WO2016173425A1 - Dérivé de glucopyranosyle, son procédé de préparation et ses utilisations - Google Patents

Dérivé de glucopyranosyle, son procédé de préparation et ses utilisations Download PDF

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WO2016173425A1
WO2016173425A1 PCT/CN2016/079634 CN2016079634W WO2016173425A1 WO 2016173425 A1 WO2016173425 A1 WO 2016173425A1 CN 2016079634 W CN2016079634 W CN 2016079634W WO 2016173425 A1 WO2016173425 A1 WO 2016173425A1
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compound
formula
inhibitor
disease
diabetic
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Zheng Gu
Jiaping Wen
Wuyong WU
Zongyuan ZHANG
Tong Qu
Wanjun TANG
Haoxiong QIN
Mengke WANG
Weihua Wang
Pengcho Tang
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Sunshine Lake Pharma Co., Ltd.
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    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings

Definitions

  • This present invention pertains to the field of pharmaceutical chemistry, which relates to a glucopyranosyl derivative as sodium dependent glucose cotransporters (SGLTs) inhibitor, and preparation processes thereof.
  • 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 (dipeptidyl peptidase-IV) inhibitors, etc.
  • these current hypoglycemic drugs have shortcomings. Biguanides can cause lactic acidosis.
  • Sulfonylureas can result in severe hypoglycemia. Glinides also can result in hypoglycemia when used inappropriately. 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 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 SGLTs 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.
  • the (S) -configuration was obtained by isolating (R, S) -diastereoisomeric mixture.
  • R, S isolating
  • the two configurations certified by biological activity test wherein in vivo pharmacodynamic activity of the (R) -configuration diastereomer is obvious better than those of the (S) -configuration diastereomer and the (R, S) -diastereoisomeric mixture.
  • the (R) -configuration diastereomer also has better pharmacokinetic properties, such as good drug absorption after oral administration, desired half-life and higher bioavailability, which has a good development prospect.
  • the present invention also provides two stereoselective methods of preparing the compound of Formula (I) , one method comprises adding an alkylzinc reagent to a formyl group through an asymmetric addition reaction to obtain a product with high ee value, the other method comprises reducing a carbonyl through stereoselective reduction to give a product.
  • the process of the invention has simple operation, high optical purity of product, high yield and convenient work-up, easy purification, which is suitable for industrial production.
  • provided herein is a method of preparing the compound having Formula (I) .
  • a method of preparing a compound of Formula (III) comprises the steps of: a) reacting compound (I-a) with trimethylchlorosilane in the present of a base (such as N-methylmorpholine) to give compound (I-b) ; b) coupling compound (I-b) with bromide (I-c) in the present of n-butyllithium to afford compound (I-d) ; c) reacting compound (I-d) with methanol under an acid condition through an etherification reaction, and removing trimethylsilyl to give compound (I-e) ; d) reacting t-butyl dimethyl chlorosilane with primary hydroxy of compound (I-e) in the present of imidazole to give compound (I-f) ; e) reacting sec-hydroxy of compound (I-f) with a suitable reagent (such as benzyl bromide) in the present of a strong base (such as sodium hydride) to give compound (I-g
  • the compound of Formula (I) can be prepared by using the scheme one after getting the compound of Formula (III) , which comprises:
  • each of PG, PG 1 and PG 2 is independently a hydroxy protecting group.
  • a new chiral center in the preparation method of the invention, can be introduced through an asymmetric addition reaction of a formyl group with a dimethyl zinc reagent in step (A) , a product with high ee value can be obtained through selection optimization of a chiral ligand in this reaction, after a simple work-up procedure, the compound of Formula (II) with optically pure can be obtained and the reaction has a high yield. And the compound of Formula (II) can suffer a simple reaction, and the hydroxy protecting groups of which can be removed to afford an optically pure compound of Formula (I) .
  • step (A) in the preparation method of the invention, the addition reaction of step (A) is carried out in the presence of a chiral ligand, and wherein the chiral ligand comprises a dihydroxy chiral ligand, Salen ligand, metal-Salen ligand or (1R, 2R) - (+) -N, N’-di (p-tolyl) sulfonyl-1, 2-cyclohexanediamine.
