WO2010012153A1 - Dérivés de la phlorizine, leur préparation et leur application - Google Patents

Dérivés de la phlorizine, leur préparation et leur application Download PDF

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WO2010012153A1
WO2010012153A1 PCT/CN2009/000705 CN2009000705W WO2010012153A1 WO 2010012153 A1 WO2010012153 A1 WO 2010012153A1 CN 2009000705 W CN2009000705 W CN 2009000705W WO 2010012153 A1 WO2010012153 A1 WO 2010012153A1
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acid
drugs
group
compound
disease
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孙伟新
赵维民
顾书华
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常州高新技术产业开发区三维工业技术研究所有限公司
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    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention generally relates to phlorizin derivatives and methods of synthesis, pharmaceutical compositions and uses thereof. Background technique
  • Phlorizin belongs to the dihydrochalcone compound and was found in the rhizome of Rosaceae (such as apples and pears) in the 19th century. In 1987, a derivative of phlorizin was reported to have an effect on the treatment of sickle cell anemia (US Patent US 4,465,058). In the same year, it was found that phlorizin and its derivatives are also effective for the treatment of cancer (US Patent US 4,684,627). Phloridin also has antihypertensive and lipid-lowering effects. Phlorizin can prevent carbohydrates from entering epidermal cells, inhibit excessive secretion of dermis, and treat secreted whitefly; phlorizin can treat psoriasis (US Pat. No.
  • Phloridin can inhibit melanocyte activity and have a dilute effect on various skin spots (US Pat. No. 6,093,408); phlorizin has certain effects on the treatment of malaria (European Patent EP0046270); phlorizin has a matrix metalloproteinase Inhibitory activity (US2004209952); In addition, phlorizin extract can also treat glycosylation end products of pathological aging, with unique functions such as enhancing memory, improving learning ability, preventing or treating osteoporosis, lowering blood sugar, dementia and delaying aging. Physiological activity and health care efficacy (U.S. Patent No. US2006189512).
  • the invention structurally reforms phloridzin and improves the bioavailability of phlorizin.
  • the invention provides a kind of phlorizin derivative containing nitrogen atom, which is a novel structure of SGLT2 inhibitor; the invention provides a method for preparing a phlorizin derivative;
  • the present invention provides a class of active phlorizin derivatives which can increase urinary glucose, inhibit renal tubular glucose reabsorption, and have an excellent blood sugar lowering activity;
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a phlorizin derivative which comprises a therapeutically effective amount of a phlorizin extract or a phlorizin derivative and a pharmaceutically acceptable carrier;
  • the present invention provides a phlorizin derivative or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, delayed wound healing, insulin resistance, blood stasis, high insulin blood Symptoms, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, arteritis
  • Drugs such as sclerosis, hypertension, metabolic syndrome (X syndrome), diabetic complications and tumors, osteoporosis, sickle cell anemia, etc.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a SGLT2 inhibitor 3'-amine methylene phlorizin derivative and one or more of the following drugs: antidiabetic drugs, drugs for treating diabetic complications, and anti-obesity Drugs, antihypertensive drugs, antiplatelet drugs, anti-atherosclerotic drugs/or hypolipidemic drugs, antioxidants, carnitine (especially L-carnitine), carnitine (especially L-carnitine) derivatives, carnitine Palmitoyltransferase inhibitors, acetylcarnitine stimulants, antitumor drugs, antidepressants, anti-senile dementia drugs, anti-gout drugs, anti-osteoporosis drugs.
  • antidiabetic drugs drugs for treating diabetic complications, and anti-obesity Drugs, antihypertensive drugs, antiplatelet drugs, anti-atherosclerotic drugs/or hypolipidemic drugs, antioxidants, carn
  • the present invention relates to a formula (I) phlorizin derivative and a pharmaceutically acceptable salt thereof:
  • R is an open-chain or cyclic secondary or tertiary amino group structure
  • C 8 alkyl group selected from the group consisting of C 3 ⁇ 4, CH(C CH 3 ) 2 , C (C ) n CH 3 , d-C 4 alkoxy CH 2 0 (C > m CH 3 , C "C 4 fluorenyl CH 2 S (CH 2 ⁇ solicitCH 3 , (C3 ⁇ 4) facedCX 3 , (C3 ⁇ 4) B CN, (C ) felicitC00H, dC 4 alkanoyl (Cft COOR ⁇ (CH 2 ) m 0H, (CH X, S0 2 (C3 ⁇ 4) m CH 3 , (CH2) B S0 2 R ⁇ C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, d - C 4 alkylamino, wherein X Is halogen, R 1 is d-C 4 alkyl, d-C 4 alkenyl, dC 4 alkynyl, m is an integer from 0
  • ⁇ and ⁇ and their attached nitrogen atom are cyclized with an oxygen, sulfur or nitrogen atom to form an optionally substituted 3- 7 membered heterocyclic ring selected from the group consisting of: hydroxy, carboxy, amino, sulfonyl, D-C 4 alkyl, hydroxy dC 4 fluorenyl, carboxy C!-alkyl, nitrogen d-C 4 alkyl, C 2 - C 4 refinery, C plant C 4 alkynyl, phenyl, Cr ⁇ C 4 -alkoxyphenyl, hydroxy C r C 4 alkylphenyl, carboxy d-C 4 alkylphenyl, halogenated Cr C 4 nonylphenyl, phenyl-C 4 fluorenyl, phenyl C 2 - C 4 -alkenyl, oxygen- or nitrogen-containing C 5 - ( ⁇ heterocyclyl, oxygen- or nitrogen-containing C 5 -C 6 heterocyclocarbonyl, oxygen-
  • the 3-7 membered heterocyclic ring described in the present invention is selected from the group consisting of piperidine, morpholine, piperazine, thiazole, imidazole, pyridine, pyrrole, Tetrahydropyrrole, pyrazine.
  • the compound of formula (I) has an activity of inhibiting sodium-dependent glucose transporter in the gut and kidney of mammals, and thus is useful for treating microvascular and macrovascular complications such as retinopathy, neuropathy, nephropathy and wound healing of diabetes and diabetes. .
  • the present invention provides a compound of the formula (I), a pharmaceutical composition using the compound of the formula (I) and a method of using the compound of the formula (I).
  • the present invention provides a medicament for treating or delaying the development or onset of a disease comprising an effective amount of a compound of the formula (I) or an optical isomer thereof, for one or more diseases or a state of mind and body of a mammal, Enantiomers, diastereomers, racemates or racemic mixtures, esters, prodrugs, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.
  • the one or more diseases or physical and mental states are: increasing high-density lipoprotein levels, enhancing memory, improving learning ability, aging, diabetes (types I and II), diabetic nephropathy, diabetic foot disease, diabetic retinopathy, diabetes sexual neuropathy, diabetic complications, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis , hypertension, metabolic syndrome (X syndrome), anemia (such as sickle cell anemia), acne, tumor, rheumatoid arthritis, arthritis, enteritis, psoriasis, multiple sclerosis, neurodegenerative disorders, congestive Heart failure, stroke, aortic stenosis, nephritis, renal failure, gout, lupus erythematosus, IgA nephropathy, appendicitis, pancreatitis, allergies (eg rhinit
  • a pharmaceutical composition for treating diabetes and related diseases as defined hereinbefore and hereinafter which comprises a therapeutically effective amount of a compound of formula (I) and an antidiabetic agent and/or other type of therapeutic agent It can be used to treat one or more diseases or physical and mental states in mammals: increase high-density lipoprotein levels, enhance memory, improve learning ability, aging, diabetes (types I and II), diabetic nephropathy, diabetic foot disease, diabetes Retinopathy, diabetic neuropathy, diabetic complications, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, BE fatness, hypertriglyceridemia , atherosclerosis, hypertension, metabolic syndrome (X syndrome), anemia (such as sickle cell anemia), acne, swelling Tumor, rheumatoid arthritis, arthritis, enteritis, psoriasis, multiple sclerosis, neurodegenerative disorders, congestive
  • the mammals referred to in the present invention include humans, horses, monkeys, pigs, rats, dogs, rabbits and the like.
