Novel N-Benzylamide Substituted Derivatives of 2-(Acylamido)acetic Acid and 2-(Acylamido)propionic Acids: Potent Neurological Agents

Abstract

A first aspect of the invention is a compound (sometimes also referred to herein as an “active agent” or “active compound”) of Formula Ia, or more particularly Formula Ib: or a pharmaceutically acceptable salt or prodrug thereof. Compositions thereof and methods of using the same (e.g. for the treatment of a neurological disease) are also described.

1 . A compound of Formula Ia: 
       
         
           
           
               
               
           
         
       
       wherein:
 R is R 2  or CH 2 X′R 5 , where X′ is O, S, or N—R 6a  and R 6a  is hydrogen, alkyl, or cycloalkyl; 
 R 1  is alkyl or cycloalkyl, each of which can be unsubstituted or substituted with from one to four independently selected electron-donating or electron-withdrawing groups; 
 R 2  is alkyl, cycloalkyl, aryl, five- or six-membered cyclic heterocyclic or heteroaromatic groups, or —X—Y—Z, where X and Y=O, S, N—R 6 , and Z=R 6 , and where R 6  is hydrogen, alkyl, or cycloalkyl, each of which is unsubstituted or substituted with from one to four electron withdrawing or electron donating groups; 
 R 5  is alkyl, alkenyl, alkynyl, or arylalkyl, each of which is unsubstituted or substituted with from one to four electron donating or electron withdrawing groups; 
 R 3a  R 3b , and R 4  are each independently hydrogen, an electron donating or electron-withdrawing group, or alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclo, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl, arylalkyloxy, arylalkylamino, arylalkylthio, heteroarylalkyloxy, heteroarylalkylamino, heteroarylalkylthio, heterocycloalkyloxy, heterocycloalkylamino, heterocycloalkylthio, arylaminooxy, heteroarylaminooxy, heterocycloaminooxy, aryloxyamino, heteroaryloxyamino, heterocyclooxyamino, arylalkyl, heteroarylalkyl, heterocycloalkyl, arylalkenyl, heteroarylalkenyl, heterocycloalkenyl, arylalkynyl, heteroarylalkynyl, heterocycloalkynyl, arylhydrazino, heteroarylhydrazino, heterocyclohydrazino, arylazo, heteroarylazo, heterocycloazo, arylalkylaminoalkyl, heteroarylalkylaminoalkyl, heterocycloalkylaminoalkyl, arylalkyloxyalkyl, heteroarylalkyloxyalkyl, heterocycloalkyloxyalkyl, each of which can be unsubstituted or substituted with from one to four independently selected electron-donating or electron-withdrawing groups; 
 wherein at least one of R 3a  and R 4  is not H; 
 and wherein at least one, or both, of R 3a  and R 4  is a primary substituent selected from the group consisting of electron donating groups, electron-withdrawing groups, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclo, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl, arylalkyloxy, arylalkylamino, arylalkylthio, heteroarylalkyloxy, heteroaryalkylamino, heteroarylalkylthio, heterocycloalkyloxy, heterocycloalkylamino, heterocycloalkylthio, arylaminooxy, heteroarylaminooxy, heterocycloaminooxy, aryloxyamino, heteroaryloxyamino, heterocyclooxyamino, arylalkyl, heteroarylalkyl, heterocycloalkyl, arylalkenyl, heteroarylalkenyl, heterocycloalkenyl, arylalkynyl, heteroarylalkynyl, heterocycloalkynyl, arylhydrazino, heteroarylhydrazino, heterocyclohydrazino, arylazo, heteroarylazo, heterocycloazo, arylalkylaminoalkyl, heteroarylalkylaminoalkyl, heterocycloalkylaminoalkyl, arylalkyloxyalkyl, heteroarylalkyloxyalkyl, heterocycloalkyloxyalkyl; 
 and which primary substituent is in turn optionally but preferably substituted with from one to four secondary substituents independently selected from the group consisting of electron-donating groups and electron-withdrawing groups; 
 or a pharmaceutically acceptable salt or prodrug thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein R is R 2 . 
     
