Claims for Patent: 10,238,631

Summary for Patent: 10,238,631

Title:	Sesquiterpene derivatives and their use in inflammation or cancer treatment
Abstract:	A new class of sesquiterpene derivative useful for treating cancerous and inflammatory diseases are disclosed. These deoxyelephantopin derivatives are effective in suppressing proliferation, migration, mobility, invasion, growth, and/or metastasis of cancer cells in a patient, or useful for enhancing an anti-proliferative effect of another anti-cancer drug on cancer cells when treating a patient, or for sensitizing and/or enhancing an anti-cancer effect of a gluthathione synthesis blocker on inhibition of triple negative breast cancer cell activity, or for treatment and/or prophylaxis of lipopolysaccharide-stimulated inflammatory response in a patient, or for all of the above. Also disclosed are methods of preparing the deoxyelephantopin derivatives.
Inventor(s):	Shyur; Lie-Fen (Taipei, TW), Lee; Kuo-Hsiung (Chapel Hill, NC), Nakagawa-Goto; Kyoko (Ishikawa, JP), Feng; Jia-Hua (Taipei, TW), Chen; Jo-Yu (New Taipei, TW), Lee; Wai-Leng (Taichung, TW), Cheng; Yu-Ting (Taichung, TW), Huang; Jing-Ying (Taipei, TW)
Assignee:	Academia Sinica (Taipei, TW)
Application Number:	15/316,700
Patent Claims:	1. A compound of Formula (I) ##STR00125## or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is selected from the group consisting of hydrogen, -carbonyl(C.sub.1-C.sub.8)alkyl(C.sub.1-C.sub.8)alkenyl, -carbonyl(C.sub.1-C.sub.8)alkyl(C.sub.1-C.sub.8)alkenyl(C.sub.1-C.sub.8)a- lkyl, -carbonyl(C.sub.1-C.sub.8)alkenyl(C.sub.6-C.sub.20)aryl, -carbonyl(C.sub.1-C.sub.8)alkenyl(C.sub.1-C.sub.8)alkoxy(C.sub.6-C.sub.20- )aryl, -carbonyl(C.sub.1-C.sub.8)alkenyl, -carbonyl(C.sub.1-C.sub.8)haloalkyl, -carbonyl(C.sub.1-C.sub.8)alkyl, -carbonyl(C.sub.1-C.sub.8)alkylOCO(C.sub.1-C.sub.8)alkyl, -carbonyl(C.sub.1-C.sub.8)alkenyl(C.sub.1-C.sub.8)alkyl(C.sub.1-C.sub.8)a- lkenyl, -carbonyl(C.sub.1-C.sub.8)alkanol(C.sub.1-C.sub.8)alkyl, -carbonyl(C.sub.1-C.sub.8)alkenyl(C.sub.1-C.sub.8)alkyl(C.sub.6-C.sub.20)- aryl, -carbonyl(C.sub.1-C.sub.8)alkenyl(C.sub.6-C.sub.20)haloaryl, -carbonyl(C.sub.1-C.sub.8)alkenyl(C.sub.3-C.sub.8)heteroaryl, -carbonyl(C.sub.6-C.sub.20)aryl, -carbonyl(C.sub.1-C.sub.8)alkoxy(C.sub.6-C.sub.20)aryl, -carbonyl(C.sub.1-C.sub.8)alkyl(C.sub.6-C.sub.20)aryl, -carbonylhalo(C.sub.6-C.sub.20)aryl, -carbonyl(C.sub.3-C.sub.8)cycloalkyl, -carbonyl(C.sub.1-C.sub.8)alkenyl(C.sub.1-C.sub.8)haloalkyl(C.sub.6-C.sub- .20)aryl, --CO-(E)C(CH.sub.3).dbd.CHCH.sub.2CH.sub.3, --CO-(E)CH.dbd.CHCH.sub.2CH.sub.3, --CO--C(CH.sub.2CH.sub.3).dbd.CH.sub.2, --CO-(E)CH.dbd.C(CH.sub.3)CH(