Diphenyl-triazole derivatives and their use as anti-gestative immuno-suppressant and anti-tumoral agents

Abstract

Compounds of formula (I), wherein X and Y are independently carbon or nitrogen but not both simultaneously carbon, R 1 is a group (II) and R 2 is a group (III), R 5 being a carbonate, carbamate or phosphate residue, are useful as anti-gestative, immuno-suppressant and anti-tumor agents

1. A nitrogen heterocyclic aromatic derivative having the following general formula: 
                 
 where X and Y are selected from N, C and CH, provided they are different from each other, or X and Y are both nitrogen;  
 R is hydrogen or —COR 8  where R 8  is a saturated or non-saturated C 1 -C 10  alphatic hydrocarbon, R 1  has the following general formula: 
                 
 
 where R 3  is hydrogen, halogen, C 1 -C 10  alkyl or C 1 -C 10  alkoxyl, R 4  is hydrogen, C 1 -C 10  alkyl or C 1 -C 10  alkoxyl, or R 3  and R 4  together form a methylendioxy group,  
 R 2  has the following general structure: 
                 
 
 and R 5  is selected from: 
                 
 
 where Z=OR 7  where R 7  is a saturated or non-saturated, linear or branched C 1 -C 10  aliphatic hydrocarbon, or R 7  has the following formula: 
                 
 
 where R, R 1 , X and Y are defined as above and R 6  is hydrogen, halogen, alkyl or alkoxyl C 1 -C 10 , or Z is NHR 8  where R 8  is a linear or branched C 1 -C 20  alkyl chain,  
 provided that when X=Y=N and R is H or —CONHCH 2 CH 3 , Z is not NHR 8  where R 8  is —CH 2 CH 3 , and provided that R 1  and R 2  are not located on two adjacent atoms of the heterocyclic aromatic ring, and further provided that when X=Y=N and R 5  is —COZ where Z=OR 7 , R 7  is a saturated or non-saturated linear or branched C 5 -C 20  aliphatic hydrocarbon.  
 
     
     
       2. The nitrogen heterocyclic aromatic derivative according to  claim 1  wherein when R 7  is a saturated or non-saturated C 1 -C 20  aliphatic hydrocarbon it is a linear or branched alkyl, alkenyl or alkinyl which may contain one or more double or triple bonds. 
     
     
       3. The nitrogen heterocyclic aromatic derivative according to  claim 1  in which alkyl or alkoxyl is a linear or branched C 1 -C 10  alkyl or alkoxyl group. 
     
     
       4. The nitrogen heterocyclic aromatic derivative according to the  claim 1  wherein the ring structure of formula (I) is: 
                 
 
     
     
       5. The nitrogen heterocyclic aromatic derivative according to  claim 1  having the following general formula: 
                 
 where R 3  is hydrogen, halogen, C 1 -C 10  alkyl or C 1 -C 10  alkoxyl, R 4  is hydrogen, C 1 -C 10  alkyl or C 1 -C 10  alkoxyl, or R 3  and R 4  together from a methylendioxy group,  
 R 5  is one of: 
                 
 
 where Z=OR 7  where R 7  is a saturated or non-saturated, linear or branched C 1 -C 20  aliphatic hydrocarbon, or is chosen from the following formula: 
                 
 
 where R, R 1 , X and Y are defined as above and R 6  is hydrogen, halogen, alkyl or alkoxyl C 1 -C 10 , or Z is NHR 8  where R 8  is a linear or branched C 1 -C 20  alkyl chain,  
 provided that when R 5  is —COZ where Z=OR 7 , R 7  is a saturated or non-saturated, linear or branched C 5 -C 10  aliphatic hydrocarbon.  
 
     
     
       6. The nitrogen heterocyclic aromatic derivative according to  claim 5 , wherein R 6 =hydrogen, R 4 =OCH 3  or OCH 2 CH 3 , R 3  is hydrogen, R 5  is COZ where Z=OR 7  where R 7  is a saturated linear alphatic C 5 -C 12  hydrocarbon. 
     
     
       7. The nitrogen heterocyclic aromatic derivative according to  claim 1  having the following structure; 
                 
 
     
     
       8. The nitrogen heterocyclic aromatic derivative according to  claim 1  having the following structure: 
                 
 
     
     
       9. The nitrogen heterocyclic aromatic derivative according to  claim 1  having the following structure: 
                 
 
     
     
       10. Nitrogen heterocyclic aromatic derivative having the following structure: 
                 
 
     
     
       11. A pharmaceutical composition comprising a nitrogen heterocyclic aromatic derivative according to  claim 1  together with a pharmaceutically acceptable diluent or carrier. 
     