  • the chiral ligand comprises a dihydroxy chiral ligand, Salen ligand, metal-Salen ligand or (1R, 2R) - (+) -N, N’-di (p-tolyl) sulfonyl-1, 2-cyclohexanediamine.
  • the dimethylzinc used in the addition reaction of step (A) is applied at 1.0 to 5.0 moles per mole of the compound of Formula (III) ; in some embodiments, preferably 1.1 to 2.0 moles per mole of the compound of Formula (III) ; in some embodiments, more preferably 1.2 to 1.6 moles per mole of the compound of Formula (III) .
  • the specification of the dimethylzinc reagent used herein may be a 1 mol/L solution of dimethylzinc in toluene.
  • step (A) in the preparation method of the invention, the addition reaction of step (A) is carried out in the presence of a chiral ligand, and wherein the chiral ligand comprises a Salen ligand or metal-Salen ligand.
  • the metal-Salen ligand may be a Zn-Salen ligand, Mn-Salenligand or Cr-Salen ligand; preferably a Cr-Salen ligand.
  • the Salen ligand is applied at 0.10 to 1.0 moles per mole of the compound of Formula (III) ; in other embodiments, the metal-Salen ligand is applied at 0.01 to 0.50 moles per mole of the compound of Formula (III) ; in yet other embodiments, the Cr-Salen ligand is applied at 0.01 to 0.20 moles per mole of the compound of Formula (III) and preferably 0.03 to 0.15 moles per mole of the compound of Formula (III) .
  • the reaction solvent is toluene, o-xylene, p-xylene, m-xylene or a combination thereof. In some embodiments, the reaction temperature is from –20 °C to 30 °C; preferably 20 °C to 30 °C.
  • the Salen ligand, Zn-Salen ligand, Mn-Salen ligand and Cr-Salen ligand are each preferably respectively selected from the following structures:
  • the addition reaction of step (A) is carried out by using a dihydroxy chiral ligand; in some embodiments, the dihydroxy chiral ligand is TADDOL, (R) -BINOL or (S) -H 8 -BINOL, preferably (R) -BINOL. In some embodiments, (R) -BINOL is applied at 0.1 to 0.9 moles per mole of the compound of Formula (III) .
  • the reaction solvent is toluene, o-xylene, p-xylene, m-xylene or a combination thereof.
  • the reaction temperature is from –20 °C to 30 °C; preferably 20 °C to 30 °C.
  • (1R, 2R) - (+) -N, N’-di (p-tolyl) sulfonyl-1, 2-cyclohexanediamine can be used as a chiral ligand in the addition reaction of step (A) ; in some embodiments, wherein the chiral ligand is applied at 0.1 to 1.0 moles per mole of the compound of Formula (III) .
  • the reaction solvent is toluene, o-xylene, p-xylene, m-xylene or a combination thereof.
  • the reaction temperature is from –20 °C to 30 °C; preferably 20 °C to 30 °C.
  • the preparation method of step (A) further comprises purifying the product (II) by trituration with a mixed solvent comprising petroleum ether and ethyl acetate; in some embodiments, the volume ratio of petroleum ether and ethyl acetate is from 4/1 to 30/1.
  • the removing step (B) is carried out in the presence of a catalyst, a hydrogen source and an acid, and wherein the catalyst comprises palladium on carbon, palladium hydroxide on carbon, palladium chloride or a combination thereof; the hydrogen source comprises hydrogen; and the acid comprises hydrochloric acid, acetic acid or a combination thereof.
  • the compound of Formula (I) also can be prepared by using the scheme two after getting the compound of Formula (III) , which comprises the steps of:
  • each of PG, PG 1 and PG 2 is independently a hydroxy protecting group.
  • a methyl group in the preparation method of the invention, first, a methyl group can be introduced through an addition reaction of an carbonyl group with methyl Grignard reagent; and then, the hydroxy group can be oxidized to form a carbonyl group, and a chiral center can be introduced through an asymmetric reduction reaction of the carbonyl; the compound of Formula (II) with a high ee value can be obtained through optimizing the conditions of the reduction reaction; the compound of Formula (II) further suffer a simple reaction and the hydroxy protecting groups of which can be removed to afford an optically pure compound of Formula (I) .