CH.sub.3).sub.2, --CO-2-thiofuranyl, --CO-benzofuran-2-yl, --CO-benzothiofuran-2-yl, --CO-(4-methylphenyl), --CO--CH.sub.2-(4-methoxyphenyl), --CO--CH.sub.2-(6-methoxynaphthalene-1-yl), --CO--CH.sub.2-(6-methoxynaphthalene-2-yl), --CO--CH.sub.2-(quinolin-8-yl), --CO--CH.sub.2-(benzothiofuran-3-yl), --CO--CH.sub.2-(benzofuran-3-yl), --CO--CH.sub.2-(napthalene-1-yl), --CO--CH(S--CH.sub.3)(6-methoxylnaphthalene-2-yl), and -carbonyl(C.sub.1-C.sub.8)alkyl(C.sub.1-C.sub.8)alkoxy(C.sub.6-C.sub.20)a- ryl. 2. The compound of claim 1, wherein R.sub.1 is hydrogen, --CO--C(CH.sub.3).dbd.CH.sub.2, --CO-(E)C(CH.sub.3).dbd.CHCH.sub.2CH.sub.3, --CO-(E)CH.dbd.CH-phenyl, --CO-(E)CH.dbd.CH-(3,4,5-trimethoxy)phenyl, --CO--CH.dbd.C(CH.sub.3).sub.2, --CO--CH(Cl).sub.2, --CO--CH.sub.2--CH(CH.sub.3).sub.2, --CO--CH.sub.2C(CH.sub.3)(CH.sub.2CH.sub.3)(OCOCH.sub.3), --CO-(E)CH.dbd.C(CH.sub.3)CH(CH.sub.3).sub.2, --CO--CH(CH.sub.3)CH.sub.2CH.sub.3, --CO-(E)CH.dbd.C(CH.sub.3)CH.sub.2CH.sub.2CH.dbd.C(CH.sub.3).sub.2, --CO--CH(CH.sub.2CH.sub.3).sub.2, --CO--CH.sub.3, --CO--CH.sub.2C(CH.sub.3)CH.sub.2CH.sub.3, --CO--C(CH.sub.2CH.sub.3).dbd.CH.sub.2, --CO--C(CH.sub.3)(CH.sub.2).sub.2CH.sub.3, --CO--C(CH.sub.2CH.sub.3)(CH.sub.2).sub.3CH.sub.3, --CO--CH(CH.sub.3)(CH.sub.2).sub.3CH.sub.3, --CO--CH.sub.2C(OH)((CH(CH.sub.3).sub.2).sub.2, --CO-(E)CH.dbd.CHCH.sub.3, --CO-(E)CH.dbd.CHCH.sub.2CH.sub.3, --CO-(E)CH.dbd.CH-(4-methoxyphenyl), --CO-(E)CH.dbd.CH-(4-methylphenyl), --CO-(E)CH.dbd.CH-(4-chlorophenyl), --CO-(E)CH.dbd.CH(furan-2-yl), --CO-2-thiofuranyl, --CO-phenyl, --CO-(4-methoxyphenyl), --CO-(4-methylphenyl), --CO-(4-bromophenyl), --CO--CH.sub.2-naphthalene-1-yl, --CO-cyclopropyl, --CO-cyclopentyl, --CO-cyclohexyl, --CO-(E)CH.dbd.CH(3-methoxyphenyl), --CO-benzofuran-2-yl, --CO-benzothiofuran-2-yl, --CO-(E)CH.dbd.CH-(thiofuran-2-yl), --CO--CH.sub.2-phenyl, --CO--CH.sub.2-(4-methoxyphenyl), --CO--CH.sub.2-(6-methoxynaphthalene-1-yl), --CO--CH.sub.2-(6-methoxynaphthalene-2-yl), --CO-(E)CH.dbd.CH-(3-trifluromethoxyphenyl), --CO-(E)CH.dbd.CH-(3-trifluromethylphenyl), --CO-(E)CH.dbd.CH-(3,4-dimethoxyphenyl), --CO-(E)CH.dbd.CH-(3-ethoxyphenyl), --CO--(CH.sub.2).sub.2-(naphthalene-1-yl), --CO--CH.sub.2-(quinolin-8-yl), --CO--CH(S--CH.sub.3)(6-methoxylnaphthalene-2-yl), --CO--CH(R--CH.sub.3)(6-methoxylnaphthalene-2-yl), --CO--C(CH.sub.3)(OCH.sub.3)-(naphthalene-2-yl), --CO--CH(S--OCH.sub.3)-(naphthalene-2-yl), --CO--CH(R--OCH.sub.3)-(naphthalene-2-yl), --CO--CH.sub.2-(benzothiofuran-3-yl), --CO--CH.sub.2-(benzofuran-3-yl), --CO-(E)CH.dbd.CH-(4-ethoxyphenyl), --CO-(E)CH.dbd.CH-(1,3-benzodioxane-5-yl), and --CO--CH.sub.2-(napthalene-1-yl). 