N-6 substituted-5′-(N-substituted carboxamide)adenosines as cardiac vasodilator and antihypertensive agents

Abstract

Compounds of the formula are disclosed, wherein R 1 , represents secondary alkyl; aralkyl; cycloalkyl; heteroaryl substituted alkyl; norbornyl; and substituted secondary alkyl, aralkyl, cycloalkyl, heteroaryl substituted alkyl, norbornyl; and para-substituted phenyl groups; and R 2 and R 3 are hydrogen or pharmacologically acceptable acyl groups. The compounds of the invention are useful as cardiovascular vasodilator or anti-hypertensive agents. The therapeutically useful compounds of the invention as well as similar 5-N and N-6 substituted adenosine 5-uronamides are prepared, in accordance with a novel process, from isopropylidene (or otherwise suitably blocked) inosine-5′-uronic acid. Isopropylideneinosine-5′-uronic acid is reacted with a suitable inorganic acid halide, such as thionyl chloride, to yield 6-halogeno-9-[2′,3′-O-isopropylidene-β-D-ribofuranosyl-5-uronic acid halide]-9H-purine. This intermediate is reacted with an amine of the general formula R 4 R 5 NH to give a 6-halogeno substituted, substituted uronic acid amide of the formula wherein X is halogen. Reaction of the latter intermediate with an amine of the formula R 1 —NH 2 , and removal of the isopropylidene (or other) blocking groups yields the compounds of the invention.

What is claimed is:  
     
       1. Compounds  A compound of the formula:                    
       wherein: 
       R 1  represents secondary alkyl having from 3 to 10 carbons,  phenylalkyl, having from 1 to 7 carbons in the alkyl chain; mono- to penta-alkoxy phenylalkyl wherein said alkoxy contains from 1 to 3 carbons and said alkyl contains from 1 to 7 carbons; monohalophenylalkyl wherein said alkyl contains from 1 to 4 carbons; cycloalkyl wherein the ring contains from 3 to 8 carbons; bicycloalkyl wherein the rings together contain from 7 to 10 carbons; thienylalkyl wherein said alkyl contains from one to four carbons; pyridylalkyl wherein said alkyl contains from one to four carbons;  
       R 2  and R 3  are hydrogen;  
       R 4  is alkyl having 1 to 7 carbon atoms; or hydroxyalkyl which contains from 1 to 4 carbons; or secondary alkyl which contains from 3-8 carbons; or allylic alkenyl which contains from 3 to 7 carbons; or cycloalkyl wherein the ring contains from 3 to 7 carbons; or phenylalkyl wherein said alkyl contains from 1 to 4 carbons; or monoalkoxy phenylalkyl wherein said alkoxy and said alkyl each contain from 1 to 4 carbons; or thienylalkyl wherein said alkyl contains from 1 to 4 carbons; and R 5  is hydrogen, or straight chain lower alkyl having 1 to 4 carbons.  
     
     
       2. Compounds  The compound of claim  1  wherein R 4  is methyl or ethyl. 
     
     
       3. Compounds  The compound of claim  1  wherein R 1  is endo-2-norbornyl, R 4  is 2-hydroxyethyl and R 5  is hydrogen. 
     
     
       4. Compounds  The compound of claim  1  wherein R 4  is ethyl and R 5  is hydrogen. 
     
     
       5. Compounds  The compound of claim  4  wherein R 1  is cyclohexyl. 
     
     
       6. Compounds  The compound of claim  4  wherein R 1  is (S)-1-phenyl-2-butyl. 
     
     
       7. Compounds  The compound of claim  4  wherein R 1  is 4-methoxyphenyl. 
     
     
       8. Compounds  The compound of claim  4  wherein R 1  is 2-(3,4,5-trimethoxyphenyl)-ethyl. 
     
     
       9. Compounds  The compound of claim  4  wherein R 1  is 3-phenylpropyl. 
     
     
       10. Compounds  The compound of claim  4  wherein R 1  is (R)-1-phenyl-ethyl. 
     
     
       11. Compounds  The compound of claim  4  wherein R 1  is 2-(2-pyridyl)ethyl. 
     
     
       12. Compounds  The compound of claim  4  wherein R 1  is (2-chloro-phenyl)-methyl. 
     
     
       13. Compounds  The compound of claim  4  wherein R 1  is (2-thienyl)methyl. 
     
     
       14. Compounds  The compound of claim  4  wherein R 1  is (R)-1-phenyl-2-propyl. 
     
     
       15. The compounds  compound of claim  1  wherein R 4  is Z—Q—(CH 2 ) n  wherein n is an integer having the values of 1 to 4; Q is selected from the group consisting of phenyl, and thienyl, or pyridyl,  and Z is one or more  H, hydroxy, halogen, alkoxy having from 1 to 4 carbon atoms, or alkyl having from 1 to 7 carbon atoms . 
     
