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Claims for Patent: 5,968,914

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Claims for Patent: 5,968,914

Title: Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides
Abstract:The subject invention discloses compounds, compositions and methods for treatment and prevention of toxicity due to chemotherapeutic agents and antiviral agents. Disclosed are acylated derivatives of non-methylated pyrimidine nucleosides. These compounds are capable of attenuating damage to the hematopoietic system in animals receiving antiviral or antineoplastic chemotherapy.
Inventor(s): von Borstel; Reid (Potomac, MD), Bamat; Michael K. (Potomac, MD)
Assignee: Pro-Neuron, Inc. (Rockville, MD)
Application Number:08/472,210
Patent Claims: 1. A method for treating cancer comprising:

(a) administering a pyrimidine nucleoside analog in a dose at least 1.5 fold greater than the normal maximum tolerated does, and

(b) administering a pharmaceutically effective amount of an acyl derivative of a non-methylated pyrimidine nucleoside selected from the group consisting of an acyl derivative of uridine, cytidine, 2'-deoxycytidine and 2'-deoxyuridine.

2. A method as in claim 1, wherein said pyrimidine nucleoside analog is selected from the group consisting of the 5-fluorouracil (5-FU), 5-FU prodrugs including Tegafur and 5'-deoxy-5-fluorouridine, 5-fluorouridine, 2'-deoxy-5-fluorouridine, prodrug derivatives of 5-fluorouridine or 2'-deoxy-5-fluorouridine, fluorocytosine, trifluoromethyl-2'-deoxyuridine, arabinosyl cytosine, prodrugs of arabinosyl cytosine, cyclocytidine, 5-aza-2'-deoxycytidine, arabinosyl 5-azacytosine, 6-azacytidine, N-phosphonoacetyl-L-aspartic acid (PALA), pyrazofurin, 6-azauridine, azaribine, thymidine, and 3-deazauridine.

3. A method as in claim 1 wherein said pyrimidine nucleoside analog is a 5-fluoropyrimidine or 5-fluoropyrimidine nucleoside analog and said acyl derivative of a non-methylated pyrimidine nucleoside is an acyl derivative of uridine, cytidine, or deoxyuridine.

4. A method as in claim 3, wherein said 5-fluorouridine or 5-fluoropyrimidine nucleoside analog is selected from the group consisting of 5-fluorouracil, 5-fluorouracil prodrugs including Tegafur and 5'-deoxy-5-fluorouridine, 5-fluorouridine, 2'-deoxy 5-fluorouridine, prodrug derivatives of 5-fluorouridine, prodrug derivatives of 2'-deoxy-5-fluorouridine, 5-fluorocytosine, 5-fluorocytidine, or prodrug derivatives of 5-fluorocytidine.

5. A method as in claim 3 wherein said 5-fluoropyrimidine or 5-fluoropyrimidine nucleoside analog is 5-fluorouracil.

6. A method as in claim 5 wherein said administering step (a) comprises administering a bolus of 900 to 2400 mg/m.sup.2 of 5-fluorouracil, and said administering step (b) comprises administering 2 to 24 hours after step (a) 1 to 10 grams of an acyl derivative of a nonmethylated pyrimidine nucleoside, wherein steps (a) and (b) are repeated 3-6 times.

7. A method as in claim 6 wherein the time interval between each repetition of step (a) is 4 to 14 days.

8. A method as in claim 5 wherein said administering step (a) comprises administering a bolus of 600 to 1000 mg/m.sup.2 of 5-fluorouracil daily for 4 to 5 consecutive days, and said administering step (b) comprises administering 2 to 12 hours after each step (a) 1 to 10 grams of an acyl derivative of a nonmethylated pyrimidine nucleoside.

9. A method as in claim 1 wherein said pyrimidine nucleoside analog is N-phosphonoacetyl-L-aspartic acid (PALA), pyrazofurin, 6-azauridine, azaribine, trifluoro-methyl-2'-deoxyuridine, or 3-deazauridine and said acyl derivative of a non-methylated pyrimidine nucleoside is an acyl derivative of uridine or cytidine.

10. A method as in claim 1 wherein said acyl derivative of a non-methylated pyrimidine nucleoside is triacetyluridine.

11. A method as in claim 1 wherein said acyl derivative of a non-methylated pyrimidine nucleoside is ethoxycarbonyluridine.

12. A method as in claim 1 wherein said acyl derivative of a non-methylated pyrimidine nucleoside is triacetylcytidine.

13. A method as in claim 1 wherein said acyl derivative of a non-methylated pyrimidine nucleoside is diacetyldeoxycytidine.

14. A method as in claim 1 wherein said pyrimidine nucleoside analog is an antineoplastic analog of cytidine and said acyl derivative of a non-methylated pyrimidine nucleoside is an acyl derivative of deoxycytidine.

