CN104672227A - Novel SGLT2 inhibitor compounds and pharmaceutical composition thereof - Google Patents

Novel SGLT2 inhibitor compounds and pharmaceutical composition thereof Download PDF

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Publication number
CN104672227A
CN104672227A CN201410610352.9A CN201410610352A CN104672227A CN 104672227 A CN104672227 A CN 104672227A CN 201410610352 A CN201410610352 A CN 201410610352A CN 104672227 A CN104672227 A CN 104672227A
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methyl
base
pyrans
tetrahydrochysene
methylol
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史东方
傅长金
蒋强华
刘伟
张长亮
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Zhenjiang New Element Pharmaceutical Technology Co Ltd
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Zhenjiang New Element Pharmaceutical Technology Co Ltd
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Priority to PCT/CN2015/093100 priority patent/WO2016070740A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
    • C07D421/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Abstract

The invention discloses novel SGLT2 inhibitor compounds shown in a formula (I), pharmaceutically acceptable salts, easily hydrolyzed pre-drug esters or isomers and a pharmaceutical composition which contains the compounds as an inhibitor of a sodium-glucose co-transporter (SGLT). The pharmaceutical composition is used for treating or delaying related diseases such as diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, rise of fatty acid or glycerinum, hyperlipemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications, atherosclerosis, hypertension and the like. The formula is shown in the description.

Description

One class New type of S GLT2 inhibitor compound and pharmaceutical composition thereof
Technical field
The present invention relates to the compound shown in a kind of general formula (I) and general formula (II), its pharmacy acceptable salt, the prodrug ester of its facile hydrolysis or its isomer, and the pharmaceutical composition containing this compound, and it is as treating preparation particularly as the purposes of the white SGLT2 inhibitor of sodium glucose co-transporter 2.
Background technology
Diabetes (diabetes) are a kind of caused by defect of insulin secretion and (or) insulin action deficiency taking hyperglycemia as the metabolism disorder syndrome of feature.Long-term hyperglycemia has infringement to many organs, causes dysfunction, and produces serious complication, as diabetic retinopathy, diabetic nephropathy, diabetic neuropathy etc.Diabetes can be divided into insulin-dependent 1 type and non-insulin-depending type 2 type two type, and wherein diabetes B is the most common, accounts for diabetic subject's more than 90%.Diabetes have become the epidemic disease of global non-infective disease class most.On November 14th, 2013 IDF (International Diabetes Federation, IDF) data presentation issued, the diabetes prevalence of 20 years old ~ 79 years old grownup in the whole world in 2013 is 8.3%, number of patients reaches 3.82 hundred million, and the whole world has 5,100,000 people and dies from the disease relevant to diabetes.The number of patients of China's diabetes in 2013 is 9,840 ten thousand, occupies first place, the whole world; By 2035, the diabetes number of patients of China was estimated to reach 1.43 hundred million.In addition, according to IDF statistics, within 2013, the whole world is used for the overhead cost of diabetes up to 5,480 hundred million dollars, and account for 11% of whole world health care spending sum, by 2035, this numeral will more than 6,273 hundred million dollars.Therefore, the continuous rising of diabetic subject's number and the enormous cost that is used for the treatment of diabetes have brought huge economy and living burden.
Pathogenic process due to diabetes complexity makes the mankind not yet find the method for radical cure so far, and many patients need accept treatment throughout one's life.Anti-diabetic chemicals conventional at present mainly contains by mechanism of action classification: sulfonylurea (Sulfonylureas), biguanides (Biguanides), alpha-glucosidase inhibitor (AGIs), thiazolidinediones (TZD), dipeptidyl peptidase 4 inhibitor (DPP-4) etc.These conventional ofhypoglycemic medicines have some inevitable toxic side effect at present.The major side effects of sulfonylureas causes hypoglycemia.The major side effects of biguanides is lactic acidosis, also can cause the infringement to liver and kidney, and occurs comprising the side effect of digestive tract such as appetite decline, Nausea and vomiting, abdominal distension, diarrhoea, dry and bitter taste.Alpha-glucosidase inhibitor main manifestations is GI side effect, as abdominal discomfort, flatulence, exhaust etc.Thiazolidinediones can cause dysfunction of liver, oedema, body weight to increase, anaemia (the Farhad M.Hasan of light moderate, Mazen Alsahli, John E.Gerich.SGLT2 inhibitors in the treatment of type 2 diabetes [J] .Diabetes Research and Clinical Practice, 2014,104 (3): 297-322).Therefore, for increasing diabetic subject provides more effective and the medicine that toxic side effect is little, the key subjects that academia, medicine sector, industry member are jointly paid close attention to and expected solution have been become.
Along with the deep understanding to diabetes pathophysiological mechanism, the drug development for different pathological physiology link gets more and more.White-2 (sodium-glucose co-transporter 2, the SGLT-2) inhibitor of sodium glucose co-transporter 2 is a kind of newly, the effective antidiabetic drug of exploitation at present.SGLT2 is only distributed in the S1 section of kidney proximal tubule, it is a kind of low-affinity, the carrier proteins of heavy body, be filtered to the glucose more than 90% in renal glomerulus to be absorbed under the activation of SGLT2, so suppress the activity of SGLT-2, the heavily absorption of proximal convoluted tubule to glucose can be blocked, and then blood sugar concentration in reduction body, reach object (the Shuo Zhang for the treatment of diabetes, Yu-Li Wang, Qun-Chao Wei, et al.Design, synthesis and biological activity of cyclohexane-bearing C-glucoside derivatives as SGLT2 inhibitors [J] .Chinese Chemical Letters, 2013, 24 (5) 24:429-432).In recent years, existing several SGLT-2 inhibitor goes on the market or enters clinical study, as the Dapagliflozin of Shi Guibao company research and development, and the Canagliflozin of Johson & Johnson's research and development, the Empagliflozin that gift comes and Bo Linge company researches and develops, the Ertugliflozin etc. of Pfizer and Merck & Co., Inc.'s research and development.
Clinical data shows, this class medicine significantly can reduce glucose level before the meal and after the meal, long-term prescription can reduce glucose toxicity (Bakris G.L., Fonseca V.A., Sharma K.Wright E.M.Renal sodium-glucose transport:role in diabetes and Potential clinical implications [J] .Kidney Inf., 2009,75:1272-1277.).SGLT2 inhibitor is compared with the method for current other treatment diabetes, there is hypoglycemic risk lower, and do not affect counter-regulatory hormones (Chao E.C., Henry R.R.SGLT2 inhibition-a novel strategy for diabetes treatment [J] .Nat.Rev.Drug Diseovery.2010,9:551-559).Glucose is excreted by urine by it, is conducive to the minimizing of body weight; Be conducive to the discharge of sodium ion, this is very favourable to improving hypertension.And this class medicine has the feature (Zhang Wenbin such as universal security and good tolerance, Gong Nian, Wang Yongxiang. kidney SGLT2 inhibitor: a kind of new oral ofhypoglycemic medicine [J]. bio-science is in progress, and 2010,41 (6): 453-456).SGLT2 inhibitor can also with other antidiabetic medicine conbined usage, auxiliary and collaborative effect is played to the treatment of diabetes.Further research and development more efficiently New type of S GLT2 inhibitor has good prospect and the market requirement.
Summary of the invention
The invention provides and comprise the inhibited compound of the white SGLT2 of sodium glucose co-transporter 2.Present invention provides pharmaceutical composition, and independently or the method for the disease using these compounds for treating to affect by SGLT2 restraining effect with other therapeutic combination and illness, as: type 1 diabetes, diabetes B, high glucose in urine disease, diabetic complication, insulin resistant (insulin resistance), metabolism syndrome (X syndrome), hyperinsulinemia (hyperinsulinemia), hypertension, hyperuricemia (hyperuricemia), obesity, oedema, metabolism of fat abnormal (dyslipidemia), chronic heart failure and atherosclerosis.
Feature of the present invention has the compound shown in general formula (I), its pharmacy acceptable salt, the prodrug ester of its facile hydrolysis or its isomer:
The prodrug ester of the compound shown in general formula (I), its pharmacy acceptable salt, its facile hydrolysis or its isomer:
Wherein,
R ', R " independently selected from H ,-OH ,-OCH 3or-OCH 2cH 3;
Y is selected from CH or N;
Z is CH;
R 1, R 2independently selected from H, halogen ,-OH ,-CN, C 1-4alkyl, C 1-4substituted alkyl, C 1-4alkoxyl group, C 1-4substituted alkoxy, C 1-4alkylthio or C 1-4substituted alkane sulphur base;
R 3for H;
R 4be selected from C 1-4alkyl, C 1-4substituted alkyl or
R 5, R 6independently selected from H, halogen ,-CN, C 1-4alkyl, C 1-4substituted alkyl, C 1-4alkoxyl group, C 1-4substituted alkoxy, C 1-4alkylthio or C 1-4substituted alkane sulphur base;
R 1and R 2described substituting group is selected from halogen, C 1-4alkoxyl group, C 1-4alkylthio ,-NH 2or-OH;
R 5and R 6described substituting group is selected from halogen, C 1-4alkoxyl group or C 1-4alkylthio.
Preferred version of the present invention, the prodrug ester of the compound described in general formula (I), its pharmacy acceptable salt, its facile hydrolysis or its isomer, the prodrug ester comprising the compound described in general formula (II) or its pharmaceutically useful salt, its facile hydrolysis:
Wherein,
R 1, R 2independently selected from H, F, Cl ,-OH ,-CN, C 1-3alkyl, C 1-3substituted alkyl, C 1-3alkoxyl group, C 1-3substituted alkoxy, C 1-3alkylthio or C 1-3substituted alkane sulphur base;
R 5, R 6independently selected from H, F, Cl ,-CN, C 1-2alkyl, C 1-2substituted alkyl, C 1-3alkoxyl group, C 1-3substituted alkoxy, C 1-3alkylthio or C 1-3substituted alkane sulphur base;
R 1and R 2described substituting group is selected from halogen, C 1-3alkoxyl group or-OH;
R 5and R 6described substituting group is selected from halogen or C 1-3alkoxyl group.
