LFA-1 antagonist compounds

Abstract

The invention relates to novel compounds having formula (I) wherein Cy, X, Y, L and R 1-6 are as defined herein. The compounds bind CD11/CD18 adhesion receptors such as Lymphocyte Function-associated Antigen-1 (LFA-1) and are therefore useful for treating disorders mediated by LFA-1 such as inflammation and autoimmune diseases.

1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 Cy is a non-aromatic carbocycle or heterocycle optionally substituted with hydroxyl, mercapto, thioalkyl, halogen, oxo, thio, amino, aminoalkyl, amidine, guanidine, nitro, alkyl, alkoxy or acyl;  
 X is a divalent hydrocarbon chain optionally substituted with hydroxyl, mercapto, halogen, amino, aminoalkyl, nitro, oxo or thio and optionally interrupted with N, O, S, SO or SO 2 ;  
 Y is a carbocycle or heterocycle optionally substituted with hydroxyl, mercapto, halogen, oxo, thio, thioalkyl, amino, aminoalkyl, carbocycle or heterocycle ring, hydrocarbon, a halo-substituted hydrocarbon, amino, amidine, guanidine, cyano, nitro, alkoxy or acyl;  
 L is a bond or a divalent hydrocarbon chain optionally substituted hydroxyl, halogen, oxo or thio and optionally interrupted with N, O, S, SO or SO 2  or an amino acid residue; less than 3 or 5 atoms  
 R 1  is H, OH, amino, O-carbocycle or alkoxy optionally substituted with amino, a carbocycle or heterocycle;  
 R 2-5  are independently H, hydroxyl, mercapto, halogen, cyano, amino, amidine, guanidine, nitro or alkoxy; or R 3  and R 4  together form a fused carbocycle or heterocycle optionally substituted with hydroxyl, halogen, oxo, thio, amino, amidine, guanidine or alkoxy;  
 R 6  is H or a hydrocarbon chain optionally substituted with a carbocycle or a heterocycle; and  
 salts, solvates and hydrates thereof;  
 with the proviso that when Y is phenyl, R 2 , R 4  and R 5  are H, R 3  is Cl and R 1  is OH then X is other than cyclohexyl.  
 
     
     
         2 . A compound according to  claim 1 , wherein Cy is a 5- or 6-member non-aromatic heterocycle optionally substituted with hydroxyl, mercapto, thioalkyl halogen, oxo, thio, amino, aminoalkyl, amidine, guanidine, nitro, alkyl, alkoxy or acyl.  
     
     
         3 . A compound according to  claim 2 , wherein said heterocycle comprises one or two heteroatoms and is optionally substituted with hydroxyl, oxo, mercapto, thio, alkyl or alkanoyl.  
     
     
         4 . A compound according to  claim 3 , wherein said heterocycle is selected from the group consisting of piperidine, piperazine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxazolidine, cyclopropapyrrolidine and thiazolidine optionally substituted with hydroxy, oxo, mercapto, thio, alkyl or alkanoyl.  
     
     
         5 . A compound according to  claim 4 , wherein said heterocycle is selected from the group consisting of piperidine, piperazine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxazolidine, thiazolidine optionally substituted with hydroxy, oxo, mercapto, thio, alkyl or alkanoyl.  
     
     
         6 . A compound according to  claim 1 , wherein Cy is a 3-6 member carbocycle optionally substituted with hydroxyl, mercapto, halogen, oxo, thio, amino, amidine, guanidine, alkyl, alkoxy or acyl.  
     
     
         7 . A compound according to  claim 6 , wherein said carbocycle is partially unsaturated.  
     
     
         8 . A compound according to  claim 7 , wherein Cy is cyclopropyl, cyclypropenyl, cyclobutyl, cyclbutenyl, cyclopentyl, cyclopentenyl cyclohexyl or cyclohexenyl.  
     
     
         9 . A compound according to  claim 1 , wherein X is a C 1-5  divalent hydrocarbon optionally having one or more carbon atoms replaced with N, O, S, SO or SO 2  and optionally being substituted with hydroxyl, oxo or thio.  
     
     
         10 . A compound according to  claim 1 , wherein X is —CH 2 —NR 6 —C(O)— wherein the carbonyl —C(O)— portion thereof is covalently bound to Cy and R 6  is H or alkyl.  
     
     
         11 . A compound according to  claim 1 , wherein Y is a carbocycle or heterocycle optionally substituted with hydroxyl or halogen.  
     
     
         12 . A compound according to  claim 11 , wherein Y is furan-2-yl, thiophene-2-yl or phenyl, wherein said phenyl is optionally substituted with halogen or hydroxyl.  
     
     
         13 . A compound according to  claim 1 , wherein L is a divalent hydrocarbon optionally having one or more carbon atoms replaced with N, O, S, SO or SO 2  and optionally being substituted with hydroxyl, halogen oxo or thio; or three carbon atoms of the hydrocarbon are replaced with an amino acid residue.  
     
     
         14 . A compound according to  claim 13 , wherein L is —CH═CH—C(O)—NR 6 —CH 2 —, —CH 2 —NR 6 —C(O)—, —C(O)—N 6 —CH 2 —, —CH(OH)—(CH 2 ) 2 —, —(CH 2 ) 2 —CH(OH)—, —(CH 2 ) 3 —, —C(O)—NR 6 —CH(R 7 )—C(O)—NR 6 —, —NR 6 —C(O)—CH(R 7 )—NR 6 —C(O)—, —CH(OH)—CH 2 —O— or —CH(OH)—CF 2 —CH 2 — wherein each R 6  is independently H or alkyl and R 7  is an amino acid side chain.  
     
     
         15 . A compound according to  claim 14 , wherein R 1  is H, OH, amino, O-carbocycle or alkoxy optionally substituted with a carbocycle.  
     
     
         16 . A compound according to  claim 15 , wherein R 1  is H or C 1-4  alkyloxy.  
     
     
         17 . A compound according to  claim 1 , wherein at least one of R 2  and R 3  is halogen and the other is H or halogen.  
     
     
         18 . A compound according to  claim 17 , wherein R 2  and R 3  are both Cl.  
     
     
         19 . A compound according to  claim 18 , wherein R 4  and R 5  are both H.  
     
     
         20 . A pharmaceutical composition comprising a compound according to  claim 1  with a pharmaceutically acceptable adjuvant, diluent or carrier.  
     
     
         21 . A method of inhibiting binding of a LFA-1 to a protein ligand comprising contacting LFA-1 with a compound of  claim 1 .  
     
     
         22 . A method of treating a disease or condition mediated by LFA-1 in a mammal comprising administering to said mammal an effective amount of a compound according to  claim 1 .  
     
     
         23 . A method according to  claim 23 , wherein said disease or condition is arthritis, psoriasis, organ transplant rejection, asthma, and inflammatory bowel disease  
     
     
         23 . A method of inhibiting an inflammatory disease or condition in a mammal comprising administering to said mammal an effective amount of a compound according to  claim 1.