3. The compound of claim 1, which is selected from the group consisting of ##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130## ##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135## ##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140## 4. A method of preparing the compound of Formula (I) ##STR00141## or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is selected from the group consisting of hydrogen, --CO--C(CH.sub.3).dbd.CH.sub.2, --CO-(E)C(CH.sub.3).dbd.CHCH.sub.2CH.sub.3, --CO-(E)CH.dbd.CH-phenyl, --CO-(E)CH.dbd.CH-(3,4,5-trimethoxy)phenyl, --CO--CH.dbd.C(CH.sub.3).sub.2, --CO--CH(Cl).sub.2, --CO--CH.sub.2--CH(CH.sub.3).sub.2, --CO--CH.sub.2C(CH.sub.3)(CH.sub.2CH.sub.3)(OCOCH.sub.3), --CO-(E)CH.dbd.C(CH.sub.3)CH(CH.sub.3).sub.2, --CO--CH(CH.sub.3)CH.sub.2CH.sub.3, --CO-(E)CH.dbd.C(CH.sub.3)CH.sub.2CH.sub.2CH.dbd.C(CH.sub.3).sub.2, --CO--CH(CH.sub.2CH.sub.3).sub.2, --CO--CH.sub.3, --CO--CH.sub.2C(CH.sub.3)CH.sub.2CH.sub.3, --CO--C(CH.sub.2CH.sub.3).dbd.CH.sub.2, --CO--C(CH.sub.3)(CH.sub.2).sub.2CH.sub.3, --CO--C(CH.sub.2CH.sub.3)(CH.sub.2).sub.3CH.sub.3, --CO--CH(CH.sub.3)(CH.sub.2).sub.3CH.sub.3, --CO--CH.sub.2C(OH)((CH(CH.sub.3).sub.2).sub.2, --CO-(E)CH.dbd.CHCH.sub.3, --CO-(E)CH.dbd.CHCH.sub.2CH.sub.3, --CO-(E)CH.dbd.CH-(4-methoxyphenyl), --CO-(E)CH.dbd.CH-(4-methylphenyl), --CO-(E)CH.dbd.CH-(4-chlorophenyl), --CO-(E)CH.dbd.CH(furan-2-yl), --CO-2-thiofuranyl, --CO-phenyl, --CO-(4-methoxyphenyl), --CO-(4-methylphenyl), --CO-(4-bromophenyl), --CO--CH.sub.2-naphthalene-1-yl, --CO-cyclopropyl, --CO-cyclopentyl, --CO-cyclohexyl, --CO-(E)CH.dbd.CH(3-methoxyphenyl), --CO-benzofuran-2-yl, --CO-benzothiofuran-2-yl, --CO-(E)CH.dbd.CH-(thiofuran-2-yl), --CO--CH.sub.2-phenyl, --CO--CH.sub.2-(4-methoxyphenyl), --CO--CH.sub.2-(6-methoxynaphthalene-1-yl), --CO--CH.sub.2-(6-methoxynaphthalene-2-yl), --CO-(E)CH.dbd.CH-(3-trifluromethoxyphenyl), --CO-(E)CH.dbd.CH-(3-trifluromethylphenyl), --CO-(E)CH.dbd.CH-(3,4-dimethoxyphenyl), --CO-(E)CH.dbd.CH-(3-ethoxyphenyl), --CO--(CH.sub.2).sub.2-(naphthalene-1-yl), --CO--CH.sub.2-(quinolin-8-yl), --CO--CH(S--CH.sub.3)(6-methoxylnaphthalene-2-yl), --CO--CH(R--CH.sub.3)(6-methoxylnaphthalene-2-yl), --CO--C(CH.sub.3)(OCH.sub.3)-(naphthalene-2-yl), --CO--CH(S--OCH.sub.3)-(naphthalene-2-yl), --CO--CH(R--OCH.sub.3)-(naphthalene-2-yl), --CO--CH.sub.2-(benzothiofuran-3-yl), --CO--CH.sub.2-(benzofuran-3-yl), --CO-(E)CH.dbd.CH-(4-ethoxyphenyl), --CO-(E)CH.dbd.CH-(1,3-benzodioxane-5-yl), and --CO--CH.sub.2-(napthalene-1-yl), the method comprising the steps of: (5) reacting the compound of Formula (II) ##STR00142## with aqueous sodium hydroxide to obtain the compound