CN104761522A - Optically pure benzyl-4-chlorophenyl C-glucoside derivatives - Google Patents

Optically pure benzyl-4-chlorophenyl C-glucoside derivatives Download PDF

Info

Publication number
CN104761522A
CN104761522A CN201410004395.2A CN201410004395A CN104761522A CN 104761522 A CN104761522 A CN 104761522A CN 201410004395 A CN201410004395 A CN 201410004395A CN 104761522 A CN104761522 A CN 104761522A
Authority
CN
China
Prior art keywords
formula
compound
benzyl
preparation
iii
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201410004395.2A
Other languages
Chinese (zh)
Other versions
CN104761522B (en
Inventor
吴永谦
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jilin Huisheng Biopharmaceutical Co ltd
Beijing Huizhiheng Biological Technology Co Ltd
Original Assignee
Shandong Xuanzhu Pharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong Xuanzhu Pharma Co Ltd filed Critical Shandong Xuanzhu Pharma Co Ltd
Priority to CN201410004395.2A priority Critical patent/CN104761522B/en
Priority to CN201610635305.9A priority patent/CN106349201B/en
Priority to JP2014043695A priority patent/JP6008892B2/en
Priority to KR1020140037632A priority patent/KR101837488B1/en
Publication of CN104761522A publication Critical patent/CN104761522A/en
Priority to HK15108213.7A priority patent/HK1207626A1/en
Application granted granted Critical
Publication of CN104761522B publication Critical patent/CN104761522B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/04—Carbocyclic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/06—Heterocyclic radicals
    • 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
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention belongs to the technical filed of medicines, and concretely relates to optically pure benzyl-4-chlorophenyl C-glucoside derivatives represented by formula (II) and formula (III), a method for preparing the above compounds and intermediates thereof, a medicinal preparation and a medicinal composition containing the compounds, and an application of the optically pure benzyl-4-chlorophenyl C-glucoside derivatives in the preparation of medicines for treating and/or preventing insulin-dependent diabetes, non-insulin dependent diabetes, insulin resistance diseases or obesity, various diabetes and relevant diseases as a sodium-glucose cotransporter (SGLT) inhibitor.

