Antiproliferative and neurotrophic molecules

Abstract

Neurotrophic and antiproliferative compounds related to the antiepileptic drug valproate are provided. These compounds are useful for promoting neuronal function as in neurodegenerative disorders and for treating neoplastic disease.

We claim:  
     
       1. Compounds of formula (I)                    
       wherein 
       R 1  is —C≡CH, —CH═CH 2 , or —CH 2 —CH 3 ,  
       R 2  is a saturated, unsaturated, branched and/or unbranched C 1 -C 30  alkyl group, optionally further comprising an aliphatic or aromatic C 3-9  cyclohydrocarbon or heterocyclic group comprising 3 to 9 atoms; and  
       M is a hydrogen or a metal atom,  
       and enantiomeres thereof and pharmaceutical acceptable salts thereof; with the proviso that the compound of formula (I) is not 2-n-propyl-4-pentynoic acid, 2-benzylpentanoic acid, 4,4′-dien-valproic acid or 2-n-propyl-4-pentenoic acid (4-en-VPA), and when R 1  is —CH 2 —CH 3 , R 2  is C 5  to C 30 . 
     
     
       2. The compounds according to  claim 1  wherein R 1  is —C≡CH or —CH═CH 2  and R 2  is unbranched and —(CH 2 ) 1-9 —CH 3 . 
     
