Methods and compositions for treating viral infections and guanine acyclic nucleosides

• US 4,199,574 A
• Filed: 03/01/1976
• Issued: 04/22/1980
• Est. Priority Date: 09/02/1974
• Status: Expired due to Term

• Current Assignee: Burroughs Wellcome Co. (GSK plc)
• Original Assignee: Burroughs Wellcome and Co.
• Inventors: Schaeffer, Howard J.
• Primary Examiner(s): Coughlan, Jr., Paul M.
• Application Number:
  US05/662,900
• Time in Patent Office: 1,513 Days
• Field of Search: 260/252, 544/244, 544/276, 424/200, 424/253
• US Class Current: 514/81
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 473/04 two oxygen atoms
• CPC Class Codes: C07D 473/16 two nitrogen atoms
• CPC Class Codes: C07D 473/24 one nitrogen and one sulfur atom
• CPC Class Codes: C07D 473/32 Nitrogen atom
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• CPC Class Codes: C07D 473/38 attached in position 6
• CPC Class Codes: C07D 473/40 with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

Abstract

9-Hydroxyethoxymethyl (and related) derivatives of certain 6-, and 2,6-substituted purines have been discovered to have potent anti-viral activities. Novel compounds and their pharmaceutically acceptable salts, pharmaceutical formulation containing the compounds of this invention, and the treatment of viral infections with these formulations are all disclosed. 9-(2-hydroxyethoxymethyl) guanine and 2-amino-9-(2-hydroxyethoxymethyl)adenine are examples of especially active compounds of this invention.

Claims

1. A substituted purine of formula (I) ##STR12## wherein X is sulphur or oxygen;

R¹ is hydroxy, R² is amino;

R³ is hydrogen, straight or branched chain or cyclic alkyl, hydroxyalkyl, benzyloxyalkyl or phenyl;

R⁴ is hydrogen, hydroxy, or lower alkyl;

R⁵ is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzoyloxy, benzoyloxyalkyl, benzyloxy, sulphamoyloxy, phosphate, carboxypropionyloxy, or acetoxy;

R⁶ is hydrogen, alkyl, hydroxyalkyl or a pharmaceutically acceptable salt thereof.

2. A substituted purine of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein X is an oxygen atom.

3. A substituted purine of formula (I) according to claim 2 wherein R¹ is hydroxy, R² is amino;

R³ is hydrogen, straight or branched chain or cyclic alkyl, hydroxyalkyl or phenyl;

R⁴ is hydrogen or hydroxy;

R⁵ is hydrogen, hydroxy, hydroxyalkyl, amino, carboxypropionyloxy, acetoxy, benzyloxy, benzoyloxy, benzoyloxyalkyl, phosphate, or sulphamoyloxy;

R⁶ is hydrogen, alkyl, or hydroxyalkyl;

or a pharmaceutically acceptable salt thereof.

4. A substituted purine of formula (I) according to claim 2 wherein R¹ is hydroxy;

R² is amino;

R⁵ is hydroxy, benzoyloxy, carboxypropionyloxy, or hydroxyalkyl and R³, R⁴ and R⁶ are all hydrogen atoms or a pharmaceutically acceptable salt thereof.

5. A substituted purine of formula (I) according to claim 1 wherein R¹ is hydroxy, E² is amino, R⁵ is hydroxy and R³, R⁴ and R⁶ are each hydrogen;

or a pharmaceutically acceptable salt thereof.

6. A substituted purine of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein X is sulphur.

7. A substituted purine of formula (I) or a pharmaceutically acceptable salt thereof according to claim 2 wherein R² is amino, R¹ and R⁵ are both hydroxy and R³, R⁴ and R⁶ are each hydrogen.

8. A substituted purine of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 wherein R¹ is hydroxy, R² is amino, R⁵ is benzoyloxy and R³, R⁴ and R⁶ are each hydrogen.

9. A substituted purine of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 wherein R¹ is hydroxy, R² is amino, R⁵ is hydroxymethyl and R³, R⁴ and R⁵ are each hydrogen.

10. A substituted purine of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 wherein R¹ is hydroxy, R² is amino, R⁵ is carboxypropionyloxy and R³, R⁴ and R⁶ are each hydrogen.

23. A method of treating a viral infection in a mammal, which comprises the administration of an effective, antiviral, non-toxic amount of a substituted purine of formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof.

24. A method of treating a viral infection as claimed in claim 23 in which X is oxygen.

25. A method according to claim 23 wherein administration is by topical application.

26. A method according to claim 23 wherein administration is by the oral route.

27. A method according to claim 23 wherein administration is by the parenteral route.

28. A method according to claim 27 wherein the compound of formula (I) is administered in doses of from 0.1 to 250 mg/kg body weight.

