CN107880006B - The compound as SGLT-2 inhibitor containing cyclohexane structure - Google Patents
The compound as SGLT-2 inhibitor containing cyclohexane structure Download PDFInfo
- Publication number
- CN107880006B CN107880006B CN201711195816.4A CN201711195816A CN107880006B CN 107880006 B CN107880006 B CN 107880006B CN 201711195816 A CN201711195816 A CN 201711195816A CN 107880006 B CN107880006 B CN 107880006B
- Authority
- CN
- China
- Prior art keywords
- compound
- application
- sglt
- agent
- reaction
- 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.)
- Active
Links
Classifications
-
- 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
Abstract
The present invention relates to the compounds as SGLT-2 inhibitor, have better choice with C- glucoside and cyclohexane structure structure, and to SGLT-2.
Description
Technical field
The application provides novel to be controlled as the compound of SGLT-2 inhibitor, containing their compositions and using them
The method for treating or preventing diabetes and related pathologies.
Background technique diabetes are the gradually debilitating illnesss to grow in intensity, lead to various capilaries and big blood vessel
Complication.The most common type type-2 diabetes mellitus of diabetes is characterized in that and the compensatory hyperinsulinaemia in a period of time
The relevant cumulative insulin resistance of hypoinsulinism afterwards.
Entitled sodium-glucose-cotransporter (the sodium-dependent glucose of SGLT Chinese
Transporters), mainly there are SGLT-1 and SGLT-2.SGLT-1 is mainly distributed on small intestine, related with the absorption of glucose,
It is distributed in that renal proximal tubules are S3 sections farther away, the glucose of reabsorption 10%, it is close bent small that SGLT-2 albumen is then distributed in kidney
Pipe is responsible for most glucose (90%) in glomerular filtrate being transported into blood again, to maintain internal blood
The stabilization and balance of sugar.SGLT protein inhibitor by block the albumen transporting mechanism, make glucose with urine discharge to
Blood glucose is reduced, thus is not relying on insulin mechanism, all there is therapeutic effect for I type and type-2 diabetes mellitus, and be not susceptible to
Hypoglycemia is dangerous, does not increase diabetic's weight.
Studies have shown that can lead to serious diarrhea or even threat to life when SGLT-1 is blocked, and SGLT-2 is suppressed
When, only lead to kidney discharge sugar, there is no apparent adverse reactions.
The SGLT-2 inhibitor found earliest is natural products phloridzin (Phlorizin), but since it is easy to be internal
Glycosidase be hydrolyzed into glucosides and phloretin, and to the poor selectivity of SGLT-1 and SGLT-2, adverse reaction is larger, therefore does not have
There is the therapeutic agent as diabetes.The existing 6 kinds of SGLT-2 inhibitor listing in the whole world at present, is respectively as follows: Canagliflozin
(canagliflozin), Dapagliflozin (Dapagliflozin), Empagliflozin (En Gelie is net), Ipragliflozin are (according to lattice
Column are net), Luseogliflozin (glug column are net) and Tofogliflozin (tofogliflozin).Wherein, Bristol Myers Squibb is public
The Dapagliflozin of department has passed through the approval of FDA, EU Committee and state food pharmaceuticals administration general bureau (CFDA) in beauty
State, Europe and Discussion on Chinese Listed.
It remains desirable, however, that more SGLT-2 inhibitor are developed, especially for the chemical combination of SGLT-2 selective depression
Object.
High Yunlong of Shandong University etc. finds that the compound that C ring is hexamethylene has better than Dapagliflozin in the course of the research
Inhibiting rate, however, not having a report that B ring is replaced with to hexamethylene at present.
This application involves the compound of Formula I of the novel ability for having and adjusting SGLT-2, above compound potentially may be used
For treating or preventing diabetes and related pathologies.The compound has novel structure, i.e., the B ring being connected with saccharide ring is flexibility
Cyclohexane structure.
Summary of the invention
The application provides substituted compound of Formula I and its tautomer, the pharmaceutical salts that can be used as SGLT-2 inhibitor.
The application, which also provides, is used to prepare the application compound or its tautomer, the method for pharmaceutical salts and intermediate.
The application also provides pharmaceutical composition, and it includes pharmaceutical carrier and at least one the application compound or its mutually variations
Structure body, pharmaceutical salts.
The application compound can be used for treating and/or preventing a variety of diseases relevant to SGLT-2 or obstacle, such as glycosuria
Disease and related pathologies, microvascular complication relevant to diabetes, macrovascular complications relevant with diabetes, cardiovascular disease
Disease, metabolic syndrome and its composition symptom, impaired glucose metabolism, obesity and Other diseases.
