Acetylenic alpha-amino acid-based sulfonamide hydroxamic acid tace inhibitors

Abstract

Compounds of the formula: are useful in treating disease conditions mediated by TNF-α, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage loss.

1 - 18 . (canceled)  
     
     
         19 . A process for preparing a compound of formula B having the formula:  
       
         
           
           
               
               
           
         
       
       B  
       wherein: 
 X is SO 2  or —P(O)—R 10 ;  
 Y is aryl or heteroaryl, with the proviso that X and Z may not be bonded to adjacent atoms of Y;  
 Z is O, NH, CH 2  or S;  
 R 1  is hydrogen, aryl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms;  
 R 2  is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl of 3-6 carbon atoms, C 4 -C 8  cycloheteroalkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms;  
 or R 1  and R 2 , together with the atom to which they are attached, may form a ring wherein R 1  and R 2  represent a divalent moiety of the formula:  
                     
 wherein  
 Q=a carbon-carbon single or double bond, O, S, SO, SO 2 , —N—R 11 , or 
 —CONR 14 ;  
 m=1-3;  
 r=1 or 2, with the proviso that when Q is a bond, r is equal to 2;  
 
 R 3  is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, C 4 -C 8  cycloheteroalkyl, aralkyl, or heteroaralkyl;  
 or R 1  and R 3 , together with the atoms to which they are attached, may form a 5 to 8 membered ring wherein R 1  and R 3  represent divalent moieties of the formulae:  
                     
 wherein Q and m are as defined above;  
 A is aryl or heteroaryl;  
 s is 0-3;  
 u is 1-4;  
 R 4  and R 5  are each, independently, hydrogen or alkyl of 1-6 carbon atoms, —CN, or —CCH;  
 R 6  is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or —C 5 -C 8 cycloheteroalkyl;  
 R 8  and R 9  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl, or —C 4 -C 8 -cycloheteroalkyl;  
 R 10  is alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl or heteroaryl;  
 R 11  is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, —S(O) n R 8 , —COOR 8 , —CONR 8 R 9 , —SO 2 NR 8 R 9  or —COR 8 ;  
 R 12  and R 13  are independently selected from H, —OR 8 , —NR 8 R 9 , alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, —COOR 8 ; —CONR 8 R 9 ; or R 12  and R 13  together form a —C 3 -C 6 -cycloalkyl of 3-6 carbon atoms or a —C 5 -C 8 -cycloheteroalkyl ring; or R 12  and R 13 , together with the carbon to which they are attached, form a carbonyl group;  
 with the proviso that R 10  and R 12  or R 11  and R 12  may form a cycloheteroalkyl ring when they are attached to adjacent atoms;  
 R 14  is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms;  
 and n is 0-2;  
 or a pharmaceutically acceptable salt thereof,  
 which comprises one of the following steps:  
 a) reacting a compound of formula V:  
                     
 wherein R 1  R 2 , R 3 , R 4 , R 6 , X, Y and Z are defined above, or a reactive derivative thereof, with  
 hydroxylamine to give a corresponding compound of formula B; or  
 b) deprotecting a compound of formula VI:  
                     
 wherein R 1  R 2 , R 3 , R 4 , R 5 , R 6 , X, Y and Z are defined above, and R 30  is a suitable protecting group to give a corresponding compound of formula B or  
 c) cleaving a resin supported hydroxamate derivative containing the group:  
                     
 to give a compound of formula B as defined above; or  
 d) resolving a mixture of optically active isomers of a compound of formula B to isolate one enantiomer or diastereomer substantially free of the other enantiomer or diastereomers; or  
 e) converting a compound of formula B into a pharmaceutically acceptable salt; or  
 f) converting a compound of formula B having a reactive substituent group or site to give a compound of formula B having a different substituent group or site.  
 