  • the oxidizing step (2) is carried out by using an oxidizing agent selected from Dess-Martin periodinane, 2-iodoxybenzoic acid or tetramethylpiperidinooxy/sodium hypochlorite in the present of a solvent selected from dichloromethane or a mixture of dichloromethane and water; in some embodiments, the reaction temperature is from –20 °C to 20 °C.
  • the reducing step (3) is carried out by using a reductant selected from sodium borohydride, sodium borohydride/cerous chloride, sodium triacetoxyborohydride, lithium tri-tert-butoxyaluminum hydride, DIBAL-H or (S) -3-methyl-1, 1, 1-triphenylbutyl-2-amine /borane; in some embodiments, the reductant preferably is sodium triacetoxyborohydride or DIBAL-H; in some embodiments, the reductant is applied at 1.0 to 2.0 moles per mole of the compound of Formula (V) .
  • the reaction solvent is methanol, ethanol, tetrahydrofuran, toluene or ethyl acetate; in some embodiments, the reaction temperature is from –78 °C to 30 °C.
  • the reagents used in step (4) for removing protecting groups from the compound of Formula (II) comprise a catalyst, a hydrogen source, a hydrogen source or an acid, wherein the hydrogen source comprises palladium on carbon, palladium hydroxide on carbon or palladium chloride; the hydrogen source comprises hydrogen; and the acid comprises hydrochloric acid or acetic acid.
  • each of PG, PG 1 and PG 2 is independently a hydroxy protecting group; the hydroxy protecting group is benzyl, triphenylmethyl, p-methoxybenzyl, t-butyldimethylsilyl, trimethylsilyl, t-butyldiphenylsilyl, triethylsilyl, triisopropylsilyl, carbobenzoxy, 2- (trimethylsilyl) ethoxymethyl, dihydropyranyl, bromoallyl, ethoxycarbonyl, acetyl or benzoyl.
  • the hydroxy protecting group is benzyl, triphenylmethyl, p-methoxybenzyl, t-butyldimethylsilyl, trimethylsilyl, t-butyldiphenylsilyl, triethylsilyl, triisopropylsilyl, carbobenzoxy, 2- (trimethylsilyl) ethoxymethyl, dihydro
  • composition comprising the compound disclosed herein and a pharmaceutically acceptable adjuvant.
  • the pharmaceutical composition further comprises 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.
  • the anti-diabetic agent other than an SGLT-2 inhibitor or antihyperglycemic agent disclosed herein is a biguanide, a sulfonylurea, a glucosidase inhibitor, a PPAR agonist (peroxisome proliferators-activated receptors agonist) , an ⁇ P2 inhibitor (adipocyte fatty acid binding protein inhibitor) , a PPAR ⁇ / ⁇ dual agonist (peroxisome proliferators-activated receptors ⁇ / ⁇ agonist) , a dipeptidyl peptidase IV (DPP-IV) inhibitor, a glinide, insulin, a glucagon-like peptide-1 (GLP-1) inhibitor, a PTP1B inhibitor (protein tyrosine phosphatase 1B inhibitor) , a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor or a combination thereof.
  • a sulfonylurea a gluco
  • the lipid-lowering agent disclosed herein is an MTP inhibitor (microsomal triglyceride transfer protein inhibitor) , an HMGCoA reductase inhibitor (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) , a squalene synthase inhibitor, a fibrate antihyperlipidemic, an ACAT inhibitor (acyl coenzyme a-cholesterol acyltransferase inhibitor) , a lipoxygenase inhibitor, a cholesterol absorption inhibitor, an ileal Na ( + ) /bile acid cotransporter inhibitor, an upregulator of LDL receptor activity, a nicotinic antihyperlipidemic drug, a bile acid sequestrant or a combination thereof.
  • MTP inhibitor microsomal triglyceride transfer protein inhibitor
  • HMGCoA reductase inhibitor 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor
  • the lipid-lowering agent disclosed herein 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 SGLT-2.
  • provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for increasing HDL level.
  • a disease for preventing or treating a disease, lessening the disease symptoms, delaying the progression or onset of the 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.
  • the compound or the pharmaceutical composition disclosed herein for use in inhibiting SGLT-2 or increasing HDL level or preventing or treating a disease, lessening the disease symptoms or delaying the progression or onset of the 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.