The application compound can be used in therapy.
The application compound can be used for preparing for treating and/or preventing a variety of diseases relevant to SGLT-2 or obstacle
Drug.
The application compound can be used alone, join with the other compound combinations of the application or with one or more other medicaments
With.
Specific embodiment
I. the application compound
In the first aspect, the application especially provides compound of formula I or its tautomer, pharmaceutical salts:
Wherein:
R1It is selected from: C1-6Alkyl, C3-6Naphthenic base or C3-6Naphthenic base C1-3Alkyl, the C1-6Alkyl can be by the cycloalkanes
Base can be replaced by hydroxyl, amino, halogen, the C3-6Naphthenic base can be by hydroxyl, amino, halogen or C1-3Alkyl replaces.
Preferably, R1Selected from C1-6 alkyl, the C1-6Alkyl can be by hydroxyl, amino, halogen by the naphthenic base
Replace.
In the second aspect, the application provides the compound or its tautomer, pharmaceutical salts for being selected from exemplary embodiment.
In preferred embodiments, the application compound has≤0.02 μM of hSGLT-2EC50Value, and its is right
The selectivity of hSGLT-2/hSGLT-1 is at 1000 times or more.
II. the other embodiments of the application
In another embodiment, the application provide composition, it includes at least one the application compound or its mutually
Tautomeric, pharmaceutical salts.
In another embodiment, the application provides pharmaceutical composition, and it includes pharmaceutical carriers and this at least one Shen
It please compound or its tautomer, pharmaceutical salts.
In another embodiment, the application provides pharmaceutical composition, and it includes pharmaceutical carrier and therapeutically effective amounts
At least one the application compound or its tautomer, pharmaceutical salts or solvate.
In another embodiment, the application offer is used to prepare the application compound or its tautomer, medicinal
The method of salt.
In another embodiment, the application offer is used to prepare the application compound or its tautomer, medicinal
The intermediate of salt.
In another embodiment, the application is provided for treating and/or preventing a variety of diseases relevant to SGLT-2
Or the method for obstacle comprising to need the patient of above-mentioned treatment and/or prevention individually or optionally with another the applicationization
Close at least one the application compound of object and/or at least one other type therapy agent combination medicine-feeding therapeutically effective amount.
Can be prevented according to the application, adjust or treatment include to the example of the SGLT-2 relevant disease of activity or illness but
It is not limited to diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes mellitus, insulin resistance, hyperinsulinemia, view
The renal syndrome of film lesion, neuropathy, nephropathy, nephrosis, acute kidney injury, the heart, acute coronary syndromes
Sign, wound healing delay, atherosclerosis and its sequelae, core function abnormality, congestive heart failure, myocardial ischemia, in
Wind, metabolic syndrome, hypertension, obesity, Fatty Liver Disease.
In another embodiment, the application is provided for treating and/or preventing diabetes, hyperglycemia, gestation sugar
Urinate the method for disease, obesity, dyslipidemia, hypertension and cognitive impairment comprising to the trouble for needing above-mentioned treatment and/or prevention
Person is individually or optionally effective with another the application compound and/or the treatment of at least one other type therapy agent combination medicine-feeding
At least one the application compound of amount.
In another embodiment, the application provides the application compound being used in therapy.
The application can be implemented in other specific forms, without departing from its spirit or essential characteristics.The application covers herein
All combinations of mentioned the application preferred aspect.It should be understood that any and all embodiment of the application is combinable
Any other embodiments or multiple embodiments describe other embodiments.It is to be further understood that embodiment is every
One individual element is its own independent embodiment.In addition, any element of embodiment is intended to and any embodiment
Any and all other factor combination is to describe other embodiments.
III. chemical
Depending on method condition, the application final product is obtained with free (neutrality) or salt form.These final products
Free form and salt are within the scope of the application.If it is required, then another form can be converted to a kind of form of compound.
Free alkali or acid can be converted to salt；Salt can be converted to free compound or another salt；It can be by the application isomers chemical combination
The mixture of object is separated into individual isomers.The application compound, its free form and salt can be with a variety of tautomerism bodily forms
Formula exists, and wherein hydrogen atom is transposed in the other parts of molecule and thus the chemical bond between the atom of molecule is reset.
It should be understood that all tautomeric forms that may be present are included in the application.
The term as used herein " alkyl " is intended to include branch and straight-chain radical of saturated aliphatic alkyl with specified carbon atom number
Group.For example, " C1-6Alkyl " indicates the alkyl with 1 to 6 carbon atom.Similarly, C3-6Naphthenic base then indicates there is 3-6 on ring
The naphthenic base of a carbon atom.
