Inhibitors of interleukin-1beta converting enzyme

Abstract

The present invention relates to novel classes of compounds which are inhibitors of interleukin-1β converting enzyme. The ICE inhibitors of this invention are characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting ICE activity and consequently, may be advantageously used as agents against IL-1-, apoptosis-, IGIF-, and IFN-γ-mediated diseases, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, degenerative diseases, and necrotic diseases. This invention also relates to methods for inhibiting ICE activity, for treating interleukin-1-, apoptosis-, IGIF- and IFN-γ-mediated diseases and decreasing IGIF and IFN-γ production using the compounds and compositions of this invention. This invention also relates to methods for preparing N-acylamino compounds.

1 - 3 . (canceled)  
     
     
         4 . A compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is selected from the group consisting of the following formulae:  
                     
 ring C is chosen from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl;  
 R 2  is:  
                     
 m is 1 or 2;  
 R 5  is selected from the group consisting of: 
 —C(O)—R 10 ,  
 —C(O)O—R 9 ,  
                     
 —S(O) 2 —R 9 ,  
 —C(O)—CH 2 —O—R 9 ,  
 —C(O)C(O)—R 10 ,  
 —R 9 ,  
 —H, and  
 —C(O)C(O)—OR 10 ;  
 
 X 5  is  
                     
 Y 2  is H 2  or O;  
 X 7  is —N(R 8 )— or —O—;  
 R 6  is selected from the group consisting of —H and —CH 3 ;  
 R 8  is selected from the group consisting of: 
 —C(O)—R 10 ,  
 —C(O)O—R 9 ,  
 —C(O)—N(H)—R 10 ,  
 —S (°) 2 —R 9 ,  
 —S(O) 2 —NH—R 10 ,  
 —C(O)—CH 2 —OR 10 ,  
 —C(O)C(O)—R 10 ;  
 —C(O)—CH 2 N(R 10 )(R 10 ) ,  
 —C(O)—CH 2 C(O)—O—R 9 ,  
 —C(O)—CH 2 C(O)—R 9 ,  
 —H, and  
 —C(O)—C(O)—OR 10 ;  
 
 each R 9  is independently selected from the group consisting of —Ar 3  and a —C 1-6  straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6  alkyl group is optionally unsaturated;  
 each R 10  is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6  cycloalkyl group, and a —C 1-6  straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6  alkyl group is optionally unsaturated;  
 R 13  is selected from the group consisting of H, Ar 3 , and a C 1-6  straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH, —OR 9 , or —CO 2 H;  
 each R 51  is independently selected from the group consisting of R 9 , —C(O)—R 9 , —C(O)—N(H)—R 9 , or each R 51  taken together forms a saturated 4-8 member carbocyclic ring or heterocyclic ring containing —O—, —S—, or —NH—;  
 each R 21  is independently selected from the group consisting of —H or a —C 1-6  straight or branched alkyl group;  
 each Ar 3  is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, and —NH—, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by -Q 1 ;  
 each Q 1  is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3  alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 , —NHR 9 , —R 9 , —C(O)—R 10 , and  
                     
 provided that when —Ar 3  is substituted with a Q 1  group which comprises one or more additional —Ar 3  groups, said additional —Ar 3  groups are not substituted with another —Ar 3 .  
 
     
     
         5 . The compound according to  claim 4 , wherein R 5  is selected from the group consisting of: 
 —C(O)—R 10 ,    —C(O)O—R 9 , and    —C(O)—NH—R 10 .    
     
     
         6 . The compound according to  claim 4 , wherein R 5  is selected from the group consisting of: 
 —S(O) 2 —R 9 ,    —S(O) 2 —NH—R 10 ,    —C(O)—C(O)—R 10 ,    —R 9 , and    —C(O)—C(O)—OR 10 .    
     