  • a method for inhibiting SGLT-2 or increasing HDL level or preventing or treating a disease, lessening the disease symptoms or delaying the progression or onset of the disease in a patient 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.
  • grammatical articles “a” , “an” and “the” are intended to include “at least one” or “one or more” unless otherwise indicated herein or clearly contradicted by the context.
  • the articles are used herein to refer to one or more than one (i.e. at least one) of the grammatical objects of the article.
  • a component means one or more components, and thus, possibly, more than one component is contemplated and may be employed or used in an implementation of the described embodiments.
  • the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate.
  • the subject is a human.
  • patient refers to a human (including adults and children) or other animal. In one embodiment, “patient” refers to a human.
  • the number of “equivalent” refers to an equivalent amount of other needed material per 1 equivalent of the basic material in accordance with equivalent relation in chemical reaction.
  • Stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomer, diastereomers, conformer (rotamer) , geometric (cis/trans) isomer, atropisomer, etc.
  • Chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • Enantiomers refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boling points, spectral properties or biological activities. Diastereomers may be separated under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.
  • Configuration refers to a spatial arrangement relationship of atoms or substituent groups of isomers cotaining a chiral center (s) .
  • “Epimer” refer to a pair of diastereomers contianing two or more chiral centers which differ in configuration at only one stereocenter and all other stereocenters in the molecules, if any, are the same in each.
  • 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, diluents, 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 the situation where the heterocyclic group is substituted by the alkyl group and the situation 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. Some common esters which have been utilized as prodrugs 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.
  • the 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.
  • 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.
  • optically active compounds 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 l 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.
  • a specific stereoisomer may be referred to as an enantiomer, and a mixture of such stereoisomers is 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.
  • a specific stereoisomer may be referred to as a diastereoisomer, and a mixture of such stereoisomers is called an diastereoisomeric mixture.
  • any asymmetric atom (e.g., carbon or the like) of the compound (s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (R) -, (S) -or (R, S) -configuration.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
  • Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric isomers, enantiomers, diastereomers, epimers, for example, by chromatography, trituration, crystallization, distillation or sublimation to isolate diastereomers.
  • racemates of final products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof.
  • Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • Preferred enantiomers can also be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) ; Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g. in solution) , a chemical equilibrium of tautomers can be reached.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerization is phenol-keto tautomerization.
  • the specific example of phenol-keto tautomerisms is pyridin-4-ol and pyridin-4 (1H) -one tautomerism. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound.
  • an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxy-carbonyl (BOC, Boc) , benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethylenoxy-carbonyl (Fmoc) .
  • hydroxy protecting group is a substituent attached to a hydroxy group that blocks or protects the hydroxy functionality in the compound.
  • Suitable hydroxy-protecting groups include benzyl (Bn) , carbobenzoxy (Cbz) , triphenylmethyl, p-methoxybenzyl (PMB) , t-butyldimethylsilyl (TBDMS) , trimethylsilyl (TMS) , t-butyldiphenylsilyl (TBDPS) , triethylsilyl (TES) , triisopropylsilyl (DIPS) , 2- (trimethylsilyl) ethoxymethyl, dihydropyranyl, bromoallyl, ethoxycarbonyl, acetyl and benzoyl, and the like.
  • a “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Common carboxy-protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl and the like.
  • protecting groups and their use see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P.J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • a “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, S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19, which is incorporated herein by reference.
  • Some non-limiting examples of pharmaceutically acceptable and nontoxic salts 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 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 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, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate,
  • 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 oil soluble 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.
  • the term “treat” , “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
  • “treat” , “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat” , “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
  • “treat” , “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • the compound disclosed herein may contain asymmetric or chiral center, therefore the compound can exist in different stereoisomers. It is intended that all stereoisomeric forms of the compounds of Formula (I) disclosed herein, including but not limited to, diastereomers, enantiomers and atropisomers and geometric (conformational) isomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • the compound of the Formula (I) can be exist in various tautomer forms, and all of the tautomers, such as those described in claims, are within the scope of the invention.
  • the compound of Formula (I) can be exist in salt forms.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • the salt may not be a pharmaceutically acceptable salt, may be an intermediate used for preparing and/or purifying the compound of Formula (I) and/or isolating an enantiomer from the compound of Formula (I) .