Term " pharmaceutical " is used to refer to herein those following compounds, substance, composition and/or dosage form: reasonable
In the range of medical judgment, suitable for contacting use with the tissue of human and animal without high toxicity, irritation, allergic reaction excessively
And/or other problems or complication and match with reasonable benefit/risk ratio.
In addition, compound of formula I can have prodrug forms.Prodrug in the application scope and spirit be in vivo convert with
Any compound of bioactivator (i.e. compound of formula I) is provided.The various forms of prodrug is as known in the art.
The application compound can be prepared with various ways known to organic synthesis field technical staff.Following sides can be used
In method and synthetic organic chemistry field known synthetic method or by its version that those skilled in the art are understood come
Synthesize the application compound.Preferred method includes but is not limited to those described below method.It is being suitable for agents useful for same and substance
And it is suitable for implementing reaction in the solvent or solvent mixture of the conversion realized.Organic synthesis field technical staff should understand that
It is that functional group present on molecule should be consistent with the conversion proposed.Sometimes this is judged to modify synthesis step
Rapid sequence selects a kind of specific program scheme rather than another kind is to obtain the application desired compound.
Reaction described in this part and technology can be used to prepare the application compounds.Equally, it is described below
In the explanation of synthetic method, it should be appreciated that all proposition reaction conditions (including solvent selection, reaction atmosphere, reaction temperature
Degree, duration of experiment and post processor) standard conditions for being used for the reaction are selected, the condition should be by art technology
Personnel readily recognize.It will be apparent for a person skilled in the art that the limitation of the substituent group compatible with reaction condition, then
Alternative must be used.
The synthesis of compound
It can be used by the illustrative methods described in following scheme and working Examples and those skilled in the art
Related open source literature program carry out preparation of compounds of formula I.
Scheme 1:
3- cyclohexenecarboxylic acid (not splitting) and HBr addition, the isolated bromo- hexahydrobenzoid acid of 3-, after acyl chloride reaction with
Phenyl alkyl ether reaction, carbonyl reduction reaction, later again with 2,3,4,6- tetra--D- trimethyl silicon substrates-D-Glucose acid lactone is anti-
It answers, extra methoxyl group obtains final product on last deprotection base and saccharide ring.
It is mentioned briefly above the synthetic route of compound, specific synthesis step is shown in embodiment part.
The characterization of compound
HPLC/MS method used in the characterization or purifying of compound:
Using following methods in Shimadzu SCL-10A liquid chromatograph and Waters ZQ mass spectrograph (desolvation gas
Body: nitrogen；Desolvation temperature: 250 DEG C；Ion source temperature: 120 DEG C；Positivity electrospray conditions) on implement analytic type HPLC/
MS (unless otherwise indicated): the linear gradient of 0%-100% solvent B lasts 2min, wherein keeping 1min in 100%B；?
220nm UV is visible；Column: Luna C18 (2) 30mm × 4.60mm；5m particle (is heated to 40 DEG C of temperature)；Flow velocity: 5mL/min；
Solvent A: 10%ACN, 90% water, 0.1%TFA；Or 10%MeOH, 90% water, 0.1%TFA；With solvent B:90%ACN,
90% water, 0.1%TFA；Or 90%MeOH, 10% water, 0.1%TFA.
Using following method, analytic type HPLC (unless otherwise indicated) is carried out on Shimadzu SIL-10A with determinization
It closes object purity (retention time that the retention time unless otherwise indicated, being listed in embodiment refers to the 1st column):
Orthogonal method:
The linear gradient of 10%-100% solvent B lasts 15min；It is visual that UV is carried out in 220nm and 254nm；Column 1:
SunFire C183.5μm,4.6x150mm；3.5 μm of column 2:Xbridge Phenyl, 4.6x150mm；Flow velocity: 1mL/min is (right
For two columns)；Solvent A: 5%MeCN-95%H2O-0.05%TFA；Solvent B:95%MeCN-5%H2O-0.05%
TFA。
Or
Zorbax method
The linear gradient of 10%-100% solvent B lasts 8min；UV visualization is carried out in 220nm；Column:
ZorbaxSBC183.5μm,4.6x75mm；Flow velocity: 2.5mL/min；Solvent A: 10%MeOH-90%H2O-0.2%H3PO4；
With solvent B:90%MeOH-90%H2O-0.2%H3PO4.
