WO2015043473A1 - Dérivés de glucopyranosyl et leurs utilisations en médecine - Google Patents

Dérivés de glucopyranosyl et leurs utilisations en médecine Download PDF

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WO2015043473A1
WO2015043473A1 PCT/CN2014/087320 CN2014087320W WO2015043473A1 WO 2015043473 A1 WO2015043473 A1 WO 2015043473A1 CN 2014087320 W CN2014087320 W CN 2014087320W WO 2015043473 A1 WO2015043473 A1 WO 2015043473A1
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alkyl
compound
methyl
alkoxy
inhibitor
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Zheng Gu
Jiaping Wen
Heran WANG
Weihua Wang
Wuyong WU
Pengcho Tang
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to glucopyranosyl derivatives as sodium dependent glucose cotransporters (SGLTs) inhibitors and pharmaceutical uses thereof, particularly pyranol derivatives represented by Formula (I) , or pharmaceutically acceptable salts or all stereisomers thereof, pharmaceutical composition containing the derivatives and their uses for treating diabetes and diabetes-related diseases.
  • SGLTs sodium dependent glucose cotransporters
  • Diabetes mellitus is a common chronic disease, characterized by hyperglycemia.
  • the onset of diabetes associates with insulin resistance in peripheral tissue, reduction of insulin in vivo and increase of gluconeogenesis in liver.
  • insulin or oral hypoglycemic drugs for treatment are needed.
  • hypoglycemic drugs comprise biguanides, sulfonylureas, insulin sensitizers, glinides, ⁇ -glucosidase inhibitors and DPP-IV inhibitors, etc.
  • these current hypoglycemic drugs have shortcomings. Biguanides can cause lactic acidosis. Sulfonylureas can result in severe hypoglycemia.
  • Insulin sensitizers can lead to edema, heart failure and weight gain.
  • ⁇ -Glucosidase inhibitors can cause abdominal bloating and diarrhea.
  • DPP-IV inhibitors need to combine with metformin to achieve the desired effect of hypoglycemia. Therefore, there is an urgent need to develop novel, safer, and more effective hypoglycemic agents.
  • glucose transporter proteins are a class of carrier proteins embedded in the cell membrane for transporting glucose. Glucose must be in virtue of glucose transporter protein to cross lipid bilayer structure of cell membranes. Glucose transporter proteins are divided into two categories. The first category includes sodium-dependent glucose transporters (SGLTs) , and the other category includes is glucose transporters (GLUTs) . Two major family members of SGLTs are SGLT-1 and SGLT-2.
  • SGLT-1 is mainly distributed in small intestine, kidney, heart and windpipe, predominantly expressed in the intestinal brush border and the distal S3 segment of the renal proximal tubule, and a few expressed in heart and windpipe, and transports glucose and galactose with a sodium to glucose ratio of 2:1.
  • SGLT-2 is mainly distributed in kidney, predominantly expressed in the distal S1 segment of the renal proximal tubule, and transports glucose with a sodium to glucose ratio of 1:1.
  • glucose is transported by SGLT through active transport against a concentration gradient with simultaneous energy consumption.
  • glucose is transported by GLUTs through facilitated diffusion along a concentration gradient without energy consumption in the transport process.
  • SGLTs is the first stage in regulation of glucose metabolism in cells, and an ideal target for treating diabetes effectively. It has been found by research that the patients with SGLT-2 impairment would excrete large amounts of urine glucose. This provides the factual basis of treating diabetes by reducing glucose uptake through inhibiting SGLT-2 activity.
  • SGLTs inhibitors inhibiting activity of SGLTs transport protein could block reabsorption of glucose in renal tubules and increase excretion of glucose in urine to normalize the plasma glucose concentration and further control the diabetes and diabetic complications. Inhibiting SGLTs would not influence the normal anti-regulatory mechanism of glucose, which may cause the risk of hypoglycemia. Meanwhile, lowering blood glucose through an increase of renal glucose excretion could promote weight loss in obese patients. It has also been found by research that the mechanism of action of SGLT2 inhibitors is independent of pancreatic ⁇ cell dysfunction or the degree of insulin resistance. Therefore, the efficacy of SGLTs inhibitors will not decrease with the severe insulin resistance or ⁇ -cell failure. SGLTs inhibitors could be used alone or in combination with other hypoglycemic agents. Therefore, SGLTs inhibitors are ideal and novel hypoglycemic agents.
  • SGLTs inhibitors can be used for treating diabetes-related complications. Such as retinopathy, neuropathy, kidney disease, insulin resistance caused by glucose metabolic disorder, hyperinsulinemia, hyperlipidemia, obesity, and so on. Meanwhile, SGLTs inhibitors also be used in combination with current treatment regimens, such as sulphonamides, thiazolidinedione, metformin, and insulin, etc, which can reduce the dose without impacting on the effectiveness of the medicine, and thereby avoid or reduce side effects, and improve patient compliance.
  • current treatment regimens such as sulphonamides, thiazolidinedione, metformin, and insulin, etc, which can reduce the dose without impacting on the effectiveness of the medicine, and thereby avoid or reduce side effects, and improve patient compliance.
  • SGLTs inhibitors particularly the SGLT-2 protein inhibitors have a good prospect as novel antidiabetic drugs.
  • R b is alkyl, alkoxyalkyl, silyl, silylalkoxyalkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein optionally each of the alkyl, alkoxyalkyl, silyl, alkenyl, cycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl is independently substituted by one or more substituents independently selected from -H, -F, -Cl, -Br, -I, hydroxy, carboxy, cyano, nitro, amino, mercapto and alkoxy;
  • R c is alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein optionally each of the alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl is independently substituted by one or more substituents independently selected from -H, -F, -Cl, -Br, -I, hydroxy, carboxy, cyano, nitro, amino and mercapto;
  • R a is hydroxy, alkyl or alkoxy, wherein optionally each of the alkyl and alkoxy is independently substituted by one or more substituents independently selected from -H, -F, -Cl, -Br, -I, hydroxy, carboxy, cyano, nitro, amino and mercapto;
  • n 0, 1, 2, 3 or 4;
  • each R 6 is independently -H, -F, -Cl or -Br.