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/di
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like) , or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
  • the compounds disclosed herein, including their salts can also be obtained in the form of their hydrates, or include other solvents such as ethanol, DMSO, and the like, used for their crystallization.
  • the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water) ; therefore, it is intended that the invention embrace both solvated and unsolvated forms.
  • any formula given herein is also intended to represent isotopically unenriched forms as well as isotopically enriched forms of the compounds.
  • Isotopically enriched compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H (deuterium, D) , 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I, respectively.
  • the compounds of the invention include isotopically enriched compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 14 C and 18 F, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • isotopically enriched compounds are useful in metabolic studies (with 14 C) , reaction kinetic studies (with, for example 2 H or 3 H) , detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F-enriched compound may be particularly desirable for PET or SPECT studies.
  • Isotopically-enriched compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • substitution with heavier isotopes, particularly deuterium (i.e., 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index.
  • deuteride refers to a compound of which any hydrogen is replaced by deuterium (i.e. 2 H or D) .
  • the deuterium disclosed herein is regarded as a substituent of a compound of Formula (I) .
  • concentration of such a heavier isotope, specifically deuterium may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium
  • such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom) , at least 4000 (60% deuterium incorporation) , at least 4500 (67.5% deuterium incorporation) , at least 5000 (75% deuterium incorporation) , at least 5500 (82.5% deuterium incorporation) , at least 6000 (90% deuterium incorporation) , at least 6333.3 (95% deuterium incorporation) , at least 6466.7 (97% deuterium incorporation) , at least 6600 (99% deuterium incorporation) , or at least 6633.3 (99.5% deuterium incorporation) .
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, acetone-d 6 , DMSO-d
  • the invention features pharmaceutical compositions that include the compound of Formula (I) , the compound listed herein, or the compound described in Examples, or a stereoisomer, a tautomer, an N-oxide, a solvate, a deuteride, a metabolite, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable adjuvant.
  • 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 adjuvant, 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 adjuvant 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 adjuvant 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,
  • Some non-limiting examples of materials which can serve as pharmaceutically acceptable adjuvants 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; fillers, 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;
  • 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, 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.
  • these diseases include diabetes mellitus type I, diabetes type II, 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.
  • 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, nateglinide) , a ⁇ -glucosidase inhibitor (e.g., acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin and salbostatin) , a PPAR agonist (e.g., balaglita
  • 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, nateglinide) , a glucosidase inhibitor (e.g., acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin and salbostatin) , a PPAR agonist (e.g., balaglitazone, ciglitazone,
  • 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, fibrate antihyperlipidemic drug, 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-HT2c 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, etc.
  • 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 oil can be conventionally employed as a solvent or suspending medium.
  • any bland non-volatile oil includes synthetic mono-or diglucosyl 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 diabetes and related diseases or improving symptoms of these diseases.
  • Such diseases include, but are 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 compounds and pharmaceutically acceptable compositions are 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 which is 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.
  • Figure 1 H-H NOESY spectrogram of the compound (I-n) , i.e. compound (I) with the protection of benzaldehyde dimethyl acetal.
  • the compound is characterized by the corresponding structure.
  • the compound of Formula (I) can be prepared by the methods described herein.
  • the following 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 ) .
  • Measure of 1 H-NMR and 13 C-NMR are performed, respectively, on Bruker Ultrashield -400 nuclear magnetic resonance spectrometer and Bruker Avance III HD 600 nuclear magnetic resonance spectrometer using deuterated chloroform (CDCl 3 ) , deuterated methanol (CD 3 OD) or deuterated DMSO (DMSO-d 6 ) as a solvent and TMS (0 ppm) or deuterated chloroform (7.26 ppm) as the reference standard.
  • the absolute configuration of the chiral carbon connected to the bridgehead carbon of compound (I) can be identified by H-H NOESY method.
  • Compound (I) react with benzaldehyde dimethyl acetal to afford compound (I-n) , H-H NOESY spectrogram of which is recorded on Bruker Avance III HD 600 nuclear magnetic resonance spectrometer by using DMSO-d 6 as a solvent, space position relations between each H atom of stereo chemical structure of a molecule can be obtained according NOE signal, and then the absolute configuration of the chiral carbon connected to the bridgehead carbon can be obtained.
