CN107880006A - The compound as the inhibitor of SGLT 2 containing cyclohexane structure - Google Patents
The compound as the inhibitor of SGLT 2 containing cyclohexane structure Download PDFInfo
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- CN107880006A CN107880006A CN201711195816.4A CN201711195816A CN107880006A CN 107880006 A CN107880006 A CN 107880006A CN 201711195816 A CN201711195816 A CN 201711195816A CN 107880006 A CN107880006 A CN 107880006A
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- 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 compound as the inhibitor of SGLT 2, and it has C glucosides and cyclohexane structure structure, and has preferably selectivity to SGLT 2.
Description
Technical field
The application provides being controlled as the compound of SGLT-2 inhibitor, containing their compositions and using them for novelty
Treatment or prevention diabetes and the method for related pathologies.
Background technology diabetes are the gradual debilitating illnesss to grow in intensity, and it causes various capilaries and big blood vessel
Complication.The most common type type ii diabetes of diabetes are characterised by and the compensatory hyperinsulinaemia in a period of time
The related 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, relevant with the absorption of glucose,
The S3 sections of renal proximal tubules farther out, the glucose of reabsorption 10% are distributed in, it is near bent small that SGLT-2 albumen is then distributed in kidney
Pipe, it is responsible for most glucose (90%) in glomerular filtrate being transported into blood again, so as to maintain internal blood
The stabilization and balance of sugar.SGLT protein inhibitors by blocking the transporting mechanism of the albumen, make glucose with urine discharge so as to
Blood glucose is reduced, thus is not relying on insulin mechanism, all there is therapeutic effect for I types and type ii diabetes, and be not susceptible to
Hypoglycemia is dangerous, does not increase diabetic's body weight.
Research shows, when SGLT-1 is blocked, can cause serious diarrhoea, or even threat to life, and SGLT-2 is suppressed
When, only cause kidney discharge sugar, not obvious adverse reaction.
The SGLT-2 inhibitor found earliest is natural products phloridzin (Phlorizin), but because it is easily internal
Glycosidase be hydrolyzed into glucosides and phloretin, and to SGLT-1 and SGLT-2 poor selectivity, adverse reaction is larger, therefore does not have
There is the medicine as diabetes.The existing 6 kinds of SGLT-2 inhibitor listing in the whole world at present, it is respectively：Canagliflozin
(canagliflozin), Dapagliflozin (Dapagliflozin), Empagliflozin (En Gelie is net), Ipragliflozin are (according to lattice
Row are net), Luseogliflozin (glug row are net) and Tofogliflozin (tofogliflozin).Wherein, Bristol Myers Squibb is public
The Dapagliflozin of department is by FDA, EU Committee and state food pharmaceuticals administration general bureau (CFDA) approval in U.S.
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 depressions
Thing.
High Yunlong of Shandong University etc. finds that C rings have for the compound of hexamethylene in research process and is better than Dapagliflozin
Inhibiting rate, however, not having the report that B rings are replaced with to hexamethylene at present.
The application is related to the compound of Formula I of the ability with regulation SGLT-2 of novelty, and above-claimed cpd potentially may be used
For treating or preventing diabetes and related pathologies.The compound has novel structure, i.e., the B rings being connected with sugared ring are flexibility
Cyclohexane structure.
The content of the invention
The application provides the substituted compound of Formula I and its dynamic isomer, pharmaceutical salts that can be used as SGLT-2 inhibitor.
The application is also provided for preparing the application compound or its dynamic isomer, 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 it mutually makes a variation
Structure body, pharmaceutical salts.
The application compound can be used for treatment and/or prevent a variety of diseases related to SGLT-2 or obstacle, such as glycosuria
Disease and related pathologies, the microvascular complication related to diabetes, the macrovascular complications related 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, which can be used for preparing, to be used to treat and/or prevents a variety of diseases related to SGLT-2 or obstacle
Medicine.
The application compound can be used alone, is combined with the other compounds of the application or join with one or more other medicaments
With.
