US2023127765A1PendingUtilityA1
Combination of t-cell checkpoint inhibitors with inhibitors of e-selectin or cxcr4, or with heterobifunctional inhibitors of both e-selectin and cxcr4
Est. expiryAug 8, 2036(~10.1 yrs left)· nominal 20-yr term from priority
A61K 31/395A61K 39/3955A61K 31/7034C07K 16/2818A61K 2039/505A61K 31/197A61P 35/00A61K 47/61A61K 31/69A61K 31/702C07K 16/2827C07K 2317/76A61K 31/7068C07K 2317/21
69
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Claims
Abstract
Compositions and methods for the treatment of diseases, disorders, and/or conditions associated with the increased regulatory T lymphocyte cell function, comprising the administration of T-cell checkpoint inhibitors in combination with E-selectin inhibitors, C-X-C Motif Chemokine Receptor 4 (CXCR4) receptor inhibitors, and/or heterobifunctional inhibitors that comprise at least one E-selectin inhibitor linked to at least one CXCR4 receptor inhibitor, are disclosed.
Claims
exact text as granted — not AI-modified1 - 28 . (canceled)
29 . A method for treating cancer comprising administering to a subject in need thereof:
(1) an effective amount of pembrolizumab; and (2) an effective amount of at least one heterobifunctional inhibitor chosen from compounds of Formula (II):
and pharmaceutically acceptable salts thereof, wherein:
R 1 is 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;
R 2 is chosen from —OH, —NH 2 , —OC(═O)Y 1 , —NHC(═O)Y 1 , and —NHC(═O)NHY 1 groups, wherein Y 1 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups;
R 3 is chosen from —CN, —CH 2 CN, and —C(═O)Y 2 groups, wherein Y 2 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OZ 1 , —NHOH, —NHOCH 3 , —NHCN, and —NZ 1 Z 2 groups, wherein Z 1 and Z 2 , 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 Z 1 and Z 2 may together form a ring;
R 4 is chosen from C 3-8 cycloalkyl groups;
R 5 is independently chosen from H, halogen, 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;
n is chosen from integers ranging from 1 to 4; and
Linker is chosen from linker groups.
30 . The method of claim 29 , wherein at least one of (1) pembrolizumab and (2) the at least one heterobifunctional inhibitor is in the form of at least one pharmaceutical composition.
31 . The method of claim 29 , wherein pembrolizumab is in the form of a first pharmaceutical composition and the at least one heterobifunctional inhibitor is in the form of a second pharmaceutical composition.
32 . The method of claim 30 , wherein said at least one pharmaceutical composition further comprises at least one pharmaceutically acceptable ingredient.
33 . The method of claim 29 , wherein the at least one heterobifunctional inhibitor is chosen from compounds of Formula (IIa):
and pharmaceutically acceptable salts thereof.
34 . The method of claim 29 , wherein the at least one heterobifunctional inhibitor is GMI-1359.
35 . The method of claim 29 , wherein the subject has received or will receive chemotherapy and/or radiotherapy.
36 . The method of claim 35 , wherein the chemotherapy comprises administering an effective amount of bortezomib and/or gemcitabine.
37 . The method of claim 29 , wherein Linker is chosen from
38 . The method of claim 29 , wherein the at least one heterobifunctional inhibitor is chosen from:
and pharmaceutically acceptable salts of any of the foregoing.
39 . The method of claim 29 , wherein the at least one heterobifunctional inhibitor is chosen from:
and pharmaceutically acceptable salts of any of the foregoing.
40 . The method of claim 29 , wherein the at least one heterobifunctional inhibitor is chosen from
and pharmaceutically acceptable salts thereof.
41 . The method of claim 29 , wherein the cancer is a solid cancer.
42 . The method of claim 29 , wherein the cancer is a liquid cancer.
43 . A method for treating cancer comprising administering to a subject in need thereof:
(1) an effective amount of at least one PD-L1 inhibitor; and (2) an effective amount of at least one heterobifunctional inhibitor chosen from compounds of Formula (II):
and pharmaceutically acceptable salts thereof, wherein:
R 1 is 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;
R 2 is chosen from —OH, —NH 2 , —OC(═O)Y 1 , —NHC(═O)Y 1 , and —NHC(═O)NHY 1 groups, wherein Y 1 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups;
R 3 is chosen from —CN, —CH 2 CN, and —C(═O)Y 2 groups, wherein Y 2 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OZ 1 , —NHOH, —NHOCH 3 , —NHCN, and —NZ 1 Z 2 groups, wherein Z 1 and Z 2 , 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 Z 1 and Z 2 may together form a ring;
R 4 is chosen from C 3-8 cycloalkyl groups;
R 5 is independently chosen from H, halogen, 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;
n is chosen from integers ranging from 1 to 4; and
Linker is chosen from linker groups.
44 . The method of claim 43 , wherein at least one of (1) the at least one PD-L1 inhibitor and (2) the at least one heterobifunctional inhibitor is in the form of at least one pharmaceutical composition.
45 . The method of claim 43 , wherein the at least one PD-L1 inhibitor is in the form of a first pharmaceutical composition and the at least one heterobifunctional inhibitor is in the form of a second pharmaceutical composition.
46 . The method of claim 44 , wherein said at least one pharmaceutical composition further comprises at least one pharmaceutically acceptable ingredient.
47 . The method of claim 43 , wherein the at least one heterobifunctional inhibitor is chosen from compounds of Formula (IIa):
and pharmaceutically acceptable salts thereof.
48 . The method of claim 43 , wherein the at least one heterobifunctional inhibitor is GMI-1359.
49 . The method of claim 43 , wherein the subject has received or will receive chemotherapy and/or radiotherapy.
50 . The method of claim 49 , wherein the chemotherapy comprises administering an effective amount of bortezomib and/or gemcitabine.
51 . The method of claim 43 , wherein Linker is chosen from
52 . The method of claim 43 , wherein the at least one heterobifunctional inhibitor is chosen from:
and pharmaceutically acceptable salts of any of the foregoing.
53 . The method of claim 43 , wherein the at least one heterobifunctional inhibitor is chosen from:
pharmaceutically acceptable salts of any of the foregoing.
54 . The method of claim 43 , wherein the at least one heterobifunctional inhibitor is chosen from
and pharmaceutically acceptable salts thereof.
55 . The method of claim 43 , wherein the cancer is a solid cancer.
56 . The method of claim 44 , wherein the cancer is a liquid cancer.
57 . A method for treating solid cancers comprising administering to a subject in need thereof:
(1) an effective amount of at least one PD-L1 inhibitor; and (2) an effective amount of at least one heterobifunctional inhibitor chosen from
and pharmaceutically acceptable salts thereof.
58 . A method for treating solid cancers comprising administering to a subject in need thereof:
(1) an effective amount of at least one PD-L1 inhibitor; and (2) an effective amount of the compoundJoin the waitlist — get patent alerts
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