Inhibitors of nucleoside metabolism
View Patent ↗The present invention provides compounds having the formula: wherein A is CH or N; B is chosen from OH, NH 2 , NHR, H or halogen; D is chosen from OH, NH 2 , NHR, H, halogen or SCH 3 ; R is an optionally substituted alkyl, aralkyl or aryl group; and X and Y are independently selected from H, OH or halogen except that when one of X and Y is hydroxy or halogen, the other is hydrogen; and Z is OH or, when X is hydroxy, Z is selected from hydrogen, halogen, hydroxy, SQ or OQ, Q is an optionally substituted alkyl, aralkyl or aryl group; or a tautomer thereof; or a pharmaceutically acceptable salt thereof; or an ester thereof; or a prodrug thereof; and compounds having the formula: wherein A, X, Y, Z and R are defined for compounds of formula (I) where first shown above; E is chosen from CO 2 H or a corresponding salt form, CO 2 R, CN, CONH 2 , CONHR or CONR 2 ; and G is chosen from NH 2 , NHCOR, NHCONHR or NHCSNHR; or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof, or a prodrug thereof. The present invention also provides the use of the above compounds as pharmaceuticals, pharmaceutical compositions containing the compounds and processes for preparing the compounds.
1. A pharmaceutically acceptable salt of a compound having the formula:
wherein A is CH or N; B is chosen from OH, NH 2 , NHR, H or halogen; D is chosen from OH, NH 2 , NHR, H, halogen or SCH 3 ; R is an alkyl, aralkyl or aryl group; and X and Y are independently selected from H, OH or halogen except that when one of X and Y is hydroxy or halogen, the other is hydrogen; and Z is OH or, when X is hydroxy, Z is selected from hydrogen, halogen, hydroxy, SQ or OQ where Q is an alkyl, aralkyl or aryl group; or a tautomer thereof; and
wherein the salt is derived from an acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, fumaric acid, succinic acid, tartaric acid, gluconic acid, citric acid, methanesulphonic acid and p-toluenesulphonic acid.
2. The pharmaceutically acceptable salt of claim 1 , wherein the salt is a hydrochloride salt.
3. The pharmaceutically acceptable salt of claim 1 , wherein one of B and/or D is NHR, and R is C 1 -C 4 alkyl.
4. The pharmaceutically acceptable salt of claim 1 , wherein either D is H, or B is OH, or both.
5. The pharmaceutically acceptable salt of claim 1 , wherein B is OH; D is H, OH or NH 2 ; X is OH or H; and Y is H.
6. The pharmaceutically acceptable salt of claim 1 , wherein Z is OH, H or methylthio.
7. The pharmaceutically acceptable salt of claim 1 , wherein Z is OH.
8. The pharmaceutically acceptable salt of claim 1 , wherein the compound has the structure:
9. The pharmaceutically acceptable salt of claim 8 , wherein the salt is a hydrochloride salt.
10. The pharmaceutically acceptable salt of claim 1 , wherein the compound has the structure:
11. The pharmaceutically acceptable salt of claim 10 , wherein the salt is a hydrochloride salt.
12. The pharmaceutically acceptable salt of claim 1 , wherein the compound has the structure:
13. The pharmaceutically acceptable salt of claim 12 , wherein the salt is a hydrochloride salt.
14. The pharmaceutically acceptable salt of claim 1 , wherein the compound has the structure:
15. The pharmaceutically acceptable salt of claim 14 , wherein the salt is a hydrochloride salt.
16. A pharmaceutical composition comprising the pharmaceutically acceptable salt of claim 1 and a pharmaceutically acceptable carrier or diluent.
17. A pharmaceutical composition for suppression of T-cell function comprising an amount of the pharmaceutically acceptable salt of claim 1 effective for inhibiting purine nucleoside phosphorylase, and a pharmaceutically acceptable carrier or diluent.
18. A pharmaceutical composition for treatment of a protozoan infection comprising an amount of the pharmaceutically acceptable salt of claim 1 effective for inhibiting at least one parasite purine nucleoside hydrolase, purine nucleoside phosphorylase and/or purine phosphoribosyl transferase, and a pharmaceutically acceptable carrier or diluent.
19. A pharmaceutical composition for prophylaxis of a protozoan infection comprising an amount of the pharmaceutically acceptable salt of claim 1 effective for inhibiting at least one parasite purine nucleoside hydrolase, purine nucleoside phosphorylase and/or purine phosphoribosyl transferase, and a pharmaceutically acceptable carrier or diluent.
20. A method for decreasing T-cell function in a mammal comprising administering to the mammal an amount of the pharmaceutically acceptable salt of claim 1 effective to decrease T-cell function in the mammal.
21. The method of claim 20 , wherein the compound inhibits purine nucleoside phosphorylase.
22. The method of claim 20 , wherein the mammal has a lymphoma.
23. The method of claim 20 , wherein the mammal has a T-cell malignancy.
24. The method of claim 20 , wherein the mammal has an autoimmune disease.
25. The method of claim 24 , wherein the autoimmune disease is arthritis.
26. The method of claim 24 , wherein the autoimmune disease is lupus.
27. The method of claim 20 , wherein the method induces immunosuppression.
28. The method of claim 27 , wherein immunosuppression is induced in the mammal for organ transplantation.
29. The method of claim 27 , wherein the mammal has an inflammatory disorder.
30. The method of claim 20 , wherein the mammal is a human.
31. A method for treatment of an infection caused by a protozoan parasite in a subject comprising administering to the subject an amount of the pharmaceutically acceptable salt of claim 1 effective for treatment of the protozoan parasite infection in the subject.
32. A method for prophylaxis of an infection caused by a protozoan parasite in a subject comprising administering to the subject an amount of the pharmaceutically acceptable salt of claim 1 effective for prophylaxis of the protozoan parasite infection in the subject.
33. A method for killing a parasite comprising administering to the parasite an amount of the pharmaceutically acceptable salt of claim 1 effective to kill the parasite.
34. The method of claim 31 , wherein the compound inhibits purine nucleoside hydrolase, purine nucleoside phosphorylase, and/or purine phosphoribosyl transferase.
35. The method of claim 32 , wherein the compound inhibits purine nucleoside hydrolase, purine nucleoside phosphorylase, and/or purine phosphoribosyl transferase.
36. The method of claim 33 , wherein the compound inhibits purine nucleoside hydrolase, purine nucleoside phosphorylase, and/or purine phosphoribosyl transferase.
37. The method of claim 31 , wherein the parasite belongs to the genus Giardia, Trichomonas, Leishmania, Trypanosoma, Crithidia, Herpetomonas, Leptomonas, Histomonas, Eimeria, Isopora and/or Plasmodium.
38. The method of claim 32 , wherein the parasite belongs to the genus Giardia, Trichomonas, Leishmania, Trypanosoma, Crithidia, Herpetomonas, Leptomonas, Histomonas, Eimeria, Isopora and/or Plasmodium.
39. The method of claim 33 , wherein the parasite belongs to the genus Giardia, Trichomonas, Leishmania, Trypanosoma, Crithidia, Herpetomonas, Leptomonas, Histomonas, Eimeria, Isopora and/or Plasmodium.
40. The method of claim 31 , wherein the parasite causes malaria.
41. The method of claim 32 , wherein the parasite causes malaria.
42. The method of claim 33 , wherein the parasite causes malaria.
43. The method of claim 31 , wherein the subject is a human.
44. The method of claim 32 , wherein the subject is a human.