CN110117304A - A kind of medicinal usage of sodium glucose co-transporter 2 white 1 and 2 inhibitor - Google Patents

A kind of medicinal usage of sodium glucose co-transporter 2 white 1 and 2 inhibitor Download PDF

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CN110117304A
CN110117304A CN201910322171.9A CN201910322171A CN110117304A CN 110117304 A CN110117304 A CN 110117304A CN 201910322171 A CN201910322171 A CN 201910322171A CN 110117304 A CN110117304 A CN 110117304A
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姬建新
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Chengdu Institute of Biology of CAS
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Abstract

The present invention relates to a kind of white 1 and 2 (SGLT1&2) inhibitor of sodium glucose co-transporter 2 include their compositions pharmaceutical synthesis method and they treatment metabolism class disease especially diabetes B purposes.

Description

A kind of medicinal usage of sodium glucose co-transporter 2 white 1 and 2 inhibitor
Technical field
The present invention relates to a kind of sodium glucose co-transporter 2 white 1 and 2 (SGLT1&2) inhibitor, include their compositions Pharmaceutical synthesis method and they treatment metabolism class disease especially diabetes B purposes.
Background technique
2012, according to World Health Organization, disease incidence of the diabetes in 18 one full year of life above adult, which is greater than, was 9%.As population increases, aging and people's life-time dilatation, diabetes morbidity can also rise.In obese people, glycosuria Sick disease incidence is higher.For root it was predicted that the year two thousand thirty, diabetes will become the seventh-largest fatal disease.
A kind of novel targets of the SGLTs as drug come over the past several decades, have developed new target drug for controlling Treat diabetes.SGLT family is made of some hypotypes, plays a part of to transport carbohydrate on cell membrane, this process and sodium ion turn Body is transported to combine.SGLT1 is mainly expressed in gastrointestinal channel, is mainly responsible for the absorption of glucose and galactolipin in small intestine.SGLT1 Kidney proximal straight tubule is existed in, facilitates the reabsorption of blood glucose herein.Being absorbed and utilized back for blood glucose is hindered by inhibiting SGLT1 Blood, to reach the target for reducing blood glucose level.
Since SGLT1 inhibiting effect may also provide a kind of alternative medicine for glycemic control, pass through SGLT1 inhibiting effect To improve glycemic control with very big attraction, because this effect can not depend on renal function.Current SGLT2 choosing Selecting property inhibitor lacks curative effect for middle severe renal impairment patient, and middle severe renal impairment patient accounts for about in all diabetics 30-40%.Although Sotagliflozin is effective to SGLT1 under maximum clinical dosage, it can partially inhibit enteron aisle SGLT1, The bigger therapeutic efficiency of the SGLT1 inhibitor only to play a role in enteron aisle is the blood glucose for reaching bigger level using titration dosage Control ability.By this mechanism, one kind can reach blood glucose control in the pervious SGLT1 inhibitor of gastrointestinal side effect Potential effect of maximum of system.It, can also be especially raw to avoid the glycosuria related side effects of SGLT2 inhibitor by this effect Grow device infection.
Summary of the invention
The present invention relates to the discoveries of a kind of new potent sodium glucose cotransporter l and 2 (SGLTl&2) inhibitor. Specific inhibitor is the inhibitor of SGLT1&2.Part of the present invention is related to the compound comprising following formula and its officinal salt and it Application method:
Or its officinal salt, in which:
R1It can be the R independently arbitrarily replaced1A、-N(R1A)(R1B)、-OR1A、-SR1A、-S(O)R1AOr-S (O)2R1A；
R1It can be and not replace, is monosubstituted or polysubstituted；
R1AIt is the C optionally replaced1-20Linear or branched alkyl group, aryl, heterocycle, amino, aminoacyl, azo, carbonyl, carboxylic Base, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, isothiocyanates, nitrile, nitro, nitroso, nitryl Base, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkenyl, alkynyl, ester, ketone, alcohol etc..
