Integrin receptor inhibitors

Abstract

Provided are compounds of formula (I) wherein A, Q, W, X, Y, Z, R 1 to R 4 , m and n are as defined herein. Compounds of the invention bind to α 4 integrin receptors and thereby inhibit binding of ligands for α 4 integrins which is useful for prophylactic and/or therapeutic treatment of diseases and conditions associated with α 4 integrins or their ligands.

We claim:  
     
         1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 A is a 5 or 6 member, saturated or unsaturated carbocycle or heterocycle optionally substituted by oxo and R 4 ;  
 Q is alkyl, alkenyl or alkynyl optionally substituted with halogen, carboxyl, alkyl or aryl, and wherein one or more carbon atoms are optionally replaced with O, N, NR 6 , S, SO, or SO 2 ;  
 X is —CR 5 — or —N—;  
 Y is H, —CHR 3 —, —CR 3 ═, or a bond;  
 Z is H, —CHR 3 —, ═CR 3 —, —NR 3 —, ═N—, O, S, SO, SO 2  or a bond, provided that when one of Y and Z is H then the other is also H;  
 W is —C(O)NR 6 —, —NR 6 C(O)—, —C(S)NR 6 —, —NR 6 C(S)—, NR 6 , O, S, SO 2 , —CH 2 —, —C—, —NR 6 SO 2 —, —SO 2 NR 6 —, —OC(O)NR 6 —, —NR 6 C(O)O—, —OC(S)NR 6 —, —NR 6 C(S)O—, —S—C(S)NR 6 —, —C(O)—, —NR 6 C(O)NR 6 — or —NR 6 C(S)NR 6 —;  
 R 1  is hydrogen or is selected from the group consisting of alkyl, alkenyl and alkynyl, each of which is optionally substituted with hydroxyl, halogen, amino, nitro, carboxyl, a carbocycle, or a heterocycle; or R 1  is a carbocycle or heterocycle optionally substituted with hydroxyl, oxo, halogen, amino, or nitro;  
 R 2  is selected from the group consisting of alkyl, alkenyl and alkynyl, each of which is optionally substituted with halogen, hydroxyl, oxo, alkoxy, amino, nitro, carboxyl, carboxamido, acyl, acyloxy, amidinyl, guanidinyl, thiol, alkylthio, or one or more carbocycle or heterocycle optionally substituted with halogen, hydroxyl, oxo, alkoxy, amino or carboxyl; or R 2  is a carbocycle or heterocycle optionally substituted with halogen, hydroxyl, oxo, alkoxy, amino, nitro, carboxyl, acyl, acyloxy, alkyl, alkenyl, alkynyl or a carbocycle or heterocycle optionally substituted with halogen, hydroxyl, oxo, alkoxy, amino or carboxyl;  
 R 3  and R 4  are independently selected from the group consisting of H, hydroxyl, halogen, amino, nitro, carboxyl, alkyl, alkenyl, alkynyl, a carbocycle and a heterocycle, wherein said alkyl, alkenyl, alkynyl, carbocycle and heterocycle groups are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, amino, oxo and carboxyl, and optionally one or more carbon atoms of said alkyl, alkenyl and alkynyl group is replaced with N, NR 6 , O, S, SO or SO 2 ;  
 R 5  is H or alkyl, alkenyl or alkynyl optionally having a carbon atom replaced with O, N or NR 6 , and optionally substituted with COOR 1 ; or R 5  together with the carbon atom from which it depends forms a double bond to an adjacent carbon or nitrogen atom of Q; or R 5  together with a non-adjacent carbon or nitrogen atom of Q form a carbocycle or heterocycle;  
 R 6  is hydrogen, alkyl, alkenyl or alkynyl;  
 m and n are independently 1, 2 or 3;  
 and salts, solvates and hydrates thereof.  
 
     
     
         2 . A compound according to  claim 1 , wherein A is a benzene ring.  
     
     
         3 . A compound according to  claim 1 , wherein Q is a alkyl chain of 1 to 3 carbon atoms in length wherein the methylene group adjacent to X is optionally replaced with oxygen.  
     
     
         4 . A compound according to  claim 3 , wherein said methylene chain is 2 carbon atoms in length.  
     
     
         5 . A compound according to  claim 4 , wherein the methylene group adjacent to X is replaced with oxygen.  
     
     
         6 . A compound according to  claim 1 , wherein R 1  is H.  
     
     
         7 . A compound according to  claim 1 , wherein X is —CR 5 — and R 5  is H.  
     
