US2023365609A1PendingUtilityA1
Highly potent multimeric e-selectin antagonists
Est. expiryOct 7, 2036(~10.2 yrs left)· nominal 20-yr term from priority
A61P 35/00A61K 47/60C07H 7/06C07H 15/26C07H 15/207A61K 31/7034A61P 35/04A61P 1/04C07H 7/04A61P 29/00A61K 47/549A61P 11/00A61P 3/10A61P 35/02A61P 1/00A61K 31/7052
76
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Claims
Abstract
Compounds, compositions, and methods for treatment and/or prevention of at least one disease, disorder, and/or condition by inhibiting binding of an E-selectin to an E-selectin ligand are disclosed. For example, highly potent multimeric E-selectin antagonist are dessorbed and pharmaceutical compositions comprising at least one of the same.
Claims
exact text as granted — not AI-modified1 - 68 . (canceled)
69 . A method for treatment of at least one acute leukocyte-mediated lung injury, the method comprising administering to a subject in need thereof an effective amount of at least one compound chosen from glycomimetic E-selectin antagonists of Formula (I):
and pharmaceutically acceptable salts thereof,
wherein
each R 1 , which may be identical or different, is independently chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, and —NHC(═O)R 5 groups, wherein each R 5 , which may be identical or different, is independently chosen from C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups;
each R 2 , which may be identical or different, is independently chosen from halo, —OY 1 , —NY 1 Y 2 , —OC(═O)Y 1 , —NHC(═O)Y 1 , and —NHC(═O)NY 1 Y 2 groups, wherein each Y 1 and each Y 2 , which may be identical or different, are independently chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 haloalkyl, C 2-12 haloalkenyl, C 2-12 haloalkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups, wherein Y 1 and Y 2 may join together along with the nitrogen atom to which they are attached to form a ring;
each R 3 , which may be identical or different, is independently chosen from
wherein each R 6 , which may be identical or different, is independently chosen from H, C 1-12 alkyl, and C 1-12 haloalkyl groups, and wherein each R 7 , which may be identical or different, is independently chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, —OY 3 , —NHOH, —NHOCH 3 , —NHCN, and —NY 3 Y 4 groups, wherein each Y 3 and each Y 4 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups, wherein Y 3 and Y 4 may join together along with the nitrogen atom to which they are attached to form a ring;
each R 4 , which may be identical or different, is independently chosen from —CN, C 1-4 alkyl, and C 1-4 haloalkyl groups;
m is 2; and
L is chosen from
wherein Q is chosen from
wherein R 8 is chosen from H and benzyl, and wherein p is chosen from integers ranging from 0 to 30.
70 . The method according to claim 69 , wherein the at least one compound is chosen from compounds having the following Formula:
and pharmaceutically acceptable salts of any of the foregoing.
71 . The method of claim 69 , wherein the at least one compound is chosen from compounds having the following Formulae:
and pharmaceutically acceptable salts of any of the foregoing.
72 . The method of claim 69 , wherein the at least one compound is chosen from compounds having the following Formulae:
73 . The method of claim 69 , wherein the at least one compound is
74 . The method of claim 69 , wherein the at least one acute leukocyte-mediated lung injury comprises acute respiratory distress syndrome.
75 . The method according to claim 74 , wherein the at least one compound is chosen from compounds having the following Formula:
and pharmaceutically acceptable salts of any of the foregoing.
76 . The method of claim 74 , wherein the at least one compound is chosen from compounds having the following Formulae:
and pharmaceutically acceptable salts of any of the foregoing.