  • a compound having Formula (II) or a stereoisomer, a geometric isomer, a tautomer, a racemate, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
  • a compound having Formula (I) or (II) wherein R 4 is -H, hydroxy, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, amino, N-methylamino, N, N-dimethylamino, N-ethylamino, N, N-diethylamino or pivaloyloxymethoxy.
  • a compound having Formula (I) or (II) wherein R a is hydroxy, C 1-6 alkyl or C 1-6 alkoxy, wherein optionally each of the C 1-6 alkyl and C 1-6 alkoxy is independently substituted by one or more substituents independently selected from -H, -F, -Cl, -Br, -I, hydroxy, carboxy, cyano, nitro, amino and mercapto.
  • provided herein is a compound having Formula (I) or (II) , wherein R a is hydroxy, methoxy, ethoxy or 1-hydroxyethoxy.
  • R b is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 -alkyl, C 1-18 silyl, C 1-18 silyl-C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 6-10 aryl, C 6-10 aryl-C 1-6 -alkyl, C 1-9 heteroaryl or C 1-9 heteroaryl-C 1-6 -alkyl, wherein optionally each of the C 1-6 alkyl, C 1-6 alkoxy-C 1-6 -alkyl, C 1-18 silyl, C 1-18 silyl-C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 6-10 aryl, C 6-10 aryl-C 1-6 -alkyl, C 1-9
  • R c is C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, C 6-10 aryl-C 1-6 -alkyl, C 1-9 heteroaryl or C 1-9 heteroaryl-C 1-6 -alkyl, wherein optionally each of the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, C 6-10 aryl-C 1-6 -alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl-C 1-6 -alkyl is independently substituted by one or more substituents independently selected from -H, -F, -Cl, -Br, -I, hydroxy, carboxy, cyano, nitro, amino and mercapto.
  • a compound having Formula (I) or (II) wherein R b is methyl, ethyl, tert-butyl, methoxymethyl, allyl, trityl, benzyl, p-methoxybenzyl, acetyl, (tert-butyl) (dimethyl) silyl, trimethylsilyl, (tert-butyl) (diphenyl) silyl, triethylsilyl, triisopropylsilyl, 2-(trimethylsilyl) ethoxymethyl or tetrahydropyranyl; and
  • R c is methyl, tert-butyl, methoxy, ethoxy, phenyl or benzyl.
  • composition comprising the compound disclosed herein, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • a pharmaceutical composition further comprising an additional therapeutic agent, wherein the additional therapeutic agent is an anti-diabetic agent other than an SGLT-2 inhibitor, an antihyperglycemic agent, an antiadipositas drug, an antihypertensive agent, an antiplatelet agent, an antiatherosclerotic drug, a lipid-lowering agent, an anti-inflammatory or a combination thereof.
  • the additional therapeutic agent is an anti-diabetic agent other than an SGLT-2 inhibitor, an antihyperglycemic agent, an antiadipositas drug, an antihypertensive agent, an antiplatelet agent, an antiatherosclerotic drug, a lipid-lowering agent, an anti-inflammatory or a combination thereof.
  • each of the anti-diabetic agent other than an SGLT-2 inhibitor and antihyperglycemic agent is independently a biguanide, a sulfonylurea, a glucosidase inhibitor, a PPAR agonist, an ⁇ P2 inhibitor, a PPAR ⁇ / ⁇ dual agonist, a dipeptidyl peptidase IV (DPP-IV) inhibitor, a meglitinide, insulin, a glucagon-like peptide-1 (GLP-1) inhibitor, a PTP1B inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor or a combination thereof.
  • DPP-IV dipeptidyl peptidase IV
  • the lipid-lowering agent is an MTP inhibitor, an HMGCoA reductase inhibitor, a squalene synthase inhibitor, a fibric acid derivative, an ACAT inhibitor, a lipoxygenase inhibitor, a cholesterol absorption inhibitor, an ileal Na (+) /bile acid cotransporter inhibitor, an upregulator of LDL receptor activity, niacin or a derivative thereof, a bile acid sequestrant or a combination thereof.
  • the lipid-lowering agent is pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin, rosuvastatin or a combination thereof.
  • provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for inhibiting the activity of SGLT-2 or increasing HDL level.
  • a disease for preventing or treating a disease, lessening a disease symptoms, delaying the progression or onset of a disease, wherein the disease is diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, a diabetic complication, atherosclerosis or hypertension.
  • diabetes diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, a diabetic complication, atherosclerosis or hypertension.
  • provided herein is a method for inhibiting the activity of SGLT-2 or increasing HDL level, comprising administering to the patient in need thereof a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein.
  • a method for preventing or treating a disease, lessening a disease symptoms, delaying the progression or onset of a disease comprising administering to the patient in need thereof a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein, wherein the disease is diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, a diabetic complication, atherosclerosis or hypertension.
  • the disease is diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, a diabetic complication, atherosclerosis or hypertension.
  • provided herein is a compound or the pharmaceutical composition disclosed herein for use in inhibiting the activity of SGLT-2 or increasing HDL level.
  • a compound or the pharmaceutical composition disclosed herein for use in preventing or treating a disease, lessening a disease symptom, delaying the progression or onset of a disease, wherein the disease is diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, a diabetic complication, atherosclerosis or hypertension.
  • the present invention provides glucopyranosyl derivatives, preparation processes and pharmaceutical uses thereof. Skilled in the art can learn from this article to properly improve the process parameters. Of particular note is that all similar substitutions and modifications to the skilled person is obvious, and they are deemed to be included in the present invention.
  • halogen refers to fluoro (F) , chloro (Cl) , bromo (Br) or iodo (I) .
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical of 1 to 20 carbon atoms. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-10 carbon atoms. In other embodiments, the alkyl group contains 1-8 carbon atoms. In other embodiments, the alkyl group contains 1-6 carbon atoms. In still other embodiments, the alkyl group contains 1-4 carbon atoms.