15. A method as in claim 14 wherein said antineoplastic analog of cytidine is arabinosyl cytosine or prodrugs thereof, cyclocytidine, 5-aza-2'-deoxycytidine, arabinosyl 5-azacytosine, or 6-azacytidine.

16. A method as in claim 1 wherein said pyrimidine nucleoside analog is an analog of uridine, said acylated derivative of a non-methylated pyrimidine nucleoside is an acylated derivative of uridine, deoxyuridine, or cytidine, and said administering step (b) also includes administering an inhibitor of uridine phosphorylase.

17. A method as in claim 16 wherein said inhibitor of uridine phosphorylase is selected from the group consisting of benzylacyclouridine, benzyloxybenzylacyclouridine, aminomethyl-benzylacyclouridine, aminomethyl-benzyloxybenzylacyclouridine, hydroxymethyl-benzylacyclouridine, hydroxymethyl-benzyloxybenzylacyclouridine, 2,2'-anhydro-5-ethyluridine, 5-benzyl barbiturate, 5-benzyloxybenzyl barbiturate, 5-benzyloxybenzyl-1 -[(1-hydroxy-2-ethoxy)methyl] barbiturate, 5-benzyloxybenzylacetyl-1-[(1-hydroxy-2-ethoxy)methyl] barbiturate, and 5-methoxybenzylacetylacyclobarbiturate.

18. A method as in claim 1 wherein said acylated derivative of a non-methylated pyrimidine nucleoside is an acylated derivative of cytidine or deoxycytidine, and said administering step (b) also includes administering an inhibitor of cytidine deaminase.

19. A method as in claim 18 wherein said inhibitor of cytidine deaminase is selected from the group consisting of tetrahydrouridine or tetrahydro-2'-deoxyuridine.

20. A method as in claim 1 wherein said acylated derivative of a non-methylated pyrimidine nucleoside is an acylated derivative of uridine, cytidine or deoxycytidine, and said administering step (b) also includes administering an inhibitor of nucleoside transport.

21. A method as in claim 20 wherein said inhibitor of nucleoside transport is selected from the group consisting of dilazep, dipyridamole, probenicid, lidoflazine or nitrobenzylthioinosine.

22. A method as in claim 1 wherein said administering step (b) also includes administering an agent which enhances hematopoiesis.

23. A method as in claim 1 wherein said administering step (b) also includes administering a compound capable of enhancing the uptake and phosphorylation of nucleosides into cells.

24. A method as in claim 1 wherein said administering step (a) also includes administering AZT.

25. A method as in claim 1 wherein said fluorinated pyrimidine is administered in conjunction with a biochemical modulator of 5-fluorouracil efficacy.

26. A method as in claim 25 wherein said modulator is an inhibitor of purine biosynthesis, an antifolate, an inhibitor of pyrimidine biosynthesis, or an inhibitor of 5-fluorouracil degradation.

27. A method as in claim 26 wherein said inhibitor of purine biosynthesis is methylmercaptopurine riboside.

28. A method as in claim 26 wherein said antifolate is methotrexate or trimetrexate.

29. A method as in claim 26 wherein said inhibitor of pyrimidine biosynthesis is PALA, brequinar, acivicin, or 6-azauridine.

30. A method as in claim 26 wherein said inhibitor of 5-fluorouracil degradation is an inhibitor of the enzyme dihydropyrimidine dehydrogenase.

31. A method as in claim 30 wherein said inhibitor of dihydropyrimidine dehydrogenase is 5-ethynyluracil, bromovinyluracil, CDHP, uracil, thymine, thymidine or benzyloxybenzyluracil.

32. A method for treating cancer comprising:

(a) administering an inhibitor of the enzyme dihydropyrimidine dehydrogenase;

(b) administering a 5-fluoropyrimidine or 5-fluoropyrimidine nucleoside analog in a dose at least 1.5 fold greater than the normal maximum tolerated dose;

(c) administering a pharmaceutically effective amount of an acyl derivative of a non-methylated pyrimidine nucleoside selected from the group consisting of an acyl derivative of uridine, cytidine, 2'-deoxycytidine, and 2'-deoxyuridine.

33. A method as in claim 32, wherein said 5-fluoropyrirnidine or 5-fluoropyrimidine nucleoside analog is selected from the group consisting of 5-fluorouracil, 5-fluorouracil prodrugs including Tegafur and 5'-deoxy-5-fluorouridine, 5-fluorouridine, 2'-deoxy-5-fluorouridine, prodrug derivatives of 5-fluorouridine , prodrug derivatives of 2'-deoxy-5-fluorouridine, 5-fluorocytosine, 5-fluorocytidine, or prodrug derivatives of 5-fluorocytidine.

34. A method as in claim 32 wherein said inhibitor of dihydropyrimidine dehydrogenase is 5-ethynyluracil, bromovinyluracil, cyanodidhydropyridine, uracil, thymine, thymidine or benzyloxybenzyluracil.

35. A method as in claim 32 wherein said administering step (a) takes place before or at the same time as said administering step (b).
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