  • the thin-layer silica gel used was Yantai Huanghai HSGF254 silica gel plate.
  • the silica gel used in column chromatography generally was Qingdao Ocean Chemical Factory 200 to 300 mesh or 300 to 400 mesh silica gel.
  • the staring materials of the present invention were known or purchased from Shanghai Accela Company, Energy Company, J&K, Chengdu Aiertai Company, Alfa Company and the like, or they could be prepared by the conventional synthesis methods in the prior art.
  • nitrogen atmosphere refers to such an atmosphere that a reaction flask was equipped with a balloon or a stainless steel autoclave filled with about 1 L of nitrogen.
  • hydrogen atmosphere refers to such an atmosphere that a reaction flask was equipped with a balloon or a stainless steel autoclave filled with about 1 L of hydrogen.
  • the solution used in the examples disclosed herein was an aqueous solution.
  • reaction temperature was room temperature
  • the room temperature is 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, petroleum ether (or n-hexane, cyclohexane or n-heptane, and the like) 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 (or n-hexane, cyclohexane or n-heptane, and the like) and ethyl acetate; B: dichloromethane and ethyl acetate; C: dichloromethane and methanol.
  • A petroleum ether (or n-hexane, cyclohexane or n-heptane, and the like) 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 (min) ; 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. The flow rate was 1.0 mL/min.
  • the LC/MS/MS system used in biological analysis test comprises Agilent 1200 series vacuum degassing furnace, binary pumps, well-plate autosampler, thermostatted column compartment, the Agilent G6430Triple Quadru pole Mass Spectrometer with an electrosprayionization (ESI) source. Quantitative analysis was carried out using MRM mode. The parameters for MRM transitions are in the Table A.
  • an Agilent 6330 series LC/MS/MS spectrometer equipped with G1312A binarypumps, a G1367A autosampler and a G1314C UV detector were used in the analysis.
  • An ESI source was used on the LC/MS/MS spectrometer.
  • the analysis was done in positive ion mode as appropriate and the MRM transition for each analyte was optimized using standard solution.
  • the mobile phase was 5 mM ammonia acetate, 0.1% MeOH in water (A) and 5 mM ammonia acetate, 0.1% MeOH in acetonitrile (B) (70: 30, v/v) .
  • the flow rate was 0.6 mL/min. Column was maintained at ambient temperature. 20 ⁇ L of the samples were injected.
  • the examples of the present invention provides the method of preparing optically pure (1R, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -1- [ (1R) -1-hydroxyethyl] -6, 8-d ioxabicyclo [3.2.1] octane-2, 3, 4-triol.
  • Those skilled in the art can learn from this article to properly improve the process parameters to implement the present invention.
  • All similar substitutions and modifications to the skilled person are obvious, and they are deemed to be included in the present invention.
  • Related person can clearly realize and apply the techniques disclosed herein by making some changes, appropriate alterations or combinations to the methods without departing from spirit, principles and scope of the present disclosure.
  • Step 1) (3R, 4S, 5R, 6R) -3, 4, 5-tris (trimethylsilyloxy) -6- (trimethylsilyloxymethyl) tetrahydropyran -2-one (I-b)
  • the reaction mixture was quenched with saturated aqueous sodium bicarbonate (100 mL) and partitioned, the aqueous phase was extracted with ethyl acetate (100 mL ⁇ 3) , and the organic phase was combined with the ethyl acetate phases.
  • the combined organic layers were washed with saturated brine (200 mL) , dried over anhydrous sodium sulfate and filtered.
  • the compound (I-m) can be prepared under the reaction conditions shown in table 1 which according to the procedure described in Example 2.
  • reaction solvent is toluene
  • Step 1) 1- [ (1R, 2S, 3S, 4R, 5S) -2, 3, 4-tris (benzyloxy) -5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octan-1-yl] ethanol (I-r)
  • Step 2) 1- [ (1R, 2S, 3S, 4R, 5S) -2, 3, 4-tris (benzyloxy) -5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -6, 8-dioxabicyclo [3.2.1] octan-1-yl] ethanone (I-s)
  • Step 3) (1R) -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 (I-m)
  • the compound (I-m) can be prepared under the reaction conditions shown in table 3 according to the procedure described in step 3 of example 4.
