Inhibitors of nucleoside metabolism

• US 6,803,455 B2
• Filed: 10/10/2002
• Issued: 10/12/2004
• Est. Priority Date: 10/14/1997
• Status: Expired due to Term

• Current Assignee: Albert Einstein College of Medicine (Yeshiva University)
• Original Assignee: Albert Einstein College of Medicine of Yeshiva University, Industrial Research Limited
• Inventors: Schramm, Vern L., Tyler, Peter Charles, Furneaux, Richard Hubert
• Primary Examiner(s): Riley, Jezia
• Application Number:
  US10/268,652
• Publication Number:
  US 20030096830A1
• Time in Patent Office: 733 Days
• Field of Search: 536/4.1, 536/23.1, 514/1, 514/44
• US Class Current: 536/4.1
• 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. A compound 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 where Q is an optionally substituted alkyl, aralkyl or aryl group;

or a tautomer thereof;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein one of B and/or D is NHR, and R is C₁-C₄ alkyl.

3. The compound of claim 1, wherein either D is H, or B is OH, or both.

4. The compound of claim 1, wherein B is OH, D is H, OH or NH₂, X is OH or H, Y is H.

5. The compound of claim 1, wherein Z is OH, H or methylthio.

6. The compound of claim 5, wherein Z is OH.

7. A pharmaceutical composition for the suppression of T-cell function comprising an amount of a compound of claim 1 effective for inhibiting purine nucleoside phosphorylase, and a pharmaceutically acceptable carrier or diluent.

8. A pharmaceutical composition for treatment and/or prophylaxis of a protozoan infection comprising an amount of a compound 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.

9. A method for decreasing T-cell function in a mammal comprising administering to the mammal a compound of claim 1, whereby said compound inhibits purine nucleoside phosphoiylase.

10. A method for treatment and/or prophylaxis of an infection caused by protozoan parasite comprising administering to a subject an amount of a compound of claim 1 effective to inhibit at least purine nucleoside hydrolase, purine nucleoside phosphorylase, and/or purine phosphoribosyl transferase.

11. A method for killing parasites comprising administering to the parasite an amount of a compound of claim 1 effective for inhibiting at least one purine nucleoside hydrolase, purine nucleoside phosphorylase, and/or purine phosphoribosyl transferase.