Aromatic-linked polyamine macrocyclic compounds with anti-HIV activity

Abstract

Polyamine macrocyclic compounds, e.g. of 10 to 15 ring members and 3 to 6 ring amine nitrogens, linked through methylene groups to an aromatic moiety, show high selective activity against HIV.

We claim:  
     
       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.