Cell adhesion inhibitors

Abstract

Cell adhesion inhibitors can interact with VLA-4 molecules and inhibits VLA-4 dependent cell adhesion. An inhibitor including a polyethylene glycol moiety can have advantageous pharmaceutical properties.

1 . A method of inhibiting VLA-4-dependent cell adhesion, comprising administering to a patient in need thereof an effective amount of a compound capable of inhibiting the binding of a ligand to VLA-4, or a pharmaceutically acceptable salt thereof, wherein the compound includes a poly(ethylene glycol) moiety.  
   
   
       2 . A method of inhibiting VLA-4-dependent cell adhesion, comprising administering to a patient in need thereof an effective amount of a compound of formula:  
     
       
         
         
             
             
         
       
     
     wherein Ar 1  is an aryl group, L 1  is a C 1 -C 4  alkylene group, R 1  is hydrogen or a moiety having the formula —R 5 -L 2 -(O-L 3 -) n OR 6 , R 2  is a C 1 -C 10  alkyl, aminoalkyl, thioalkyl, arylalkyl, or hydroxyalkyl group, or a moiety having the formula —R 5 -L 2 -(O-L 3 -) n OR 6 , R 3  is hydrogen or a C 1 -C 6  alkyl group, R 4  is an aralkyl group, and at least one of R 1  or R 2  includes a moiety having the formula —R 5 -L 2 -(O-L 3 -) n OR 6 , wherein: 
 each R 5 , independently, is a bond, —C(O)—, —C(O)—O—, —O—C(O)—, —S(O) p —O—, —O—S(O) p —, —C(O)—N(R a )—, —O—C(O)—N(R a )—, —N(R a )—C(O)—, —N(R a )—C(O)—O—, —O—S(O) p —N(R a )—, —N(R a )—S(O) p —O—, —N(R a )—C(O)—N(R b )—, —N(R a )—S(O) p —N(R b )—, —C(O)—N(R a )—S(O) p —, —S(O) p —N(R a )—C(O)—, —C(O)—N(R a )—S(O) p —N(R b )—, —C(O)—O—S(O) p —N(R a )—, —N(R a )—S(O) p —N(R b )—C(O)—, —N(R a )—S(O) p —O—C(O)—, —S(O) p —N(R a )—, —N(R a )—S(O) p —, —N(R a )—, —S(O) p —, —O—, —S—, or —(C(R a )(R b )) q —, wherein each of R a  and R b , independently, is hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; p is 1 or 2; and q is 1, 2, 3, or 4;  
 each L 2 , independently, is a bond, aryl, heteroaryl, cycloalkyl, heterocyclyl, or a C 1 -C 20  alkylene group, wherein L 2  is optionally interrupted or terminated by one or more of —C(O)—, —C(O)—O—, —O—C(O)—, —S(O) p —O—, —O—S(O) p —, —C(O)—N(R a )—, —O—C(O)—N(R a )—, —N(R a )—C(O)—, —N(R a )—C(O)—O—, —O—S(O) p —N(R a )—, —N(R a )—S(O) p —O—, —N(R a )—C(O)—N(R b )—, —N(R a )—S(O) p —N(R b )—, —C(O)—N(R a )—S(O) p —, —S(O) p —N(R a )—C(O)—, —C(O)—N(R a )—S(O) p —N(R b )—, —C(O)—O—S(O) p —N(R a )—, —N(R a )—S(O) p —N(R b )—C(O)—, —N(R a )—S(O) p —O—C(O)—, —S(O) p —N(R a )—, —N(R a )—S(O) p —, —N(R a )—, —S(O) p —, —O—, —S—, or —(C(R a )(R b )) q —, wherein each of R a  and R b , independently, is hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; p is 1 or 2; and q is 1, 2, 3, or 4;  
 each L 3 , independently, is a C 1 -C 6  alkylene group;  
 each R 6 , independently, is hydrogen, a C 1 -C 6  alkyl group, an aryl group, a moiety having the formula:  
                     
 or a moiety having the formula:  
                     
 wherein R 2  is a C 1 -C 10  alkyl, aminoalkyl, thioalkyl, arylalkyl, or hydroxyalkyl group; and  
 n is an integer chosen such that the compound has a molecular weight between 400 and 70,000;  
 or a pharmaceutically acceptable salt thereof;  
 provided that when Ar 1  is phenyl, L 1  is —CH 2 CH 2 —, R 2  is 2-methylpropyl, R 3  is methyl, and R 4  is 4-((N′-2-methylphenyl)ureido)benzyl, R 1  is not —N(H)—C(O)—CH 2 CH 2 —(OCH 2 CH 2 ) n —OCH 3  where n is selected such that R 1  has a molecular weight of approximately 20,000, and R 1  is not —N(H)—C(O)—(CH 2 ) 5 —N(H)—C(O)—CH 2 CH 2 —(OCH 2 CH 2 ) n —OCH 3 , where n is selected such that R 1  has a molecular weight of approximately 20,000, 30,000 or 50,000.  
 
