CN108610385A - A kind of medicinal usage of white 1 inhibitor of sodium glucose co-transporter 2 - Google Patents

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

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CN108610385A
CN108610385A CN201810370550.0A CN201810370550A CN108610385A CN 108610385 A CN108610385 A CN 108610385A CN 201810370550 A CN201810370550 A CN 201810370550A CN 108610385 A CN108610385 A CN 108610385A
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compound
base
heterocycle
hydroxyl
group
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姬建新
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Chengdu Institute of Biology of CAS
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Chengdu Institute of Biology of CAS
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Priority to CN201910322156.4A priority patent/CN110117303A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical

Abstract

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

Description

A kind of medicinal usage of white 1 inhibitor of sodium glucose co-transporter 2
Technical field
The present invention relates to a kind of sodium glucose co-transporter 2 white 1 (SGLT1) inhibitor, include the medicine of their compositions Object synthetic method and they treatment metabolism class disease especially diabetes B purposes.
Background technology
2012, according to World Health Organization, incidence of the diabetes in 18 one full year of life above adult, which is more than, was 9%.As population increases, aging and people's life-time dilatation, diabetes morbidity can also rise.In obese people, glycosuria Sick incidence 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 families are made of some hypotypes, play a part of to transport carbohydrate on cell membrane, this process turns with sodium ion 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, contributes to 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 There is very big attraction to improve glycemic control, because this effect can not depend on renal function.Current SGLT2 choosings 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 partly 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.By this effect, the glycosuria related side effects of SGLT2 inhibitor can also be avoided, it is especially raw Grow device infection.
Invention content
The present invention relates to a kind of discoveries of new potent sodium glucose cotransporter l (SGLTl) inhibitor.Specifically Inhibitor is the selective depressant of SGLT1.The cell that specific inhibitor is tested in vitro has high SGLT-1 activity. The characteristic absorbed by SGLT-1 sugar in delay intestines is shown in activity in vivo test.Inhibitor shows low systemic exposure Characteristic.
Part of the present invention is related to the compound comprising following formula and its application method of officinal salt and they：
Wherein：
R1Can be the R independently arbitrarily replaced1A、-N(R1A)(R1B)、-OR1A、-SR1A、-S(O)R1AOr-S (O)2R1A；
R1Can 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, nitre Acyl group, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkenyl, alkynyl, ester, ketone, alcohol etc..
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.；
R2Can 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 R3ASubstitution；
R3ACan be arbitrary 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 halogen, hydroxyl, the alkyl of arbitrary carbochain or alkoxy, single or multiple glycosyls, appoint Heterocycle, ester group, sulfanyl, mercaptan, the amino etc. of meaning substitution.
R4、R5、R6It can be equal or different, can be identical substitution or different substitutions.
X is optional various oxides of one or more N, O, S, C or corresponding.
The invention further relates to the pharmaceutical composition for including the compound disclosed herein, and treated using them or Manage angiocardiopathy, metabolic disease (especially diabetes and various complication), intestines problem, kidney trouble and certain classes The method of the cancer of type.
We test growth inhibition effect of the compound to SGLT1, and test result is found：Should have highly significant The activity for inhibiting SGLT1 shows that its IC50 is 17.84 ± 3.32 mcg/mls by measuring its half-inhibition concentration, so as to It is contemplated as SGLT1 inhibitor medicaments with the expected compound or pharmaceutically acceptable salt thereof and especially prevents type-2 diabetes mellitus namely non- The purposes of non-insulin dependent diabetes object.
In conclusion the uniqueness on the compound existing structure that we prepare, and have and inhibit to grind in terms of SGLT1 effects The novelty studied carefully, and it is found that uncommon low systemic exposure in pharmacokinetics test, it is expected to become inhibition SGLT1 and the drug candidate for treating diabetes.The compound belongs to unexpected discovery for the potent inhibition of SGLT1, has Exact originality.