29. A method according to claim 28, wherein the doses are repeated at least twice daily.

30. A method as claimed in claim 23 wherein the substituted purine compound is 9-(2-hydroxyethoxymethyl)guanine, 9(2-benzoyloxyethoxymethyl)guanine, 9-(3-hydroxypropoxymethyl) guanine, or 9-{2-(3-carboxypropionyloxy)ethoxymethyl}guanine,

31. A method of claim 23 in which the substituted purine is selected from the group consisting of:

9-(3-Benzoylpropoxymethyl)guanine;

9-[1-(2-Hydroxyethoxy)ethyl]guanine; and

9-Ethoxymethylguanine.

38. The compound or pharmaceutically acceptable salt of claim 1 wherein R⁵ is acetoxy.

60. The method of claim 23 in which the alkyl has from 1 to 12 carbon atoms.

61. A method according to claim 25 wherein the compound of formula (I) is administered in doses of from 0.1 to 250 mg/kg body weight.

62. A method according to claim 26 wherein the compound of formula (I) is administered in doses of from 0.1 to 250 mg/kg body weight.

69. The purine or pharmaceutically acceptable salt of claim 3 wherein R⁵ is acetoxy.

70. The purine or pharmaceutically acceptable salt of claim 3 wherein R⁵ is phosphate.

71. The method of claim 23 in which R⁵ is acetoxy.

72. The method of claim 23 in which R⁵ is phosphate.

73. The method of claim 23 in which R⁵ is carboxypropionyloxy.

81. The purine or pharmaceutically acceptable salt of claim 2 in which R⁵ is carboxypropionyloxy.

11. A pharmaceutical composition which comprises an effective non-toxic antiviral treatment amount of a substituted purine of the formula (I) ##STR13## wherein X is sulphur or oxygen;

R¹ is hydroxy, R² is amino;

R³ is hydrogen, straight or branched chain or cyclic alkyl, hydroxyalkyl, benzoylalkyl or phenyl;

R⁴ is hydrogen, hydroxy, or alkyl;

R⁵ is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzoyloxy, benzoyloxyalkyl, benzyloxy, sulphamoyloxy, phosphate, carboxypropionyloxy, or acetoxy;

R⁶ is hydrogen, alkyl, or hydroxyalkyl;

or a pharmaceutically acceptable salt thereof;

together with a pharmaceutically acceptable carrier therefor.

12. A pharmaceutical composition as claimed in claim 11 in which X is oxygen.

13. A pharmaceutical composition as claimed in claim 11 in which R² is amino, R¹ and R⁵ are both hydroxy and R³, R⁴ and R⁶ are each hydrogen.

14. A pharmaceutical composition as claimed in claim 11, which is in the form of an ointment or cream.

15. A pharmaceutical composition as claimed in claim 11, which is in the form of a tablet.

16. A pharmaceutical composition for oral or parenteral administration as claimed in claim 11, comprising the compound in an amount of 1 to 250 mg per unit dose.

17. A pharmaceutical composition as claimed in claim 16 for parenteral administration or eye or nose drops comprising the compound in a concentration from 0.1 to 10% in an aqueous medium.

18. A pharmaceutical composition as claimed in claim 11 in a form for topical administration comprising the compound in a concentration from 0.1 to 10%.

19. A pharmaceutical composition as claimed in claim 18 comprising the compound in a concentration of 1%.

21. The composition according to claim 11 in which the amount is 1 to 250 mg.

22. A pharmaceutical composition of claim 11 in which the substituted purine is selected from the group consisting of:

9-(3-Benzoylpropoxymethyl)guanine;

9-[1-(2-Hydroxyethoxy)ethyl]guanine;

9-Ethoxymethylguanine; and

9-(4-Hydroxy-n-butoxymethyl)guanine hemihydrate.

52. A pharmaceutical composition as claimed in claim 12 which is in the form of a ointment or cream.

53. A pharmaceutical composition as claimed in claim 13 which is in the form of an ointment or cream.

54. A pharmaceutical composition as claimed in claim 12 which is in the form of a tablet.

55. A pharmaceutical composition as claimed in claim 13 which is in the form of a tablet.

56. A pharmaceutical composition as claimed in claim 12 comprising the compound in an amount of 1 to 250 mg per unit dose.

57. A pharmaceutical composition as claimed in claim 13 comprising the compound in an amount of 1 to 250 mg per unit dose.

58. A pharmaceutical composition as claimed in claim 12 in a form for topical administration comprising the compound in a concentration from 0.1 to 10%.