   
   
       3 . The method of  claim 2 , wherein the patient is need of treatment of a VLA-4 mediated disease.  
   
   
       4 . The method of  claim 3 , wherein the VLA-4 mediated disease is EAE, asthma, or inflammatory bowel disease.  
   
   
       5 . The method of  claim 2 , wherein R 4  is a N-arylurea-substituted aryl group.  
   
   
       6 . The method of  claim 2 , wherein R 4  has the formula:  
     
       
         
         
             
             
         
       
     
   
   
       7 . The method of  claim 6 , wherein L 1  is a C 1 , C 2  or C 3  alkylene group.  
   
   
       8 . The method of  claim 7 , wherein Ar 1  is phenyl optionally substituted by 1, 2, 3, 4 or 5 halo groups.  
   
   
       9 . The method of  claim 2 , wherein R 1  is a moiety having the formula —R 5 -L 2 -(O-L 3 -) n OR 6 .  
   
   
       10 . The method of  claim 9 , wherein R 1  is in an anti configuration.  
   
   
       11 . The method of  claim 9 , wherein R 1  is in a syn configuration  
   
   
       12 . The method of  claim 9 , wherein each L 3  is —CH 2 —CH 2 —.  
   
   
       13 . The method of  claim 2 , wherein R 5  is —N(R a )—C(O)—.  
   
   
       14 . The method of  claim 2 , wherein R 6  is C 1 -C 6  alkyl.  
   
   
       15 . The method of  claim 2 , wherein R 2  is 2-methylpropyl.  
   
   
       16 . The method of  claim 15 , wherein L 1  is —CH 2 —CH 2 —.  
   
   
       17 . The method of  claim 15 , wherein R 1  is a moiety having the formula —R 5 -L 2 -(O-L 3 -) n OR 6 .  
   
   
       18 . The method of  claim 17 , wherein each L 3  is —CH 2 —CH 2 —.  
   
   
       19 . The method of  claim 18 , wherein R 6  is —CH 3 .  
   
   
       20 . The method of  claim 2 , wherein R 1  is hydrogen and R 2  is a moiety having the formula —R 5 -L 2 -(O-L 3 -) n OR 6 .  
   
   
       21 . The method of  claim 20 , wherein —R 5 -L 2 - is —(CH 2 ) 4 —N(H)—C(O)—(CH 2 ) 5 —N(H)—C(O)—(CH 2 ) 2 —.  
   
   
       22 . The method of  claim 21 , wherein each L 3  is —CH 2 —CH 2 —.  
   
   
       23 . The method of  claim 21 , wherein R 6  is —CH 3 .  
   
   
       24 . The method of  claim 2 , wherein the compound is water soluble.  
   
   
       25 . A method of making a cell adhesion inhibitor comprising modifying a compound with a water soluble polymer.  
   
   
       26 . The method of  claim 25 , further comprising converting the modified compound to a cell adhesion inhibitor.  
   
   
       27 . The method of  claim 25 , wherein the compound is a cell adhesion inhibitor.  
   
   
       28 . The method of  claim 27 , wherein the water soluble polymer includes a poly(ethylene glycol) moiety or a poly(propylene glycol) moiety.  
   
   
       29 . The method of  claim 25 , wherein the water soluble polymer includes a poly(oxyalkylene) moiety.  
   
   
       30 . The method of  claim 29 , wherein the water soluble polymer includes a poly(ethylene glycol) moiety or a poly(propylene glycol) moiety.  
   
   
       31 . The method of  claim 25 , wherein the compound includes a nucleophilic group and the water soluble polymer includes an electrophilic group.  
   
   
       32 . The method of  claim 31 , wherein the electrophilic group is an activated ester group.  
   
   
       33 . The method of  claim 32 , wherein the nucleophilic group is an amine.  
   
   
       34 . The method of  claim 33 , wherein the water soluble polymer includes a poly(ethylene glycol) moiety.  
   
   
       35 . A method of making a cell adhesion inhibitor comprising converting a 4-hydroxyproline moiety to a 4-aminoproline moiety.  
   
   
       36 . The method of  claim 35 , wherein the conversion is a stereospecific conversion.  
   
   
       37 . The method of  claim 36 , further comprising incorporating the 4-aminoproline moiety in a cell adhesion inhibitor.  
   
   
       38 . The method of  claim 37 , further comprising modifying the 4-aminoproline moiety with a water soluble polymer.  
   
   
       39 . The method of  claim 38 , wherein the water soluble polymer includes a poly(oxyalkylene) moiety.  
   
   
       40 . The method of  claim 39 , wherein the water soluble polymer includes a poly(ethylene glycol) moiety or a poly(propylene glycol) moiety.