of Formula (I), ##STR00143## wherein R.sub.1 is hydrogen; and (6) reacting the compound of Formula (I), wherein R.sub.1 is hydrogen, with 1-naphthylacetic acid, diethyl azodicarboxylate (DEAD) and triphenylphosphine (PPh3) to afford the compound of Formula (I), wherein R.sub.1 is --CO--CH.sub.2-(napthalene-1-yl); or (7) reacting the compound of Formula (I), wherein R, is hydrogen, with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) dimethylaminopyridine (DMAP), and a compound of Formula (III) R.sub.2COOH Formula (III), wherein R.sub.2 is selected from the group consisting of --CO--C(CH.sub.3).dbd.CH.sub.2, --CO-(E)C(CH.sub.3).dbd.CHCH.sub.2CH.sub.3, --CO-(E)CH.dbd.CH-phenyl, --CO-(E)CH.dbd.CH-(3,4,5-trimethoxy)phenyl, --CO--CH.dbd.C(CH.sub.3).sub.2, --CO--CH(Cl).sub.2, --CO--CH.sub.2--CH(CH.sub.3).sub.2, --CO--CH.sub.2C(CH.sub.3)(CH.sub.2CH.sub.3)(OCOCH.sub.3), --CO-(E)CH.dbd.C(CH.sub.3)CH(CH.sub.3).sub.2, --CO--C(CH.sub.3)CH.sub.2CH.sub.3, --CO-(E)CH.dbd.C(CH.sub.3)CH.sub.2CH.sub.2CH.dbd.C(CH.sub.3).sub.2, --CO--CH(CH.sub.2CH.sub.3).sub.2, --CO--CH.sub.3, --CO--CH.sub.2C(CH.sub.3)CH.sub.2CH.sub.3, --CO--C(CH.sub.2CH.sub.3).dbd.CH.sub.2, --CO--C(CH.sub.3)(CH.sub.2).sub.2CH.sub.3, --CO--C(CH.sub.2CH.sub.3)(CH.sub.2).sub.3CH.sub.3, --CO--CH(CH.sub.3)(CH.sub.2).sub.3CH.sub.3, --CO--CH.sub.2C(OH)((CH(CH.sub.3).sub.2).sub.2, --CO-(E)CH.dbd.CHCH.sub.3, --CO-(E)CH.dbd.CHCH.sub.2CH.sub.3, --CO-(E)CH.dbd.CH-(4-methoxyphenyl), --CO-(E)CH.dbd.CH-(4-methylphenyl), --CO-(E)CH.dbd.CH(4-chlorophenyl), --CO-(E)CH.dbd.CH(furan-2-yl), --CO-2-thiofuranyl, --CO-phenyl, --CO--CH.sub.2-naphthalene-1-yl, --CO-(E)CH.dbd.CH(3-methoxyphenyl), --CO-benzofuran-2-yl, --CO-benzothiofuran-2-yl, --CO-(E)CH.dbd.CH-(thiofuran-2-yl), --CO--CH.sub.2-phenyl, --CO--CH.sub.2-(4-methoxyphenyl), --CO--CH.sub.2-(6-methoxynaphthalene-1-yl), --CO--CH.sub.2-(6-methoxynaphthalene-2-yl), --CO-(E)CH.dbd.CH-(3-trifluromethoxyphenyl), --CO-(E)CH.dbd.CH-(3-trifluromethylphenyl), --CO-(E)CH.dbd.CH-(3,4-dimethoxyphenyl), --CO-(E)CH.dbd.CH-(3-ethoxyphenyl), --CO--(CH.sub.2).sub.2-(naphthalene-1-yl), --CO--CH.sub.2-(quinolin-8-yl), --CO--CH(S--CH.sub.3)(6-methoxylnaphthalene-2-yl), --(CO--CH(R--CH.sub.3)(6-methoxylnaphthalene-2-yl), --CO--C(CH.sub.3)(OCH.sub.3)-(naphthalene-2-yl), --CO--CH(S--OCH.sub.3)-(naphthalene-2-yl), --CO--CH(R--OCH.sub.3)-(naphthalene-2-yl), --CO--CH.sub.2-(benzothiofuran-3-yl), --CO--CH.sub.2-(benzofuran-3-yl), --CO-(E)CH.dbd.CH-(4-ethoxyphenyl), or --CO-(E)CH.dbd.CH-(1,3-benzodioxane-5-yl), and --CO--CH.sub.2-(napthalene-1-yl), to obtain the compound of Formula (I), wherein R.sub.1 is selected from the group consisting of --CO--C(CH.sub.3).dbd.CH.sub.2, --CO-(E)C(CH.sub.3).dbd.CHCH.sub.2CH.sub.3, --CO-(E)CH.dbd.CH-phenyl, --CO-(E)CH.dbd.CH-(3,4,5-trimethoxy)phenyl, --CO--CH.dbd.C(CH.sub.3).sub.2, --CO--CH(Cl.sub.2), --CO--CH.sub.2--CH(CH.sub.3).sub.2, --CO--CH.sub.2C(CH.sub.3)(CH.sub.2CH.sub.3)(OCOCH.sub.3), --CO-(E)CH.dbd.C(CH.sub.3)CH(CH.sub.3).sub.2, --CO--CH(CH.sub.3)CH.sub.2CH.sub.3, --CO-(E)CH.dbd.C(CH.sub.3)CH.sub.2CH.sub.2CH.dbd.C(CH.sub.3).sub.2, --CO--CH--(CH.sub.2CH.sub.3).sub.2, --CO--CH.sub.3, --CO--CH.sub.2C(CH.sub.3)CH.sub.2CH.sub.3, --CO--C(CH.sub.2CH.sub.3).dbd.CH.sub.2, --CO--C(CH.sub.3)(CH.sub.2).sub.2CH.sub.3, --CO--C(CH.sub.2CH.sub.3)(CH.sub.2).sub.3CH.sub.3, --CO--CH(CH.sub.3)(CH.sub.2)CH.sub.3, --CO--CH.sub.2C(OH)((CH(CH.sub.3).sub.2).sub.2, --CO-(E)CH.dbd.CHCH.sub.3, --CO-(E)CH.dbd.CHCH.sub.2CH.sub.3, --CO-(E)CH.dbd.CH-(4-methoxyphenyl), --CO-(E)CH.dbd.CH-(4-methylphenyl), --CO-(E)CH.dbd.CH-(4-chlorophenyl), --CO-(E)CH.dbd.CH(furan-2-yl), --CO-2-thiofuranyl, --CO-phenyl, --CO--CH.sub.2-naphthalene-1-yl, --CO-(E)CH.dbd.CH(3-methoxyphenyl), --CO-benzofuran-2-yl, --CO-benzothiofuran-2-yl, --CO-(E)CH.dbd.CH-(thiofuran-2-yl), --CO--CH.sub.2-phenyl, --CO--CH.sub.2-(4-methoxyphenyl), --CO--CH.sub.2-(6-methoxynaphthalene-1-yl), --CO--CH.sub.2-(6-methoxynaphthalene-2-yl), --CO-(E)CH.dbd.CH-(3-trifluromethoxyphenyl), --CO-(E)CH.dbd.CH-(3-trifluromethylphenyl), --CO-(E)CH.dbd.CH-(3,4-dimethoxyphenyl), --CO-(E)CH.dbd.CH-(3-ethoxyphenyl), --CO--(CH.sub.2).sub.2-(naphthalene-1-yl), --CO--CH.sub.2-(quinolin-8-yl), --CO--CH(S--CH.sub.3)(6-methoxylnaphthalene-2-yl), --CO--CH(R--CH.sub.3)(6-methoxylnaphthalene-2-yl), --CO--C(CH.sub.3)(OCH.sub.3)-(naphthalene-2-yl), --CO--CH(S--OCH.sub.3)-(naphthalene-2-yl), --CO--CH(R--OCH.sub.3)-(naphthalene-2-yl), --CO--CH.sub.2-(benzothiofuran-3-yl), --CO--CH.sub.2-(benzofuran-3-yl), --CO-(E)CH.dbd.CH-(4-ethoxyphenyl), --CO-(E)CH.dbd.CH-(1,3-benzodioxane-5-yl), and --CO--CH.sub.2-(napthalene-1-yl); or (8) reacting the compound of Formula (I), wherein R.sub.1 is hydrogen, with triethylamine and a compound of Formula (IV) R.sub.3COCl Formula (IV), wherein R.sub.3 is -(4-methoxyphenyl), -(4-methylphenyl), -(4-bromophenyl), -cyclopropyl, -cyclopentyl, or cyclohexyl to obtain the compound of Formula (I), wherein R.sub.1 is --CO-(4-methoxyphenyl), --CO-(4-methylphenyl), --CO-(4-bromophenyl), --CO-cyclopropyl, --CO-cyclopentyl, or --CO-cyclohexyl. 5. A composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable diluent or carrier. 6. A method for inhibition of proliferation, migration, mobility, invasion, growth, and/or metastasis of cancer cells in a patient, comprising: administering to the patient a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 1. 