Pendant amines and derivatives as inhibitors of leukotriene a4 hydrolase

Abstract

where R1a, R1b, R1c, R1d, R1c, R3, R4a, R4c, R4d, R6, R7, and R8 are described herein as , single stereoisomers or as mixtures of stereoisomers, or pharmaceutically acceptable salts, solvates, clathrates, polymorphs, ammonium ions, N-oxides or prodrugs thereof; which are leukotriene A4 hydrolase inhibitors and therefore useful in treating inflammatory disorders. Pharmaceutical compositions including the compounds described herein and methods of preparing the compounds described herein are also provided.

What is claimed is: 
     
         1 . A compound having the following formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1a , R 1b , R 1c , R 1d  and R 1e  are independently hydrogen, halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 13 —OR 10 , —R 13 —C(═O)OR 10 , or —R 13 —C(═O)R 10 ; 
 R 3  is a direct bond, —O—, —R 12 —O—, —O—R 12 —, —O—R 12 —O—, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain, —R 13 — 0  C(═O)R 13 , —R 13 —O—R 13 —C(═O)R 13 , —R 13 C(═O)R 13 —O—R 13 , —R 13 —O—R 13 C(OH) —R 13 , —R 13 C(OH)—R 13 —O—R 13 , or —R 13 —N(R 10 )—R 13 —; 
 R 4a  is a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; 
 R 4b  is a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; 
 R 4c  is a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; 
 R 4d  is a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, an optionally substituted straight or branched alkynylene chain, or —R 13 —N(R 10 )—R 13 —; 
 R 6  is hydrogen, halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; 
 R 7  is hydrogen, halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; 
 R 8  is halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; —R 13 —N(R 10 )(R 14 ), —R 13 —NH—O(R 14 ), or —R 13 —OR 10 ; 
 or R 8  is R 13 —NH 2  when R 3  is —O—, —R 13 —N(R 10 )—R 13 —, or an optionally substituted straight or branched alkylene chain; 
 or R 8  is R 13 —NH—OH when R 4c  is a direct bond, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; 
 each R 10  is independently hydrogen, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; 
 each R 12  is independently an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; 
 each R 13  is independently a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain; and 
 each R 14  is independently hydrogen, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; 
 as a single stereoisomer or as a mixture of stereoisomers; 
 or a pharmaceutically acceptable salt, ammonium ion, or N-oxide thereof. 
 
     
     
         2 . A compound according to  claim 1  wherein R 8  is —R 13 —N(R 10 )(R 14 ). 
     
     
         3 . A compound according to  claim 2  wherein R 13  is a direct bond or optionally substituted straight or branched alkylene, R 13  is hydrogen or optionally substituted straight or branched alkylene, and R 14  is optionally substituted alkyl, haloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, or optionally substituted heteroarylalkyl. 
     
     
         4 . A compound according to  claim 1  wherein R 8  is —R 13 —OR 10 . 
     
     
         5 . A compound according to  claim 4  wherein R 13  is a direct bond and R 10  is optionally substituted alkyl. 
     
     
         6 . A compound according to  claim 1  wherein R 8  is R 13 —NH 2  when R 3  is —O—, —R 13 —N(R 10 )—R 13 —, or an optionally substituted straight or branched alkylene chain. 
     
     
         7 . A compound according to  claim 1  wherein R 8  is R 13 —NH—OH when R 4c  is a direct bond, an optionally substituted straight or branched alkenylene chain, or an optionally substituted straight or branched alkynylene chain. 
     
     
         8 . A compound according to  claim 1  wherein R 4d  is —R 13 —N(R 10 )—R 13 —. 
     
     
         9 . A compound according to  claim 1  wherein R 4 a, R 4b , and R 4c  are independently a direct bond or an optionally substituted straight or branched alkenylene chain. 
     
     
         10 . A compound according to  claim 1  wherein R 3  is —O—, —R 12 —O—, —O— R 12 —, an optionally substituted straight or branched alkylene chain, R 13 —C(═O)R 13 , —R 13 —O—R 13 —(═O)R 13 , —R 13 —C(═O)R 13 —O—R 13 , —R 13 —O—R 13 —C(OH)—R 13 , —R 13 —C(OH)—R 13 —O—R 13  or —R 13 —N(R 10 )—R 13 —. 
     
     
         11 . A compound according to  claim 10  wherein R 3  is —O—. 
     
     
         12 . A compound according to  claim 10  wherein R 3  is —R 13 —C(═O)R 13 . 
     
     
         13 . A compound according to  claim 10  wherein R 3  is —R 13 —N(R 10 )—R 13 . 
     
     
         14 . A compound according to  claim 10  wherein R 3  is —R 13 —C(OH)—R 13 —O—R 13 . 
     
     
         15 . A compound according to  claim 10  wherein R 3  is —R 13 —C(═O)R 13 —O—R 13 . 
     
     
         16 . A compound according to  claim 10  wherein R 3  is an optionally substituted alkylene chain. 
     
     
         17 . A compound according to  claim 1  comprising a formula of any of the compounds in the Table below: 
       
         
           
                 
                 
               
                     
                 
                   Compound Formula 
                   Compound Name 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   2-amino-N 5 -(4-(benzyloxy)phenyl)- N 1 -methylpentanediamide 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   4-amino-N 1 -(4- phenoxyphenyl)pentanediamide 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   2-amino-N 1 -(2-chloroethyl)-N 5 -(4- phenoxyphenyl)pentanediamide 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   methyl N 5 -(4-(4-(1H-pyrrol-1- yl)phenoxy)phenyl)glutaminate 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (2S)-2-amino-N-(4- benzylphenyl)pentanediamide 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   methyl (2S)-2-amino-4-({4-[4-(1H- pyrrol-1-yl)phenoxy]phenyl} carbamoyl)butanoate 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   methyl 3-{[(2R)-2-amino-4-[(4- phenoxyphenyl)carbamoyl]butyl}car- bamoyl}propanoate 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (2R)-2-amino-N-{4-[4-(1H-pyrrol-1- yl)phenoxy]phenyl}-N′-[2-(pyrrolidin- 1-yl)ethyl]pentanediamide 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (2S)-2-amino-N-[2-(pyridin-2- yl)ethyl]-N′-{4-[4-(1H-pyrrol-1- yl)phenoxy]phenyl}pentanediamide 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (2R)-2-amino-N-[2-(1H-imidazol-5- yl)ethyl]-N′-{4-[4-(1H-pyrrol-1- yl)phenoxy]phenyl}pentanediamide 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (2S)-2-amino-N-(2-chloroethyl)-N′- (4-phenoxyphenyl)pentanediamide 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   ethyl 3-[(2R)-2-amino-4-[(4- phenoxyphenyl)carbamoyl]butana- mido]propanoate 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (2R)-2-amino-N-(4- phenoxyphenyl)pentanediamide 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (2S)-2-amino-N-[4- (benzyloxy)phenyl]-N′- hydroxypentanediamide 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (2S)-2-amino-N-benzyl-N′-[4- (benzyloxy)phenyl]pentanediamide 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (2S)-2-amino-N-[4- (benzyloxy)phenyl]-N′,N′- dimethylpentanediamide 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   (2S)-2-amio-N-[4- (benzyloxy)phenyl]-N′- methylpentanediamide 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   methyl (2S)-2-amino-4-{[4-(2- hydroxy-2- phenylethoxy)phen- yl]carbamoyl}butanoate 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   methyl (2S)-2-amino-4-{[4- (phenylamino)phen- yl]carbamoyl}butanoate