Pyrimidine compounds and methods for making and using the same

• US 20030040524A1
• Filed: 06/27/2002
• Published: 02/27/2003
• Est. Priority Date: 02/01/2001
• Status: Abandoned Application

• Current Assignee: Aleem Gangjee
• Original Assignee: Aleem Gangjee
• Inventors: Gangjee, Aleem
• Application Number:
  US10/185,562
• Publication Number:
  US 20030040524A1
• Time in Patent Office: Days
• US Class Current: 514/269
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 33/08 for Pneumocystis carinii
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/56 One oxygen atom and one sulfur atom

Abstract

This invention discloses compounds, and pharmaceutically acceptable salts, solvates and prodrugs thereof, useful in therapeutically and/or prophylactically treating patients with an illness. Such illnesses include cancer, and secondary infections caused by Pneumocystis carinii, Toxoplasma gondii, Mycobacterium tuberculosis, and Mycobacterium avium. The compounds themselves, methods of making these compounds, and methods of using these compounds are all disclosed. The compounds include 5-thiapyrimidines.

Claims

1. A compound, and pharmaceutically acceptable salts thereof, having formula (1):

2. The compound of claim 1, wherein Z is S.

3. The compound of claim 2, wherein R is substituted or unsubstituted aryl.

4. The compound of claim 3, wherein R is naphthyl.

5. The compound of claim 3, wherein R is 2,5-dimethyoxyphenyl.

6. A method of treating a patient for an illness by inhibiting dihydrofolate reductase and/or thymidylate synthase comprising:

administering an effective amount of a compound having formula (1);

wherein R is an aryl ring or alkylaryl ring optionally substituted with one or more substituents independently selected from C_1-6 alkyl groups, C_2-6 alkenyl groups, C_2-6alkynyl groups, C_1-6 alkoxy groups, halogens, nitro groups, aryl groups, C_1-6 acyl groups, carboxylic acids, carboxylic esters, hydroxyl groups, mercapto groups, polycarbo groups, and p-aroyl-L-glutamate;

wherein Z is S, Se, O, NH, CH₂; and

wherein R₁ is H or a straight, branched or cyclic alkyl group having up to about six carbons optionally substituted with one or more halogen, hydroxyl or amine group to said patient.

7. The method of claim 6, wherein said compound is incorporated in a suitable pharmaceutical carrier.

8. The method of claim 6, wherein said illness is cancer.

9. The method of claim 6, wherein said illness is selected from the group consisting of infection caused by Pneumocystis carinii, Toxoplasma gondii, Mycobacterium tuberculosis and Mycobacterium avium.

10. The method of claim 7, wherein said carrier is selected from the group consisting of physiologic saline and 5% dextrose for injection.

11. The method of claim 7, including administering said compound by a method selected from the group consisting of parenteral administration, oral administration and topical administration.

12. The method of claim 6, wherein Z is S.

13. The method of claim 12, wherein R is substituted or unsubstituted aryl.

14. The method of claim 13, wherein R is naphthyl.

15. The method of claim 13, wherein R is 2,5-dimethyoxyphenyl.

16. A method for synthesizing a thiapyrimidine compound comprising:

a) mixing 2,4-diamino-6-oxopyrimidine with a sulfur containing substituent;

b) refluxing the mixture of step a);

c) adding iodine to the refluxed mixture of step b);

d) refluxing the mixture of step c);

e) cooling the mixture of step d); and

f) removing the precipitate that forms upon cooling;

wherein the molar ratio of 2,4-diamino-6-oxopyrimidine to sulfur containing substituent is between about 1;

1 and 1;

3 and the molar ratio of 2,4-diamino-6-oxopyrimidine to iodine is between about 1;

2 and 1;

4.

17. The method of claim 16, wherein said sulfur containing substituent is contained in a solvent.

18. The method of claim 16, wherein the precipitate recovered in step f) is further washed with ethyl acetate, ethanol and ethyl ether.

19. The method of claim 18, wherein said washed precipitate is further mixed with a solvent, refluxed for at least two minutes, cooled, and the precipitate that forms upon cooling is removed.

20. A method for synthesizing a compound of formula (1)