Cell adhesion inhibitors

A cell adhesion inhibitor having Formula (I)

• A—B (I),
• wherein
• A is selected from the group consisting of aliphatic acyl optionally substituted with N-alkyl- or N-arylamido;
• aroyl;
• alkyl- or arylsulfonyl;
• aralkylcarbonyl optionally substituted with aryl;
• alkoxycarbonyl;
• aralkyloxycarbonyl;
• cycloalkylcarbonyl optionally fused with aryl;
• alkylsulfonyl;
• aralkylsulfonyl;
• arylsulfonyl;
• cycloalkylsulfonyl optionally fused with aryl;
• aralkoxycarbonyl;
• aryloxycarbonyl;
• cycloalkyloxycarbonyl;
• alkenoyl optionally substituted with aryl;
• alkenylsulfonyl optionally substituted with aryl;
• alkynoyl optionally substituted with aryl;
• alkynylsulfonyl optionally substituted with aryl;
• cycloalkenylcarbonyl;
• cycloalkenylsulfonyl;
• cycloalkylalkanoyl;
• cylcoalkylalkylsulfonyl;
• arylaroyl, biarylsulfonyl;
• alkoxysulfonyl;
• aralkoxysulfonyl;
• aryloxysulfonyl;
• N-arylurea-substituted alkanoyl;
• N-arylurea-substituted alkylsulfonyl;
• cycloalkenyl-substituted carbonyl;
• cycloalkenyl-substituted sulfonyl;
• alkenoxycarbonyl optionally substituted with aryl;
• alkenoxysulfonyl optionally substituted with aryl;
• alkynoxycarbonyl optionally substituted with aryl;
• alkynoxysulfonyl optionally substituted with aryl;
• acylamino-substituted alkanoyl;
• acylamino-substituted alkylsulfonyl;
• aminocarbonyl-substituted alkanoyl;
• carbamoyl-substituted alkanoyl;
• carbamoyl-substituted alkylsulfonyl;
• carboxyalkyl-substituted aralkoyl;
• carboxyalkyl-substituted aralkylsulfonyl;
• oxocarbocyclyl-fused aroyl;
• oxocarbocyclyl-fused arylsulfonyl;
• N′,N′-alkyl, arylhydrazinocarbonyl;
• aryloxy-substituted alkanoyl;
• alkenyl;
• alkynyl;
• cycloalkyl;
• aryl-fused cycloalkyl;
• cycloalkenyl;
• aryl;
• aryl-substituted alkyl;
• aryl-substituted alkenyl or alkynyl;
• cycloalkyl-substituted alkyl;
• cycloalkenyl-substituted cylcoalkyl;
• biaryl;
• alkoxy;
• alkenoxy;
• alkynoxy;
• aryl-substituted alkoxy;
• alkylamino;
• alkenylamino;
• alkynylamino;
• aryl-substituted alkylamino;
• aryl-substituted alkenylamino;
• aryl-substituted alkynylamino;
• aryloxy;
• arylamino;
• N′-alkylurea-substituted alkyl;
• N-arylurea-substituted alkyl;
• alkylcarbonylamino-substituted alkyl;
• carboxyalkyl-substituted aralkyl;
• oxocarbocyclyl-fused aryl;
• arylurea-substituted arylalkylcarbonylamino;
• arylalkylcarbonylamino;
• and arylurea-substituted arylurea;
• and
• B is of Formula IIa
• wherein
• A1 is selected from the group consisting of NR1, O, S, (CR1R2)r, and N[(CR1R2)m(C═Y)A2R1];
• A2 is selected from the group consisting of O, NR2, S, and (CR1R2)r;
• X is selected from the group consisting of CH2, O, and S;
• Y is H2 or O;
• r=0 or 1;
• n=0, 1, 2, 3, 4, or 5;
• m=1, 2, 3, or 4;
• W is selected from the group consisting of CO2H, SO3H, PO4H2, tetrazole, and H;
• each of R1 and R2, independently, is selected from the group consisting of H, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocycle, and alkyl optionally substituted with cycloalkyl, cycloalkenyl, heterocycle, alkenyl, alkynyl, alkoxyl, hydroxyl, halogen, aralkoxy, thioalkoxy, carboxy, alkoxycarbonyl, or carboxamide;
• R3 is R1, or alkyl substituted with heteroaryl, aminocarbonyl, amino, guanidine, amido, urea, alkylcarbonyl, or alkoxyaryl;
• each of R5 and R6, independently, is selected from the group consisting of H, OR1, halogen, alkyl, SR1, NZR12, and NR1R2;
• Z is CO, or (CR1R2)n;
• and
• R12 is selected from the group consisting of H, alkyl, cycloalkenyl, aryl, aralkyl, heterocycle;
• alkyl optionally substituted with cycloalkyl, heterocycle, alkoxyl, hydroxyl, halogen, aralkoxy, thioalkoxy, carboxy, alkoxycarbonyl, carboxamide, and aralkoxy,
• provided that A contains at least one cyclic moiety.

