Cell adhesion inhibitors

Abstract

A cell adhesion inhibitor of the general formula: R 3 -L-L′-R 1 is disclosed. An inhibitor of the present invention interacts with VLA-4 molecules and inhibits VLA-4 dependent cell adhesion. Also disclosed are methods for preparing and using such a cell adhesion inhibitor, as well as pharmaceutical compositions containing the same.

1 . A compound having the formula:  
       R 3 -L-L 1 -R 1    wherein    R 1  is Z 1 -L a -Z 2  in which 
 Z 1  is aryl optionally substituted with Cy, —CO—R d , halogen, oxo, or aryl-substituted alkenyl;  
 L a  is —O—C(O)—, —C(O)—O—, —C(O)—NR c —, —NR c —C(O)—, or —SO 2 —; and  
 Z 2  is heteroaryl, heterocyclyl, or a bond;  
 where Cy represents cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;  
   L′ is                          in which 
 Y 1  is —NR c —C(O)—, + 13 NR  c —, —NR c —S(O) 2 —, or —NR c —C(NR d )—;  
 R 2  is H or C 1-5  alkyl;  
 Y 2  is a bond or —C(R h )(R i )—; and  
 X is —C(O)OR c ;  
 where each of R c , R d , R h , and R i , independently, is H or C 1-5  alkyl;  
   L is                          in which 
 Y 3  is a bond, C 1-5  alkyl, or C 1-5  alkenyl; and  
 Y 4  is a bond, —C(O)—NR c —, —C(O)—, —NR c —, or —O—, where R c  is H or C 1-5  alkyl; and  
   R 3  is a moiety of the formula:                          in which 
 R 4  is Z 5 -L c -Z 6 -, where 
 Z 5  is aryl, aryl-C 1-10 -alkyl, aryl-C 1-10 -alkenyl, aryl-C 1-10 -alkynyl, heteroaryl, heteroaryl-C 1-10 -alkyl, heteroaryl-C 1-10 -alkenyl, or heteroaryl-C 1-10 -alkynyl;  
 L c  is —C(O)—, —S(O) m —, —O—C(O)—, —C(O)—O—, —C(O)—NR c —, —NR c —C(O)—, —NR c —C(O)—NR d —, SO 2 —NR c —, —NR c —SO 2 —, —O—, —NR c —, or a bond, where each of R c  and R d , independently, is H or C 1-5  alkyl; and  
 Z 6  is aryl, aryl-C 1-10 -alkyl, heterocyclyl, heterocyclyl-C 1-10 -alkyl, heteroaryl, heteroaryl-C 1-10 -alkyl, or a bond;  
 
 Y 5  is selected from the group consisting of —CO—, —O—CO—, —SO 2 — and —PO 2 —;  
 R 5  is hydrogen, aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl-substituted alkyl, or R 5  and R 6  may be taken together with the atoms to which they are attached to form a heterocycle of 5 to 7 members; and  
 R 6  is alkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aralkyl, aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkenoxy, alkynoxy, aralkoxy, aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, arylamino, heterocyclyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl substituted aralkyl, oxocarbocyclyl-fused aryl, or an amino acid side chain selected from the group consisting of arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, cyclohexylalanine, leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, phenylalanine, phenylglycine, tyrosine, tryptophan, proline, alanine, ornithine, histidine, glutamine, norvaline, valine, threonine, serine, beta-cyanoalanine, 2-aminobutyric acid and allothreonine;  
   each of R c  and R d , independently, is selected from the group consisting of H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, Cy, and Cy-C 1-10  alkyl; wherein each of alkyl, alkenyl, alkynyl and Cy is optionally substituted with one to four substituents independently selected from R g ;    R g  is halogen, amino, carboxy, —COO—C 1-4  alkyl, —P(O)(OH) 2 , —P(O)(OH)(O—C 1-4  alkyl), —P(O)(C 1-4  alkyl) 2 , —P(O)(OH)(C 1-4  alkyl), —P(O)(O—C 1-4  alkyl)(C 1-4  alkyl), —SO 2 —C 1-4  alkyl, —CO—NH 2 , —CO—NH(C 1-4  alkyl), —CO—N(C 1-4  alkyl) 2 , C 1-4  alkyl, C 1-4  alkoxy, aryl, aryl-C 1-4  alkoxy, hydroxy, CF 3 , or aryloxy; and    m is 0, 1 or 2.    
   
   
       2 . The compound of  claim 1 , wherein Z 5  is aryl; L c  is —NR c —C(O)—NR d —; and Z 6  is aryl.  
   
   
       3 . The compound of  claim 2 , wherein R 4  is o-methylphenyl-ureido-phenyl-CH 2 —.  
   
