Multimeric VLA-4 antagonists comprising polymer moieties

A conjugate of the formula I:

• B is a polymer moiety comprising at least one polymeric unit, the polymer moiety having an average molecular weight of from about 20,000 to 60,000;
• q is from about 2 to about 20;
• A at each occurrence is independently a compound of formula II
• or a pharmaceutically acceptable salt thereof, wherein
• each polymeric unit is derived only from alkylene oxide monomers selected from the group consisting of ethylene oxide, propylene oxide, isopropylene oxide, butylene oxide, and mixtures thereof, and the polymer moiety contains optional linker groups between polymeric units;
• J is a group of formula (b):
• wherein
• m is 1;
• n is an integer equal to 0, 1 or 2;
• and
• R is hydrogen, R101, R204, or R205,
• Ar1 is selected from the group consisting of phenyl and heteroaryl, wherein Ar1 is optionally covalently bound to the polymer moiety wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar1,
• and where Ar1 is optionally substituted with from 1 to 3 groups that are independently R201, C3-C10 cycloalkyl optionally substituted with R201, heterocycloalkyl optionally substituted with R201, or C1-C6 alkyl optionally substituted with R201;
• Ar2 is phenyl, wherein Ar2 is optionally covalently bound to the polymer moiety and wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar2,
• and where Ar2 is optionally substituted with from 1 to 3 groups that are independently R201, C3-C10 cycloalkyl optionally substituted with R201, heterocycloalkyl optionally substituted with R201, or C1-C6 alkyl optionally substituted with R201;
• X is selected from the group consisting of —NR1—, —O—, —S—, —SO—, —SO2, and optionally substituted —CH2— which is optionally covalently bound to the polymer moiety wherein, in each case, the polymer moiety optionally comprises a linker which covalently links the polymer moiety;
• where R1 is selected from the group consisting of hydrogen and alkyl;
• T is a group of formula (d)
• wherein G is optionally substituted pyrido, wherein said pyrido optionally further comprises a covalent bond to a polymer moiety which optionally comprises a linker;
• R6 is a covalent bond to a polymer moiety which optionally comprises a linker, or R6 is —H, R201, or —CH2C(O)R17, wherein R17 is —OH, —OR18, or —NHR18, wherein R18 is R201, R204, or R205;
• R101 is alkyl optionally substituted with from 1 to 3 groups independently selected from R201, R202, R203, R204, and R205, where
• R201 is alkoxy, acyl, acylamino, acyloxy, amino, mono- or di(C1-C5)alkylamino, aminoacyl, aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, —C(O)O—(C1-C6)alkyl, or —C(O)O-aryl;
• R202 is C3-C10 cycloalkyl optionally substituted with from 1 to 5 groups which are independently oxo, thioxo, R201, heterocycloalkyl optionally substituted with R201, aryl optionally substituted with R201, or heteroaryl optionally substituted with R201;
• R203 is heterocycloalkyl optionally substituted with from 1 to 5 groups which are independently oxo, thioxo, R201, or C1-C5 alkyl optionally substituted with R201;
• R204 is aryl optionally substituted with from 1 to 3 groups that are independently R201, C3-C10 cycloalkyl optionally substituted with R201, heterocycloalkyl optionally substituted with R201, or C1-C5 alkyl optionally substituted with R201;
• R205 is heteroaryl optionally substituted with from 1 to 3 groups that are independently R201, C3-C10 cycloalkyl optionally substituted with R201, heterocycloalkyl optionally substituted with R201, or C1-C5 alkyl optionally substituted with R201;
• and
• R55 is —OH or a hydrolyzable ester, or R55 forms a hydrolyzable polymer ester with the polymer moiety, optionally through a linker;
• wherein each heteroaryl contains up to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
• wherein each heterocycloalkyl independently contains up to 10 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen;7
• provided that:
• A. at least one of J, R55, and T contains a covalent bond to the polymer moiety;
• and
• B. the conjugate of formula I has a molecular weight of no more than about 80,000.