Aliphatic amino carboxylic and amino phosphonic acids, amino nitriles and amino tetrazoles as cellular rescue agents

Abstract

Novel compounds of the formula I are described: wherein: R 1 =(CH 2 ) m CH 3 where m is 0 or an integer in the range from 1 to 16, or an alkenyl, alkynyl, alkoxy, alkylthio, or alkyl sulfinyl group having from 2 to 17 carbon atoms, R 2 =H, CH 3 or CH 2 CH 3 R 3 =H or CH 3 R 4 =H or CH 3 R 5 =lower alkyl having from 1 to 5 carbon atoms n is an integer in the range from 1 to 3, and X is carboxyl (COOH) or carbalkoxy (COOR 5 ), cyano (C≡N), phosphonic acid (PO 3 H 2 ), phosphonate ester (PO 3 [R 5 ] 2 ) or 5-tetrazole, and pharmaceutically acceptable salts thereof. Preferably, the compounds are optically pure enantiomers of the R- or S-configuration in which R 3 =R 4 =R 5 =H, R 2 =CH 3 and R 1 is a saturated aliphatic chain of one to five carbon atoms. The compounds are useful as cellular rescue agents.

1 . A compound of the Formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is (CH 2 ) m CH 3  where m is 0 or an integer in the range from 1 to 16, or an alkenyl, alkynyl, alkoxy, alkylthio, or alkyl sulfinyl group having from 2 to 17 carbon atoms, wherein R 1  may be optionally substituted with one or more substituents selected from hydroxy, aldehyde, oxo, lower acyloxy, halogen, thio, sulfoxide and sulfone,  
 R 2  ((=)) is H, CH 3  or CH 2 CH 3 ,  
 R 3  ((=)) is H or CH 3 ,  
 R 4  ((=)) is H or CH 3 ,  
 n is an integer in the range from 1 to 3,  
 X is carbalkoxy (COOR 5 ), cyano (C≡N), phosphonic acid (PO 3 H 2 ), phosphonate ester (PO 3 [R 5 ] 2 ) or 5-tetrazole,  
 R 5  is lower alkyl having from 1 to 5 carbon atoms, and  
 R 1 , R 2  and R 3  are each different so that the carbon atom to which they are attached is chiral and the compound of Formula I is a substantially pure enantiomer in the R or S configuration or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound of the Formula I according to  claim 1  wherein: 
 R 1  ((=)) is (CH 2 ) m CH 3  where m is 0 or an integer in the range from 1 to 16,    R 2  ((=)) is CH 3 ,    R 3  ((=)) is H,    R 4  ((=)) is H or CH 3 ,    n is an integer in the range from 1 to 3,    X is carbalkoxy (COOR 5 ), cyano (C≡N), phosphonic acid (PO 3 H 2 ), phosphonate ester (PO 3 [R 5 ] 2 ) or 5-tetrazole, and    R 5  is lower alkyl having from 1 to 5 carbon atoms,    or a pharmaceutically acceptable salt thereof.    
     
     
         3 . A compound of the Formula I according to  claim 1  wherein: 
 R 1  ((=)) is (CH 2 ) m CH 3  where m is 0 or an integer in the range from 1 to 16,    R 2  ((=)) is CH 3 ,    R 3  ((=)) is H,    R 4  ((=)) is H or CH 3 ,    n is an integer in the range from 1 to 3,    X is carbalkoxy (COOR 5 ), cyano (C≡N), phosphonic acid (PO 3 H 2 ), phosphonate ester (PO 3 [R 5 ] 2 ) or 5-tetrazole, and R 5  is lower alkyl having from 1 to 5 carbon atoms,    as a substantially pure enantiomer in the R-configuration, or a pharmaceutically acceptable salt thereof.    
     
     
         4 . A compound of the formula I according to  claim 1  wherein: 
 R 1  ((=)) is (CH 2 ) m CH 3  where m is 0 or an integer in the range from 1 to 16,    R 2  ((=)) is CH 3 ,    R 3  ((=)) is H,    R 4  ((=)) is H or CH 3 ,    n is an integer in the range from 1 to 3,    X is carbalkoxy (COOR 5 ), cyano (C≡N), phosphonic acid (PO 3 H 2 ), phosphonate ester (PO 3 [R 5 ] 2 ) or 5-tetrazole, and    R 5  is lower alkyl having from 1 to 5 carbon atoms,    as a substantially pure enantiomer in the S-configuration, or a pharmaceutically acceptable salt thereof.    
     