     
       3. The compound according to  claim 2  wherein R 2  is —(CH 2 ) 3-6 —CH 3 . 
     
     
       4. The compounds according to  claim 2  wherein R 2  is —(CH 2 ) 4-5 —CH 3 . 
     
     
       5. The compounds according to  claim 4  wherein R 1  is —C≡CH. 
     
     
       6. The S enantiomer of the compounds according to  claim 1 . 
     
     
       7. The compounds according to  claim 1 , selected from the group consisting of: 
       2-n-prop-1 1 -enyl-4-pentynoic acid  
       2-n-prop-2 1 -enyl-4-pentynoic acid  
       2-i-propyl-4-pentynoic acid  
       2-i-propenyl-4-pentynoic acid  
       2-n-but-1 1 -enyl-4-pentynoic acid  
       2-n-but-2 1 -enyl-4-pentynoic acid  
       2-n-but-3 1 -enyl-4-pentynoic acid  
       2-(1 1 -methylbutyl)-4-pentynoic acid  
       2-(1 1 -methylprop-1 1 -enyl)-4-pentynoic acid  
       2-(1 1 -methylprop-2 1 -enyl)-4-pentynoic acid  
       2-(2 1 -methylpropyl)-4-pentynoic acid  
       2-(2 1 -methylprop-1 1 -enyl)-4-pentynoic acid  
       2-(2 1 -methylprop-2 1 -enyl)-4-pentynoic acid  
       2-tert.-butyl-4-pentynoic acid  
       2-n-pentyl-4-pentynoic acid  
       2-(1 1 -methylbutyl)-4-pentynoic acid  
       2-(2 1 -methylbutyl)-4-pentynoic acid  
       2-(3 1 -methylbutyl)-4-pentynoic acid  
       2-(3 1 -dimethylpropyl)-4-pentynoic acid  
       2-(1 1 ,1 1 -dimethylpropyl)-4-pentynoic acid  
       2-(2 1 ,2 1 -dimethylpropyl)-4-pentynoic acid  
       2-n-hexyl-4-pentynoic acid  
       2-n-hex-1 1 -enyl-4-pentynoic acid  
       2-n-hex-2 1 -enyl-4-pentynoic acid  
       2-n-hex-3 1 -enyl-4-pentynoic acid  
       2-n-hex-4 1 -enyl-4-pentynoic acid  
       2-n-hex-5 1 -enyl-4-pentynoic acid  
       2-(1 1 -methylpentyl)-4-pentynoic acid  
       2-(1 1 -methylpent-1 1 -enyl)-4-pentynoic acid  
       2-(1 1 -methylpent-2 1 -enyl)-4-pentynoic acid  
       2-(1 1 -methylpent-3 1 -enyl)-4-pentynoic acid  
       2-(1 1 -methylpent-4 1 -enyl)-4-pentynoic acid  
       2-(2 1 -methylpentyl)-4-pentynoic acid  
       2-(2 1 -methylpent-1 1 -enyl)-4-pentynoic acid  
       2-(2 1 -methylpent-2 1 -enyl)-4-pentynoic acid  
       2-(2 1 -methylpent-3 1 -enyl)-4-pentynoic acid  
       2-(2 1 -methylpent-4 1 -enyl)-4-pentynoic acid  
       2-(3 1 -methylpentyl)-4-pentynoic acid  
       2-(3 1 -methylpent-1 1 -enyl)-4-pentynoic acid  
       2-(3 1 -methylpent-2 1 -enyl)-4-pentynoic acid  
       2-(3 1 -methylpent-3 1 -enyl)-4-pentynoic acid  
       2-(3 1 -methylpent-4 1 -enyl)-4-pentynoic acid  
       2-(4 1 -methylpentyl)-4-pentynoic acid  
       2-(4 1 -methylpent-1 1 -enyl)-4-pentynoic acid  
       2-(4 1 -methylpent-2 1 -enyl)-4-pentynoic acid  
       2-(4 1 -methylpent-3 1 -enyl)-4-pentynoic acid  
       2-(4 1 -methylpent-4 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,1 1 -dimethylbutyl)-4-pentynoic acid  
       2-(1 1 ,1 1 -dimethylbut-2 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,1 1 -dimethylbut-3 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,2 1 -dimethylbutyl)-4-pentynoic acid  
       2-(1 1 ,2 1 -dimethylbut-1 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,2 1 ,dimethylbut-3 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,3 1 ,dimethylbutyl)-4-pentynoic acid  
       2-(1 1 ,3 1 -dimethylbut-1 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,2 1 -dimethylbut-2 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,3 1 -dimethylbut-3 1 -enyl)-4-pentynoic acid  
       2-(2 1 ,2 1 -dimethylbutyl)-4-pentynoic acid  
       2-(2 1 ,2 1 -dimethylbut-3 1 -enyl)-4-pentynoic acid  
       2-(2 1 ,3 1 -dimethylbutyl)-4-pentynoic acid  
       2-(2 1 ,3 1 -dimethylbut-1 1 -enyl)-4-pentynoic acid  
       2-(2 1 ,3 1 -dimethylbut-2 1 -enyl)-4-pentynoic acid  
       2-(2 1 ,3 1 -dimethylbut-3 1 -enyl)-4-pentynoic acid  
       2-(3 1 ,3 1 -dimethylbutyl)-4-pentynoic acid  
       2-(3 1 ,3 1 -dimethylbut-1 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,1 1 ,2 1 -trimethylpropyl)-4-pentynoic acid  
       2-(1 1 ,1 1 ,2 1 -trimethylprop-2 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,2 1 ,2 1 -trimethylpropyl)-4-pentynoic acid  
       2-n-heptyl-4-pentynoic acid  
       2-)1 1 -methylhexyl)-4-pentynoic acid  
       2-(2 1 -methylhexyl)-4-pentynoic acid  
       2-(3 1 -methylhexyl)-4-pentynoic acid  
       2-(4 1 -methylhexyl)-4-pentynoic acid  
       2-(5 1 -methylhexyl)-4-pentynoic acid  
       2-(1 1 ,1 1 -dimethylpentyl)-4-pentynoic acid  
       2-(1 1 ,2 1 -dimethylpentyl)-4-pentynoic acid  
       2-(1 1 ,3 1 -dimethylpentyl)-4-pentynoic acid  
       2-(1 1 ,4 1 -dimethylpentyl)-4-pentynoic acid  
       2-(2 1 ,2 1 -dimethylpentyl)-4-pentynoic acid  
       2-(2 1 ,3 1 -dimethylpentyl)-4-pentynoic acid  
       2-(2 1 ,4 1 -dimethylpentyl)-4-pentynoic acid  
       2-(3 1 ,3 1 -dimethylpentyl)-4-pentynoic acid  
       2-(3 1 ,4 1 -dimethylpentyl)-4-pentynoic acid  
       2-(4 1 ,4 1 -dimethylpentyl)-4-pentynoic acid  
       2-(1 1 ,1 1 ,2 1 -trimethylbutyl)-4-pentynoic acid  
       2-(1 1 ,1 1 ,3 1 -trimethylbutyl)-4-pentynoic acid  
       2-(1 1 ,2 1 ,3 1 -trimethylbutyl)-4-pentynoic acid  
       2-(2 1 ,2 1 ,3 1 -trimethylbutyl)-4-pentynoic acid  
       2-(2 1 ,3 1 ,3 1 -trimethylbutyl)-4-pentynoic acid.  
     