R1AIncluding with flowering structure:
R1BIt is hydrogen or is equal to R1A；
R2The C independently arbitrarily replaced1-10Linear or branched alkyl group, C1-10Straight or branched alkoxyl, aryl, heterocycle, Amino, aminoacyl, azo, carbonyl, carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, different sulphur cyanogen Acid esters, nitrile, nitro, nitroso, nitroxyl, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkenyl, Alkynyl, ester, ketone, alcohol etc.；
R2It can be and not replace, is monosubstituted or polysubstituted；
R3It is hydrogen or the C optionally replaced1-10Alkyl, C1-10Naphthenic base or multicomponent heterocycle, the optional substitution are with one Or multiple R3AReplace；
R3AIt can be any substituted C1-10Linear or branched alkyl group, C1-10Straight or branched alkoxyl, aryl, heterocycle Base, amino, aminoacyl, azo, carbonyl, carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, different sulphur Cyanate, nitrile, nitro, nitroso, nitroxyl, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkene Base, alkynyl, ester, ketone, alcohol etc.；
R4、R5、R6Can be independently hydrogen, deuterium hydrogen, the alkyl of any carbochain, aryl, carbonyl, single or multiple glycosyls, appoint Heterocycle, the ester group etc. that meaning replaces.
R4、R5、R6It can be equal or different, can be identical substitution or different substitutions.
X1It is optional one or more N, O, S, C.
X2It is the optional various oxides of one or more N, O, S, C or corresponding.
The invention further relates to the pharmaceutical composition comprising the compound disclosed herein, and treated using them or Manage cardiovascular disease, metabolic disease (especially diabetes and various complication), intestines problem, kidney trouble and certain classes The method of the cancer of type.
We test the compound to the growth inhibition effect of SGLT1, and test result discovery: this has highly significant The activity for inhibiting SGLT1 is 38.81 ± 7.17 mcg/mls in IC50, is shown by measuring its half-inhibitory concentration: should The above pharmacodynamic result formula compound has unexpected inhibition SGLT1 effect.We test the compound pair The growth inhibition effect of SGLT2, test result discovery: this has the highly significant activity for inhibiting SGLT2, is in IC50 10.22 ± 4.52 mcg/mls are shown by measuring its half-inhibitory concentration: the above pharmacodynamic result formula compound There is unexpected inhibition SGLT2 effect.It thus it can be expected that the compound or pharmaceutically acceptable salt thereof is contemplated as SGLT1&2 Inhibitor medicaments especially prevent and treat the purposes of type-2 diabetes mellitus namely Non-Insulin Dependent Diabetes Mellitus drug.
In conclusion the uniqueness on the compound existing structure that we prepare, and have and inhibit SGLT1&2 effect aspect The novelty of research, and good bioavilability is found in pharmacokinetics test, it is expected to become inhibition SGLT1&2 And the drug candidate for the treatment of diabetes.The compound belongs to unexpected discovery, there is exact originality.
Specific embodiment
Mandatory declaration, the embodiment of the present invention are for illustrating the invention and not limiting the invention.According to this hair The simple modifications that bright essence carries out the present invention belong to the scope of protection of present invention.
When description above illustrates the present invention, while the purpose for providing embodiment is the reality illustrated the present invention Operating process and meaning of the present invention.When entering in the claims in the present invention and its equivalency range, real application of the invention Including all general variations, cooperation, or improve.
Embodiment
The preparation (3) of (4- (benzyl oxygroup) phenyl) (the bromo- 2- aminomethyl phenyl of 5-) methanol:
It is slow in THF (100mL) solution to 4- benzyloxy bromobenzene (10.0g, 38mmol) under -78 DEG C of nitrogen protections Addition n-BuLi (2.5M, in hexane, 8.8mL, 22mmol).By reaction stirring 30 minutes.It is slowly added to be dissolved in THF Bromo- 2- tolyl aldehyde (8g, the 40mmol) solution of 5- in (8ml).After reaction two hours, temperature is slowly increased to 0 DEG C, with full And NH4Cl aqueous solution is quenched, and is diluted with methyl tertiary butyl ether(MTBE), H2The washing of O and NaCl aqueous solution, passes through MgSO4Dry, filtering, and It is concentrated under vacuum.Residue is purified by flash chromatography on silica gel, petrol ether/ethyl acetate=20:1.Product is nothing The compound 3 (9.2g, yield 60%) of color clear oil.