Description

The C-glycosides derivatives of optically pure benzyl-4-chloro-phenyl-
Technical field
The invention belongs to medical art, be specifically related to C-glycosides derivatives or its medicinal acceptable salt of optically pure benzyl-4-chloro-phenyl-, prepare the method for these compounds and intermediate thereof, pharmaceutical preparation containing these compounds and pharmaceutical composition, and the C-glycosides derivatives of optically pure benzyl-4-chloro-phenyl-of the present invention or its medicinal acceptable salt treat and/or prevent various diabetes (comprising diabetes and the non insulin dependent diabetes of insulin-dependent) or various diabetes related diseases (comprising insulin resistance disease and obesity) as white (SGLT) inhibitor of sodium glucose co-transporter 2 in preparation medicine in application.
Background technology
Nearly 100,000,000 people in the whole world suffer from type ii diabetes, it is characterized in that because of the hyperglycemia caused by excessive hepatic glucose generation and periphery insulin resistance.Hyperglycemia is considered to the Major Risk Factors forming diabetic complication, and may be directly related with the impaired insulin secretion of late Type II diabetes.Therefore can estimate that the normalizing of Regular Insulin can improve the blood sugar of type ii diabetes patient.Current existing diabetes medicament great majority are Insulin-secreting agent or euglycemic agent, as sulfonylurea, meglitinide, thiazolidinediones and N1,N1-Dimethylbiguanide etc., there is potential side effect, as easily caused body weight increase, hypoglycemia, lactic acidosis etc., therefore, developmental function mechanism novelty, safe and effective antidiabetic medicine is needed badly.
At kidney, glucose freely from glomerular filtration (about 180g/ days), but almost heavily can absorb at proximal convoluted tubule active transport.Wherein two the heavily absorptions of sodium-glucose transporter to glucose have played vital role, i.e. SGLT-1 and SGLT-2, and the effect of SGLT-2 is particularly outstanding.SGLT-2 is only at the transmembrane protein of the S1 section specifically expressing of proximal tubule, one of its topmost physiological action absorbs the sugared part flow through in uriniferous tubules blood, account for 90% of Reabsorption, SGLT-2 transports with the ratio of sodium-glucose 1: 1, SGLT-2 inhibitor can suppress blood sugar in the absorption of uriniferous tubules, and sugared part is discharged in a large number from urine.And SGLT-1 mainly expresses at distal convoluted tubule, account for 10% of Reabsorption, SGLT-1 and transport with the ratio of sodium-glucose 2: 1.SGLT-1 is have also discovered in addition in enteron aisle and its hetero-organization.These transporters are played a role by Na+/ATP enzyme pump, and are transferred back in blood by glucose transporter 2 (GLUT2).What this showed most possibly to develop into drug target is SGLT-2 transporter, and being its absolute Reabsorption to glucose on the one hand, is that it is only expressed in kidney on the other hand.In the research to familial form ephrosis glucose in urine, also demonstrate that the feasibility of this approach.Familial ephrosis glucose in urine main manifestations is the glucose in urine (about 10-120g/ days) of non-quantitative, but patient's general status is good, does not find the disadvantageous long term negative effect of health.This optimum glucose in urine is mainly caused by the sudden change of SGLT-2 transporter gene, and this shows optionally to suppress can not produce adverse consequences except induction glycosuria to the pharmacology of SGLT-2.Evidence suggests that one of SGLT-2 inhibitor important clinical advantage not easily causes hypoglycemia.And suppress SGLT-1 can cause sugar-semi-lactosi malabsorption syndrome, dehydration can be caused, and evidence suggests that SGLT-1 inhibitor will delay the absorption of carbohydrate, individuality can be caused to be difficult to the gastrointestinal symptom tolerated, and select high SGLT-2 inhibitor can not block the effect of SGLT-1 at intestinal transport absorption glucose, therefore not easily cause gastrointestinal symptom.In addition, SGLT-1 is equally highly expressed in human body cardiac muscular tissue, may cause the new or organic disease of heart function to it after blocking.Therefore, the medicine of compound to research treatment diabetes that there is highly selective to SGLT-2 is developed significant.
SGLT-2 inhibitor suppresses the heavily absorption of kidney sugar to treat hyperglycemia by acting on SGLT-2 transporter, and the treatment for diabetes provides new approach.Although this approach can not directly act on the physiopathology of type ii diabetes, reduce blood sugar by the excretion increasing renal glucose sugar, the deficiency of net energy can be caused, promote weight loss and indirectly improve obesity symptom.Research finds that these medicines and existing ofhypoglycemic medicine or Regular Insulin share, and hypoglycemic risk occurs lower, and has the effect of potential reduction body weight.Such medicine does not rely on function and the insulin resistant of beta cell, therefore SGLT-2 inhibitor is in the effective situation of general diabetic, also has good curative effect to the diabetic subject of biguanides, DPP-4 inhibitor class pharmacological agent failure simultaneously.Therefore, this type of medicine in the future also can with the antidiabetic drug combined utilization such as biguanides, DPP-4 inhibitor class.
Wherein, WO0127128, US2005209166 etc. patent document discloses a series of compound as SGLT-2 inhibitor.
The applicant also discloses a series of C-glucosides class SGLT-2 inhibitor compound at patent WO2013/000275A1, and wherein compound 4 couples of SGLT-2 have good restraining effect and good selectivity, and its structural formula is
This compound is the mixture of steric isomer, and it has asymmetric center, there is multiple optical isomer.Consider that in prior art, a lot of chiral mixture medicine exists the toxic side effect easily producing the unknown, reduce the potential problems such as drug effect and quality control difficulties, greatly can increase R&D risk, and optically pure steric isomer has safer relative to chiral mixture, the probability producing toxic side effect is lower, better and the easier advantage of quality control of stability, and optically pure steric isomer also has in pharmacodynamics, the characteristic of the potential improvement of pharmacokinetics and toxicology aspect, therefore, exploitation has highly selective to SGLT-2, rapid-action, efficiently, safety, and the single stereoisomers of good stability, quality control in producing follow-up medicament research and development and Marketed drugs is significant.
Summary of the invention
Technical scheme of the present invention is as follows:
1. the stereoisomeric compounds of compound shown in formula (I) or its medicinal acceptable salt, is selected from formula (II), (III), (IV) and (V):
its name is called (2S, 3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
its name is called (2S, 3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3r, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
its name is called (2R, 3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
its name is called (2R, 3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3r, 5S)-two ring [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol.
2. the preparation method of formula (II) compound described in the present invention further claimed above-mentioned 1, this preparation method's reaction scheme is:
Wherein, X represents fluorine, chlorine, bromine or iodine,
G representation hydroxy protecting group, is selected from TMS, triethyl silyl, benzyl, to methoxy-benzyl, to nitrobenzyl, pivaloyl group, allyl group, methoxyl methyl, benzyloxymethyl or trimethylsilyl ethyl etc., is preferably TMS.
Preparation process:
By formula b, i.e. (1R, 3r, 5S)-two rings [3.1.0] hexane-3-base methanesulfonates, (described organic solvent can be selected from N-Methyl pyrrolidone, N to be dissolved in organic solvent, dinethylformamide, tetrahydrofuran (THF), dioxane and acetonitrile, be preferably N-Methyl pyrrolidone) in, add formula a, control temperature reacts under 0 DEG C to 70 DEG C condition, prepare formula c, formula c with be obtained by reacting formula d-1, formula d-1 carries out deprotection and obtains formula d-2, and formula d-2 is reacted production e temperature-78 DEG C to 30 DEG C of range of condition, and formula e obtains formula (II) compound through purifying.
Above-mentioned formula e purifying obtains formula (II) compound can adopt following purification process, but is not limited only to following method.
Purification process: formula e is carried out hydroxyl protection reaction production f, formula f and carry out deprotection reaction production (II) compound.
Wherein, G ' representation hydroxy protecting group; be selected from ethanoyl, TMS, triethyl silyl, benzyl, to methoxy-benzyl, to nitrobenzyl, pivaloyl group, allyl group, methoxyl methyl, benzyloxymethyl, trimethylsilyl ethyl, propionyl, isobutyryl or benzoyl etc., be preferably ethanoyl, pivaloyl group, propionyl, isobutyryl or benzoyl.
Formula II compound of the present invention can adopt the method that describes in above-mentioned flow process and/or other technology known to persons of ordinary skill in the art to synthesize, but is not limited only to aforesaid method.
3. the preparation method of formula (III) compound described in the present invention further claimed above-mentioned 1, this preparation method's reaction scheme is:
Wherein, X represents fluorine, chlorine, bromine or iodine,
G representation hydroxy protecting group, is selected from TMS, triethyl silyl, benzyl, to methoxy-benzyl, to nitrobenzyl, pivaloyl group, allyl group, methoxyl methyl, benzyloxymethyl or trimethylsilyl ethyl etc., is preferably TMS.
Preparation process:
Formula a is dissolved in organic solvent (described organic solvent can be selected from toluene, DMF, tetrahydrofuran (THF), dioxane and acetonitrile, is preferably toluene), add formula b, control temperature reacts under 0 DEG C to 70 DEG C condition, prepares formula c ', formula c ' with be obtained by reacting formula d '-1, formula d '-1 carries out deprotection and obtains formula d '-2, and formula d '-2 is reacted production e ' temperature-78 DEG C to 30 DEG C of range of condition, and formula e ' obtains formula (I II) compound through purifying.
Above-mentioned formula e ' purifying obtains formula (III) compound can adopt following purification process, but is not limited only to following method.
Purification process: formula e ' is carried out hydroxyl protection reaction production f ', formula f ' and carry out deprotection reaction production (III) compound.
Wherein, G ' representation hydroxy protecting group; be selected from ethanoyl, TMS, triethyl silyl, benzyl, to methoxy-benzyl, to nitrobenzyl, pivaloyl group, allyl group, methoxyl methyl, benzyloxymethyl, trimethylsilyl ethyl, propionyl, isobutyryl or benzoyl etc., be preferably ethanoyl, pivaloyl group, propionyl, isobutyryl or benzoyl.
Formula (III) compound can adopt the method that describes in above-mentioned flow process and/or other technology known to persons of ordinary skill in the art to synthesize, but is not limited only to aforesaid method.
4. the intermediate of the further claimed formula II compound as follows of the present invention,
5. the intermediate of further claimed formula as follows (II) compound of the present invention,
Wherein, X represents bromine or iodine.
6. the intermediate of the present invention's further claimed formula as follows (I II) compound,
7. the intermediate of further claimed formula as follows (III) compound of the present invention,
Wherein, X represents bromine or iodine.
Described " medicinal acceptable salt " comprises an alkali metal salt, as sodium salt, sylvite, lithium salts etc.; Alkaline earth salt, as calcium salt, magnesium salts etc.; Other metal-salts, as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts, as ammonium salt; Organic alkali salt, as tertiary octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidinesalt, diethylamine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-styroyl amine salt, piperazine salt, tetramethyl-amine salt, three (methylol) aminomethane salt etc.; Halogen acid salt, as hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt, as nitrate, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulfonate, as mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate, as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt, as acetate, malate, fumarate, succinate, Citrate trianion, tartrate, oxalate, maleate etc.; Amino acid salts, as glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.