     
         7 . The compound according to  claim 5 , wherein: 
 m is 1;    R 13  is H or a C 1-4  straight or branched alkyl group optionally substituted with —Ar 3 , —OH, —OR 9 , —CO 2 H, wherein the R 9  is a C 1-4  branched or straight chain alkyl group; wherein Ar 3  is morpholinyl or phenyl, wherein the phenyl is optionally substituted with Q 1 ;    R 21  is —H or —CH 3 ;    R 51  is a C 1-6  straight or branched alkyl group optionally substituted with —Ar 3 , wherein Ar 3  is phenyl, optionally substituted by -Q 1 ;    each Ar 3  cyclic group is independently selected from the set consisting of phenyl, naphthyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, thiazolyl, isoxazolyl, benzotriazolyl, benzimidazolyl, thienothienyl, imidazolyl, thiadiazolyl, benzo[b]thiophenyl, pyridyl, benzofuranyl, and indolyl, and said cyclic group optionally being singly or multiply substituted by -Q 1 ;    each Q 1  is independently selected from the group consisting of —NH 2 , —Cl, —F, —Br, —OH, —R 9 , —NH—R 5  wherein R 5  is —C(O)—R 10  or —S(O) 2 —R 9 , —OR 5  wherein R 5  is —C(O)—R 10 , —OR 9 , —NHR 9 , and                          wherein each R 9  and R 10  are independently a —C 1-6  straight or branched alkyl group optionally substituted with —Ar 3  wherein Ar 3  is phenyl;    provided that when —Ar 3  is substituted with a Q 1  group which comprises one or more additional —Ar 3  groups, said additional —Ar 3  groups are not substituted with another —Ar 3 .    
     
     
         8 . A compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 m is 1 or 2;  
 R 1  is selected from the group consisting of the following formulae:  
                     
 wherein X 5  is N;  
                     
 ring C is chosen from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl;  
 R 3  is selected from the group consisting of: 
 —CN,  
 —C(O)—H,  
 —C(O)—CH 2 -T-R 11 ,  
 —C(O)—CH 2 —F,  
 —C═N—O—R 9 , and  
 —CO—Ar 2 ;  
 
 R 5  is selected from the group consisting of: 
 —C(O)—R 10 ,  
 —C(O)O—R 9 ,  
                     
 —S(O) 2 —R 9 ,  
 —C(O)—CH 2 —O—R 9 ,  
 —C(O)C(O)—R 10 ,  
 —R 9 , 
 —H, and  
 
 
 —C(O)C(O)—OR 10 ,  
 Y 2  is H 2  or O;  
 X 7  is —N(R 8 )— or —O—;  
 each T 1  is independently selected from the group consisting of —O—, —S—, —S(O)—, and —S(O) 2 —;  
 R 6  is selected from the group consisting of —H and —CH 3 ;  
 R 8  is selected from the group consisting of: 
 —C(O)—R 10 ,  
 —C(O)O—R 9 ,  
 —C(O)—NH—R 10 ,  
 —S(O) 2 —R 9 ,  
 —S(O) 2 —NH—R 10 ,  
 —C(O)—CH 2 —OR 10 ,  
 —C(O)C(O)—R 10 ,  
 —C(O)—CH 2 —N(R 10 )(R 10 ) ,  
 —C(O)—CH 2 C(O)—O—R 9 ,  
 —C(O)—CH 2 C(O)—R 9 ,  
 —H, and  
 —C(O)—C(O)—OR 10 ;  
 
 each R 9  is independently selected from the group consisting of —Ar 3  and a —C 1-6  straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6  alkyl group is optionally unsaturated;  
 each R 10  is independently selected from the group consisting of —H, —Ar 3 , a —C 3-6  cycloalkyl group, and a —C 1-6  straight or branched alkyl group optionally substituted with —Ar 3 , wherein the —C 1-6  alkyl group is optionally unsaturated;  
 each R 11  is independently selected from the group consisting of: 
 —Ar 4 ,  
 —(CH 2 ) 1-3 —Ar 4 ,  
 —H, and  
 —C(O)—Ar 4 ;  
 
 R 13  is selected from the group consisting of H, Ar 3 , and a C 1-6  straight or branched alkyl group optionally substituted with —Ar 3 , —CONH 2 , —OR 5 , —OH, —OR 9 , or —CO 2 H;  
 OR 13  is optionally —N(H)—OH;  
 each R 21  is independently selected from the group consisting of —H or a —C 1-6  straight or branched alkyl group;  
 Ar 2  is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by -Q 1  or phenyl, optionally substituted by Q 1 :  
                     
 wherein each Y is independently selected from the group consisting of O and S;  
 each Ar 3  is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N— and —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by -Q 1 ;  
 each Ar 4  is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from —O—, —S—, —SO—, SO 2 , ═N—, —NH—, —N(R 5 )—, and —N(R 9 )— said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by -Q 1 ;  
 each Q 1  is independently selected from the group consisting of —NH 2 , —CO 2 H, —Cl, —F, —Br, —I, —NO 2 , —CN, ═O, —OH, -perfluoro C 1-3  alkyl, R 5 , —OR 5 , —NHR 5 , —OR 9 , —NHR 9 , —R 9 , —C(O)—R 10 , and  
                     
 provided that when —Ar 3  is substituted with a Q 1  group which comprises one or more additional —Ar 3  groups, said additional —Ar 3  groups are not substituted with another —Ar 3 .  
 