General formula (I) compound can contain unsymmetrical carbon, therefore can exist using the form of the mixture of optically pure diastereomer, non-enantiomer mixture, diastereomer racemic modification, diastereomeric racemic modification or exist as mesomeride compound.The present invention includes all these forms.The mixture of non-enantiomer mixture, diastereomeric racemic modification or diastereomeric racemic modification can pass through ordinary method, such as, be separated with HPLC etc. by column chromatography, tlc.
Preferred compound shown in general formula of the present invention (I) includes, but are not limited to:
(3R, 4S, 5S, 6R)-2-{3-[(5-(4-fluorophenyl) selenophen-2-base) methyl]-4-aminomethyl phenyl }-6-methylol-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol
(2S, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
(2S, 3R, 4R, 5S, 6R)-2-{3-{ [5-(3,4-difluorophenyl) selenophen-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
(2S, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-chloro-phenyl-) selenophen-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
The chloro-3-{ of (2S, 3R, 4R, 5S, 6R)-2-{4-[5-(4-fluorophenyl) selenophen-2-base] methyl } phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
(2R, 3S, 4R, 5R, 6S)-2-methylol-6-{4-methyl-3-[(5-phenyl selenophen-2-base) methyl] phenyl } tetrahydrochysene-2H-pyrans-3,4,5-triol
(2S, 3R, 4R, 5S, 6R)-2-{5-[(5-(4-fluorophenyl) selenophen-2-base) methyl]-2-methoxyl group-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
(2S, 3R, 4R, 5S, 6R)-2-{5-[(5-(4-ethyl-sulfide phenyl) selenophen-2-base) methyl]-2-methoxyl group-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
4-{5-{2-methyl-5-[(2S, 3R, 4R, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-base] benzyl } selenophen-2-base } cyanobenzene
(3R, 4S, 5S, 6R)-2-{5-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-2-hydroxy-4-methyl phenyl }-6-methylol-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol
(2S, 3R, 4R, 5S, 6R)-2-{5-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-2-hydroxy-4-methyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
(2S, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl)-1,3-selenazoles-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
(2R, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl)-1,3-selenazoles-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
(2R, 3S, 4R, 5R, 6S)-2-methylol-6-{3-{ [5-(4-p-methoxy-phenyl) selenophen-2-base] methyl }-4-aminomethyl phenyl } tetrahydrochysene-2H-pyrans-3,4,5-triol
(2R, 3S, 4R, 5R, 6S)-2-methylol-6-{4-methyl-3-{ [5-(4-aminomethyl phenyl) selenophen-2-base] methyl } phenyl } tetrahydrochysene-2H-pyrans-3,4,5-triol
(3R, 4S, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-2,3,4,5-tetrol
Or its pharmaceutically useful salt or its all steric isomer.
The present invention relates to the compound described in general formula (I), its pharmacy acceptable salt, the prodrug ester of its facile hydrolysis or its isomer and prepare the purposes in sodium-glucose transporter inhibitor.
Further, the present invention relates to the compound described in general formula (I), its pharmacy acceptable salt, the prodrug ester of its facile hydrolysis or its isomer are for the preparation for the treatment of or the purposes that delays in the medicine of following advancing of disease or outbreak, wherein said disease is selected from diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, the level of the rising of lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndrome, diabetic complication or atherosclerosis or hypertension.
The invention still further relates to a kind of treat the rising of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, lipid acid or glycerine level, hyperlipidaemia, obesity, hypertriglyceridemia, X syndrome, diabetic complication or atherosclerosis or hypertensive method, described method comprises the compound described in general formula (I) or its pharmaceutically useful salt or the steric isomer of the effective therapeutic dose of patient giving needs treatment.
The invention still further relates to as treatment or delay following advancing of disease or outbreak medicine general formula (I) described in compound or its pharmaceutically useful salt or its steric isomer, wherein said disease is selected from the level of the rising of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndrome, diabetic complication or atherosclerosis or hypertension.
Further again, the present invention relates to a kind of pharmaceutical composition, described composition comprises compound described in the general formula of effective dose (I) or its pharmaceutically useful salt or its all steric isomer and pharmaceutically useful carrier.This pharmaceutical composition is for the preparation for the treatment of or the purposes that delays in the medicine of following advancing of disease or outbreak, and wherein said disease is selected from the level of the rising of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndrome, diabetic complication or atherosclerosis or hypertension.
The invention still further relates to a kind of treat the rising of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, lipid acid or glycerine level, hyperlipidaemia, obesity, hypertriglyceridemia, X syndrome, diabetic complication or atherosclerosis or hypertensive method, described method comprise the effective therapeutic dose of patient giving needs treatment containing the pharmaceutical composition described in general formula (I).
The invention still further relates to as treatment or delay following advancing of disease or outbreak medicine containing the pharmaceutical composition described in general formula (I), wherein said disease is selected from the level of the rising of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndrome, diabetic complication or atherosclerosis or hypertension.
Detailed description of the invention
Unless there are other statements, following use term in the specification and in the claims has following implication.
" hydrogen " of the present invention, refers to protium (1H), and it is the major stable isotropic substance of protium.
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, atomic iodine.
" alkyl " of the present invention refers to that the paraffin section containing 1-8 carbon atom removes the alkyl of the straight or branched that a hydrogen atom derives, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methyl butyl, 3-methyl butyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethyl-butyl, 2-ethyl-butyl, 1, 1, 2-thmethylpropyl, 1, 2, 2-thmethylpropyl, 1-ethyl-1-methyl-propyl and 1-Ethyl-2-Methyl propyl group etc.Term " C 1-4alkyl " and " C 1-3alkyl " refer in above-mentioned example the specific examples containing 1-4 and 1-3 carbon atom.
" alkoxyl group " of the present invention refers to-O-(unsubstituted alkyl) and-O-(unsubstituted cycloalkyl) group, and it represents-O-(unsubstituted alkyl) further, and wherein the definition of alkyl is described above.Non-limiting example comprises methoxyl group, oxyethyl group, propoxy-, butoxy etc.
" alkylthio " of the present invention refers to-S-(unsubstituted alkyl) and-S-(unsubstituted cycloalkyl) group, and it represents-S-(unsubstituted alkyl) further, and wherein the definition of alkyl is described above.Embodiment comprises methylthio group, ethylmercapto group, rosickyite base etc. without limitation.
" hydroxyl " of the present invention refers to-OH group.
" amino " of the present invention refers to-NH 2group.
" cyano group " of the present invention refers to-CN group.
" pharmaceutically-acceptable salts " of the present invention refers to the salt of basic metal, alkaline-earth metal, ammonium, alkylammonium or inorganic or organic acid salt.The example can comprise sodium salt, sylvite, calcium salt, ammonium salt, aluminium salt, triethyl ammonium salt, formate, acetate, propionic salt, butyrates, trifluoroacetate, maleate, tartrate, Citrate trianion, stearate, succinate, ethylsuccinate, Lactobionate, gluconate, benzoate, mesylate, esilate, 2-isethionate, benzene sulfonate, tosilate, dodecyl sulfate, malate, aspartate, glutaminate, adipate, the salt of halfcystine, the salt of N-acetylcystein, hydrochloride, hydrobromate, phosphoric acid salt, vitriol, hydriodate, hydrochloride, oxalate, picrate, the salt formed with acrylic ester polymer.
" pharmaceutical composition " described in the present invention represent containing on one or more compounds described herein or its physiology/compound of pharmaceutically useful salt or prodrug or other chemical compositions, and other components such as physiology/pharmaceutically useful carrier or vehicle.The object of pharmaceutical composition promotes the administration to organism, is beneficial to the absorption of activeconstituents and then plays biological activity.
" prodrug " described in the present invention refers at the compound just after transforming in organism with pharmacological action.Prodrug itself does not have biological activity or activity very low, becomes activated material after internal metabolism.The object of this process is the bioavailability increasing medicine, strengthens targeting, reduces the Side effect etc. of medicine.
" isomer " described in the present invention comprises all differences to stereoisomerism, diastereo-isomerism and tautomeric form.When a key represents with a wedge, this to show that in three-dimensional this key will from paper out, and when a key is shade, this shows that this key will return in paper in three-dimensional.
The present invention is claimed further comprises arbitrary compound recited above, it will learn acceptable salt, the prodrug ester of its facile hydrolysis or the pharmaceutical composition of its isomer and other active pharmaceutical ingredients.
The present invention also comprises above-mentioned arbitrary compound, its pharmacy acceptable salt, the prodrug ester of its facile hydrolysis or its isomer, can be mixed with clinically by manner known in the art or pharmaceutically acceptable arbitrary formulation, with oral, parenteral, rectum or be applied to through modes such as lung administrations the patient needing this treatment.During for oral administration, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.When making oral preparations, the weighting agent of matters, tackiness agent, disintegrating agent, lubricant etc. can be added.During for administered parenterally, can injection be made, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When making injection, ordinary method in existing pharmacy field can be adopted to produce, during preparation injection, can not additives be added, also can add suitable additives according to the character of medicine.During for rectal administration, can be made into suppository etc.For through lung administration time, can be made into inhalation or sprays etc.
Present invention also offers the application because being subject to sodium glucose co-transporter 2 white matter SGLT2 to suppress disease or the illness affected in preparation treatment or prevention of the compounds of this invention, its pharmacy acceptable salt, the prodrug ester of its facile hydrolysis, its isomer or pharmaceutical composition.
Present invention also offers the compounds of this invention, its pharmacy acceptable salt, the prodrug ester of its facile hydrolysis, its isomer or pharmaceutical composition to be suitable for treating or the application of prevention metabolic disease in preparation.