The present invention is the claimed pharmaceutical composition comprising formula of the present invention (II) and/or formula (III) compound or its medicinal acceptable salt and one or more pharmaceutical carriers and/or thinner also, can make pharmaceutically acceptable arbitrary formulation.With oral, parenteral, rectum or be applied to through modes such as lung administrations and need its patient.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, suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc. can be added.During for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When making injection, the 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.The compound 0.005g to 10g shown in formula (I) containing physiology significant quantity in per unit preparation can be 0.005g, 0.01g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, 10g etc.
The pharmaceutical composition of the further claimed formula of the present invention (II) of the present invention and/or formula (III) compound or its medicinal acceptable salt and other active pharmaceutical ingredients; other active pharmaceutical ingredients described can be one or more ofhypoglycemic medicines, described ofhypoglycemic medicine be selected from ofhypoglycemic medicine be selected from phosphoric acid Xi Gelieting, Vildagliptin, BMS-477118, SYR-322, Li Gelieting, for Ge Lieting, Jimmy Ge Lieting, N1,N1-Dimethylbiguanide, phenformin, Yi Xina peptide or Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] etc.
The present invention also claimed formula of the present invention (II) and/formula (III) compound or its medicinal acceptable salt of comprising is preparing the application treated and/or prevented in the medicine of various diabetes or various diabetes related diseases.Described diabetes comprise diabetes (type i diabetes) and the non insulin dependent diabetes (type ii diabetes) of insulin-dependent, and described diabetes related diseases comprises insulin resistance disease and obesity etc.
The present invention is the claimed method treating and/or preventing various diabetes (comprising diabetes and the non insulin dependent diabetes of insulin-dependent) or various diabetes related diseases (comprising insulin resistance disease and obesity) further, the method comprise to needs its formula of the present invention (II) comprising the administration effective dose of people and/or formula (III) compound or its medicinal acceptable salt.
The compounds of this invention has following characteristics:
(1) the compounds of this invention has the selectivity of height to SGLT-2, can being used for the treatment of and/or preventing the diabetes of various Mammals (comprising the mankind) and the various diseases caused by diabetes by safety.
(2) the compounds of this invention has efficient restraining effect and significant hypoglycemic activity to SGLT-2, rapid-action, toxic side effect is little, security is high.
(3) the compounds of this invention shows good physico-chemical property, and purity is high, and good stability is easy to control the quality, is applicable to carrying out large-scale commercial production.
4, embodiment
For simplicity, well-known abbreviation used in the present invention includes but not limited to:
Me: methyl;
Et: ethyl;
Ms: methyl sulphonyl;
Ac: ethanoyl;
TBS: t-butyldimethylsilyi;
THF: tetrahydrofuran (THF);
DMAP:4-Dimethylamino pyridine;
DIPEA:N, N-diisopropylethylamine;
N-BuLi: n-Butyl Lithium;
TMS: TMS.
In the present invention, room temperature refers to 10 DEG C to 30 DEG C.
Set forth the compounds of this invention beneficial effect further below by way of pharmacological evaluation, but this should be interpreted as the compounds of this invention only has following beneficial effect.
the external activity experiment of experimental example 1 the compounds of this invention
Trial-product: formula II of the present invention, formula (III), formula IV and formula (V) compound, its chemical name and preparation method are shown in the preparation embodiment of each compound.
Contrast medicine 1: compound 4 in patent WO2013/000275A1, self-control (preparation method is with reference to patent WO2013/000275A1), its structural formula is as follows:
compound 4, i.e. formula (I) compound.
The implication representated by abbreviation of following middle experiment is as follows:
NMG N-methyl glucose osamine (N-methyl-glucosamine)
KRH Krebs-Ringer-Henseleit
Experimental technique: SGLT-2 and the SGLT-1 sequence of people is transfected into stably express on Chinese hamster ovary cell, by T suppression cell to [ 14c]-mark-R-methyl-D-glucopyranose glycosides (AMG) the dependent absorption of sodium, record 503nhibiting concentration IC50, carry out determination of activity.
Buffer A(KRH-Na +)：120mM NaCl，4.7mM KCl，1.2mM MgCl 2，2.2mMCaCl 2，10mM HEPES(PH7.4with1mM Tris)。
Buffer A-(KRH-NMG)：120mM NMG，4.7mM KCl，1.2mM MgCl 2，2.2mM CaCl 2，10mM HEPES(PH74with1mM Tris)。
Buffer D：120mM NaCl，4.7mM KCl，1.2mM MgCl 2，2.2mM CaCl 2，10mM HEPES，0.5mM phlorizin(PH7.4with1mM Tris)。
Experimental technique: sequence stably express on Chinese hamster ovary celI of SGLT-2 and SGLT-1 of people, is cell cultures 12 hours on 96 orifice plates, uses KRH-Na +(Buffer A) or KRH-NMG (Buffer A-) buffered soln 200 μ L/ hole, rinse 3 times.Again with add containing Buffer A or Buffer A-plus [ 14c] the damping fluid 100 μ L/ hole of-AMG (10 μ Ci/mL), hatch 1 hour for 37 DEG C.Then, add ice-cold buffered soln (Buffer D) 100 μ L and stop test, clean 5 times.Add ice-cold lysis buffer (100mM NaOH) solution 20 μ L/ hole again, 600rpm is centrifugal, 5 minutes, and Microscint40 solution 80 μ L/ hole, and 600rpm is centrifugal, 5 minutes.Finally with scintillation counting technique MicroBeta Trilux (purchased from PerkinElmer company) detect [ 14c] radioactivity of-AMG, calculate 503nhibiting concentration IC50.
Experimental result and conclusion:
The restraining effect evaluation result of table 1 the compounds of this invention
As shown in Table 1, formula (II) compound has good restraining effect and good selectivity to SGLT-2, compared with contrast medicine 1, shows obvious advantage.
the Pharmacokinetics in Rat experiment of experimental example 2 the compounds of this invention
Animal subject: 6-8 male SD rat in age in week (purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.), 3/compound, body weight 200-240g.
Trial-product: formula (II) compound, its chemical name and preparation method are shown in following embodiment 1.
Contrast medicine 1: compound 4 in patent WO2013/000275A1, self-control (preparation method is with reference to patent WO2013/000275A1), its structural formula is as follows:
compound 4, i.e. formula (I) compound.
Contrast medicine 2: compound 22 in patent WO2013/000275A1, self-control (preparation method is with reference to patent WO2013/000275A1), its structural formula is as follows:
compound 22.
Solvent: 0.5%MC (methylcellulose gum) solution+0.1%SDS (sodium lauryl sulphate).
Experimental technique:
Gastric infusion (PO) medication refers to table 2
P of Rats K (pharmacokinetics) medication of table 2 compound
Blood sampling: 0.17 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 30 hours, 48 hours, 54 hours, 72 hours, each time point takes 200 μ about L whole bloods, 4 DEG C of conditions in low-temperature and high-speed whizzer (5415R, Eppendorf), 8000 revs/min, centrifugal 6 minutes separated plasmas, blood plasma is in-80 DEG C of Refrigerator stores.
Plasma sample analysis: precision pipettes 20 μ L blood plasma, add mark MTBE (methyl tertiary butyl ether) solution (containing the clean 25ng/mL of interior mark Da Gelie) in 600 μ l, after 1500 revs/min of vortex 10min, centrifugal 5min (12000 revs/min), get 400 μ L supernatant liquors, nitrogen dries up, with 200 μ L redissolution liquid (acetonitriles: water=7: 3) redissolve, vortex 10min, uses LC-MS/MS (API4000, Aplplied Biosystems) to analyze.
P of Rats K (pharmacokinetics) evaluation result (PO) of table 3 compound
T 1/2represent the transformation period
Tmax represents the peak time of medicine at blood plasma
Cmax representative reaches plasma drug level during peak
AUC lastrepresent area under the drug-time curve 0 → t
AUC infrepresent area under the drug-time curve 0 → ∞
Conclusion: from table 3 experimental result, the peak time of formula (II) compound Plasma Concentration in rat body is shorter, onset is rapid, and with contrast medicine 1 with contrast medicine 2 and compare, exposed amount is higher, there is significant difference, illustrate that formula (II) compound has obvious progress.
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following examples.
In an embodiment, the starting compound used is commercially available, available from AlfaAesar (Tianjin) Chemical Co., Ltd., Chemical Reagent Co., Ltd., Sinopharm Group, Tianjin Fu Yu Fine Chemical Co., Ltd, Shanghai Bang Cheng Chemical Co., Ltd., Tianjin Guang Cheng chemical reagent company limited, Tianjin company such as recovery Fine Chemical Co., Ltd, Tianjin Kermel Chemical Reagent Co., Ltd. etc.
embodiment 1 (2S, 3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-two ring [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-triol (formula (II) compound)
(1) preparation of the bromo-2-chloro-benzoyl chloride of 5-
Bromo-for 5-2-chloro-benzoic acid (270g, 1.15mol) is suspended in methylene dichloride (2700mL), adds DMF (1mL), under 0 DEG C of condition, drip oxalyl chloride (288mL, 3.46mol).Dropwise, move to 20 DEG C of reaction 3h, reaction solution becomes clarification, and TLC (tlc) shows reaction to be completed, and obtains product at 30 ~ 35 DEG C of rotary evaporations, is directly used in next step reaction.
(2) preparation of (the bromo-2-chloro-phenyl-of 5-) (4-p-methoxy-phenyl) ketone
Under nitrogen protection; by aluminum trichloride (anhydrous) (155g; 1.16mol) be suspended in methylene dichloride (2050mL); under-5 DEG C of conditions; disposablely add methyl-phenoxide (125mL, 1.15mol), after stirring 20min; drip the dichloromethane solution (300mL) of the bromo-2-chloro-benzoyl chloride of 5-,-5 DEG C of reaction 3h.TLC shows reaction to be completed, and pours in 2N hydrochloric acid, layering.Get organic phase, with saturated sodium bicarbonate solution wash twice, wash with saturated nacl aqueous solution again, anhydrous sodium sulfate drying, rotary evaporation obtains solid.Add after ethanol (150mL) washes and starches 30min, filter, filter cake is dried to obtain product (265g, productive rate 71%).
(3) preparation of the chloro-2-of the bromo-1-of 4-(4-methoxy-benzyl) benzene
By (the bromo-2-chloro-phenyl-of 5-) (4-p-methoxy-phenyl) ketone (265g, 0.81mol) be dissolved in methylene dichloride (515mL) with acetonitrile (1030mL), add triethyl silicane (352mL, 2.22mol).Under nitrogen protection, under 0 DEG C of condition, drip boron trifluoride diethyl etherate (273mL, 2.22mol).Dropwise, stir 20min, move to room temperature reaction 2h.TLC shows reaction to be completed, and adds methyl tertiary butyl ether (1.5L) and saturated sodium bicarbonate solution (1.5L), after stirring 30min, separate organic phase, with saturated sodium bicarbonate solution wash four times, saturated nacl aqueous solution washes once, anhydrous sodium sulfate drying, rotary evaporation obtains oily matter, add ethanol, stirring at room temperature 30min, under ice bath, stir 30min, separate out a large amount of solid, filter, filtration cakes torrefaction is obtained product (226g, productive rate 89%).
(4) preparation of 4-(the bromo-2-chlorobenzyl of 5-) phenol
Under nitrogen protection; lucifuge; by the chloro-2-of bromo-for 4-1-(4-methoxy-benzyl) benzene (226g; 0.73mol) be dissolved in methylene dichloride (2240mL); methylene dichloride (1416mL) solution of boron tribromide (357g, 1.42mol) is slowly dripped under-78 DEG C of conditions.Dropwise, move to room temperature reaction 2h.TLC shows reaction to be completed, slowly water is dripped under ice-water bath condition, get methylene dichloride phase, residue aqueous phase uses methylene dichloride (1L) extracting twice again, merge organic phase, wash with water twice, saturated nacl aqueous solution washes once, anhydrous sodium sulfate drying, rotary evaporation obtains product (210g, productive rate 97%).
(5) (1R, 3r, 5S)-two preparation of ring [3.1.0] hexane-3-alcohol