     
       8. The compounds according to  claim 7  selected from the group consisting of 2-n-butyl-4-pentynoic acid, 2-n-pentyl-4- pentynoic acid and 2-n-hexyl-4-pentynoic acid. 
     
     
       9. The compounds according to  claim 8  wherein the compounds are selected from the group consisting of 2-n-pentyl-4-pentynoic acid and 2-n-hexyl-4-pentynoic acid. 
     
     
       10. A method of preparing compounds having the general formula (I)                    
       wherein 
       R 1  is —C≡CH, —CH═CH 2 , or —CH 2 —CH 3 ,  
       R 2  is saturated, unsaturated, branched and/or unbranched C 1-30  alkyl group, optionally substituted with an aliphatic of aromatic C 3-9  cyclohydrocarbon or heterocyclic group; and  
       M is a hydrogen or a metal atom, comprising;  
       combining a malonic acid diester with a first halide having the general formula (VII)  
       
         
           R 2 —X   (VII)  
         
       
        wherein R 2  has the meaning given previously; or halogen, to form a 2-alkyl malonic acid diester, and combining the 2-alkyl malonic acid diester with a second halide having the general formula (VIII)  
       
         
           R 1 —CH 2 —X   (VIII)  
         
       
        wherein R 1  has the meaning given previously; or  
        combining the malonic acid diester with the second halide having the general formula (VIII) to form a 2-alkyl malonic acid diester; and  
        combining the first halide having the general formula (VII) to form a compound of formula (IX)                    
        wherein R 5  is an alkyl group; and hydrolyzing and decarboxylating the compound of formula (IX) to form the compound of formula (I) to a salt.  
     
