Claims for Patent: 8,119,808

Summary for Patent: 8,119,808

Title:	Tetrahydroquinoline derivatives as cannabinoid receptor modulators
Abstract:	The invention provides for compounds of formula I ##STR00001## wherein the substitutents are as described herein. Further provided are methods of using such compounds for the treatment of eating disorders, metabolic disorders, obesity, cognitive disorders, neurological disorders, pain disorders, inflammation disorders, in the promotion of smoking cessation and for the treatment of other psychiatric disorders Also provided are pharmaceutical compositions containing such compounds and pharmaceutical combinations of the compounds of the invention with other therapeutic agents.
Inventor(s):	Sun; Chongqing (East Windsor, NJ), Sitkoff; Doree (Dresher, PA), Ewing; William R. (Yardley, PA), Huang; Yanting (Pennington, NJ), Ellsworth; Bruce A. (Princeton, NJ), Sulsky; Richard B. (West Trenton, NJ), Pendri; Annapurna (Glastonbury, CT), Gerritz; Samuel (Guilford, CT), Murugesan; Natesan (Princeton Junction, NJ), Gu; Zhengxiang (Princeton, NJ)
Assignee:	Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:	12/984,628
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,119,808
Patent Claims:	1. A compound of Formula I: ##STR00259## or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R.sub.1 is selected from the group consisting of hydrogen, alkyl, halo and CN; R.sub.2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, acyl, halo, CF.sub.3, CN, nitro, phenyl, thienyl, pyridinyl, oxopyridinyl, oxopyrrolidinyl, oxopiperidinyl, imidazolyl, pyrazolyl and OR.sub.11, NR.sub.12R.sub.12a, wherein phenyl, thienyl, pyridinyl, oxopyridinyl, oxopyrrolidinyl, oxopiperidinyl, imidazolyl and pyrazolyl may each be optionally substituted; R.sub.3 is selected from the group consisting of hydrogen, alkyl, halo and CN; R.sub.4 is selected from the group consisting of hydrogen, alkyl, halo and CN; R.sub.5 is selected from the group consisting of alkyl, cycloalkyl, phenyl, thienyl, pyrazinyl, pyridinyl, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl and isothiazolyl, wherein alkyl, cycloalkyl, phenyl, thienyl, pyrazinyl, pyridinyl, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl and isothiazolyl may each optionally be substituted; R.sub.6 and R.sub.6a are each independently selected from the group consisting of hydrogen and alkyl; R.sub.2 and R.sub.7a are each independently selected from the group consisting of hydrogen and alkyl; R.sub.8 is hydrogen; R.sub.9 is selected from the group consisting of hydrogen and alkyl; R.sub.10 is selected from the group consisting of alkyl, alkenyl, alkoxy, cycloalkyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolidinonyl, furanyl, isooxazolyl, piperidinyl, morpholinyl, phenyl, pyridinyl, benzothiadiazolyl and NR.sub.12R.sub.12a, wherein alkyl, alkenyl, alkoxy, cycloalkyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolidinonyl, furanyl, isooxazolyl, piperidinyl, morpholinyl, phenyl, pyridinyl, benzothiadiazolyl may each optionally be substituted; R.sub.11 is phenyl; R.sub.12 and R.sub.12a are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl and phenyl; or R.sub.12 and R.sub.12a taken together form morpholine, piperidine or pyrrolidine; X is selected from the group consisting of (CR.sub.14R.sub.14a).sub.n, CO and S(O).sub.2; Y is selected from the group consisting of S(O).sub.2, SO.sub.2N(R.sub.15) and C(O)C(O); R.sub.14 and R.sub.14a are each hydrogen; R.sub.15 is selected from the group consisting of hydrogen and alkyl; or R.sub.15 and R.sub.10 taken together can form morpholine, piperidine or oxazolidinone; n is an integer of 0, 1 or 2; and provided that when Y is S(O).sub.2 and R.sub.5 is other than alkyl, R.sub.10 is not optionally substituted phenyl. 2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer, wherein: R.sub.1 is hydrogen; R.sub.2 is selected from the group consisting of hydrogen, halo, CN and optionally substituted phenyl; R.sub.3 is hydrogen; R.sub.4 is hydrogen; R.sub.5 is selected from the group consisting of alkyl and optionally substituted phenyl; R.sub.6 and R.sub.6a are each hydrogen; R.sub.7 and R.sub.7a are each hydrogen; R.sub.8 is hydrogen; R.sub.9 is hydrogen; and X is CH.sub.2. 