Under 0 DEG C of condition, zinc ethyl (7.16L, 7.14mol) is added drop-wise in methylene dichloride (9L), dropwise, time in bottle without white cigarette, slowly drip the dichloromethane solution (1L) of trifluoroacetic acid (816g, 7.16mol).Dropwise, after stirring 30min, drip the dichloromethane solution (1L) of methylene iodide (1918g, 7.14mol).Dropwise, after stirring 30min, drip the dichloromethane solution (800mL) of pentamethylene-3-alkene-1-alcohol (200g, 2.38mol), dropwise, rise to room temperature reaction 30min.TLC display reacts completely, pour in saturated ammonium chloride, after stirring 10min, separatory, water intaking uses methylene dichloride (2L) to extract once mutually, gets that organic phase saturated sodium sulfite is washed, saturated sodium bicarbonate is washed, saturated sodium-chloride washs, anhydrous sodium sulfate drying, residuum obtains product (112g, productive rate 48%) through column chromatography.
(6) (1R, 3r, 5S)-two preparation of ring [3.1.0] hexane-3-base methanesulfonates
Under ice-water bath condition, by (1R, 3r, 5S)-two rings [3.1.0] hexane-3-alcohol (112g, 1.14mol) be dissolved in methylene dichloride (1250mL), after adding triethylamine (174g, 1.69mol), slow dropping Methanesulfonyl chloride (197g, 1.72mol).Dropwise, under 0 DEG C of condition, react 30min.TLC display reacts completely, and be poured into water by reaction solution, separatory, get organic phase dilute hydrochloric acid and wash once, wash twice with water, then wash with saturated sodium-chloride, anhydrous sodium sulfate drying, rotary evaporation obtains product (138g, productive rate 68%).
(7) preparation of (1R, 3s, 5S)-3-(4-(the bromo-2-chlorobenzyl of 5-) phenoxy group) two rings [3.1.0] hexane
By (1R, 3r, 5S)-two rings [3.1.0] hexane-3-base methanesulfonates (138g, 0.78mol) be dissolved in N-Methyl pyrrolidone (2.1L), add 4-(the bromo-2-chlorobenzyl of 5-) phenol (210g again, 0.71mol), cesium carbonate (462g, 1.42mol), benzyltriethylammoinium chloride (5.46g, 24mmol).After stirring at room temperature 10min, move to 50 DEG C of conditioned responses and spend the night.TLC display reacts completely, after adding water, with sherwood oil and methyl tertiary butyl ether (sherwood oil: methyl tertiary butyl ether=1: mixing solutions extracting twice 1), merge organic phase, with saturated sodium bicarbonate solution wash twice, saturated sodium-chloride washes twice, anhydrous sodium sulfate drying, rotary evaporation, residuum is through column chromatography (sherwood oil: ethyl acetate=50: 1) obtain product (135g, productive rate 50%).
Molecular formula: C 19h 18brClO molecular weight: 377.71
1H-NMR(400MHz，CDCl 3)δ：7.28-7.21(m，3H)，7.07-7.05(d，2H)，6.82-6.78(m，2H)，4.42-4.35(m，1H)，3.98(s，2H)，2.36-2.31(m，2H)，1.96-1.90(m，2H)，1.40-1.33(m，2H)，0.47-0.44(m，1H)，0.07-0.02(m，1H).
(8) preparation of (3R, 4S, 5R, 6R)-3,4,5-tri-((TMS) oxygen base)-6-(((TMS) oxygen base) methyl) tetrahydrochysene-2H-pyran-2-one
(D)-(+)-gluconic acid-1,5-lactone (85g, 0.47mol) is suspended in THF (tetrahydrofuran (THF)) (932mL); add N-methylmorpholine (405mL, 4.78mol), under nitrogen protection; be cooled to-5 DEG C; by TMSCl (trimethylchlorosilane) (360mL, 4.78mol), dropwise; stirring at room temperature 1h; 35 DEG C are stirred 5 hours, and maintain 25 DEG C of stirrings and spend the night, TLC detection reaction completes.Add toluene (200mL), drip water (1L) under ice-water bath, get organic phase, with SODIUM PHOSPHATE, MONOBASIC wash once, wash once, saturated nacl aqueous solution washes once, dryly concentratedly to obtain product (218g, productive rate 100%).
(9) (3R, 4S, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) preparation of-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol
Under nitrogen protection; by (1R; 3s; 5S)-3-(4-(the bromo-2-chlorobenzyl of 5-) phenoxy group) two rings [3.1.0] hexane (135g, 0.358mol) are dissolved in tetrahydrofuran (THF) (813mL) with toluene (813mL), after being cooled to-78 DEG C; drip n-Butyl Lithium (194mL; 0.465mol), dropwise, after stirring 2h.Extract this reaction solution with syringe and be added to (3R, 4S, 5R, 6R)-3,4,5-tri-((TMS) oxygen base)-6-(((TMS) oxygen base) methyl) tetrahydrochysene-2H-pyran-2-one (218g, in toluene (950mL) solution 0.47mol), after continuing to stir 1h, add methylsulphonic acid (44.9mL, methyl alcohol (1.2L) solution 2.15mol), stirs 1h, rises to room temperature reaction and spend the night at-78 DEG C.TLC detection reaction is complete, adds saturated sodium bicarbonate solution cancellation, and ethyl acetate (2L) extracts, and gets organic phases washed with water, after saturated nacl aqueous solution washes, anhydrous sodium sulfate drying, rotary evaporation obtains product (173g, productive rate 98%).
(10) (3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) preparation of-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
Under-78 DEG C and nitrogen protection condition; by (3R; 4S; 5S; 6R)-2-(3-(4-(((1R; 3s, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4; 5-triol (173g; 0.352mol) be dissolved in methylene dichloride (2L) with triethyl silicane (180mL, 1.05mol), slowly drip boron trifluoride diethyl etherate (134mL; 1.05mol); dropwise, at-78 DEG C, react 1h, slowly rise to room temperature reaction 1h.HPLC detection reaction is complete, and instillation saturated sodium bicarbonate solution, ethyl acetate (1L) extracts, and organic phase is washed through water, saturated nacl aqueous solution, anhydrous sodium sulfate drying, and rotary evaporation obtains product (143g, productive rate 88%).
(11) (2R, 3R, 4R, 5S, 6S)-2-(acetoxy-methyl)-6-(3-(4-(((1R, 3s, 5S)-two ring [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-tri-base triacetate
By (3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (143g, 0.311mol) is dissolved in methylene dichloride (720mL), add pyridine (252mL, 3.11mol) with DMAP (DMAP) (1.9g, 15.6mmol), then drip diacetyl oxide (292mL under ice-water bath, 3.11mol), after stirring at room temperature 3h.Add shrend to go out reaction, ethyl acetate (1.5L) extracts, and gets organic layer, dilute hydrochloric acid wash three times, saturated sodium bicarbonate washes once, washes, saturated sodium-chloride is washed, anhydrous sodium sulfate drying, rotary evaporation, residuum obtains product (81g, productive rate 42%) through ethyl alcohol recrystallization.
(12) (2S, 3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-two ring [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-triol
By (2R, 3R, 4R, 5S, 6S)-2-(acetoxy-methyl)-6-(3-(4-(((1R, 3s, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) tetrahydrochysene-2H-pyrans-3,4,5-tri-base triacetate (81g, 0.129mol) is dissolved in the mixed solvent of tetrahydrofuran (THF) (313mL), methyl alcohol (470mL) and water (156mL), adds monohydrate lithium hydroxide (6.32g, 150mmol), stirred overnight at room temperature.TLC display reacts completely, and rotary evaporation is except desolventizing, and add ethyl acetate (400mL) and dissolve, organic phase is through saturated sodium-chloride water solution, KHSO 4the aqueous solution is washed, wash twice, anhydrous sodium sulfate drying, rotary evaporation, and residuum is prepared into end product (54.2g, productive rate 91%) through C18 reversed-phase preparative chromatography.
Molecular formula: C 25h 29clO 6molecular weight: 460.95 LC-MS (m/z): 478.3 [M+NH 4] +
1H-NMR(400MHz，MeOD)δ：7.35-7.26(m，3H)，7.08-7.06(d，2H)，6.76-6.74(d，2H)，4.45-4.41(m，1H)，4.10-4.00(m，3H)，3.89-3.88(d，1H)，3.71-3.69(m，1H)，3.45-3.38(m，3H)，3.31-3.26(m，1H)，2.34-2.29(m，2H)，1.87-1.81(m，2H)，1.37-1.33(m，2H)，0.43-0.42(m，1H)，0.11-0.10(m，1H).
embodiment 2:(2S, 3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3r, 5S)-two ring [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (formula (III) compound)preparation
(1) preparation of (1R, 3r, 5S)-3-(4-(the bromo-2-chlorobenzyl of 5-) phenoxy group) two rings [3.1.0] hexane
4-(the bromo-2-chlorobenzyl of the 5-) phenol (29.7g that will prepare according to embodiment 1 step (1)-(4) method, 0.10mol) be dissolved in toluene (450mL), add sodium hydroxide (8g successively, 0.20mol), water (27mL), (1R for preparing according to embodiment 1 step (5)-(6) method, 3r, 5S)-two rings [3.1.0] hexane-3-base methanesulfonates (17.6g, 0.10mol), benzyltriethylammoinium chloride (1.05g, 4.61mmol).70 DEG C of reaction 2h.TLC display reacts completely, and add ethyl acetate 500mL extraction, organic phase is dry, and rotary evaporation is except desolventizing, and residuum is through silica gel column chromatography (sherwood oil: ethyl acetate=50: 1) obtain product (10.1g, productive rate 27%).
Molecular formula: C 19h 18brClO molecular weight: 377.71
1H-NMR(400MHz，CDCl 3)δ：7.28-7.21(m，3H)，7.07-7.05(d，2H)，6.76-6.72(d，2H)，4.79-4.76(m，1H)，3.98(s，2H)，2.22-2.16(m，2H)，2.05-2.01(m，2H)，1.35-1.31(m，2H)，0.62-0.58(m，1H)，0.51-0.46(m，1H).
(2) (3R, 4S, 5S, 6R)-2-(3-(4-(((1R, 3r, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) preparation of-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol
By (1R; 3r, 5S)-3-(4-(the bromo-2-chlorobenzyl of 5-) phenoxy group) two rings [3.1.0] hexane (1.5g, 3.97mmol) are dissolved in tetrahydrofuran (THF) (100mL); under nitrogen protection ,-78 DEG C are cooled to.Drip n-Butyl Lithium (2mL, 4.8mmol), after dropwising, under-78 DEG C of conditions, stir 1h.Drip (3R, 4S, 5R, 6R)-3,4, toluene (25mL) solution of 5-tri-((TMS) oxygen base)-6-(((TMS) oxygen base) methyl) tetrahydrochysene-2H-pyran-2-one (3.0g, 6.4mmol), keeps-78 DEG C to react 1h.Add methyl alcohol (50mL) solution of methylsulfonic acid (3.8g, 39.6mmol) again, after keeping-78 DEG C to react 0.5h, room temperature reaction 18h.By reaction solution saturated sodium bicarbonate aqueous solution (100mL) cancellation, then use ethyl acetate (100mL × 3) to extract, merge organic phase, with anhydrous sodium sulfate drying, filter, get filtrate through concentrating under reduced pressure except desolventizing obtains product (1.5g, productive rate 77%).
(3) (3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3r, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) preparation of-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
By ((3R, 4S, 5S, 6R)-2-(3-(4-(((1R, 3r, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol (1.40g, 2.86mmol) be dissolved in the mixing solutions of methylene dichloride (40mL) and acetonitrile (40mL), add triethyl silicane (1.0g, 8.6mmol), under stirring at room temperature, drip boron trifluoride diethyl etherate (1.2g, 8.45mmol), after adding, room temperature reaction 16h.Saturated sodium bicarbonate aqueous solution (100mL) is added in reaction system, add ethyl acetate (100mL × 3) extraction again, merge organic phase, with anhydrous sodium sulfate drying, filter, get filtrate through concentrating under reduced pressure except desolventizing obtains thick product (1.0g, productive rate 76%).
(4) (2R, 3R, 4R, 5S, 6S)-2-(acetoxy-methyl)-6-(3-(4-((1R, 3r, 5S)-two ring [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-tri-base triacetate
By ((3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3r, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3, 4, 5-triol (1.0g, 2.2mmol) be dissolved in methylene dichloride (40mL), add pyridine (1.76mL) and DMAP (13mg), diacetyl oxide (2.07mL) is dripped under condition of ice bath, stirring at room temperature 3h, add water (10mL) cancellation reaction, layering obtains organic phase, aqueous phase ethyl acetate (50mL × 2) extracts, merge organic phase, anhydrous sodium sulfate drying, silica gel column chromatography (sherwood oil: ethyl acetate=2: 1) obtain product (400mg, productive rate 29%).
(5) (2S, 3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3r, 5S)-two ring [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-triol
By (2R, 3R, 4R, 5S, 6S)-2-(acetoxy-methyl)-6-(3-(4-((1R, 3r, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) tetrahydrochysene-2H-pyrans-3,4,5-tri-base triacetate (400mg, 0.64mmol) is dissolved in the mixed solvent of tetrahydrofuran (THF) (5mL), water (5mL) and methyl alcohol (5mL), add monohydrate lithium hydroxide (107.5mg, 2.56mmol), stirring at room temperature 2h, TLC display reaction completes.Rotary evaporation is except after desolventizing, and residuum is through silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1) obtain end product (200mg, productive rate 68%).
Molecular formula: C 25h 29clO 6molecular weight: 460.95
1H-NMR(400MHz，MeOD)d:7.23-7.38(m，3H)，7.07(m，2H)，6.69(m，2H)，4.79(m，1H)，4.06-4.11(m，1H)，3.94-4.05(m，2H)，3.87(m，1H)，3.64-3.73(m，1H)，3.36-3.24(m，4H)，2.19(m，2H)，1.88-2.02(m，2H)，1.26-1.41(m，2H)，0.52-0.60(m，1H)，0.39-0.50(m，1H).
embodiment 3:(2R, 3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-two ring [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-triol (formula IV compound)
(1) (3R, 4S, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) preparation of-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol
By (1R; 3s, 5S)-3-(4-(the bromo-2-chlorobenzyl of 5-) phenoxy group) two rings [3.1.0] hexane (5g, 13.3mmol) are dissolved in tetrahydrofuran (THF) (100mL); under nitrogen protection, be cooled to-78 DEG C.Drip n-BuLi (6.7mL, 15.8mmol), drip rear-78 DEG C of stirring reactions 1 hour.By (3R, 4S, 5R, 6R)-3,4,5-tri-((TMS) oxygen base)-6-(((TMS) oxygen base) methyl) tetrahydrochysene-2H-pyran-2-one (10g, 21.4mmol) is dissolved in toluene (50mL), drop to again in reaction system, keep-78 DEG C to react 1 hour.Add methylsulfonic acid (12.7g, 132mmol) again and be dissolved in methyl alcohol (60mL) solution, room temperature reaction 18 hours.By reaction solution saturated sodium bicarbonate aqueous solution (100mL) cancellation, then use ethyl acetate (100mL × 3) to extract, merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume removes desolventizing and obtains product (4.5g, productive rate 69%).
(2) (3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) preparation of-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
By (3R, 4S, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol (4g, 8.16mmol) is dissolved in the mixing solutions of methylene dichloride (30mL) and acetonitrile (30mL), add triethyl silicane (2.86g, 24.6mmol), under stirring at room temperature, drip boron trifluoride diethyl etherate (3.43g, 24.2mmol), rear room temperature reaction 16 hours are added.Saturated sodium bicarbonate aqueous solution (50mL) is added in reaction system, add ethyl acetate (50mL × 3) extraction again, merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume is except the thick product silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1) purifying obtains product (2mg, productive rate 53%) of desolventizing gained.
(3) (2R, 3R, 4R, 5S, 6R)-2-(acetoxy-methyl)-6-(3-(4-(((1R, 3s, 5S)-two ring [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-tri-base triacetate
By (3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol (1.0g, 2.17mmol) be dissolved in methylene dichloride (20mL), add DIPEA (2.8g, 21.7mmol), the DMAP (25mg) of diacetyl oxide (2.2g, 21.7mmol) and catalytic amount.Stirring at room temperature 2h, reaction mixture 1N hydrochloric acid (15mL) washs, layering obtains organic phase, organic phase anhydrous sodium sulfate drying, filter, filtrate reduced in volume is except desolventizing gained crude product silica gel column chromatography (sherwood oil: ethyl acetate=5: 1) purifying obtains product (0.55g, productive rate 40%).
(4) (2R, 3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-two ring [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-triol
By (2R, 3R, 4R, 5S, 6R)-2-(acetoxy-methyl)-6-(3-(4-(((1R, 3s, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) tetrahydrochysene-2H-pyrans-3,4,5-tri-base triacetate (0.55g, 0.87mmol) is dissolved in the mixed solvent (25mL of water, methyl alcohol and tetrahydrofuran (THF), 2: 2: 1) in, add monohydrate lithium hydroxide (0.37g, 8.7mmol), stirred overnight at room temperature.Rotary evaporation is except after desolventizing, add ethyl acetate (10mL × 3) extraction, merge organic phase, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is except desolventizing gained crude product silica gel column chromatography (methylene dichloride: methyl alcohol=10: 1) purifying obtains end product (0.27mg, productive rate 67.5%).
Molecular formula: C 25h 29clO 6molecular weight: 460.95
1H-NMR(400MHz，MeOD)d：7.21-7.31(m，3H)，6.93-7.09(m，2H)，6.74-6.79(m，2H)，4.53-4.63(m，1H)，4.39-4.48(m，1H)，4.14-4.20(m，1H)，3.89-4.11(m，5H)，3.82(m，1H)，3.67(m，1H)，2.32(m，2H)，1.84(m，2H)，1.34(m，2H)，0.43(m，1H)，0.10(m，1H).
embodiment 4:(2R, 3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3r, 5S)-two ring [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-triol (formula (V) compound)
(1) preparation of the chloro-5-iodobenzoyl chloride of 2-
By chloro-for 2-5-iodo-benzoic acid (10.0g, 35.5mmol) be suspended in methylene dichloride (200mL), add N, dinethylformamide (0.05mL), oxalyl chloride (11.3g is dripped at 0 DEG C, 89.0mmol), after dropwising, rise to stirring at room temperature 4 hours.Gained settled solution rotary evaporation is gone out desolventizing, obtains product (10.7g, productive rate 100%), be not purifiedly directly used in the next step.
(2) preparation of (the chloro-5-iodophenyl of 2-) (4-p-methoxy-phenyl) ketone
Chloro-for 2-5-iodobenzoyl chloride (10.7g, 35.5mmol) be dissolved in methylene dichloride (200mL), ice-water bath cools, and adds aluminum chloride (10.4g, 78.2mmol).Drip methylene dichloride (50mL) solution being dissolved with methyl-phenoxide (4.2g, 38.9mmol) again, after dropwising, rise to room temperature, stir 3 hours.Reaction solution is poured into cancellation in frozen water, add 3mol/L hydrochloric acid, separatory, aqueous phase dichloromethane extraction (150mL × 2), organic phase merges, and saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, concentrating under reduced pressure, crude product is through silica gel column chromatography (ethyl acetate: sherwood oil=0 ~ 1: 100) purifying obtains product (12.0g, productive rate 91%).
(3) preparation of 1-chlorine-4-iodine-2-(4-methoxy-benzyl) benzene
By (the chloro-5-iodophenyl of 2-) (4-p-methoxy-phenyl) ketone (12.0g, 32.2mmol) with triethyl silicane (9.86g, 84.8mmol) be dissolved in acetonitrile (200mL), boron trifluoride ethyl ether complex (13.7g is added at 0 DEG C, 96.5mmol), after dropwising, be warming up to 70 DEG C, stir 3 hours.Be cooled to room temperature, add saturated sodium bicarbonate solution cancellation, extraction into ethyl acetate (200mL × 3), organic phase merges, saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, concentrating under reduced pressure, crude product is through silica gel column chromatography (ethyl acetate: sherwood oil=0 ~ 1: 100) purifying obtains product (10.0g, productive rate 87%).
(4) preparation of 4-(2-chloro-5-iodine benzyl) phenol
Be dissolved in methylene dichloride (150mL) by 1-chlorine-4-iodine-2-(4-methoxy-benzyl) benzene (10.0g, 27.9mmol), ice-water bath cools, drip boron tribromide (21g, 83.7mmol), after dropwising, rise to room temperature, stir 3 hours.Add saturated sodium bicarbonate solution cancellation, separatory, aqueous phase is with dichloromethane extraction (150mL × 2), organic phase merges, saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, concentrating under reduced pressure, crude product is through silica gel column chromatography (ethyl acetate: sherwood oil=0 ~ 1: 20) purifying obtains product (8.5g, productive rate 88%).
(5) preparation of (4-(2-chloro-5-iodine benzyl) phenyl oxygen base) t-butyldimethyl silane
By 4-(2-chloro-5-iodine benzyl) phenol (8.5g, 24.7mmol) with triethylamine (5.0g, 49.5mmol) be dissolved in methylene dichloride (200mL), TERT-BUTYL DIMETHYL CHLORO SILANE (5.6g is added at 0 DEG C, 37.1mmol) with 4-(dimethylamino) pyridine (305mg, 2.5mmol), stirring at room temperature is risen to after adding 18 hours.Add water (100mL), separatory, aqueous phase is with dichloromethane extraction (100mL × 2), organic phase merges, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, crude product is through silica gel column chromatography (ethyl acetate: sherwood oil=0 ~ 1: 100) purifying obtains product (10.0g, productive rate 88%).
(6) (3R, 4S, 5S, 6R)-2-(3-(4-((t-butyldimethylsilyi) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-triol
By (4-(2-chloro-5-iodine benzyl) phenyl oxygen base) t-butyldimethyl silane (10.0g, 21.8mmol) be dissolved in the mixing solutions of anhydrous tetrahydro furan (80mL) and toluene (80mL), be cooled to-78 DEG C, slow dropping n-Butyl Lithium (2.4mol/L hexane solution) (13.6mL, 32.6mmol),-78 DEG C are reacted 2 hours, be warming up to-60 DEG C, (3R will be dissolved with, 4S, 5R, 6R)-3, 4, 5-tri-((TMS) oxygen base)-6-(((TMS) oxygen base) methyl) tetrahydrochysene-2H-pyran-2-one (15.3g, toluene (60mL) solution 32.7mmol), disposablely join in reaction solution, react 2 hours at-60 DEG C.Dropping is dissolved with methylsulphonic acid (14.6g, 152.1mmol) methyl alcohol (50mL) solution, and after dropwising, stirred at ambient temperature reacts 17 hours.Add saturated sodium bicarbonate solution cancellation, separatory, aqueous phase is extracted with ethyl acetate (200mL × 3), merge organic phase, saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product (9.0g), is not purifiedly directly used in the next step.
(7) preparation of (3R, 4S, 5S, 6R)-2-(the chloro-3-of 4-(4-hydroxybenzyl) phenyl)-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol
By (3R, 4S, 5S, 6R)-2-(3-(4-((t-butyldimethylsilyi) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3, 4, 5-triol crude product (9.0g) is dissolved in tetrahydrofuran (THF) (70mL), add three hydration tetrabutyl ammonium fluoride (22.1g, 70mmol), stirred at ambient temperature 2 hours, concentrating under reduced pressure, add ethyl acetate (400mL) and water (200mL), separatory, organic phase washed with water washing (200mL × 3), saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product (6.5g), not purifiedly be directly used in the next step.
(8) preparation of (3R, 4R, 5S, 6R)-2-(the chloro-3-of 4-(4-hydroxybenzyl) phenyl)-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
By (3R, 4S, 5S, 6R)-2-(the chloro-3-of 4-(4-hydroxybenzyl) phenyl)-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol crude product (6.5g) and triethyl silicane (4.03g, 34.7mmol) be dissolved in the mixed solvent of methylene dichloride (100mL) and acetonitrile (100mL), boron trifluoride ethyl ether complex (5.6g is dripped at 0 DEG C, 39.5mmol), after dropwising, rise to room temperature, stir 16 hours.Add saturated sodium bicarbonate solution cancellation, extraction into ethyl acetate (250mL × 3), organic phase merges, saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, concentrating under reduced pressure, crude product is through silica gel column chromatography (methyl alcohol: methylene dichloride=0 ~ 1: 15) purifying obtains product (3.8g, 3 step productive rates 46%).
(9) (3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3r, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) preparation of-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
By (3R, 4R, 5S, 6R)-2-(the chloro-3-of 4-(4-hydroxybenzyl) phenyl)-6-(methylol) tetrahydrochysene-2H-pyrans-3, 4, 5-triol (3.8g, 10mmol) with (1R, 3r, 5S)-two rings [3.1.0] hexane-3-base methanesulfonates (3.5g, 20mmol) be suspended in toluene (100mL) and water (10mL), add sodium hydroxide (1.0g successively, 25mmol) with benzyltriethylammoinium chloride (114mg, 0.5mmol), be heated to 80 DEG C of reactions 16 hours, be cooled to room temperature, add water (50mL), separatory, aqueous phase is extracted with ethyl acetate (50mL × 3), organic phase merges, saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product (5.0g), not purifiedly be directly used in the next step.
(10) (2R, 3R, 4R, 5S, 6R)-2-(acetoxy-methyl)-6-(3-(4-(((1R, 3r, 5S)-two ring [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-tri-base triacetate
By (3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3r, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3, 4, 5-triol crude product (5.0g) is dissolved in methylene dichloride (50mL), add pyridine (7.9g, 100mmol) with 4-(dimethylamino) pyridine (122mg, 1mmol), diacetyl oxide (10.2g is added under ice bath, 100mmol), rise to room temperature, stir 4 hours, add water, extraction into ethyl acetate (150mL × 3), organic phase merges, use 1mol/L salt acid elution (150mL × 3) successively, saturated sodium bicarbonate solution washing (150mL), saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, concentrating under reduced pressure, crude product is through silica gel column chromatography (ethyl acetate: sherwood oil=0 ~ 1: 4) purifying obtains product (350mg, 2 step productive rates 5.6%).
(11) (2R, 3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3r, 5S)-two ring [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-triol
By (2R, 3R, 4R, 5S, 6R)-2-(acetoxy-methyl)-6-(3-(4-(((1R, 3r, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-) tetrahydrochysene-2H-pyrans-3,4,5-tri-base triacetate (350mg, 0.56mmol) be dissolved in (1: 2: 2) (25mL) in the mixed solvent of water, methyl alcohol and tetrahydrofuran (THF), add LiOHH 2o (118mg, 2.8mmol), stirring at room temperature 16 hours, concentrating under reduced pressure, adds water (20mL), extraction into ethyl acetate (30mL × 3), merge organic phase, saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, concentrating under reduced pressure, crude product is through silica gel column chromatography (methyl alcohol: methylene dichloride=0 ~ 1: 15) purifying obtains product (140mg, productive rate 54.7%).
Molecular formula: C 25h 29clO 6molecular weight: 460.95
1H-NMR(400MHz，MeOD)δ:7.29-7.31(m，3H)，7.04-7.07(m，2H)，6.68-6.71(m，2H)，4.77-4.81(m，1H)，4.57-4.61(m，1H)，4.15-4.19(m，1H)，3.98-4.05(4H，m)，3.92-3.93(m，1H)，3.80-3.83(m，1H)，3.63-3.68(m，1H)，2.16-2.21(m，2H)，1.94-1.97(m，2H)，1.24-1.34(m，2H)，0.54-0.56(m，1H)，0.39-0.49(m，1H)。