     
       11. The method according to  claim 10  wherein R 1  is —C≡CH and R 2  is —(CH 2 ) 1-9 —CH 3 . 
     
     
       12. The method according to  claim 11  wherein R 2  is —(CH 2 ) 3-6 —CH 3 ). 
     
     
       13. The method according to  claim 12  wherein R 2  is —(CH 2 ) 4-5 —CH 3 . 
     
     
       14. The method according to  claim 10  wherein the method is used to prepare a compound selected from the group consisting of: 
       2-n-prop-1 1 -enyl-4-pentynoic acid  
       2-n-prop-2 1 -enyl-4-pentynoic acid  
       2-i-propyl-4-pentynoic acid  
       2-i-propenyl-4-pentynoic acid  
       2-n-butyl-4-pentynoic acid  
       2-n-but-1 1 -enyl-4-pentynoic acid  
       2-n-but-2 1 -enyl-4-pentynoic acid  
       2-n-but-3 1 -enyl-4-pentynoic acid  
       2-(1 1 -methylbutyl)-4-pentynoic acid  
       2-(1 1 -methylprop-2 1 -enyl)-4-pentynoic acid  
       2-(1 1 -methylprop-2 1 -enyl)-4-pentynoic acid  
       2-(2 1 -methylpropyl)-4-pentynoic acid  
       2-(2 1 -methylprop-1 1 -enyl)-4-pentynoic acid  
       2-(2 1 -methylprop-2 1 -enyl)-4-pentynoic acid  
       2-tert.-butyl-4-pentynoic acid  
       2-n-pentyl-4-pentynoic acid  
       2-(1 1 -methylbutyl)-4-pentynoic acid  
       2-(2 1 -methylbutyl)-4-pentynoic acid  
       2-(3 1 -methylbutyl)-4-pentynoic acid  
       2-(1 1 ,1 1 -dimethylpropyl)-4-pentynoic acid  
       2-(1 1 ,2 1 -dimethylpropyl)-4-pentynoic acid  
       2-(2 1 ,2 1 -dimethylpropyl)-4-pentynoic acid  
       2-n-hexyl-4-pentynoic acid  
       2-n-hex-1 1 -enyl-4-pentynoic acid  
       2-n-hex-2 1 -enyl-4-pentynoic acid  
       2-n-hex-3 1 -enyl-4-pentynoic acid  
       2-n-hex-4 1 -enyl-4-pentynoic acid  
       2-n-hex-5 1 -enyl-4-pentynoic acid  
       2-(1 1 -methylpentyl)-4-pentynoic acid  
       2-(1 1 -methylpent-1 1 -enyl)-4-pentynoic acid  
       2-(1 1 -methylpent-2 1 -enyl)-4-pentynoic acid  
       2-(1 1 -methylpent-3 1 -enyl)-4-pentynoic acid  
       2-(1 1 -methylpent-4 1 -enyl)-4-pentynoic acid  
       2-(2 1 -methylpentyl)-4-pentynoic acid  
       2-(2 1 -methylpent-1 1 -enyl)-4-pentynoic acid  
       2-(2 1 -methylpent-2 1 -enyl)-4-pentynoic acid  
       2-(2 1 -methylpent-3 1 -enyl)-4-pentynoic acid  
       2-(2 1 -methylpent-4 1 -enyl)-4-pentynoic acid  
       2-(3 1 -methylpentyl)-4-pentynoic acid  
       2-(3 1 -methylpent-1 1 -enyl)-4-pentynoic acid  
       2-(3 1 -methylpent-2 1 -enyl)-4-pentynoic acid  
       2-(3 1 -methylpent-3 1 -enyl)-4-pentynoic acid  
       2-(3 1 -methylpent-4 1 -enyl)-4-pentynoic acid  
       2-(4 1 -methylpentyl)-4-pentynoic acid  
       2-(4 1 -methylpent-1 1 -enyl)-4-pentynoic acid  
       2-(4 1 -methylpent-2 1 -enyl)-4-pentynoic acid  
       2-(4 1 -methylpent-3 1 -enyl)-4-pentynoic acid  
       2-(4 1 -methylpent-4 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,1 1 -dimethylbutyl)-4-pentynoic acid  
       2-(1 1 ,1 1 -dimethylbut-2 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,1 1 -dimethylbut-3 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,2 1 -dimethylbutyl)-4-pentynoic acid  
       2-(1 1 ,2 1 -dimethylbut-1 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,2 1 ,dimethylbut-2 1 -enyl)-4pentynoic acid  
       2-(1 1 ,2 1 ,dimethylbut-3 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,3 1 -dimethylbutyl)-4-pentynoic acid  
       2-(1 1 ,3 1 -dimethylbut-1 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,3 1 -dimethylbut-2 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,3 1 -dimethylbut-3 1 -enyl)-4-pentynoic acid  
       2-(2 1 ,2 1 -dimethylbutyl)-4-pentynoic acid  
       2-(2 1 ,2 1 -dimethylbut-3 1 -enyl)-4-pentynoic acid  
       2-(2 1 ,3 1 -dimethylbutyl)-4-pentynoic acid  
       2-(2 1 ,3 1 -dimethylbut-1 1 -enyl)-4-pentynoic acid  
       2-(2 1 ,3 1 -dimethylbut-2 1 -enyl)-4-pentynoic acid  
       2-(2 1 ,3 1 -dimethylbut-3 1 -enyl)-4-pentynoic acid  
       2-)3 1 ,3 1 -dimethylbutyl)-4-pentynoic acid  
       2-(3 1 ,3 1 -dimethylbut-1 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,1 1 ,2 1 -trimethylpropyl)-4-pentynoic acid  
       2-(1 1 ,1 1 ,2 1 -trimethylprop-2 1 -enyl)-4-pentynoic acid  
       2-(1 1 ,2 1 ,2 1 -trimethylpropyl)-4-pentynoic acid  
       2-n-heptyl-4-pentynoic acid  
       2-)1 1 -methylhexyl)-4-pentynoic acid  
       2-(2 1 -methylhexyl)-4-pentynoic acid  
       2-(3 1 -methylhexyl)-4-pentynoic acid  
       2-(4 1 -methylhexyl)-4-pentynoic acid  
       2-(5 1 -methylhexyl)-4-pentynoic acid  
       2-(1 1 ,1 1 -dimethylpentyl)-4-pentynoic acid  
       2-(1 1 ,2 1 -dimethylpentyl)-4-pentynoic acid  
       2-(1 1 ,3 1 -dimethylpentyl)-4-pentynoic acid  
       2-(1 1 ,4 1 -dimethylpentyl)-4-pentynoic acid  
       2-(2 1 ,2 1 -dimethylpentyl)-4-pentynoic acid  
       2-(2 1 ,3 1 -dimethylpentyl)-4-pentynoic acid  
       2-(2 1 ,4 1 -dimethylpentyl)-4-pentynoic acid  
       2-(3 1 ,3 1 -dimethylpentyl)-4-pentynoic acid  
       2-(3 1 ,4 1 -dimethylpentyl)-4-pentynoic acid  
       2-(4 1 ,4 1 -dimethylpentyl)-4-pentynoic acid  
       2-(1 1 ,1 1 ,2 1 -trimethylbutyl)-4-pentynoic acid  
       2-(1 1 ,1 1 ,3 1 -trimethylbutyl)-4-pentynoic acid  
       2-(1 1 ,2 1 ,3 1 -trimethylbutyl)-4-pentynoic acid  
       2-(2 1 ,2 1 ,3 1 -trimethylbutyl)-4-pentynoic acid  
       2-(2 11 ,3 1 ,3 1 -trimethylbutyl)-4-pentynoic acid.  
     