     
         8 . A compound according to  claim 1 , wherein both Y and Z are hydrogen.  
     
     
         9 . A compound according to  claim 1 , wherein both Y and Z are a bond thereby forming a 5 member ring with X.  
     
     
         10 . A compound according to  claim 1 , wherein W is —NR 6 — and R 6  is H or C 1-4  alkyl.  
     
     
         11 . A compound according to  claim 10 , wherein R 2  is a D or L-amino acid residue wherein the alpha amino group is optionally an acyl group.  
     
     
         12 . A compound according to  claim 11 , wherein said amino acid is tyrosine.  
     
     
         13 . A compound according to  claim 10 , wherein R 2  is N-acetyl-tyrosine, D-tyrosine, phenylalanine, benzoyl, isonipecotoyl, 4-methoxyphenylacetyl, 1-fluorenyl-carbonyl, 1-naphthoyl, 2-naphthoyl, 3-hydroxy-phenylalanine, 3-iodo-tyrosine, 3-fluoro-tyrosine, 3chloro-tyrosone, 4-(4-hydroxyphenyl)-benzoyl, 2,3,5,6-tetrafluoro-tyrosine, 6-hydroxynaphthoyl, 2-phenyl-3-(4-hydroxyphenyl)propanoyl and N-acetyl-3-(4-hydroxyphenyl)proline.  
     
     
         14 . A compound according to  claim 1  having the formula (II):  
       
         
           
           
               
               
           
         
       
       wherein 
 Q is alkyl, alkenyl or alkynyl optionally substituted with halogen, carboxyl, alkyl or aryl, and wherein one or more carbon atoms are optionally replaced with O, N, NR 6 , S, SO, or SO 2 ;  
 R 1  is hydrogen or is selected from the group consisting of alkyl, alkenyl and alkynyl, each of which is optionally substituted with hydroxyl, halogen, amino, nitro, carboxyl, a carbocycle, or a heterocycle; or R 1  is a carbocycle or heterocycle optionally substituted with hydroxyl, oxo, halogen, amino, or nitro;  
 R 3  and R 4  are independently selected from the group consisting of H, hydroxyl, halogen, amino, nitro, carboxyl, alkyl, alkenyl, alkynyl, a carbocycle and a heterocycle, wherein said alkyl, alkenyl, alkynyl, carbocycle and heterocycle groups are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, amino, oxo and carboxyl, and optionally one or more carbon atoms of said alkyl, alkenyl and alkynyl group is replaced with N, NR 6 , O, S, SO or SO 2 ;  
 R 6  is hydrogen, alkyl, alkenyl or alkynyl;  
 R 7  is hydrogen, hydroxyl, halogen, alkyl, alkoxy or halogen substituted alkyl;  
 R 8  is H, alkyl, alkenyl or alkynyl;  
 R 9  is H or NR 11 R 11 , wherein R 11  and R 11 , are independently H, acyl or and amino acid residue; or one of R 11  and R 11 , together with R 8  form a heterocycle;  
 R 10  is O or S;  
 m and n are independently 1, 2 or 3;  
 p is an integer from 1 to 5;  
 and salts, solvates and hydrates thereof.  
 
     
     
         15 . A compound according to  claim 14 , wherein one of R 11  and R 11 , together with R 8  form a 5-member heterocycle while the other of R 11  and R 11 , is H or C 1-4  alkanoyl.  
     
     
         16 . A compound according to  claim 15 , wherein R 5  is OH at the para position.  
     
     
         17 . A compound according to  claim 1  selected from the group consisting of  
       
         
           
           
               
               
           
         
       
       and salts, solvates and hydrates thereof.  
     
     
         18 . A method of treating a disease or condition mediated by α 4  integrin receptors or ligands of α 4  integrin receptors in a mammal comprising administering to said mammal an effective amount of a compound of according to  claim 1 .  
     
     
         19 . A method according to  claim 18 , wherein said disease or condition is selected from the group consisting of rheumatoid arthritis, asthma, psoriasis, multiple sclerosis, inflammatory bowel disease including ulcerative colitis, pouchitis and Crohn's disease, Celiac disease, nontropical Sprue, graft-versus-host disease, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, pericholangitis, chronic sinusitis, chronic bronchitis, pneumonitis, collagen disease, eczema, and systemic lupus erythematosis.  
     
     
         20 . A method of inhibiting binding of an α 4  integrin to a protein ligand comprising contacting said α 4  integrin with a compound of  claim 1.