Claims (15)

1. the stereoisomeric compounds of compound shown in formula (I) or its medicinal acceptable salt, wherein said stereoisomeric compounds is selected from formula (II) compound and formula (III) compound:
its name is called (2S, 3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3s, 5S)-two rings [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol
its name is called (2S, 3R, 4R, 5S, 6R)-2-(3-(4-(((1R, 3r, 5S)-two ring [3.1.0] hexane-3-base) oxygen base) benzyl)-4-chloro-phenyl-)-6-(methylol) tetrahydrochysene-2H-pyrans-3,4,5-triol.
2. the preparation method of formula according to claim 1 (II) compound, the method comprises, and is dissolved in by formula b in organic solvent, adds formula a, and control temperature reacts under 0 DEG C to 70 DEG C condition, prepares formula c, formula c with be obtained by reacting formula d-1, formula d-1 carries out deprotection and obtains formula d-2, and formula d-2 is reacted production e temperature-78 DEG C to 30 DEG C of range of condition, and formula e obtains formula II compound through purifying,
Wherein, X represents fluorine, chlorine, bromine or iodine,
G representation hydroxy protecting group; be selected from TMS, triethyl silyl, benzyl, to methoxy-benzyl, to nitrobenzyl, pivaloyl group, allyl group, methoxyl methyl, benzyloxymethyl or trimethylsilyl ethyl; preferably, described G is selected from TMS.
3. the preparation method of formula according to claim 2 (II) compound, wherein said organic solvent is selected from N-Methyl pyrrolidone, DMF, tetrahydrofuran (THF), dioxane and acetonitrile, is preferably N-Methyl pyrrolidone.
4. the preparation method of formula according to claim 2 (II) compound; the purification process that formula e purifying obtains formula (II) compound is: formula e is carried out hydroxyl protection reaction production f; formula f carries out deprotection reaction production (II) compound
Wherein, G ' representation hydroxy protecting group; be selected from ethanoyl, TMS, triethyl silyl, benzyl, to methoxy-benzyl, to nitrobenzyl, pivaloyl group, allyl group, methoxyl methyl, benzyloxymethyl, trimethylsilyl ethyl, propionyl, isobutyryl or benzoyl; preferably, described G ' is selected from ethanoyl, pivaloyl group, propionyl, isobutyryl or benzoyl.
5. the preparation method of formula according to claim 1 (III) compound, the method comprises, and is dissolved in by formula a in organic solvent, adds formula b, and control temperature reacts under 0 DEG C to 70 DEG C condition, prepares formula c ', formula c ' with be obtained by reacting formula d '-1, formula d '-1 carries out deprotection and obtains formula d '-2, and formula d '-2 is reacted production e ' temperature-78 DEG C to 30 DEG C of range of condition, and formula e ' obtains formula (III) compound through purifying,
Wherein, X represents fluorine, chlorine, bromine or iodine,
G representation hydroxy protecting group; be selected from TMS, triethyl silyl, benzyl, to methoxy-benzyl, to nitrobenzyl, pivaloyl group, allyl group, methoxyl methyl, benzyloxymethyl or trimethylsilyl ethyl; preferably, described G is selected from TMS.
6. the preparation method of formula according to claim 5 (III) compound, wherein said organic solvent can be selected from toluene, DMF, tetrahydrofuran (THF), dioxane and acetonitrile, is preferably toluene.
7. the preparation method of formula according to claim 5 (III) compound; the purification process that formula e ' purifying obtains formula (III) compound is: formula e ' is carried out hydroxyl protection reaction production f '; formula f ' carries out deprotection reaction production (III) compound
Wherein, G ' representation hydroxy protecting group; be selected from ethanoyl, TMS, triethyl silyl, benzyl, to methoxy-benzyl, to nitrobenzyl, pivaloyl group, allyl group, methoxyl methyl, benzyloxymethyl, trimethylsilyl ethyl, propionyl, isobutyryl or benzoyl; preferably, described G ' is selected from ethanoyl, pivaloyl group, propionyl, isobutyryl or benzoyl.
8. the intermediate of formula (II) compound as follows,
9. the intermediate of formula (II) compound as follows,
Wherein, X represents bromine or iodine.
10. the intermediate of formula (III) compound as follows,
The intermediate of 11. formula III compounds as follows,
Wherein, X represents bromine or iodine.
12. pharmaceutical compositions comprising formula according to claim 1 (II) and/or formula (III) compound or its medicinal acceptable salt and one or more pharmaceutical carriers and/or thinner are pharmaceutically acceptable arbitrary formulation.
13. pharmaceutical compositions as claimed in claim 12, also comprise one or more ofhypoglycemic medicines, described ofhypoglycemic medicine be selected from phosphoric acid Xi Gelieting, Vildagliptin, BMS-477118, SYR-322, Li Gelieting, for Ge Lieting, Jimmy Ge Lieting, N1,N1-Dimethylbiguanide, phenformin, Yi Xina peptide or Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37].
Application in the medicine that 14. formulas according to claim 1 (II) and/or formula (III) compound or its medicinal acceptable salt treat and/or prevent diabetes (comprising diabetes and the non insulin dependent diabetes of insulin-dependent) or diabetes related diseases (comprising insulin resistance disease and obesity) as the white inhibitor of sodium glucose co-transporter 2 in preparation.
15. methods treating and/or preventing diabetes (comprising diabetes and the non insulin dependent diabetes of insulin-dependent) or diabetes related diseases (comprising insulin resistance disease and obesity), the method comprises the formula according to claim 1 (II) comprising the administration effective dose of people and/or formula (I II) compound or its medicinal acceptable salt that need it.
CN201410004395.2A 2014-01-03 2014-01-03 Optically pure benzyl-4-chlorophenyl C-glucoside derivatives Active CN104761522B (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CN201410004395.2A CN104761522B (en) 2014-01-03 2014-01-03 Optically pure benzyl-4-chlorophenyl C-glucoside derivatives
CN201610635305.9A CN106349201B (en) 2014-01-03 2014-01-03 The C- glycosides derivatives of optically pure benzyl -4- chlorphenyls
JP2014043695A JP6008892B2 (en) 2014-01-03 2014-03-06 Optically pure benzyl-4-chlorophenyl-C-glucoside derivative
KR1020140037632A KR101837488B1 (en) 2014-01-03 2014-03-31 Optically pure benzyl-4-chlorophenyl-c-glucoside derivative
HK15108213.7A HK1207626A1 (en) 2014-01-03 2015-08-25 Optically pure benzyl-4-chlorophenyl c-glucoside derivative -4- c-