     
         3 . The compound of  claim 1 , wherein R is CH 2 X′R 5 . 
     
     
         4 . The compound of  claim 1 , wherein R 3b  is H. 
     
     
         5 . The compound of  claim 1 , wherein R 1  is CH 3 . 
     
     
         6 . The compound of  claim 1  where R 2  is 2-furan, 2-thiazole, 2-oxazole, 2-pyridine, 2-pyrimidine, 2-pyridazine, N(H)OCH 3 , and N(CH 3 )OCH 3 , or N(H)N(H)CO 2 CH 3 . 
     
     
         7 . The compound of  claim 1  wherein X is O, and where R 5  is CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CHCH 2 , CH 2 CCH. 
     
     
         8 . The compound of  claim 1  where either or both of R 3a  and R 4  are OCH 2 C 6 H 4 (m-F), OCF 3 , N 3 , CCCH 2 OCH 3 , CH 2 OCH 3 , (CH 2 ) 3 OCH 3 , C(N 2 )CF 3 , C(O)C 6 H 5  or CF 3 . 
     
     
         9 . The compound of  claim 1 , wherein said compound is a compound of Formula Ib: 
       
         
           
           
               
               
           
         
       
       wherein:
 R is: 
 
       
         
           
           
               
               
           
         
          N(R′)OR′, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 OCH(CH 3 ) 2 , CH 2 OCD 3 , CH 2 OCD 2 CD 3 , CH 2 OCD 2 CH 3 , CH 2 OCD(CH 3 ) 2 , CH 2 OCD(CD 3 ) 2 , CH 2 OCF 2 H, CH 3 , CD 3 , CF 3 , CH 2 F, CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , C(CH 3 ) 3 ; 
         each R′ is independently selected H or lower alkyl, unsubstituted or substituted with 1-3 electron-withdrawing or electron-donating groups; 
         X′ is a covalent bond or a linker that consist of one, two, or three connected atoms and which the atoms may or may not be substituted (such as a C1 to C3 carbon chain, optionally containing one or two heteroatoms independently selected from N, O, and S, which chain may be substituted or unsubstituted with one or more electron-withdrawing or electron-donating groups); 
         Y′ is an aromatic or heteroaromatic moiety, unsubstituted or substituted with 1-3 electron-withdrawing or electron-donating groups; and 
         Z′ is H, F, Cl, Br, I, CF 3 , CN, OCF 3 , or N 3 ; 
       
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         10 . The compound of  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         11 . The compound of  claim 1  in substantially pure form. 
     
     
         12 . The compound of  claim 1  in the D-amino acid configuration, the L-amino acid configuration, or as a racemic mixture thereof. 
     
     
         13 . The compound of  claim 1  in the D-amino acid configuration. 
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 11  in a pharmaceutically acceptable carrier. 
     
     
         15 . The composition of  claim 14 , further comprising at least one additional neurological active agent. 
     
     
         16 . The composition of  claim 14  in oral administration form. 
     
     
         17 . A method of treating a neurological disorder in a mammalian subject in need thereof, comprising administering said subject a compound of  claim 1  in a treatment effective amount. 
     
     
         18 . The method of  claim 17 , wherein said neurological disorder is acute or chronic pain, migraine, neuropathic pain, fibromyalgia, bipolar disorders, convulsions, a seizure disorder, mania, epilepsy, epileptogenesis, dyskinesia, tremors, anxiety, depression, or ischemia. 
     
     
         19 . The method of  claim 17 , wherein said neurological disorder is epilepsy. 
     
     
         20 . The method of  claim 17 , wherein said neurological disorder is neuropathic pain. 
     
     
         21 . The method of  claim 17 , wherein said subject is a human subject. 
     
     
         22 . The method of  claim 17 , further comprising concurrently administering said subject at least one additional neurological active agent in a treatment effective amount. 
     
     
         23 . (canceled)