Claims for Patent: 7,803,778

Summary for Patent: 7,803,778

Title:	Glucose transport inhibitors and methods of use
Abstract:	Provided are compounds having an inhibitory effect on sodium-dependent glucose cotransporter SGLT. The invention also provides pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions which are affected by SGLT inhibition.
Inventor(s):	Chen; Yuanwei (North Haven, CT), Feng; Yan (Shanghai, CN), Xu; Baihua (Shanghai, CN), Lv; Binhua (Shanghai, CN), Dong; Jiajia (Shanghai, CN), Seed; Brian (Derry, NH), Hadd; Michael J. (San Diego, CA)
Assignee:	Theracos, Inc. (Sunnyvale, CA)
Application Number:	11/752,226
Patent Claims:	1. A compound of Formula I: ##STR00082## wherein M is a member selected from the group consisting of methylene optionally substituted with one to two substituents independently selected from halo, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 cycloalkyloxy; and C.sub.3-C.sub.5 1,1-cycloalkylene optionally substituted with one to two substituents independently selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl and C.sub.3-C.sub.6 cycloalkyloxy; or optionally, M represents a single bond; X is a member selected from the group consisting of oxygen; sulfur; SO; SO.sub.2; methylene optionally substituted with one to two substituents independently selected from halo, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 cycloalkyloxy; C.sub.3-C.sub.5 1,1-cycloalkylene optionally substituted with one to two substituents independently selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl and C.sub.3-C.sub.6 cycloalkyloxy; and NH optionally substituted with a substituent independently selected from C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl and (C.sub.1-C.sub.4 alkyl)carbonyl; Y is a member selected from the group consisting of (CH.sub.2).sub.n; (CH.sub.2).sub.mCH.dbd.CH; CH.dbd.CH(CH.sub.2).sub.m; CH.sub.2CH.dbd.CHCH.sub.2; (CH.sub.2).sub.mC(O); C(O)(CH.sub.2).sub.m; and (O)C(CH.sub.2).sub.mC(O); wherein n is an integer from 1 to 3, m is an integer from 0 to 2, and each hydrogen independently is optionally replaced with a substituent independently selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl and C.sub.3-C.sub.6 cycloalkyloxy; Z is a member selected from the group consisting of oxygen; sulfur; SO; SO.sub.2; 1,1-cyclopropylene; carbonyl; and methylene optionally substituted with one to two substituents independently selected from halo, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl and C.sub.3-C.sub.6 cycloalkyloxy; R.sup.1 is a member selected from the group consisting of hydrogen, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.10 cycloalkyl, (C.sub.3-C.sub.10)cycloalkyl-(C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.4 alkenyl)C.sub.1-C.sub.3 alkyloxy, (C.sub.2-C.sub.4 alkynyl)C.sub.1-C.sub.3 alkyloxy, (C.sub.3-C.sub.10 cycloalkyl)C.sub.2-C.sub.4 alkenyl, C.sub.3-C.sub.6 cycloalkylidenmethyl, (C.sub.3-C.sub.10 cycloalkyloxy)C.sub.1-C.sub.3 alkyl, C.sub.5-C.sub.10 cycloalkenyl, (C.sub.5-C.sub.10)cycloalkenyl-(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.4 alkyloxy)C.sub.1-C.sub.3 alkyl, (C.sub.1-C.sub.4 alkylamino)C.sub.1-C.sub.3 alkyl, di-(C.sub.1-C.sub.3 alkylamino)C.sub.1-C.sub.3 alkyl, aryl, heteroaryl, (C.sub.1-C.sub.4 alkyl)carbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxycarbonyl, aminocarbonyl, (C.sub.1-C.sub.4 alkyl)aminocarbonyl, di-(C.sub.1-C.sub.3 alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C.sub.1-C.sub.4 alkyl)piperazin-1-ylcarbonyl, (C.sub.1-C.sub.4 alkyloxy)carbonyl, amino, C.sub.1-C.sub.4 alkylamino, di-(C.sub.1-C.sub.3 alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-(C.sub.1-C.sub.4 alkyl)piperazin-1-yl, (C.sub.1-C.sub.4 alkyl)carbonylamino, arylcarbonylamino, C.sub.1-C.sub.4 alkylsulfonylamino, arylsulfonylamino, heteroarylcarbonylamino, C.sub.1-C.sub.6 alkyloxy, C.sub.3-C.sub.10 cycloalkyloxy, C.sub.5-C.sub.7 cycloalkenyloxy, aryloxy, heteroaryloxy, (aryl)C.sub.1-C.sub.3 alkyloxy, (heteroaryl)C.sub.1-C.sub.3 