-ethynyluracil and 5-propynyluracil. Other such inactivators include:
Prodrugs of 5-fluorouracil are compounds which are metabolised in vivo to 5-fluorouracil and include 5-fluorouridine, 5-fluoro-2-deoxyuridine, 5-fluoro
REFERENCES:
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Martinez et al., (J. Org. Chem. 31 (10), pp. 3263-3267, 1996).
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Boyd Frank Leslie
Krenitsky Thomas Anthony
Dees Jos,e G.
Glaxo Wellcome Inc.
Hrubiec Robert T.
Qazi Sabiha N.
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