The preparation (4) of 2- (4- (benzyl oxygroup) benzyl) bromo- 1- methylbenzene of -4-:
(4- (benzyl oxygroup) phenyl) (the bromo- 2- aminomethyl phenyl of 5-) methanol (9.9.2g, 24mmol) is dissolved in 40mL bis- In chloromethanes, triethyl-silicane (5mL, 31mmol) and boron trifluoride ether (4.5mL, 36mmol) are sequentially added.It will reaction It is stirred at room temperature 3 hours or more, to after reaction with saturation NaHCO3Aqueous solution is slowly quenched, and stirs 5 minutes.Reaction solution It is diluted with methyl tertiary butyl ether(MTBE), saturation NaCl aqueous solution washing, organic layer passes through MgSO4Dry, filtering, is concentrated under vacuum. Residue is passed through into silica gel flash chromatography, petrol ether/ethyl acetate=30:1.Obtain 8.8g white solid product, yield 98%.
(3- (4- (benzyl oxygroup) benzyl) -4- aminomethyl phenyl) ((5R, 6S) -6- hydroxyl -2,2- dimethyl tetrahydro Furans simultaneously [2,3-d] [l, 3] dioxole -5- base) ketone preparation (6):
Under -78 DEG C of nitrogen protections, to 2- (4- (benzyl oxygroup) benzyl) bromo- 1- methylbenzene of -4- (8.8g, 24mmol) solution in THF (37mL) is slowly added n-BuLi (2.5M, in hexane, 10.6mL, 26.2mmol), and 30min is stirred into reaction, is denoted as solution A.Meanwhile under 0 DEG C of nitrogen protection, to ((3aS, 5R, 6S, 6aS) -6- hydroxyl -2,2- Dimethyl-tetrahydrofuran simultaneously [2,3-d] [[1,3] dioxole -5- base) (Lin Ji) ketone (6.6g, 24mmol) It is added in THF (37mL) solution tert-butyl magnesium chloride (1.0M, in THF, 26.2mL, 26.2mmol), reaction stirring 20min, It is denoted as solution B.Then solution B is added slowly in solution A by separatory funnel at -78 DEG C.Kept for -78 DEG C react 3 hours, Then it is to slowly warm up to room temperature, with saturation NH4Cl aqueous solution is quenched, and ethyl acetate extracts three times.Merge organic layer, with saturation NaCl aqueous solution washes twice, and anhydrous magnesium sulfate dries, filters, concentration.Residue is passed through into silicagel column flash chromatography, dichloromethane Alkane: methanol=100:1.Provide white foam solid product 9.8g, 71% yield.
(5S, 6R) -5- ((3- (4- (benzyl oxygroup) phenyl) -4- aminomethyl phenyl) (hydroxyl) methyl) -2,2- dimethyl The preparation (7) of tetrahydrofuran [2,3-d] [1,3] dioxole -6- alcohol:
At room temperature, by (3- (4- (benzyl oxygroup) benzyl) -4- aminomethyl phenyl) ((5R, 6S) -6- hydroxyl -2,2- bis- Methyltetrahydrofuran simultaneously [2,3-d] [l, 3] dioxole -5- base) preparation (2.1g, 5.0mmol) of ketone is dissolved in In 30mL methanol, be added Cerous chloride heptahydrate (2.0g, 6.0mmol), be then slowly added sodium borohydride solution (70mg, 2.1mmol, in 1mL, 1M NaOH aqueous solution).Reaction is kept being stirred at room temperature 30 minutes, then with saturation NH4Cl aqueous solution It is quenched.Aqueous solution is extracted with ethyl acetate 3 times, merges organic phase, and saturated salt solution washes twice, and anhydrous magnesium sulfate is dry, mistake Filter, concentration.Crude product does not need purifying and is directly used in reaction (2.0g, 95% yield in next step.)
(3S, 4R, 5S, 6S) -6- (3- (4- (benzyl oxygroup) benzyl) -4- aminomethyl phenyl) pyrans -2 tetrahydro -2H-, The preparation (8) of 3,4,5- tetracetate:
At 100 DEG C of reaction condition, under nitrogen protection, by (5S, 6R) -5- ((3- (4- (benzyl oxygroup) phenyl) -4- first Base phenyl) (hydroxyl) methyl) -2,2- dimethyl-tetrahydrofuran [2,3-d] [1,3] dioxole -6- alcohol preparation (2.0g) is handled 22 hours with 1:1 acetic acid/water (20mL).The reaction is cooled to room temperatures, are concentrated under vacuum, and pass through methanol twice After azeotropic band water removes most water, dry concentrated residues object is obtained after again with toluene azeotropic distillation is primary.