Present invention also offers the compounds of this invention, its pharmacy acceptable salt, the prodrug ester of its facile hydrolysis, its isomer or pharmaceutical composition for the preparation for the treatment of or the purposes that delays in the medicine of following advancing of disease or outbreak, wherein said disease is selected from the rising of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndrome, diabetic complication or atherosclerosis or hypertension.
Present invention also offers the compounds of this invention, its pharmacy acceptable salt, the prodrug ester of its facile hydrolysis, its isomer or pharmaceutical composition in the purposes preparing sodium glucose co-transporter 2 white 2 (SGLT2) inhibitor.
The compounds of this invention has following characteristics:
(1) the compounds of this invention is remarkable to the restraining effect of white 2 (SGLT2) of sodium glucose co-transporter 2 and blood sugar reducing function, can be safely used to prevention and/treat the diabetes of various Mammals (comprising the mankind) and the various diseases caused by diabetes.
(2) the compounds of this invention shows good physico-chemical property, and toxicity is low, and side effect is little.
Accompanying drawing explanation
Below, describe embodiment of the present invention in detail by reference to the accompanying drawings, wherein:
Fig. 1 is that compound transports the inhibition test result of glucose to hSGLT2 in HEK293 transfection cell strain
Fig. 2 is the single-dose blood glucose curve of compound 10 in embodiment 1
Fig. 3 is the single-dose blood glucose curve of compound 13 in embodiment 4
Embodiment
Provide following Preparations and embodiment, enable those skilled in the art more clearly understand and implement the present invention.They should not be interpreted as limiting the scope of the invention, and are only its illustration and representative.
Synthetic example
Embodiment 1
(3R, 4S, 5S, 6R)-2-{3-[(5-(4-fluorophenyl) selenophen-2-base) methyl]-4-aminomethyl phenyl }-6-methylol-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol (7) and (2S, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-4-aminomethyl phenyl } synthesis of-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (10)
Steps A: by D-Glucose acid lactone (5.0g, 28.1mmol) with N-methylmorpholine (23.3g, 222mmol) be dissolved in THF (50mL), under ice-water bath, drip trimethylchlorosilane (18.3g, 168mmol).Continue stirring 1 hour after adding at such a temperature, be then naturally warmed up to stirred overnight at room temperature.Add toluene (200mL), under ice-water bath, in controlling, temperature is no more than 10 DEG C and drips frozen water (200mL).Layering, collected organic layer, water layer toluene (50mL) extracts.The organic layer merged washs with saturated biphosphate sodium water solution (70mL × 2), water (50mL) and saturated aqueous common salt (50mL) successively, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, obtain 2,3,4,6-tetra--O-trimethyl silicon based-D-Glucose acid lactone (1) (13.0g).Yield is 99.2%.
Step B: selenophen (6.76g, 28.7mmol) is dissolved in methylene dichloride (75mL), adds Hydrogen bromide (10), then under ice-water bath, adds NBS (5.08g, 28.5mmol) through about 40 minutes in batches.Finish, be naturally warmed up to room temperature and continue stirring 4 hours.Add water (50mL), layering, collected organic layer, water layer uses methylene dichloride (50mL) to extract again.Organic layers with water (20mL × 2) washing merged, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, obtain 2-bromine selenophen (2) (5.10g).Yield is 83.7%.
Step C: to containing compound 2 (2.50g, 11.9mmol), 4-fluorobenzoic boric acid (2.0g, sodium carbonate (3.79g is added in the mixture of 14.3mmol), toluene (100mL) and water (20mL), 35.8mmol) He four (triphenyl phosphorus) palladium (250mg, 0.216mmol), gained mixture under a nitrogen return stirring spend the night.Cool to room temperature, through diatomite filtration, filter cake a small amount of methyl tertiary butyl ether (MTBE) washs.Collect the organic layer in filtrate, water layer MTBE (40mL × 3) extracts.The organic over anhydrous dried over sodium sulfate merged.Remove solvent under reduced pressure, product, through column chromatography purification (200 ~ 300 order silica gel, sherwood oil wash-out), obtains 2-(4-fluorophenyl) selenophen (3) (1.80g).Yield is 67.2%.
Step D: 2-methyl-5-iodo-benzoic acid (2.0g, 7.63mmol) is dissolved in anhydrous methylene chloride (50mL), add sulfur oxychloride (10mL), gained mixture stirs 1 hour under reflux.Remove solvent under reduced pressure, add anhydrous methylene chloride (50mL), under ice-water bath, add Aluminum chloride anhydrous (1.22g, 9.15mmol) and compound 3 (1.80g successively, 7.99mmol), gained mixture at room temperature stirs and spends the night.Add water (30mL), layering, collected organic layer, water layer methylene dichloride (50mL) extraction, the organic over anhydrous dried over sodium sulfate of merging.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:10 ~ 1:5 wash-out), obtain [5-(4-fluorophenyl) selenophen-2-base] (the iodo-2-aminomethyl phenyl of 5-) ketone (4) (2.80g).Yield is 74.7%.
1H NMR(CDCl 3，400MHz)δ7.77(d，J＝2.0Hz，1H)，7.74-7.71(m，1H)，7.64-7.58(m，3H)，7.46-7.45(m，1H)，7.16-7.12(m，2H)，7.08-7.06(m，1H)，2.35(s，3H)。
Step e: compound 4 (2.6g, 5.54mmol) is dissolved in methyl alcohol (50mL), at room temperature adds sodium borohydride (630mg, 16.7mmol) in batches, finish, gained mixture at room temperature continues stirring 1.5 hours.With water (10mL) cancellation reaction, remove most of solvent under reduced pressure.Add water (30mL), with ethyl acetate (30mL × 3) extraction, organic layer saturated aqueous common salt (20mL) washing of merging, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, obtain [5-(4-fluorophenyl) selenophen-2-base] (the iodo-2-aminomethyl phenyl of 5-) methyl alcohol (5) (3.1g).This compound is not purified is directly used in next step reaction.
Step F: compound 5 crude product (3.1g) is dissolved in methylene dichloride (50mL), trifluoroacetic acid (2mL) is added under ice-water bath, then drip triethyl silicane (0.73g, 6.28mmol), gained mixture at room temperature stirs 0.5 hour.Add water (20mL), by saturated sodium bicarbonate aqueous solution adjust ph to neutral, layering, collected organic layer, water layer methylene dichloride (40mL) extracts.The organic layer merged saturated aqueous common salt (15mL) washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product, through column chromatography purification (200 ~ 300 order silica gel, sherwood oil wash-out), obtains 2-(4-fluorophenyl)-5-(the iodo-2-methyl-benzyl of 5-) selenophen (6) (2.2g).Step e and F two-step reaction total recovery are 87.2%.
1H NMR(CDCl 3，400MHz)δ7.59(d，J＝1.6Hz，1H)，7.54-7.52(m，1H)，7.47-7.43(m，2H)，7.20(d，J＝7.6Hz，1H)，7.06-6.94(m，2H)，6.88-6.87(m，1H)，6.86(d，J＝1.6Hz，1H)，4.13(s，2H)，2.30(s，3H)。
Step G: by compound 6 (1.5g, 3.29mmol) with compound 1 (1.85g, 3.96mmol) be dissolved in anhydrous THF (15mL), under-40 ~-60 DEG C and nitrogen, drip 0.5M (trimethyl silane) to methylate lithium (13.2mL, 6.6mmol), after adding, continue stirring 2 hours.Then drip methyl alcohol (15mL) solution of methanesulfonic (1.3mL, 20.0mmol) at such a temperature, be naturally warmed up to stirred overnight at room temperature.Add saturated aqueous common salt (70mL), with ethyl acetate (30mL × 3) extraction, organic layer saturated aqueous common salt (20mL) washing of merging, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:20 ~ 8:1 wash-out), obtain (3R, 4S, 5S, 6R)-2-{3-[(5-(4-fluorophenyl) selenophen-2-base) methyl]-4-aminomethyl phenyl }-6-methylol-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol (7) (1.2g).Yield is 58.3%.
1H NMR(CD 3OD，400MHz)δ7.43(d，J＝1.6Hz，1H)，7.36-7.30(m，3H)，7.10-7.05(m，2H)，6.92-6.88(m，2H)，6.76(d，J＝5.0Hz，1H)，4.09-4.07(m，2H)，3.88-3.84(m，1H)，3.78-3.69(m，2H)，3.53-3.50(m，1H)，3.40-3.36(m，1H)，3.07(s，1H)，3.02(s，3H)，2.17(s，3H)。MS(EI，m/z)：545.2[M+Na] +。
Step H: by compound 7 (1.2g, 2.30mmol) be dissolved in methylene dichloride (12mL), then under-30 ~-40 DEG C and nitrogen, triethyl silicane (0.8g is added, 6.85mmol), drip boron trifluoride diethyl etherate (0.98g again, 6.90mmol), after adding, be naturally warmed up to stirred overnight at room temperature.Remove solvent under reduced pressure, add water (25mL), with ethyl acetate (25mL × 3) extraction, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:1 ~ 8:1 wash-out), obtain (3R, 4R, 5S, 6R)-2-{3-[(5-(4-fluorophenyl) selenophen-2-base) methyl]-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (8) (810mg).Yield is 71.7%.
Step I: by compound 8 (350mg, 0.712mmol) be dissolved in THF (10mL), add N-methylmorpholine (432mg, 4.27mmol) with DMAP (8.7mg, 0.071mmol), then under ice-water bath, drip diacetyl oxide (437mg, 4.28mmol), stir and be naturally warmed up to stirred overnight at room temperature after 0.5 hour.Remove solvent under reduced pressure, add ethyl acetate (40mL), gained solution uses 10% citric acid (10mL), saturated sodium bicarbonate aqueous solution (10mL) and saturated aqueous common salt (5mL) to wash successively, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, obtain 450mg off-white color solid.By this solid suspension in ethanol (4.5mL), be warmed up to and reflux and continue stirring 0.5 hour, be then slowly cooled to room temperature, filter, collect filter cake.Ethanol (13.5mL) recrystallization used again by filter cake, obtain (2R, 3R, 4R, 5S, 6S)-2-acetyl-o-methyl-6-{3-[(5-(4-fluorophenyl) selenophen-2-base) methyl]-4-aminomethyl phenyl } tetrahydrochysene-2H-pyrans-3,4,5-triacetate (9) (275mg).Yield is 58.5%.