  • the prodrug of the compound (I) according to the present invention includes, but is not limited to, one or more of the compounds (I), and/or a phenolic hydroxy acylate such as an acetyl, propionyl, butyryl product and one or more Alcoholic hydroxyl and/or phenolic hydroxybenzyl, methyl, ethyl, and the like.
  • a phenolic hydroxy acylate such as an acetyl, propionyl, butyryl product and one or more Alcoholic hydroxyl and/or phenolic hydroxybenzyl, methyl, ethyl, and the like.
  • the pathologically aged glycosylation end product related diseases of the present invention include, but are not limited to, one or more of diabetes, Alzheimer's disease, atherosclerosis, kidney disease, osteoarthritis, osteoporosis, aging and the like. .
  • the matrix metalloproteinase pathological diseases of the present invention include, but are not limited to, atherosclerosis, central nervous system inflammation, Alzheimer's disease, asthma, skin aging, rheumatoid arthritis, osteoarthritis, Osteoporosis, septic arthritis, endometriosis, corneal ulcer adhesion, bone disease, proteinuria, abdominal aortic aneurysm, degenerative cartilage loss, hyperactivity sclerosis, myelin nerve loss, liver fibrosis , nephroglomerular disease, rupture of the blastum, enteritis, periodontal disease, age-related macular degeneration, diabetic retinal disease, vitreoretinal retina, retinal dysplasia, ophthalmia, corneal ulcer, Sjogren's complications, ocular myopia, tumor metastasis One or more.
  • the mitochondrial diseases of the present invention include, but are not limited to, ophthalmoplegia, muscle lesions, movement disorders, seizures, myoclonus, stroke, optic neuropathy, sensorineural hearing loss, dementia, peripheral neuropathy, dystonia, spinal cord Lesions, cardiomyopathy, cataracts, pigmented retinopathy, metabolic acidosis, nausea, vomiting, liver disease, kidney disease, pseudo-intestinal obstruction, iron granulocyte anemia, diabetes, pancreatic exocrine dysfunction, and hypoparathyroidism One or more.
  • the abnormal energy metabolism diseases according to the present invention include, but are not limited to, diseases caused by trauma, ischemia and reperfusion injury, such as trauma, poisoning, shock, altitude sickness, radiation sickness, pneumoconiosis, electric shock caused by various acute chemical and physical factors.
  • cardiac conduction abnormalities including artificial cardiac pacing, cardiovascular interventional therapy, valvular disease, atherosclerosis, coronary heart disease, (including sudden death), congenital heart disease, high Blood pressure, infection Endocarditis, pulmonary heart disease, pericarditis, cardiomyopathy, peripheral vascular disease (including multiple arteritis, Raynaud's syndrome, thromboangiitis obliterans, occlusive arteriosclerosis, etc.), heart transplant surgery, Neuralgia, neuritis, various peripheral neuropathy, various spinal diseases, acute cerebrovascular diseases (including cerebral infarction, cerebral embolism, cerebral hemorrhage, subarachnoid hemorrhage, etc.), intracranial tumors, central nervous system infections (including viruses) And bacterial encephalitis, meningitis, etc.), dyskinesia (Parkinson's disease, chorea, hepatolenticular degeneration, dystonia, convulsion
  • Demyelinating diseases including multiple sclerosis, optic neuromyelitis, leukodystrophy), musculoskeletal diseases (including muscular dystrophy, myotonic myopathy, myasthenia gravis, Inflammatory myopathy, metabolic myopathy, periodic paralysis, autonomic diseases (including Raynaud's disease, erythema limb pain, diencephalon syndrome), Mi Disseminated intravascular coagulation; diseases caused by factors such as insulin resistance and endocrine, such as obesity, hypoglycemia caused by various causes, insulin resistance syndrome, metabolic syndrome, malnutrition (nutrition, thinness, malignant malnutrition, Secondary protein energy malnutrition), enteral nutrition, parenteral nutrition, water and electrolyte metabolism disorders, acid-base balance disorders, diabetes, diabetes cardiovascular disease, diabetic peripheral neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot, pregnancy And diabetes, diabetes complicated by infection, acute
  • the diabetic complications referred to in the present invention include, but are not limited to, diabetic nephropathy, diabetic foot disease, diabetic retinopathy, diabetic neuropathy, and the like.
  • X Syndrome also known as metabolic syndrome
  • X Syndrome also known as metabolic syndrome
  • the diseases, diseases, and diseases collectively referred to as "X Syndrome” are centered on obesity, combined with blood pressure, blood sugar, elevated triglycerides, and/or decreased HDL-C, which is insulin resistance.
  • the resulting sugar, lipid metabolism disorder combined with the emergence of a variety of metabolic diseases as a clinical feature of a group of severely affected health syndrome. Detailed in Johannsson J. Clin. Endocrinol. Metab., 82, 727-34 (1997).
  • other types of therapeutic agents includes drugs for treating diabetic complications, anti-obesity drugs, antihypertensive drugs, antiplatelet drugs, antiatherogenic drugs or hypolipidemic drugs, antioxidants, meat.
  • Alkali especially L-carnitine
  • carnitine derivatives especially L-carnitine derivatives such as acetylcarnitine, propionylcarnitine
  • carnitine palmitoyltransferase inhibitors carnitine octanoyl Transferase inhibitors
  • acetylcarnitine stimulants antitumor drugs, anti-gout drugs, osteoporosis drugs, antidepressants, anemia drugs, Alzheimer's drugs, anti-inflammatory drugs, immunological drugs and root bark
  • One or more of the glycoside extracts One or more of the glycoside extracts.
  • the weight ratio of the active ingredient structural formula (I) of the present invention to one or more other types of therapeutic agents is 1: 0.001-1: 0.1, the preferred weight ratio is 1. : 0. 0001-1: 0. 01 range.
  • R is an open or cyclic secondary or tertiary amine structure NRA.
  • R is an open or cyclic secondary or tertiary amino group structure N I ⁇
  • the nitrogen atom to which they are attached is cyclized with an oxygen, sulfur or nitrogen atom to form an optionally substituted 3-7 membered heterocyclic ring selected from the group consisting of: hydroxy, carboxy, amino, sulfonyl, CrC 4 Sulfhydryl, hydroxy d-C 4 alkyl, carboxyl D_C 4 fluorenyl, amino dC 4 fluorenyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, dC 4 alkoxyphenyl, hydroxy dC 4 nonylphenyl, carboxy dC 4 alkyl Phenyl, halo dC 4 alkylphenyl, phenyl dC 4 alkyl, phenyl C 2 -C 4 alkenyl, oxygenated or nitrogenous ( 5 -(: 5 heterocyclyl, oxygenated or nitrogenous) C 5 -C e heterocyclic carbonyl, oxygen-
  • the 3-7 membered heterocyclic ring described in the present invention is selected from the group consisting of piperidine, morpholine, piperazine, thiazole, imidazole, pyridine, pyrrole, tetrahydropyrrole, pyrazine.
  • the compound of the formula (I) of the present invention can be produced by a method as shown below.
  • the primary and secondary amines are CrC. Fatty amines, amino acids, aromatic amines, unsaturated fatty amines, cycloalkylamines, heterocycloalkylamines, unsaturated cycloalkylamines, unsaturated heterocyclic mercaptoamines.
  • the solvent may be any conventional solvent which does not interfere with the reaction, such as water; alcohol (e.g., methanol, ethanol, propanol); ester (e.g., ethyl acetate); halogenated hydrocarbon (e.g., dichloromethane); amide (e.g., dimethyl) Formamide); ethers (such as tetrahydrofuran); nitriles (acetonitrile), etc., or mixtures thereof.
