US2021379024A1PendingUtilityA1
Method of modulating tigit and pd-1 signalling pathways using 1,2,4-oxadiazole compounds
Assignee: AURIGENE DISCOVERY TECH LTDPriority: Mar 14, 2018Filed: Mar 13, 2019Published: Dec 9, 2021
Est. expiryMar 14, 2038(~11.7 yrs left)· nominal 20-yr term from priority
Inventors:Pottayil Govindan Nair SasikumarMuralidhara RamachandraSeetharamaiah Setty Sudarshan NaremaddepalliGundala Chennakrishnareddy
C07D 413/12C07D 413/06C07D 271/06C07D 413/04A61P 33/10A61P 33/12A61P 33/06A61P 33/02A61P 31/02A61P 31/20A61P 31/18A61P 31/16A61P 31/22A61P 31/14A61P 33/00A61P 31/10A61P 31/04A61P 35/02A61P 31/00A61P 29/00A61P 37/06A61P 35/00A61K 31/4245Y02A50/30
59
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Claims
Abstract
The present invention relates to method of modulating TIGIT signaling pathway and PD-1 signaling pathway. The invention also encompasses the use of the compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the treatment of diseases or disorders mediated by both TIGIT signaling pathway and PD-1 signaling pathway.
Claims
exact text as granted — not AI-modified1 . A method of modulating T cell immunoreceptor with Ig and ITIM domains (TIGIT) signaling pathway and programmed cell death 1 (PD-1) signaling pathway in a subject, comprising administering to the subject with compound of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein,
R 1 represents hydrogen, —(C 1 -C 6 )alkyl optionally substituted with —OH, —COOH, aryl, heteroaryl, or aryl-OH;
R 2 represents hydrogen, —(C 1 -C 6 )alkyl optionally substituted with —OH, —SH, C(O)NH 2 , —COOH, aryl, heteroaryl, or aryl-OH;
R a represents hydrogen; or R a and R 2 taken together with the atom to which they are attached form a pyrrolidine ring;
R 3 represents hydrogen or a group represented by formula (I′),
represents point of attachment;
R b represents hydrogen; or R b and R c taken together with the atoms to which they are attached form a pyrrolidine ring;
R c represents hydrogen, —(C 1 -C 6 )alkyl optionally substituted with —OH, —C(O)NH 2 , COOH, aryl, or aryl-OH.
2 . The method of claim 1 , wherein R 1 represents hydrogen, —(C 1 -C 6 )alkyl optionally substituted with —OH, —COOH, phenyl, imidazolyl, or (p-OH)phenyl.
3 - 8 . (canceled)
9 . The method of claim 1 , wherein R 3 represents
wherein
represents point of attachment;
R b represents hydrogen; or R b and R c taken together with the atoms to which they are attached form a pyrrolidine ring;
R c represents hydrogen, —(C 1 -C 6 )alkyl optionally substituted with —OH, —C(O)NH 2 , COOH, phenyl, or (p-OH)phenyl.
10 . (canceled)
11 . The method of claim 1 , wherein the compound is represented by compound of formula (IA),
wherein, R 1 , R 2 , R a , R b , and R c are as defined in claim 1 .
12 . The method of claim 11 , wherein
R 1 represents —(C 1 -C 6 )alkyl optionally substituted with —OH, —COOH, imidazolyl, phenyl, or (p-OH)phenyl; R 2 represents hydrogen, —(C 1 -C 6 )alkyl substituted with —OH, —SH, —COOH, phenyl, imidazolyl, or (p-OH)phenyl; R a represents hydrogen; or R a and R 2 taken together with the atom to which they are attached form a pyrrolidine ring; R b represents hydrogen; or R b and R c taken together with the atoms to which they are attached form a pyrrolidine ring; R c represents hydrogen, —(C 1 -C 6 )alkyl optionally substituted with —OH, —C(O)NH 2 , —COOH, phenyl, or (p-OH)phenyl.
13 . (canceled)
14 . The method of claim 1 , wherein the compound is represented by compound of formula (IB),
wherein, R 1 , R 2 and R a , are as defined in claim 1 .