59. A pharmaceutical composition as claimed in claim 13 in a form for topical administration comprising the compound in a concentration from 0.1 to 10%.

74. The composition of claim 12 in which R⁵ is phosphate.

75. The composition of claim 12 in which R⁵ is carboxypropionyloxy.

76. The composition of claim 12 in which R⁵ is acetoxy.

20. A purine selected from the group consisting of:

9-(3-Benzoylpropoxymethyl)guanine

9-[1-(2-Hydroxyethoxy)ethyl]guanine

9-Ethoxymethylguanine and

9-(4-Hydroxy-n-butoxymethyl)guanine hemihydrate.

32. 9-(2-Formyloxyethoxymethyl) guanine or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising an effective non-toxic antiviral infection treatment amount of 9-(2-formyloxyethoxymethyl)guanine or a pharmaceutically acceptable salt thereof and a pharmaceutical acceptable carrier therefor.

34. A method of treating a susceptible viral infection in a mammal which comprises administering an effective non-toxic anti-viral amount of 9-(2-formyloxyethoxymethyl)guanine or a pharmaceutically acceptable salt thereof to said mammal.

35. The compound of the formula I ##STR14## wherein X is sulphur or oxygen, R¹ is hydroxy;

R² is amino;

R³ is hydrogen, straight or branch chain or cyclic alkyl, hydroxyalkyl, benzyloxyalkyl or phenyl;

R⁴ is hydrogen, hydroxy or alkyl;

R⁵ is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzyloxy, benzoyloxy, benzoyloxymethyl, sulphamoyloxy, phosphate or straight chain or cyclic acyloxy having from 1 to 8 carbon atoms;

R⁶ is hydrogen or alkyl, or a pharmaceutically acceptable salt thereof.

36. The compound or pharmaceutically acceptable salt of claim 35 wherein R⁵ is straight chain or cyclic acyloxy having from 1 to 8 carbon atoms.

37. The compound or pharmaceutically acceptable of claim 36 wherein R⁵ is straight chain acyloxy.

50. A pharmaceutical composition containing an effective non-toxic antiviral treatment amount of the compound or salt of claim 35 and a pharmaceutically acceptable carrier therefore.

51. A method of treating a susceptible viral infection in a mammal having said viral infection which comprises the administration of an effective antiviral non-toxic amount of the compound or salt of claim 35.

63. The pharmaceutical composition of claim 50 comprising wherein R⁵ is straight chain or cyclic acyloxy having 1 to 8 carbon atoms.

64. The pharmaceutical composition of claim 50 wherein R⁵ is straight chain acyloxy.

65. The pharmaceutical composition of claim 50 wherein R⁵ is acetoxy.

66. The method of claim 51 wherein R⁵ is straight chain or cyclic acyloxy having 1 to 8 carbon atoms.

67. The method of claim 51 wherein R⁵ is straight chain acyloxy.

68. The method of claim 51 wherein R⁵ is acetoxy.

39. 9-(2-hydroxyethoxymethyl)guanine.

40. A pharmaceutically acceptable salt of 9-(2-hydroxyethoxymethyl)guanine.

41. A pharmaceutical composition comprising an effective non-toxic antiviral treatment amount of 9-(2-hydroxyethoxymethyl) guanine or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier therefore.

42. The composition of claim 41 in a form for oral administration.

43. The composition of claim 41 in a form for parenteral administration.

44. The composition of claim 41 in a form for topical administration.

45. The method of treating a susceptible viral infection in a mammal having said viral infection which comprises the administration of an effective antiviral non-toxic amount of 9-(2-hydroxyethoxymethyl)guanine or a pharmaceutically acceptable salt thereof.

46. The method of claim 45 in which the administration is oral.

47. The method of claim 45 in which the administration is parenteral.

48. The method of claim 45 in which the administration is topical.

49. The method of claim 45 in which the viral infection is caused by a herpes virus.

77. 9-[2-(3-carboxypropionyloxy)ethoxymethyl]guanine.

78. A pharmaceutically acceptable salt of:

9-[2-(3-carboxypropionyloxy)ethoxymethyl]guanine.

79. A pharmaceutical composition comprising an effective non-toxic antiviral infection treatment amount of 9-[2-(3-carboxypropionyloxy)ethoxymethyl]guanine or a pharmaceutically acceptable salt thereof.

80. A method of treating a susceptible viral infection in a mammal which comprises administering an effective non-toxic antiviral amount of 9-[2-(3-carboxypropionyloxy)ethoxymethyl]guanine or a pharmaceutically acceptable salt thereof to said mammal.