Cell adhesion inhibitors
View Patent ↗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 salt thereof, wherein:
X is selected from the group consisting of —CO 2 H, —SO 2 R 5 , and —SO 3 H;
Y is —CO—;
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, 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 alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl;
R 5 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, or alkynyl; and
n is 0, 1 or 2.
2. The cell adhesion inhibitory 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.
3. The cell adhesion inhibitory compound according to claim 1 , wherein R 2 is hydrogen or methyl.
4. The cell adhesion inhibitory compound according to claim 3 , wherein R 2 is hydrogen.
5. The cell adhesion inhibitory 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, and asparagine side-chain.
6. The cell adhesion inhibitory compound according to claim 5 , wherein R 3 is selected from the group consisting of isobutyl, 2-(methylthio)-ethyl, 3-(hydroxypropylthio)-methyl, 2-(methylsulfonyl)-ethyl and 4-acetylamino-butyl, 4-(methylsulfonylamino)-butyl.
7. The cell adhesion inhibitory compound according to claim 1 , wherein R 4 is methyl.
8. The cell adhesion inhibitory compound according to claim 1 , wherein n is 1.
9. A pharmaceutical composition comprising a cell adhesion inhibitory compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of —CO 2 H, —SO 2 R 5 , and —SO 3 H;
Y is —CO—;
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, 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 alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl;
R 5 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, or alkynyl; and
n is 0, 1 or 2;
in an amount effective for prevention, inhibition or suppression of cell adhesion;
and a pharmaceutically acceptable carrier.