alkyloxy, C.sub.1-C.sub.4 alkylsulfanyl, C.sub.1-C.sub.4 alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, C.sub.3-C.sub.10 cycloalkylsulfanyl, C.sub.3-C.sub.10 cycloalkylsulfinyl, C.sub.3-C.sub.10 cycloalkylsulfonyl, C.sub.5-C.sub.10 cycloalkenylsulfanyl, C.sub.5-C.sub.10 cycloalkenylsulfinyl, C.sub.5-C.sub.10 cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, hydroxy, cyano or nitro; wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups or portions are optionally partly or completely fluorinated and optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkyl, and in cycloalkyl and cycloalkenyl groups one or two methylene groups are optionally replaced independently of one another by O, S, CO, SO or SO.sub.2, and in N-heterocycloalkyl groups a methylene group is optionally replaced by CO or SO.sub.2; R.sup.2 is a member selected from the group consisting of hydrogen, halo, hydroxy, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C.sub.4 alkyloxy, C.sub.3-C.sub.10 cycloalkyloxy, cyano and nitro, wherein alkyl groups or portions are optionally mono- or polysubstituted by fluorine, or in the event that R.sup.1 and R.sup.2 are bound to two adjacent C atoms of the phenyl ring, R.sup.1 and R.sup.2 are optionally joined together such that R.sup.1 and R.sup.2 together form a C.sub.3-C.sub.5 alkylene, C.sub.3-C.sub.5 alkenylene or butadienylene bridge, which is optionally partly or completely fluorinated and optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkyl, and wherein one or two methylene groups are optionally replaced independently of one another by O, S, CO, SO, SO.sub.2 or NR.sup.a, and wherein one or two methyne groups are optionally replaced by an N atom; R.sup.3 is a member selected from the group consisting of hydrogen, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.10 cycloalkyl, (C.sub.3-C.sub.10)cycloalkyl-(C.sub.1-C.sub.3)alkyl, C.sub.5-C.sub.10 cycloalkenyl, (C.sub.5-C.sub.10)cycloalkenyl-(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.4 alkyloxy)C.sub.1-C.sub.3 alkyl, (C.sub.3-C.sub.10 cycloalkyloxy)C.sub.1-C.sub.3 alkyl, (C.sub.1-C.sub.4 alkylamino)C.sub.1-C.sub.3 alkyl, di-(C.sub.1-C.sub.3 alkylamino)C.sub.1-C.sub.3 alkyl, (C.sub.3-C.sub.10 cycloalkyl)C.sub.2-C.sub.4 alkenyl, C.sub.3-C.sub.6 cycloalkylidenmethyl, aryl, heteroaryl, (C.sub.1-C.sub.4 alkyl)carbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, (C.sub.1-C.sub.4 alkyl)aminocarbonyl, di-(C.sub.1-C.sub.3 alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C.sub.1-C.sub.4 alkyl)piperazin-1-ylcarbonyl, hydroxycarbonyl, (C.sub.1-C.sub.4 alkyloxy)carbonyl, alkylamino, di-(C.sub.1-C.sub.3 alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-(C.sub.1-C.sub.4 alkyl)piperazin-1-yl, (C.sub.1-C.sub.4 alkyl)carbonylamino, arylcarbonylamino, heteroaryl-carbonylamino, C.sub.1-C.sub.4 alkylsulfonylamino, arylsulfonylamino, C.sub.1-C.sub.6 alkyloxy, C.sub.3-C.sub.10 cycloalkyloxy, C.sub.5-C.sub.7 cycloalkenyloxy, aryloxy, heteroaryloxy, (C.sub.2-C.sub.4 alkenyl)C.sub.1-C.sub.3 alkyloxy, (C.sub.2-C.sub.4 alkynyl)C.sub.1-C.sub.3 alkyloxy, (aryl)C.sub.1-C.sub.3 alkyloxy, (heteroaryl)C.sub.1-C.sub.3 alkyloxy, C.sub.1-C.sub.4 alkylsulfanyl, C.sub.1-C.sub.4 alkylsulfinyl, alkylsulfonyl, C.sub.3-C.sub.10 cycloalkylsulfanyl, C.sub.3-C.sub.10 cycloalkylsulfinyl, C.sub.3-C.sub.10cycloalkylsulfonyl, C.sub.5-C.sub.10 cycloalkenylsulfanyl, C.sub.5-C.sub.10 cycloalkenylsulfinyl, C.sub.5-C.sub.10 cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, amino, hydroxy, cyano or nitro, wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups or portions are optionally partly or completely fluorinated and optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkyl, and in cycloalkyl and cycloalkenyl groups one or two methylene groups are optionally replaced independently of one another by O, S, CO, SO or SO.sub.2, and in N-heterocycloalkyl groups a methylene group is optionally replaced by CO or SO.sub.2; R.sup.4 is a member selected from the group consisting