  • alcohol e.g., methanol, ethanol, propanol
  • ester e.g., ethyl acetate
  • halogenated hydrocarbon e.g., dichloromethane
  • amide e.g., dimethyl
  • Formamide e.g., dimethyl
  • ethers such as tetrahydrofuran
  • nitriles acetonitrile
  • the reaction can be carried out at a low temperature to a heating temperature, preferably at a temperature of from -10 Torr to 100 °C, particularly preferably from 0 °C to 80 °
  • the compound (Ia) of the present invention can be obtained by extracting roots, stems, leaves or fruits of Rosaceae or Fagaceae, and then purifying it with macroporous resin or polyamide to obtain ruthenium purine of ruthenium purity.
  • the protic solvent in the present invention includes various alcohols such as water, pyridine, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, and t-butanol.
  • the related compound (1) is obtained.
  • the specific process is -
  • the specific process is:
  • HDL-C high density lipoprotein cholesterol
  • HPLC high performance liquid chromatography
  • ESIMS electrospray ionization mass spectrometry
  • mRNA messenger ribonucleic acid
  • cDNA Complementary Deoxyribonucleic Acid
  • lower alkyl when used alone or as part of another group, includes both straight chain and branched hydrocarbons having from 1 to 8 carbon atoms
  • alkyl and alk When used alone or as part of another group, it includes straight chain and branched hydrocarbons having from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, in a straight chain, more preferably from 1 to 8 carbon atoms.
  • cyclo when used alone or as part of another group, includes saturated or partially saturated (containing 1 or 2 double bonds) containing 1-3 rings.
  • Cycloalkyl including monocyclic, dicycloalkyl and tricycloalkyl, containing a total of from 3 to 20 carbon atoms forming a ring, preferably forming from 3 to 10 carbon atoms of the ring, said ring being fused to one Or 2 aromatic rings as described for p-aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclo Hexenyl,
  • any of the above groups may be substituted by any one of the following substituents: for example, halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, aryl fluorenyl, cycloalkyl, decylamino, chain Decanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/or any alkyl substituent.
  • cycloalkenyl as used herein, alone or as part of another group, refers to a cyclic hydrocarbon containing from 3 to 12 carbon atoms, preferably from 5 to 10 carbon atoms and from 1 to 2 double bonds.
  • the cycloalkenyl group includes a cyclopentenyl group, a cyclohexyl group, a cyclooctenyl group, a cyclohexadienyl group, a cycloheptadienyl group, which may be optionally substituted as defined in the cycloalkyl group.
  • alkanoyl as used herein, alone or as part of another group, refers to an alkyl group that is linked to a carbonyl group.
  • lower chain dilute when used alone or as part of another group, refers to a straight or branched chain group of 2 to 8 carbon atoms
  • alkenyl when used alone or as another group, it means 2-20 carbon atoms, preferably 2-12 carbon atoms, more preferably a linear or branched group having 2-8 carbon atoms in a straight chain.
  • lower alkynyl refers to a straight or branched chain group of 2 to 8 carbon atoms
  • alkynyl is used herein. When used alone or as part of another group, it means 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably a linear or branched group having 2 to 8 carbon atoms in the straight chain.
  • substituents for example halogen , alkyl, heptoxy, hydroxy, aryl, aryloxy, aralkyl,
  • aralkyl when used alone or as part of another group, refer to alkyl, alkenyl and, as defined above, having an aryl substituent. Alkenyl group.
  • alkylene When an alkyl group as defined above has a single bond linking other groups on two different carbon atoms, they are referred to as “alkylene” and may be optionally substituted as defined above for “alkyl”.
  • alkenylene When an alkenyl group as defined above and an alkynyl group as defined above have a single bond connecting two different carbon atoms, respectively, they are referred to as “alkenylene” and “subalkynylene”, and may be as above The definitions of “alkenyl” and “alkynyl” are optionally substituted.
  • halogen when used alone or as part of another group, means chlorine, bromine, Fluorine and iodine.
  • metal ion refers to alkali metal ions such as sodium, potassium, lithium and alkaline earth metal ions such as magnesium, calcium, zinc and aluminum.
  • aryl as used herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6-10 carbons in the ring portion (eg, phenyl or naphthyl includes 1-naphthyl and 2-naphthyl), and may optionally include 1-3 other rings fused to a carbocyclic ring and a heterocyclic ring (such as an aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring) ), E.g
  • 1, 2 or 3 groups selected from the group consisting of: hydrogen, halo, haloalkyl, fluorenyl, haloalkyl, alkoxy, halogenated oxygen Alkenyl, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cyclodecyl-fluorenyl, heterocycloalkyl, heterocycloalkyl fluorenyl, aryl, heteroaryl, aryl , aryloxy, aryloxyindenyl, aryloxy, decyloxycarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, aryl Nitro, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, thio, nitro, cyano, amino, substituted amino, wherein the amino group includes 1 or 2
  • the terms “lower alkoxy”, “alkoxy”, “aryloxy” or “aralkyloxy”, when used alone or as part of another group, include attached to an oxygen atom. Any of the above fluorenyl, aralkyl or aryl groups.
  • substituted amino when used alone or as part of another group, refers to an amino group substituted with one or two substituents which may be the same or different, for example, a fluorenyl group.
  • substituents may be further substituted with a carboxylic acid and/or any of the alkyl substituents listed above.
  • amino substituents may form a 1-pyrrolidinyl group, a 1-piperidinyl group, a 1-azetidinyl group, a 4-morpholinyl group, a 4-thiomorpholinyl group together with a nitrogen moiety to which they are attached.
  • lower alkylthio when used alone or as part of another group, include attached to an oxygen atom. Any of the above fluorenyl, arylalkyl or aryl groups.
  • acyl refers to an organic group attached to a carbonyl group; examples of acyl groups include any alkyl substituent attached to a carbonyl group.
  • alkanoyl group an alkenoyl group, an aroyl group, an aryl chain decanoyl group, a heteroaroyl group, a cycloalkanoyl group, a heterocycloalkanoyl group.
  • heterocyclyl refers to a 5, 6 or 7 member saturation comprising from 1 to 3 heteroatoms such as nitrogen, oxygen and/or sulfur. Or an unsaturated ring (including an aromatic ring), and such a ring may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclic fluorenyl ring (such as benzothiophene and fluorenyl) and may include N-oxide.
  • the heteroaryl group may optionally contain from 1 substituent, such as any of the above fluorenyl substituents. Examples of the heterocyclic group include the following groups -
  • heterocycloalkyl refers to a heterocycloalkyl group as defined above attached to a ((3 ⁇ 4)" chain through a carbon atom or a hetero atom.
  • heteroarylkyl or “heteroarylalkenyl” as used herein, alone or as part of another group, refers to a (CH 2 ) n chain, an alkylene group, as defined above, bonded through a carbon atom or a hetero atom.
  • a heteroaryl group as defined above on the alkenyl or alkenylene group.
  • 5, 6, 7-membered carbocyclic or heterocyclic ring is a cyclo-glycol, cycloalkenyl, heteroaryl or heterocyclic aryl group, such as thiadiazole, tetrazole, imidazole or malignant. Oxazole.
  • polyhaloalkyl when used herein, refers to one containing 2-9, preferably 2-5 halo substituents, such as fluorine or chlorine, preferably fluorine defined as "embankment” group, such as CF 3, CF 3 CH 2 or CF 3 CF 2 C3 ⁇ 4.
  • polyhaloalkoxy refers to an “alkoxy” or “decyloxy” group as defined above, containing 2-9, preferably 2-5, halo substituents, such as fluoro or chloro, preferably fluoro.
  • Base " such as CF 3 0, CF 3 CH 2 0 or CF 3 CF 2 C 0.
  • heterocyclic amines and aromatic heterocyclic amines of R in the formula (I) of the present invention include, but are not limited to, groups having or without amino substitution: azetidinyl, benzimidazolyl, benzofuranyl, benzene Thiazolyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, oxazolyl, porphyrinyl, furyl, imidazolyl, indanyl, fluorenyl , pyridazinyl, oxazolyl, isobenzofuranyl, isodecyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthopyridyl, oxadiazolyl, oxazoline, isomer Oxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridaziny
  • R in the formula (I) of the present invention may be an optionally substituted piperazine including, but not limited to, 4-methylpiperazine, cinnamylpiperazine, benzylpiperazine, phenylpiperazine, trimetazidine, ciprofloxacin.