Or
Analytic type LC/MS method
Gradient: 0-100%B lasts 3min, then keeps 0.75min in 100%B；UV visualization is carried out in 220nm；Column:
Waters XBridge UPLC BEH C18,2.1 × 50mm, 1.7- μm of particle；Mobile phase A: the 5:95 with 10mM ammonium acetate
Acetonitrile: water；Or 5:95 has the acetonitrile of 0.05%TFA: water；Mobile phase B: the 95:5 acetonitrile with 10mM ammonium acetate: water；Or
Person 95:5 has the acetonitrile of 0.05%TFA: water；Temperature: 50 DEG C；Flow velocity: 1.11mL/min.
NMR employed in the characterization of compound
It is obtained using the Bruker conversion light spectrometer operated at 400MHz1H NMR spectra (unless otherwise indicated).
The report spectroscopic data in the form of chemical shift (multiplicity, hydrogen number, coupling constant (being indicated by Hz)), and for1H
It is reported in the form of the ppm (δ unit) relative to internal standard object (tetramethylsilane=0ppm) for NMR spectra, or
Referring to residual solvent peak, (CD3SOCD2H 2.49ppm, CD2HOD 3.30ppm, CHD2CN 1.94, CHCl3 are
7.26ppm, CDHCl2 5.32ppm.
IV. biology
External hSGLT-1/hSGLT-2 measurement
Intracellular Ca2+ measurement based on FDSS
Using pDEST 3 × flag gene expression system generate expression hSGLT-1/hSGLT-2 cell line and by its
Cultivate in culture medium comprising following components: F12 (Gibco number 11765), 10% deprive the fetal calf serum of lipid, 250 μ g/
ML bleomycin (zeocin) and 500 μ g/mL G418.It is surveyed to implement the calcium flux based on fluorescence imaging plate readout instrument (FLIPR)
It is fixed to measure intracellular Ca2+Reaction, is put down the cell for expressing hSGLT-2 with 20,000 cells/20 μ L culture mediums/hole density
It is layered in phenol red and serum-free DMEM (the Gibco number 21063-029) in 384 orifice plates (BD Biocoat number 356697) simultaneously
It is incubated overnight.Using BD kit number 80500-310 or 80500-301, there is the third sulphur of 1.7mM using 20 holes μ L/ at 37 DEG C
Relax (probenecid) and Fluo-3 hanks buffer salt solution (Hank ' s buffered salt solution) by cell
Incubate 30min.Compound is dissolved in DMSO and is diluted to expectation concentration with measurement buffer and with 3 × solution (20 μ L/
Hole) it is added in cell.Fluorescence/luminescence reader FDSS (Hamamatsu) is run to read intracellular Ca2+Response.
Untested compound is configured to 10 μM of solution, 5 times of dilution, obtains a series of samples to be tested every time.By above-mentioned
IC is calculated using origin software after method test50Value, test result are as shown in table 1.
Table 1
As seen from Table 1, this application provides a kind of the SGLT-2 inhibitor with novel structure, the change being currently prepared
It closes object activity and is slightly below Dapagliflozin etc., but there is preferable selectivity, subsequently through the fractionation and substitution of chiral structure
The modification of base is expected to obtain the compound of better effect.By the data of embodiment 1-3, those skilled in the art can be reasonable
Deducing compound with similar structure also has preferable selectivity.
V. it applies
The application compound has the activity as SGLT-2 regulator, and thus can be used for treating and SGLT-2 activity phase
The disease of pass.Via adjusting SGLT-2, the application compound can be preferably used as adjusting insulin and/or intestinal hormones (such as
GLP-1, GIP, PYY, CCK and amylin) generation/secretion.
Therefore, the application compound can be administered to mammal (the preferably mankind) to treat various symptom and illness, including
But be not limited to treat, prevent or slow down the progress of following disease: diabetes and related pathologies, capilary relevant to diabetes are simultaneously
Send out disease, macrovascular complications relevant to diabetes, cardiovascular disease, metabolic syndrome and its various composition symptom, inflammatory disease
Disease and Other diseases.Therefore it is believed that the application compound can be used for preventing, inhibit or treat diabetes, hyperglycemia, glucose
Tolerance is impaired, gestational diabetes mellitus, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, diabetes
Property nephrosis, acute kidney injury, the renal syndrome of the heart, acute coronary syndrome, wound healing delay, atherosclerosis and
Its sequelae (acute coronary syndrome, myocardial infarction, angina pectoris, peripheral artery disease, intermittent claudication, myocardial ischemia,
Apoplexy, heart failure), metabolic syndrome, hypertension, obesity, Fatty Liver Disease, dyslipidemia, hyperlipidemia, high triglyceride
Mass formed by blood stasis, hypercholesterolemia, low HDL, high LDL, reangiostenosis, peripheral arterial disease, lipid disorders disease, such as NASH are (non-
Alcoholic fatty liver is scorching), hepatopathys, neurodegenerative disease, the cognition such as NAFLD (nonalcoholic fatty liver disease) and cirrhosis damage
Wound, dull-witted and treatment side effect relevant to diabetes, lipodystrophy and the sclerotin as caused by corticosteroid treatment are dredged
Loose disease.