  • alkyl group examples include methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, n-pentyl, 1-methyl-butyl, 2-methyl-butyl, 3-methyl-l-butyl, neopentyl, 3, 3-dimethyl-propyl, n-hexyl and 2-methyl-pentyl.
  • the alkyl group containing 1 to 6 carbon atoms described herein is a lower alkyl group.
  • the alkyl group is optionally substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, hydroxy, cyano, amino, carboxy and carboxylic ester.
  • haloalkyl refers to an alkyl group substituted with one or more halogen atoms. Some non-limiting examples of the haloalkyl group include fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1, 1-dichloroethyl and 1, 2-dichloropropyl.
  • alkoxy refers to an alkyl-O-group. Some non-limiting examples of the alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy and neopentyloxy.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms, wherein the alkoxy group is as defined herein.
  • Some non-limiting examples of the haloalkoxy group include difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy and perfluoroethoxy.
  • alkylamino refers to an amino group substituted with one or two alkyl groups.
  • alkylamino group include methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, n-pentylamino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino and N-methyl-n-propylamino.
  • alkoxyalkyl refers to an alkyl group substituted with one or more alkoxy groups. Some non-limiting examples of the alkoxyalkyl group include methoxymethyl, ethoxymethyl, methoxyethyl and ethoxyethyl.
  • silyl refers to a group having wherein each of R 21 , R 22 and R 23 is independently alkyl, haloalkyl or aryl.
  • Some non-limiting examples of the silyl group include (tert-butyl) (dimethyl) silyl, trimethylsilyl, (tert-butyl) (diphenyl) silyl, triethylsilyl and triisopropylsilyl.
  • silylalkoxyalkyl refers to an alkoxyalkyl group substituted with one or more silyl groups, wherein the alkoxyalkyl group and the silyl group are as defined herein.
  • silylalkoxyalkyl group include 2- (trimethylsilyl) ethoxymethyl.
  • alkenyl refers to a linear or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms, or two to eight carbon atoms, or two to six carbon atoms, or two to four carbon atoms, with at least one site of unsaturation, i. e. , a carbon-carbon, sp 2 double bond, wherein the alkenyl radical is optionally substituted independently with one or more substituents described herein, and includes radicals having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • alkynyl refers to a linear or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms, or two to eight carbon atoms, or two to six carbon atoms, or two to four carbon atoms, with at least one site of unsaturation, i. e. , a carbon-carbon, sp triple bond, wherein the alkynyl radical is optionally substituted independently with one or more substituents described herein.
  • alkynyl group examples include ethynyl (-C ⁇ CH) , prop-1-yn-1-yl (propargyl, -CH 2 C ⁇ CH) , prop-2-yn-1-yl (-CH 2 C ⁇ CH) , but-1-yn-1-yl, but-2-yn-1-yl, pent-1-yn-1-yl, pent-2-yn-1-yl, 3-methylbut-1-yn-1-yl, hex-1-yn-1-yl, hept-1-yn-1-yl and oct-1-yn-1-yl.
  • cycloalkyl refers to a saturated or partially saturated monocyclic or polycyclic (fused, bridged and/or spiro ring) , non-aromatic carbon ring containing 3 to n carbon atoms.
  • n is an integer from 3 to 30. In other embodiments, n is an integer from 3 to 15. In other embodiments, n is an integer from 3 to 10.
  • cycloalkyl group examples include cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinanyl, adamantly, bicycle [3.2.1] octyl and spiro [4.5] decyl.
  • the cycloalkyl group is optionally substituted by one or more substituents independently selected from halogen, hydroxy, carboxy, cyano, nitro, amino, acyl, alkenyl, alkynyl, carbonyl, mercapto, lower alkyl, cycloalkyl, lower alkylthio, lower alkoxy, lower hydroxyalkyl, lower alkylamino, lower alkylcarbonyl, lower alkyl-thio-lower alkyl, lower alkyl-sulfinyl, lower alkoxycarbonyl and lower alkylaminocarbonyl.
  • the cycloalkyl group relates to unsubstituted saturated monocyclic ring.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic (fused, bridged and/or spiro ring) , non-aromatic carbon ring containing 3 to n carbon atoms having one or more heteroatoms independently selected from oxygen, sulfur, selenium, nitrogen, phosphorus or silicon.
  • n is an integer from 3 to 20.
  • n is an integer from 3 to 15.
  • n is an integer from 3 to 10.
  • n is an integer from 3 to 6.
  • heterocyclyl group examples include oxetanyl, tetrahydrofuranyl, pyranyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, imidazolinyl, oxazolidinyl, pyrazolidinyl, pyrrolinyl, oxo-2 (1H) -pyridyl and oxazolidin-2-one-5-yl.
  • the heterocyclyl group is optionally substituted by one or more substituents independently selected from halogen, hydroxy, carboxy, cyano, nitro, amino, acyl, alkenyl, alkynyl, carbonyl, mercapto, lower alkyl, heteroalkyl, lower alkylthio, lower alkoxy, lower hydroxyalkyl, lower alkylamino, lower alkylcarbonyl, lower alkyl-thio-lower alkyl, lower alkyl-sulfinyl, lower alkoxycarbonyl and lower alkylaminocarbonyl.
  • the heterocyclyl group relates to unsubstituted saturated monocycle.
  • aryl refers to a cyclic hydrocarbon system of a monocyclic ring or multicyclic ring fused (each ring in the system shares an adjacent pair of atoms with another ring in the system) and/or connected (each ring in the system connected with another ring in the system by a single bond or a double bond) together, and also refers to a monocyclic aromatic hydrocarbon or multicyclic system having monocyclic aromatic ring or multicyclic hydrocarbon ring fused to one or more cycloalkyl and/or heterocyclyl.
  • the aryl group is a monocyclic aryl ring, 8 to 16 carbon atoms multicyclic ring, benzocycloalkyl, or benzoheterocyclicalkyl.