Under 0 DEG C of ice-water bath, above-mentioned residue and DMAP (60mg, 0.5mmol) are dissolved in 30mL methylene chloride, And triethylamine (6.2mL, 45mmol) is added, acetic anhydride (3.8mL, 40mmol) then is added.Reaction is stirred at room temperature overnight, Then it is quenched with saturated sodium bicarbonate aqueous solution, ethyl acetate extracts three times.By combined organic phase saturated common salt water washing Twice, anhydrous magnesium sulfate is dry, filters, and is concentrated under vacuum.Residue is passed through into silica gel flash chromatography, petroleum ether: Ethyl acetate=5:1.The product of 1.65g white foam is obtained, is the ɑ of 1:1, β Anomeric Mixture, yield 80%.
(3S, 4R, 5S, 6S) -6- (3- (4- hydroxyphenylmethyl) -4- aminomethyl phenyl) tetrahydro -2H- pyrans -2,3,4,5- four The preparation (9) of acetic acid esters:
By (3S, 4R, 5S, 6S) -6- (3- (4- (benzyl oxygroup) benzyl) -4- aminomethyl phenyl) tetrahydro -2H- pyrans - 2,3,4,5- tetracetates (1.65g, 2.8mmo 1) are dissolved in 20mLTHF, then be added 10%Pd/C (0.5g, 0.22mmol), under hydrogen, it carries out adding hydrogen 2-3 hours under atmospheric pressure.Reaction solution is filtered by diatomite, dense under vacuum Contracting, obtained phenol, which is not required to be further purified, to be directly used in next step, 98% yield.
(2S, 3S, 4R, 5S, 6R) -2- (3- (4- hydroxyphenylmethyl) -4- aminomethyl phenyl) -6- (methylsulfany) tetrahydro -2H- The preparation (10) of three base triacetate of pyrans -3,4,5-:
By (3S, 4R, 5S, 6S) -6- (3- (4- hydroxyphenylmethyl) -4- aminomethyl phenyl) tetrahydro -2H- pyrans -2,3,4,5- Tetracetate (1.3g, 2.8mmol) and thiocarbamide (1.0g, 13mmol) merging are dissolved in 44mL dioxanes.TMSOTf is added (2.4mL,13mmol).By reaction solution 80 DEG C heat 3 hours, after being cooled to room temperature, be successively slowly added to iodomethane (1.1mL, 15mmol) and DIPEA (6mL, 35mmol).Reaction is stirred overnight, and is quenched with saturation sodium bisulfate, ethyl acetate extraction 3 It is secondary, merge organic phase, is washed twice with saturated salt solution.Anhydrous magnesium sulfate dries, filters, and concentration, crude product passes through column layer of silica gel Analysis purifying, petroleum ether: ethyl acetate=5:1.Provide 0.9g white foam compound, 88% yield.
(2S, 3S, 4R, 5S, 6R) -2- (3- (4- (cyclopropane methoxyl group) benzyl) -4- aminomethyl phenyl) -6- (sulfidomethyl) The preparation (11) of three base triacetate of tetrahydro -2H- pyrans -3,4,5-:
By (2S, 3S, 4R, 5S, 6R) -2- (3- (4- hydroxyphenylmethyl) -4- aminomethyl phenyl) -6- (methylsulfany) tetrahydro - 2H- pyrans -3,4, tri- base triacetate (0.9g, 1.8mmol) of 5- are dissolved in 20mL n,N-Dimethylformamide, then successively It is added potassium carbonate (2.76g, 20mmol), potassium iodide (1.0g, 6.0mmol) and bromomethyl cyclopropane (0.81mL, 6.0mmol), Sealing.Reaction solution is stirred overnight at 40 DEG C, TCL monitoring reaction.It is quenched after completion of the reaction with saturated sodium bicarbonate, methyl- tert fourth Base ether extracts 3 times, merges organic phase, with saturated common salt water washing 3 times.Anhydrous magnesium sulfate dries, filters, and concentration obtains pale yellow Color solid chemical compound crude product.By in crude product ultrasonic disperse to the mixed solution of 30mL petroleum ether and ethyl acetate, petroleum ether: acetic acid Ethyl ester=10:1.A large amount of white solids are obtained at this time, are filtered, and washed twice with the mixed solution of petroleum ether and ethyl acetate, Obtain pure compound as white solid 11 (0.6g, 88% yield).