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410004395.2A CN104761522B (en) 2014-01-03 2014-01-03 Optically pure benzyl-4-chlorophenyl C-glucoside derivatives

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN201610635305.9A Division CN106349201B (en) 2014-01-03 2014-01-03 The C- glycosides derivatives of optically pure benzyl -4- chlorphenyls

Publications (2)

Publication Number Publication Date
CN104761522A true CN104761522A (en) 2015-07-08
CN104761522B CN104761522B (en) 2017-02-15

Family

ID=53643666

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201410004395.2A Active CN104761522B (en) 2014-01-03 2014-01-03 Optically pure benzyl-4-chlorophenyl C-glucoside derivatives
CN201610635305.9A Active CN106349201B (en) 2014-01-03 2014-01-03 The C- glycosides derivatives of optically pure benzyl -4- chlorphenyls

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201610635305.9A Active CN106349201B (en) 2014-01-03 2014-01-03 The C- glycosides derivatives of optically pure benzyl -4- chlorphenyls

Country Status (4)

Country Link
JP (1) JP6008892B2 (en)
KR (1) KR101837488B1 (en)
CN (2) CN104761522B (en)
HK (1) HK1207626A1 (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105153137A (en) * 2015-09-17 2015-12-16 上海应用技术学院 Preparation method of empagliflozin
WO2017206827A1 (en) * 2016-05-28 2017-12-07 山东轩竹医药科技有限公司 Crystal form of sodium-glucose cotransporter 2 inhibitor
CN108285439A (en) * 2017-01-09 2018-07-17 江苏天士力帝益药业有限公司 A kind of 2 inhibitor of carbon glycoside class sodium glucose transporter body
CN108699098A (en) * 2016-01-04 2018-10-23 第药品株式会社 C- glucose glycoside derivates or its pharmaceutically acceptable salt, the preparation method and pharmaceutical composition comprising it with fused benzene rings
WO2019185026A1 (en) * 2018-03-30 2019-10-03 南京明德新药研发有限公司 Glucoside derivatives acting as inhibitors of sglts, and use thereof
CN112047915A (en) * 2019-06-05 2020-12-08 吉林惠升生物制药有限公司 Novel preparation process of C-glycoside derivatives
CN113045525A (en) * 2021-05-31 2021-06-29 北京惠之衡生物科技有限公司 Preparation method of C-glucoside derivative and preparation thereof
CN113248554A (en) * 2021-06-25 2021-08-13 北京惠之衡生物科技有限公司 Method for synthesizing impurities of C-glucoside derivatives
CN113248464A (en) * 2021-05-31 2021-08-13 北京惠之衡生物科技有限公司 Synthesis method of C-glycoside derivatives
CN113336733A (en) * 2021-05-31 2021-09-03 北京惠之衡生物科技有限公司 Preparation method of L-proline co-crystal of SGLT-2 inhibitor
CN113372315A (en) * 2021-08-12 2021-09-10 北京惠之衡生物科技有限公司 Method for synthesizing impurities of C-glucoside derivatives
CN115073271A (en) * 2022-06-08 2022-09-20 苏州敬业医药化工有限公司 Preparation method of 4' - (5-bromo-2-chlorobenzyl) phenol

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110551088B (en) * 2018-06-01 2022-10-21 北京惠之衡生物科技有限公司 Deuterium-modified benzyl-4-chlorophenyl C-glycoside derivatives
CN110683998A (en) * 2019-11-20 2020-01-14 杭州华东医药集团浙江华义制药有限公司 Preparation method of empagliflozin intermediate

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1653075A (en) * 2002-05-20 2005-08-10 百时美施贵宝公司 C-aryl glucoside SGLT2 inhibitors and method
WO2013000275A1 (en) * 2011-06-25 2013-01-03 山东轩竹医药科技有限公司 C-glycoside derivatives
CN103030617A (en) * 2004-03-16 2013-04-10 贝林格尔.英格海姆国际有限公司 Glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101260130A (en) * 2003-01-03 2008-09-10 布里斯托尔-迈尔斯斯奎布公司 Methods of producing C-aryl glucoside SGLT2 inhibitors
US7772191B2 (en) * 2005-05-10 2010-08-10 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
LT2548871T (en) * 2010-03-18 2017-09-25 Daiichi Sankyo Company, Limited Cycloalkyl-substituted imidazole derivative
WO2012025857A1 (en) * 2010-08-23 2012-03-01 Hetero Research Foundation Cycloalkyl methoxybenzyl phenyl pyran derivatives as sodium dependent glucose co transporter (sglt2) inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1653075A (en) * 2002-05-20 2005-08-10 百时美施贵宝公司 C-aryl glucoside SGLT2 inhibitors and method
CN103030617A (en) * 2004-03-16 2013-04-10 贝林格尔.英格海姆国际有限公司 Glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2013000275A1 (en) * 2011-06-25 2013-01-03 山东轩竹医药科技有限公司 C-glycoside derivatives

