Acyclic pyrrolo [2,3-d]pyrimidine analogs as antiviral agents

• US 4,968,686 A
• Filed: 06/21/1989
• Issued: 11/06/1990
• Est. Priority Date: 04/08/1988
• Status: Expired due to Term

• Current Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Townsend, Leroy B., Pudlo, Jeffrey S., Shipman, Charles Jr., Drach, John G.
• Primary Examiner(s): Shen, Cecilia
• Application Number:
  US07/369,262
• Time in Patent Office: 503 Days
• Field of Search: 544/232, 544/280, 514/258
• US Class Current: 514/265.1
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

This invention relates to the use of acyclic substituted pyrrolo[2,3-d]pyrimidine nucleoside analogs in the treatment of viral infections. Such substituted compounds retain antiviral properties present in their parent compounds, yet exhibit significantly decreased levels of cytotoxicity, thereby having therapeutic potential as antiviral agents.

Claims

1. A compound selected from the group consisting of compounds of the following formula and pharmaceutically acceptable salts thereof:

##STR6## where R₁ is NH₂, NHOH, OH or H;

R₂ is CSNH₂, Cl, Br, I, F, 2-buten-1-yl,

5-(1-hydroxyethyl or 5-(1-methoxyethyl);

R₃ is H, NH₂ or Br; and

R₄ is (1,3-dihydroxy-2-propoxy)methyl,

(2-hydroxyethoxy)methyl,

(2-acetoxyethoxy)methyl, 2-hydroxy-1-(1,3-dihydroxy-2-propoxy)ethyl,

(2-phosphonylmethoxy)ethyl or 3-hydroxy-2-phosphonylmethoxypropyl.

2. The compound of claim 1 wherein R₁ is NH₂, R₂ is Cl, R₃ is H and R₄ is (2-hydroxyethoxy)methyl.

3. The compound of claim 1 wherein R₁ is NH₂, R₂ is Br, R₃ is H and R₄ is (2-hydroxyethoxy)methyl.

4. The compound of claim 1 wherein R₁ is NH₂, R₂ is I, R₃ is H and R₄ is (2-hydroxyethoxy)methyl.

5. The compound of claim 1 wherein R₁ is NH₂, R₂ is thiocarboxamide, R₃ is H and R₄ is (2-hydroxyethoxy)methyl.

6. The compound of claim 1 wherein R₁ is NH₂, R₂ is Cl, R₃ is H and R₄ is (1,3-dihydroxy-2-propoxy)methyl.

7. The compound of claim 1 wherein R₁ is NH₂, R₂ is Br, R₃ is H and R₄ is (1,3-dihydroxy-2-propoxy)methyl.

8. The compound of claim 1 wherein R₁ is NH₂, R₂ is I, R₃ is H and R₄ is (1,3-dihydroxy-2-propoxy)methyl.

9. The compound of claim 1 wherein R₁ is NH₂, R₂ is thiocarboxamide, R₃ is H and R₄ is (1,3-dihydroxy-2-propoxy)methyl.

10. The compound of claim 1 wherein R₁ is NH₂, R₂ is thiocarboxamide, R₃ is H and R₄ is 2-hydroxy-1-(1,3-dihydroxy-2-propoxy)ethyl.

