Inhibitors of nucleoside metabolism

• US 20050026936A1
• Filed: 09/02/2004
• Published: 02/03/2005
• Est. Priority Date: 10/14/1997
• Status: Active Grant

• Current Assignee: Albert Einstein College of Medicine (Yeshiva University)
• Original Assignee: Peter Charles Tyler, Richard Bubert Furneaux, Vern L. Schramm
• Inventors: Furneaux, Richard Bubert, Schramm, Vern L., Tyler, Peter Charles
• Granted Patent: US 7,211,653 B2
• Time in Patent Office: Days
• US Class Current: 514/262.100
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom

Abstract

The present invention provides compounds having the formula:
wherein A is CH or N; B is chosen from OH, NH₂, NHR, H or halogen; D is chosen from OH, NH₂, NHR, H, halogen or SCH₃; 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 CO₂H or a corresponding salt form, CO₂R, CN, CONH₂, CONHR or CONR₂; and G is chosen from NH₂, 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.

Claims

1-39. -39. (cancelled)

40. A compound having the structure:

41. A pharmaceutical composition comprising the compound of claim 40 and a pharmaceutically acceptable carrier or diluent.

42. A pharmaceutical composition for suppression of T-cell function comprising an amount of the compound of claim 40 effective for inhibiting purine nucleoside phosphorylase, and a pharmaceutically acceptable carrier or diluent.

43. A pharmaceutical composition for treatment of a protozoan infection comprising an amount of the compound of claim 40 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.

44. A pharmaceutical composition for prophylaxis of a protozoan infection comprising an amount of the compound of claim 40 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.

45. A method for decreasing T-cell function in a mammal comprising administering to the mammal an amount of the compound of claim 40 effective to decrease T-cell function in the mammal.

46. The method of claim 45, wherein the compound inhibits purine nucleoside phosphorylase.

47. The method of claim 45, wherein the mammal has a lymphoma.

48. The method of claim 45, wherein the mammal has a T-cell malignancy.

49. The method of claim 45, wherein the mammal has an autoimmune disease.

50. The method of claim 49, wherein the autoimmune disease is arthritis.

51. The method of claim 49, wherein the autoimmune disease is lupus.

52. The method of claim 45, wherein the method induces immunosuppression.

53. The method of claim 52, wherein immunosuppression is induced in the mammal for organ transplantation.

54. The method of claim 52, wherein the mammal has an inflammatory disorder.

55. The method of claim 45, wherein the mammal is a human.

56. A method for treatment of an infection caused by a protozoan parasite in a subject comprising administering to the subject an amount of the compound of claim 40 effective for treatment of the protozoan parasite infection in the subject.

57. A method for prophylaxis of an infection caused by a protozoan parasite in a subject comprising administering to the subject an amount of the compound of claim 40 effective for prophylaxis of the protozoan parasite infection in the subject.

58. A method for killing a parasite comprising administering to the parasite an amount of the compound of claim 40 effective to kill the parasite.

59. The method of claim 56, wherein the compound inhibits purine nucleoside hydrolase, purine nucleoside phosphorylase, and/or purine phosphoribosyl transferase.

60. The method of claim 57, wherein the compound inhibits purine nucleoside hydrolase, purine nucleoside phosphorylase, and/or purine phosphoribosyl transferase.

61. The method of claim 58, wherein the compound inhibits purine nucleoside hydrolase, purine nucleoside phosphorylase, and/or purine phosphoribosyl transferase.

62. The method of claim 56, wherein the parasite belongs to the genus Giardia, Trichomonas, Leishmania, Trypanosoma, Crithidia, Herpetomonas, Leptomonas, Histomonas, Eimeria, Isopora and/or Plasmodium.

63. The method of claim 57, wherein the parasite belongs to the genus Giardia, Trichomonas, Leishmania, Trypanosoma, Crithidia, Herpetomonas, Leptomonas, Histomonas, Eimeria, Isopora and/or Plasmodium.

64. The method of claim 58, wherein the parasite belongs to the genus Giardia, Trichomonas, Leishmania, Trypanosoma, Crithidia, Herpetomonas, Leptomonas, Histomonas, Eimeria, Isopora and/or Plasmodium.

65. The method of claim 56, wherein the parasite causes malaria.

66. The method of claim 57, wherein the parasite causes malaria.

67. The method of claim 58, wherein the parasite causes malaria.

68. The method of claim 56, wherein the subject is a human.

69. The method of claim 57, wherein the subject is a human.