of hydrogen, halo, hydroxy, cyano, nitro, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 cycloalkyloxy and C.sub.1-C.sub.3 alkyloxy, wherein alkyl groups or portions may be mono- or polysubstituted by fluorine, or if R.sup.3 and R.sup.4 are bound to two adjacent C atoms of the phenyl ring, R.sup.3 and R.sup.4 are optionally joined together such that R.sup.3 and R.sup.4 together form a C.sub.3-C.sub.5 alkylene, C.sub.3-C.sub.5 alkenylene or butadienylene bridge, which is optionally partly or completely fluorinated and optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkyl, and wherein one or two methylene groups can be replaced independently of one another by O, S, CO, SO, SO.sub.2 or NR.sup.a, and wherein in the case of a butadienylene bridge one or two methyne groups are optionally replaced by an N atom; R.sup.5 is a member selected from the group consisting of hydrogen, halo, hydroxy, cyano, nitro, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.10 cycloalkyl and C.sub.1-C.sub.3 alkyloxy, wherein alkyl groups or portions may be mono- or polysubstituted by fluorine; and R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are each members independently selected from the group consisting of hydroxy, (C.sub.1-C.sub.18 alkyl)carbonyloxy, (C.sub.1-C.sub.18 alkyl)oxycarbonyloxy, arylcarbonyloxy, aryl-(C.sub.1-C.sub.3 alkyl)carbonyloxy, hydrogen, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, (C.sub.3-C.sub.10)cycloalkyl-(C.sub.1-C.sub.3)alkyl, (C.sub.5-C.sub.7)cycloalkenyl-(C.sub.1-C.sub.3)alkyl, aryl-(C.sub.1-C.sub.3)alkyl, heteroaryl-(C.sub.1-C.sub.3)alkyl, C.sub.1-C.sub.6 alkyloxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, (C.sub.3-C.sub.7)cycloalkyloxy, C.sub.5-C.sub.7 cycloalkenyloxy, aryloxy, heteroaryloxy, (C.sub.3-C.sub.7)cycloalkyl-(C.sub.1-C.sub.3)alkyloxy, (C.sub.5-C.sub.7)cycloalkenyl-(C.sub.1-C.sub.3)alkyloxy, aryl-(C.sub.1-C.sub.3)alkyloxy, heteroaryl-(C.sub.1-C.sub.3)alkyloxy, aminocarbonyl, hydroxycarbonyl, (C.sub.1-C.sub.4 alkyl)aminocarbonyl, di-(C.sub.1-C.sub.3 alkyl)aminocarbonyl, (C.sub.1-C.sub.4 alkyloxy)carbonyl, aminocarbonyl-(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.4 alkyl)aminocarbonyl-(C.sub.1-C.sub.3)alkyl, di-(C.sub.1-C.sub.3 alkyl)aminocarbonyl-(C.sub.1-C.sub.3)alkyl, hydroxycarbonyl-(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.4 alkyloxy)carbonyl-(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.7)cycloalkyloxy-(C.sub.1-C.sub.3)alkyl, (C.sub.5-C.sub.7)cycloalkenyloxy-(C.sub.1-C.sub.3)alkyl, aryloxy-(C.sub.1-C.sub.3)alkyl, heteroaryloxy-(C.sub.1-C.sub.3)alkyl, C.sub.1-C.sub.4 alkylsulfonyloxy, arylsulfonyloxy, aryl-(C.sub.1-C.sub.3)alkyl-sulfonyloxy, trimethylsilyloxy, t-butyldimethylsilyloxy, and cyano, wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups or portions are optionally partly or completely fluorinated and optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkyl, and in cycloalkyl and cycloalkenyl groups one or two methylene groups are optionally replaced independently of one another by NR.sup.a, O, S, CO, SO or SO.sub.2; R.sup.a is a member selected from the group consisting of H, C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 alkylcarbonyl; and pharmaceutically acceptable salts thereof. 2. A compound of claim 1, wherein X is O. 3. A compound of claim 1, wherein M is CH.sub.2. 4. A compound of claim 1, wherein Y is CH.sub.2 or C(O). 5. A compound of claim 1, wherein Z is selected from the group consisting of methylene, 1,1-cyclopropylene, methylmethylene, fluoromethylene, dimethylmethylene, difluoromethylene and fluoromethylmethylene. 6. A compound of claim 1, wherein at least one of R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is hydroxy. 7. A compound of claim 1, wherein at least two of R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are hydroxy. 8. A compound of claim 1, wherein M is CH.sub.1; X is O; Y is CH.sub.2 or C(O); Z is selected from the group consisting of methylene, 1,1-cyclopropylene, methylmethylene, fluoromethylene, dimethylmethylene, difluoromethylene and fluoromethylmethylene; and at least two of R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are hydroxy. 