Embodiment
I. the application compound
In the first aspect, the application especially provides compound of formula I or its dynamic isomer, pharmaceutical salts：
Wherein：
R1It is selected from：C1-6Alkyl, C3-6Cycloalkyl or C3-6Cycloalkyl C1-3Alkyl, the C1-6Alkyl can be by the cycloalkanes
Base can be substituted by hydroxyl, amino, halogen, the C3-6Cycloalkyl can be by hydroxyl, amino, halogen or C1-3Alkyl substitutes.
Preferably, R1Selected from C1-6 alkyl, the C1-6Alkyl can be by hydroxyl, amino, halogen by the cycloalkyl
Substitution.
In second aspect, the application provides compound or its dynamic isomer, pharmaceutical salts selected from exemplary embodiment.
In preferred embodiments, the application compound has≤0.02 μM of hSGLT-2EC50Value, and its is right
HSGLT-2/hSGLT-1 selectivity is more than 1000 times.
II. the other embodiments of the application
In another embodiment, the application provides composition, and it includes at least one the application compound or its is mutual
Tautomeric, pharmaceutical salts.
In another embodiment, the application provides pharmaceutical composition, and it includes pharmaceutical carrier and this at least one Shen
Please compound or its dynamic isomer, pharmaceutical salts.
In another embodiment, the application provides pharmaceutical composition, and it includes pharmaceutical carrier and therapeutically effective amount
At least one the application compound or its dynamic isomer, pharmaceutical salts or solvate.
In another embodiment, the application is provided for preparing the application compound or its dynamic isomer, medicinal
The method of salt.
In another embodiment, the application is provided for preparing the application compound or its dynamic isomer, medicinal
The intermediate of salt.
In another embodiment, the application is provided for treating and/or preventing a variety of diseases related to SGLT-2
Or the method for obstacle, it include to the patient of the above-mentioned treatment of needs and/or prevention individually or optionally with another the applicationization
At least one the application compound of compound and/or at least one other type therapy agent combination medicine-feeding therapeutically effective amount.
Can be prevented according to the application, adjusted or treated include to the example of the SGLT-2 related diseases of activity or illness but
It is not limited to diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes mellitus, insulin resistance, hyperinsulinemia, view
Film lesion, DPN, nephropathy, nephrosis, acute injury of kidney, heart kidney syndrome, 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 provide for treat and/or prevent diabetes, hyperglycemia, gestation sugar
The method of disease, obesity, dyslipidemia, hypertension and cognitive impairment is urinated, it includes the trouble to the above-mentioned treatment of needs 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 appreciated that any and all embodiment of the application can combine
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 key element of embodiment is intended to and any embodiment
Any and all other factor combination is to describe other embodiments.
III. it is 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 in the range of the application.If it is required, then a kind of form of compound can be changed into another form.
Free alkali or acid can be changed into salt；Salt can be changed into free cpds or another salt；Can be by the application isomers chemical combination
The mixture of thing is separated into single isomers.The application compound, its free form and salt can be with a variety of tautomerism bodily forms
Formula is present, 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 appreciated that all tautomeric forms that may be present are included in the application.
Term " alkyl " used herein is intended to include with the side chain for specifying carbon number and straight-chain radical of saturated aliphatic alkyl
Group.For example, " C1-6Alkyl " represents there is 1 alkyl to 6 carbon atoms.Similarly, C3-6Cycloalkyl then represents there is 3-6 on ring
The cycloalkyl of individual carbon atom.
Term " pharmaceutical " is used to refer to following those compounds, material, composition and/or formulation herein：Reasonable
In the range of medical judgment, it is suitable for contacting use with the tissue of human and animal and without high toxicity, excitant, allergic reaction excessively
And/or other problems or complication and match with rational benefit/risk ratio.
In addition, compound of formula I can have prodrug forms.Prodrug in the application scope and spirit 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 its version for being understood by those skilled in the art come
Synthesize the application compound.Method for optimizing includes but is not limited to those described below method.Suitable for agents useful for same and material
And implement reaction in the solvent or solvent mixture suitable for be realized conversion.Organic synthesis field technical staff should be understood
It is that functional group present on molecule should be consistent with the conversion proposed.Sometimes this needs is judged to change synthesis step
Rapid order or a kind of specific program scheme of selection rather than another to obtain the application desired compound.