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105153137A (en) * 2015-09-17 2015-12-16 上海应用技术学院 Preparation method of empagliflozin
CN108699098A (en) * 2016-01-04 2018-10-23 第药品株式会社 C- glucose glycoside derivates or its pharmaceutically acceptable salt, the preparation method and pharmaceutical composition comprising it with fused benzene rings
CN108699098B (en) * 2016-01-04 2022-01-25 第一药品株式会社 C-glucoside derivative having fused benzene ring or pharmaceutically acceptable salt thereof, preparation method thereof, and pharmaceutical composition comprising same
CN109476624B (en) * 2016-05-28 2021-07-09 吉林惠升生物制药有限公司 Crystalline forms of a sodium-glucose cotransporter 2 inhibitor
WO2017206827A1 (en) * 2016-05-28 2017-12-07 山东轩竹医药科技有限公司 Crystal form of sodium-glucose cotransporter 2 inhibitor
CN109476624A (en) * 2016-05-28 2019-03-15 海南轩竹医药科技有限公司 The crystal form of white 2 inhibitor of sodium glucose co-transporter 2
US10793588B2 (en) 2016-05-28 2020-10-06 Ji Lin Hui Sheng Bio-Pharmaceutical Co., Ltd. Crystal form of sodium-glucose cotransporter 2 inhibitor
CN108285439A (en) * 2017-01-09 2018-07-17 江苏天士力帝益药业有限公司 A kind of 2 inhibitor of carbon glycoside class sodium glucose transporter body
CN108285439B (en) * 2017-01-09 2023-05-02 江苏天士力帝益药业有限公司 Carbonoside sodium glucose transport protein body 2 inhibitor
WO2019185026A1 (en) * 2018-03-30 2019-10-03 南京明德新药研发有限公司 Glucoside derivatives acting as inhibitors of sglts, and use thereof
CN112047915B (en) * 2019-06-05 2023-02-17 北京惠之衡生物科技有限公司 Novel preparation process of C-glycoside derivatives
CN112047915A (en) * 2019-06-05 2020-12-08 吉林惠升生物制药有限公司 Novel preparation process of C-glycoside derivatives
CN113248464A (en) * 2021-05-31 2021-08-13 北京惠之衡生物科技有限公司 Synthesis method of C-glycoside derivatives
CN113336733A (en) * 2021-05-31 2021-09-03 北京惠之衡生物科技有限公司 Preparation method of L-proline co-crystal of SGLT-2 inhibitor
CN113045525A (en) * 2021-05-31 2021-06-29 北京惠之衡生物科技有限公司 Preparation method of C-glucoside derivative and preparation thereof
CN113336733B (en) * 2021-05-31 2022-02-18 北京惠之衡生物科技有限公司 Preparation method of L-proline co-crystal of SGLT-2 inhibitor
CN113248554A (en) * 2021-06-25 2021-08-13 北京惠之衡生物科技有限公司 Method for synthesizing impurities of C-glucoside derivatives
CN113735921A (en) * 2021-06-25 2021-12-03 北京惠之衡生物科技有限公司 Method for synthesizing impurities of C-glucoside derivatives
CN113372315A (en) * 2021-08-12 2021-09-10 北京惠之衡生物科技有限公司 Method for synthesizing impurities of C-glucoside derivatives
CN115073271A (en) * 2022-06-08 2022-09-20 苏州敬业医药化工有限公司 Preparation method of 4' - (5-bromo-2-chlorobenzyl) phenol

Also Published As

Publication number Publication date
CN104761522B (en) 2017-02-15
JP6008892B2 (en) 2016-10-19
CN106349201B (en) 2018-09-18
JP2015129106A (en) 2015-07-16
HK1207626A1 (en) 2016-02-05
CN106349201A (en) 2017-01-25
KR20150081220A (en) 2015-07-13
KR101837488B1 (en) 2018-03-12

Similar Documents

Publication Publication Date Title
CN104761522B (en) Optically pure benzyl-4-chlorophenyl C-glucoside derivatives
CN102656165B (en) Glycoside derivatives and uses thereof
JP4115105B2 (en) Pyrazole derivative
EP2725031B1 (en) C-glycoside derivatives
CN102827122B (en) Glucoside derivate
CN105518014B (en) C aryl glucosides derivative, its preparation method and its application in medicine
CN103748090B (en) Glycosides derivatives and for treating the purposes of diabetes
BR112012008939B1 (en) PROCESS FOR PREPARING COMPOUNDS USEFUL AS SGLT2 INHIBITORS
EP2530079A1 (en) Phenyl c-glucoside derivatives, preparation methods and uses thereof
EP2891654B1 (en) Optically pure benzyl-4-chlorophenyl-C-glucoside derivatives as SGLT inhibitors (diabetes mellitus)
CN101495494A (en) Fused ring spiroketal derivative and use thereof as drug for treating diabetes
WO2004099230A1 (en) Monosaccharide compounds
US9914688B2 (en) Optically pure benzyl-4-chlorophenyl-C-glucoside derivative
CN104619713A (en) Oxabicyclo derivatives, preparation method and use thereof
CN102146066A (en) C-glucoside derivatives containing saturated six-membered ring as well as preparation method and application thereof
ES2928634T3 (en) C-mannoside compounds useful for the treatment of urinary tract infections
CN104109154A (en) C-aryl glucoside derivative, preparation method and applications thereof
CN103270033B (en) C-aryl glucoside derivative and its preparation method and application
CN104817554A (en) Glucoside derivatives and pharmaceutical compositions thereof
CN103421068A (en) Heteroaryl phosphamide compounds with antiviral activity
CN111518157B (en) Triptolide derivative and preparation method and application thereof
CN110551088B (en) Deuterium-modified benzyl-4-chlorophenyl C-glycoside derivatives
CN116217621B (en) Nucleoside double-prodrug, synthesis method and application
CN104250239B (en) The polycyclic carboxylic acid derivates of fragrance
CN114599643A (en) Aryl glucoside derivative

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
EXSB Decision made by sipo to initiate substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1207626

Country of ref document: HK

C14 Grant of patent or utility model
GR01 Patent grant
REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1207626

Country of ref document: HK

TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20171226

Address after: Room 4905, exhibition square, 1 Hong Kong Bay Road, Wan Chai, Hongkong, China

Co-patentee after: XUANZHU PHARMA Co.,Ltd.

Patentee after: SIHUAN PHARMACEUTICAL HOLDINGS Group Ltd.

Address before: Tianchen Avenue, Ji'nan hi tech Development Zone of Shandong Province, No. 2518 250101

Patentee before: XUANZHU PHARMA Co.,Ltd.

TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20190715

Address after: 250101 No. 2518 Tianchen Road, Jinan High-tech Zone, Shandong Province

Patentee after: XUANZHU PHARMA Co.,Ltd.

Address before: Room 4905, Office Building, Exhibition Plaza, 1 Harbour Road, Wanchai, Hong Kong, China

Co-patentee before: XUANZHU PHARMA Co.,Ltd.

Patentee before: SIHUAN PHARMACEUTICAL HOLDINGS Group Ltd.

TR01 Transfer of patent right

Effective date of registration: 20191018

Address after: Room 510, building 2, No. 88, Kechuang 6th Street, Beijing Economic and Technological Development Zone, Beijing 100176

Patentee after: Xuanzhu (Beijing) Pharmaceutical Technology Co.,Ltd.

Address before: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 2518

Patentee before: XUANZHU PHARMA Co.,Ltd.

TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20200925

Address after: 135000 No. 666, Kangmei Avenue, Meihekou City, Tonghua City, Jilin Province

Patentee after: Jilin Huisheng biopharmaceutical Co.,Ltd.

Patentee after: Beijing huizhiheng Biotechnology Co.,Ltd.

Address before: Room 510, building 2, No. 88, Kechuang 6th Street, Beijing Economic and Technological Development Zone, Beijing 100176

Patentee before: Xuanzhu (Beijing) Pharmaceutical Technology Co.,Ltd.

TR01 Transfer of patent right
CP03 Change of name, title or address

Address after: 135007 No. 666, Kangmei Avenue, Meihekou City, Tonghua City, Jilin Province

Patentee after: Jilin Huisheng Biopharmaceutical Co.,Ltd.

Patentee after: Beijing huizhiheng Biotechnology Co.,Ltd.

Address before: NO.666 Kangmei Avenue, Meihekou City, Tonghua City, Jilin Province

Patentee before: Jilin Huisheng biopharmaceutical Co.,Ltd.

Patentee before: Beijing huizhiheng Biotechnology Co.,Ltd.

CP03 Change of name, title or address
PE01 Entry into force of the registration of the contract for pledge of patent right
PE01 Entry into force of the registration of the contract for pledge of patent right

Denomination of invention: Optically pure C-glycoside derivatives of benzyl-4-chlorophenyl

Effective date of registration: 20231013

Granted publication date: 20170215

Pledgee: Jilin Bank Co.,Ltd. Tonghua Meihekou Branch

Pledgor: Jilin Huisheng Biopharmaceutical Co.,Ltd.

Registration number: Y2023220000102

PC01 Cancellation of the registration of the contract for pledge of patent right

Granted publication date: 20170215

Pledgee: Jilin Bank Co.,Ltd. Tonghua Meihekou Branch

Pledgor: Jilin Huisheng Biopharmaceutical Co.,Ltd.

Registration number: Y2023220000102