Dosage form (pharmaceutical composition) suitable for administration can contain about 1 milligram to about 2000 milligrams active constituent/dosage unit.
In these medical compositions, with the total weight of composition, active constituent usually by with about 0.1 weight % to 95 weight %'s
Amount exists.
Exemplary capsule agent for oral administration contain at least one the application compound (250mg), lactose (75mg) and
Magnesium stearate (15mg).It passes the mixture through 60 mesh sieves and is packaged into No. 1 gelatine capsule.
Typical injectable formulation can be prepared as follows: be set at least one the application compound (250mg) with sterile manner
It is lyophilized and seals in bottle, with sterile manner.For carry out using, vial content is mixed with 2mL physiological saline, with generate
Injectable formulation.
The application range includes at least one the applicationization that (combining individually or with pharmaceutical carrier) includes therapeutically effective amount
Close pharmaceutical composition of the object as active constituent.Optionally, the application compound can be used alone, with the other compounds of the application
Combination is combined with one or more other therapeutic agents (such as antidiabetic or other pharmaceutically active substances).
The application compound can be with other SGLT-2 regulators or its one or more that can be used for treating above-mentioned illness
Its suitable therapeutic agent combination, the therapeutic agent includes: antidiabetic, antihyperglycemic agents, anti-hyperinsulinemia agent, anti-view
The agent of film lesion, anti-neuropathy agent, anti-nephropathy agent, antiatherosclerotic, antiischemic agents, rescinnamine, anti-obesity
Agent, lipidemia agent, anti hypertriglyceridemia agent, anti-hypercholesterolemiccompounds agent, anti-restenosis agent, resists anti-lipid abnormal agent
Pancreatitis agent, lipid lowering agent, anoretic, memory enhancers, anti-dull-witted agent, cognition promotor, appetite inhibitor, heart failure therapy
Agent, peripheral arterial disease therapeutic agent and anti-inflammatory agent.
If desired, the application compound can be with one or more other type antidiabetic agent and/or one kind or more
The other type therapy agent combinations of kind, can be administered orally, with one dosage type low temperature with separated oral dosage form or by being administered to
Medicine.Optionally with the application SGLT-2 receptor modulators associated with other type antidiabetic agent can be a kind of, two kinds, three kinds
Or more antidiabetic or antihyperglycemic agents, the antidiabetic or antihyperglycemic agents can be taken orally with one dosage type low temperature to
Medicine, with separated oral dosage form or by drug administration by injection to generate other pharmacologic benefits.
With the application compound associated with antidiabetic include but is not limited to insulin secretagogue element or insulin sensitizer,
Other SGLT-2 receptor modulators or other antidiabetics.These medicaments include but is not limited to inhibitors of dipeptidyl IV
(DPP4i；For example, sitagliptin, saxagliptin, Egelieting, vildagliptin), (such as melbine, benzene second are double for biguanides
Guanidine), sulfonyl ureas (such as glibenclamide, Glimepiride, Glipizide), glucosidase inhibitor (such as acarbose,
Miglitol), PPAR gamma agonist (such as thiazolidinediones (such as Rosiglitazone, Pioglitazone), PPAR α/γ it is dual swash
Dynamic agent (such as Mo Geliezha, replace Ge Liezha, aleglitazar), activators of glucokinase (such as Fyfe, M.C.T.et al., Drugs
Of the Future, 34 (8): described in 641-653 (2009), and by this, it is incorporated herein by reference), it is other
SGLT-2 receptor modulators (such as TAK-875), GPR119 receptor modulators (such as MBX-2952, PSN821, APD597),
GPR120 receptor modulators (such as institute in such as Shimpukade, B.etal.J.Med.Chem.2012,55 (9), 4511-4515
State), sodium-glucose transporter -2 (SGLT2) inhibitor (such as Dapagliflozin, canagliflozin, Yi Palie are net, Rui Gelie is net),
11b-HSD-1 inhibitor (such as MK-0736, BI35585, BMS-823778 and LY2523199), MGAT inhibitor are (such as such as
Barlind,J.G.et al.Bioorg.Med.Chem.Lett.2013,23(9),2721-2726；Or US
Described in 20130143843A1), amylin analogs (such as pramlintide) and/or insulin.About for treating diabetes
Summary that is current and that therapy newly occur can be found in: Mohler, M.L.etal., MedicinalReseaRch Reviews, 29
(1):125-195(2009),andMizuno,C.S.etal.,Current Medicinal Chemistry,15:61-74
(2008)。
The SGLT-2 receptor modulators of Formulas I are also optionally combined with the medicament for treating diabetic complication.These
Medicament includes pkc inhibitor and/or AGE inhibitor.