  • the optionally substituted heterocyclic amine and aromatic heterocyclic amine other than piperazine in the present invention may be substituted with reference to the above piperazine-based substituent.
  • Preferred substituents for R in the formula (I) of the present invention are independently selected from N-morpholinyl, N-hexahydropyridyl, N-tetrahydropyrrolyl, NN-methylpiperazinyl, N-piperazinyl.
  • substituent groups for R in the formula (I) of the present invention are independently selected from the group consisting of ruthenium-morpholinyl, anthracene-hexahydropyridyl, anthracene-tetrahydropyrrolyl, anthracene-indole-methylpiperazinyl, anthracene- Piperazinyl, ⁇ -sarcosinyl, ⁇ -methylaminoethanol, ⁇ -3-methylpiperidinyl, indole-3-methylmethylpiperidinyl, hydrazine-trimetazinyl, guanidine-cinnamon Piperazinyl, hydrazine-phenylpiperazine, hydrazine-benzylpiperazine, hydrazine-tetrahydrofurfuryl piperazine, ⁇ - ⁇ -alanine, ⁇ -L-aspartate, ⁇ -lysine Acid, guanidine-aminocaproic
  • the phlorizin derivative (I) of the present invention or a pharmaceutically acceptable salt thereof includes an intramolecular salt, a solvate thereof or a hydrate thereof.
  • the compounds of the invention are possible as internal salts or zwitterions, since under degraded conditions, the deprotonated acidic moiety in the compound, such as a carboxyl group, may be an anion, and the charge may be a protonated or alkylated basic moiety such as a quaternary nitrogen atom.
  • the cationic charge is internally balanced.
  • An isolated compound having an internal equilibrium charge and thus not associated with an intermolecular counterion can also be considered a "free form" compound.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a phlorizin derivative or a tautomer thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides a process for the preparation of a pharmaceutical composition
  • a pharmaceutical composition comprising a phlorizin derivative or a tautomer thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier, which comprises deriving phlorizin
  • the substance or tautomer thereof, or a pharmaceutically acceptable solvate thereof, is mixed or dissolved with a pharmaceutically acceptable carrier.
  • compositions and components include both human and veterinary compounds, compositions and components, and if desired, the compositions may be packaged with written or printed instructions for use.
  • the pharmaceutically acceptable salts of the compounds of the invention can be synthesized from the compounds of the invention which comprise a basic or acidic moiety by conventional chemical methods.
  • the salt of the basic compound is passed through an ion exchange column or by passing the free base with a chemistry meter.
  • the amount or excess of the desired salt-forming mineral or organic acid is prepared by reaction in various combinations of suitable solvents or solvents.
  • salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.
  • compositions of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by reacting a basic compound of the invention with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and organic acids such as acetic acid, propionic acid, and the like.
  • succinic acid glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, chloric acid, citric acid, fumaric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, Benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, rhein, taurine, oleanolic acid, ursolic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, B Alkanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.
  • Preferred organic or inorganic acids in the present invention include acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, citric acid, maleic acid, 7 salicylic acid, rhein, taurine, fumaric acid. , oxalic acid, light ethyl sulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid.
  • a suitable "pharmaceutically acceptable salt” means a salt prepared from a pharmaceutically acceptable non-toxic base, including an inorganic base and an organic base.
  • Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, divalent iron salts, lithium salts, magnesium salts, manganese salts, divalent manganese salts, potassium salts, sodium salts, zinc salts. Salt and so on. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.
  • Salts derived from pharmaceutically acceptable non-toxic organic bases include the salts of the following bases: primary, secondary and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines and basic ion exchange resins such as arginine, Betaine, caffeine, choline, hydrazine, ⁇ '-dibenzylethylenediamine, diethylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, ⁇ -ethylmorpholine, ⁇ -ethylpiperidine, glucosamine, berberine, glucosamine, histidine, hamamine (hydrabamine isopropylamine, lysine, methyl glucosamine, morpholine) , piperazine, piperidine, poly'amine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tri
  • Preferred organic or inorganic bases in the present invention include glucosamine, methyl glucosamine, caffeine, triethylamine, potassium hydroxide, sodium hydroxide.
  • the compounds of the present invention include all stereoisomers, either in the form of a mixture or in the form of a pure isomer.
  • the bright compound can form an asymmetric center on any of the chiral carbon atoms, including any of the R substituents.
  • the compounds of formula (I) may exist in enantiomeric or diastereomeric forms or as mixtures thereof.
  • the preparation method can use a racemate, an enantiomer or a diastereomer as a raw material. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods such as chromatography, chemical resolution or fractional crystallization.
  • a therapeutically effective amount of the compound of structure (I) as a first active ingredient may be used in combination with one or more other types of antidiabetic drugs and/or one or more other than the second active ingredient, as needed.
  • the pharmaceutical compositions of other types of therapeutic agents are administered in combination, and they may be administered orally in the same dosage form, in separate dosage forms, or by injection.
  • the ratio of the therapeutically effective amount of the compound of the structure (I) as the first active ingredient in the pharmaceutical composition of the present invention to one or more other types of therapeutic agents as the second active ingredient is 1: 0001-1: 0. 01.
  • the most suitable composition is a unit preparation, and the dosage of the active ingredient usually varies depending on the route of administration, the age and the condition of the patient, or the severity of the disease to be treated, usually 01 ⁇ 100 ⁇ /kg/day, more preferably 0. 05- 50mg/kg/day.
  • the dose is from 0.001 to 1000 mg/kg/day, preferably from 0.01 to 100 mg/kg/day, more preferably from 0.05 to 50 mg/kg/day.
  • parenteral administration the dose is from 0.005 to 100 mg/kg/day, preferably from 0 to 100 mg/kg/day, more preferably from 0.05 to 5 mg/kg/day.
  • the SGLT2 inhibitor of the compound D may be optionally combined with other types of anti-diabetic drugs to form a pharmaceutical composition, and other types of drugs may be one or more anti-diabetic drugs or anti-hyperglycemic drugs, including insulin, insulin derivatives. , insulin-like agents, insulin resistance improvers, gluconeogenesis inhibitors, glucose absorption inhibitors, renal glucose reuptake inhibitors, beta 3 adrenergic receptor agonists, insulin secretagogues or insulin sensitizers and other antibiotics Diabetic drugs.
  • Antidiabetic drugs with different mechanisms of action from SGLT2 inhibitors including bifidos, sulfonylureas, glucosidase inhibitors, peroxisome proliferator-activated receptor Y (PPAR Y)
  • PPAR Y peroxisome proliferator-activated receptor Y
  • thiazolidinedione aP2 inhibitor, PPAR a / Y dual agonist, dipeptidyl peptidase IV (DP4) inhibitor and / or meglitinide
  • DP4 dipeptidyl peptidase IV
  • insulin glucagon-like peptide-1
  • GLP-1 glucagon-like peptide-1
  • PTPIB protein tyrosine phosphatase IB
  • glycogen phosphorylase inhibitor and/or a glucose-6-phosphatase inhibitor.
  • SGLT2 inhibitor of formula (I) include anti-fatty drugs, anti-spasmodic drugs, anti-platelet drugs, anti-atherosclerotic drugs, and/or hypocholesterolemic drugs.
  • the SGLT2 inhibitor of structure (I) may also optionally be administered in combination with a drug for the treatment of diabetic complications.
  • a drug for the treatment of diabetic complications include PKC inhibitors and / or AGE inhibitors.
  • Antihyperglycemic effect of a compound of structure (I) in combination with one or more other antidiabetic agents The effect greater than the use of these drugs alone is also greater than the anti-glucose effect after the combination with these drugs.