  • Some non-limiting examples of the aryl group include phenyl, 1-naphthyl, 2-naphthyl, anthryl, p-aminophenyl, 2-aminophenyl, p-carboxyphenyl, 2-carboxyphenyl, p-trifluoromethylphenyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, o-cyanophenyl, m-cyanophenyl, p-cyanophenyl, 2, 6-dinitrophenyl, benzodioxanyl, benzodioxolyl, chromanyl and benzodihydroindolyl.
  • the aryl group is optionally substituted by one or more substituents independently selected from halogen, hydroxy, carboxy, cyano, nitro, amino, acyl, alkenyl, alkynyl, carbonyl, mercapto, lower alkyl, cycloalkyl, heterocyclicalkyl, lower alkylthio, lower alkoxy, lower hydroxyalkyl, lower alkylamino, lower alkylcarbonyl, lower alkyl-thio-lower alkyl, lower alkyl-sulfinyl, lower alkoxycarbonyl, lower alkylaminocarbonyl, aryl, aryl-lower alkylcarbonyl, aryl-lower alkylthio, aryl-lower alkyl-sulfinyl, aryl-lower alkyl-sulfinyl-lower alky, aryl-lower alkoxycarbonyl, arylalkylaminocarbonyl and ary
  • aralkyl refers to an alkyl group substituted by one or more aryl groups.
  • the aralkyl group refers to "lower aralkyl” group having one or more aryl groups attached to an alkyl group having one to six carbon atoms.
  • Some non-limiting examples of such group include benzyl, diphenylmethyl, phenylethyl, p-tolylmethyl and phenylpropyl.
  • the aralkyl group can be further substituted by halo, alkyl, alkoxy, haloalkyl or haloalkoxy.
  • heteroaryl refers to an aryl group having one or more heteroatoms.
  • the heteroatom is oxygen, sulfur, selenium, nitrogen, phosphorus or silicon.
  • Some non-limiting examples of the heteroaryl group include furanyl, thiophenyl, pyrrolyl, pyridinyl, quinolinyl, thiazolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, indolyl, imidazolyl, tetrazolyl, 2-formylfuranyl, 3-formylpyridinyl, 4-methylimidazolyl, 5-methylthiazolyl, 2,5-dimethylfuranyl, 3-acetoxyindolyl, benzopyranyl, and benzofuranyl.
  • the heteroaryl group is optionally substituted by one or more substituents independently selected from halogen, hydroxy, carboxy, cyano, nitro, amino, acyl, alkenyl, alkynyl, carbonyl, mercapto, lower alkyl, cycloalkyl, heterocyclicalkyl, lower alkylthio, lower alkoxy, lower hydroxyalkyl, lower alkylamino, lower alkylcarbonyl, lower alkyl-thio-lower alkyl, lower alkyl-sulfinyl, lower alkoxycarbonyl, lower alkylaminocarbonyl, aryl, aryl-lower alkylcarbonyl, aryl-lower alkylthio, aryl-lower alkyl-sulfinyl, aryl-lower alkyl-sulfinyl-lower alky, aryl-lower alkoxycarbonyl, arylalkylaminocarbonyl, ary
  • the heteroaryl group is substituted by one, two or three substituents independently selected from halogen, cyano, hydroxy, carboxy, amino, lower alkyl, cycloalkyl, heterocyclicalkyl, aryl and heteroaryl.
  • heteroarylalkyl refers to an alkyl group substituted with one or more heteroaryl radicals, wherein the heteroaryl radical and the alkyl group are as defined herein.
  • heteroarylalkyl group include pyridin-2-ylmethyl, thiazol-2-ylethyl, midazol-2-ylethyl, pyrimidin-2-ylpropyl and pyrimidin-2-ylmethyl.
  • nitro refers to -NO 2 .
  • mercapto refers to -SH.
  • hydroxy refers to -OH.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, and other chemical components such as physiologically/pharmaceutically acceptable carriers excipients, diulentsdiluents, adjuvants, vihicles, and other additional therapeutic agents, such as anti-diabetic agents, antihyperglycemic agents, antiadipositas agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, lipid-lowering agents, anti-inflammatory agents, etc.
  • the purpose of the pharmaceutical composition is to facilitate administration of a compound to an organism.
  • heterocyclic group optionally substituted by an alkyl group means that the alkyl may or may not be present, and the description includes situations where the heterocyclic group is substituted by the alkyl group and situations where the heterocyclic group is not substituted by the alkyl group.
  • prodrug refers to a compound that is transformed in vivo into a compound of Formula (I) . Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation to the parent form in blood or tissue.
  • Prodrugs of the compounds disclosed herein may be, for example, esters. Esters that may be utilized as prodrugs in the present invention are phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound disclosed herein that contains a hydroxy group may be acylated at this position in its prodrug form.
  • prodrug forms include phosphates such as those phosphate compounds derived from the phosphonation of a hydroxy group on the parent compound.
  • phosphates such as those phosphate compounds derived from the phosphonation of a hydroxy group on the parent compound.
  • a thorough discussion of prodrugs is provided in Higuchi et al. , Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S. Symposium Series; Roche, et al. ed. , Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al. , Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al, Prodrugs of Phosphates and Phosphonates, J. Med. Chem. , 2008, 51, 2328-2345, all of which are incorporated herein by reference in their entireties.
  • metabolite refers to a product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzyme cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds disclosed herein, including metabolites produced by contacting a compound disclosed herein with a mammal for a sufficient time period.
  • Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical and chemical differences by methods well known to those skilled in the art, such as by chromatography, crystallization, distillation, or sublimation.
  • Enantionmers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reacting with an appropriate optically active compound (e. g. , chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride) , separating the diastereoisomers and converting (e. g. , hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e. g. , chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • the intermediates and compounds of the invention may exist in tautomeric forms and all such tautomeric forms are within the scope of the invention.
  • Many organic compounds exist in optically active forms i. e. , they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center (s) .
  • the prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • racemic mixture or “racemate” refers to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • structures depicted herein are also meant to include all isomeric (e. g.
  • enantiomeric, diastereomeric, and geometric (or conformational) ) forms of the structure for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, or geometric (or conformational) mixtures of the present compounds are within the scope disclosed herein.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • pharmaceutically acceptable salts refers to organic or inorganic salts of a compound disclosed herein.