The SGLT-2 receptor modulators of Formulas I are also optionally combined with one or more reduction appetite agent, the reduction food
Agent is intended to as (for example) diethylpropion, phendimetrazine, Phentermine, orlistat, sibutramine, lorcaserin, pramlintide, support pyrrole
Ester, MCHR1 receptor antagonist, oxyntomodulin, naltrexone, amylin peptide, NPY Y5 receptor modulators, NPY Y2 receptor tune
Agent, NPY Y4 receptor modulators, west are saved for taking charge of he, 5HT2c receptor modulators etc..The compound of structure I can also be with pancreas hyperglycemia
Agonist (such as Exenatide, Liraglutide, GPR-1 (1-36) amide, GLP-1 (7-36) of plain 1 receptor of sample peptide (GLP-1R)
Amide, GLP-1 (7-37)) combination is (disclosed in U.S. Patent No. 5,614,492 of such as Habener, by reference
The disclosure content of the patent is incorporated herein), the medicament can via injection, through intranasal or given by percutaneous or buccal device
Medicine.About for treat the current of obesity and newly there is therapy summary can be found in: Melnikova, I.et al., Nature
Reviews Drug Discovery,5:369-370(2006)；Jones,D.,Nature Reviews:Drug
Discovery,8:833-834(2009)；Obici,S.,Endocrinology,150(6):2512-2517(2009)；and
Elangbam,C.S.,Vet.Pathol.,46(1):10-24(2009)。
When being combined with the application compound, above-mentioned other therapeutic agents can be in above-mentioned patent or by ordinary skill
The amount that personnel determine in other ways uses.
By the application, it will be apparent for a person skilled in the art that make each component in the application combination product (no matter
With single formulation be administered or be administered in same time by same way with divided mode) between contact minimum these shapes
Formula and other forms.
The application compound can be administered alone or with one or more other therapeutic agent combination medicine-feedings." combination medicine-feeding " or
" combination treatment " means to be administered simultaneously the application compound and one or more other therapeutic agents to treated mammal.Work as group
When closing administration, each component can be administered simultaneously or sequential administration in any order in different time points.Therefore, administration each group can be separated
Divide but the time is close enough to provide desired response to treatment.
The application compound also acts as the test for being related to SGLT-2 receptor or standard or reference compound in measurement, example
Such as it is used as quality standard or control.Above compound may be provided in commercial kit for being related to SGLT-2 or anti-diabetic
Active study of pharmacy.For example, the application compound can be used as reference in measurement with compare its known activity with unknown
Active compound.This will ensure that experimenter is appropriately carried out measurement and provides and compares foundation, especially test compound as ginseng
In the case of the derivative for examining compound.When the new measurement of research and development or scheme, the application compound can be used to test its validity.
The application compound can also be used to be related in the diagnostic assay of SGLT-2.
It is evident that the application other feature, gives described show during being described below exemplary implementation scheme
Example property embodiment is for illustrating the application and being not intended to limit the application.
Embodiment
Embodiment 1
40% hydrobromic acid solution (50ml, 0.36mol) is added in 3- cyclohexenecarboxylic acid II (commercially available 25g, 0.2mol) at room temperature,
It is stirred to react 6h, ethyl acetate extraction is concentrated, and silica gel chromatograph post separation obtains 3- bromo- hexahydrobenzoid acid III (8.2g, yield
40%).
By 3-Br- hexahydrobenzoid acid III (4.1g, 20mmol) anhydrous DMF (0.1ml) and methylene chloride (20ml) in ice water
Lower stirring is bathed, is added dropwise oxalyl chloride (2.6ml, 30mmol), continues to stir 2h after being added dropwise to reaction solution clarification.It removes under reduced pressure molten
Agent is added methylene chloride (5ml) in residue and methyl phenyl ethers anisole, ice salt bath is cooled to -10 DEG C hereinafter, anhydrous aluminum chloride is added portionwise
0.6g*5 times, control reaction temperature is no more than 0 DEG C, the reaction was continued after addition 3h.Mixed liquor is added in trash ice, pH is adjusted
To neutrality, stood after stirring.Organic phase is separated, with methylene chloride aqueous phase extracted 5ml*2 times, merges organic phase.Organic phase is with full
With brine It 10ml*2 times, filter, be concentrated to get white solid IV4.8g.