3. The compound of claim 2 or a pharmaceutically acceptable salt or stereoisomer, wherein: Y is selected from the group consisting of S(O).sub.2 and SO.sub.2N(R.sub.15). 4. The compound of claim 3 or a pharmaceutically acceptable salt or stereoisomer, wherein: Y is S(O).sub.2. 5. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of: Pyridine-3-sulfonic acid[1-(3-chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-amide; Pyridine-2-sulfonic acid[1-(3-chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-amide; Thiophene-2-sulfonic acid[1-(3-chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-amide; N-(6-Chloro-1-isopentyl-1,2,3,4-tetrahydroquinolin-3-yl)benzenesulfonamid- e; N-(6-Chloro-1-butyl-1,2,3,4-tetrahydroquinolin-3-yl)benzenesulfonamide; N,N-Dimethylamino-1-sulfonic acid (1-benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-amide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)ethanesulfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-2,2,2-trifluoroetha- nesulfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-2-(naphthalen-1-yl)- ethanesulfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)benzo(c)[1,2,5]thiaz- ole-4-sulfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-5-bromothiophene-2-- sulfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-4,5-dibromothiophen- e-2-sulfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-4,5-dichlorothiophe- ne-2-sulfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-1-methyl-1H-imidazo- le-4-sulfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-1,2-dimethyl-1H-imi- dazole-4-sulfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-5-chloro-1,3-dimeth- yl-1H-pyrazole-4-sulfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-3,5-dimethylisoxazo- le-4-sulfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-thiophene-3-sulfona- mide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-thiophene-2-su- lfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-5-(oxazol- -5-yl)thiophene-2-sulfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-5-(pyridin-2-yl)thi- ophene-2-sulfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-5-bromo-6-chloro pyridine-3-sulfonamide; N-(1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)-6-morpholino chloro pyridine-3-sulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-2-acetami- do-4-methyl thiazole-5-sulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-3,5-dimet- hylisoxazole-4-sulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-1-methyl-- 1H-imidazole-4-sulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-5-chloro-- 1,2-dimethyl-1H-imidazole-4-sulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-1,2-dimet- hyl-1H-imidazole-4-sulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-5-(oxazol- -5-yl)-thiophene-2-sulfonamide; N-(1-Benzyl-6-(4-fluoro phenyl)-1,2,3,4-tetrahydro quinolin-3-yl)-5-(isoxazole-3-yl)thiophene-2-sulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-5-chlorot- hiophene-2-sulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-5-methyl-- 2-(trifluoromethyl)furan-3-sulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)pyridine-2- -sulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)pyridine-3- -sulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-5-(triflu- omethyl)pyridine-2-sulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)me- thanesulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)(pyridin-3- -yl)methanesulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)(pyridin-4- -yl)methanesulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)(pyridin-2- -yl)methanesulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-2-phenyle- thene sulfonamide; (S)-Piperidine-1-sulfonic acid (1-benzyl-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-amide; Morpholine-4-sulfonic acid [1-(3-chloro-benzyl)-6-cyano-1,2,3,4-tetrahydro-quinolin-3-yl]-amide; N-(1-Benzyl-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-2-oxooxazolidine-3-s- ulfonamide; N-(1-Benzyl-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-cyclohexylamino-3-su- lfonamide; N-(1-Benzyl-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-anilinyl-3- -sulfonamide; N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-2-oxo-2-p- henylacetamide; and Ethyl 2-(1-benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-ylamino)-2-ox- oacetate. 