  • Pharmaceutically acceptable salts are well known in the art. For example, the pharmaceutically acceptable salts are described in detail in Berge et al. , J. Pharmacol Sci, 1977, 66: 1-19, which is incorporated herein by reference in its entirety.
  • non-limiting examples of the pharmaceutically acceptable salt formed by non-toxic acid include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid or salts obtained by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid or salts obtained by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, sodium malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionat
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oilsoluble or dispersable products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfonate or aryl sulfonate.
  • solvate refers to an association or complex of one or more solvent molecules and a compound disclosed herein.
  • solvents that form solvates include water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate refers to the complex where the solvent molecule is water.
  • the invention features pharmaceutical compositions that include a compound of Formula (I) or Formula 1 to 25, a compound listed herein, or a compound named in Examples 1 to 25, or a stereoisomer, a geometric isomer, a tautomer, a racemate, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the amount of the compound in the compositions disclosed herein is an effective and detectable amount for inhibiting sodium-dependent glucose transporters (SGLTs) activity in biological samples or patients.
  • SGLTs sodium-dependent glucose transporters
  • certain of the compounds disclosed herein can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof.
  • pharmaceutically acceptable derivative include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adducts or derivatives which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • compositions disclosed herein further comprise a pharmaceutically acceptable carrier, a diluent, an adjuvant, or a vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Some non-limiting examples of materials which can serve as pharmaceutically acceptable carriers include ion exchangers; aluminium; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; wool fat; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as
  • Compounds disclosed herein can be administered as the sole pharmaceutical agent or in combination with one or more other additional therapeutic (pharmaceutical) agents where the combination causes no unacceptable adverse effects. This may be of particular relevance for the treatment of diabetes, diabetic complications and other related diseases. Some non-limiting examples of these diseases include diabetes mellitus type I, diabetes type II, diabeticretinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis and hypertension.
  • these diseases include diabetes mellitus type I, diabetes type II, diabeticretinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis and hypertension.
  • the additional therapeutic agents include an anti-diabetic agent other than an SGLT-2 inhibitor, an antihyperglycemic agent, an antiadipositas drug, an antihypertensive agent, an antiplatelet agent, an antiatherosclerotic drug, a lipid-lowering agent, an anti-inflammatory or a combination thereof.
  • the anti-diabetic agents other than an SGLT-2 inhibitor include, but are not limited to a biguanide (e. g. , phenformin and metformin) , a sulfonylurea (e. g. , acetohexamide, diabinese, glibenclamide, glipizide, gliclazide, glimepiride, glipentide, gliquidone, tolazamide and tolbutamide) , a meglitinide, a glinide (e. g. , repaglinide and nateglinide) , a glucosidase inhibitor (e. g.
  • a biguanide e. g. , phenformin and metformin
  • a sulfonylurea e. g. , acetohexamide, diabinese, glibenclamide, glipizide,
  • acarbose e.g., acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q and salbostatin
  • a PPAR agonist e. g.
  • sitagliptin sitagliptin, vidagliptin, alogliptin and saxagliptin
  • GLP-1 glucagon-like peptide-1
  • PTP-1B protein tyrosine phosphatases-1B inhibitor
  • trodusquemine hyrtiosal extract and compounds are disclosed by Zhang, S. et al.
  • insulin an insulin mimetic, a glycogen phosphorylase inhibitor, a VPAC2 receptor agonist, a glucokinase activator, a glycogen phosphorylase inhibitor or a glucose-6-phosphatase inhibitor, an ⁇ P2 inhibitor, an acetyl-CoA carboxylase-2 (ACC-2) inhibitor, a phosphodiesterase (PDE) -10 inhibitor, a diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitor, a glucose transporter 4 (GLUT4) regulator and a glutamine -fructose-6 -phosphate amidotransferase (GFAT) inhibitor.
  • ACC-2 acetyl-CoA carboxylase-2
  • PDE phosphodiesterase
  • DGAT diacylglycerol acyltransferase
  • GLUT4 glucose transporter 4
  • GFAT glutamine -fructose-6 -phosphate amidotransferase
  • the antihyperglycemic agents include, but are not limited to, a biguanide (e. g. , phenformin and metformin) , a sulfonylurea (e. g. , acetohexamide, diabinese, glibenclamide, glipizide, gliclazide, glimepiride, glipentide, gliquidone, tolazamide and tolbutamide) , a meglitinide, a glinide (e. g. , repaglinide and nateglinide) , a glucosidase inhibitor (e. g.
  • a biguanide e. g. , phenformin and metformin
  • a sulfonylurea e. g. , acetohexamide, diabinese, glibenclamide, glipizide, gliclazide, gli
  • acarbose e.g., acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q and salbostatin
  • a PPAR agonist e. g.
  • sitagliptin sitagliptin, vidagliptin, alogliptin and saxagliptin
  • GLP-1 glucagon-like peptide-1
  • PTP-1B protein tyrosine phosphatases-1B inhibitor
  • trodusquemine hyrtiosal extract and compounds are disclosed by Zhang, S. et al.
  • insulin an insulin mimetic, a glycogen phosphorylase inhibitor, a VPAC2 receptor agonist, a glucokinase activator, a glycogen phosphorylase inhibitor or a glucose-6-phosphatase inhibitor, an ⁇ P2 inhibitor, an acetyl-CoA carboxylase-2 (ACC-2) inhibitor, a phosphodiesterase (PDE) -10 inhibitor, a diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitor, a glucose transporter 4 (GLUT4) regulator and a glutamine -fructose-6 -phosphate amidotransferase (GFAT) inhibitor.
  • ACC-2 acetyl-CoA carboxylase-2
  • PDE phosphodiesterase
  • DGAT diacylglycerol acyltransferase
  • GLUT4 glucose transporter 4
  • GFAT glutamine -fructose-6 -phosphate amidotransferase
  • the lipid-lowering agents include, but are not limited to, an MTP inhibitor, an HMGCoA reductase inhibitor, a squalene synthase inhibitor, a fibric acid derivative, an ACAT inhibitor, a lipoxygenase inhibitor, a cholesterol absorption inhibitor, an ileal Na (+) /bile acid cotransporter inhibitor, an upregulators of LDL receptor activity, a bile acid sequestrant or niacin and a derivative thereof.
