Boronic ester and acid compounds, synthesis and uses

Abstract

Disclosed herein is a method for reducing the rate of degradation of proteins in an animal, comprising contacting cells of the animal with certain boronic ester and acid compounds. Also disclosed herein are novel boronic ester and acid compounds, their synthesis and uses.

1 . A compound having the formula (1a)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof; wherein 
 P is R 7 —C(O)—, R 7 —NH—C(O), R 7 —O—C(O)—, or R 7 —SO 2 —, where R 7  is heteroaryl;  
 B 1 , at each occurrence, is CH;  
 X 1 , at each occurrence, is —(O)—NH—;  
 X 2  is —(O)—NH—;  
 R is hydrogen or alkyl, or R forms together with the adjacent R 1 , or when A is zero, forms together with the adjacent R 2 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy;  
 R 1 , at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or CH 2 —R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;  
 R 2  is one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;  
 R 3  is one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;  
 R 5 , in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —W—R 6 , where W is a chalcogen and R 6  is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;  
 Z 1  and Z 2  are independently one of alkyl, hydroxy, alkoxy, or aryloxy, or together Z 1  and Z 2  form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and  
 A is 0, 1, or 2.  
 
   
   
       2 . The compound of  claim 1 , wherein R 7  is selected from the group consisting of thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolylo, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, and phenoxazinyl.  
   
   
       3 . The compound of  claim 1 , wherein A is 0.  
   
   
       4 . The compound of  claim 1 , wherein R is hydrogen or C 1-8  alkyl.  
   
   
       5 . The compound of  claim 1 , wherein: 
 R 1 , at each occurrence, and R 2  and R 3  are each independently one of hydrogen, C 1-8  alkyl, C 3-10  cycloalkyl, C 6-10  aryl, a 5-, 6-, 9- or 10-membered heteroaryl group, or —CH 2 —R 5 ;    R 5 , in each instance, is one of C 6-10  aryl, C 6-10 ar(C 1-6 )alkyl, C 1-6 alk(C 6-10 )aryl, C 3-10 cycloalkyl, C 1-8  alkoxy, C 1-8  alkylthio or a 5-, 6-, 9-, or 10-membered heteroaryl group;    where the ring portion of any of said aryl, aralkyl, alkaryl or 6-, 6-, 9-, or 10-membered heteroaryl groups of R 1 , R 2 , R 3  and R 5  can be optionally substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C 3-8  cycloalkyl, C 1-6 alkyl(C 3-8 )cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyano, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C 1-6 )alkoxy, trifluoromethyl, halogen, C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl(C 1-6 )alkyl, C 6-10 aryl(C 1-6 )alkoxy, hydroxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 6-10 arylthio, C 6-10 arylsulfinyl, C 6-10 arylsulfonyl, C 6-10 aryl, C 1-6 alkyl-(C 6-10 )aryl, and halo(C 6-10 )aryl.    
   
   
       6 . The compound of  claim 1 , wherein: 
 A is zero;    R is hydrogen or C 1-8  alkyl; and    R 3  is C 1-6  alkyl.    
   
   
       7 . The compound of  claim 1 , wherein R 3  is C 1-12  alkyl.  
   
   
       8 . The compound of  claim 1 , wherein R 3  is C 1-6  alkyl.  
   
   
       9 . The compound of  claim 1 , wherein R 3  is C 4  alkyl.  
   
   
       10 . The compound of  claim 1 , wherein R 3  is isobutyl.  
   
   
       11 . The compound of  claim 1 , wherein R 2  is one of isobutyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-pyridylmethyl, 6-quinolinylmethyl, 3-indoylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(2′-pyridylmethoxy)-benzyl, 4-(benzyloxy)benzyl, benzylnaphthylmethyl or phenethyl.  
   
   
       12 . The compound of  claim 1 , wherein Z 1  and Z 2  are independently one of C 1-6  alkyl, hydroxy, C 1-6  alkoxy, or C 6-10  aryloxy.  
   
   
       13 . The compound of  claim 1 , wherein Z 1  and Z 2  are both hydroxy.  
   
   
       14 . The compound of  claim 1 , wherein Z 1  and Z 2  together form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfloropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.