A cell adhesion inhibitor having Formula (I)

• A—B (I),
• wherein
• A comprises a VLA-4 specificity determinant which does not impart significant IIb/IIIa activity and is selected from the group consisting of aliphatic acyl optionally substituted with N-alkyl- or N-arylamido;
• aroyl;
• alkyl- or arylsulfonyl;
• aralkylcarbonyl optionally substituted with aryl;
• alkoxycarbonyl;
• aralkyloxycarbonyl;
• cycloalkylcarbonyl optionally fused with aryl;
• alkylsulfonyl;
• aralkylsulfonyl;
• arylsulfonyl;
• cycloalkylsulfonyl optionally fused with aryl;
• aralkoxycarbonyl;
• aryloxycarbonyl;
• cycloalkyloxycarbonyl;
• alkenoyl optionally substituted with aryl;
• alkenylsulfonyl optionally substituted with aryl;
• alkynoyl optionally substituted with aryl;
• alkynylsulfonyl optionally substituted with aryl;
• cycloalkenylcarbonyl;
• cycloalkenylsulfonyl;
• cycloalkylalkanoyl;
• cylcoalkylalkylsulfonyl;
• arylaroyl, biarylsulfonyl;
• alkoxysulfonyl;
• aralkoxysulfonyl;
• aryloxysulfonyl;
• N-arylurea-substituted alkanoyl;
• N-arylurea-substituted alkylsulfonyl;
• cycloalkenyl-substituted carbonyl;
• cycloalkenyl-substituted sulfonyl;
• alkenoxycarbonyl optionally substituted with aryl;
• alkenoxysulfonyl optionally substituted with aryl;
• alkynoxycarbonyl optionally substituted with aryl;
• alkynoxysulfonyl optionally substituted with aryl;
• acylamino-substituted alkanoyl;
• acylamino-substituted alkylsulfonyl;
• aminocarbonyl-substituted alkanoyl;
• carbamoyl-substituted alkanoyl;
• carbamoyl-substituted alkylsulfonyl;
• heterocyclylalkanoyl;
• carboxyalkyl-substituted aralkoyl;
• carboxyalkyl-substituted aralkylsulfonyl;
• oxocarbocyclyl-fused aroyl;
• oxocarbocyclyl-fused arylsulfonyl;
• N′, N′-alkyl, arylhydrazinocarbonyl;
• aryloxy-substituted alkanoyl;
• alkenyl;
• alkynyl;
• cycloalkyl;
• aryl-fused cycloalkyl;
• cycloalkenyl;
• aryl;
• aryl-substituted alkyl;
• aryl-substituted alkenyl;
• aryl-substituted alkynyl;
• cycloalkyl-substituted alkyl;
• cycloalkenyl-substituted cylcoalkyl;
• biaryl;
• alkoxy;
• alkenoxy;
• alkynoxy;
• aryl-substituted alkoxy;
• alkylamino;
• alkenylamino;
• alkynylamino;
• aryl-substituted alkylamino;
• aryl-substituted alkenylamino;
• aryl-substituted alkynylamino;
• aryloxy;
• arylamino;
• N-alkylurea-substituted alkyl;
• N-arylurea-substituted alkyl;
• alkylcarbonylamino-substituted alkyl;
• heterocyclyl;
• heterocyclyl-substituted amino;
• carboxyalkyl substituted aralkyl;
• oxocarbocyclyl-fused aryl;
• alkylaminocarbonyl;
• arylamino carbonyl and aralkylaminocarbonyl optionally substituted with bis(alkylsulfonyl)amino, alkoxycarbonylamino or alkenyl;
• heterocyclylsulfonyl;
• heterocyclyloxycarbonyl;
• mono- or di-alkylaminocarbonyl optionally substituted with aryl;
• mono- or di-aralkylaminocarbonyl;
• mono- or di-arylaminocarbonyl;
• (aryl)(alkyl)aminocarbonyl;
• mono- or di-cycloalkylaminocarbonyl;
• heterocyclylaminocarbonyl;
• (alkyl)(heterocyclyl)aminocarbonyl;
• (aralkyl)(heterocyclyl)aminocarbonyl;
• alkylaminosulfonyl;
• arylaminosulfonyl;
• alkenyl- or alkynyl-aminocarbonyl optionally substituted with aryl;
• alkenyl- or alkynyl-aminosulfonyl optionally substituted with aryl;
• heterocyclylaminosulfonyl;
• aryl-substituted alkenoxy;
• aryl-substituted alkynoxy;