The 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 are warm
Degree, duration of experiment and post processor) standard conditions 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 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 prepare compound of formula I.
Scheme 1：
3- cyclohexenecarboxylic acids (not splitting) and HBr additions, the isolated bromo- hexahydrobenzoid acids of 3-, after acyl chloride reaction with
Phenyl alkyl ether reaction, carbonyl reduction reaction, afterwards again with 2,3,4,6- tetra--D- trimethyls silicon substrates-D-Glucose acid lactone is anti-
Should, unnecessary methoxyl group obtains end-product on last deprotection base and sugared ring.
The synthetic route of compound is mentioned briefly above, specific synthesis step is shown in embodiment part.
The sign of compound
HPLC/MS methods used in the sign of compound or purifying：
Using following methods in Shimadzu SCL-10A liquid chromatographs and Waters ZQ mass spectrograph (desolvation gas
Body：Nitrogen；Desolvation temperature：250℃；Ion source temperature：120℃；Positivity electrospray conditions) on implement analytic type HPLC/
MS (unless otherwise indicated)：0%-100% solvents B linear gradient lasts 2min, wherein keeping 1min in 100%B；
220nm UV are visible；Post：Luna C18(2)30mm×4.60mm；5m particles (are heated to 40 DEG C of temperature)；Flow velocity：5mL/min；
Solvent orange 2 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
Compound purity (retention time unless otherwise indicated, being listed in embodiment refers to the retention time on the 1st column)：
Orthogonal methods：
10%-100% solvents B linear gradient lasts 15min；It is visual that UV is carried out in 220nm and 254nm；Post 1：
SunFire C183.5μm,4.6x150mm；Post 2：Xbridge Phenyl 3.5μm,4.6x150mm；Flow velocity：1mL/min is (right
For two posts)；Solvent orange 2 A：5%MeCN-95%H2O-0.05%TFA；Solvent B：95%MeCN-5%H2O-0.05%
TFA。
Or
Zorbax methods
10%-100% solvents B linear gradient lasts 8min；UV visualizations are carried out in 220nm；Post：
ZorbaxSBC183.5μm,4.6x75mm；Flow velocity：2.5mL/min；Solvent orange 2 A：10%MeOH-90%H2O-0.2%H3PO4；
With solvent B：90%MeOH-90%H2O-0.2%H3PO4.
Or
Analytic type LC/MS methods
Gradient：0-100%B lasts 3min, then keeps 0.75min in 100%B；UV visualizations are carried out in 220nm；Post：
Waters XBridge UPLC BEH C18,2.1 × 50mm, 1.7- μm of particle；Mobile phase A：5 with 10mM ammonium acetates:95
Acetonitrile:Water；Or 5:95 have 0.05%TFA acetonitrile:Water；Mobile phase B：95 with 10mM ammonium acetates:5 acetonitriles:Water；Or
Person 95:5 have 0.05%TFA acetonitrile:Water；Temperature：50℃；Flow velocity：1.11mL/min.
NMR employed in the sign of compound
Obtained using the Bruker conversion lights spectrometer operated under 400MHz1H NMR spectras (unless otherwise indicated).
The report spectroscopic data in the form of chemical shift (multiplicity, hydrogen number, coupling constant (being represented by Hz)), and for1H
Reported for NMR spectra in the form of the ppm (δ units) relative to internal standard thing (tetramethylsilane=0ppm), or
With reference 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 measure
Intracellular Ca2+ measure based on FDSS
Using 3 × flag of pDEST gene expression systems generate expression hSGLT-1/hSGLT-2 cell line and by its
Cultivated in culture medium comprising following components：F12 (Gibco numberings 11765), 10% deprive the hyclone of lipid, 250 μ g/
ML bleomycins (zeocin) and 500 μ g/mL G418.Surveyed to implement the calcium flux based on fluorescence imaging plate readout instrument (FLIPR)
It is fixed to measure intracellular Ca2+Reaction, the cell for expressing hSGLT-2 is put down with the density in the μ L culture mediums of 20,000 cells/20/hole
It is layered in the phenol red and serum-free DMEM (Gibco numbering 21063-029) on 384 orifice plates (BD Biocoat numberings 356697) simultaneously
It is incubated overnight.Using BD kit numbering 80500-310 or 80500-301, there is the sulphurs of 1.7mM third using 20 μ L/ holes 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 and with measure buffer solution with 3 × solution (20 μ L/
Hole) it is added in cell.Fluorescence/luminescence reader FDSS (Hamamatsu) is run to read intracellular Ca2+Response.