7. The method of claim 6, wherein the cancer is selected from the group consisting of breast cancer, melanoma, drug-resistant melanoma, brain tumor, lung cancer, lymphoma, neuroepithelioma, kidney cancer, prostate cancer, stomach cancer, colon cancer, and uterus cancer. 8. A method for enhancement of an anti-proliferative effect of another anti-cancer drug on cancer cells when treating a patient, comprising: administering to the patient a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 1. 9. The method of claim 8, wherein the another anti-cancer drug is selected from the group consisting of PLX4032, buthionine sulfoximine, sulfasalazine paclitaxel, docetaxel, cisplatin, oxaliplatin, betulinic acid, 4-S-cysteaminyl catechol, 4-S-cysteaminyl phenol, everolimus, bortezomib, carboplatin, dacarbazine, celecoxib, temozolomide, sorafenib, thalidomide, lenalidomide, valproic acid, vinblastine, imatinib mesylate, bosentan, apomine, arsenic trioxide, carmustine, lambrolizuma, anti-CTLA-4 drug, anti-PD-1 drug, ipilimumab, doxorubicin, MEK inhibitor, capecitabine, PARP inhibitor, and tamoxifen. 10. The method of claim 8, wherein the compound or the pharmaceutically acceptable salt thereof exhibits synergism with the another anti-cancer drug. 11. A method for sensitizing and/or enhancing an anti-cancer effect of a gluthathione synthesis blocker on inhibition of triple negative breast cancer cell activity in a patient, comprising: administering to the patient a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 1. 12. The method of claim 11, wherein the gluthathione synthesis blocker is a gamma-glutamylcysteine synthetase inhibitor or a cystine/glutamate transporter inhibitor. 13. A method for treatment and/or prophylaxis of lipopolysaccharide-stimulated inflammatory response in a patient, comprising: administering to the patient a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 1. 14. The method of claim 13, wherein the lipopolysaccharide-stimulated inflammatory response is associated with an inflammatory disease selected from the group consisting of inflammatory dermatoses, inflammatory bowel disease, hypersensitivity lung disease, asthma, allergic rhinitis, autoimmune diseases, acute and chronic inflammatory diseases, Sjogren's syndrome, human immunodeficiency virus infection, and cancer. 