77 . The method of claim 74 , wherein the at least one compound is chosen from compounds having the following Formulae:
78 . The method of claim 74 , wherein the at least one compound is
79 . A method for treatment of at least one inflammatory bowel disease, the method comprising administering to a subject in need thereof an effective amount of at least one compound chosen from glycomimetic E-selectin antagonists of Formula (I):
and pharmaceutically acceptable salts thereof,
wherein
each R 1 , which may be identical or different, is independently chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, and —NHC(═O)R 5 groups, wherein each R 5 , which may be identical or different, is independently chosen from C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups;
each R 2 , which may be identical or different, is independently chosen from halo, —OY 1 , —NY 1 Y 2 , —OC(═O)Y 1 , —NHC(═O)Y 1 , and —NHC(═O)NY 1 Y 2 groups, wherein each Y 1 and each Y 2 , which may be identical or different, are independently chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 haloalkyl, C 2-12 haloalkenyl, C 2-12 haloalkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups, wherein Y 1 and Y 2 may join together along with the nitrogen atom to which they are attached to form a ring;
each R 3 , which may be identical or different, is independently chosen from
wherein each R 6 , which may be identical or different, is independently chosen from H, C 1-12 alkyl, and C 1-12 haloalkyl groups, and wherein each R 7 , which may be identical or different, is independently chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, —OY 3 , —NHOH, —NHOCH 3 , —NHCN, and —NY 3 Y 4 groups, wherein each Y 3 and each Y 4 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups, wherein Y 3 and Y 4 may join together along with the nitrogen atom to which they are attached to form a ring;
each R 4 , which may be identical or different, is independently chosen from —CN, C 1-4 alkyl, and C 1-4 haloalkyl groups;
m is 2; and
L is chosen from
wherein Q is chosen from
wherein R 8 is chosen from H and benzyl, and wherein p is chosen from integers ranging from 0 to 30.
80 . The method according to claim 79 , wherein the at least one compound is chosen from compounds having the following Formula:
and pharmaceutically acceptable salts of any of the foregoing.
81 . The method of claim 79 , wherein the at least one compound is chosen from compounds having the following Formulae:
and pharmaceutically acceptable salts of any of the foregoing.
82 . The method of claim 79 , wherein the at least one compound is chosen from compounds having the following Formulae:
83 . The method of claim 79 , wherein the at least one compound is
84 . The method of claim 79 , wherein the at least one inflammatory bowel disease comprises ulcerative colitis.
85 . The method of claim 79 , wherein the at least one inflammatory bowel disease comprises Crohn's disease.
86 . The method according to claim 85 , wherein the at least one compound is chosen from compounds having the following Formula:
and pharmaceutically acceptable salts of any of the foregoing.
87 . The method of claim 85 , wherein the at least one compound is chosen from compounds having the following Formulae:
and pharmaceutically acceptable salts of any of the foregoing.
88 . The method of claim 85 , wherein the at least one compound is chosen from compounds having the following Formulae:
89 . The method of claim 85 , wherein the at least one compound is
90 . A method for treatment of diabetes, the method comprising administering to a subject in need thereof an effective amount of at least one compound chosen from glycomimetic E-selectin antagonists of Formula (I):
and pharmaceutically acceptable salts thereof,
wherein
each R 1 , which may be identical or different, is independently chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, and —NHC(═O)R 5 groups, wherein each R 5 , which may be identical or different, is independently chosen from C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups;
each R 2 , which may be identical or different, is independently chosen from halo, —OY 1 , —NY 1 Y 2 , —OC(═O)Y 1 , —NHC(═O)Y 1 , and —NHC(═O)NY 1 Y 2 groups, wherein each Y 1 and each Y 2 , which may be identical or different, are independently chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 haloalkyl, C 2-12 haloalkenyl, C 2-12 haloalkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups, wherein Y 1 and Y 2 may join together along with the nitrogen atom to which they are attached to form a ring;
each R 3 , which may be identical or different, is independently chosen from
wherein each R 6 , which may be identical or different, is independently chosen from H, C 1-12 alkyl, and C 1-12 haloalkyl groups, and wherein each R 7 , which may be identical or different, is independently chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, —OY 3 , —NHOH, —NHOCH 3 , —NHCN, and —NY 3 Y 4 groups, wherein each Y 3 and each Y 4 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups, wherein Y 3 and Y 4 may join together along with the nitrogen atom to which they are attached to form a ring;
each R 4 , which may be identical or different, is independently chosen from —CN, C 1-4 alkyl, and C 1-4 haloalkyl groups;
m is 2; and
L is chosen from
wherein Q is chosen from
wherein R 8 is chosen from H and benzyl, and wherein p is chosen from integers ranging from 0 to 30.