9. A compound of claim 1, wherein M is CH.sub.2; X is O; Y is selected from the group consisting of CH.sub.2 optionally substituted with C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy, and C(O); Z is selected from the group consisting of methylene, 1,1-cyclopropylene, methylmethylene, fluoromethylene, dimethylmethylene, difluoromethylene and fluoromethylmethylene; and at least two of R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are hydroxy. 10. A compound having the formula: ##STR00083## wherein Y is selected from the group consisting of (CH.sub.2).sub.n, (CH.sub.2).sub.mCH.dbd.CH, CH.dbd.CH(CH.sub.2).sub.m and CH.sub.2CH.dbd.CHCH.sub.2, wherein n is an integer from 1 to 3, m is an integer from 0 to 2, and each hydrogen independently may be optionally replaced with a substituent independently selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl and C.sub.3-C.sub.6 cycloalkyloxy; R.sup.1 is selected from the group consisting of hydrogen, halo, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl, (C.sub.3-C.sub.10 cycloalkyl)C.sub.1-C.sub.3 alkyl, (C.sub.3-C.sub.10 cycloalkyloxy)C.sub.1-C.sub.3 alkyl, (C.sub.1-C.sub.4 alkyloxy)C.sub.1-C.sub.3 alkyl, (C.sub.1-C.sub.4 alkylamino)C.sub.1-C.sub.3 alkyl, di-(C.sub.1-C.sub.3 alkylamino)C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.6 alkyloxy, C.sub.3-C.sub.10 cycloalkyloxy, hydroxy, cyano and nitro; and R.sup.3 is selected from the group consisting of hydrogen, halo, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl, (C.sub.3-C.sub.10 cycloalkyl)C.sub.1-C.sub.3 alkyl, (C.sub.3-C.sub.10 cycloalkyloxy)C.sub.1-C.sub.3 alkyl, (C.sub.1-C.sub.4 alkyloxy)C.sub.1-C.sub.3 alkyl, (C.sub.1-C.sub.4 alkylamino)C.sub.1-C.sub.3 alkyl, di-(C.sub.1-C.sub.3 alkylamino)C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.6 alkyloxy, C.sub.3-C.sub.10 cycloalkyloxy, hydroxy, cyano and nitro, wherein in cycloalkyl groups or portions, one or two methylene groups are optionally replaced independently of one another by O, S, CO, SO or SO.sub.2. 11. A pharmaceutical composition comprising a compound of claim 1 in a pharmaceutically acceptable carrier. 12. A pharmaceutical combination comprising a compound of claim 1 and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, a lipid-lowering/lipid-modulating agent, an agent for treating diabetic complications, an anti-obesity agent, an antihypertensive agent, an antihyperuricemic agent, and an agent for treating chronic heart failure or atherosclerosis. 13. The pharmaceutical combination of claim 12, wherein the therapeutic agent is at least one antidiabetic agent. 14. The pharmaceutical combination of claim 13, wherein the antidiabetic agent is at least one agent selected from the group consisting of insulin, a sulfonylurea, an insulin secretion enhancer, a biguanide, a sulfonylurea/biguanide combination, a meglitinide, a thiazolidinedione, a thiazolidinedione/biguanide combination, an oxadiazolidinedione, a PPAR-gamma agonist, a PPAR-alpha/gamma dual agonist, a PPAR-alpha/gamma/delta pan agonist, a retinoid X receptor agonist, an alpha-glucosidase inhibitor, a stimulant of insulin receptor tyrosine kinase, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a fructose 1,6-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, an imidazoline derivative, a hepatic gluconeogenesis inhibitor, D-chiroinositol, a glycogen synthase kinase-3 inhibitor, an incretin mimetic, a glucagon receptor antagonist, GLP-1, a GLP-1 analog, a GLP-1 receptor agonist, amylin, an amylin analog or agonist, an aP2 inhibitor, a beta-3 adrenergic receptor agonist and an insulin sensitivity enhancer. 