  • Step 4) (1R, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -1- [ (1R) -1- hydroxyethyl] -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol (I)
  • the (R, S) -diastereoisomeric mixture i.e. (1R, 2S, 3S, 4R, 5S) -5- [4-chloro-3- [ (4-ethoxyphenyl) methyl] phenyl] -1- (1-hydroxyethyl-6, 8-dioxabi cyclo [3.2.1] octane-2, 3, 4-triol, was prepared by using the method described in PCT/CN2014/087587 (WO2015043511) , the (R) -configuration isomer and the (S) -configuration isomer were isolated from the mixture using Calesep PUMP 250 preparative chromatograph (Shanghai Sunyear) and Novasep LC-50 preparative column (Novasep) .
  • the following methods can be used to determine the inhibitory activity of the compound (I) , and (S) -configuration isomer and (R, S) -diastereoisomeric mixture thereof disclosed herein for 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 ⁇ 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 under CO 2 . 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.
  • Table 4 The results of inhibitory activity of the compound (I) , and (S) -configuration isomer and (R, S) -diastereoisomeric mixture thereof for SGLT-2 and SGLT-2.
  • the glucose was purchased from Cheng Du Kelong Chemical Reagent Company.
  • Glycosuria test was determined on Roche Biochemistry Analyzer.
  • Experiment animals such as machins and C57BL/6 mice, were weighed after overnight fasting for 15 hours, fasting blood-glucose was measured, and the animals were grouped randomly based on the weight and fasting blood-glucose, and then each administered group was administered with the corresponding test compound by gavage once at dose of 5 mg/kg, blank group was administered with menstruum. Blood glucose was measured at 15 min after adminitration (i.e.
  • each group was adminitered with glucose by gavage (2.5 g/kg) after the measurement of 0 point blood glucose, and then blood samples were collected at 15 min, 30 min, 60 min, 120 min from vein after administration of glucose, blood glucose was measured continuously by glucometer; the rate of decrease of area under curve of glucose in 120 min after glucose load (AUC Glu 0-120min ) was calculated.
  • Each group was placed in a metabolic cage respectively after the measurement of 120 min lood glucose, urine was collected in metabolic cage from 0 h to 24 h and 24 h to 48 h after administration, and the amount of urine at each time point was recorded, urine sugar was measured by automatic biochemical analyzer, the animals ate and drank freely during the process of urine collection. The results were shown as table 5 and table 6:
  • Table 5 The results of promoting glycosuria excretion test of compound (I) and (S) -configuration isomer thereof in mice.
  • Table 6 The results of promoting glycosuria excretion test of compound (I) and (S) -configuration isomer thereof in machins.
  • the intravenous injection groups were administered at a dose of 2 mg/kg and the gavage groups were administered at a dose of 5 mg/kg.
  • Blood samples were collected at 0, 0.083 (only intravenous injection group) , 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 h from vein (about 0.2 mL) and placed into EDTAK 2 anticoagulative tube.
  • Table 7 The results of pharmacokinetic test in rats after administration of compound (I) by oral
  • Table 8 the results of pharmacokinetic test in rats after administration of compound (I) by intravenous injection
  • the compound (I) disclosed herein shows excellent pharmacokinetic properties when administered by intravenous injection or oral, including better absorption, ideal half-life (T 1/2 ) and good oral bioavailability (F) , and which is much better than (S) -configuration isomer thereof in absorption, half-life and exposure (AUC last ) , i.e. which has better pharmacokinetic properties.

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Abstract

La présente invention concerne un dérivé de glucopyranosyle comme inhibiteur des co-transporteurs de glucose dépendant du sodium (SGLT), des procédés de préparation de celui-ci, et des utilisations pharmaceutiques de celui-ci, des compositions pharmaceutiques contenant le composé et leurs utilisations pour traiter le diabète et les maladies associées au diabète. Le procédé selon l'invention est simple à mettre en œuvre, permet d'obtenir un produit de pureté optique élevée, un rendement élevé et un traitement final simple, une purification simple, ce qui le rend compatible avec une production à l'échelle industrielle.