Step J: by compound 9 (275mg, 0.417mmol) be suspended in the mixture of THF (4mL), methyl alcohol (6mL) and water (2mL), add hydronium(ion) Lithium Oxide 98min (26mg, 0.620mmol), gained mixture at room temperature stirs 2 hours.Remove most of solvent under reduced pressure.Add water (10mL), with 2M salt acid for adjusting pH value to 2 ~ 3, ethyl acetate (15mL × 3) extracts, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:1 ~ 8:1 wash-out), obtain (2S, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (10) (170mg).Yield is 83.0%.
1H NMR(CD 3OD，400MHz)δ7.40-7.36(m，2H)，7.22(d，J＝1.2Hz，1H)，7.16-7.14(m，2H)，7.07-7.05(m，1H)，6.97-6.93(m，2H)，6.79-6.78(m，1H)，4.10(s，2H)，4.03-4.00(m，1H)，3.80-3.77(m，1H)，3.62-3.59(m，1H)，3.35-3.20(m，4H)，2.21(s，3H)。MS(EI，m/z)：493.1[M+H] +，515.1[M+Na] +。
Embodiment 2
(2S, 3R, 4R, 5S, 6R)-2-{3-{ [5-(3,4-difluorophenyl) selenophen-2-base] methyl }-4-aminomethyl phenyl } synthesis of-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (11)
Preparation method is see embodiment 1, and wherein in embodiment 1 step C, 4-fluorobenzoic boric acid 3,4-difluorobenzene boric acid substitutes.
1H NMR(CD 3OD，500MHz)δ7.40-7.36(m，1H)，7.31(s，1H)，7.28(d，J＝4.0Hz，1H)，7.25-7.23(m，2H)，7.22-7.14(m，2H)，6.90(d，J＝3.5Hz，1H)，4.20-4.19(m，2H)，4.12-4.10(m，1H)，3.89-3.87(m，1H)，3.71-3.68(m，1H)，3.47-3.36(m，4H)，2.29(s，3H)。MS(EI，m/z)：533.1[M+Na] +。
Embodiment 3
(2S, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-chloro-phenyl-) selenophen-2-base] methyl }-4-aminomethyl phenyl } synthesis of-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (12)
Preparation method is see embodiment 1, and wherein in embodiment 1 step C, 4-fluorobenzoic boric acid 4-chlorophenylboronic acid substitutes.
1H NMR(CD 3OD，500MHz)δ7.46-7.44(m，2H)，7.31-7.29(m，4H)，7.25-7.24(m，1H)，7.16-7.14(m，1H)，6.90-6.89(m，1H)，4.23-4.19(m，2H)，4.16-4.08(m，1H)，3.89-3.87(m，1H)，3.71-3.68(m，1H)，3.48-3.36(m，4H)，2.30(s，3H)。MS(EI，m/z)：531.0[M+Na] +。
Embodiment 4
The chloro-3-{ of (2S, 3R, 4R, 5S, 6R)-2-{4-[5-(4-fluorophenyl) selenophen-2-base] methyl } phenyl } synthesis of-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (13)
Preparation method is see embodiment 1, and wherein in embodiment 1 step D, the chloro-5-iodo-benzoic acid of 2-methyl-5-iodo-benzoic acid 2-substitutes.
1H NMR(CD 3OD，500MHz)δ7.50-7.47(m，3H)，7.38-7.36(m，1H)，7.33-7.30(m，1H)，7.24-7.23(m，1H)，7.06-7.02(m，2H)，6.98-6.97(m，1H)，4.35-4.27(m，2H)，4.13-4.08(m，1H)，3.89-3.86(m，1H)，3.71-3.68(m，1H)，3.47-3.38(m，4H)。MS(EI，m/z)：547.0[M+Cl] -。
Embodiment 5
(2S, 3R, 4R, 5S, 6R)-2-methylol-6-{4-methyl-3-[(5-phenyl-selenophen-2-base) methyl] phenyl } synthesis of tetrahydrochysene-2H-pyrans-3,4,5-triol (14)
Preparation method is see embodiment 1, and wherein in embodiment 1 step C, 4-fluorobenzoic boric acid phenylo boric acid substitutes.
1H NMR(CD 3OD，500MHz)δ7.46-7.45(m，2H)，7.32-7.28(m，4H)，7.24-7.19(m，2H)，7.16-7.14(m，1H)，6.89-6.88(m，1H)，4.23-4.16(m，2H)，4.12-4.08(m，1H)，3.89-3.87(m，1H)，3.71-3.68(m，1H)，3.48-3.36(m，4H)，2.31(s，3H)。MS(EI，m/z)：473.1[M-H] -。
Embodiment 6
(2S, 3R, 4R, 5S, 6R)-2-{5-[(5-(4-fluorophenyl) selenophen-2-base) methyl]-2-methoxyl group-4-aminomethyl phenyl } synthesis of-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (24)
Steps A: by 2-methyl-4-HBA (3.04g, 20.0mmol) be dissolved in DMF (50mL), add methyl iodide (9.12g, 64.2mmol) and salt of wormwood (8.28g, 60.0mmol), gained mixture spends the night 50 DEG C of stirrings.Cool to room temperature, adds water (200mL), extracts with MTBE (50mL × 3).Organic layers with water (30mL × 3) washing merged, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, obtain 4-methoxyl group-2-methyl-toluate (15) (3.89g).This product is not purified is directly used in next step reaction.
Step B: compound 15 crude product (3.66g) is dissolved in methyl alcohol (73mL), adds iodine (5.0g, 19.7mmol) and Silver Nitrate (5.14g, 30.3mmol), and gained mixture stirs and spends the night at 30 DEG C.Cross and filter insolubles, filter cake washs by a small amount of ethyl acetate again, collects filtrate.Remove most of solvent under reduced pressure, then use ethyl acetate (80mL) to dissolve, with water (20mL × 2) washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product, through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:25 ~ 1:10 wash-out), obtains the iodo-4-methoxyl group of 5--2-methyl-toluate (16) (5.7g).Steps A and B two-step reaction total recovery are 99%.
1H NMR(CDCl 3，500MHz)δ8.37(s，1H)，6.64(s，1H)，3.92(s，3H)，3.86(s，3H)，2.60(s，3H)。
Step C: compound 16 (2.4g, 7.84mmol) is dissolved in methyl alcohol (50mL), add THF (25mL) and 4M aqueous sodium hydroxide solution (25mL), gained mixture at room temperature stirs 5 hours.Remove most of solvent under reduced pressure, add water (50mL), with 2M salt acid for adjusting pH value to 2 ~ 3, with ethyl acetate (40mL × 3) extraction, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, obtain the iodo-4-methoxyl group of 5--2-tolyl acid (17) (2.1g).Yield is 91.7%.
Step D: compound 17 (1.26g, 4.31mmol) is dissolved in anhydrous methylene chloride (50mL), add sulfur oxychloride (15mL), gained mixture stirs 1 hour under reflux.Remove solvent under reduced pressure, then add anhydrous methylene chloride (50mL), under ice-water bath, add Aluminum chloride anhydrous (750mg, 5.62mmol) and compound 3 (970mg, 4.31mmol) successively.Naturally be warmed up to room temperature, gained mixture at room temperature stirs and spends the night.Add water (30mL), layering, collected organic layer, water layer methylene dichloride (50mL) extraction, the organic over anhydrous dried over sodium sulfate of merging.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:10 ~ 1:2 wash-out), obtain [5-(4-fluorophenyl) selenophen-2-base]-(the iodo-4-methoxyl group of 5--2-aminomethyl phenyl) ketone (18) (1.50g).Yield is 69.7%.
1H NMR(CDCl 3，500MHz)δ7.92(s，1H)，7.61-7.58(m，3H)，7.43(d，J＝4.5Hz，1H)，7.13-7.09(m，2H)，6.73(s，1H)，3.94(s，3H)，2.42(s，3H)。
Step e: by compound 18 (1.50g, 3.0mmol) be dissolved in methyl alcohol (30mL) and methylene dichloride (30mL), add sodium borohydride (1.14g, 30.2mmol) under room temperature, gained mixture at room temperature continues stirring 1.5 hours in batches.With water (7mL) cancellation reaction, remove most of solvent under reduced pressure.Then water (30mL) is added, with dichloromethane extraction (30mL × 3), organic layer saturated aqueous common salt (20mL) washing of merging, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, obtain [5-(4-fluorophenyl) selenophen-2-base]-(the iodo-4-methoxyl group of 5--2-aminomethyl phenyl) methyl alcohol (19) (1.6g).This compound is not purified is directly used in next step reaction.
Step F: compound 19 crude product (1.6g) is dissolved in methylene dichloride (50mL), trifluoroacetic acid (2mL) is added under ice-water bath, then drip triethyl silicane (870mg, 7.48mmol), gained mixture at room temperature stirs 0.5 hour.Add water (20mL), by saturated sodium bicarbonate aqueous solution adjust ph to neutral.Layering, collected organic layer, water layer methylene dichloride (50mL) extracts.The organic layer merged saturated aqueous common salt (20mL) washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:100 wash-out), obtain 2-(4-fluorophenyl)-5-(the iodo-4-methoxyl group of 5--2-methyl-benzyl) selenophen (20) (1.3g).Step e and F two-step reaction total recovery are 89.3%.