15. The pharmaceutical combination of claim 14, wherein the antidiabetic agent is at least one agent selected from the group consisting of insulin, metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, rosiglitazone, isaglitazone, netoglitazone, rivoglitazone, repaglinide, nateglinide, exenatide, muraglitazar, naveglitazar, tesaglitazar, peliglitazar, farglitazar, metaglidasen, sitagliptin, vildagliptin, denagliptin, saxagliptin, solabegron and pramlintide. 16. The pharmaceutical combination of claim 12, wherein the therapeutic agent is at least one anti-obesity agent selected from the group consisting of a serotonin-norepinephrine reuptake inhibitor, a norepinephrine-dopamine reuptake inhibitor, a selective serotonin reuptake inhibitor, a selective norepinephrine reuptake inhibitor, a norepinephrine releasing stimulant, an anorexiant, a dopamine agonist, an H.sub.3-histamine antagonist, a 5-HT2c receptor agonist, a beta-3 adrenergic receptor agonist, a cholecystokinin agonist, a lipase inhibitor, an antidepressant/acetylcholinesterase inhibitor combination, a gamma-aminobutyric acid receptor antagonist, leptin, a leptin analog or leptin receptor agonist, an NPY receptor antagonist or modulator, ciliary neurotrophic factor, a thyroid hormone receptor-beta agonist, a cannabinoid CB1 receptor antagonist, and a melanin-concentrating hormone receptor antagonist. 17. The pharmaceutical combination of claim 16, wherein the anti-obesity agent is at least one agent selected from the group consisting of rimonabant, orlistat, sibutramine, topiramate, zonisamide, dextroamphetamine, phentermine, phenylpropanolamine, diethylpropion, mazindol, doprexin and Axokine. 18. The pharmaceutical combination of claim 12, wherein the therapeutic agent is at least one lipid-lowering/lipid-modulating agent selected from the group consisting of a hydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric acid derivative, a PPAR-alpha agonist, a PPAR-delta agonist, an acyl-coenzyme A:cholesterol acyltransferase inhibitor, probucol, a thyroid hormone receptor agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a lipoprotein-associated phospholipase A2 inhibitor, a microsomal triglyceride transfer protein inhibitor, a low density lipoprotein receptor activator, a lipoxygenase inhibitor, a carnitine palmitoyl-transferase inhibitor, a squalene synthase inhibitor, a nicotinic acid derivative, a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, and a cholesterol ester transfer protein inhibitor. 19. The pharmaceutical combination of claim 18, wherein the lipid-lowering/lipid-modulating agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, atavastatin, rosuvastatin, colestipol, cholestyramine, colestilan, colesevelam, fenofibrate, gemfibrozil, clofibrate, avasimibe, eflucimibe, eldacimibe, lecimibide, liothyronine, levothyroxine, rilapladib, darapladib, etomoxir, acipimox and torcetrapib. 20. A method for treating a condition selected from the group consisting of: type 1 or type II diabetes mellitus, hyperglycemia, diabetic complications, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity, edema, dyslipidemia, chronic heart failure, or atherosclerosis, which comprises administering an effective amount of a compound of claim 1 to a subject having said condition. 21. The method of claim 20, further comprising administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of an antidiabetic agent, a lipid-lowering/lipid-modulating agent, an agent for treating diabetic complications, an anti-obesity agent, an antihypertensive agent, an antihyperuricemic agent, and an agent for treating chronic heart failure or atherosclerosis. 22. A method of treating type I or type II diabetes comprising administering to a patient having type I or type II diabetes a therapeutically effective amount of a compound of claim 1 alone or in combination with at least one other therapeutic agent selected from the group consisting of an antidiabetic agent, a lipid-lowering/lipid-modulation agent, an agent for treating diabetic complications, an anti-obesity agent, an antihypertensive agent, an antihyperuricemic agent, and an agent for treating chronic heart failure or atherosclerosis. 