Cell adhesion inhibitors

Abstract

The present invention relates to novel compounds that are useful for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies. This invention also relates to pharmaceutical formulations comprising these compounds and methods of using them for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies. The compounds and pharmaceutical compositions of this invention can be used as therapeutic or prophylactic agents. They are particularly well-suited for treatment of many inflammatory and autoimmune diseases.

1 . A cell adhesion inhibitory compound of formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable derivative thereof, 
 wherein:  
 X is —CO 2 H;  
 Y is selected from the group consisting of —CO—, —CH 2 —, —SO 2 — and —PO 2 —;  
 R 1  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, N-alkylurea-substituted alkyl, alkylcarbonylamino-substituted alkyl, and aminocarbonyl-substituted alkyl;  
 R 2  is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl;  
 R 3  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, hydroxy-substituted alkyl, alkoxy-substituted alkyl, amino-substituted alkyl, thiol-substituted alkyl, alkylsulfonyl-substituted alkyl, (hydroxy-substituted alkylthio)-substituted alkyl, thioalkoxy-substituted alkyl, acylamino-substituted alkyl, alkylsulfonylamino-substituted alkyl, [N-(alkyl, alkenyl or alkynyl)-or N,N-[dialkyl, dialkenyl, dialkynyl or (alkyl,alkenyl)-amino]carbonyl-substituted alkyl, carboxyl-substituted alkyl, dialkylamino-substituted acylaminoalkyl, and and amino acid side chains selected from arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, alanine, ornithine, glutamine, valine, threonine, serine, aspartic acid, beta-cyanoalanine, and allothreonine;  
 R 4  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, amido, aminocarbonyl, mono- or dialkylaminocarbonyl, mono- or diacylaminocarbonyl, aliphatic acyl, alkyl optionally substituted with substitutents selected from the group consisting of amino, carboxy, hydroxy, mercapto, mono- or dialkylamino, mono- or diacylamino, alkoxy, alkenoxy, thioalkoxy, thioalkenoxy, and thioalkynoxy; and  
 n is 0, 1 or 2.  
 
     
     
         2 . The compound according to  claim 1 , wherein R 4  is selected from the group consisting of alkyl, cycloalkyl, alkyenyl, cycloalkenyl, and alkynyl.  
     
     
         3 . The compound according to  claim 1 , wherein R 1  is selected from the group consisting of cyanomethyl, cyclohexylmethyl, methyl, n-hexyl, t-butoxy, t-butylamino, 5-(N′-t-butylurea)pentyl, 2,2-dimethylpropyl, and hydroxyethylthiomethyl.  
     
     
         4 . The compound according to  claim 1 , wherein R 1  is selected from the group consisting of cyanomethyl, cyclohexylmethyl, methyl, n-hexyl, t-butoxy, t-butylamino, 5-(N′-t-butylurea)pentyl, and 2,2-dimethylpropyl.  
     
     
         5 . The compound according to  claim 1 , wherein R 2  is hydrogen or methyl.  
     
     
         6 . The compound according to  claim 5 , wherein R 2  is hydrogen.  
     
     
         7 . The compound according to  claim 1 , wherein R 3  is selected from the group consisting of 2-(methylsulfonyl)-ethyl, 3-(hydroxy-propylthio)-methyl, 4-(methylsulfonylamino)-butyl, 4-acetylaminobutyl, aminomethyl, butyl, hydroxymethyl, isobutyl, methyl, methylthiomethyl, propyl, N,N-(methylpropargyl)-amino, 2-(methylthio)-ethyl, 2-(N,N-dimethylamino)-ethyl, 4-amino-butyl, t-butoxy-carbonylaminomethyl, sec-butyl, t-butyl, N,N-dimethyl-aminocarbonylmethyl, 1,1-ethano, 1-hydroxyethyl, 1-methoxyethyl, carbonylmethyl, 2-methylsulfinylethyl, asparagine side-chain, 4-(methylurea)butyl, 4-methylsulfonylaminobutyl, hydroxymethylthiomethyl, 2-methylsulfonylethyl, 4-propionylaminobutyl, 4-ethoxycarbonylaminobutyl, methoxycarbonylaminobutyl, carbomethoxymethylthiomethyl, 4-t-butylureabutyl, carboxymethylthiomethyl, dimethylamidomethylthiomethyl, acetylaminopropyl, 3-methylureapropyl, 4-trifluoroacetylaminobutyl, dimethylaminomethylthiomethyl, dimethylaminoethylthiomethyl, and 4-(dimethylaminoacetylamino)butyl.  
     