  • the lipid-lowering agent is selected from pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin and rosuvastatin.
  • the anti-obesity agents include CB-1 antagonists (such as rimonabant, taranabant, surinabant, otenabant, SLV319 and AVE1625) , gut-selective MTP inhibitors (such as dirlotapide, mitratapide and implitapide) , CCKa agonists, 5-HT 2c agonists (such as lorcaserin) , MCR4 agonists, lipase inhibitors (such as cetilistat) , PYY 3-36 , opioid antagonist (such as naltrexone) , oleoyl-estrone, obinepitide, pramlintide, tesofensine, leptin, liraglutide, bromocriptine, orlistat, exenatide, AOD-9604 and sibutramide.
  • CB-1 antagonists such as rimonabant, taranabant, surinabant, oten
  • the suitable anti-inflammatory agents include genital tract/urinary tract infection preventatives and treatments.
  • exemplary agents include cranberries (Vaccinium macrocarpon) and cranberry derivatives, such as cranberry juice, cranberry extracts or flavonols of cranberries.
  • other suitable anti-inflammatory agents include, but are not limited to, aspirin, non-steroidal anti-inflammatory drugs, glucocorticosteroid, sulfasalazine and selective cyclooxygenase-2 inhibitors.
  • compositions disclosed herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection and infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions disclosed herein include aqueous and oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1, 3-butanediol.
  • acceptable vehicles and solvents that include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, non-volatile can be conventionally employed as a solvent or suspending medium.
  • the non-volatile oil includes synthetic mono-or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives, which are useful in the preparation of injectables, can be used as natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • the amount of the compound or the compound in the compositions disclosed herein is an effective and detectable amount for inhibiting sodium-dependent glucose transporters (SGLTs) activity, especially SGLT-2 activity.
  • SGLT-2 is responsible for reabsorption of D-glucose from kidney spherule filtrate, which inhibits glucose reabsorption in blood vessel and this is beneficial to reduce glucose concentrations in blood.
  • the compound of the invention would be used for preventing and treating the type II diabetes and related diseases or improving symptoms of these diseases.
  • Such diseases include, but not limited to, diabetes, especially type II diabetes, and diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis and hypertension.
  • compounds or pharmaceutical compositions disclosed herein also suit for preventing or treating the damage of diabetes in later stages, such as kidney disease, retinopathy, neuropathy, myocardial infarction, peripheral arterial disease, thrombosis, arteriosclerosis, inflammation, immunological diseases, autoimmune diseases such as AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer's disease, schizophrenia and infectious diseases.
  • diabetes in later stages, such as kidney disease, retinopathy, neuropathy, myocardial infarction, peripheral arterial disease, thrombosis, arteriosclerosis, inflammation, immunological diseases, autoimmune diseases such as AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer's disease, schizophrenia and infectious diseases.
  • these compounds are also useful for veterinary treatment of animals such as companion animals, exotic animals and farm animals, including mammals, rodents, and the like.
  • animals such as companion animals, exotic animals and farm animals, including mammals, rodents, and the like.
  • the animals disclosed herein include horses, dogs, and cats.
  • the compounds disclosed herein include the pharmaceutically acceptable derivatives thereof.
  • an “effective amount” or “effective dose” of the compound or pharmaceutically acceptable composition is an amount that is effective in treating or lessening the severity of one or more of the aforementioned disorders.
  • the compound or the pharmaceutically acceptable composition disclosed herein is effective administered in a fairly wide dose range.
  • the daily dose is from about 0.1 mg to 1000 mg per person, the compounds or pharmaceutically acceptable compositions can be administered in a single dose or in several divided doses a day.
  • the compounds and compositions, according to the method disclosed herein may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • a compound or composition can also be administered with one or more other therapeutic agents as discussed above.
  • the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for Formula (I) , above, except where further noted.
  • the following non-limiting schemes and examples are presented to further exemplify the invention.
  • the structures of the compounds were identified by nuclear magnetic resonance (e. g. , 1 H-NMR and 13 C-NMR) .
  • 1 H-NMR and 13 C-NMR chemical shifts were recorded as ppm (10 -6 ) .
  • 1 H-NMR and 13 C-NMR were performed on a Bruker Ultrashield-400 spectrometer.
  • the appropriate solvent was deuterated-chloroform (CDCl 3 ) , deuterated-methanol (CD 3 OD) or deuterated-dimethyl sulfoxide (DMSO-d 6 ) .
  • MS spectra were determined on Agilen-6120 Quadrupole LC/MS mass spectrometer.
  • the thin-layer silica gel used was Yantai Huanghai HSGF 254 silica gel plate.
  • the silica gel used in column chromatography generally was Qingdao Ocean Chemical Factory 300 to 400 mesh silica gel.
  • the staring materials of the present invention were purchased from Shanghai Accela Company, Energy Company, J&K, Chengdu Aiertai Company, Alfa Company and the like, or they were prepared by conventional synthesis methods in the prior art.
  • nitrogen atmosphere refers to an atmosphere in a reaction flask equipped with a balloon or a stainless steel autoclave filled with about 1 L nitrogen.
  • hydrogen atmosphere refers to an atmosphere in a reaction flask equipped with a balloon or a stainless steel autoclave filled with about 1 L hydrogen.
  • the solution used in the examples disclosed herein was an aqueous solution.
  • reaction temperature was room temperature.
  • the room temperature was from 20°C to 30°C.
  • the reaction process in the examples was monitored by thin layer chromatography (TLC) .
  • TLC thin layer chromatography
  • the solvent system for development of a TLC plate comprised dichloromethane and methanol, dichloromethane and ethyl acetate, or petroleum ether and ethyl acetate.
  • the volume ratio of the solvents in the solvent system was adjusted according to the polarity of the compounds.