   
       4 . The compound of  claim 3 , wherein Y 5  is —CO— or —O—CO—.  
   
   
       5 . The compound of  claim 4 , wherein R 5  is H or C 1-2  alkyl.  
   
   
       6 . The compound of  claim 5 , wherein R 6  is an amino acid side chain selected from the group consisting of leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, alanine, norvaline, valine and 2-aminobutyric acid.  
   
   
       7 . The compound of  claim 6 , wherein R 6  is the side chain of leucine or isoleucine.  
   
   
       8 . The compound of  claim 1 , wherein Z 1  is phenyl optionally substituted with Cy, —CO—R d , halogen, oxo, or aryl-substituted alkenyl.  
   
   
       9 . The compound of  claim 1 , wherein L a  is —SO 2 —.  
   
   
       10 . The compound of  claim 1 , wherein Z 2  is azetidine, pyrrole, pyrrolidine, imidazole, piperidine, or morpholine.  
   
   
       11 . The compound of  claim 1 , wherein said compound is 5192, 5283, 6696, 6697, 6714, 7234, 7256, 7578, 7662, 8221, 8308, 8309, 8341, 8342, 8343, 8367, 8368, 8469, 8491, 8554, 8555, 8571, 8642, 8685, 8689, 8690, 8698, 8749, 8758, 8796, 8797, 8809, 9120, 9169, 9171, 9182, 9227, 9264, 9315, 9418, 9621, 7200, 7328, 7399, 7855, 8205, 8290, 8291, 8294, 8295, 8582, 8583, 8585, 8586, 8628, 8674, 8723, 8746, or 8629.  
   
   
       12 . The compound of  claim 1 , wherein the compound is modified with a polyethylene glycol.  
   
   
       13 . A composition comprising a pharmaceutical carrier and a compound having the formula:  
       R 3 -L-L′-R 1    wherein    R 1  is Z 1 -L a -Z 2 -, in which 
 Z 1  is aryl optionally substituted with Cy, —CO—R d , halogen, oxo, or aryl-substituted alkenyl;  
 L a  is —O—C(O)—, —C(O)—O—, —C(O)—NR c —, —NR c —C(O)—, or —SO 2 —; and  
 Z 2  is heteroaryl, heterocyclyl, or a bond;  
 where Cy represents cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;  
   L′ is                          in which 
 Y 1  is —NR c —C(O)—, —NR c —, —NR c —S(O) 2 —, or —NR c —C(NR d )— 
 R 2  is H or C 1-5  alkyl;  
 Y 2  is a bond or —C(R h )(R i )—; and  
 X is —C(O)OR c ;  
 where each of R c , R d , R h , and R i , independently, is H or C 1-5  alkyl;  
   L is                          in which 
 Y 3  is a bond, C 1-5  alkyl, or C 1-5  alkenyl; and  
 Y 4  is a bond, —C(O)—NR c —, —C(O)—, —NR c —, or —O—, where R c  is H or C 1-5  alkyl; and  
   R 3  is a moiety of the formula:                          in which 
 R 4  is Z 5 -L c -Z 6 -, where 
 Z 5  is aryl, aryl-C 1-10 -alkyl, aryl-C 1-10 -alkenyl, aryl-C 1-10 -alkynyl, heteroaryl, heteroaryl-C 1-10 -alkyl, heteroaryl-C 1-10 -alkenyl, or heteroaryl-C 1-10 -alkynyl;  
 L c  is —C(O)—, —S(O) m —, —O—C(O)—, —C(O)—O—, —C(O)—NR c —, —NR c —C(O)—, —NR c —C(O)—NR d —, —SO 2 —NR c —, —NR c —SO 2 —, —O—, —NR c —, or a bond, where each of R c  and R d , independently, is H or C 1-5  alkyl; and  
 Z 6  is aryl, aryl-C 1-10 -alkyl, heterocyclyl, heterocyclyl-C 1-10 -alkyl, heteroaryl, heteroaryl-C 1-10 -alkyl, or a bond;  
 