23. A compound of the formula: ##STR00084## wherein Q is selected from the group consisting of hydroxy, a protected hydroxy group, and C.sub.2-C.sub.5 alkenyl; X is selected from the group consisting of oxygen; sulfur; SO; SO.sub.2; methylene optionally substituted with one to two substituents independently selected from halo, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 cycloalkyloxy; C.sub.3-C.sub.5 1,1-cycloalkylene optionally substituted with one to two substituents independently selected from halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl and C.sub.3-C.sub.6 cycloalkyloxy; and NH optionally substituted with a substituent independently selected from C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl and (C.sub.1-C.sub.4 alkyl)carbonyl; Z is a member selected from the group consisting of oxygen; sulfur; SO; SO.sub.2; 1,1-cyclopropylene; carbonyl; and methylene optionally substituted with one to two substituents independently selected from halo, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 cycloalkyl and C.sub.3-C.sub.6 cycloalkyloxy; R.sup.1 is a member selected from the group consisting of hydrogen, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.10 cycloalkyl, (C.sub.3-C.sub.10)cycloalkyl-(C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.4 alkenyl)C.sub.1-C.sub.3 alkyloxy, (C.sub.2-C.sub.4 alkynyl)C.sub.1-C.sub.3 alkyloxy, (C.sub.3-C.sub.10 cycloalkyl)C.sub.2-C.sub.4 alkenyl, C.sub.3-C.sub.6 cycloalkylidenmethyl, (C.sub.3-C.sub.10 cycloalkyloxy)C.sub.1-C.sub.3 alkyl, C.sub.5-C.sub.10 cycloalkenyl, (C.sub.5-C.sub.10)cycloalkenyl-(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.4 alkyloxy)C.sub.1-C.sub.3 alkyl, (C.sub.1-C.sub.4 alkylamino)C.sub.1-C.sub.3 alkyl, di-(C.sub.1-C.sub.3 alkylamino)C.sub.1-C.sub.3 alkyl, aryl, heteroaryl, (C.sub.1-C.sub.4 alkyl)carbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxycarbonyl, aminocarbonyl, (C.sub.1-C.sub.4 alkyl)aminocarbonyl, di-(C.sub.1-C.sub.3 alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C.sub.1-C.sub.4 alkyl)piperazin-1-ylcarbonyl, (C.sub.1-C.sub.4 alkyloxy)carbonyl, amino, C.sub.1-C.sub.4 alkylamino, di-(C.sub.1-C.sub.3 alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-(C.sub.1-C.sub.4 alkyl)piperazin-1-yl, (C.sub.1-C.sub.4 alkyl)carbonylamino, arylcarbonylamino, C.sub.1-C.sub.4 alkylsulfonylamino, arylsulfonylamino, heteroarylcarbonylamino, C.sub.1-C.sub.6 alkyloxy, C.sub.3-C.sub.10 cycloalkyloxy, C.sub.5-C.sub.7 cycloalkenyloxy, aryloxy, heteroaryloxy, (aryl)C.sub.1-C.sub.3 alkyloxy, (heteroaryl)C.sub.1-C.sub.3 alkyloxy, C.sub.1-C.sub.4 alkylsulfanyl, C.sub.1-C.sub.4 alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, C.sub.3-C.sub.10 cycloalkylsulfanyl, C.sub.3-C.sub.10 cycloalkylsulfinyl, C.sub.3-C.sub.10 cycloalkylsulfonyl, C.sub.5-C.sub.10 cycloalkenylsulfanyl, C.sub.5-C.sub.10 cycloalkenylsulfinyl, C.sub.5-C.sub.10 cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, hydroxy, cyano or nitro; wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups or portions are optionally partly or completely fluorinated and optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkyl, and in cycloalkyl and cycloalkenyl groups one or two methylene groups are optionally replaced independently of one another by O, S, CO, SO or SO.sub.2, and in N-heterocycloalkyl groups a methylene group is optionally replaced by CO or SO.sub.2; R.sup.2 is a member selected from the group consisting of hydrogen, halo, hydroxy, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C.sub.4 alkyloxy, C.sub.3-C.sub.10 cycloalkyloxy, cyano and nitro, wherein alkyl groups or portions are optionally mono- or polysubstituted by fluorine, or in the event that R.sup.1 and R.sup.2 are bound to two adjacent C atoms of the phenyl ring, R.sup.1 and R.sup.2 are optionally joined together such that R.sup.1 and R.sup.2 together form a C.sub.3-C.sub.5 alkylene, C.sub.3-C.sub.5 alkenylene or butadienylene bridge, which is optionally partly or completely fluorinated or mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkyl, and wherein one or two methylene groups are optionally replaced independently of one another by O, S, CO, SO, SO.sub.2 or NR.sup.a, and wherein one or two methyne groups are optionally replaced by an N atom; R.sup.3 is a member selected from the group consisting of hydrogen, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.10 cycloalkyl, (C.sub.3-C.sub.10)cycloalkyl-(C.sub.1-C.sub.3)alkyl, C.sub.5-C.sub.10 cycloalkenyl, (C.sub.5-C.sub.10)cycloalkenyl-(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.4 alkyloxy)C.sub.1-C.sub.3 alkyl, (C.sub.3-C.sub.10 cycloalkyloxy)C.sub.1-C.sub.3 alkyl, (C.sub.1-C.sub.4 alkylamino)C.sub.1-C.sub.3 alkyl, di-(C.sub.1-C.sub.3 alkylamino)C.sub.1-C.sub.3 alkyl, (C.sub.3-C.sub.10 cycloalkyl)C.sub.2-C.sub.4 alkenyl, C.sub.3-C.sub.6 cycloalkylidenmethyl, aryl, heteroaryl, (C.sub.1-C.sub.4 alkyl)carbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, (C.sub.1-C.sub.4 alkyl)aminocarbonyl, di-(C.sub.1-C.sub.3 alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C.sub.1-C.sub.4 alkyl)piperazin-1-ylcarbonyl, hydroxycarbonyl, (C.sub.1-C.sub.4 alkyloxy)carbonyl, C.sub.1-C.sub.4 alkylamino, di-(C.sub.1-C.sub.3 alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-(C.sub.1-C.sub.4 alkyl)piperazin-1-yl, (C.sub.1-C.sub.4 alkyl)carbonylamino, arylcarbonylamino, heteroaryl-carbonylamino, C.sub.1-C.sub.4 alkylsulfonylamino, arylsulfonylamino, C.sub.1-C.sub.6 alkyloxy, C.sub.3-C.sub.10 cycloalkyloxy, C.sub.5-C.sub.7 cycloalkenyloxy, aryloxy, heteroaryloxy, (C.sub.2-C.sub.4 alkenyl)C.sub.1-C.sub.3 alkyloxy, (C.sub.2-C.sub.4 alkynyl)C.sub.1-C.sub.3 alkyloxy, (aryl)C.sub.1-C.sub.3 alkyloxy, (heteroaryl)C.sub.1-C.sub.3 alkyloxy, C.sub.1-C.sub.4 alkylsulfanyl, C.sub.1-C.sub.4 alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, C.sub.3-C.sub.10 cycloalkylsulfanyl, C.sub.3-C.sub.10 cycloalkylsulfinyl, C.sub.3-C.sub.10 cycloalkylsulfonyl, C.sub.5-C.sub.10 cycloalkenylsulfanyl, C.sub.5-C.sub.10 cycloalkenylsulfinyl, cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, amino, hydroxy, cyano or nitro, wherein alkyl, alkenyl, alkynyl, cycloalkyl- and cycloalkenyl groups or portions are optionally partly or completely fluorinated and optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkyl, and in cycloalkyl and cycloalkenyl groups one or two methylene groups are optionally replaced independently of one another by O, S, CO, SO or SO.sub.2, and in N-heterocycloalkyl groups a methylene group is optionally replaced by CO or SO.sub.2; R.sup.4 is a member selected from the group consisting of hydrogen, halo, hydroxy, cyano, nitro, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 cycloalkyloxy and C.sub.1-C.sub.3 alkyloxy, wherein alkyl groups or portions may be mono- or polysubstituted by fluorine, or if R.sup.3 and R.sup.4 are bound to two adjacent C atoms of the phenyl ring, R.sup.3 and R.sup.4 are optionally joined together such that R.sup.3 and R.sup.4 together form a C.sub.3-C.sub.5 alkylene, C.sub.3-C.sub.5 alkenylene or butadienylene bridge, which is optionally partly or completely fluorinated and optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkyl, and wherein one or two methylene groups can be replaced independently of one another by O, S, CO, SO, SO.sub.2 or NR.sup.a, and wherein in the case of a butadienylene bridge one or two methyne groups are optionally replaced by an N atom; R.sup.5 is a member selected from the group consisting of hydrogen, halo, hydroxy, cyano, nitro, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.10 cycloalkyl and C.sub.1-C.sub.3 alkyloxy, wherein alkyl groups or portions may be mono- or polysubstituted by fluorine; and R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are each members independently selected from the group consisting of hydroxy, (C.sub.1-C.sub.18 alkyl)carbonyloxy, (C.sub.1-C.sub.18 alkyl)oxycarbonyloxy, arylcarbonyloxy, aryl-(C.sub.1-C.sub.3 