• arylurea-substituted arylalkylcarbonylamino, heteroarylamido-substituted arylalkylcarbonylamino, and arylurea-substituted arylurea;
• and
• B is of Formula IIa
• wherein
• A1 is selected from the group consisting of NR1, O, S, (CR1R2)r, and N[(CR1R2)m(C═Y)A2R1];
• A2 is selected from the group consisting of O, NR2, S, and (CR1R2)r;
• X is selected from the group consisting of CH2, O, and S;
• Y is H2 or O;
• r=0 or 1;
• n=0, 1, 2, 3, 4, or 5;
• m=1, 2, 3, or 4;
• W is selected from the group consisting of CO2H, SO3H, PO4H2, tetrazole, and H;
• each of R1 and R2, independently, is selected from the group consisting of H, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocycle, and alkyl optionally substituted with cycloalkyl, cycloalkenyl, heterocycle, alkenyl, alkynyl, alkoxyl, hydroxyl, halogen, aralkoxy, thioalkoxy, carboxy, alkoxycarbonyl, or carboxamide;
• R3 is R1, or alkyl substituted with heteroaryl, aminocarbonyl, amino, guanidine, amido, urea, alkylcarbonyl, or alkoxyaryl;
• each of R5 and R6, independently, is selected from the group consisting of H, OR1, halogen, alkyl, SR1, NZR12, and NR1R2;
• Z is CO or (CR1R2)n;
• and
• R12 is selected from the group consisting of H, alkyl, cycloalkenyl, aryl, aralkyl, heterocycle;
• alkyl optionally substituted with cycloalkyl, heterocycle, alkoxyl, hydroxyl, halogen, aralkoxy, thioalkoxy, carboxy, alkoxycarbonyl, carboxamide, and aralkoxy
• provided that the cell adhesion inhibitor does not impart GP IIbIIIa activity.

A cell adhesion inhibitor having Formula (I)

• A—B (I),
• wherein
• A comprises a VLA-4 specificity determinant which does not impart significant IIb/IIIa activity and is selected from the group consisting of aliphatic acyl optionally substituted with N-alkyl- or N-arylamido;
• aroyl;
• heterocycloyl;
• alkyl- or arylsulfonyl;
• aralkylcarbonyl optionally substituted with aryl;
• heterocycloalkylcarbonyl;
• alkoxycarbonyl;
• aralkyloxycarbonyl;
• cycloalkylcarbonyl optionally fused with aryl;
• heterocycloalkoxycarbonyl;
• alkylaminocarbonyl;
• arylamino carbonyl and aralkylaminocarbonyl optionally substituted with bis(alkylsulfonyl)amino, alkoxycarbonylamino or alkenyl;
• alkylsulfonyl;
• aralkylsulfonyl;
• arylsulfonyl;
• cycloalkylsulfonyl optionally fused with aryl;
• heterocyclylsulfonyl;
• heterocyclylalkylsulfonyl;
• aralkoxycarbonyl;
• aryloxycarbonyl;
• cycloalkyloxycarbonyl;
• heterocyclyloxycarbonyl;
• heterocyclylalkoxycarbonyl;
• mono- or di-alkylaminocarbonyl optionally substituted with aryl;
• (alkyl)(aralkyl)aminocarbonyl;
• mono- or di-aralkylaminocarbonyl;
• mono- or di-arylaminocarbonyl;
• (aryl)(alkyl)aminocarbonyl;
• mono- or di-cycloalkylaminocarbonyl;
• heterocyclylaminocarbonyl;
• heterocyclylalkylaminocarbonyl;
• (alkyl)(heterocyclyl)aminocarbonyl;
• (alkyl)(heterocyclylalkyl)aminocarbonyl;
• (aralkyl)(heterocyclyl)aminocarbonyl;
• (aralkyl)(heterocyclylalkyl)aminocarbonyl;
• alkenoyl optionally substituted with aryl;
• alkenylsulfonyl optionally substituted with aryl;
• alkynoyl optionally substituted with aryl;
• alkynylsulfonyl optionally substituted with aryl;
• cycloalkenylcarbonyl;
• cycloalkenylsulfonyl;
• cycloalkylalkanoyl;
• cylcoalkylalkylsulfonyl;
• arylaroyl, biarylsulfonyl;
• alkoxysulfonyl;
• aralkoxysulfonyl;