  • the elution system of column chromatography comprised: A: petroleum ether and ethyl acetate, B: dichloromethane and ethyl acetate, and C: dichloromethane and methanol.
  • A petroleum ether and ethyl acetate
  • B dichloromethane and ethyl acetate
  • C dichloromethane and methanol.
  • the volume ratio of the solvents in the elution system was adjusted according to the polarity of the compounds, and sometimes it was also adjusted by adding a basic agent such as aqueous ammonia or an acidic agent such as acetic acid.
  • HPLC refers to High Performance Liquid Chromatography.
  • HPLC was determined on Agilent 1200DAD high pressure liquid chromatography spectrometer (Zorbax Eclipse Plus C18 150 ⁇ 4.6 mm chromatographic column) .
  • the test condition of HPLC the run time was 30 minutes; the column temperature was 35°C; the detection was carried out at the wavelength of 210 nm and 254 nm using PDA detector; the mobile phase was H 2 O (A) and acetonitrile (B) ; and the flow rate was 1.0 mL/min.
  • Compound (I-a) can react with trimethylchlorosilane in the presence of N-methylmorpholine to afford compound (I-b) .
  • Coupling reaction of compound (I-b) with bromide fragment (S) in the presence of n-butyllithium can give compound (I-c) .
  • Compound (I-c) can react with methanol in the presence of an acid to afford compound (I-d) .
  • Compound (I-d) can react with tert-butyldimethylsilyl chloride in the presence of a base to afford compound (I-e) .
  • Compound (I-e) can react with benzyl bromide in the presence of a base to afford compound (I-f) .
  • Compound (I-f) can react with tetrabutylammonium iodide in a polar solvent to afford compound (I-g) .
  • Compound (I-g) can be converted to compound (I-h) in the presence of an oxidizing agent; compound (I-h) can react with methanal in the presence of a base to afford compound (I-i) .
  • Cyclization of compound (I-i) in the presence of an acid can afford compound (I-j) .
  • Oxidizing reaction of compound (I-j) can afford compound (I-k) .
  • Compound (I-k) can be oxidized to afford compound (I-v) .
  • Compound (I-v) can react with a polar solvent (such as methanol, ethanol or isopropanol) , ammonium hydroxide and methylamine hydrochloride (or dimethylamine hydrochloride) in the presence of an acid or a base to give compound (I-m-a) .
  • a polar solvent such as methanol, ethanol or isopropanol
  • ammonium hydroxide and methylamine hydrochloride or dimethylamine hydrochloride
  • the protecting group of compound (I-v) can be removed in the presence of an acid or by Pd/C catalysis under H 2 to afford compound (I-o) .
  • Compound (I-o) can react with dimethylamine hydrochloride in the presence of a base to give compound (I-B) .
  • Compound (I-v) can react with chloromethyl pivalate under alkaline conditions to give compound (I-m-c) .
  • the protecting group of compound (I-m-c) can be removed in the presence of an acid or by Pd/C catalysis under H 2 to afford compound (I-C) .
  • Compound (I-v) can react with (trimethylsilyl) diazomethane in a polar solvent to afford compound (I-n) .
  • Compound (I-n) can react with a halogenating agent under alkaline conditions to give compound (I-m-d) .
  • the protecting group of compound (I-m-d) can be removed in the presence of an acid or by Pd/C catalysis under H 2 to afford compound (I-D) .
  • Compound (I-k) can react with hydroxylamine hydrochloride or N-methylhydroxylamine hydrochloride in a polar solvent under alkaline conditions to afford compound (I-w) .
  • the protecting group of compound (I-w) can be removed in the presence of an acid or by Pd/C catalysis under H 2 to afford compound (I-E) .
  • Compound (I-k) can react with hydroxylamine hydrochloride and dicyclohexylcarbodiimide under a base to give compound (I-y) .
  • the protecting group of compound (I-y) can be removed in the presence of boron trichloride at-78°C to give compound (I-J) .
  • Step 1) (3R, 4S, 5R, 6R) -3, 4, 5-tris (trimethylsilyloxy) -6- (trimethylsilyloxymethyl) tetrahydropyran-2-one 1b
  • Step 2) (2S, 3R, 4S, 5R, 6R) -2- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -3, 4, 5-tris (trimethylsilyloxy) -6-(trimethylsilyloxymethyl) tetrahydropyran-2-ol 1c
  • the mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate at 0°C, .
  • the organic layer was washed with water (100 mL ⁇ 2) and saturated aqueous sodium chloride (100 mL ⁇ 2) , dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound 1e as yellow oil (119 g, 100%) .
  • the crude product was used without further purification.