91 . The method according to claim 90 , wherein the at least one compound is chosen from compounds having the following Formula:
and pharmaceutically acceptable salts of any of the foregoing.
92 . The method of claim 90 , wherein the at least one compound is chosen from compounds having the following Formulae:
and pharmaceutically acceptable salts of any of the foregoing.
93 . The method of claim 90 , wherein the at least one compound is chosen from compounds having the following Formulae:
94 . The method of claim 90 , wherein the at least one compound is
95 . A method for treatment of at least one disease, disorder, and/or condition where an increase in white blood cells is useful, the method comprising administering to a subject in need thereof an effective amount of at least one compound chosen from glycomimetic E-selectin antagonists of Formula (I):
and pharmaceutically acceptable salts thereof,
wherein
each R 1 , which may be identical or different, is independently chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, and —NHC(═O)R 5 groups, wherein each R 5 , which may be identical or different, is independently chosen from C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups;
each R 2 , which may be identical or different, is independently chosen from halo, —OY 1 , —NY 1 Y 2 , —OC(═O)Y 1 , —NHC(═O)Y 1 , and —NHC(═O)NY 1 Y 2 groups, wherein each Y 1 and each Y 2 , which may be identical or different, are independently chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 haloalkyl, C 2-12 haloalkenyl, C 2-12 haloalkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups, wherein Y 1 and Y 2 may join together along with the nitrogen atom to which they are attached to form a ring;
each R 3 , which may be identical or different, is independently chosen from
wherein each R 6 , which may be identical or different, is independently chosen from H, C 1-12 alkyl, and C 1-12 haloalkyl groups, and wherein each R 7 , which may be identical or different, is independently chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, —OY 3 , —NHOH, —NHOCH 3 , —NHCN, and —NY 3 Y 4 groups, wherein each Y 3 and each Y 4 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups, wherein Y 3 and Y 4 may join together along with the nitrogen atom to which they are attached to form a ring;
each R 4 , which may be identical or different, is independently chosen from —CN, C 1-4 alkyl, and C 1-4 haloalkyl groups;
m is 2; and
L is chosen from
wherein Q is chosen from
wherein R 8 is chosen from H and benzyl, and wherein p is chosen from integers ranging from 0 to 30.
96 . The method according to claim 95 , wherein the at least one compound is chosen from compounds having the following Formulae:
and pharmaceutically acceptable salts of any of the foregoing.
97 . The method of claim 95 , wherein the at least one compound is chosen from compounds having the following Formulae:
and pharmaceutically acceptable salts of any of the foregoing.
98 . The method of claim 95 , wherein the at least one compound is chosen from compounds having the following Formulae:
99 . The method of claim 95 , wherein the at least one compound is
100 . The method according to claim 95 , wherein the at least one disease, disorder, and/or condition is a hematopoietic deficit in the patient resulting from radiation exposure.
101 . The method according to claim 100 , wherein the at least one compound is chosen from compounds having the following Formulae:
and pharmaceutically acceptable salts of any of the foregoing.
102 . The method of claim 100 , wherein the at least one compound is chosen from compounds having the following Formulae:
and pharmaceutically acceptable salts of any of the foregoing.
103 . The method of claim 100 , wherein the at least one compound is chosen from compounds having the following Formulae:
104 . The method of claim 100 , wherein the at least one compound isJoin the waitlist — get patent alerts
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