 Y 5  is selected from the group consisting of —CO—, —O—CO—, —SO 2 — and —PO 2 —;  
 R 5  is hydrogen, aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl-substituted alkyl, or R 5  and R 6  may be taken together with the atoms to which they are attached to form a heterocycle of 5 to 7 members; and  
 R 6  is alkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aralkyl, aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkenoxy, alkynoxy, aralkoxy, aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, arylamino, heterocyclyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl substituted aralkyl, oxocarbocyclyl-fused aryl, or an amino acid side chain selected from the group consisting of arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, cyclohexylalanine, leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, phenylalanine, phenylglycine, tyrosine, tryptophan, proline, alanine, ornithine, histidine, glutamine, norvaline, valine, threonine, serine, beta-cyanoalanine, 2-aminobutyric acid and allothreonine;  
   each of R c  and R d , independently, is selected from the group consisting of H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, Cy, and Cy-C 1-10  alkyl; wherein each of alkyl, alkenyl, alkynyl and Cy is optionally substituted with one to four substituents independently selected from R g ;    R g  is halogen, amino, carboxy, —COO—C 1-4  alkyl, —P(O)(OH) 2 , —P(O)(OH)(O—C 1-4  alkyl), —P(O)(C 1-4  alkyl) 2 , —P(O)(OH)(C 1-4  alkyl), —P(O)(O—C 1-4  alkyl)(C 1-4  alkyl), —SO 2 —C 1-4  alkyl, —CO—NH 2 , —CO—NH(C 1-4  alkyl), —CO—N(C 1-4  alkyl) 2 , C 1-4  alkyl, C 1-4  alkoxy, aryl, aryl-C 1-4  alkoxy, hydroxy, CF 3 , or aryloxy; and    m is 0, 1 or 2.    
   
   
       14 . The composition of  claim 13 , wherein Z 5  is aryl; L c  is —NR c —C(O)—NR d —; and Z 6  is aryl.  
   
   
       15 . The composition of  claim 14 , wherein R 4  is o-methylphenyl-ureido-phenyl-CH 2 —.  
   
   
       16 . The composition of  claim 15 , wherein Y 5  is —CO— or —O—CO—.  
   
   
       17 . The composition of  claim 16 , wherein R 5  is H or C 1-2  alkyl.  
   
   
       18 . The composition of  claim 17 , wherein R 6  is an amino acid side chain selected from the group consisting of leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, alanine, norvaline, valine and 2-aminobutyric acid.  
   
   
       19 . The composition of  claim 18 , wherein R 6  is the side chain of leucine or isoleucine.  
   
   
       20 . The composition of  claim 13 , wherein Z 1  is phenyl optionally substituted with Cy, —CO—R d , halogen, oxo, or aryl-substituted alkenyl.  
   
   
       21 . The composition of  claim 13 , wherein L a  is —SO2—.  
   
   
       22 . The composition of  claim 13 , wherein Z 2  is azetidine, pyrrole, pyrrolidine, imidazole, piperidine, or morpholine.  
   
   
       23 . The composition of  claim 13 , wherein said compound is 5192, 5283, 6696, 6697, 6714, 7234, 7256, 7578, 7662, 8221, 8308, 8309, 8341, 8342, 8343, 8367, 8368, 8469, 8491, 8554, 8555, 8571, 8642, 8685, 8689, 8690, 8698, 8749, 8758, 8796, 8797, 8809, 9120, 9169, 9171, 9182, 9227, 9264, 9315, 9418, 9621, 7200, 7328, 7399, 7855, 8205, 8290, 8291, 8294, 8295, 8582, 8583, 8585, 8586, 8628, 8674, 8723, 8746, or 8629.  
   
   
       24 . The composition of  claim 13 , wherein the compound is modified with a polyethylene glycol.  
   
   
       25 . A method of inhibiting VLA-4-dependent cell adhesion, comprising administering to a patient in need thereof an effective amount of a compound of the following formula:  
       R 3 -L-L′-R 1    wherein    R 1  is Z 1 -L a -Z 2 -, in which 
 Z 1  is aryl optionally substituted with Cy, —CO—R d , halogen, oxo, or aryl-substituted alkenyl;  
 L a  is —O—C(O)—, —C(O)—O—, —C(O)—NR c —, —NR c —C(O)—, or —SO 2 —; and  
 Z 2  is heteroaryl, heterocyclyl, or a bond;  
 where Cy represents cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;  
   L 1  is                          in which 
 Y 1  is —NR c —C(O)—, —NR c —, —NR c —S(O) 2 —, or —NR c —C(NR d )— 
 R 2  is H or C 1-5  alkyl;  
 Y 2  is a bond or —C(R h )(R i )_; and  
 X is —C(O)OR c ;  
 where each of R c , R d , R h , and R i , independently, is H or C 1-5  alkyl;  
   L is                          in which 
 Y 3  is a bond, C 1-5  alkyl, or C 1-5  alkenyl; and  
 Y 4  is a bond, —C(O)—NR c —, —C(O)—, —NR c —, or —O—, where R c  is H or C 1-5  alkyl; and  
   R 3  is a moiety of the formula:                          in which 
 R 4  is Z 5 -L c -Z 6 -, where 
 Z 5  is aryl, aryl-C 1-10 -alkyl, aryl-C 1-10 -alkenyl, aryl-C 1-10 -alkynyl, heteroaryl, heteroaryl-C 1-10 -alkyl, heteroaryl-C 1-10 -alkenyl, or heteroaryl-C 1-10 -alkynyl;  
 L c  is —C(O)—, —S(O) m —, —O—C(O)—, —C(O)—O—, —C(O)—NR c —, —NR c —C(O)—, —NR c —C(O)—NR d —, —SO 2 —NR c —, —NR c —SO 2 —, —O—, —NR c —, or a bond, where each of R c  and R d , independently, is H or C 1-5  alkyl; and  
 Z 6  is aryl, aryl-C 1-10 -alkyl, heterocyclyl, heterocyclyl-C 1-10 -alkyl, heteroaryl, heteroaryl-C 1-10 -alkyl, or a bond;  
 