  • Other antidiabetic agents may be oral hypoglycemic agents, preferably biguanides such as metformin or phenformin and its salts, most preferably metformin hydrochloride.
  • oral antidiabetic agents may also be preferably sulfonylureas such as glibenclamide, glipizide, glimepiride, gliclazide, gliclazone, chlorpropamide, etc., most preferably glibenclamide And glimepiride.
  • sulfonylureas such as glibenclamide, glipizide, glimepiride, gliclazide, gliclazone, chlorpropamide, etc., most preferably glibenclamide And glimepiride.
  • oral anti-diabetic agents may also preferably be glucosidase inhibitors such as acarbose, voglibose, miglitol.
  • oral antidiabetic agents may also preferably be thiazolidinediones such as rosiglitazone, pioglitazone, englitazone, ciglitazone, iglitazone, troglitazone, faglitazone, Rivoglitazone, Risarestat. Daglitazone, NSC363916, BRN3621848. BRN 5769524, BRN 5549627, BRN 5595208, BRN 5600016, AIDS012476, DRF-2189, 5-Nmebontd ⁇ Add 4743 > AD5075, ZINC01166114, ZINC01154723, BAS00285492.
  • the sulfonylurea and thiazole homodione can be combined in a tablet with the compound of structure (I) in an amount of less than about 150 mg of the oral antidiabetic agent.
  • GLP-1 glucagon-like peptide-1
  • GLP-1 such as GLP-1 (1-36) amide, GLP-1 (7-36) amide, GLP-1 (1- 36) amide, GLP-1 (7-37) amide, GLP-1 (S3- 20- 32), GLP-1 (S3- 11-14), GLP-1 (S6-14), GLP-1 (S8 (e.g., U.S. Patent 5,714,492 to Habener, Chinese Patent No. 1884278, Shanghai Institute of Materia Medica, Chinese Academy of Sciences), and AC2993 (Amylen) and LY-315902 (Lilly), which can be administered by injection, intranasal, transdermal or oral devices. Give medication.
  • GLP-1 glucagon-like peptide-1
  • S8 e.g., U.S. Patent 5,714,492 to Habener, Chinese Patent No. 1884278, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
  • AC2993 Amylen
  • the meglitinide used in combination with the compound of formula (I) of the invention is preferably repaglinide, nateglinide, KAD1229 (PF/Kissei), most preferably repaglinide.
  • Other oral antidiabetic agents may also be PPAR a / Y dual agonists such as AR-H039242 (Astra/Zeneca) ⁇ GW- 409544 (Glaxo- Wellcome), KRP297 (Kyorin Merck) and by Murakami et al.
  • anti-diabetic agents may be, for example, aP2 inhibitors disclosed in U.S. Application Serial No. 09/391,053, filed on Sep. 7, 1999, and U.S. Provisional Application No. 60/127,745, filed on Apr. 5, 1999. Pick Use the dosage form set forth in the above application. Preferred compounds are preferably designated in the above application.
  • oral anti-diabetic agents may also be DP4 inhibitors, such as the patents W099/38501, 099/46272, W099/67279, Nugh-DPP728A, published by Hughes et al, Biochemistry, 38 (36), 11597-11603, 1999 ( TSL-225, published by Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540, uses the dosage forms described in the above references.
  • a hypolipidemic or lipid lowering agent which may optionally be used in combination with a compound of formula (I) of the invention includes one or more MTP inhibitors, beryllonic acid, HMG-CoA reductase inhibitor, squalene synthetase Inhibitors, niacin derivatives, up-regulation of LDL receptor activity, lipoxygenase inhibitors, ACAT inhibitors, cholesterol absorption inhibitors, ileal sodium 7-cholesterine cotransporter inhibitors, bile acid sequestrants.
  • the hypolipidemic agent can be an MTP inhibitor, including but not limited to US 5,958,872, US 5,739, 135, US 5,712, 279, US 5, 760, 246, US 5, 827, 875, US 5, 588, 983, US 5,962, 440, each of the preferred MTP inhibitors disclosed in the above patents are preferred. All of the above U.S. patents are incorporated herein by reference.
  • the hypolipidemic drug may be benbutin, including but not limited to, clofibrate, bezafibrate, fenofibrate, gemfibrozil, ciprofibrate, cribbet, probucol.
  • the hypolipidemic drug may be an HMG-CoA reductase inhibitor including, but not limited to, pravastatin, mevastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, ivavastatin, nigra Statins, visastatin, rosuvastatin, pravastatin, etc.
  • HMG-CoA reductase inhibitor including, but not limited to, pravastatin, mevastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, ivavastatin, nigra Statins, visastatin, rosuvastatin, pravastatin, etc.
  • pravastatin including, but not limited to, pravastatin, mevastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, ivavastatin,
  • the hypolipidemic drug may be a squalane synthase inhibitor, including but not limited to alpha _ in US Patent 5,712,396. Phosphono-sulfonate, a compound disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, 1869-1871.
  • hypocholesterolemic drugs include, but are not limited to, cholic acid chelating agents such as cholera, colestipol, cholesterol absorption inhibitors such as ezetimibe, niacin such as niacin, acipimox, and other drugs such as pro Clocoan, pantethine, etc.
  • hypolipidemic agents may also be lipoxygenase inhibitors, including 15-lipoxygenase (15-L0) inhibitors such as the benzimidazole derivatives disclosed in W097/12615, 15-15 disclosed in W097/12613. L0 inhibitors, isothiazolone disclosed in 96/38144, and "weak food-induced atherosclerosis in rabbits by a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties," by Sendobry et al. , Brit. J.
  • the compound of formula (I) and the hypolipidemic agent can be administered together in the same oral dosage form or in separate oral dosage forms at the same time.
  • Preferred hypolipidemic drugs are pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, ivavastatin, nevastatin, visastatin, rosuvastatin, and pravastatin.
  • Anti-obesity agents which may optionally be used in combination with a compound of formula (I) of the invention include one or more 3 adrenergic agonists, lipase inhibitors, serotonin (and dopamine) reuptake inhibitors, thyroid beta receptors Drugs, anorectic agents, sputum antagonists, MC4 agonists.
  • the anti-obesity agent may be a beta 3 adrenergic agonist, including, but not limited to, a ⁇ 3 adrenergic agonist in AJ9677 (Takeda/Dainippon), L750355 (Merck), and US5541204, US5770615, US5491134, US5776983, and US5488064.
  • the anti-obesity agent may be a lipase inhibitor, including but not limited to orlistat, ATL-962 (Alizyme) o anti-obesity drugs may be serotonin (and dopamine) reuptake inhibitors including, but not limited to, sibutramine, Topira, axokine 0
  • anti-obesity agents include, but are not limited to, anorectic agents such as dextroamphetamine, phentermine, phenylpropanolamine, and horseshoe.
  • Antiplatelet agents which may optionally be used in combination with a compound of formula (I) of the present invention include abciximab, ticlopidine, dimiadam, aspirin, anagrelide, tirofiban, eptifibatide, clopidogrel.
  • Anti-spasmodic drugs which may optionally be used in combination with a compound of formula (I) of the invention include ACE inhibitors such as enalapril, captopril, quinapril, benazepril, perindopril, calcium Antagonists such as amlodipine, nifedipine, nitrendipine, nimodipine, nicardipine, diltiazem, verapamil, alpha-blockers including terazosin, more Salazosin, prazosin, diuretics including gas chlorothiazide, furosemide, spironolactone, indapamide, amiloride, central systemic agents including reserpine, clonidine, guanfacine, angiotensin II II antagonists include losartan, valsartan, telmisartan, blockers including mitoxolol, propranolol, atenolol,
  • Carnitine derivatives include, but are not limited to, carnitine, L-carnitine, L-carnitine hydrochloride, L-carnitine chloride, Acetyl L-carnitine, Propionyl L-carnitine, Butyryl L-Carnitine, and the like. L-carnitine is preferred.
