US2014178303A1PendingUtilityA1
Heterobifunctional pan-selectin inhibitors
Est. expirySep 2, 2025(expired)· nominal 20-yr term from priority
A61P 37/00A61P 3/10A61P 9/14A61P 37/02A61P 35/04A61P 43/00A61P 37/08A61P 9/10A61P 9/00A61P 7/00A61P 37/06A61P 7/02A61P 25/00A61P 35/00A61P 31/04A61P 29/00A61P 35/02A61P 31/00A61P 17/02A61P 17/06A61P 1/00A61P 13/12A61P 19/10A61P 1/04A61P 17/04A61P 11/00A61P 11/16A61P 19/08A61P 21/04A61P 19/02A61P 11/06A61K 47/549C07H 15/22A61K 31/706C07H 15/26C07H 17/00
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Claims
Abstract
Compounds and methods are provided for modulating in vitro and in vivo processes mediated by selectin binding. More specifically, selectin modulators and their use are described, wherein the selectin modulators that modulate (e.g., inhibit or enhance) a selectin-mediated function comprise particular glycomimetics alone or linked to a member of a class of compounds termed BASAs (Benzyl Amino Sulfonic Acids) or a member of a class of compounds termed BACAs (Benzyl Amino Carboxylic Acids).
Claims
exact text as granted — not AI-modified1 - 25 . (canceled)
26 . 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 R 8 are independently selected where n=2;
R 2 =H, —C(═O)OX where X is C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or C 5 -C 14 aryl; —C(═O)NH(CH 2 ) n NH 2 , —[C(═O)NH(CH 2 ) n NHC(═O)] m (L) m Z, 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, —NH 2 , —NH—C(═O)—NHX, or —NH—C(═O)—X where n=0-2 and X is independently selected from C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl,
and any of the above ring compounds may be substituted with one to three independently selected of Cl, F, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 5 -C 14 aryl, or OY where Y is H, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 5 -C 14 aryl;
6′ sulfated GlcNAc, 6′ carboxylated GlcNAc, 6′ sulfated GalNAc, 6′ sulfated galactose, 6′ carboxylated galactose, or
where R 9 is aryl, heteroaryl, cyclohexane, t-butane, adamantane, or triazole, and any of R 9 may be substituted with one to three independently selected of Cl, F, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or OY where Y is H, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or C 5 -C 14 aryl;
or
where R 10 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, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or OY where Y is H, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl;
R 5 =H;
R 6 =H, fucose, mannose, arabinose, galactose or polyols;
R 7 =H, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or
and
R 8 =H, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl,
where n=0-3 and X is independently selected from H, OH, Cl, F, N 3 , NH 2 , C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 5 -C 14 aryl, OC 1 -C 8 alkanyl, OC 2 -C 8 alkenyl, OC 2 -C 8 alkynyl, and OC 5 -C 14 aryl, and any of the above ring compounds may be substituted with one to three independently selected of Cl, F, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 5 -C 14 aryl or OY where Y is H, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 5 -C 14 aryl.
27 . 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 R 8 are independently selected where n=2;
R 2 =H, —C(═O)OX where X is C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or C 5 -C 14 aryl; —C(═O)NH(CH 2 ) n NH 2 , —[C(═O)NH(CH 2 ) n NHC(═O)] m (L) m Z, 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, —NH 2 , —NH—C(═O)—NHX, or —NH—C(═O)—X where n=0-2 and X is independently selected from C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl,
and any of the above ring compounds may be substituted with one to three independently selected of Cl, F, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 5 -C 14 aryl, or OY where Y is H, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 5 -C 14 aryl;
6′ sulfated GlcNAc, 6′ carboxylated GlcNAc, 6′ sulfated GalNAc, 6′ sulfated galactose, 6′ carboxylated galactose, or
where R 9 is aryl, heteroaryl, cyclohexane, t-butane, adamantane, or triazole, and any of R 9 may be substituted with one to three independently selected of Cl, F, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or OY where Y is H, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or C 5 -C 14 aryl;
or
where R 10 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, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or OY where Y is H, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl;
R 5 =H;
R 6 =H, fucose, mannose, arabinose, galactose or polyols;
R 7 =H, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or
and
R 8 =H, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl,
where n=0-3 and X is independently selected from H, OH, Cl, F, N 3 , NH 2 , C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 5 -C 14 aryl, OC 1 -C 8 alkanyl, OC 2 -C 8 alkenyl, OC 2 -C 8 alkynyl, and OC 5 -C 14 aryl, and any of the above ring compounds may be substituted with one to three independently selected of Cl, F, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 5 -C 14 aryl or OY where Y is H, C 1 -C 8 alkanyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 5 -C 14 ary; wherein said compound further comprises a diagnostic or therapeutic agent.
28 . The method according to claim 26 or 27 , wherein R 6 is fucose.
29 . The method according to claim 26 or 27 , wherein R 7 is H.
30 . The method according to claim 26 or 27 , wherein R 4 is
31 . The method according to claim 26 or 27 , wherein R 4 is
where R 9 is defined according to claim 26 or 27 .
32 . The method according to claim 31 , wherein R 9 is cyclohexane.
33 . The method according to claim 26 or 27 , wherein R 6 is galactose.
34 . The method according to claim 26 or 27 , wherein R 2 is [C(═O)NH(CH 2 ) n NHC(═O)] m (L) m Z, where n, m, L and Z are defined according to claim 26 or 27 .
35 . The method according to claim 34 , wherein Z is
36 . The method according to claim 34 , wherein L is
and wherein the terminal carbonyl group of said L is attached to Z.
37 . The method according to claim 26 or 27 , wherein R 3 is —O—C(═O)—X or —NH—C(═O)—X, where X is defined according to claim 26 or 27 .
38 . The method according to claim 37 , wherein X is
39 . The method according to claim 26 or 27 , wherein R 1 is:
40 . The method according to claim 26 or 27 , wherein said compound has the formula XLV:
41 . The method according to claim 26 or 27 , wherein said compound has the formula L:
42 . The method according to claim 26 or 27 , wherein said physiologically acceptable salt is a sodium salt or a potassium salt.
43 . The method according to claim 26 or 27 , wherein the compound is administered in combination with a pharmaceutically acceptable carrier or diluent.
44 . The method according to claim 26 or 27 , wherein the compound is attached to a diagnostic or therapeutic agent.Cited by (0)
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