Testing compound is configured to 10 μM of solution, 5 times of dilution, obtains a series of testing samples every time.By above-mentioned
IC is calculated using origin softwares after method test50Value, test result are as shown in table 1.
Table 1
As seen from Table 1, this application provides a kind of SGLT-2 inhibitor with novel structure, the change being currently prepared
Compound activity is slightly below Dapagliflozin etc., but with preferably selectivity, subsequently through the fractionation and substitution of chiral structure
The modification of base, it is expected to obtain better compound.By embodiment 1-3 data, those skilled in the art can be reasonable
Deduce that the compound with similar structures also has preferable selectivity.
V. apply
The application compound has the activity as SGLT-2 conditioning agents, and thus can be used for treatment and SGLT-2 activity phases
The disease of pass.Via regulation 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 treat various symptom and illness to mammal (the preferably mankind), including
But it is not limited to treat, prevent or slow down the progress of following disease：Diabetes and related pathologies, the capilary related to diabetes are simultaneously
Send out disease, the macrovascular complications related to diabetes, angiocardiopathy, 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, suppress or treating diabetes, hyperglycemia, glucose
Tolerance is impaired, gestational diabetes mellitus, insulin resistance, hyperinsulinemia, PVR, DPN, nephropathy, diabetes
Property nephrosis, acute injury of kidney, heart kidney syndrome, acute coronary syndrome, wound healing delay, atherosclerosis and
Its sequelae (acute coronary syndrome, miocardial infarction, angina pectoris, peripheral artery disease, Charcot's syndrome, myocardial ischemia,
Apoplexy, heart failure), metabolic syndrome, hypertension, obesity, Fatty Liver Disease, dyslipidemia, high fat of blood, 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), hepatopathy, neurodegenerative disease, the cognition such as NAFLD (NASH disease) and hepatic sclerosis damage
Wound, the side effect that dull-witted and treatment is related to diabetes, lipodystrophy and sclerotin is dredged as caused by corticosteroid treatment
Loose disease.
Formulation (pharmaceutical composition) suitable for administration can contain about 1 milligram to about 2000 milligrams active component/dosage unit.
In these medical compositions, with the gross weight meter of composition, active component generally by with about 0.1 weight % to 95 weight %'s
Amount is present.
Exemplary capsule agent for oral administration contain at least one the application compound (250mg), lactose (75mg) and
Magnesium stearate (15mg).Pass the mixture through 60 mesh sieves and be packaged into No. 1 gelatine capsule.
Typical injectable formulation can be prepared as follows：At least one the application compound (250mg) is put with sterile manner
Freeze and seal in bottle, with sterile manner.To be used, vial content is mixed with 2mL physiological saline, to produce
Injectable formulation.
The application scope includes and (combined individually or with pharmaceutical carrier) at least one the applicationization for including therapeutically effective amount
Pharmaceutical composition of the compound as active component.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 with other SGLT-2 conditioning agents or it is one or more can be used for treating above-mentioned illness its
Its suitable therapeutic agent combination, the therapeutic agent include：Antidiabetic, antihyperglycemic agents, anti-hyperinsulinemia agent, anti-view
The agent of film lesion, anti-DPN agent, anti-nephropathy agent, antiatherosclerotic, antiischemic agents, rescinnamine, anti-obesity
It is agent, anti-lipid abnormal agent, lipidemia agent, anti hypertriglyceridemia agent, anti-hypercholesterolemiccompounds agent, anti-restenosis agent, anti-
Pancreatitis agent, lipid lowering agent, anoretic, memory enhancers, anti-dull-witted agent, cognition accelerator, appetite inhibitor, heart failure therapy
Agent, peripheral arterial disease therapeutic agent and antiinflammatory.