Under nitrogen atmosphere, THF (50ml) and sodium borohydride (0.77g, 20mmol) is added in above-mentioned white solid.Stir 1h
Afterwards, ice salt bath be cooled to -10 DEG C hereinafter, anhydrous aluminum chloride is added portionwise 0.6g*5 times and control reaction temperature be no more than 0 DEG C, delay
Slowly being warming up to 0 DEG C is stirred to react 3h, then heated overnight at reflux.Decompression steams THF, is cooled to room temperature, and slowly plus water removed
Measure sodium borohydride.Stir 3h in ice bath, be extracted with ethyl acetate, merge organic phase, saturated common salt water washing, drying, filtering,
Concentration, residue obtain white solid V3.9g with re crystallization from toluene.
Under anhydrous and oxygen-free condition, ice salt bath are cooling, 2,3,4,6- tetra--D- trimethyl silicon substrates-D-Glucose acid lactone
(10mmol, the compounds Shi Changyong intermediate such as synthesis Dapagliflozin, can be obtained using N-methylmorpholine/THF condition) is dissolved in 15ml
In tetrahydrofuran, the tetrahydrofuran that the LiCl that 20ml contains methyl Grignard and 1mol/L that concentration is 1mol/L is added dropwise is molten
The KI (0.02-0.03g) of catalytic amount is added in liquid, stirs 2h.The tetrahydrofuran solution 10ml of suspension V (3.1g) is added dropwise, control is anti-
Temperature is answered not higher than -10 DEG C, the reaction was continued 3h.The methanol solution 40ml of methanesulfonic acid (MSA, 4ml) is added dropwise, switchs to ice bath 2h, room
Temperature is stirred overnight.Saturated sodium bicarbonate 5ml quenching reaction is added dropwise, adjusts pH to 8, boils off organic solvent.Ethyl acetate extraction 3
Secondary * 10ml, saturated sodium chloride solution wash 2 * 20ml, filter after anhydrous slufuric acid ammonium is dry, filtrate rotary evaporation obtains yellowish
Color grease 2.55g.
Light yellow oil is dissolved in acetonitrile/dichloromethane solution 30ml of 1:1, is cooled to -10 to -5 DEG C, three second are added
Then base silane 5.5ml is added dropwise 3.3ml boron trifluoride etherate, stirs 6h under ice bath.Saturated sodium bicarbonate 20ml is added
Quenching reaction continuously adds saturated sodium bicarbonate solution and adjusts pH to 8-9, boils off organic solvent.Ethyl acetate extracts * three times
10ml, saturated sodium chloride solution wash twice * 20ml, filter after anhydrous slufuric acid ammonium is dry, filtrate is beaten in 50% ethanol solution
Slurry overnight, filters, with pure water * 10ml three times, is dried to obtain the compound of formula I 1.89g that R1 is methyl.(HPLC normalization
98.9%) it is that method, which measures purity,.
LC-MS:[M+H] 366.45.
1H NMR(400MHz,CDCl3): 1.41-1.63 (9H, m), 1.87 (1H, m), 2.53 (2H, d), 3.38 (1H, d),
3.51 (2H, d), 3.60 (3H, m), 3.72 (1H, t), 3.84 (3H, s), 3.96 (1H, t), 4.37 (1H, t), 4.52 (2H, t),
6.81 (2H, d), 7.15 (2H, d).
Experimental example 2:
Using above-mentioned the same terms, methyl phenyl ethers anisole is changed to phenetole, obtains R1For the compound of formula I 1.97g (HPLC of ethyl
97.8%) purity is.
LC-MS:[M+H] 380.47.
1H NMR(400MHz,CDCl3): 1.28 (3H, t), 1.40-1.64 (9H, m), 1.85 (1H, m), 2.53 (2H, d),
3.36 (1H, d), 3.52 (2H, d), 3.60 (3H, m), 3.72 (1H, t), 4.01 (3H, m), 4.38 (1H, t), 4.52 (2H, t),
6.80 (2H, d), 7.13 (2H, d).
Embodiment 3:
Using above-mentioned the same terms, methyl phenyl ethers anisole is changed to propyloxy phenyl base ether, obtains R1For the compound of formula I of isopropyl
2.03g (HPLC purity is 98.0%).