  • Carnitine palmitoyltransferase inhibitors include, but are not limited to, malonyl-CoA, succinyl-CoA, methylmalonyl-CoA, 2-bromopalmitic acid, Yitoo-Sil, glycidol (eg clomoxir, etomoxir) ) et al. (Zhang Fanglin et al., Foreign Medical Endocrinology Manual, 2005, 22 (3): 166-169).
  • the therapeutic blood-suppressing drugs used in combination with the compound of the formula (I) of the present invention include, but are not limited to, ferrous sulfate, ferrous fumarate, iron dextran, sorbitan iron citrate, vitamins, glucocorticoids, androgens, and erythrocytes. Producer, folic acid, vitamin B12.
  • the therapeutic gout drugs used in combination with the compound of formula (I) of the present invention include, but are not limited to, colchicine, indomethacin, ibuprofen, naproxen, phenylbutazone, fustatin, inflammatory pain, xixihua, meiluoxi Kang, allopurinol, potassium citrate, sodium bicarbonate, probenecid, benzbromarone, thiazolone, sulfonylpyrazole, gout, etc.
  • the antidepressant drugs used in combination with the compound of the formula (I) of the present invention are tricyclics, monoamine oxidase inhibitors, serotonin reuptake inhibitors, acetylcholine reuptake inhibitors and the like.
  • the antidepressant may be a tricyclic drug including, but not limited to, imipramine, clomipramine, amitriptyline, doxepin, normimethamine, nortriptyline.
  • Antidepressant drugs can be tetracyclic drugs including, but not limited to, mianserin, maprotiline.
  • the antidepressant drug may be a monoamine oxidase inhibitor including, but not limited to, phenethyl hydrazine, phenylpropanolamine, morphine.
  • the antidepressant agent can be a selective 5-HT reuptake inhibitor including, but not limited to, fluoxetine, paroxetine, sertraline, citalopram, and flufen samine. .
  • Antidepressant drugs may be 5-HT and NE reuptake inhibitors, including ⁇ not limited to venlafaxine, venlafaxine.
  • the antidepressant may also be other drugs including, but not limited to, reboxetine, buppe, trazodone, nefazodone, dextrozapine, luteapine, amfepramone.
  • the medicament for treating dementia used in combination with the compound of the formula (I) of the present invention includes, but is not limited to, tetrahydroaminoacridine (tacrine), tetrahydroxyaminoacridine, physostigmine, heptene lenola, galantamine , koji lecithin (trichlorfon), donepezil hydrochloride, huperzine A, carraga tartaric acid, nominin, risperidone, moclobemide, lazabe, Saberuzole, Istemide, Selegiline, Propofolline, New Qufusi, Apelis, Nefiracetam, Linoleide, Montesalin, Nitrorelin, Azo Ping, ZT-1, prasalam, diphenylmex, epoxone, oxazolidine, meclofenoxate, piracetam, pyrithione, acetyl
  • the osteoporosis drugs used in combination with the compound of the formula (I) of the present invention are bone resorption inhibitors, bone formation promoting agents, bone mineralizing substances and other osteoporosis drugs.
  • Bone resorption inhibitors include, but are not limited to, bisphosphonates, estrogens, calcitonin, progestins, isoflavones, guanidinium salts.
  • Bisphosphonates include, but are not limited to, etidronate, clodronate, tiludronate, pamidronate, alendronate, risedronate, incadronate, zoledronate , dtidronate, ibandronate.
  • Estrogens include, but are not limited to, raloxifene, clomiphene citrate, tamoxifen, dr 0 l 0X if ene , noforxidine, idoxifene, apeledoxifene, lasofoxifene, Tibolone, Nilestriol.
  • Calcitonin includes, but is not limited to, dense calcium, procalcin, salcat 0 nin.
  • Bone formation promoters include, but are not limited to, fluoride (telidine), parathyroid hormone (PTH), anabolic steroids, human immunoglobulin (IGF)
  • Other drugs for the treatment of osteoporosis may also be statins, zinc alaninate (AHZ), cathepsin K inhibitors, endostein receptor blockers, neuropeptides, growth factors (insulin-like growth factors, Transforming growth factor, bone morphogenetic protein), osteoprotegerin (osteoprotegerin 0PG).
  • statins zinc alaninate (AHZ)
  • cathepsin K inhibitors cathepsin K inhibitors
  • endostein receptor blockers neuropeptides
  • growth factors insulin-like growth factors, Transforming growth factor, bone morphogenetic protein
  • osteoprotegerin osteoprotegerin 0PG
  • Anti-inflammatory drugs for use in combination with a compound of formula (I) of the present invention include, but are not limited to, aspirin, phenylbutazone, naproxen, fenbufen, ibuprofen, indomethacin, nabumetone, diflunisal, Acetaminophen, benolyl ester, salicylic acid, etofenamate, etodolac, ketoprofen, diclofenac, penicillamine, celecoxib, nimesulide, meloxicam, losolo Fen, leflunomide, non-Prazin, benzoxamide, oxaprozin, sulindac, antipyrine, auranofin, piroxicam, imidazoxil, tommettine, meclofenamic acid Assimin.
  • the antitumor drug used in combination with the compound of the formula (I) of the present invention may be an alkylating agent, an antitumor antibiotic, a dihydrofolate reductase inhibitor, an anthraquinone, a pyrimidine, a topoisomerase inhibitor, or a tumor angiogenesis inhibitor. Agents, natural medicines, etc.
  • Alkylating agents include, but are not limited to, cyclophosphamide, nitrogen mustard, thiotepa, nadropaplatin, oxaliplatin, melphalan, nitrite, carmustine, lomustine, semustine, nis Mustine, ramustine, temozolomide, mitoxazole amine, troxidone, mesamine.
  • Antitumor antibiotics include, but are not limited to, doxorubicin, mitomycin, bleomycin, gentamicin, epirubicin, Mitomycin, daunorubicin, aclarithromycin, erythromycin, mitoxantrone, idarubicin, pirarubicin, pentopirin.
  • Dihydrofolate reductase inhibitors include, but are not limited to, methotrexate, hexamethylene melamine.
  • Terpenoids include ⁇ not limited to ⁇ .
  • Pyrimidine drugs include, but are not limited to, fluorouracil, carmofur.
  • Anti-tumor natural drugs include, but are not limited to, camptothecin, vincristine, paclitaxel, colchicine, green gluten, compound acetate gossypol, Kanglaite (barley extract), elemene (artemisia oil extract), Harringtonine, Polyporus polysaccharide, Lycium barbarum polysaccharide, Lentinus edodes polysaccharide, Ginseng polysaccharide, Tremella polysaccharide, Yunzhi polysaccharide, Rehmannia polysaccharide, Lycium barbarum polysaccharide, Kiwi polysaccharide, Astragalus polysaccharide, Angelica polysaccharide, Gynostemma polysaccharide, Radix polysaccharide, Prickly ash Add polysaccharides, Achyranthes polysaccharides, etc.
  • Topoisomerase inhibitors include, but are not limited to, irinotecan, topotecan, and rebitantan.
  • Tumor angiogenesis inhibitors include, but are not limited to, suramin, thalidomide, fumagillin, monoclonal antibodies, bamstat, and marimastat.
  • the compound (I) of the invention is used for preparing a medicament for treating tumor, wherein the tumor comprises acute myeloid leukemia, chronic myeloid leukemia, renal transparent cancer, breast cancer, lymphocytic leukemia, prostate cancer, liver cancer, lymphoma, lung cancer , gastric cancer, esophageal cancer, colon cancer and other tumors.
  • the immunosuppressive drugs used in combination with the compound of the formula ⁇ ) of the present invention include guanidine, not limited to prednisone, prednisolone, dexamethasone, hydrocortisone, danazol, cyclophosphamide, cyclosporin 4, mold Phenolic acid ester, leflunomide, tripterygium wilfordii, azathioprine, heparin-warfarin, dimetamol, tacrolimus, sirolimus, kalemycin (imidazole, immunoglobulin, Eicosapentaenoic acid, docosahexaenoic acid (DHA), escital, daximab, rituximab, infliximab, interferon.