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, it can be administered orally, with separated oral dosage form or by being administered to one dosage type low temperature
Medicine.Optionally with the application SGLT-2 receptor modulators associated with other type antidiabetic agent can be it is a kind of, two kinds, three kinds
Or more kind antidiabetic or antihyperglycemic agents, the antidiabetic or antihyperglycemic agents can orally be given with one dosage type low temperature
Medicine, with separated oral dosage form or by drug administration by injection to produce 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, BMS-477118, 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 agonists (such as thiazolidinediones (such as Rosiglitazone, Pioglitazone), PPAR α/γ it is dual swash
Dynamic agent (such as Mo Geliezha, for 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.On 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 also optionally reduce appetite agent with one or more and are combined, described to reduce food
Be intended to agent for (such as) diethylpropion, phendimetrazine, Phentermine, orlistat, sibutramine, lorcaserin, pramlintide, support pyrrole
Ester, MCHR1 receptor antagonists, oxyntomodulin, naltrexone, amylin peptide, NPY Y5 receptor modulators, NPY Y2 acceptors are adjusted
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 hyperglycaemia
Activator (such as Exenatide, Liraglutide, GPR-1 (1-36) acid amides, the GLP-1 (7-36) of the plain acceptor of sample peptide 1 (GLP-1R)
Acid amides, GLP-1 (7-37)) combination is (disclosed in such as Habener U.S. Patent No. 5,614,492, 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.It can be found on the summary for treating the current of obesity and therapy newly occur：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 with above-mentioned patent or by ordinary skill
The amount that personnel otherwise determine 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 minimize 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 in different time points sequential administration in any order.Therefore, administration each group can be separated
Point but the time it is close enough to provide desired response to treatment.
The application compound also acts as standard or reference compound in the test for being related to SGLT-2 acceptors or measure, example
Such as it is used as quality standard or control.Above-claimed cpd, which may be provided in commercial kit, to be used to be related to SGLT-2 or anti-diabetic
The study of pharmacy of activity.For example, the application compound can be used as measure in reference with compare its known activity with have it is unknown
The compound of activity.This will ensure that experimenter is appropriately carried out determining and provided and compares foundation, be ginseng especially in test compound
In the case of examining the derivative of compound.When the new measure 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 SGLT-2 diagnostic assay.
It is evident that the application further feature, gives described show during being described below exemplary
Example property embodiment is for illustrating the application and be not intended to limit the application.
Embodiment
Embodiment 1
3- cyclohexenecarboxylic acids II (commercially available 25g, 0.2mol) adds 40% hydrobromic acid solution (50ml, 0.36mol) at room temperature,
Stirring reaction 6h, ethyl acetate extraction, concentration, silica gel chromatograph post separation, obtains 3- bromo- hexahydrobenzoid acid III (8.2g, yield
40%).
By 3-Br- hexahydrobenzoid acids III (4.1g, 20mmol) dry DMF (0.1ml) and dichloromethane (20ml) in frozen water
Lower stirring is bathed, oxalyl chloride (2.6ml, 30mmol) is added dropwise, continues to stir 2h after being added dropwise to reaction solution clarification.Remove under reduced pressure molten
Agent, dichloromethane (5ml) is added in residue and methyl phenyl ethers anisole, ice salt bath are cooled to less than -10 DEG C, anhydrous Aluminum chloride is added portionwise
0.6g*5 times, controlling reaction temperature is no more than 0 DEG C, continues to react 3h after addition.Mixed liquor is added in trash ice, adjusts pH
To neutrality, stood after stirring.Organic phase is separated, with dichloromethane aqueous phase extracted 5ml*2 times, merges organic phase.Organic phase is with full
With brine It 10ml*2 times, filter, be concentrated to give white solid IV4.8g.
