Cannabinoid receptor type 2 (CB2) modulators and uses thereof
Inventors
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11957689-B2
Publication Date
2024-04-16
Expiration Date
Abstract
Disclosed herein are compounds, compositions, and methods for modulating the Cannabinoid receptor 2 (CB2) with the compounds and compositions disclosed herein. Also described are methods of treating diseases or conditions that are mediated by the action of Cannabinoid receptor 2 (CB2) or that we benefit from modulating the Cannabinoid receptor 2 (CB2).
Core Innovation
The invention relates to substituted 1,8-naphthyridine-3-carboxamide derivatives and related naphthyridine, quinoline, and pyrido[2,3-b]pyrazine carboxamide derivatives. The disclosed compounds retain a heterocyclic carboxamide scaffold while varying substituents such as fluoro, chloro, methoxy, difluoromethoxy, cyanopyridyl, pyridyl, morpholinoethyl, cycloalkyl, bicyclic, spiro[3.3]heptan-2-yl, and bicyclo[1.1.1]pentan-1-yl groups, with stereochemically defined compounds, salts, solvates, stereoisomers, and isotopically labeled forms including deuterium.
The disclosure includes Formula (A), Formula (X), and related embodiments with variable substituents and multiple numbered compounds. Some compounds are described as CB2R modulators with CB2R antagonist and CB2R inverse agonist activities, and the material also describes receptor binding and functional testing for CB1 and CB2, including CB2 cAMP functional assays.
The compounds are tied to treatment of cancer in a mammal in need thereof by administering a compound selected from a defined numbered set, or a pharmaceutically acceptable salt or stereoisomer thereof. The provided material also includes combination treatment with immune checkpoint inhibitors, including anti-PD-1 and anti-PD-L1 agents, and describes synthetic preparation and analytical characterization of the compounds.
Claims Coverage
The claims center on a method of treating a broad list of cancers in a mammal by administering a compound selected from a numbered set of naphthyridine carboxamide derivatives, including pharmaceutically acceptable salts or stereoisomers. Across the provided items, there are three main inventive feature groups: administration of the selected compound set, narrowing to solid tumors or specific cancer types, and combination with immune checkpoint inhibitors.
Administering a selected numbered compound for cancer treatment
A method for treating bladder cancer, colon cancer, brain cancer, breast cancer, endometrial cancer, heart cancer, kidney cancer, lung cancer, liver cancer, uterine cancer, blood and lymphatic cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, or skin cancer in a mammal in need thereof by administering a compound selected from a set of numbered compounds, or a pharmaceutically acceptable salt or stereoisomer thereof.
Solid tumor limitation
The method wherein the cancer is a solid tumor.
Specific cancer-type restriction
The method wherein the cancer is prostate cancer, breast cancer, colon cancer, or lung cancer.
Combination with an immune checkpoint inhibitor
The method further includes administering at least one immune checkpoint inhibitor to a mammal in need thereof.
Immune checkpoint inhibitor as anti-PD-1 or anti-PD-L1
The immune checkpoint inhibitor is either an anti-PD-1 or an anti-PD-L1 agent.
Named anti-PD-1 or anti-PD-L1 agents
The anti-PD-1 or anti-PD-L1 agent is selected from nivolumab, pembrolizumab, cemiplimab, labrolizumab, avelumab, durvalumab, or atezolizumab.
Overall, the claims are directed to administering a selected numbered compound set, including salts or stereoisomers, to treat the stated cancers in a mammal, with dependent refinements to solid tumors, particular cancer types, and combination therapy with immune checkpoint inhibitors, specifically anti-PD-1 or anti-PD-L1 agents.
Stated Advantages
Improved bioavailability/PK is stated for certain compounds depending on substituent changes.
Treating CB2-mediated diseases, including cancer, by modulating CB2 activity.
Reducing immunosuppression and proliferation in a CB2-dependent tumor microenvironment.
Documented Applications
Treating bladder cancer, colon cancer, brain cancer, breast cancer, endometrial cancer, heart cancer, kidney cancer, lung cancer, liver cancer, uterine cancer, blood and lymphatic cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, or skin cancer in a mammal in need thereof.
Treating a solid tumor cancer.
Treating prostate cancer, breast cancer, colon cancer, or lung cancer.
Combination treatment by administering at least one immune checkpoint inhibitor, including anti-PD-1 or anti-PD-L1 agents such as nivolumab, pembrolizumab, cemiplimab, labrolizumab, avelumab, durvalumab, or atezolizumab.
Receptor binding and functional testing are described for CB1 and CB2, including CB2 cAMP functional assays.
Immunology-related in vitro evaluation is described using mixed lymphocyte reaction and T-cell exhaustion assays.
In vivo B16F10 tumor growth inhibition is described, including combination with anti-PD-1/PD-L1.
In vivo pharmacokinetic evaluation is described using LC-MS/MS.
Interested in licensing this patent?