     
       15. The method according to  claim 10  wherein the method is used to prepare at least one compound selected from the group consisting of 2-n-butyl-4-pentynoic acid, 2-n-pentyl-4-pentynoic acid and 2-n-hexyl-4-pentynoic acid. 
     
     
       16. A S- enantiomer of a compound of formula  ( I )                    
       
         wherein  
       
         R   1    is —C≡CH, R   2    is a saturated, unsaturated, branched and/or unbranched C   1   -C   30    alkyl group, optionally further comprising an aliphatic or aromatic C   3-9    cyclohydrocarbon or heterocyclic group comprising  3  to  9  atoms; and M is a hydrogen or a metal atom, and pharmaceutical acceptable salts thereof; with the proviso that the compound of formula  ( I )  is not  2   - n - propyl -   4   - pentynoic acid.   
     
     
       17. A compound according to  claim 16  wherein R 2    is — ( CH   2 ) 3-6   —CH   3   .   
     
     
       18. A compound according to  claim 16  wherein R 2    is — ( CH   2 ) 4-5   —CH   3   .   
     
     
       19. A compound according to  claim 16  selected from the group consisting of: 
           2   - n - prop -   1     1 - enyl -   4   - pentynoic acid    
           2   - n - prop -   2     1 - enyl -   4   - pentynoic acid    
           2   - i - propyl -   4   - pentynoic acid    
           2   - i - propenyl -   4   - pentynoic acid    
           2   - n - butyl -   4   - pentynoic acid    
           2   - n - but -   1     1 - enyl -   4   - pentynoic acid    
           2   - n - but -   2     1 - enyl -   4   - pentynoic acid    
           2   - n - but -   3     1 - enyl -   4   - pentynoic acid    
           2   -(   1     1 - methylbutyl )-   4   - pentynoic acid    
           2   -(   1     1 - methylprop -   1     1 - enyl )-   4   - pentynoic acid    
           2   -(   1     1 - methylprop -   2     1 - enyl )-   4   - pentynoic acid    
           2   -(   2     1 - methylpropyl )-   4   - pentynoic acid    
           2   -(   2     1 - methylprop -   1     1 - enyl )-   4   - pentynoic acid    
           2   -(   2     1 - methylprop -   2     1 - enyl )-   4   - pentynoic acid    
           2   - tert. - butyl -   4   - pentynoic acid    
           2   - n - pentyl -   4   - pentynoic acid    
           2   -(   1     1 - methylbutyl )-   4   - pentynoic acid    
           2   -(   2     1 - methylbutyl )-   4   - pentynoic acid    
           2   -(   3     1 - methylbutyl )-   4   - pentynoic acid    
           2   -(   1     1   , 1     1 - dimethylpropyl )-   4   - pentynoic acid    
           2   -(   1     1   , 2     1 - dimethylpropyl )-   4   - pentynoic acid    
           2   -(   2     1   , 2     1 - dimethylpropyl )-   4   - pentynoic acid    
           2   - n - hexyl -   4   - pentynoic acid    
           2   - n - hex -   1     1 - enyl -   4   - pentynoic acid    
           2   - n - hex -   2     1 - enyl -   4   - pentynoic acid    
           2   - n - hex -   3     1 - enyl -   4   - pentynoic acid    
           2   - n - hex -   4     1 - enyl -   4   - pentynoic acid    
           2   - n - hex -   5     1 - enyl -   4   - pentynoic acid    
           2   -(   1     1 - methylpentyl )-   4   - pentynoic acid    
           2   -(   1     1 - methylpent -   1     1 - enyl )-   4   - pentynoic acid    
           2   -(   1     1 - methylpent -   2     1 - enyl )-   4   - pentynoic acid    
           2   -(   1     1 - methylpent -   3     1 - enyl )-   4   - pentynoic acid    
           2   -(   1     1 - methylpent -   4     1 - enyl )-   4   - pentynoic acid    
           2   -(   2     1 - methylpentyl )-   4   - pentynoic acid    
           2   -(   2     1 - methylpent -   1     1 - enyl )-   4   - pentynoic acid    
           2   -(   2     1 - methylpent -   2     1 - enyl )-   4   - pentynoic acid    
           2   -(   2     1 - methylpent -   3     1 - enyl )-   4   - pentynoic acid    
           2   -(   2     1 - methylpent -   4     1 - enyl )-   4   - pentynoic acid    
           2   -(   3     1 - methylpentyl )-   4   - pentynoic acid    
           2   -(   3     1 - methylpent -   1     1 - enyl )-   4   - pentynoic acid    
           2   -(   3     1 - methylpent -   2     1 - enyl )-   4   - pentynoic acid    
           2   -(   3     1 - methylpent -   3     1 - enyl )-   4   - pentynoic acid    