Specific implementation mode
Mandatory declaration, the embodiment of the present invention are for illustrating rather than limitation of the present 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
(2S, 3S, 4R, 5S, 6R) -2- (3- (4- ((E) -4 methoxyl group -4- oxygen-butyl -1- alkenyls) benzyl) -4- methyl Phenyl) -6- (methylsulfany) tetrahydrochysene -2H- pyrans -3,4,5- three base triacetate preparation (2)：
By (2S, 3S, 4R, 5S, 6R) -2- (3- (4- chlorophenylmethyls) -4- aminomethyl phenyls) -6- (methylsulfany) tetrahydrochysenes -2H- Pyrans -3,4, tri- base triacetates (10g, 19mmol) of 5- are fitted into microwave vial, sequentially add 3-butenoic acid methyl esters (5.7g, 57mmol), tris(dibenzylideneacetone) dipalladium (Pd2dba3, 1.74g, 1.9mmol), three (tertiary butyl) tetrafluoro boric acid phosphonium salts (2.2g, 7.6mmol), dicyclohexylmethylamine (11.1g, 57mmol) and N-Methyl pyrrolidone (100mL).Reaction bulb is placed in In microwave, nitrogen protection, 160 DEG C of heating stirrings are reacted 40 minutes.After completion of the reaction, it is cooled to room temperature, reaction solution is in diatomite Upper filtering, ethyl acetate washing.Organic layer uses water successively, is saturated niter cake, saturated common salt water washing.Anhydrous magnesium sulfate is dry Dry, crude product is concentrated under reduced pressure to obtain in filtering.Crude product 100-200 mesh silica gel column chromatographies, with 5%~20% ethyl acetate/petroleum ether ladder Degree elutes to obtain pale yellow foam solid product (3g, 27%), unreacted raw material (2S, 3S, 4R, 5S, 6R) -2- (3- (4- chlorine Benzyl) -4- aminomethyl phenyls) -6- (methylsulfany) tetrahydrochysene -2H- pyrans -3,4,5- three base triacetate recycle.
(2S, 3S, 4R, 5S, 6R) -2- (3- (4- (4- methoxyl group -4- oxygen-butyls) benzyl) -4- aminomethyl phenyls) -6- (first Base sulfenyl) tetrahydrochysene -2H- pyrans -3,4,5- three base triacetate preparation (3)：
By (2S, 3S, 4R, 5S, 6R) -2- (3- (4- ((E) -4 methoxyl group -4- oxygen-butyl -1- alkenyls) benzyl) -4- first Base phenyl) -6- (methylsulfany) tetrahydrochysene -2H- pyrans -3,4, tri- base triacetates (3g, 5mmol) of 5- are dissolved in 1:1(V:V) In THF/ methanol solutions, Pd/C (10% is wet, 200mg) is then added, hydrogenation 3 hours at 35 DEG C of hydrogen balloon on cover.TCL points Plate pads diatomite filtering, ethyl acetate washing after completion of the reaction.Be concentrated under reduced pressure to give light yellow solid target product (3g, 99% Yield).
4- (4- (2- methyl -5- ((2S, 3R, 4R, 5S, 6R) -3,4,5- trihydroxies -6- (methylsulfany) tetrahydrochysene -2H- pyrroles Mutter -2- bases) benzyl) phenyl) and butyric acid preparation (4)：
By (2S, 3S, 4R, 5S, 6R) -2- (3- (4- (4- methoxyl group -4- oxygen-butyls) benzyl) -4- aminomethyl phenyls) -6- (methylsulfany) tetrahydrochysene -2H- pyrans -3,4, tri- base triacetates (3g, 5mmol) of 5- are dissolved in methanol/THF/ water (50mL, body Product ratio 2:1:2) in mixed solution, Lithium hydroxide monohydrate (2.1g, 50mmol) is added, and it is small that reaction is stirred at room temperature 1 When.TCL contact plates are acidified to pH=1-2 after the completion of reaction with saturation niter cake.Acidic aqueous phase is extracted with ethyl acetate 3 times, closes And organic phase, saturated salt solution wash twice, foaming solid crude product is concentrated under reduced pressure to obtain in anhydrous magnesium sulfate drying, filtering.Slightly Product is dissolved with 30% sodium bicarbonate aqueous solution, and ethyl acetate is extracted twice removing impurity.Alkaline water phase saturation niter cake It is acidified to pH=1-2, then is extracted with ethyl acetate 3 times.Merge organic phase, saturated salt solution washes twice, and anhydrous magnesium sulfate is dry Dry, white solid target compound (2g, 89% yield) is concentrated under reduced pressure to obtain in filtering.
It is prepared by compound 5：
By 4- (4- (2- methyl -5- ((2S, 3R, 4R, 5S, 6R) -3,4,5- trihydroxies -6- (methylsulfany) tetrahydrochysenes -2H- Pyrans -2- bases) benzyl) phenyl) butyric acid (1g, 2.2mmol) is dissolved in 4mL DMF, and sequentially adding 2-, (7- aoxidizes three nitrogen of benzo Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU, 1g, 2.6mmol), DIPEA (0.77mL, 4.4mmol) and 1- (2- aminoethyls) pyrrolidines (297mg, 2.6mmol).It is stirred to react at room temperature 3 hours.TCL contact plates, with saturation after the completion of reaction Sodium bicarbonate is quenched, and ethyl acetate extracts 3 times, merges organic phase, saturated common salt water washing 3 times.Anhydrous sodium sulfate is dried, filtering Concentration, crude product pass through 100-200 mesh silica gel column purifications, dichloromethane：Methanol=20：1 elution, concentrated solvent obtain foam-like White solid target compound (500mg, 42% yield).