1H NMR(CDCl 3，400MHz)δ7.63(s，1H)，7.46-7.43(m，2H)，7.19(d，J＝4.0Hz，1H)，7.05-7.01(m，2H)，6.87-6.86(m，1H)，6.67(s，1H)，4.09(s，2H)，3.89(s，3H)，2.32(s，3H)。
Step G: by compound 20 (300mg, 0.618mmol) with compound 1 (375mg, 0.803mmol) be dissolved in anhydrous THF (5mL), under-40 ~-60 DEG C and nitrogen, drip 0.5M (trimethyl silane) to methylate lithium (2.5mL, 1.25mmol).After adding, continue stirring 2.5 hours, gained mixture drips methyl alcohol (4mL) solution of methanesulfonic (0.24mL, 3.69mmol) at such a temperature, is then naturally warmed up to stirred overnight at room temperature.Add saturated aqueous common salt (20mL), extract by ethyl acetate (15mL × 3).The organic layer merged saturated aqueous common salt (10mL) washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:1 ~ 8:1 wash-out), obtain (3R, 4S, 5S, 6R)-2-{5-[(5-(4-fluorophenyl) selenophen-2-base) methyl]-2-methoxyl group-4-aminomethyl phenyl }-6-methylol-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol (21) (110mg).Yield is 32.3%.
Step H: by compound 21 (100mg, 0.181mmol) be dissolved in methylene dichloride (20mL), under-30 ~-40 DEG C and nitrogen, add triethyl silicane (64mg, 0.55mmol), drip boron trifluoride diethyl etherate (77mg, 0.543mmol) again.After adding, be naturally warmed up to room temperature and continue stirring 6 hours.Add water (15mL), layering, collected organic layer, water layer methylene dichloride (15mL × 2) extraction, the organic over anhydrous dried over sodium sulfate of merging.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:1 ~ 8:1 wash-out), obtain (3R, 4R, 5S, 6R)-2-{5-[(5-(4-fluorophenyl) selenophen-2-base) methyl]-2-methoxyl group-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (22) (60mg).Yield is 63.6%.
Step I: by compound 22 (60mg, 0.115mmol) be dissolved in THF (10mL), add N-methylmorpholine (0.50mL) and DMAP (10mg, 0.082mmol), then under ice-water bath, drip diacetyl oxide (0.5mL), stir and be naturally warmed up to stirring at room temperature 6 hours after 0.5 hour.Remove solvent under reduced pressure.Add ethyl acetate (30mL), then use 10% citric acid (5mL), saturated sodium bicarbonate aqueous solution (5mL) and saturated aqueous common salt (5mL) to wash successively, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, obtain 100mg off-white color solid.By this solid suspension in ethanol (3mL), be warmed up to and reflux and continue stirring 0.5 hour, be then slowly cooled to room temperature, filter, collect filter cake, obtain (2R, 3R, 4R, 5S, 6S)-2-acetyl-o-methyl-6-{5-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-2-methoxyl group-4-aminomethyl phenyl } tetrahydrochysene-2H-pyrans-3,4,5-triacetate (23) (50mg).Yield is 63.1%.
Step J: by compound 23 (50mg, 0.0725mmol) be suspended in the mixture of THF (2mL), methyl alcohol (3mL) and water (2mL), add hydronium(ion) Lithium Oxide 98min (5mg, 0.119mmol), gained mixture at room temperature stirs 1 hour.Add water (15mL), with 2M salt acid for adjusting pH value to 2 ~ 3, ethyl acetate (15mL × 3) extracts, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=4:1 wash-out), obtain (2S, 3R, 4R, 5S, 6R)-2-{5-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-2-methoxyl group-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (24).
1H NMR(CD 3OD，400MHz)δ7.52-7.48(m，2H)，7.32(s，1H)，7.25(d，J＝3.6Hz，1H)，7.09-7.04(m，2H)，6.89(d，J＝3.6Hz，1H)，6.83(s，1H)，4.67(d，J＝9.2Hz，1H)，4.16(s，2H)，3.89-3.84(m，4H)，3.71-3.69(m，1H)，3.60-3.48(m，2H)，3.42-3.40(m，2H)，2.33(s，3H)。MS(EI，m/z)：545.1[M+Na] +。
Embodiment 7
(2S, 3R, 4R, 5S, 6R)-2-{5-[(5-(4-ethyl-sulfide phenyl) selenophen-2-base) methyl]-2-methoxyl group-4-aminomethyl phenyl } synthesis of-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (25)
By the return stirring 6 hours under a nitrogen of the mixture containing compound 23 (50mg, 0.0725mmol), sulfur alcohol sodium (20mg, 0.238mmol) and toluene (2mL).Be cooled to room temperature, add water (10mL), stir 20 minutes.Ethyl acetate (10mL × 3) extraction of gained mixture, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=3:1 wash-out), obtain (2S, 3R, 4R, 5S, 6R)-2-{5-[(5-(4-ethyl-sulfide phenyl) selenophen-2-base) methyl]-2-methoxyl group-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (25).
1H NMR(CD 3OD，300MHz)δ7.50-7.45(m，2H)，7.23-7.22(m，2H)，7.06-7.00(m，2H)，6.88(d，J＝3.6Hz，1H)，6.81(s，1H)，4.63(d，J＝9.3Hz，1H)，4.42-4.38(m，1H)，4.19-4.13(m，3H)，3.81(s，3H)，3.57-3.50(m，3H)，3.47-3.35(m，2H)，2.30(s，3H)，1.99(s，3H)。MS(EI，m/z)：587.2[M+Na] +。
Embodiment 8
4-{5-{2-methyl-5-[(2S, 3R, 4R, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-base] phenyl } selenophen-2-base } synthesis of cyanobenzene (33)
Steps A: to containing compound 2 (14.7g, 70.0mmol), 4-cyanophenylboronic acid (12.35g, cesium carbonate (57.04g is added in the mixture of 84.0mmol), glycol dimethyl ether (150mL), ethanol (150mL) and water (150mL), 175.1mmol) He four (triphenyl phosphorus) palladium (1.47g, 1.27mmol), gained mixture under a nitrogen return stirring spend the night.Cool to room temperature, through diatomite filtration, a small amount of MTBE of filter cake washs.Collect the organic layer in filtrate, water layer MTBE (400mL × 3) extracts.The organic over anhydrous dried over sodium sulfate merged.Remove solvent under reduced pressure, product, through column chromatography purification (200 ~ 300 order silica gel, sherwood oil wash-out), obtains 2-(4-cyano-phenyl) selenophen (26) (8.3g).Yield is 51.1%.
Step B, C, D and E are respectively see the step D in embodiment 1, E, F and G.
Step F: by compound 30 (3.5g, 6.62mmol) be dissolved in THF (150mL), add N-methylmorpholine (13.4g, 132mmol) with DMAP (80.8mg, 0.661mmol), then under ice-water bath, drip diacetyl oxide (13.53g, 132mmol), stir and be naturally warmed up to stirring at room temperature 7 hours after 0.5 hour.Remove solvent under reduced pressure, add ethyl acetate (200mL), use saturated sodium bicarbonate aqueous solution (50mL) and saturated aqueous common salt (50mL) washing successively, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:5 ~ 1:2 wash-out), obtain (3R, 4S, 5R, 6R)-6-acetyl-o-methyl-2-{3-[(5-(4-cyano-phenyl) selenophen-2-base) methyl]-4-aminomethyl phenyl }-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triacetate (31) (2.9g).Yield is 62.9%.
Step G: by compound 31 (2.9g, 4.16mmol) be dissolved in methylene dichloride (100mL), then under-30 ~-40 DEG C and nitrogen, triethyl silicane (1.45g is added, 12.5mmol), drip boron trifluoride diethyl etherate (1.78g again, 12.5mmol), after adding, be naturally warmed up to stirring at room temperature 6 hours.Add water (100mL), layering, collected organic layer, water layer methylene dichloride (100mL) extraction, the organic over anhydrous dried over sodium sulfate of merging.Remove solvent under reduced pressure, product, through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:5 wash-out), obtains 1.9g white solid.By this solid suspension in ethanol (19mL), be warmed up to and reflux and continue stirring 0.5 hour, be then slowly cooled to room temperature, filter, collect filter cake.Ethanol (19mL) recrystallization used again by filter cake, obtain (2R, 3R, 4R, 5S, 6S)-2-acetyl-o-methyl-6-{3-[(5-(4-cyano-phenyl) selenophen-2-base) methyl]-4-aminomethyl phenyl } tetrahydrochysene-2H-pyrans-3,4,5-triacetate (32) (1.4g).Yield is 50.5%.
Step H: by compound 32 (1.4g, 2.10mmol) be suspended in the mixture of THF (30mL), methyl alcohol (30mL) and water (20mL), hydronium(ion) Lithium Oxide 98min (132mg is added under ice-water bath, 3.15mmol), gained mixture stirs 1.5 hours at such a temperature.Remove most of solvent under reduced pressure.Add water (100mL), with 2M salt acid for adjusting pH value to 2 ~ 3, ethyl acetate (50mL × 3) extracts, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:1 ~ 8:1 wash-out), obtain 4-{5-{2-methyl-5-[(2S, 3R, 4R, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-bases] phenyl } selenophen-2-base } cyanobenzene (33) (885mg).Yield is 84.6%.
1H NMR(CD 3OD，500MHz)δ7.64(s，4H)，7.51(d，J＝3.5Hz，1H)，7.32(s，1H)，7.25(d，J＝3.5Hz，1H)，7.15(d，J＝3.0Hz，1H)，6.97(d，J＝3.5Hz，1H)，4.26-4.19(m，2H)，4.12-4.10(m，1H)，3.89-3.86(m，1H)，3.71-3.68(m，1H)，3.48-3.35(m，4H)，2.21(s，3H)。MS(EI，m/z)：522.1[M+Na] +。
Embodiment 9
(3R, 4S, 5S, 6R)-2-{5-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-2-hydroxy-4-methyl phenyl }-6-methylol-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol (36) and (2S, 3R, 4R, 5S, 6R)-2-{5-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-2-hydroxy-4-methyl phenyl } synthesis of-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (37)
Steps A: by compound 20 (900mg, 1.86mmol) be dissolved in anhydrous methylene chloride (40mL), then under ice-water bath, add the dichloromethane solution (1.4mL) of 4.0M boron tribromide, gained mixture at room temperature stirs 2 hours.Reaction solution is poured into water.Layering, collects organic phase, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product, through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:30 wash-out), obtains the iodo-2-methyl-toluate (34) (600mg) of 4-hydroxyl-5-.Yield is 68.6%.