(2S, 3S, 4R, 5S, 6R) -2- (3- (4- (cyclopropane methoxyl group) benzyl) -4- aminomethyl phenyl) -6- (sulfidomethyl) The preparation (12) of tetrahydro -2H- pyrans -3,4,5- triol:
By (2S, 3S, 4R, 5S, 6R) -2- (3- (4- (cyclopropane methoxyl group) benzyl) -4- aminomethyl phenyl) -6- (sulphur first Base) tetrahydro -2H- pyrans -3,4,5- three base triacetate (0.6g, 1.1mmol) be distributed to 30mL vol/vol methanol: THF: water= In the mixed solution of 2:1:2, lithium hydroxide (240mg, 10mmol) then is added.It places reaction liquid into 60 DEG C of oil baths and heats instead It answers 1 hour.After completion of the reaction, pH=1-2 is adjusted with saturation sodium bisulfate, and be extracted with ethyl acetate 3 times, merged organic Phase, anhydrous magnesium sulfate dry, filter, concentration.Crude product passes through silica gel column purification, methylene chloride: methanol=30:1.Provide white bubble Foam shape solid 0.44g, yield 95%.1H NMR (400MHz, MeOD) δ 7.21-7.12 (m, 3H), 7.04 (d, J=8.6Hz, 2H), 6.83-6.78 (m, 2H), 4.40 (d, J=9.4Hz, 1H), 4.14 (d, J=9.1Hz, 1H), 3.93 (s, 2H), 3.77 (d, J=6.9Hz, 2H), 3.43 (ddt, J=14.9,12.2,6.1Hz, 3H), 2.21 (s, 3H), 2.15 (s, 3H), 1.28- 1.17(m,1H),0.64–0.56(m,2H),0.36–0.30(m,2H).HRMS(ESI)calcd for C24H30O5S[M+H]+: 431.1847；found:431.1856.
Biological test:
According to document (Journal of Medicinal Chemistry 2017,60,710-721, Discovery of LX2761,a Sodium-Dependent Glucose Cotransporter 1(SGLT1)Inhibitor Restricted To the Intestinal Lumen, for theTreatment of Diabetes) record method carry out SGLT1 and The inhibitory activity of SGLT2 is tested.
The experimental results showed that the compounds of this invention inhibits SGLT1 and inhibits active equal < 150nM of SGLT2.

Claims (18)

1. a kind of compound such as following formula:
Or its officinal salt, in which:
R1It can be the R independently arbitrarily replaced1A、-N(R1A)(R1B)、-OR1A、-SR1A、-S(O)R1AOr-S (O)2R1A；
R1It can be and not replace, is monosubstituted or polysubstituted；
R1AIt is the C optionally replaced1-20Linear or branched alkyl group, aryl, heterocycle, amino, aminoacyl, azo, carbonyl, carboxyl, Cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, isothiocyanates, nitrile, nitro, nitroso, nitroxyl, Oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkenyl, alkynyl, ester, ketone, alcohol etc.；R1AIncluding following Structure:
R1BIt is hydrogen or is equal to R1A；
R2The C independently arbitrarily replaced1-10Linear or branched alkyl group, C1-10Straight or branched alkoxyl, aryl, heterocycle, ammonia Base, aminoacyl, azo, carbonyl, carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, isothiocyanic acid Ester, nitrile, nitro, nitroso, nitroxyl, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkenyl, alkynes Base, ester, ketone, alcohol etc.；
R2It can be and not replace, is monosubstituted or polysubstituted；
R3It is hydrogen or the C optionally replaced1-10Alkyl, C1-10Naphthenic base or multicomponent heterocycle, the optional substitution are with one or more A R3AReplace；
R3AIt can be any substituted C1-10Linear or branched alkyl group, C1-10Straight or branched alkoxyl, aryl, heterocycle, ammonia Base, aminoacyl, azo, carbonyl, carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, isothiocyanic acid Ester, nitrile, nitro, nitroso, nitroxyl, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkenyl, alkynes Base, ester, ketone, alcohol etc.；
R4、R5、R6Can be independently hydrogen, deuterium hydrogen, the alkyl of any carbochain, aryl, carbonyl, single or multiple glycosyls, arbitrarily take Heterocycle, the ester group in generation etc.；
R4、R5、R6It can be equal or different, can be identical substitution or different substitutions；
X1It is optional one or more N, O, S, C；
X2It is the optional various oxides of one or more N, O, S, C or corresponding.