It is prepared by compound 6：
By 4- (4- (2- methyl -5- ((2S, 3R, 4R, 5S, 6R) -3,4,5- trihydroxies -6- (methylsulfany) tetrahydrochysenes -2H- Pyrans -2- bases) benzyl) phenyl) butyric acid (100mg, 0.22mmol) is dissolved in 4mL DMF, sequentially add HATU (125mg, 0.33mmol), DIPEA (77 μ L, 0.44mmol) and 1- (pyrrolidinylcarbonyl methyl) piperazine (51mg, 0.26mmol).Room temperature Under be stirred to react 3 hours.TCL contact plates, are quenched after the completion of reaction with saturated sodium bicarbonate, and ethyl acetate extracts 3 times, are merged organic Phase, saturated common salt water washing 3 times.Anhydrous sodium sulfate is dried, and filtering and concentrating, crude product passes through 100-200 mesh silica gel column purifications, dichloro Methane：Methanol=30：1 elution, concentrated solvent obtain foamy white solid target compound (30mg, 22% yield).
It is prepared by compound 7：
By 4- (4- (2- methyl -5- ((2S, 3R, 4R, 5S, 6R) -3,4,5- trihydroxies -6- (methylsulfany) tetrahydrochysenes -2H- Pyrans -2- bases) benzyl) phenyl) butyric acid (100mg, 0.22mmol) is dissolved in 2mL DMF, sequentially add HATU (125mg, 0.33mmol), DIPEA (77 μ L, 0.44mmol) and 1- amino-N- (2- methoxyl groups) cyclopropane -1- formamides (41mg, 0.26mmol).It is stirred to react at room temperature 3 hours.TCL contact plates, are quenched after the completion of reaction with saturated sodium bicarbonate, ethyl acetate extraction It takes 3 times, merges organic phase, saturated common salt water washing 3 times.Anhydrous sodium sulfate is dried, filtering and concentrating, crude product 100-200 mesh silicon Rubber column gel column purifies, dichloromethane：Methanol=30：1 elution, concentrated solvent, obtain foamy white solid target compound (28mg, 21% yield).
It is prepared by compound 8：
By 4- (4- (2- methyl -5- ((2S, 3R, 4R, 5S, 6R) -3,4,5- trihydroxies -6- (methylsulfany) tetrahydrochysenes -2H- Pyrans -2- bases) benzyl) phenyl) butyric acid (100mg, 0.22mmol) is dissolved in 2mL DMF, sequentially add HATU (125mg, 0.33mmol), DIPEA (77 μ L, 0.44mmol) and 2- amino-2-methyls-N- (2- (pyridin-4-yl) ethyl) propionamide (54mg, 0.26mmol).It is stirred to react at room temperature 3 hours.TCL contact plates, are quenched after the completion of reaction with saturated sodium bicarbonate, acetic acid Ethyl ester extracts 3 times, merges organic phase, saturated common salt water washing 3 times.Anhydrous sodium sulfate is dried, and filtering and concentrating, crude product passes through 100- 200 mesh silica gel column purifications, dichloromethane：Methanol=30：1 elution, concentrated solvent obtain foamy white solid target compound (80mg, 57% yield).
It is prepared by compound 9：
By 4- (4- (2- methyl -5- ((2S, 3R, 4R, 5S, 6R) -3,4,5- trihydroxies -6- (methylsulfany) tetrahydrochysenes -2H- Pyrans -2- bases) benzyl) phenyl) butyric acid (100mg, 0.22mmol) is dissolved in DMF, sequentially add HATU (125mg, 0.33mmol), DIPEA (77 μ L, 0.44mmol) and 2- amino-N- (4- fluorophenyls) -2- methyl propanamides (51mg, 0.26mmol).It is stirred to react at room temperature 3 hours.TCL contact plates, are quenched after the completion of reaction with saturated sodium bicarbonate, ethyl acetate extraction It takes 3 times, merges organic phase, saturated common salt water washing 3 times.Anhydrous sodium sulfate is dried, and filtering and concentrating, crude product passes through 100-200 mesh Silica gel column purification, dichloromethane：Methanol=30：1 elution, concentrated solvent obtain foamy white solid target compound (70mg, 51%).
It is prepared by compound 10：
By 4- (4- (2- methyl -5- ((2S, 3R, 4R, 5S, 6R) -3,4,5- trihydroxies -6- (methylsulfany) tetrahydrochysenes -2H- Pyrans -2- bases) benzyl) phenyl) butyric acid (100mg, 0.22mmol) is dissolved in DMF, sequentially add HATU (125mg, 0.33mmol), DIPEA (77 μ L, 0.44mmol) and methyl (azetidine -3- carbonyls)-L-PROLINE methyl esters (55mg, 0.26mmol).It is stirred to react at room temperature 3 hours.TCL contact plates, are quenched after the completion of reaction with saturated sodium bicarbonate, ethyl acetate extraction It takes 3 times, merges organic phase, saturated common salt water washing 3 times.Anhydrous sodium sulfate is dried, and filtering and concentrating, crude product passes through 100-200 mesh Silica gel column purification, dichloromethane：Methanol=30：1 elution, concentrated solvent obtain foamy white solid target compound (32mg, 23% yield).1H NMR (400MHz, MeOD) δ 7.22-7.07 (m, 7H), 4.48 (dd, J=8.6,3.6Hz, 1H), 4.40 (dd, J=9.4,1.5Hz, 1H), 4.30-4.00 (m, 5H), 3.98 (s, 2H), 3.79-3.71 (m, 3H), 3.71-3.59 (m, 1H), 3.56-3.36 (m, 5H), 2.62 (t, J=7.4Hz, 2H), 2.39-2.24 (m, 1H), 2.22 (s, 3H), 2.16 (s, 3H), 2.11 (t, J=7.3Hz, 2H), 2.07-1.84 (m, 5H) .HRMS (ESI) calcd for C34H44N2O8S[M+H]+: 641.2852；found:641.2856.