     
       16. Compounds  The compound of claim  1  wherein R 1  is cycloalkyl or bicycloalkyl.  
     
     
       17. Compounds  The compound of claim  16  wherein R 4  is ethyl, and R 5  is H. 
     
     
       18. Compounds  The compound of claim  16  wherein R 4  is methyl, and R 5  is H. 
     
     
       19. Compounds  The compound of claim  16  wherein R 4  is isopropyl, and R 5  is H. 
     
     
       20. Compounds  The compound of claim  16  wherein R 4  is 3-pentyl, and R 5  is H. 
     
     
       21. Compounds  The compound of claim  16  wherein R 4  is allyl, and R 5  is H. 
     
     
       22. Compounds  The compound of claim  16  wherein R 4  is (2-methyl) propyl, and R 5  is H. 
     
     
       23. Compounds  The compound of claim  16  wherein R 4  is cyclopropyl, and R 5  is H. 
     
     
       24. Compounds  The compound of claim  16  wherein R 4  is phenylmethyl, and R 5  is H. 
     
     
       25. Compounds  The compound of claim  16  wherein R 4  is 2-methoxyphenylmethyl, and R 5  is H. 
     
     
       26. Compounds  The compound of claim  16  wherein R 4  is 2-thienylmethyl, and R 5  is H. 
     
     
       27. Compounds  The compound of claim  16  wherein R 4  is 2-phenylmethyl, and R 5  is H. 
     
     
       28. Compounds  The compound of claim  16  wherein R 4  is methyl, and R 5  is methyl. 
     
     
       29. Compounds  The compound of claim  16  wherein R 4  is n-butyl, and R 5  is methyl. 
     
     
       30. Compounds  The compound of claim  16  wherein R 4  is ethyl, and R 5  is ethyl. 
     
     
       31. Compounds  The compound of claim  1  wherein R 1  is                    
       and R 4  and R 5  are methyl. 
     
     
       32. A pharmaceutical composition comprising a compound of claim  1  in admixture with one or more pharmaceutically acceptable carriers. 
     
     
       33. A method of administering to humans or animals of the mammalian species a vasodilator or anti-hypertensive compound in a therapeutically effective does to achieve a vasodilatory or anti-hypertensive effect, the compound having the formula                    
       wherein: 
       R 1  represents secondary alkyl having from 3 to 10 carbons; phenylalkyl, having from one to seven carbon atoms in the alkyl chain; mono- to penta-alkoxy phenylalkyl wherein said alkoxy contains from 1 to 3 carbons and said alkyl contains from 1 to 7 carbons; monohalophenylalkyl wherein said alkyl contains from 1 to 4 carbons; cycloalkyl wherein the ring contains from 3 to 8 carbons; bicycloalkyl wherein the rings together contain from 7 to 10 carbons; thienylalkyl wherein said alkyl contains from one to four carbons; pyridylalkyl wherein said alkyl contains from one to four carbons;  
       R 2  and R 3  are hydrogen;  
       R 4  is alkyl having 1 to 7 carbon atoms; or hydroxyalkyl which contains from 1 to 4 carbons; or secondary alkyl which contains from 3-8 carbons; or allylic alkenyl which contains from 3 to 7 carbons; or cycloalkyl wherein the ring contains from 3 to 7 carbons; or phenylalkyl wherein said alkyl contains from 1 to 4 carbons; or monoalkoxy phenylalkyl wherein said alkoxy and said alkyl each contain from 1 to 4 carbons; or thienylalkyl wherein said alkyl contains from 1 to 4 carbons; and  
       R 5  is hydrogen, or straight chain lower alkyl having 1 to 4 carbons.  
     
     
       34. The method of claim  33  wherein in the formula of the administered compound R 4  is ethyl and R 5  is hydrogen. 
     
     
       35. The method of claim  33  wherein in the formula of the administered compound R 1  is 3-pentyl.