15. A method of combination therapy for inhibition of proliferation, migration, invasion, and/or metastasis of cancer cells in a patient in need thereof, comprising: administering to the patient in need thereof a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 1 and a therapeutically effective amount of one other anti-cancer agent selected from the group consisting of PLX4032, buthionine sulfoximine, sulfasalazine paclitaxel, docetaxel, cisplatin, oxaliplatin, betulinic acid, 4-S-cysteaminyl catechol, 4-S-cysteaminyl phenol, everolimus, bortezomib, carboplatin, dacarbazine, celecoxib, temozolomide, sorafenib, thalidomide, lenalidomide, valproic acid, vinblastine, imatinib mesylate, bosentan, apomine, arsenic trioxide, carmustine, lambrolizuma, anti-CTLA-4 drug, anti-PD-1 drug, ipilimumab, doxorubicin, MEK inhibitor, capecitabine, PARP inhibitor, and tamoxifen. 16. A method for inhibition of proliferation, migration, mobility, invasion, growth, and/or metastasis of cancer cells in a patient, comprising: administering to the patient a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of claim 2. 17. A method for enhancement of an anti-proliferative effect of another anti-cancer drug on cancer cells when treating a patient, comprising: administering to the patient a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 2. 18. A method for sensitizing and/or enhancing an anti-cancer effect of a gluthathione synthesis blocker on inhibition of triple negative breast cancer cell activity in a patient, comprising: administering to the patient a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 2. 19. A method for treatment and/or prophylaxis of lipopolysaccharide-stimulated inflammatory response in a patient, comprising: administering to the patient a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 2. 20. A method of combination therapy for inhibition of proliferation, migration, invasion, and/or metastasis of cancer cells in a patient in need thereof, comprising: administering to the patient in need thereof a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 2 and a therapeutically effective amount of one other anti-cancer agent selected from the group consisting of PLX4032, buthionine sulfoximine, sulfasalazine paclitaxel, docetaxel, cisplatin, oxaliplatin, betulinic acid, 4-S-cysteaminyl catechol, 4-S-cysteaminyl phenol, everolimus, bortezomib, carboplatin, dacarbazine, celecoxib, temozolomide, sorafenib, thalidomide, lenalidomide, valproic acid, vinblastine, imatinib mesylate, bosentan, apomine, arsenic trioxide, carmustine, lambrolizuma, anti-CTLA-4 drug, anti-PD-1 drug, ipilimumab, doxorubicin, MEK inhibitor, capecitabine, PARP inhibitor, and tamoxifen.

Details for Patent 10,238,631

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bristol-myers Squibb Company	YERVOY	ipilimumab	Injection	125377	03/25/2011		2039-04-25