alkyl)carbonyloxy, hydrogen, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, (C.sub.3-C.sub.10)cycloalkyl-(C.sub.1-C.sub.3)alkyl, (C.sub.5-C.sub.7)cycloalkenyl-(C.sub.1-C.sub.3)alkyl, aryl-(C.sub.1-C.sub.3)alkyl, heteroaryl-(C.sub.1-C.sub.3)alkyl, C.sub.1-C.sub.6 alkyloxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, (C.sub.3-C.sub.7)cycloalkyloxy, C.sub.5-C.sub.7 cycloalkenyloxy, aryloxy, heteroaryloxy, (C.sub.3-C.sub.7)cycloalkyl-(C.sub.1-C.sub.3)alkyloxy, (C.sub.5-C.sub.7)cycloalkenyl-(C.sub.1-C.sub.3)alkyloxy, aryl-(C.sub.1-C.sub.3)alkyloxy, heteroaryl-(C.sub.1-C.sub.3)alkyloxy, aminocarbonyl, hydroxycarbonyl, (C.sub.1-C.sub.4 alkyl)aminocarbonyl, di-(C.sub.1-C.sub.3 alkyl)aminocarbonyl, (C.sub.1-C.sub.4 alkyloxy)carbonyl, aminocarbonyl-(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.4 alkyl)aminocarbonyl-(C.sub.1-C.sub.3)alkyl, di-(C.sub.1-C.sub.3 alkyl)aminocarbonyl-(C.sub.1-C.sub.3)alkyl, hydroxycarbonyl-(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.4 alkyloxy)carbonyl-(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.7)cycloalkyloxy-(C.sub.1-C.sub.3)alkyl, (C.sub.5-C.sub.7)cycloalkenyloxy-(C.sub.1-C.sub.3)alkyl, aryloxy-(C.sub.1-C.sub.3)alkyl, heteroaryloxy-(C.sub.1-C.sub.3)alkyl, C.sub.1-C.sub.4 alkylsulfonyloxy, arylsulfonyloxy, aryl-(C.sub.1-C.sub.3)alkyl-sulfonyloxy, trimethylsilyloxy, t-butyldimethylsilyloxy, and cyano, wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups or portions are optionally partly or completely fluorinated and optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkyl, and in cycloalkyl and cycloalkenyl groups one or two methylene groups are optionally replaced independently of one another by NR.sup.a, O, S, CO, SO or SO.sub.2; and R.sup.a is a member selected from the group consisting of H, C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 alkylcarbonyl. 24. The compound 5-chloro-6-(4-ethylbenzyl)-6'-(hydroxymethyl)-2,3,3',4',5',6'-hexahydrosp- iro[indene-1,2'-pyran]-3',4',5'-triol, or a pharmaceutically acceptable salt thereof. 25. A compound of claim 1, selected from the group consisting of 5-chloro-6-(4-ethylbenzyl)-3-(2-hydroxyethyl)-6'-(hydroxymethyl)-2,3,3',4- ',5',6'-hexahydrospiro[indene-1,2'-pyran]-3',4',5'-triol; 5-chloro-6-(4-ethylbenzyl)-6'-(hydroxymethyl)-2,3,3',4',5',6'-hexahydrosp- iro[indene-1,2'-pyran]-3,3',4',5'-tetraol; 5-chloro-6-(4-ethylbenzyl)-6'-(hydroxymethyl)-3-methoxy-2,3,3',4',5',6'-h- exahydrospiro[indene-1,2'-pyran]-3',4',5'-triol; 5-chloro-6-(4-ethylbenzyl)-3-fluoro-6'-(hydroxymethyl)-2,3,3',4',5',6'-he- xahydrospiro[indene-1,2'-pyran]-3',4',5'-triol; 5-chloro-6'-(hydroxymethyl)-6-(4-(tetrahydrofuran-3-yloxy)benzyl)-2,3,3',- 4',5',6'-hexahydrospiro[indene-1,2'-pyran]-3',4',5'-triol; 5-chloro-6-(4-ethylbenzyl)-3',4',5'-trihydroxy-2,3,3',4',5',6'-hexahydros- piro[indene-1,2'-pyran]-6'-yl)methyl methyl carbonate; 5-chloro-6-(4-ethylbenzyl)-3',4',5'-trihydroxy-2,3,3',4',5',6'-hexahydros- piro[indene-1,2'-pyran]-6'-yl)methyl ethyl carbonate; 5-chloro-6-(4-ethoxybenzyl)-3',4',5'-trihydroxy-2,3,3',4',5',6'-hexahydro- spiro[indene-1,2'-pyran]-6'-yl)methyl isopropyl carbonate; and 5-chloro-6-(4-ethoxybenzyl)-3',4',5'-trihydroxy-2,3,3',4',5',6'-hexahydro- spiro[indene-1,2'-pyran]-6'-yl)methyl 3,3-dimethylbutanoate or a pharmaceutically acceptable salt or prodrug thereof. 26. A pharmaceutical composition comprising a compound of claim 24 in a pharmaceutically acceptable carrier. 27. A pharmaceutical composition comprising a compound of claim 25, in a pharmaceutically acceptable carrier. 28. A method for treating a condition selected from the group consisting of: type 1 or type II diabetes mellitus, hyperglycemia, diabetic complications, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity, edema, dyslipidemia, chronic heart failure, or atherosclerosis, which comprises administering an effective amount of a compound of claim 24 or 25 to a subject having said condition. 29. A compound of claim 24 or 25 which is the 1S,3'R,4'S,5'R,6'R isomer.

Details for Patent 7,803,778

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		2026-05-23