 Y 5  is selected from the group consisting of —CO—, —O—CO—, —SO 2 — and —PO 2 —;  
 R 5  is hydrogen, aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl-substituted alkyl, or R 5  and R 6  may be taken together with the atoms to which they are attached to form a heterocycle of 5 to 7 members; and  
 R 6  is alkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aralkyl, aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkenoxy, alkynoxy, aralkoxy, aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, arylamino, heterocyclyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl substituted aralkyl, oxocarbocyclyl-fused aryl, or an amino acid side chain selected from the group consisting of arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, cyclohexylalanine, leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, phenylalanine, phenylglycine, tyrosine, tryptophan, proline, alanine, ornithine, histidine, glutamine, norvaline, valine, threonine, serine, beta-cyanoalanine, 2-aminobutyric acid and allothreonine;  
   each of R c  and R d , independently, is selected from the group consisting of H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, Cy, and Cy-C 1-10  alkyl; wherein each of alkyl, alkenyl, alkynyl and Cy is optionally substituted with one to four substituents independently selected from R g ;    R g  is halogen, amino, carboxy, —COO—C 1-4  alkyl, —P(O)(OH) 2 , —P(O)(OH)(O—C 1-4  alkyl), —P(O)(C 1-4  alkyl) 2 , —P(O)(OH)(C 1-4  alkyl), —P(O)(O—C 1-4  alkyl)(C 1-4  alkyl), —SO 2 —C 1-4  alkyl, —CO—NH 2 , —CO—NH(C 1-4  alkyl), —CO—N(C 1-4  alkyl) 2 , C 1-4  alkyl, C 1-4  alkoxy, aryl, aryl-C 1-4  alkoxy, hydroxy, CF 3 , or aryloxy; and    m is 0, 1 or 2.    
   
   
       26 . The method of  claim 25 , wherein Z 5  is aryl; L c  is —NR c —C(O)—NR d —; and Z 6  is aryl.  
   
   
       27 . The method of  claim 26 , wherein R 4  is o-methylphenyl-ureido-phenyl-CH 2 —.  
   
   
       28 . The method of  claim 27 , wherein Y 5  is —CO— or —O—CO—.  
   
   
       29 . The method of  claim 28 , wherein R 5  is H or C 1-2  alkyl.  
   
   
       30 . The method of  claim 29 , wherein R 6  is an amino acid side chain selected from the group consisting of leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, alanine, norvaline, valine and 2-aminobutyric acid.  
   
   
       31 . The method of  claim 30 , wherein R 6  is the side chain of leucine or isoleucine.  
   
   
       32 . The method of  claim 25 , wherein Z 1  is phenyl optionally substituted with Cy, —CO—R d , halogen, oxo, or aryl-substituted alkenyl.  
   
   
       33 . The method of  claim 25 , wherein L a  is —SO 2 —.  
   
   
       34 . The method of  claim 25 , wherein Z 2  is azetidine, pyrrole, pyrrolidine, imidazole, piperidine, or morpholine.  
   
   
       35 . The method of  claim 25 , wherein said compound is 5192, 5283, 6696, 6697, 6714, 7234, 7256, 7578, 7662, 8221, 8308, 8309, 8341, 8342, 8343, 8367, 8368, 8469, 8491, 8554, 8555, 8571, 8642, 8685, 8689, 8690, 8698, 8749, 8758, 8796, 8797, 8809, 9120, 9169, 9171, 9182, 9227, 9264, 9315, 9418, 9621, 7200, 7328, 7399, 7855, 8205, 8290, 8291, 8294, 8295, 8582, 8583, 8585, 8586, 8628, 8674, 8723, 8746, or 8629.  
   
   
       36 . The method of  claim 25 , wherein the compound is modified with a polyethylene glycol.