           2   -(   3     1 - methylpent -   4     1 - enyl )-   4   - pentynoic acid    
           2   -(   4     1 - methylpentyl )-   4   - pentynoic acid    
           2   -(   4     1 - methylpent -   1     1 - enyl )-   4   - pentynoic acid    
           2   -(   4     1 - methylpent -   2     1 - enyl )-   4   - pentynoic acid    
           2   -(   4     1 - methylpent -   3     1 - enyl )-   4   - pentynoic acid    
           2   -(   4     1 - methylpent -   4     1 - enyl )-   4   - pentynoic acid    
           2   -(   1     1 -   1     1 - dimethylbutyl )-   4   - pentynoic acid    
           2   -(   1     1 -   1     1 - dimethylbut -   1     1 - enyl )-   4   - pentynoic acid    
           2   -(   1     1 -   1     1 - dimethylbut -   3     1 - enyl )-   4   - pentynoic acid    
           2   -(   1     1 -   2     1 - dimethylbutyl )-   4   - pentynoic acid    
           2   -(   1     1 -   2     1 - dimethylbut -   1     1 - enyl )-   4   - pentynoic acid    
           2   -(   1     1 -   2     1 - dimethylbut -   2     1 - enyl )-   4   - pentynoic acid    
           2   -(   1     1 -   2     1 - dimethylbut -   3     1 - enyl )-   4   - pentynoic acid    
           2   -(   1     1 -   3     1 - dimethylbutyl )-   4   - pentynoic acid    
           2   -(   1     1 -   3     1 - dimethylbut -   1     1 - enyl )-   4   - pentynoic acid    
           2   -(   1     1 -   3     1 - dimethylbut -   2     1 - enyl )-   4   - pentynoic acid    
           2   -(   1     1 -   3     1 - dimethylbut -   3     1 - enyl )-   4   - pentynoic acid    
           2   -(   2     1 -   2     1 - dimethylbutyl )-   4   - pentynoic acid    
           2   -(   2     1 -   2     1 - dimethylbut -   3     1 - enyl )-   4   - pentynoic acid    
           2   -(   2     1 -   3     1 - dimethylbutyl )-   4   - pentynoic acid    
           2   -(   2     1 -   3     1 - dimethylbut -   1     1 - enyl )-   4   - pentynoic acid    
           2   -(   2     1 -   3     1 - dimethylbut -   2     1 - enyl )-   4   - pentynoic acid    
           2   -(   2     1 -   3     1 - dimethylbut -   3     1 - enyl )-   4   - pentynoic acid    
           2   -(   3     1 -   3     1 - dimethylbutyl )-   4   - pentynoic acid    
           2   -(   3     1 -   3     1 - dimethylbut -   1     1 - enyl )-   4   - pentynoic acid    
           2   -(   1     1 -   1     1 -   2     1 - trimethylpropyl )-   4   - pentynoic acid    
           2   -(   1     1 -   1     1 -   2     1 - trimethylprop -   2   - enyl )-   4   - pentynoic acid    
           2   -(   1     1 -   2     1 -   2     1 - trimethylpropyl )-   4   - pentynoic acid    
           2   - n - heptyl -   4   - pentynoic acid    
           2   -(   1     1 - methylhexyl )-   4   - pentynoic acid    
           2   -(   2     1 - methylhexyl )-   4   - pentynoic acid    
           2   -(   3     1 - methylhexyl )-   4   - pentynoic acid    
           2   -(   4     1 - methylhexyl )-   4   - pentynoic acid    
           2   -(   5     1 - methylhexyl )-   4   - pentynoic acid    
           2   -(   1     1   , 1     1 - dimethylpentyl )-   4   - pentynoic acid    
           2   -(   1     1   , 2     1 - dimethylpentyl )-   4   - pentynoic acid    
           2   -(   1     1   , 3     1 - dimethylpentyl )-   4   - pentynoic acid    
           2   -(   1     1   , 4     1 - dimethylpentyl )-   4   - pentynoic acid    
           2   -(   2     1   , 2     1 - dimethylpentyl )-   4   - pentynoic acid    
           2   -(   2     1   , 3     1 - dimethylpentyl )-   4   - pentynoic acid    
           2   -(   2     1   , 4     1 - dimethylpentyl )-   4   - pentynoic acid    
           2   -(   3     1   , 3     1 - dimethylpentyl )-   4   - pentynoic acid    
           2   -(   3     1   , 4     1 - dimethylpentyl )-   4   - pentynoic acid    
           2   -(   4     1   , 4     1 - dimethylpentyl )-   4   - pentynoic acid    
           2   -(   1     1   , 1     1   , 2     1 - trimethylbutyl )-   4   - pentynoic acid    
           2   -(   1     1   , 1     1   , 3     1 - trimethylbutyl )-   4   - pentynoic acid    
           2   -(   1     1   , 2     1   , 3     1 - trimethylbutyl )-   4   - pentynoic acid    
           2   -(   2     1   , 2     1   , 3     1 - trimethylbutyl )-   4   - pentynoic acid    
           2   -(   2     1   , 3     1   , 3     1 - trimethylbutyl )-   4   - pentynoic acid.   
     