PCT/CN2016/079634 2015-04-30 2016-04-19 Dérivé de glucopyranosyle, son procédé de préparation et ses utilisations WO2016173425A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107778336A (zh) * 2016-08-24 2018-03-09 广东东阳光药业有限公司 吡喃葡萄糖基衍生物的结晶形式
CN109970822A (zh) * 2017-12-27 2019-07-05 上海科胜药物研发有限公司 一种合成埃格列净中间体的制备方法
US10555930B2 (en) 2015-11-27 2020-02-11 North & South Brother Pharmacy Investment Company Limited Complex of a glucopyranosyl derivative and preparation method and use thereof
CN114796250A (zh) * 2021-01-27 2022-07-29 宜昌东阳光长江药业股份有限公司 一种含有吡喃葡萄糖基衍生物的药物组合物

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106674294B (zh) * 2015-11-06 2020-07-07 广东东阳光药业有限公司 吡喃葡萄糖基衍生物的结晶形式
CN108239123B (zh) * 2016-12-27 2021-08-27 宜昌东阳光长江药业股份有限公司 吡喃葡萄糖基衍生物的共晶、制备方法和应用
WO2020143653A1 (fr) * 2019-01-08 2020-07-16 广东东阳光药业有限公司 Procédé de préparation d'un dérivé de glucopyranosyle et d'un intermédiaire associé
CN113330017B (zh) * 2019-12-19 2023-01-31 上海研健新药研发有限公司 一种SGLTs抑制剂的纯化方法及其应用
CN111748004A (zh) * 2020-06-30 2020-10-09 药璞(上海)医药科技有限公司 一种高纯度达格列净中间体的晶型及其制备方法
WO2022007838A1 (fr) * 2020-07-08 2022-01-13 Dongguan Hec New Drug R & D Co., Ltd. Procédé de préparation de dérivés de glucopyranosyle et intermédiaires de ceux-ci
WO2022204907A1 (fr) * 2021-03-30 2022-10-06 Sunshine Lake Pharma Co., Ltd. Procédé de préparation d'un co-cristal d'acide l-pyroglutamique et d'un dérivé de glucopyranosyle

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015027963A1 (fr) * 2013-09-02 2015-03-05 四川海思科制药有限公司 Dérivé à noyau aromatique, composition pharmaceutique et utilisation associée
WO2015043511A1 (fr) * 2013-09-27 2015-04-02 Sunshine Lake Pharma Co., Ltd. Dérivés de glucopyranosyl et leurs utilisations en médecine
WO2015043473A1 (fr) * 2013-09-25 2015-04-02 Sunshine Lake Pharma Co., Ltd. Dérivés de glucopyranosyl et leurs utilisations en médecine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015027963A1 (fr) * 2013-09-02 2015-03-05 四川海思科制药有限公司 Dérivé à noyau aromatique, composition pharmaceutique et utilisation associée
WO2015043473A1 (fr) * 2013-09-25 2015-04-02 Sunshine Lake Pharma Co., Ltd. Dérivés de glucopyranosyl et leurs utilisations en médecine
WO2015043511A1 (fr) * 2013-09-27 2015-04-02 Sunshine Lake Pharma Co., Ltd. Dérivés de glucopyranosyl et leurs utilisations en médecine

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10555930B2 (en) 2015-11-27 2020-02-11 North & South Brother Pharmacy Investment Company Limited Complex of a glucopyranosyl derivative and preparation method and use thereof
CN107778336A (zh) * 2016-08-24 2018-03-09 广东东阳光药业有限公司 吡喃葡萄糖基衍生物的结晶形式
CN107778336B (zh) * 2016-08-24 2022-09-27 宜昌东阳光长江药业股份有限公司 吡喃葡萄糖基衍生物的结晶形式
CN109970822A (zh) * 2017-12-27 2019-07-05 上海科胜药物研发有限公司 一种合成埃格列净中间体的制备方法
CN109970822B (zh) * 2017-12-27 2023-03-28 上海科胜药物研发有限公司 一种合成埃格列净中间体的制备方法
CN114796250A (zh) * 2021-01-27 2022-07-29 宜昌东阳光长江药业股份有限公司 一种含有吡喃葡萄糖基衍生物的药物组合物
WO2022161377A1 (fr) * 2021-01-27 2022-08-04 Sunshine Lake Pharma Co., Ltd. Composition pharmaceutique comprenant un dérivé de glucopyranosyle

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