Heterobifunctional pan-selectin inhibitors

A method of inhibiting rejection of a transplanted tissue in a patient wherein said patient is a recipient of the transplanted tissue, comprising administering to the patient a compound of formula (I):

• or a physiologically acceptable salt thereof, wherein:
• where n=0-2, and R8 are independently selected where n=2;
• R2=H, —C(═O)OX where X is C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl or C5-C14 aryl;
• —C(═O)NH(CH2)nNH2, —[C(═O)NH(CH2)nNHC(═O)]m(L)mZ, where n=0-30, m=0-1, L is a linker, and Z is a benzyl amino sulfonic acid, a benzyl amino carboxylic acid, or a polyethylene glycol;
• —O—C(═O)—X, —NH2, —NH—C(═O)—NHX, or —NH—C(═O)—X where n=0-2 and X is independently selected from C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl,
• and any of the above ring compounds may be substituted with one to three independently selected of Cl, F, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C14 aryl, or OY where Y is H, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl, or C5-C14 aryl;
• 6′ sulfated GlcNAc, 6′ carboxylated GlcNAc, 6′ sulfated GalNAc, 6′ sulfated galactose, 6′ carboxylated galactose, or
• where R9 is aryl, heteroaryl, cyclohexane, t-butane, adamantane, or triazole, and any of R9 may be substituted with one to three independently selected of Cl, F, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl or OY where Y is H, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl or C5-C14 aryl;
• or
• where R10 is aryl, heteroaryl,
• where n=0-10, and any one of the above ring compounds may be substituted with one to three independently selected of Cl, F, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl or OY where Y is H, C1-C8 alkanyl, C2-C8 alkenyl or C2-C8 alkynyl;
• R5=H;
• R6=H, fucose, mannose, arabinose, galactose or polyols;
• R7=H, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl or
• and
• R8=H, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl,
• where n=0-3 and X is independently selected from H, OH, Cl, F, N3, NH2, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C14 aryl, OC1-C8 alkanyl, OC2-C8 alkenyl, OC2-C8 alkynyl, and OC5-C14 aryl, and any of the above ring compounds may be substituted with one to three independently selected of Cl, F, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C14 aryl or OY where Y is H, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl, or C5-C14 aryl.

A method of targeting an agent to a selectin-expressing cell, comprising contacting said selectin-expressing cell with a compound of formula (I):

• or a physiologically acceptable salt thereof, wherein:
• where n=0-2, and R8 are independently selected where n=2;
• R2=H, —C(═O)OX where X is C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl or C5-C14 aryl;
• —C(═O)NH(CH2)nNH2, —[C(═O)NH(CH2)nNHC(═O)]m(L)mZ, where n=0-30, m=0-1, L is a linker, and Z is a benzyl amino sulfonic acid, a benzyl amino carboxylic acid, or a polyethylene glycol;
• —O—C(═O)—X, —NH2, —NH—C(═O)—NHX, or —NH—C(═O)—X where n=0-2 and X is independently selected from C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl,
• and any of the above ring compounds may be substituted with one to three independently selected of Cl, F, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C14 aryl, or OY where Y is H, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl, or C5-C14 aryl;
• 6′ sulfated GlcNAc, 6′ carboxylated GlcNAc, 6′ sulfated GalNAc, 6′ sulfated galactose, 6′ carboxylated galactose, or
• where R9 is aryl, heteroaryl, cyclohexane, t-butane, adamantane, or triazole, and any of R9 may be substituted with one to three independently selected of Cl, F, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl or OY where Y is H, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl or C5-C14 aryl;
• or
• where R10 is aryl, heteroaryl,
• where n=0-10, and any one of the above ring compounds may be substituted with one to three independently selected of Cl, F, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl or OY where Y is H, C1-C8 alkanyl, C2-C8 alkenyl or C2-C8 alkynyl;
• R5=H;
• R6=H, fucose, mannose, arabinose, galactose or polyols;
• R7=H, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl or
• and
• R8=H, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl,
• where n=0-3 and X is independently selected from H, OH, Cl, F, N3, NH2, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C14 aryl, OC1-C8 alkanyl, OC2-C8 alkenyl, OC2-C8 alkynyl, and OC5-C14 aryl, and any of the above ring compounds may be substituted with one to three independently selected of Cl, F, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C14 aryl or OY where Y is H, C1-C8 alkanyl, C2-C8 alkenyl, C2-C8 alkynyl, or C5-C14 ary;
• wherein said compound further comprises a diagnostic or therapeutic agent.