  • guanidine not limited to prednisone, prednisolone, dexamethasone, hydrocortisone, danazol, cyclophosphamide
  • Antioxidants for use in combination with the compounds of formula (I) of the present invention include, but are not limited to, glutathione, vitamin E, vitamins (:, vitamin A, superoxide dismutase (SOD), archoprotein, hemagglutinin, tea Polyphenols, taurine, uric acid, thioglycoprotein, probucol, glutamate, succinate, ubiquinone, chlorophyllin, coenzyme Q, homocysteine, menaquinone, alpha-lipoic acid , dantrolene, polyphenol flavonoids, lecithin, ursodeoxycholic acid, coenzyme, linoleic acid, chondroitin sulfate, oleanolic acid, inositol, silymarin, biphenyl diester, potassium aspartate Magnesium, glycyrrhizin, methionine, nucleic acid, glucuronolactone, propyl
  • composition of the present invention is prepared into a pharmaceutical preparation comprising an orally administered preparation, an injectable preparation or a topically administered preparation, wherein:
  • Oral administration preparations include ordinary tablets, sustained release tablets, granules, hard or soft capsules, syrups, solutions, emulsions; carriers for oral administration include fillers, disintegrators, binders, lubricants Agent, colorant, flavoring agent or Other conventional additives, including starch, lactose, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, polyvinylpyrrolidone, hypromellose, magnesium stearate, silica and poly Yamanite 80, sodium decyl sulfate;
  • the preparation for administration by injection includes a sterile injection aqueous solution, a sterile injection oil-in-water microemulsion, a sterile powder for injection; a carrier for injecting the preparation preparation includes a solvent for injection, an additional agent for injection, and the specific injection solvent includes Water for injection, oil for injection such as soybean oil, solubilizer for injection such as ethanol, propylene glycol, polyethylene glycol, glycerin, isotonic substances such as sodium chloride, glucose;
  • the topical preparation is a patch, a suppository, a cream, a cream, a gel, a solution, a suspension or a targeted preparation, wherein the targeted preparation comprises a liposome, a microsphere, a nanoparticle, an inclusion.
  • monoclonal antibody conjugates; carriers for topical formulations include conventional carriers for pharmaceutically acceptable topical administration.
  • the pharmaceutical preparation forms of the present invention include: intravenous, intramuscular, peritoneal, subcutaneous, oral, rectal suppository insertion, vaginal suppository insertion, targeted administration, inhalation, gavage, nasal feeding, sublingual administration , a drip method, a micro-needle administration, a continuous administration system, and a topical administration, a topical administration method such as a skin preparation, or an implantable continuous administration release system, wherein the skin preparation carrier comprises a skeleton material such as hydrophobic Polysiloxane and hydrophilic polyvinyl alcohol, etc., controlled release film materials such as polysiloxane and ethylene-vinyl acetate copolymer, pressure sensitive adhesives such as polyisobutylene, polysiloxane and polyacrylate, the active ingredients are generally Dispersed in pressure sensitive adhesive; the polymer materials selected for the implantable continuous drug delivery system include polylactic acid-glycolic acid copolymer, polyethylene glycol polylactic acid copolymer
  • a pharmaceutical composition comprising a compound of structure (I) in association with a pharmaceutically acceptable carrier or diluent, which may or may not contain another anti-diabetic agent, and/or Or antihyperlipidemic drugs, or other types of therapeutic drugs.
  • the pharmaceutical composition can be formulated using conventional solid or liquid carriers or diluents, as well as some type of pharmaceutical additive suitable for the desired mode of administration.
  • the compound can be administered to a mammal or the like by a oral route, for example, in the form of a tablet, a capsule, a granule or a powder, including humans, monkeys, dogs, pigs, rats, etc., or they can be administered parenterally in the form of an injection preparation. They are administered, or they can be administered nasally or in the form of a transdermal patch.
  • the dosage is preferably between 10 and 2000 rag/day, which may be administered in a single dose or in divided doses, one to four times daily.
  • the SGLT2 inhibitor activity of the compounds of the invention can be determined by using an assay system as described below.
  • SGLT2 activity The mRNA sequence of human SGLT2 was cloned from human kidney mRNA by reverse transcription and amplification using standard molecular biology techniques (GenBank #M95549). The cDNA sequence was stably transfected into CH0 cells, and the clones were assayed for SGLT2 activity as described generally by Ryan (1994). Basically, as described by Ryan et al., the following modifications were made to evaluate the inhibition of SGLT2 activity in the cell line selected for cloning.
  • MicroScint scintillation fluid shake the cells for 1 hour and then quantify ["C]AMG on a TopCourrt scintillation counter. Control experiments can be performed with and without sodium chloride. For the determination of EC50 values, triplicate plates were averaged on the assay plate at a 21 og interval with a concentration of 10 inhibitors (Ryan MJ, Johnson G, Kirk J, Fuerstenberg SM, Zager RA) And Torok-Storb B. 1994. HK-2: An immortalized proximal tubular epithelial cell line obtained from normal adult kidneys. Kidney International 45:48-57). detailed description .
  • the molecular structure of the present invention may exist as stereoisomers, which are prepared by chiral reagent directed synthesis, chemical resolution or chiral column to obtain simple stereoisomers. These stereoisomers are not fully described in this embodiment. However, the invention is not limited.
  • the phlorizin (0.25g, 0.58mmol) was dissolved in 25raL absolute ethanol and poured into a round bottom flask. Stir it with a magnetic stirrer and control the temperature at 3-10 °C. Slowly add to the phlorizin ethanol solution. A 37% aqueous solution of formaldehyde (0.059 niL, 0.87 iraiol) was stirred for 30 min. Further, pyrrolidine (0.066 mL, 0.87 mmol) was slowly added dropwise, and the temperature was controlled at 0 to 70 ° C.
  • HPLC test instrument Shimadzu LC-10A, column: C18 column (4.6*150mm, 5 ⁇ m), flow rate: 1. Oml/min, column temperature: 40 ⁇ , detection wavelength: 284nm, mobile phase: 60% phosphoric acid aqueous solution (2mmol/L) +40% methanol, retention time: 2.953min
  • HPLC test instrument Shimadzu LC-10A, column: C18 column (4.6*150 legs, 5um), flow rate: lml/min, column temperature: 35°C, detection wavelength: 284nm, mobile phase: 80% water, 20 % methanol ⁇ 40% water, 60% methanol, 0 ⁇ 16rain, retention time: 14.707min
  • IR cm- 1 3360, 1616, 1543, 1517, 1078, 987, 832
  • the phlorizin (0.25 g, 0.58 ramol) was dissolved in 25 mL of anhydrous isopropanol and poured into a round bottom flask. The mixture was stirred with a magnetic stirrer. The temperature was controlled at 3 to 10 ° C, and the solution was slow to the phlorizin ethanol solution. A 37% aqueous solution of formaldehyde (0.059 mL, 0.87 mmol) was added dropwise and stirring was continued for 20 min. N-methylpiperazine (0.096 mL, 0.87 ramol) was added dropwise slowly, the temperature was controlled at 3-10 ° C, and the reaction was further stirred for 60 min. At the end of the reaction, the mother liquid was evaporated to dryness at 40 ° C, and an appropriate amount of methanol was added to recrystallize. Light yellow cluster crystal. Weighing 0.2g, the yield is 80%.
  • HPLC test instrument Shimadzu LC-10A, column: C18 column (4.6*150mm, 5um), flow rate: 0.8ml/min, Column temperature: 40 ° C, Detection wavelength: 284nn! , Mobile phase: 70% aqueous phosphoric acid solution (2mm 0 l/L) +30% methanol, retention time: 3.581min
  • IR cm-1 3433, 3401, 1613, 1538, 1514, 1212, 1074
  • Example 2 For the procedure, see Example 1, except that N-methyl-N-0-hydroxyethylamine was used instead of tetrahydropyrrole. A pale yellow crystal was obtained with a yield of 62%.