15 . The method of claim 14 , wherein
R 1 represents —(C 1 -C 6 )alkyl optionally substituted with —OH or (p-OH)phenyl; R 2 represents hydrogen, —(C 1 -C 6 )alkyl substituted with phenyl or (p-OH)phenyl; R a and R 2 taken together with the atom to which they are attached form a pyrrolidine ring.
16 . The method of claim 1 , wherein the compound is
Compound
No.
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
or a pharmaceutically acceptable salt or a stereoisomer thereof.
17 .- 18 . (canceled)
19 . The method of claim 1 , wherein the subject is suffering from a disease or disorder selected from cancer, immune disorders, immunodeficiency disorders, inflammatory disorders, infectious diseases, and transplant rejection.
20 . The method of claim 19 , wherein the disease or disorder is cancer.
21 - 23 . (canceled)
24 . The method of claim 19 , wherein the disease is an infectious disease.
25 . The method of claim 24 , wherein the infectious disease is a bacterial infection, a viral infection, a fungal infection, or a parasitic infection.
26 - 36 . (canceled)
37 . A method of treating a disease or disorder mediated by both TIGIT signalling pathway and PD-1 signalling pathway comprising administering a therapeutically effective amount of compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salts thereof as defined in claim 1 .
38 . The method of claim 37 , wherein the disease or disorder is selected from cancer, immune disorders, immunodeficiency disorders, inflammatory disorders, infectious diseases, and transplant rejection.
39 . The method of claim 38 , wherein the cancer is selected from blastoma, breast cancer, epithelial cancer, colon cancer, lung cancer, melanoma, prostate cancer, renal cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, uterine cancer, ovarian cancer, colorectal cancer, rectal cancer, cancer of the anal region, cancer of the peritoneum, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, cervical cancer, vaginal cancer, vulval cancer, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma, cancer of the urethra, cancer of the penis, chronic or acute leukemia, solid tumors of childhood, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T cell lymphoma, mesothelioma, thymic carcinoma, myeloma, cancer of the bladder, cancer of the ureter, carcinoma of the renal pelvis, liver cancer, pancreatic cancer, post-transplant lymphoproliferative disorder (PTLD), neoplasm of the central nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid cancer, salivary gland carcinoma, squamous cell cancer, abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), Meigs' syndrome, Merkel cell carcinoma, and environmentally induced cancers.
40 . The method of claim 38 , wherein the infectious disease is a bacterial infection, a viral infection, a fungal infection, or a parasitic infection.
41 - 48 . (canceled)
49 . A method of modulating T cell immunoreceptor with Ig and ITIM domains (TIGIT) signaling pathway in a subject, comprising administering to the subject with compound of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein,
R 1 represents hydrogen, —(C 1 -C 6 )alkyl optionally substituted with —OH, —COOH, aryl, heteroaryl, or aryl-OH;
R 2 represents hydrogen, —(C 1 -C 6 )alkyl optionally substituted with —OH, —SH, C(O)NH 2 , —COOH, aryl, heteroaryl, or aryl-OH;
R a represents hydrogen; or R a and R 2 taken together with the atom to which they are attached form a pyrrolidine ring;
R 3 represents hydrogen or a group represented by formula (I′),
represents point of attachment;
R b represents hydrogen; or R b and R c taken together with the atoms to which they are attached form a pyrrolidine ring;
R c represents hydrogen, —(C 1 -C 6 )alkyl optionally substituted with —OH, —C(O)NH 2 , COOH, aryl, or aryl-OH.
50 - 61 . (canceled)
62 . The method of claim 37 , wherein the treatment of a disease or disorder is inhibiting growth of tumor cells and/or metastasis.
63 . The method of claim 62 , wherein the tumor cells are of a cancer selected from small cell lung cancer, multiple myeloma, bladder carcinoma, primary ductal carcinoma, ovarian carcinoma, Hodgkin's lymphoma, gastric carcinoma, acute myeloid leukemia, and pancreatic cancer.Cited by (0)
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