11. The compound of claim 1 wherein R₁ is OH, R₂ is Cl, R₃ is H and R₄ is (1,3-dihydroxy-2-propoxy)methyl.

12. The compound of claim 1 wherein R₁ is NHOH, R₂ is Cl, R₃ is H and R₄ is (1,3-dihydroxy-2-propoxy)methyl.

13. The compound of claim 1 wherein R₁ is OH, R₂ is Br, R₃ is H and R₄ is (1,3-dihydroxy-2-propoxy)methyl.

14. The compound of claim 1 wherein R₁ is NHOH, R₂ is Br, R₃ is H and R₄ is (1,3-dihydroxy-2-propoxy)methyl.

15. The compound of claim 1 wherein R₁ is NHOH, R₂ is I, R₃ is H and R₄ is (1,3-dihydroxy-2-propoxy)methyl.

16. The compound of claim 1 wherein R₁ is wherein R₁ is OH, R₂ is I, R₃ is H and R₄ is (1,3-dihydroxy-2-propoxy)methyl.

17. The compound of claim 1 wherein R₃ is NH₂.

18. The compound of claim 1 wherein R₃ is Br.

19. A method of treating mammalian cells infected with a mammalian infectious virus selected from the group consisting of human cytomegalovirus and herpes simplex virus, the method comprising the step of contacting said cells with a composition comprising a therapeutically effective amount of a compound selected from the group consisting of compounds of the following formula or a pharmaceutically acceptable salt thereof:

##STR7## where R₁ is NH₂, NHOH, OH or H;

R₂ is CSNH₂, Cl, Br, I, F, 2-buten-1-yl,

5-(1-hydroxyethyl) or 5-(1-methoxyethyl);

R₃ is H, NH₂ or Br; and

R₄ is (1,3-dihydroxy-2-propoxy)methyl,

(2-hydroxyethoxy)methyl,

(2-acetoxyethoxy)methyl, 2-hydroxy-1-(1,3-dihydroxy-2-propoxy)ethyl,

(2-phosphonylmethoxy)ethyl or 3-hydroxy-2-phosphonylmethoxypropyl,

wherein said contacting of said cells comprises in vivo administration of said composition to the infected mammal.

20. The method of claim 19 wherein said contacting of said cells comprises invivo administration of said composition to a mammal.

21. The method of claim 19 wherein said cells are human cells.

22. The method of claim 20 wherein said mammal is a human.

23. The method of claim 19 wherein the virus is human cytomegalovirus.

24. The method of claim 19 wherein the virus is herpes simplex virus type 1.

25. The method of claim 19 wherein R₁ is NH₂, R₂ is a halogen group, R₃ is H and R₄ is (1,3-dihydroxy-2-propoxy)methyl.

26. The method of claim 19 wherein R₁ is NHOH, R₂ is a halogen group, R₃ is H and R₄ is (1,3-dihydroxy-2-propoxy)methyl.

27. The method of claim 19 wherein R₁ is NH₂, R₂ is a halogen group, R₃ is H and R₄ is (2-hydroxyethoxy)methyl.

28. The method of claim 25 wherein R₂ is Cl.

29. The method of claim 25 wherein R₂ is Br.

30. The method of claim 25 wherein R₂ is I.

31. The method of claim 26 wherein R₂ is Cl.

32. The method of claim 26 wherein R₂ is Br.

33. The method of claim 26 wherein R₂ is I.

34. The method of claim 27 wherein R₂ is Cl.

35. The method of claim 27 wherein R₂ is Br.

36. The method of claim 27 wherein R₂ is I.

37. The method of claim 19 wherein R₁ is NH₂, R₂ is CSNH₂, R₃ is H and R₄ is (1,3-dihydroxy-2-propoxy)methyl.

38. The method of claim 19 wherein R₁ is NH₂, R₂ is CSNH₂, R₃ is H and R₄ is (2-hydroxyethoxy)methyl.

39. The method of claim 19 wherein R₃ is NH₂.

40. The method of claim 19 wherein R₃ is Br.

41. A composition comprising a compound selected from the group consisting of compounds of the following formula and pharmaceutically acceptable salts thereof:

##STR8## where R₁ is NH₂, NHOH, OH or H;

R₂ CSNH₂, Cl, Br, I, F, 2-buten-1-yl,

5-(1-hydroxyethyl) or 5-(1-methoxyethoxy);

R₃ is H, NH₂ or Br; and

R₄ is (1,3-dihydroxy-2-propoxy)methyl,

(2-hydroxyethoxy)methyl,

(2-acetoxyethoxy)methyl, 2-hydroxy-1-(1,3-dihydroxy-2-propoxy)ethyl,

(2-phosphonylmethoxy)ethyl or 3-hydroxy-2-phosphonylmethoxypropyl;

and a pharmaceutically acceptable carrier.