Claims (18)

1. a kind of compound such as following formula：
Or its officinal salt, wherein：
R1Can be the R independently arbitrarily replaced1A、-N(R1A)(R1B)、-OR1A、-SR1A、-S(O)R1AOr-S (O)2R1A；
R1Can 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..
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.；
R2Can 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 R3ASubstitution；
R3ACan be arbitrary 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 halogen, hydroxyl, the alkyl of arbitrary carbochain or alkoxy, single or multiple glycosyls, arbitrarily take Heterocycle, ester group, sulfanyl, mercaptan, the amino in generation etc..
R4、R5、R6It can be equal or different, can be identical substitution or different substitutions.
X is 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、R6Can be halogen, hydroxyl, the alkyl of arbitrary carbochain or alkoxy, list A or multiple glycosyls, the heterocycle arbitrarily replaced, ester group, sulfanyl, mercaptan, amino；Especially hydroxyl, ester group, mercaptan, sulfane Base.
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 halogen or the alkoxy of arbitrary 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, aryl, heterocycle, amino, aminoacyl, azo, carbonyl, carboxyl, cyanogen Base, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, isothiocyanates, nitrile, nitro, nitroso, nitroxyl, oxygen Base, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkenyl, alkynyl, ester, ketone, alcohol etc..
X1It is 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 It is to use one or more R to state optionally substitution2ASubstitution；
Each R2AIt is independently arbitrary 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, the optional substitution is to use one or more R7ASubstitution.
Each R7AIt is independently arbitrary substituted C1-10Linear or branched alkyl group, C1-10Straight or branched alkoxyl, naphthenic base, virtue Base, heterocycle, amino, aminoacyl, azo, carbonyl, carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imido Base, isothiocyanates, nitrile, nitro, nitroso, nitroxyl, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, sulphur Urea, urea alkenyl, alkynyl, ester, ketone, alcohol etc..
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 R7AIt is five yuan or hexa-member heterocycle, especially nafoxidine ring.
14. a kind of pharmaceutical composition, it includes the compound of any one of preceding claims and officinal salt excipient and dilutions Agent.
15. the application in claim 1-14 in treating and improving angiocardiopathy and metabolic disease patient.
16. the application in claim 1-14 in treating and improving diabetic.
17. the application in claim 1-14 in treating and improving diabetic's complication, including microvascular complication meeting Caused retinopathy, nephrosis and the nervous system disease.And angiocardiopathy caused by big vascular syndrome.
18. the wherein described patients of claim 15-18 had taken or had just taken other therapeutic drug, including blood pressure lowering at present Medicine, hypolipidemic, antidiabetic, hypoglycemic agent, slimming drugs or appetite inhibitor.
CN201810370550.0A 2018-04-23 2018-04-23 A kind of medicinal usage of white 1 inhibitor of sodium glucose co-transporter 2 Pending CN108610385A (en)

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CN201910322156.4A CN110117303A (en) 2018-04-23 2019-04-22 A kind of medicinal usage of white 1 inhibitor of sodium glucose co-transporter 2

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WO2021227440A1 (en) * 2020-05-15 2021-11-18 上海喆邺生物科技有限公司 A class of aryl glucoside derivatives, preparation method therefor and application thereof
CN114423775A (en) * 2020-05-15 2022-04-29 上海喆邺生物科技有限公司 Aryl glucoside derivatives, and preparation method and application thereof
CN114599643A (en) * 2020-05-15 2022-06-07 上海喆邺生物科技有限公司 Aryl glucoside derivative

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