  • the phlorizin was weighed in a 250 ml round bottom flask, dissolved in 30 ml of ethanol and stirred at room temperature to make a uniform; 1. 5 ml of 37% formaldehyde aqueous solution was added dropwise to the ethanol solution and stirred for 10 minutes; A solution of 2.3 g of trimetazidine hydrochloride in 15 ml of water was added dropwise, and stirred at room temperature for 2-3 hours.
  • reaction solution was concentrated under reduced pressure at 35 - 4 CTC to hexane, dissolved in ethanol, and then the acetone solution was added dropwise to precipitated a white solid, which was suction filtered and dried in a vacuum oven at 40 ° C to obtain a white powder.
  • Example 10 The procedure of Example 10 was carried out to give a white powder, yield 87%.
  • Example 20 Preparation of 3 '-(N, N-dipropylaminomethylene) phlorizin
  • Example 22 Preparation of 3, - (N, N-diisopropylaminomethylene) phloridin
  • Example 23 Preparation of 3'-(N,N-dichloroethylaminomethylene) phlorizin
  • Example 24 Preparation of 3'-(N-methyl-N-methoxycarbonylmethylaminomethylene) phlorizin
  • Example 25 Preparation of V-(((R)-3-hydroxymethylpiperidin-1-yl)-methylene) phlorizin
  • Human fibronectin (Human FN) is an adhesion protein in the extracellular matrix.
  • Larainin LN is a group of extracellular matrix glycoproteins, which are the main components of the non-collatile structure of the matrix membrane. They are an important indicator of the pathogenesis of diabetes and its complications.
  • Phloridin derivatives 3'-(hexahydropyridin-1-yl-methylene) phloridzin, 3'-(N, N-diethylaminomethylene) phlorizin
  • This experiment was performed on a human vascular endothelial cell model with low glucose (5.5 ⁇ M) (normal control), high glucose (30 ⁇ ) (diabetic nephropathy model) and high glucose + phlorizin derivative (50 g/ After 48 hours of treatment (administration), fibronectin and human laminin immunohistochemical staining were performed.
  • extracellular matrix endothelin (ET 1 ) and fibronectin (FN) was observed by low glucose stimulation group (normal control), high glucose stimulation group (diabetes model), and drug treatment comparison to observe the content of 3 ⁇ 4 Anti-extracellular matrix secretion activity.
  • the 2 - ⁇ CT method is a simple method for analyzing the relative changes in gene expression in real-time quantitative PCR experiments. * METHODS 25, 402 - 408 (2001) doi: 10. 1006/meth. 2001. 1262, available online at http://www. idealibrary.com
  • Time x represents an arbitrary time point
  • Time 0 represents a target gene expression that is 1 times the amount corrected by GAPDH.
  • the amount of the target sequence is determined by internal homogenization relative to the reference factor: amount of targets - ⁇ ⁇ results show that the phlorizin derivative has significant antisecretory activity (see Table 1), its resistance to ET-1
  • the secretory activity is: 3' - (hexahydropyridine-1-yl-methylene) phloridin >3, mono(4-methylpiperidine-1-yl-methylene) phloridin > suede Glycosides; its antisecretory activity against FN is 3'-(hexahydropyridine-1-yl-methylene) phloridin > phlorizin >3' ⁇ (4-methylpiperidine-1-yl- Methylene) phlorizin.
  • High-fat diet (basic feed plus sucrose, refined lard, egg yolk powder in proportion 60: 22: 8:
  • Glucose tolerance before administration total amount of 24h urine protein, biochemical indicators of liver and kidney function.
  • the STZ injection advance food situation (based on weekly record statistics) is shown in Figure 2.
  • biochemical indicators such as postprandial blood glucose of the animals in each group before the administration had no significant difference between the groups.
  • 3' - (N-tromethetazinyl-methylene) phlorizin has a significant effect on postprandial blood glucose.
  • Postprandial blood glucose in the low-dose group decreased by 23.7% compared with the model group, and the high-dose group decreased by 53.3. %, showed a dose-dependent relationship (P ⁇ 0.001) : the amount of 24h urine protein in the high-dose group also decreased significantly (P ⁇ 0.05).
  • the effect of each drug group on postprandial blood glucose and 24h urine protein was not limited to postprandial blood glucose.
  • 3'-(N-trometazinyl-methylene) phlorizin has a slight effect on reducing urinary protein.
  • the total amount of urinary protein in the lower dose group was decreased by 11.3% compared with the model group, and the high-dose group was decreased.
  • P ⁇ 0.05 the high-dose group was decreased.
  • Renal pathological changes HE staining, under light microscope x200 and x400, can compare the volume of glomeruli, the number of glomerular intrinsic cells, the proliferation of extracellular matrix, and interstitial fibrosis.
  • 3' - (N-tromethetazinyl-methylene) phloridzin can improve the general condition of diabetic nephropathy model rats
  • Figure 1 shows the pre-dose weight profile
  • Figure 2 shows the weekly food intake statistics before STZ injection.
  • Figure 3 shows the effect of 3'-(N-trimetazinyl-methylene) phlorizin on body weight.
  • Figure 4 is a photograph of the Contro group under He staining x200.
  • Figure 5 is a photograph of the Model Group under He staining x200.
  • Figure 6 is a photograph of the Gen-S group under He staining x200.
  • Figure 7 is a photograph of the Gen-H group under He staining x200.
  • Figure 8 is a photograph of the Hetro stained x400 in the Contro group.
  • Figure 9 is a photograph of the Model group under He staining x400.
  • Figure 10 is a photograph of the Gen-S group under He staining x400.
  • Figure 11 is a photograph of the Gen-H group under He dye x400.

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Abstract

Cette invention concerne des dérivés de la phlorizine de formule (I), leur préparation et leur utilisation dans la fabrication de compositions pharmaceutiques. Lesdits composés présentent une activité inhibitrice du SGLT2 et peuvent être utilisés pour traiter les maladies métaboliques comme le diabète et ses complications.
PCT/CN2009/000705 2008-07-29 2009-06-24 Dérivés de la phlorizine, leur préparation et leur application WO2010012153A1 (fr)

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CN104045671A (zh) * 2013-03-16 2014-09-17 永州一东生物技术有限责任公司 一种从苹果根皮中提取纯化根皮苷的方法
WO2019106122A1 (fr) 2017-12-01 2019-06-06 Sanofi Nouveaux conjugués constitués d'un agent pharmaceutique et d'une fraction pouvant se lier à une protéine de détection du glucose
US11090364B2 (en) 2016-06-02 2021-08-17 Sanofi Conjugates of a pharmaceutical agent and a moiety capable of binding to a glucose sensing protein
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CN111870694B (zh) * 2020-07-20 2022-01-14 重庆大学 Sglt2抑制剂的用途
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2401806A1 (es) * 2011-10-11 2013-04-24 Servicio Andaluz De Salud Uso de una composición que comprende un poli-organosiloxano.
CN104045671A (zh) * 2013-03-16 2014-09-17 永州一东生物技术有限责任公司 一种从苹果根皮中提取纯化根皮苷的方法
US11090364B2 (en) 2016-06-02 2021-08-17 Sanofi Conjugates of a pharmaceutical agent and a moiety capable of binding to a glucose sensing protein
WO2019106122A1 (fr) 2017-12-01 2019-06-06 Sanofi Nouveaux conjugués constitués d'un agent pharmaceutique et d'une fraction pouvant se lier à une protéine de détection du glucose
CN113804790A (zh) * 2021-09-18 2021-12-17 四川新希望畜牧科技有限公司 一种同时检测添加剂、l-肉碱和d-肉碱的方法
CN114414809A (zh) * 2022-03-28 2022-04-29 中元伯瑞生物科技(珠海横琴)有限公司 用于诊断尘肺病的生物标志物的应用
CN114414809B (zh) * 2022-03-28 2022-06-21 中元伯瑞生物科技(珠海横琴)有限公司 用于诊断尘肺病的生物标志物的应用

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