     
         5 . A compound according to  claim 3 , wherein said compound of formula I is selected from the group consisting of: 
 Methyl (R)-3-(2-heptylamino)propionate;    Methyl (R)-3-[N-(2-heptyl)-N-methylamino]propionate;    (R)-2-(2-Pentylamino)acetonitrile;    (R)-2-[N-(2-Pentyl)-N-methylamino]acetonitrile;    (R)-3-(2-Heptylamino)propionitrile;    (R)-3-[N-(2-Heptyl)-N-methylamino]propionitrile;    (R)-2-(2-Pentylamino)ethanephosphonic acid;    (R)-2-[N-(2-Pentyl)-N-methylamino]ethanephosphonic acid; and    (R)-2-(2-Heptylamino)ethane-5-tetrazole.    
     
     
         6 . A compound according to  claim 4 , wherein said compound of formula I is selected from the group consisting of: 
 Methyl (S)-2-(2-heptylamino)acetate;    Methyl (S)-2-[N-(2-heptyl)-N-methylamino]acetate;    (S)-2-(2-Heptylamino)acetonitrile;    (S)-2-[N-(2-Heptyl)-N-methylamino]acetonitrile;    (S)-2-(2-Heptylamino)ethanephosphonic acid; and    (S)-2-[N-(2-Heptyl)-N-methylamino]ethanephosphonic acid.    
     
     
         7 . A compound is selected from the group consisting of: 
 Methyl 2-[N-(2-propyl)-N-methylamino]acetate;    Methyl 2-[N-(1-hexyl)-N-methylamino]acetate;    Methyl 3-[N-(1-hexyl)-N-methylamino]propionate;    2-(1-Hexylamino)acetonitrile;    2-[N-(1-Hexyl)-N-methylamino]acetonitrile;    3-(3-Pentylamino)propionitrile;    3-[N-(3-Pentyl)-N-methylamino]propionitrile;    2-(2-Propylamino)ethanephosphonic acid; and    2-[N-(2-Propyl)-N-methylamino]ethanephosphonic acid.    
     
     
         8 . A compound according to  claim 1  in the form of a hydrochloride salt.  
     
     
         9 . A compound according to  claim 1  wherein m is an integer from 1 to 12.  
     
     
         10 . A compound according to  claim 1  wherein m is an integer from 1 to 9.  
     
     
         11 . A composition for comprising a compound having the formula I as claimed in  claim 1  in admixture with a suitable diluent or carrier.  
     
     
         12 . A composition according to  claim 11 , wherein in the compound of Formula I: 
 R 1  is (CH 2 ) m CH 3  where m is 0 or an integer in the range from 1 to 16,    R 2  ((=)) is CH 3 ,    R 3  ((=)) is H,    R 4  ((=)) is H or CH 3 ,    n is an integer in the range from 1 to 3,    X is carbalkoxy (COOR 5 ), cyano (C≡N), phosphonic acid (PO 3 H 2 ), phosphonate ester (PO 3 [R 5 ] 2 ) or 5-tetrazole, and    R 5 =lower alkyl having from 1 to 5 carbon atoms.    
     
     
         13 . A composition according to  claim 11 , wherein said compound of formula I is selected from the group consisting of: 
 Methyl (R)-3-(2-heptylamino)propionate;    Methyl (R)-3-[N-(2-heptyl)-N-methylamino]propionate;    (R)-2-(2-Pentylamino)acetonitrile;    (R)-2-[N-(2-Pentyl)-N-methylamino]acetonitrile;    (R)-3-(2-Heptylamino)propionitrile;    (R)-3-[N-(2-Heptyl)-N-methylamino]propionitrile;    (R)-2-(2-Pentylamino)ethanephosphonic acid;    (R)-2-[N-(2-Pentyl)-N-methylamino]ethanephosphonic acid; and    (R)-2-(2-Heptylamino)ethane-5-tetrazole.    
     
     
         14 . A composition according to  claim 11 , wherein said compound of formula I is selected from the group consisting of: 
 Methyl (S)-2-(2-heptylamino)acetate;    Methyl (S)-2-[N-(2-heptyl)-N-methylamino]acetate;    (S)-2-(2-Heptylamino)acetonitrile;    (S)-2-[N-(2-Heptyl)-N-methylamino]acetonitrile;    (S)-2-(2-Heptylamino)ethanephosphonic acid; and    (S)-2-[N-(2-Heptyl)-N-methylamino]ethanephosphonic acid.    
     