LC-MS:395.50 [M+H].
1H NMR(400MHz,CDCl3): 1.25 (6H, d), 1.43-1.61 (9H, m), 1.84 (1H, m), 2.51 (2H, d),
3.39 (1H, d), 3.52 (2H, d), 3.62 (3H, m), 3.71 (1H, t), 3.97 (1H, t), 4.34 (1H, t), 4.51 (2H, t),
4.70 (1H, m), 6.83 (2H, d), 7.16 (2H, d).
Claims (5)
1. compound of formula I,
Wherein: R1It is selected from: methyl, ethyl or isopropyl.
2. the preparation method of compound described in claim 1, which is characterized in that its reaction route is as shown in reaction equation
3. including the pharmaceutical composition of claim 1 compound.
4. claim 1 compound is preparing the application in SGLT-2 inhibitor medicaments.
5. application as claimed in claim 4, which is characterized in that the drug is used to prepare treatment diabetes, hyperglycemia, grape
Impaired glucose tolerance, gestational diabetes mellitus, insulin resistance, hyperinsulinemia drug application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711195816.4A CN107880006B (en) | 2017-11-24 | 2017-11-24 | The compound as SGLT-2 inhibitor containing cyclohexane structure |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711195816.4A CN107880006B (en) | 2017-11-24 | 2017-11-24 | The compound as SGLT-2 inhibitor containing cyclohexane structure |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107880006A CN107880006A (en) | 2018-04-06 |
| CN107880006B true CN107880006B (en) | 2019-07-02 |
Family
ID=61775161
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711195816.4A Active CN107880006B (en) | 2017-11-24 | 2017-11-24 | The compound as SGLT-2 inhibitor containing cyclohexane structure |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107880006B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104861002A (en) * | 2014-02-26 | 2015-08-26 | 天津药物研究院 | 3,6-anhydroglucose structure-containing phenyl C-glucoside derivatives and their preparation method and use |
-
2017
- 2017-11-24 CN CN201711195816.4A patent/CN107880006B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN107880006A (en) | 2018-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2712033C2 (en) | Deuterated derivative of chenodeoxycholic acid and pharmaceutical composition containing said compound | |
| CN106146475B (en) | Bisindole maleimide derivative and its preparation method and application | |
| DE69531098T2 (en) | PIPERIDINE AND PYRROLIDINE | |
| CN110003092A (en) | Prepare the method and its crystal form of MDM2 inhibitor | |
| CN104903296A (en) | Dihydropyrazole GPR40 modulators | |
| EP3191453B1 (en) | Phenyl-(aza)cycloalkyl carboxylic acid gpr120 modulators | |
| CN106810582A (en) | The compound of glucopyranosyl derivatives, preparation method and application | |
| KR20160092015A (en) | Crystalline form of (s)-(2-(6-chloro-7-methyl-1h-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1 -yl)(5-methoxy-2-(2h-1,2,3-triazol-2-yl)phenyl)methanone and its use as orexin receptor antagonists | |
| CN106458987B (en) | For treating the pyrrolidines GPR40 regulator of disease such as diabetes | |
| CN106674294A (en) | Crystal form of glucopyranose derivative | |
| CN107880006B (en) | The compound as SGLT-2 inhibitor containing cyclohexane structure | |
| CN107903231B (en) | The compound as SGLT-2 inhibitor containing adamantane structure | |
| CN108699098A (en) | C- glucose glycoside derivates or its pharmaceutically acceptable salt, the preparation method and pharmaceutical composition comprising it with fused benzene rings | |
| CN107903247B (en) | The compound as SGLT-2 inhibitor containing hydroxy piperidine structure | |
| EP4163287A1 (en) | A class of aryl glucoside derivatives, preparation method therefor and application thereof | |
| CN111039880B (en) | Application of miconazole and derivative thereof as TGR5 agonist | |
| WO2019000224A1 (en) | Bisindolylmaleimide derivative and preparation method and use thereof | |
| JP6197113B2 (en) | Novel SGLT1 inhibitor | |
| CN107778336A (en) | The crystal form of glucopyranosyl derivatives | |
| TW200301114A (en) | Crystals of taxane derivative and process for the production thereof | |
| CN106674245B (en) | The preparation of glucopyranosyl derivatives and application pharmaceutically | |
| CN105801564B (en) | Piperazine ketone compounds and its application | |
| JPS632279B2 (en) | ||
| CN104292210B (en) | Nitric oxide donors class compound containing pyridine, preparation method and the usage | |
| JP7273997B2 (en) | Crystal forms of SGLT inhibitors and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |