Aromatic-linked polyamine macrocyclic compounds with anti-HIV activity

1. A pharmaceutical composition active against HIV comprising as an active ingredient a linked cyclic compound of formula I,

Z-R-A-R′-Y  (I)

in which Z and Y are identical cyclic polyamine moieties having from 10 to 15 ring members and from 3 to 6 4 amine nitrogens in the ring spaced by 2 or more carbon atoms from each other, said amine nitrogens being the only ring heteroatoms,

A is an unsubstituted aromatic or heteroaromatic moiety other than quinoline,

R and R′ are each methylene linked to nitrogen atoms in Z and Y,

the amine nitrogen atoms being otherwise unsubstituted, in admixture or association with a pharmaceutically acceptable diluent or carrier.

2. A composition according to claim 1 , wherein in the compound of formula I, each moiety Z and Y has 14 ring members and 4 amine nitrogens in the ring.

3. A pharmaceutical composition according to claim 1 , wherein the active against HIV comprising as an active ingredient is 1,1′-[1,3-phenylenebis(methylene)]-bis-1,4,8,11-tetra-azacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

4. A pharmaceutical composition according to claim 1 , wherein the active against HIV comprising as an active ingredient is 1,1′-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-tetra-azacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

5. A pharmaceutical composition according to claim 1 , wherein the active against HIV comprising as an active ingredient is a bis-zinc complex of 1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

6. A pharmaceutical composition according to claim 1 , wherein the active against HIV comprising as an active ingredient is a bis-copper complex of 1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

7. A pharmaceutical composition according to claim 1 , wherein the active against HIV comprising as an active ingredient is 1,1′-[3,3′-biphenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

8. A pharmaceutical composition according to claim 1 , wherein the active against HIV comprising as an active ingredient is 11,11′-[1,4-phenylene-bis-(methylene)]-bis-1,4,7,11-tetraazacyclotetradecane 11 , 11 ′- [ 1 , 4 - phenylene - bis -( methylene )]- bis - 1 , 4 , 7 , 11 - tetraazacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

9. A pharmaceutical composition according to claim 1 , wherein the active against HIV comprising as an active ingredient is 1,11′-[1,4-phenylene-bis-(methylene)]-1,4,8,11-tetraazacyclotetradecane-1,4,7,11-tetraazacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

10. A pharmaceutical composition according to claim 1 , wherein the active against HIV comprising as an active ingredient is 1,1′-[2,6-pyridine-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

11. A pharmaceutical composition according to claim 1 , wherein the active against HIV comprising as an active ingredient is 1,1-[3,5-pyridine-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

12. A pharmaceutical composition according to claim 1 , wherein the active against HIV comprising as an active ingredient is 1,1′-[2,5-thiophene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

13. A pharmaceutical composition according to claim 1 , wherein the active against HIV comprising as an active ingredient is 1,1′-[4,4′-(2,2′-bipyridine)-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

14. A pharmaceutical composition according to claim 1 , wherein the active against HIV comprising as an active ingredient is 1,1′-[2,9-(1,10-phenanthroline)-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

15. A pharmaceutical composition according to claim 1 , wherein the active against HIV comprising as an active ingredient is 1,1′-[1,3-phenylene-bis-(methylene)]-bis-1,4,7,10-tetraazacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

16. A pharmaceutical composition according to claim 1 , wherein the active against HIV comprising as an active ingredient is 1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,7,10-tetraazacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

17. The compound of claim 1 , which is A pharmaceutical composition active against HIV comprising as an active ingredient 1,1′-[5-nitro-1,3-phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

18. The compound of claim 1 , which is 1′1′-[2,4,5,6-tetrachloro-1,3-phenyleneis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane A pharmaceutical composition active against HIV comprising as an active ingredient 1 ′ 1 ′- [ 2 , 4 , 5 , 6 - tetrachloro - 1 , 3 - phenylenebis ( methylene ) ]bis - 1 , 4 , 8 , 11 - tetraazacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

19. The compound of claim 1 , which is A pharmaceutical composition active against HIV comprising as an active ingredient 1,1′-[2,3,5,6-tetrafluoro-1,4-phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

20. The compound of claim 1 , which is A pharmaceutical composition active against HIV comprising as an active ingredient 1,1′-[1,4-naphthylene-bis-(methylene)]bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

21. The compound of claim 1 , which is A pharmaceutical composition active against HIV comprising as an active ingredient 1,1′-[1,3-phenylenebis-(methylene)]bis-1,5,9-triazacyclododecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

22. The compound of claim 1 , which is 1,1′-[1,4-phenylene-bis-(methylene)]-1,5,9-triazacyclododecane A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 1 , 4 - phenylene - bis -( methylene )]- bis - 1 , 5 , 9 - triazacyclododecane in acid addition salt form in admixture or association with a pharmaceutically acceptable diluent or carrier.

23. The compound of claim 1 , which is a bis-zinc complex of 1,1′[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane.

24. The compound of claim 1 , which is 1,1′-[3,3′-biphenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form.

25. The compound of claim 1 , which is 1,1′-[2,6-pyridine-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form.

26. The compound of claim 1 , which is 1,1′-[3,5-pyridine-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form.

27. The compound of claim 1 , which is 1,1′-[2,5-thiophene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form.

28. The compound of claim 1 , which is 1,1′-[4,4′-(2,2′-bipyridine)-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form.

29. The compound of claim 1 , which is 1,1′-[2,9-(1,10-phenanthroline)-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in acid addition salt form.

30. The compound of claim 1 , which is 1,1′-[1,3-phenylene-bis-(methylene)]-bis-1,4,7,10-tetraazacyclotetradecane in acid addition salt form.

31. The compound of claim 1 , which is 1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,7,10-tetraazacyclotetradecane in acid addition salt form.

32. The compound of claim 1 , which is A pharmaceutical composition active against HIV comprising as an active ingredient 1,1′-[2,5-dimethyl-1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

33. The compound of claim 1 , which is A pharmaceutical composition active against HIV comprising as an active ingredient 1,1′-[2,5-dichloro-1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

34. The compound of claim 1 , which is A pharmaceutical composition active against HIV comprising as an active ingredient 1,1′-[2-bromo-1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

35. The compound of claim 1 , which is A pharmaceutical composition active against HIV comprising as an active ingredient 1,1′-[6-phenyl-2,4-pyridinebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

36. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 1 , 3 - phenylenebis ( methylene )]- bis - 1 , 4 , 8 , 11 - tetra - azacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

37. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 1 , 4 - phenylenebis ( methylene )]- bis - 1 , 4 , 8 , 11 - tetra - azacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

38. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 3 , 3 ′ - biphenylene - bis -( methylene )]- bis - 1 , 4 , 8 , 11 - tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

39. A pharmaceutical composition active against HIV comprising as an active ingredient 11 , 11 ′- [ 1 , 4 - phenylene - bis -( methylene )]- bis - 1 , 4 , 7 , 11 - tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

40. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 2 , 6 - pyridine - bis -( methylene )]- bis - 1 , 4 , 8 , 11 - tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

41. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 - [ 3 , 5 - pyridine - bis -( methylene )]- bis - 1 , 4 , 8 , 11 - tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

42. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 2 , 5 - thiophene - bis -( methylene )]- bis - 1 , 4 , 8 , 11 - tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

43. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 4 , 4 ′ -( 2 , 2 ′ - bipyridine )- bis -( methylene )]- bis - 1 , 4 , 8 , 11 - tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

44. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 2 , 9 -( 1 , 10 - phenanthroline )- bis -( methylene )]- bis - 1 , 4 , 8 , 11 - tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

45. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 1 , 3 - phenylene - bis -( methylene )]- bis - 1 , 4 , 7 , 10 - tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

46. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 1 , 4 - phenylene - bis -( methylene )]- bis - 1 , 4 , 7 , 10 - tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

47. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 5 - nitro - 1 , 3 - phenylenebis ( methylene ) ]bis - 1 , 4 , 8 , 11 - tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

48. A pharmaceutical composition active against HIV comprising as an active ingredient 1 ′ 1 ′- [ 2 , 4 , 5 , 6 - tetrachloro - 1 , 3 - phenylenebis ( methylene ) ]bis - 1 , 4 , 8 , 11 - tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

49. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 2 , 3 , 5 , 6 - tetra - fluoro - 1 , 4 - phenylenebis ( methylene ) ]bis - 1 , 4 , 8 , 11 - tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

50. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 1 , 4 - naphthylene - bis -( methylene ) ]bis - 1 , 4 , 8 , 11 - tetraazacyclotetradecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

51. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 1 , 3 - phenylenebis -( methylene ) ]bis - 1 , 5 , 9 - triazacyclododecane in admixture or association with a pharmaceutically acceptable diluent or carrier.

52. A pharmaceutical composition active against HIV comprising as an active ingredient 1 , 1 ′- [ 1 , 4 - phenylene - bis -( methylene )]- bis - 1 , 5 , 9 - triazacyclododecane in admixture or association with a pharmaceutically acceptable diluent or carrier.