     
         8 . The compound according to  claim 7 , wherein R 3  is selected from the group consisting of 2-(methylsulfonyl)-ethyl, 3-(hydroxypropylthio)-methyl, 4-(methylsulfonylamino)-butyl, 4-acetylaminobutyl, aminomethyl, butyl, hydroxymethyl, isobutyl, methyl, methylthiomethyl, propyl, N,N-(methylpropargyl)-amino, 2-(methylthio)-ethyl, 2-(N,N-dimethylamino)-ethyl, 4-amino-butyl, t-butoxy-carbonylaminomethyl, sec-butyl, t-butyl, N,N-dimethyl-aminocarbonylmethyl, 1,1-ethano, 1-hydroxyethyl, 1-methoxyethyl, carbonylmethyl, 2-methylsulfinylethyl, and asparagine side chain.  
     
     
         9 . The compound according to  claim 7 , wherein R 3  is selected from the group consisting of 2-(methylsulfonyl)-ethyl, 3-(hydroxypropylthio)-methyl, 4-(methylsulfonylamino)-butyl, 4-acetylaminobutyl, isobutyl, 2-(methylthio)-ethyl, and 4-(ethoxycarbonylamino)butyl.  
     
     
         10 . The compound according to  claim 9 , wherein R 3  is selected from the group consisting of 2-(methylsulfonyl)-ethyl, 3-(hydroxypropylthio)-methyl, 4-(methylsulfonylamino)-butyl, 4-acetylaminobutyl, isobutyl, and 2-(methylthio)-ethyl.  
     
     
         11 . The compound according to  claim 1 , wherein R 4  is selected from the group consisting of methyl, 4-methylsulfonylamino, 4-propionylamino, n-pentyl, carboxymethyl, 2-carboxyethyl, allyl, ethynyl, 2-propenyl, 2-propynyl, and propyl.  
     
     
         12 . The compound according to  claim 11 , wherein R 4  is methyl.  
     
     
         13 . The compound according to  claim 11 , wherein R 4  is allyl or ethynyl.  
     
     
         14 . The compound according to  claim 1 , wherein Y is —CO—, —CH 2 — or —SO 2 —.  
     
     
         15 . The cell adhesion inhibitory compound according to  claim 14 , wherein Y is —CO—.  
     
     
         16 . The cell adhesion inhibitory compound according to  claim 1 , wherein n is 1.  
     
     
         17 . A pharmaceutical composition comprising a compound according to  claim 1  in an amount effective for prevention, inhibition or suppression of VLA-4 mediated cell adhesion and a pharmaceutically acceptable carrier.  
     
     
         18 . The pharmaceutical composition according to  claim 17 , further comprising an agent selected from the group consisting of corticosteriods, bronchodilators, antiasthmatics, antiinflammatories, antirheumatics, immunosuppressants, antimetabolites, immunonodulators, antipsoriatics and antidiabetics.  
     
     
         19 . A method of preventing, inhibiting or suppressing cell adhesion in a mammal comprising the step of administering to said mammal the pharmaceutical composition according to  claim 17 .  
     
     
         20 . The method according to  claim 19 , wherein said method is used for preventing, inhibiting or suppressing cell adhesion-associated inflammation.  
     
     
         21 . The method according to  claim 20 , wherein said method is used for preventing, inhibiting or suppressing cell adhesion-associated immune or autoimmune response.  
     
     
         22 . The method according to  claim 19 , wherein said method is used to treat or prevent a disease selected from the group consisting of asthma, arthritis, psoriasis, transplantation rejection, multiple sclerosis, diabetes and inflammatory bowel disease.