Step B: by compound 34 (400mg, 0.849mmol) be dissolved in acetone (40mL), add chloromethyl methyl ether (102mg, 1.267mmol) and salt of wormwood (176mg, 1.275mmol), gained mixture at room temperature stirs and spends the night.Remove most of solvent under reduced pressure, add water (20mL), with ethyl acetate (15mL × 3) extraction, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, sherwood oil wash-out), obtain 2-(the fluorine-based base of 4-)-5-[the iodo-4-of 5-(methoxymethoxy)-2-methyl-benzyl] selenophen (35) (380mg).Yield is 86.9%.
MS(EI，m/z)：516.1[M+Na] +。
Step C: by compound 35 (380mg, 0.738mmol) with compound 1 (448mg, 0.960mmol) be dissolved in anhydrous THF (5mL), under-40 ~-60 DEG C and nitrogen, drip 0.5M (trimethyl silane) to methylate lithium (3mL, 1.5mmol).After adding, continue stirring 2.5 hours, gained mixture drips methyl alcohol (4mL) solution of methanesulfonic (0.3mL) at such a temperature, is then naturally warmed up to stirred overnight at room temperature.Add saturated aqueous common salt (20mL), extract by ethyl acetate (15mL × 3).The organic layer merged saturated aqueous common salt (10mL) washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=4:1 wash-out), obtain (3R, 4S, 5S, 6R)-2-{5-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-2-hydroxy-4-methyl phenyl }-6-methylol-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol (36) (150mg).Yield is 37.8%.
1H NMR(CD 3OD，500MHz)δ7.47-7.45(m，2H)，7.36(m，1H)，7.22(d，J＝3.8Hz，1H)，7.05-7.01(m，2H)，6.86(d，J＝3.8Hz，1H)，6.65(s，1H)，4.16-4.06(m，2H)，3.88-3.87(m，2H)，3.80-3.76(m，1H)，3.65-3.62(m，1H)，3.53-3.49(m，1H)，3.37-3.35(m，1H)，3.19(s，3H)，2.22(s，3H)。MS(EI，m/z)：561.1[M+Na] +。
Step D: by compound 36 (150mg, 0.279mmol) be dissolved in methylene dichloride (10mL), then under-30 ~-40 DEG C and nitrogen, triethyl silicane (98mg is added, 0.840mmol), drip boron trifluoride diethyl etherate (119mg, 0.838mmol) again.After adding, be naturally warmed up to room temperature and continue stirring 6 hours.Add water (15mL), layering, collected organic layer, water layer methylene dichloride (15mL × 2) extraction, the organic over anhydrous dried over sodium sulfate of merging.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=3:1 ~ 50:1 wash-out), products therefrom utilizes petrol ether/ethyl acetate recrystallization, obtains (2S, 3R, 4R, 5S, 6R)-2-{5-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-2-hydroxy-4-methyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (37) (24mg).Yield is 17.0%.
1H NMR(CD 3OD，300MHz)δ7.52-7.47(m，2H)，7.25-7.24(m，2H)，7.09-7.03(m，2H)，6.88(d，J＝3.9Hz，1H)，6.68(s，1H)，4.12(s，2H)，3.91-3.87(m，1H)，3.76-3.71(m，1H)，3.62-3.43(m，5H)，2.24(s，3H)。MS(EI，m/z)：531.1[M+Na] +。
Embodiment 10
(2S, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl)-1,3-selenazoles-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (50) and (2R, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl)-1,3-selenazoles-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3, the synthesis of 4,5-triol (51)
Steps A: 4-fluoro acetophenone (3.0g, 21.7mmol) is dissolved in acetic acid (10mL), then drips bromine (3.47g, 21.7mmol), gained mixture at room temperature stirs 4 hours.Add water (50mL), with ethyl acetate (30mL × 3) extraction, organic layer saturated aqueous common salt (15mL × 2) washing of merging, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, products therefrom sherwood oil recrystallization, obtain the bromo-1-of 2-(4-fluorophenyl) ethyl ketone (38) (2.2g).Yield is 46.7%.
Step B: be suspended in by selenium powder (5.11g, 64.7mmol) in dehydrated alcohol (100mL), add sodium borohydride (2.94g, 77.7mmol) in batches at 0 ~ 5 DEG C, continues stirring 30 minutes at such a temperature after adding.Then in mixture, slowly instill Butyltriphenylphosphonium chloride (10g, 64.7mmol), add rear continuation stirring 30 minutes.Add dehydrated alcohol (50mL) solution of iodine (8.2g, 32.3mmol) and potassiumiodide (2.15g, 13.0mmol) again, continue stirring 30 minutes.Remove solvent under reduced pressure, add water (200mL), with methylene dichloride (100mL × 2) extraction, organic phase 1% sodium bicarbonate aqueous solution (40mL × 2) washing of mixing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, products therefrom methylene dichloride/sherwood oil recrystallization, obtain 4-tolyl acid and cross two selenic anhydrides (39) (9.0g).Yield is 70.2%.
Step C: compound 39 (9.0g, 22.7mmol) is dissolved in benzene (50mL), add 1M potassium hydroxide methanol solution (21mL), gained mixture at room temperature stirs 20 minutes.Remove solvent under reduced pressure, add sherwood oil (60mL), filter to obtain mixture (40) (6.7g) of 4-tolyl acid selenium potassium and selenium.Yield is 93.3%.
Step D: by the mixture of diethyl malonate (74.1g, 462.6mmol) and sodium (2.56g, 111.3mmol) under a nitrogen 50 DEG C be stirred to solid and all dissolve.Then add 3-bromo-4-methyl oil of mirbane (10g, 46.29mmol), gained mixture heats up and spends the night 70 DEG C of stirrings.Remove most of solvent under reduced pressure, then add ethyl acetate (50mL) dilution.Under ice-water bath, this mixed solution is poured in 1M hydrochloric acid again, with ethyl acetate (100mL × 3) extraction, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:50 ~ 1:10 wash-out), obtain 2-(2-dimethyl-5-nitrophenyl) ethyl maleate (41) (10.0g).Yield is 73.2%.
Step e: compound 41 (10.0g, 33.9mmol) is dissolved in methyl alcohol (60mL), then adds 25% sodium hydroxide (20mL), and gained mixture at room temperature stirs and spends the night.Remove partial solvent under reduced pressure, then add water (100mL), with MTBE (30mL × 2) washing, collect aqueous phase.Aqueous phase dilute hydrochloric acid adjust ph to 2 ~ 3, then use ethyl acetate (50mL × 3) to extract, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, obtain 2-(2-dimethyl-5-nitrophenyl) toxilic acid (42) (7.0g).This compound is not purified is directly used in next step reaction.
Step F: by the mixture of compound 42 crude product (7.0g) and toluene (70mL) at nitrogen and stirred at reflux 3 hours.Remove partial solvent under reduced pressure, gained mixture cool to room temperature, then be cooled to 0 ~ 5 DEG C with ice-water bath.Filter, obtain 2-(2-dimethyl-5-nitrophenyl) acetic acid (43) (4.0g).Step e and F two-step reaction total recovery are 60.5%.
Step G: be suspended in by compound 43 (2.7g, 13.8mmol) in methylene dichloride (30mL), add sulfur oxychloride (6mL) and DMF (2), gained mixture stirs 1 hour under reflux.Remove solvent under reduced pressure, add anhydrous THF (30mL), be then added dropwise in strong aqua (30mL) at 0 ~ 5 DEG C, add rear continuation stirring 10 minutes.Remove about half solvent under reduced pressure, add water (50mL), extract by ethyl acetate (30mL × 3), remove solvent under reduced pressure, product, through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:1 ~ 5:1 wash-out), adds toluene (50mL) and Vanadium Pentoxide in FLAKES (9.8g in products obtained therefrom, 69.0mmol), gained mixture stirs under reflux and spends the night.Cool to room temperature, filter, filter cake ethyl acetate is washed, and closes organic liquid.Remove solvent under reduced pressure, product, through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:20 ~ 1:10 wash-out), obtains 2-(2-methyl-5-nitrophenyl) acetonitrile (44) (1.1g).Yield is 47.7%.
1H NMR(DMSO-d 6，300MHz)δ8.26(s，1H)，8.12-8.11(m，1H)，7.55(d，J＝8.4Hz，1H)，4.19(s，2H)，2.43(s，3H)。
Step H: by compound 44 (1.2g, 6.81mmol) be dissolved in anhydrous THF (20mL), add compound 40 (6.5g, 20.6mmol), then under 0 ~ 5 DEG C and nitrogen, boron trifluoride diethyl etherate (4.8g is dripped, 33.8mmol), stirring 6 hours is continued after adding at such a temperature.Reaction solution is poured in frozen water, extract by ethyl acetate (20mL × 3), remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:5 ~ 1:1 wash-out), obtain 2-(2-methyl-5-nitrophenyl) seleno ethanamide (45) (1.1g).Yield is 62.8%.
1H NMR(DMSO-d 6，300MHz)δ10.60(s，1H)，10.19(s，1H)，8.16(s，1H)，8.03(d，J＝8.4Hz，1H)，7.45(d，J＝8.4Hz，1H)，4.03(s，2H)，2.41(s，3H)。
Step I: the mixture containing compound 38 (840mg, 3.87mmol), compound 45 (1.0g, 3.89mmol) and ethanol (50mL) is stirred 3 hours under reflux.Remove solvent under reduced pressure, products therefrom sherwood oil recrystallization, obtain 5-(4-fluorophenyl)-2-(2-methyl-5-nitro benzyl)-1,3-selenazoles (46) (1.7g).This compound is not purified is directly used in next step reaction.