• alkylaminosulfonyl;
• aryloxysulfonyl;
• arylaminosulfonyl;
• N-arylurea-substituted alkanoyl;
• N-arylurea-substituted alkylsulfonyl;
• cycloalkenyl-substituted carbonyl;
• cycloalkenyl-substituted sulfonyl;
• alkenoxycarbonyl optionally substituted with aryl;
• alkenoxysulfonyl optionally substituted with aryl;
• alkynoxycarbonyl optionally substituted with aryl;
• alkynoxysulfonyl optionally substituted with aryl;
• alkenyl- or alkynyl-aminocarbonyl optionally substituted with aryl;
• alkenyl- or alkynylaminosulfonyl optionally substituted with aryl;
• acylamino-substituted alkanoyl;
• acylamino-substituted alkylsulfonyl;
• aminocarbonyl-substituted alkanoyl;
• carbamoyl-substituted alkanoyl;
• carbamoyl-substituted alkylsulfonyl;
• heterocyclylalkanoyl;
• heterocyclylaminosulfonyl;
• carboxyalkyl-substituted aralkoyl;
• carboxyalkyl-substituted aralkylsulfonyl;
• oxocarbocyclyl-fused aroyl;
• oxocarbocyclyl-fused arylsulfonyl;
• heterocyclylalkanoyl;
• N′,N′-alkyl, arylhydrazinocarbonyl;
• aryloxy-substituted alkanoyl;
• heterocyclylalkylsulfonyl;
• alkenyl;
• alkynyl;
• cycloalkyl;
• aryl-fused cycloalkyl;
• cycloalkenyl;
• aryl;
• aryl-substituted alkyl;
• aryl-substituted alkenyl;
• aryl-substituted alkynyl;
• cycloalkyl-substituted alkyl;
• cycloalkenyl-substituted cylcoalkyl;
• biaryl;
• alkoxy;
• alkenoxy;
• alkynoxy;
• aryl-substituted alkoxy;
• aryl-substituted alkenoxy;
• aryl-substituted alkynoxy;
• alkylamino;
• alkenylamino;
• alkynylamino;
• aryl-substituted alkylamino;
• aryl-substituted alkenylamino;
• aryl-substituted alkynylamino;
• aryloxy;
• arylamino;
• N-alkylurea-substituted alkyl;
• N-arylurea-substituted alkyl;
• alkylcarbonylamino-substituted alkyl;
• aminocarbonyl-substituted alkyl;
• heterocyclyl;
• heterocyclyl-substituted alkyl;
• heterocyclyl-substituted amino;
• carboxyalkyl-substituted aralkyl;
• oxocarbocyclyl-fused aryl and heterocyclylalkyl;
• and
• B is of Formula IIa
• wherein
• A1 is selected from the group consisting of NR1, O, S, (CR1R2)r, and N[(CR1R2)m(C═Y)A2R1];
• A2 is selected from the group consisting of O, NR2, S, and (CR1R2)r;
• X is selected from the group consisting of CH2, O, and S;
• Y is H2 or O;
• r=0 or 1;
• n=0, 1, 2, 3, 4, or 5;
• m=1, 2, 3, or 4;
• W is selected from the group consisting of CO2H, SO3H, PO4H2, tetrazole, and H;
• each of R1 and R2, independently, is selected from the group consisting of H, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocycle, and alkyl optionally substituted with cycloalkyl, cycloalkenyl, heterocycle, alkenyl, alkynyl, alkoxyl, hydroxyl, halogen, aralkoxy, thioalkoxy, carboxy, alkoxycarbonyl, or carboxamide;
• R3 is R1, or alkyl substituted with heteroaryl, aminocarbonyl, amino, guanidine, amido, urea, alkylcarbonyl, or alkoxyaryl;
• each of R5 and R6, independently, is selected from the group consisting of H, OR1, halogen, alkyl, SR1, NZR12, and NR1R2;
• Z is CO or (CR1R2)n;
• and
• R12 is selected from the group consisting of H, alkyl, cycloalkenyl, aryl, aralkyl, heterocycle;
• alkyl optionally substituted with cycloalkyl, heterocycle, alkoxyl, hydroxyl, halogen, aralkoxy, thioalkoxy, carboxy, alkoxycarbonyl, carboxamide, and aralkoxy;
• provide that the cell adhesion inhibitor does not impart any GP IIbIIIa activity.