     
       20. A compound according to  claim 19  wherein the compounds are selected from the group consisting of  2 - n - pentyl -   4   - pentynoic acid and  2   - n - hexyl -   4   - pentynoic acid.   
     
     
       21.  2 - n - pentyl -   4   - pentynoic acid and enantiomers thereof and pharmaceutically acceptable salts thereof.   
     
     
       22. A S- enantiomer of the compounds of    claim 21    and pharmaceutically acceptable salts thereof.   
     
     
       23. A method of preparing a compound having the general formula ( I )                    
       
         wherein R 
         1  
         is —C≡CH, R 
         2  
         is a saturated, unbranched C 
         5  
         alkyl group; and M is a hydrogen or a metal atom, comprising:  
       
         combining a malonic acid diester with a first halide having the general formula  ( VII )  
       
         
             R   2 — X    ( VII )  
         
       
         wherein R   2    has the meaning given previously to form a  2   - pentyl malonic acid diester, and combining the  2   - pentyl malonic acid diester with a second halide having the general formula  ( VIII )  
       
         
             R   1   —CH   2   —X    ( VIII )  
         
       
         wherein R   1    has the meaning given previously; or combining the malonic acid diester with the second halide having the general formula  ( VIII )  to form a  2   - pentyl malonic acid diester; and combining the first halide having the general formula  ( VII )  to form a compound of formula  ( IX )                    
         wherein R   5    is an alkyl group; and hydrolyzing and decarboxylating the compound of formula  ( IX )  to form the compound of formula  ( I ) ; and optionally converting the compound of formula  ( I )  to a salt.