     
     
         20 . The process according to  claim 19 , further comprising the optional steps in which formula V is prepared by: 
 1a) reacting an amino acid derivative having the formula                          wherein R 1  and R 2  are as defined in  claim 19;  and R 40  is hydrogen or a suitable carboxylic acid protecting group, with a compound having the formula                          wherein R 4 , R 5 , R 6 , X and Z are as defined in  claim 19 , with the proviso that R 6  is not hydrogen; and J is fluorine, bromine or chlorine to form an amino derivative;    2a) alkylating the amino derivative with R 3 J, wherein R 3  is as defined in  claim 19  and J is defined above, and a base in a polar aprotic solvent to form a sulfonamnide derivative; and    3a) converting the sulfonamide to the compound of formula V; or    1b) reacting an N-substituted amino acid derivative having the formula                          wherein R 1 , R 2  and R 3  are as defined in  claim 19 , with the proviso that R 3  is not hydrogen; and    R 40 is hydrogen or a suitable carboxylic acid protecting group, with the above compound having the formula                          wherein R 4,  R 5 , R 6 , X, Z and J are as defined above to form a sulfonamide derivative; and    2b) converting the sulfonamide to the compound of formula V.    
     
     
         21 . The process according to  claim 20 , wherein R 30  is t-butyl, benzyl, trialkylsilyl and R 40 is hydrogen or methyl.  
     
     
         22 . The process according to  claim 20 , wherein the base is potassium carbonate or sodium hydride.  
     
     
         23 . The process according to  claim 20 , wherein the polar aprotic solvent is acetone, N,N-dimethylformamide (DMF) or tetrahydrofuran (THF).  
     
     
         24 . The process according to  claim 20 , wherein Y is a phenyl ring substituted at the 1- and 4-positions by X and Z, respectively, or a pharmaceutically acceptable salt thereof.  
     
     
         25 . The process according to  claim 24 , wherein X is SO 2 .  
     
     
         26 . The process according to  claim 25 , wherein Z is oxygen.  
     
     
         27 . The process according to  claim 26 , wherein R 4  and R 5  are hydrogen.  
     
     
         28 . The process according to  claim 27 , wherein R 6  is —CH 2 OH or methyl.  
     
     
         29 . The process according to  claim 28 , wherein R 1  and R 3 , together with the atoms to which they are attached, form a piperazine, piperidine, tetrahydroisoquinoline, morpholine, thiomorpholine or diazepine ring.  
     
     
         30 . The process according to  claim 29 , wherein R 1 , R 2  or R 3  is hydrogen.  
     
     
         31 . The process according to  claim 26 , further comprising the optional steps of: 
 1a) alkylating a compound of formula I, or a salt or solvate thereof:                          into a compound of formula II                          wherein R 4 , R 5  and R 6  are as defined in  claim 26 , with the proviso that R 6  is not hydrogen; or    1b) alkylating phenol, or a salt or solvate thereof, into a compound of formula IV:                          wherein R 4 , R 5  and R 6  are as defined in  claim 26 , with the proviso that R 6  is not hydrogen; and    2b) reacting the compound of formula IV, or the salt or solvate thereof, with chlorosulfonic acid to prepare the above compound of formula II.    
     
     
         32 . The process according to  claim 31 , further comprising the step of reacting the compound of formula II, or the salt or solvate thereof, with a halogenating agent to give a compound of formula III:  
       
         
           
           
               
               
           
         
       
       wherein R 4 , R 5  and R 6  are as defined in  claim 31 , with the proviso that R 6  is not hydrogen; and J is fluorine, bromine or chlorine.  
     
     
         33 . The process according to  claim 32 , wherein the halogenating agent is selected from the group consisting of thionyl chloride, chlorosulfonic acid, oxalyl chloride, phosphorus pentachloride, fluorosulfonic acid and thionyl bromide.  
     
     
         34 . The process according to  claim 33 , wherein the resultant sulfonyl chloride, fluoride or bromide, is optionally converted into a triazolide derivative, an imidazolide derivative or a benzothiazolide derivative by reacting the sulfonyl chloride, fluoride or bromide compound with 1,2,4-triazole, imidazole or benzotriazole to provide a compound of formula III in which J is 1,2,4-triazolyl, imidazol-yl or benzotriazolyl, respectively.