     
     
         9 - 41 . (canceled)  
     
     
         42 . A pharmaceutical composition comprising an ICE inhibitor according to any one of claims  4 - 8  and  154  in an amount effective for treating or preventing an IL-1-mediated disease and a pharmaceutically acceptable carrier.  
     
     
         43 . A pharmaceutical composition comprising an ICE inhibitor according to any one of claims  4 - 8  and  154  in an amount effective for treating or preventing an apoptosis-mediated disease and a pharmaceutically acceptable carrier.  
     
     
         44 - 54 . (canceled)  
     
     
         55 . A method for treating or preventing a disease selected from the group consisting of an IL-1 mediated disease, an apoptosis mediated disease, an inflammatory disease, an autoimmune disease, a destructive bone disorder, a proliferative disorder, an infectious disease, a degenerative disease, a necrotic disease, osteoarthritis, pancreatitis, asthma, adult respiratory distress syndrome, glomeralonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, graft vs host disease, osteoporosis, multiple myeloma-related bone disorder, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, Shigellosis, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, and neurological damage due to stroke in a patient comprising the step of administering to said patient a pharmaceutical composition according to any one of claims  4 - 8  and  154 .  
     
     
         56 . The method according to  claim 55 , wherein the disease is selected from the group consisting of osteoarthritis, acute pancreatitis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, psoriasis, and Alzeheimer's disease.  
     
     
         57 - 139 . (canceled)  
     
     
         140 . A process for preparing an N-acylamino compound, comprising the steps of: 
 a) mixing a carboxylic acid with an N-alloc-protected amine in the presence of an inert solvent, triphenylphoshine, a nucleophilic scavenger, and tetrakis-triphenyl phosphine palladium(0) at ambient temperature under an inert atmosphere; and    b) adding to the step a) mixture, HOBT and EDC; and    optionally comprising the further step of:    c) hydrolyzing the step b) mixture in the presence of a solution comprising an acid and H 2 O, wherein the step b) mixture is optionally concentrated.    
     
     
         141 - 153 . (canceled)  
     
     
         154 . The compound according to  claim 6 , wherein: 
 m is 1;    R 13  is H or a C 1-4  straight or branched alkyl group optionally substituted with —Ar 3 , —OH, —OR 9 , —CO 2 H, wherein the R 9  is a C 1-4  branched or straight chain alkyl group; wherein Ar 3  is morpholinyl or phenyl, wherein the phenyl is optionally substituted with Q 1 ;    R 21  is —H or —CH 3 ;    R 51  is a C 1-6  straight or branched alkyl group optionally substituted with —Ar 3 , wherein Ar 3  is phenyl, optionally substituted by -Q 1 ;    each Ar 3  cyclic group is independently selected from the set consisting of phenyl, naphthyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, thiazolyl, isoxazolyl, benzotriazolyl, benzimidazolyl, thienothienyl, imidazolyl, thiadiazolyl, benzo[b]thiophenyl, pyridyl, benzofuranyl, and indolyl, and said cyclic group optionally being singly or multiply substituted by -Q 1 ;    each Q 1  is independently selected from the group consisting of —NH 2 , —Cl, —F, —Br, —OH, —R 9 , —NH—R 5  wherein R 5  is —C(O)—R 10  or —S(O) 2 —R 9 , —OR 5  wherein R 5  is —C(O)—R 10 , —OR 9 , —NHR 9 , and                          wherein each R 9  and R 10  are independently a —C 1-6  straight or branched alkyl group optionally substituted with —Ar 3  wherein Ar 3  is phenyl;    provided that when —Ar 3  is substituted with a Q 1  group which comprises one or more additional —Ar 3  groups, said additional —Ar 3  groups are not substituted with another —Ar 3 .