Step J: compound 46 crude product (1.7g) is dissolved in DMF (30mL), adds 5% palladium carbon (340mg), and gained mixture spends the night 50 DEG C of hydrogenated at normal pressure reactions.By diatomite filtration, in filtrate, add water (120mL), with ethyl acetate (20mL × 3) extraction, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:4 ~ 1:3 wash-out), obtain 3-{ [5-(4-fluorophenyl)-1,3-selenazoles-2-base] methyl }-4-monomethylaniline (47) (880mg).Step I and J two-step reaction total recovery are 65.9%.
Step K: by compound 47 (780mg, 2.26mmol) be dissolved in the mixture of sulfuric acid (5mL) and water (50mL), Sodium Nitrite (163.7mg is dripped at 0 ~ 5 DEG C, water (5mL) solution 2.37mmol), drips rear continuation stirring 10 minutes.Then in this reaction solution, drip water (15mL) solution of potassiumiodide (1.125g, 6.78mmol), after dripping, at 0 ~ 5 DEG C, continue stirring 1 hour.With ethyl acetate (20mL × 3) extraction, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:100 wash-out), obtain 5-(4-fluorophenyl)-2-(the iodo-2-methyl-benzyl of 5-)-1,3-selenazoles (48) (620mg).Yield is 60.1%.
1H NMR(DMSO-d 6，300MHz)δ8.48(s，1H)，7.98-7.93(m，2H)，7.74(s，1H)，7.58-7.55(m，1H)，7.27-7.21(m，2H)，7.05-7.03(m，1H)，4.33(s，2H)，2.27(s，3H)。
Step L: by compound 48 (300mg, 0.657mmol) with compound 1 (399mg, 0.855mmol) be dissolved in anhydrous THF (2mL), under-40 ~-60 DEG C and nitrogen, drip 0.5M (trimethyl silane) to methylate lithium (2.6mL, 1.30mmol).After adding, continue stirring 2 hours, gained mixture drips methyl alcohol (2mL) solution of methanesulfonic (0.26mL, 4.00mmol) at such a temperature, is then naturally warmed up to stirred overnight at room temperature.Add saturated aqueous common salt (20mL), extract by ethyl acetate (15mL × 3).The organic layer merged saturated aqueous common salt (10mL) washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:5 wash-out), obtain (3R, 4S, 5S, 6R)-2-{5-[(5-(the fluoro-phenyl of 4-)-selenophen-2-base) methyl]-2-methoxyl group-4-methylphenyl }-6-methylol-2-methoxy-tetrahydro-2H-pyrans-3,4,5-triol (49) (200mg).Yield is 58.3%.MS(EI，m/z)：546.1[M+Na] +。
Step M: by compound 49 (170mg, 0.325mmol) be dissolved in methylene dichloride (20mL), then under-30 ~-40 DEG C and nitrogen, triethyl silicane (113mg is added, 0.972mmol), drip boron trifluoride diethyl etherate (138mg, 0.972mmol) again.After adding, be naturally warmed up to room temperature and continue stirring 6 hours.Add water (15mL), collected organic layer, water layer methylene dichloride (15mL × 2) extraction, the organic over anhydrous dried over sodium sulfate of merging.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=1:1 ~ 4:1 wash-out), obtain (2S, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl)-1,3-selenazoles-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (50) and (2R, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl)-1,3-selenazoles-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (51).
Compound 50 1h NMR (CD 3oD, 300MHz) δ 8.16 (s, 1H), 7.92-7.87 (m, 2H), 7.41 (s, 1H), 7.32-7.30 (m, 1H), 7.21-7.19 (m, 1H), 7.15-7.09 (m, 2H), 4.34 (s, 2H), 4.15-4.12 (m, 1H), 3.90-3.86 (m, 1H), 3.73-3.67 (m, 1H), 3.48-3.33 (m, 4H), 2.31 (s, 3H).MS(EI，m/z)：516.1[M+Na] +。
Compound 51 1h NMR (CD 3oD, 300MHz) δ 8.17 (s, 1H), 7.93-7.89 (m, 2H), 7.45 (s, 1H), 7.36-7.32 (m, 1H), 7.24-7.10 (m, 3H), 4.62-4.61 (m, 1H), 4.33 (s, 2H), 4.22-4.21 (m, 1H), 4.13-4.00 (m, 3H), 3.87-3.82 (m, 1H), 3.71-3.65 (m, 1H), 2.31 (s, 3H).MS(EI，m/z)：516.1[M+Na] +。
Embodiment 11
(2R, 3S, 4R, 5R, 6S)-2-methylol-6-{3-{ [5-(4-p-methoxy-phenyl) selenophen-2-base] methyl }-4-aminomethyl phenyl } synthesis of tetrahydrochysene-2H-pyrans-3,4,5-triol (52)
Preparation method is see embodiment 1, and wherein in embodiment 1 step C, 4-fluorobenzoic boric acid 4-methoxyphenylboronic acid substitutes.
1H NMR(CD 3OD，500MHz)δ7.38(d，J＝8.5Hz，2H)，7.31(s，1H)，7.23-7.22(m，1H)，7.15-7.13(m，2H)，6.87-6.83(m，3H)，4.18-4.17(m，2H)，4.11-4.10(m，1H)，3.89-3.87(m，1H)，3.78(s，3H)，3.71-3.67(m，1H)，3.48-3.35(m，4H)，2.30(s，3H)。MS(EI，m/z)：527.1[M+Na] +。
Embodiment 12
(2R, 3S, 4R, 5R, 6S)-2-methylol-6-{4-methyl-3-{ [5-(4-aminomethyl phenyl) selenophen-2-base] methyl } phenyl } synthesis of tetrahydrochysene-2H-pyrans-3,4,5-triol (53)
Preparation method is see embodiment 1, and wherein in embodiment 1 step C, 4-fluorobenzoic boric acid 4-methylphenylboronic acid substitutes.
1H NMR(CD 3OD，500MHz)δ7.36-7.31(m，3H)，7.24-7.22(m，2H)，7.16-7.10(m，3H)，6.87-6.85(m，1H)，4.18(s，2H)，4.12-4.09(m，1H)，3.90-3.86(m，1H)，3.72-3.67(m，1H)，3.47-3.35(m，4H)，2.30(s，6H)。MS(EI，m/z)：511.1[M+Na] +。
Embodiment 13
(3R, 4S, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-4-aminomethyl phenyl } synthesis of-6-methylol tetrahydrochysene-2H-pyrans-2,3,4,5-tetrol (54)
By compound 6 (200mg, 0.439mmol) with compound 1 (267mg, 0.572mmol) be dissolved in anhydrous THF (3mL), under-40 ~-60 DEG C and nitrogen, drip 0.5M (trimethyl silane) to methylate lithium (1.8mL), after adding, continue stirring 2 hours.Then drip water (2mL) solution of methanesulfonic (0.17mL) at such a temperature, be naturally warmed up to stirred overnight at room temperature.Add appropriate saturated aqueous common salt, with ethyl acetate (15mL × 3) extraction, organic phase saturated aqueous common salt (10mL) washing of merging, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, product is through column chromatography purification (200 ~ 300 order silica gel, ethyl acetate: sherwood oil=4:1 ~ 8:1 wash-out), products therefrom uses re-crystallizing in ethyl acetate again, obtains (3R, 4S, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-4-aminomethyl phenyl }-6-methylol tetrahydrochysene-2H-pyrans-2,3,4,5-tetrol (54).
1H NMR(MeOD，500MHz)δ7.59(s，1H)，7.49-7.46(m，3H)，7.24-7.23(m，1H)，7.17-7.15(m，1H)，7.07-7.03(m，2H)，6.89-6.88(m，1H)，4.25-4.22(m，2H)，3.96-3.94(m，2H)，3.90-3.78(m，2H)，3.51-3.49(m，1H)，3.29-3.27(m，2H)，2.31(s，3H)。MS(EI，m/z)：531.2[M+Na] +。
Compound transports the inhibition test of glucose to hSGLT2 in HEK293 transfection cell strain
One, experimental procedure
1. HEK293-hSGLT2 is surely turned cell by 2 × 10 5individual/hole is inoculated in 24 orifice plates, cultivates 3 days.
2. test the same day, with pre-treatment buffer (10mM HEPES, 5mM Tris, 140mM choline chloride 60,2mM KCl, 1mM CaCl 2, 1mM MgCl 2, pH7.4) and wash 2 times cells, then add appropriate pre-treatment buffer, hatch 20 minutes in 37 DEG C.
3. then remove pre-treatment buffer, then add transport buffer (10mM HEPES, 5mM Tris, 140mM NaCl, 2mM KCl, 1mM CaCl 2, 1mM MgCl 2, pH7.4), final concentration is 20uM 14c-methyl alpha-D-glucose glycosides ( 14c-AMG) and final concentration be the compound of 50nM, as testing compound hole.
4. establish simultaneously do not add compound well (other condition is same as above), as Positive control wells; If do not add compound and pre-treatment buffer (not containing Na +) substitute transport buffer (other condition is same as above) use, as negative control hole.
5. hatch 2 hours 30 minutes in 37 DEG C.The cleaning buffer solution (pre-treatment buffer containing 10mM AMG) adding precooling again washes 2 times cells, finally adds 0.2M NaOH dissolved cell, and collecting cell fragment also adds machine testing isotropic substance on appropriate scintillation solution 14the intensity of radioactivity (CPM value) of C.
6. calculation formula is as follows:
Two, experimental result
The part of compounds 10,11,12,13,14,24,25,33,36,37,50,51,52,53 and 54 of synthesis is tested according to above-mentioned experimental procedure, obtain compound and the results are shown in Figure 1 when concentration is 50nM to the inhibition test that hSGLT2 in HEK293 transfection cell strain transports glucose, these compounds exhibit go out the restraining effect good to hSGLT2.