2. the compound of claim 1, wherein R3It is to appoint monobasic C1-10Alkyl or hydrogen；Especially methyl, ethyl.
3. the compound of claim 1, wherein R4、R5、R6It can be hydrogen, deuterium hydrogen, the alkyl of any carbochain, single or multiple sugar Base carbonyl, especially hydrogen and carbonyl.
4. the compound of claim 1, wherein R2It is the C optionally replaced1-4Linear or branched alkyl group；Especially methyl, ethyl.
5. the compound of claim 1, wherein R2It is the alkoxy of halogen or any carbochain.
6. the compound of claim 1, wherein R2It is the monosubstituted or polysubstituted of any position.
7. the compound of claim 1, wherein R1It is R1A。
8. the compound of claim 1, wherein R1It is OR1A。
9. the compound of claim 1, wherein R1It is the monosubstituted or polysubstituted of any position.
10. the compound of claim 1, is expressed from the next:
Wherein:
R7It is the C optionally replaced1-20Linear or branched alkyl group, naphthenic base, aryl, heterocycle, amino, aminoacyl, azo, carbonyl, Carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, isothiocyanates, nitrile, nitro, nitroso, nitre Acyl group, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkenyl, alkynyl, ester, ketone, alcohol etc., and include The various deuterated objects of above-mentioned substituent group；
X2It is the optional various oxides of one or more N, O, S, C or corresponding；
R2It is independently halogen, hydroxyl or the C optionally replaced1-10Linear or branched alkyl group, C1-10Straight or branched alkoxyl, institute Stating optionally substitution is with one or more R2AReplace；
Each R2AIt is independently any substituted C1-10Linear or branched alkyl group, C1-10Straight or branched alkoxyl, aryl, heterocycle Base, amino, aminoacyl, azo, carbonyl, carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, different sulphur Cyanate, nitrile, nitro, nitroso, nitroxyl, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkene Base, alkynyl, ester, ketone, alcohol etc..
11. the compound of claim 1, is expressed from the next:
Wherein:
R7It is the C optionally replaced1-20Linear or branched alkyl group, naphthenic base, aryl, heterocycle, amino, aminoacyl, azo, carbonyl, Carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, isothiocyanates, nitrile, nitro, nitroso, nitre Acyl group, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkenyl, alkynyl, ester, ketone, alcohol etc., and include The various deuterated objects of above-mentioned substituent group.
12. the compound of claim 11, wherein R7It is the C optionally replaced1-20Linear or branched alkyl group.
13. the compound of claim 11, wherein R7It is naphthenic base, alkynyl.
14. a kind of pharmaceutical composition, it includes the compound of any one of preceding claims and officinal salt excipient and dilutions Agent.
15. treating and improving the application in cardiovascular disease and metabolic disease patient in claim 1-14.
16. treating and improving the application in diabetic in claim 1-14.
17. treating and improving the application in diabetic's complication, including microvascular complication meeting in claim 1-14 Caused retinopathy, nephrosis and the nervous system disease.And cardiovascular disease caused by big vascular syndrome.
18. wherein the patient had taken or had just taken at present other therapeutic drug, including blood pressure lowering to claim 15-18 Medicine, hypolipidemic, antidiabetic, hypoglycemic agent, slimming drugs or appetite inhibitor.
CN201910322171.9A 2018-04-23 2019-04-22 A kind of medicinal usage of sodium glucose co-transporter 2 white 1 and 2 inhibitor Pending CN110117304A (en)

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