Cyclopropyl derivatives and methods of use

Abstract

The disclosure relates to cyclopropyl derivatives and methods of use. In some embodiments, the disclosure relates to methods of managing medical disorders with pharmaceutical compositions disclosed herein administered to subject in need thereof. In certain embodiments, the disclosure relates to methods of managing mental disorders, mood disorders, pain, and fibromyalgia and related conditions with pharmaceutical compositions disclosed herein.

1 . A compound comprising formula I: 
       
         
           
           
               
               
           
         
         or salts thereof wherein, 
         A ring is a carbocyclyl, aryl, or heterocyclyl; 
         n is 0, 1, 2, 3, 4, or 5; 
         X and Y are the same or different O, S, NR 4 ; 
         R 1  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 1  is optionally substituted with one or more, the same or different, R 5 ; 
         R 2  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 2  is optionally substituted with one or more, the same or different, R 5 ; 
         R 3  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3  is optionally substituted with one or more, the same or different, R 5 ; 
         R 4  is hydrogen, alkyl, hydroxy, amino, formyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4  is optionally substituted with one or more, the same or different, R 5 ; 
         R 5  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5  is optionally substituted with one or more, the same or different, R 6 ; and 
         R 6  is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl. 
       
     
     
         2 . A compound of formula I, wherein formula I is formula IA, IB, IC, or ID wherein:
 formula IA is   
       
         
           
           
               
               
           
         
         formula IB is 
       
       
         
           
           
               
               
           
         
         formula IC is 
       
       
         
           
           
               
               
           
         
       
       and
 formula ID is 
 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound of  claim 1 , wherein the A ring is aryl. 
     
     
         4 . A compound of  claim 1 , wherein X is oxygen. 
     
     
         5 . A compound of  claim 1 , wherein Y is NR 4 . 
     
     
         5 . A compound of  claim 1 , wherein R 3  is hydrogen or C 1-4 alkyl. 
     
     
         6 . A compound of  claim 1 , wherein R 2  is hydrogen or C 1-4 alkyl. 
     
     
         7 . A compound of  claim 1 , wherein R 1  is a hydrogen, halogen, or alkoxy. 
     
     
         8 . A compound of  claim 1  selected from:
 (1S,2S)-methyl 2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate, 
 (1S,2S)-2-((methylamino)methyl)-1-phenylcyclopropanecarboxylic acid, 
 (1S,2S)-methyl 1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate, 
 (1S,2S)-1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, 
 (1S,2S)-methyl 1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate, 
 (1S,2S)-1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, 
 (1S,2S)-methyl 1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate, 
 (1S,2S)-1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, 
 (1S,2S)-methyl 1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate, 
 (1S,2S)-1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, 
 (1S,2S)-methyl 1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate, 
 (1S,2S)-1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, 
 (1S,2S)-methyl 1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate, 
 (1S,2S)-1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, 
 (1S,2S)-methyl 1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate, 
 (1S,2S)-1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, 
 (1S,2S)-methyl 2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylate, 
 (1S,2S)-2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylic acid, 
 (1S,2S)-methyl 1-([1,1′-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylate, and 
 (1S,2S)-1-([1,1′-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, or salts thereof. 
 
     
     
         9 . A compound of  claim 1  selected from:
 (1S,2S)-methyl 2-((methylamino)methyl)-1-phenylcyclopropanecarboxylate, 
 (1S,2S)-2-((methylamino)methyl)-1-phenylcyclopropanecarboxylic acid, 
 (1R,2R)-methyl 1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate, 
 (1R,2R)-1-(3,4-dichlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, 
 (1R,2R)-methyl 1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate, 
 (1R,2R)-1-(3,4-dibromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, 
 (1R,2R)-methyl 1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate, 
 (1R,2R)-1-(3,4-dimethoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, 
 (1R,2R)-methyl 1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate, 
 (1R,2R)-1-(2-chlorophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, 
 (1R,2R)-methyl 1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylate, 
 (1R,2R)-1-(4-bromophenyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, 
 (1R,2R)-methyl 1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate, 
 (1R,2R)-1-(4-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, 
 (1R,2R)-methyl 1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylate, 
 (1R,2R)-1-(2-methoxyphenyl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, 
 (1R,2R)-methyl 2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylate, 
 (1R,2R)-2-((methylamino)methyl)-1-(naphthalen-2-yl)cyclopropanecarboxylic acid, 
 (1R,2R)-methyl 1-([1,1′-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylate, and 
 (1R,2R)-1-([1,1′-biphenyl]-4-yl)-2-((methylamino)methyl)cyclopropanecarboxylic acid, or salts thereof. 
 
     
     
         10 . A composition comprising a compound of  claim 1  in greater than 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 99.5% diastereomeric excess. 
     
     
         11 . An isolated composition of a compound of  claim 1  in substantially pure form. 
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 1  or pharmaceutically acceptable salt or prodrug thereof. 
     
     
         13 . A pharmaceutical composition of  claim 12  further comprising a second therapeutic agent. 
     
     
         14 . A method of treating or preventing a medical disorder comprising administering a pharmaceutical composition of  claim 12  to a subject diagnosed with, exhibiting symptoms of, or at risk of a medical disorder. 
     
     
         15 . The method of  claim 14 , wherein the medical disorder is mental disorder. 
     
     
         16 . A method of managing neuropathic pain comprising administering a pharmaceutical composition of  claim 12  to a subject in need thereof. 
     
     
         17 . A method of treating fibromyalgia comprising administering a pharmaceutical composition of  claim 12  to a subject in need thereof. 
     
     
         18 . A process of producing a compound of formula I comprising mixing a metal catalyst, a compound of formula II,
 formula II   
       
         
           
           
               
               
           
         
       
       and a compound of formula III,
 formula III 
 
       
         
           
           
               
               
           
         
         under conditions such that a compound of formula I is formed. 
       
     
     
         19 . The process of  claim 18 , wherein the metal catalyst is a chiral catalyst. 
     
     
         20 . The process of  claim 18 , wherein the metal catalyst is Rh 2 (S-biTISP) 2 , Rh 2 (S-DOSP) 4 , or Rh 2 (S-PTAD) 4 .