     
       12. The pharmaceutical composition comprising a nitrogen heterocyclic aromatic derivative according to  claim 10  in the form of a transdermal skin patch. 
     
     
       13. The pharmaceutical composition comprising a nitrogen heterocyclic aromatic derivative according to  claim 10  for intravenous administration. 
     
     
       14. The pharmaceutical composition according to  claim 11  wherein the diluent or carrier is a vegetable oil or an ester of fatty acid suitable for an epicutaneous, subcutaneous or intramuscular administration. 
     
     
       15. The pharmaceutical composition according to  claim 14  wherein the diluent is sesame oil, corn oil, peanut oil, cotton seed oil or ethyl oleate. 
     
     
       16. The pharmaceutical composition according to  claim 11  also including anti-microbic agent. 
     
     
       17. The pharmaceutical composition according to  claim 11  also including an anti-oxidative agent. 
     
     
       18. The pharmaceutical composition according to  claim 11  which contains from 1 to 10% (w/v) of the nitrogen heterocyclic aromatic derivative. 
     
     
       19. A method of terminating pregnancy in a mammal comprising administering an effective amount of a nitrogen heterocyclic aromatic derivative of  claim 1 . 
     
     
       20. A method of reducing the humoral and cellular immunological response of a mammal comprising administering an effective amount of a nitrogen heterocyclic aromatic derivative having the following general formula: 
                 
 where X and Y are selected from N, C and CH, provided they are different from each other, or X and Y are both nitrogen;  
 R is hydrogen or —COR 8  where R 8  is a saturated or non-saturated C 1 -C 10  aliphatic hydrocarbon, R 1  has the following general formula: 
                 
 
 where R 3  is hydrogen, halogen,C 1 -C 10  alkyl or C 1 -C 10  alkoxyl, R 4  is hydrogen, C 1 -C 10  alkyl or C 1 -C 10  alkoxyl, or R 3  and R 4  together form a methylendioxy group;  
 R 2  has the following general structure: 
                 
 
 and R 5  is selected from: 
                 
 
 where Z=OR 7  where R 7  is a saturated or non-saturated, linear or branched C 1 -C 10  aliphatic hydrocarbon, or R 7  has the following formula: 
                 
 
 where R, R 1 , X and Y are defined as above and R 6  is hydrogen, halogen, alkyl or alkoxyl C 1 -C 10 , or Z is NHR 8  where R 8  is a linear or branched C 1 -C 20  alkyl chain,  
 provided that when X=Y=N and R is H or —CONHCH 2 CH 3 , Z is not NHR 8  where R 8  is —CH 2 CH 3 , and provided that R 1  and R 2  are not located on two adjacent atoms of the heterocyclic aromatic ring, and further provided that when X=Y=N and R 5  is —COZ where Z=OR 7 , R 7  is a saturated or non-saturated linear or branched C 5 -C 20  aliphatic hydrocarbon.  
 
     
     
       21. A method of treating a tumor susceptible to therapy comprising administering an effective amount of a nitrogen heterocyclic aromatic derivative having the following general formula: 
                 
 where X and Y are selected from N, C and CH, provided they are different from each other, or X and Y are both nitrogen;  
 R is hydrogen or —COR 8  where R 8  is a saturated or non-saturated C 1 -C 10  aliphatic hydrocarbon, R 1  has the following general formula: 
                 
 
 where R 3  is hydrogen, halogen, C 1 -C 10  alkyl or C 1 -C 10  alkoxyl, R 4  is hydrogen, C 1 -C 10  alkyl or C 1 -C 10  alkoxyl, or R 3  and R 4  together form a methylendioxy group;  
 R 2  has the following general structure: 
                 
 
 and R 5  is selected from: 
                 
 
 where Z=OR 7  where R 7  is a saturated or non-saturated, linear or branched C 1 -C 10  aliphatic hydrocarbon, or R 7  has the following formula: 
                 
 
 where R, R 1 , X and Y are defined as above and R 6  is hydrogen, halogen, alkyl or alkoxyl C 1 -C 10 , or Z is NHR 8  where R 8  is a linear or branched C 1 -C 20  alkyl chain,  
 provided that when X=Y=N and R is H or —CONHCH 2 CH 3 , Z is not NHR 8  where R 8  is —CH 2 CH 3 , and provided that R 1  and R 2  are not located on two adjacent atoms of the heterocyclic aromatic ring, and further provided that when X=Y=N and R 5  is —COZ where Z=OR 7 , R 7  is a saturated or non-saturated linear or branched C 5 -C 20  aliphatic hydrocarbon.  
 
     
     
       22. A pharmaceutical composition comprising a nitrogen heterocyclic aromatic derivative according to  claim 10  together with a pharmaceutically acceptable carrier or diluent.