6. A pharmaceutical composition comprising a compound of claim 1 in an amount sufficient to treat obesity or to induce smoking cessation and a pharmaceutically acceptable carrier or diluent. 7. A pharmaceutical composition comprising a combination of a composition according to claim 6 and an additional anti-obesity agent selected from the group consisting of melanocortin receptor (MC4R) agonists; melanin-concentrating hormone receptor (MCHR) antagonists; growth hormone secretagogue receptor (GHSR) antagonists; galanin receptor modulators; orexin antagonists; CCK agonists; GLP-1 agonists and other Pre-proglucagon-derived peptides; NPY1 or NPY5 antagonists; NPY2 and NPY4 modulators; corticotropin releasing factor agonists; histamine receptor-3 (H3) modulators; aP2 inhibitors; PPAR gamma modulators; PPAR delta modulators; acetyl-CoA carboxylase (ACC) inhibitors; 11-.beta.-HSD-1 inhibitors; adiponectin receptor modulators; beta 3 adrenergic agonists; thyroid receptor beta modulator; lipase inhibitors, serotonin receptor agonists, monoamine reuptake inhibitors or releasing agents, anorectic agents, topiramate; ciliary neurotrophic factor, brain-derived neurotrophic factor; leptin and leptin receptor modulators, SR-141716 and SLV-319 (ibipinabant); appetite suppressants; anti-diabetic agents; anti-hyperlipidemia agents; hypolipidemic agents selected from the group consisting of mevastatin; lovastatin; mevinolin; pravastatin; simvastatin fluvastatin; cerivastatin; atorvastatin; pitavastatin; nisvastatin; itavastatin; rosuvastatin; visastatin; SC-45355; dichloroacetate; imidazole analogs of mevalonolactone; 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives; 2,3-disubstituted pyrrole, furan and thiophene derivatives; naphthyl analogs of mevalonolactone; octahydronaphthalenes; quinoline and pyridine derivatives; and phosphinic acid compounds; hypocholesterolemic agents; lipid-modulating agents selected from a phytoestrogen compound selected from isolated soy bean protein, soy protein concentrate, soy flour, isoflavone, genistein, daidzein, glycitein or equol, or phytosterols, phytostanol and tocotrienol; a beta-lactam cholesterol absorption inhibitor; an HDL upregulator selected from an LXR agonist, a PPAR .alpha.-agonist and an FXR agonist; an LDL catabolism promoter; a sodium-proton exchange inhibitor; an LDL-receptor inducer; steroidal glycoside; an anti-oxidant selected from beta-carotene, ascorbic acid, .alpha.-tocopherol, retinol, Vitamin C antihomocysteine agent, folic acid, a folate, Vitamin B6, Vitamin B12 and Vitamin E; isoniazid; a cholesterol absorption inhibitor; an HMG-CoA synthase inhibitor; a lanosterol demethylase inhibitor; a PPAR .delta. agonist for treating dyslipidemia; a sterol regulating element binding protein-I selected from a sphingolipid, ceramide, neutral sphingomyelenase or fragment thereof; cholesterol-lowering agents; lipid-lowering agents; HDL-raising agent, anti-hypertensive agents selected from beta adrenergic blockers; L-type channel blockers selected from diltiazem, verapamil, nifedipine, amlodipine and mybefradil; T-type calcium channel blockers selected from diltiazem, verapamil, nifedipine, amlodipine and mybefradil; diuretics selected from chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride and spironolactone; renin inhibitors; ACE inhibitors selected from captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril and lisinopril; AT-1 receptor antagonists selected from losartan, irbesartan and valsartan; ET receptor antagonists selected from sitaxsentan and atrsentan; Dual ET/AII antagonists; neutral endopeptidase inhibitors; vasopepsidase inhibitors and dual NEP-ACE inhibitors selected from omapatrilat and gemopatrilat; and nitrates. 8. A pharmaceutical combination according to claim 7 wherein the anti-diabetic agent is an oral antihyperglycemic agent selected from the group consisting of biguanides, metformin, phenformin, metformin HCl and pharmaceutically acceptable salts of the foregoing. 9. A method for treatment of obesity which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in claim 1.

Details for Patent 8,119,808

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	03/13/1924		2023-07-11