Under blanket of nitrogen, above-mentioned white solid is added into THF (50ml) and sodium borohydride (0.77g, 20mmol).Stir 1h
Afterwards, ice salt bath is cooled to less than -10 DEG C, anhydrous Aluminum chloride is added portionwise 0.6g*5 times and controlling reaction temperature is no more than 0 DEG C, delay
Slowly 0 DEG C of stirring reaction 3h is warming up to, then heated overnight at reflux.Decompression steams THF, is cooled to room temperature, and slowly plus water removed
Measure sodium borohydride.3h is stirred in ice bath, is 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 cooling, 2,3,4,6- tetra--D- trimethyls silicon substrates-D-Glucose acid lactone
(often using intermediate during the compound such as 10mmol, synthesis Dapagliflozin, can obtain using N-methylmorpholine/THF conditions) is dissolved in 15ml
In tetrahydrofuran, dropwise addition 20ml contains the methyl Grignard that concentration is 1mol/L and 1mol/L LiCl tetrahydrofuran is molten
Liquid, the KI (0.02-0.03g) of catalytic amount is added, stir 2h.Suspension V (3.1g) tetrahydrofuran solution 10ml is added dropwise, control is anti-
Answer temperature to be not higher than -10 DEG C, continue to react 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 is added dropwise reaction is quenched, adjust pH to 8, boil off organic solvent.Ethyl acetate extraction 3
Secondary * 10ml, saturated nacl aqueous solution wash 2 * 20ml, and anhydrous slufuric acid ammonium filters after drying, and filtrate rotary evaporation obtains yellowish
Color grease 2.55g.
Pale yellow oil is dissolved in 1:1 acetonitrile/dichloromethane solution 30ml, -10 to -5 DEG C are cooled to, add three second
Base silane 5.5ml, 3.3ml boron trifluoride etherates are then added dropwise, 6h is stirred under ice bath.Add saturated sodium bicarbonate 20ml
Reaction is quenched, continuously adds saturated sodium bicarbonate solution regulation pH to 8-9, boils off organic solvent.Ethyl acetate extracts * three times
10ml, saturated nacl aqueous solution wash twice * 20ml, and anhydrous slufuric acid ammonium is filtered after drying, and 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 is normalized
Method measures purity as 98.9%).
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 (8)
1. compound of formula I or its dynamic isomer, pharmaceutical salts,
Wherein：R1It is selected from：C1-6Alkyl, C3-6Cycloalkyl or C3-6Cycloalkyl-C1-3Alkyl, the C1-6Alkyl can be by the cycloalkanes
Base can be substituted by hydroxyl, amino, halogen, the C3-6Cycloalkyl can be by hydroxyl, amino, halogen or C1-3Alkyl substitutes.
2. compound as claimed in claim 1, it is characterised in that R1Selected from C1-6Alkyl, the C1-6Alkyl can be by the ring
Alkyl can be substituted by hydroxyl, amino, halogen.
3. compound as claimed in claim 1, it is characterised in that R1Selected from methyl, ethyl or isopropyl.
4. the preparation method of compound described in claim 1-3, it is characterised in that its reaction scheme is as shown in reaction equation
5. claim 1-3 compounds, the application of its dynamic isomer, pharmaceutical salts as SGLT-2 inhibitor.
6. include claim 1-3 compounds, its dynamic isomer, the pharmaceutical composition of pharmaceutical salts.
7. claim 1-3 compounds, the application of its dynamic isomer, pharmaceutical salts in pharmacy.
8. the application described in claim 7, it is characterised in that the medicine is resistance to for treating diabetes, hyperglycemia, glucose
Amount is impaired, gestational diabetes mellitus, insulin resistance, hyperinsulinemia, PVR, DPN, nephropathy, diabetic keratopathy
Nephrosis, acute injury of kidney, heart kidney syndrome, acute coronary syndrome, wound healing delay, atherosclerosis and its
Sequelae, core function abnormality, congestive heart failure, myocardial ischemia, apoplexy, metabolic syndrome, hypertension, obesity, fat
Liver disease.
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