Compound merges to high lipid food the drug effect that STZ induces C57 mouse hyperglycemia model
One, model is set up
Ablactation C57BL/6J male mice (the SPF level in 3 week age, body weight 13-14g, by Shanghai, western pul-Bi Kai laboratory animal limited liability company provides, conformity certification number: SCXK (Shanghai) 2008-0016), employing lipid content is the high fat diet (working in coordination with medical bioengineering limited liability company purchased from Jiangsu Province) of 30%.Raise in independent air-feeding cage (IVC), air purity 10000 grades, pressure differential environment 20 ~ 50Pa, temperature 20 ~ 25 DEG C, humidity 40 ~ 70%, round the clock light and shade alt time 12 hours (h)/12h, 10, every cage, observe weekly the change of body weight, blood glucose target, raise 3 weeks continuously.Intact animal (not modeling) control group, gives normal normal diet.
High fat diet starts to inject U-9889 (STZ) on the 3rd week, injected dose is that 100mg/kg (injects twice, every minor tick 5 days), measure non-fasting plasma glucose after 2nd injection STZ 72h, the animal of blood sugar <12mmol/L can add injection STZ 100mg/kg.
Two, method for preparation of drug
Fully ground by compound combination before administration or disperse, and be dissolved in or be suspended in 1%CMC-Na and 0.5%Tween-80 solution, after suspendible prepares, magnetic agitation 2h, needs constant volume.
Three, grouping and administration
After having injected STZ, animal continues high lipid food nursing, inject after 1 week and measure non-fasting plasma glucose, select the animal of glucose level 12 ~ 18mmol/L, 3 groups are divided into: (1) Normal group according to glucose level and weight average, (2) model group, (3) compound 10 groups, (4) compound 13 groups.Model comparison and Normal group give isometric 1%CMC-Na and 0.5%Tween-80 solution (see table 1) all simultaneously.
Table 1. divides into groups, dosage is arranged and dosage regimen
Four, the mensuration of plasma glucose time course
Before administration, after administration 1,2,4, the blood sampling of 6h afterbody, blood sugar test paper method measures the change curve of blood sugar.Experimental data statistical method represents with mean value and standard deviation (or standard error), and statistical method adopts variance analysis and one-way ANOVA etc.
Five. single-dose plasma glucose time course
In intact animal and model group 6h, blood sugar maintains maintenance level substantially, compound 10 and compound 13 single-dose all obviously can reduce this model glucose level, can blood sugar be reduced in administration 1h, and sustainable more than the 6h of hypoglycemic effect (see Fig. 2, Fig. 3).

Claims (8)

1. the prodrug ester of the compound shown in general formula (I), its pharmacy acceptable salt, its facile hydrolysis or its isomer:
Wherein,
R ', R " independently selected from H ,-OH ,-OCH 3or-OCH 2cH 3;
Y is selected from CH or N;
Z is CH;
R 1, R 2independently selected from H, halogen ,-OH ,-CN, C 1-4alkyl, C 1-4substituted alkyl, C 1-4alkoxyl group, C 1-4substituted alkoxy, C 1-4alkylthio or C 1-4substituted alkane sulphur base;
R 3for H;
R 4be selected from C 1-4alkyl, C 1-4substituted alkyl or
R 5, R 6independently selected from H, halogen ,-CN, C 1-4alkyl, C 1-4substituted alkyl, C 1-4alkoxyl group, C 1-4substituted alkoxy, C 1-4alkylthio or C 1-4substituted alkane sulphur base;
R 1and R 2described substituting group is selected from halogen, C 1-4alkoxyl group, C 1-4alkylthio ,-NH 2or-OH;
R 5and R 6described substituting group is selected from halogen, C 1-4alkoxyl group or C 1-4alkylthio.
2. the prodrug ester of the compound shown in general formula according to claim 1 (I), its pharmacy acceptable salt, its facile hydrolysis or its isomer, the prodrug ester comprising the compound shown in general formula (II) or its pharmaceutically useful salt, its facile hydrolysis:
Wherein,
R 1, R 2independently selected from H, F, Cl ,-OH ,-CN, C 1-3alkyl, C 1-3substituted alkyl, C 1-3alkoxyl group, C 1-3substituted alkoxy, C 1-3alkylthio or C 1-3substituted alkane sulphur base;
R 5, R 6independently selected from H, F, Cl ,-CN, C 1-2alkyl, C 1-2substituted alkyl, C 1-3alkoxyl group, C 1-3substituted alkoxy, C 1-3alkylthio or C 1-3substituted alkane sulphur base;
R 1and R 2described substituting group is selected from halogen, C 1-3alkoxyl group or-OH;
R 5and R 6described substituting group is selected from halogen or C 1-3alkoxyl group.
3., according to prodrug ester or its isomer of the compound of claim 1,2 described in any one, its pharmacy acceptable salt, its facile hydrolysis, described compound is selected from:
(3R, 4S, 5S, 6R)-2-{3-[(5-(4-fluorophenyl) selenophen-2-base) methyl]-4-aminomethyl phenyl }-6-methylol-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol
(2S, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
(2S, 3R, 4R, 5S, 6R)-2-{3-{ [5-(3,4-difluorophenyl) selenophen-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
(2S, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-chloro-phenyl-) selenophen-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
The chloro-3-{ of (2S, 3R, 4R, 5S, 6R)-2-{4-[5-(4-fluorophenyl) selenophen-2-base] methyl } phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
(2R, 3S, 4R, 5R, 6S)-2-methylol-6-{4-methyl-3-[(5-phenyl selenophen-2-base) methyl] phenyl } tetrahydrochysene-2H-pyrans-3,4,5-triol
(2S, 3R, 4R, 5S, 6R)-2-{5-[(5-(4-fluorophenyl) selenophen-2-base) methyl]-2-methoxyl group-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
(2S, 3R, 4R, 5S, 6R)-2-{5-[(5-(4-ethyl-sulfide phenyl) selenophen-2-base) methyl]-2-methoxyl group-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
4-{5-{2-methyl-5-[(2S, 3R, 4R, 5S, 6R)-3,4,5-trihydroxy--6-(methylol) tetrahydrochysene-2H-pyrans-2-base] benzyl } selenophen-2-base } cyanobenzene
(3R, 4S, 5S, 6R)-2-{5-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-2-hydroxy-4-methyl phenyl }-6-methylol-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol
(2S, 3R, 4R, 5S, 6R)-2-{5-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-2-hydroxy-4-methyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
(2S, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl)-1,3-selenazoles-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
(2R, 3R, 4R, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl)-1,3-selenazoles-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
(2R, 3S, 4R, 5R, 6S)-2-methylol-6-{3-{ [5-(4-p-methoxy-phenyl) selenophen-2-base] methyl }-4-aminomethyl phenyl } tetrahydrochysene-2H-pyrans-3,4,5-triol
(2R, 3S, 4R, 5R, 6S)-2-methylol-6-{4-methyl-3-{ [5-(4-aminomethyl phenyl) selenophen-2-base] methyl } phenyl } tetrahydrochysene-2H-pyrans-3,4,5-triol
(3R, 4S, 5S, 6R)-2-{3-{ [5-(4-fluorophenyl) selenophen-2-base] methyl }-4-aminomethyl phenyl }-6-(methylol) tetrahydrochysene-2H-pyrans-2,3,4,5-tetrol
4. a pharmaceutical composition, it comprises treatment effective dose according to the prodrug ester of the compound of claims 1 to 3 described in any one, its pharmacy acceptable salt, its facile hydrolysis or its isomer and pharmaceutically useful carrier.
5. according to prodrug ester or its isomer of the compound of Claims 1 to 4 described in any one, its pharmacy acceptable salt, its facile hydrolysis, and the application because being subject to the white SGLT2 of sodium glucose co-transporter 2 to suppress disease or the illness affected in preparation treatment or prevention of its pharmaceutical composition.
6. the prodrug ester of the compound according to any one in Claims 1 to 5, its pharmacy acceptable salt, its facile hydrolysis or its isomer, and its pharmaceutical composition is suitable in preparation the application treating or prevent metabolic disease.
7. according to the compound of claim 1 ~ 6 described in any one, its pharmacy acceptable salt, the prodrug ester of its facile hydrolysis or its isomer, and its pharmaceutical composition is for the preparation for the treatment of or the purposes that delays in the medicine of following advancing of disease or outbreak, wherein said disease is selected from diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, the rising of lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndrome, diabetic complication, atherosclerosis or hypertension.
8. the prodrug ester of the compound according to the general formula (I) of claim 1 ~ 7 described in any one, its pharmacy acceptable salt, its facile hydrolysis or its isomer, and its pharmaceutical composition is for the preparation of the purposes of sodium glucose co-transporter 2 white 2 (SGLT2) inhibitor.
CN201410610352.9A 2013-11-28 2014-11-03 Novel SGLT2 inhibitor compounds and pharmaceutical composition thereof Pending CN104672227A (en)

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WO2016070740A1 (en) * 2013-11-28 2016-05-12 镇江新元素医药科技有限公司 A class of new type sglt2 inhibitor compound and a pharmaceutical composition thereof
WO2016074566A1 (en) * 2014-11-10 2016-05-19 镇江新元素医药科技有限公司 Glucoside derivative and pharmaceutical composition thereof

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WO2012041898A1 (en) * 2010-09-29 2012-04-05 Celon Pharma Sp. Z O.O. Combination of sglt2 inhibitor and a sugar compound for the treatment of diabetes
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WO2012041898A1 (en) * 2010-09-29 2012-04-05 Celon Pharma Sp. Z O.O. Combination of sglt2 inhibitor and a sugar compound for the treatment of diabetes
WO2012140120A1 (en) * 2011-04-13 2012-10-18 Janssen Pharmaceutica Nv Process for the preparation of compounds useful as inhibitors of sglt2
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016070740A1 (en) * 2013-11-28 2016-05-12 镇江新元素医药科技有限公司 A class of new type sglt2 inhibitor compound and a pharmaceutical composition thereof
WO2016074566A1 (en) * 2014-11-10 2016-05-19 镇江新元素医药科技有限公司 Glucoside derivative and pharmaceutical composition thereof

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