Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1993-07-23
2001-07-31
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S049000, C514S050000, C514S256000, C536S028200, C536S028540, C544S309000, C544S313000
Reexamination Certificate
active
06268374
ABSTRACT:
The present invention relates to certain enzyme inactivators which are useful in medicine, particularly cancer chemotherapy, especially in combination with antimetabolite antineoplastic agents such as 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 about 8 and 20 minutes) by the enzyme dihydropyrimidine 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)).
Unfortunately BVU is toxic to humans.
It has now been discovered that a group of 5-substituted uracil derivatives are inactivators of uracil reductase; they increase the level and half life of 5-fluorouracil in plasma and enhance the activity of 5-fluorouracil. They also reduce the normally encountered variations of 5-fluorouracil plasma levels between subjects.
REFERENCES:
patent: 4124765 (1978-11-01), Kurono et al.
patent: 4381344 (1983-04-01), Rideout et al.
patent: 4719214 (1988-01-01), Shealy
patent: 4863927 (1989-09-01), Tolman et al.
patent: 5643913 (1997-07-01), Spector et al.
patent: 2522369C2 (1988-11-01), None
patent: 0 272 065A2 (1988-06-01), None
patent: 0 337 599A1 (1989-10-01), None
patent: 0 356 166 A2 (1990-02-01), None
patent: 0 371 139A1 (1990-06-01), None
patent: 0 409 575A1 (1991-01-01), None
patent: 92/01452 (1992-02-01), None
International Search Report and Annex thereto for International Application No. PCT/GB91/01650 mailed Jan. 8, 1992.
Parker, W. B. et al., “Metabolism and Mechanism of Action of 5-Fluorouracil”,Pharmacol. and Ther.,48, 381-395 (1990).
Fardos N.M. Naguib et al., “Structure-Activity Relationship of Ligands of Dihydrouracil Dehydrogenase from Mouse Liver”,Biochemical Pharmacology,38(9), 1471-1480 (1989).
Masaaki Iigo et al., “Enhancing Effect of Bromovinyldeoxyuridine on Antitumor Activity of 5′-Deoxy-5-Fluorouridine Against Adenocarcinoma 755 in Mice”,Biochemical Pharmacology,38(12), 1885-1889 (1989).
Thornburg, Lora D. et al., “Mechanism-Based Inhibition of Thymine Hydroxylase”,J. American Chemical Society,111, 7632-7633 (1989).
Kunihiko Tatsumi et al., “Inhibitory Effects of Pyrimidine, Barbituric Acid and Pyridine Derivatives on 5-Fluorouracil Degradation in Rat Liver Extracts”,Japan. J. Cancer Research(Gann), 78, 748-755 (1987) (cited in European Search Report).
Tuchman, M. et al.,Chemical Abstracts,104:14633m (1986) (cited in European Search Report).
Desgranges, C. et al., “Effect of (E)-5-(1-Bromovinyl)uracil on the Catabolism and Antitumor Activity of 5-Fluorouracil in Rats and Leukemic Mice”,Cancer Research,46, 1094-1101 (1986).
Ho, D. H. et al., “Distribution and Inhibition of Dihydrouracil Dehydrogenase Activities in Human Tissues Using 5-Fluorouracil as a Substrate”,Anticancer Research,6(4), 781-784 (1986).
Fujii, S. et al., “Cancer—chemotherapy with 5-fluorouracil and its derivatives”,Int. Congr. Ser.-Excerpta Med.,729 Cancer Chemotherapy: Challenges Future, 117-25 (1986).
Chu, M. Y. W. et al., “Potentiation of 5 Fluoro-2′-Deoxy Uridine Anti Neoplastic Activity by the Uridine Phosphorylase Benzyl Acyclo Uridine and Benzyloxybenzyl Acyclo Uridine”,Cancer Research,44(5), 1852-1856 (1984).
Farka{haeck over (s)}, Jirí, “Synthesis of 1,2,4-Triazine-3,5(2H,4H)-Diones Containing Electronegative Substituents in Position 6”,Collection Czechoslovak Chem. Commun.,48(9), 2676-2681 (1983).
Robins, Morris J. et al., “Nucleic Acid Related Compounds. 39. Efficient Conversion of 5-Iodo to 5-Alkynyl and Derived 5-Substituted Uracil Bases and Nucleosides”,J. Organic Chemistry,48(11), 1854-62(1983).
Kundu, Nitya G. et al., “Studies on Uracil Derivatives and Analogs. Syntheses of 5-(&bgr;-Trimethylsilyl)ethynyluracil and 5-Ethynyluracil”,J. Heterocyclic Chem.,19(3), 463-4(1982).
Robins, Morris J. et al., “Nucleic Acid Related Compounds. 38. Smooth and high-yield iodination and chlorination at C-5 of uracil bases and p-toluyl-protected nucleosides”,Canada J. Chemistry,60(5), 554-7(1982).
Barr, Philip J. et al., “Synthesis of Some 5-Halogenovinyl Derivatives of Uracil and their Conversion into 2′-Deoxyribonucleosides”,J. Chemical Society Perkin Trans.,1(16), 1665-70(1981).
Krenitsky, T.A. et al., “Purine Nucleoside Synthesis, an Efficient Method Employing Nucleoside Phosphorylases”,Biochemistry,20 3615-3621(1981).
Robins, Morris J. et al., “Nucleic Acid Related Compounds. 31. Smooth and Efficient Palladium-Copper Catalyzed Coupling of Terminal Alkynes with 5-Iodouracil Nucleosides”,Tetrahedron Let,22(5), 421-4(1981).
Bleackley, R.C. et al., “Replacement of the Iodine Atom of 5-Iodouracil by the 5-Cyano Group”,Nucleic Acid Chemistry,vol. 2,927-30(1978).
Hein, L. et al., Preparation of 5-Trifluoromethyluracil,Z. Chem.,17(11), 415-16 (1977) (Translation).
Barr, P.J. et al., “Incorporation of 5-substituted uracil derivatives into nucleic acids. Part IV. The synthesis of 5-ethynyluracil”,Nucleic Acids Research,3(10), 2845(1976) (cited in European Search Report).
Jones, A.S. et al., “A method for the rapid preparation of 5-vinyluracil in high yield”,Nucleic Acids Research,1(1), 105-7 (1974).
Jones et al. “Synthesis and Antiviral Properties of (2)-5-(2-Bromovinyl)-2′-deoxyuridime”,J Med Chem(1981) 24, pp. 759-760.
Porter David J. T.
Rahim Saad G.
Spector Thomas
Glaxo Wellcome Inc.
Lemanowicz John L.
O'Sullivan Peter
LandOfFree
Uracil reductase inactivators does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Uracil reductase inactivators, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Uracil reductase inactivators will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2440746