  • Step 1) ethyl (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylate 5a
  • Step 2) ethyl (1S, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -2, 3, 4-trihydroxy-6, 8-dioxabicyclo [3.2.1] octane-1-carboxylate 5
  • Step 1) isopropyl (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylate 6a
  • Step 2) isopropyl (1S, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -2, 3, 4-trihydroxy-6, 8-dioxabicyclo [3.2.1] octane-1-carboxylate 6
  • Step 1) (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -6, 8 -dioxabicyclo [3.2.1] octane-1-carboxamide 7a
  • Step 2) (1S, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -2, 3, 4-trihydroxy-6, 8-dioxabicyclo [3.2.1] octane-1-carboxamide 7
  • Step 1) (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -N-methyl-6, 8-dioxabicyclo [3.2.1] octane-1-carboxamide 8a
  • Step 2) (1S, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -2, 3, 4-trihydroxy-N-methyl-6, 8-dioxabicyclo [3.2.1] octane-1-carboxamide 8
  • Step 1) (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -N, N-dimethyl -6,8-dioxabicyclo [3.2.1] octane-1-carboxamide 9a
  • Step 2 (1S, 2S, 3S, 4R, 5S) -5- [4-Chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -2, 3, 4-trihydroxy-N, N-dimethyl-6, 8-dioxabicyclo [3.2.1] octane-1-carboxamide 9
  • Step 1) (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxy-3-fluorophenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octane-1-carbaldehyde 11b
  • Step 2) (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxy-3-fluorophenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylic acid 11c
  • Step 1) ethyl (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxy-3-fluorophenyl) methyl] phenyl] -6,8-dioxabicyclo [3.2.1] octane-1-carboxylate 12a
  • Step 2) ethyl (1S, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxy-3-fluoro-phenyl) methyl] phenyl] -2, 3, 4-trihydroxy-6, 8-dioxabicyclo [3.2.1] octane-1-carboxylate 12
  • Step 2) isopropyl (1S, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxy-3-fluoro-phenyl) methyl] phenyl] -2, 3, 4-trihydroxy -6,8-dioxabicyclo [3.2.1] octane-1-carboxylate 13
  • Step 1) (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxy-3-fluoro-phenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxamide 14a
  • Step 2 (1S, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxy-3-fluoro-phenyl) methyl] phenyl] -2, 3, 4-trihydroxy-6, 8-dioxabicyclo [3.2.1] octane-1-carboxamide 14
  • Step 2 (1S, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxy-3-fluoro-phenyl) methyl] phenyl] -2, 3, 4-trihydroxy-N-methyl -6,8-dioxabicyclo [3.2.1] octane-1-carboxamide 15
  • Step 1) 2-dimethylpropanoyloxymethyl (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylate 17a
  • Step 2) 2-dimethylpropanoyloxymethyl (1S, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -2,3, 4-trihydroxy-6, 8-dioxabicyclo [3.2.1] octane-1-carboxylate 17
  • Step 1) 1- [ (1R, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octan-1-yl] ethanol 18a
  • Step 2) 1- [ (1R, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octan-1-yl] ethanoe 18
  • Step 1) 1- [ (1R, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octan-1-yl] ethanoe oxime 20a
  • Step 2) 1- [ (1S, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -2, 3, 4-trihydroxy-6, 8-dioxabicyclo [3.2.1] octan-1-yl] ethanone oxime 20
  • Step 1) (1E) - (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octane-1-carbaldehyde oxime 21a
  • Step 2) (1E) - (1S, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -2, 3, 4-trihydroxy-6, 8-dioxabicyclo [3.2.1] octane-1-carbaldehyde oxime 21
  • Step 1) N-methoxy-1- [ (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octan-1-yl] methanimine 22a
  • Step 2) (E) - (1S, 2S, 3S, 4R, 5S) -5- (4-chloro-3- (4-ethoxybenzyl) phenyl) -2, 3, 4-trihydroxy-6, 8-dioxabicyclo [3.2.1] octane-1-carbaldehyde O-methyl oxime 22
  • Step 1) 2- [ (E) - [ (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octan-1-yl] methyleneamino] oxyethanol 23a
  • Step 2) (E) - (1S, 2S, 3S, 4R, 5S) -5- (4-chloro-3- (4-ethoxybenzyl) phenyl) -2, 3, 4-trihydroxy-6, 8-dioxabicyclo [3.2.1] octane-1-carbaldehyde O- (2-hydroxyethyl) oxime 23
  • Step 1) (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -1-ethynyl-6,8-dioxabicyclo [3.2.1] octane 24a
  • Step 2) (1S, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -2, 3, 4-trihydroxy-6, 8-dioxabicyclo [3.2.1] octane-1-carbonitrile 24
  • Step 1) (1S, 2S, 3S, 4R, 5S) -2, 3, 4-tribenzyloxy-5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octane-1-carbonitrile 25a
  • Step 2) (1S, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -2, 3, 4-trihydroxy-6, 8-dioxabicyclo [3.2.1] octane-1-carbonitrile 25
  • the following methods can be used to determine the inhibitory activity of the compounds described in the invention against SGLT-1 and SGLT-2.
  • ⁇ -Methylglucoside was purchased from Sigma, Cat. No. M9376-100G.
  • N-methyl-D-glucosamine was purchased from Sigma, Cat. No. M2004-100G.
  • Phloridzin was purchased from Sigma, Cat. No. P3449-1G.
  • 96-Well plate was purchased from Corning, Cat. No. 3903.
  • Mock-transfected FIP-in CHO cells (3 x 10 4 cells) and expressing human SGLT1/SGLT2 CHO cells were seeded into 96-well plates respectively. The cells were incubated for 12 hours. Each well of the 96-well plates was washed with 150 ⁇ L of sodium-free buffer once. To each well was added 50 ⁇ L of sodium-containing buffer containing test compounds having different concentrations and 0.5 ⁇ M [ 14 C] -AMG. The incubation mixture was incubated at 37°C for 1 hour. To each well was added 150 ⁇ L of precooled sodium-free buffer to terminate the reaction. The cell pellet was washed with sodium–free buffer three times and the residual liquid in well was removed.

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Abstract

La présente invention concerne des dérivés de glucopyranosyl utilisés comme inhibiteurs des co-transporteurs du glucose dépendants du sodium (SGLT), et des utilisations pharmaceutiques de ceux-ci, en particulier des dérivés de 6,8-dioxabicyclo [3.2.1] octane représentés par la formule (I), ou des sels pharmaceutiquement acceptables de ceux-ci, ou tous les stéréoisomères de ceux-ci, une composition pharmaceutique contenant ces dérivés et leurs utilisations pour le traitement de maladies diabétiques et de maladies associées au diabète.
PCT/CN2014/087320 2013-09-25 2014-09-24 Dérivés de glucopyranosyl et leurs utilisations en médecine Ceased WO2015043473A1 (fr)

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WO2016173425A1 (fr) * 2015-04-30 2016-11-03 Sunshine Lake Pharma Co., Ltd. Dérivé de glucopyranosyle, son procédé de préparation et ses utilisations
CN113135966A (zh) * 2020-01-20 2021-07-20 华润双鹤药业股份有限公司 杂环类葡萄糖苷的二环衍生物及其制备方法和用途

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CN117430571B (zh) * 2022-07-15 2025-08-29 宜昌东阳光长江药业股份有限公司 一种制备吡喃葡萄糖基衍生物的关键中间体及其制备方法

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