     
         15 . A composition comprising a compound selected from the group consisting of: 
 Methyl 2-[N-(2-propyl)-N-methylamino]acetate;    Methyl 2-[N-(1-hexyl)-N-methylamino]acetate;    Methyl 3-[N-(1-hexyl)-N-methylamino]propionate;    2-(1-Hexylamino)acetonitrile;    2-[N-(1-Hexyl)-N-methylamino]acetonitrile;    3-(3-Pentylamino)propionitrile;    3-[N-(3-Pentyl)-N-methylamino]propionitrile;    2-(2-Propylamino)ethanephosphonic acid; and    2-[N-(2-Propyl)-N-methylamino]ethanephosphonic acid    in admixture with a suitable diluent or carrier.    
     
     
         16 . A composition according to  claim 11 , wherein the compound of Formula I is in the form of a hydrochloride salt.  
     
     
         17 . A method for the treatment a disease in which cell death occurs by apoptosis comprising administering an effective amount of a compound of formula I to an animal in need thereof, wherein the compound of formula I is:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is (CH 2 ) m CH 3  where m is 0 or an integer in the range from 1 to 16, or an alkenyl, alkynyl, alkoxy, alkylthio, or alkyl sulfinyl group having from 2 to 17 carbon atoms, wherein R 1  may be optionally substituted with one or more substituents selected from hydroxy, aldehyde, oxo, lower acyloxy, halogen, thio, sulfoxide and sulfone,  
 R 2  ((=)) is H, CH 3  or CH 2 CH 3 ,  
 R 3  ((=)) is H or CH 3 ,  
 R 4  ((=)) is H or CH 3 ,  
 n is an integer in the range from 1 to 3,  
 X is carbalkoxy (COOR 5 ), cyano (C≡N), phosphonic acid (PO 3 H 2 ), phosphonate ester (PO 3 [R 5 ] 2 ) or 5-tetrazole, and  
 R 5  is lower alkyl having from 1 to 5 carbon atoms,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         18 . A method according to  claim 17 , wherein 
 R 1  is (CH 2 ) m CH 3  where m is 0 or an integer in the range from 1 to 16,    R 2  ((=)) is CH 3 ,    R 3  ((=)) is H,    R 4  ((=)) is H or CH 3 ,    n is an integer in the range from 1 to 3,    X is carbalkoxy (COOR 5 ), cyano (C≡N), phosphonic acid (PO 3 H 2 ), phosphonate ester (PO 3 [R 5 ] 2 ) or 5-tetrazole,    and R 5  is lower alkyl having 1 to 5 carbon atoms,    or a pharmaceutically acceptable salt thereof.    
     
     
         19 . A method according to  claim 17  wherein the compound of the Formula I is a substantially pure enantiomer in the R configuration.  
     
     
         20 . A method according to  claim 17  wherein the compound of the Formula I is a substantially pure enantiomer in the S configuration.  
     
     
         21 . A method according to  claim 17  wherein said compound of Formula I is selected from the group consisting of: 
 2-(2-Propylamino)acetonitrile;    (R)-2-(2-Pentylamino)acetonitrile;    2-(1-Hexylamino)acetonitrile;    (S)-2-(2-Heptylamino)acetonitrile;    (R)-3-(2-Heptylamino)propionitrile;    2-[N-(2-Propyl)-N-methylamino]acetonitrile;    (R)-2-[N-(2-Pentyl)-N-methylamino]acetonitrile;    2-[N-(1-Hexyl)-N-methylamino]acetonitrile;    (S)-2-[N-(2-Heptyl)-N-methylamino]acetonitrile;    (R)-3-[N-(2-Heptyl)-N-methylamino]propionitrile;    2-(2-Propylamino)ethanephosphonic acid;    (R)-2-(2-Pentylamino)ethanephosphonic acid;    (S)-2-(2-Heptylamino)ethanephosphonic acid;    2-[N-(2-Propyl)-N-methylamino]ethanephosphonic acid;    (S)-2-[N-(2-Heptyl)-N-methylamino]ethanephosphonic acid; and    (R)-2-(2-Heptylamino)ethane-5-tetrazole.    
     
     
         22 . A method according to of  claim 17  wherein the disease is selected from the group consisting of stroke, head trauma, Bell's palsy, spinal cord injury, Alzheimer's disease, Parkinson's disease, Pick's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, cardiac myopathies, nephropathy, retinopathy, diabetic complications, glaucoma and idiopathic neuropathies.  
     
     
         23 . A method according to of  claim 17  for the treatment of a human.  
     
     
         24 . (canceled)