CN108285439A - A kind of 2 inhibitor of carbon glycoside class sodium glucose transporter body - Google Patents
A kind of 2 inhibitor of carbon glycoside class sodium glucose transporter body Download PDFInfo
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- CN108285439A CN108285439A CN201711416357.8A CN201711416357A CN108285439A CN 108285439 A CN108285439 A CN 108285439A CN 201711416357 A CN201711416357 A CN 201711416357A CN 108285439 A CN108285439 A CN 108285439A
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- acid
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- sodium glucose
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- 0 CC[C@](C[C@]([C@@]1O)O)O[C@]1*(cc1Cc(cc2)ccc2O*C*(CC)=C)ccc1Cl Chemical compound CC[C@](C[C@]([C@@]1O)O)O[C@]1*(cc1Cc(cc2)ccc2O*C*(CC)=C)ccc1Cl 0.000 description 1
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to a kind of 2 inhibitor of carbon glycoside class sodium glucose transporter body, preparation method and use, 2 inhibitor of carbon glycoside class sodium glucose transporter body of the invention, the structures with general formula (I)
Description
Technical field
The present invention relates to the relevant chemical drugs field of diabetes, and in particular to a kind of carbon glycoside class sodium glucose transport protein
2 type sodium of lean type structure-glucose transporter (SGLT-2) inhibitor.The invention also discloses preparation method and uses.
Background technology
Diabetes be it is a kind of caused by defect of insulin secretion and (or) insulin action deficiency characterized by hyperglycemia
Metabolic disorder syndrome, be divided into two kinds of 1 type (T1DM) and 2 types (T2DM), the former is since pancreaticβ-cell cannot generate foot
Caused by enough insulin (insulin absolutely lacks), teenager is mostly occurred in, the latter is due to hypoinsulinism or pancreas islet
Caused by element resists (insulin opposite lack), in being more common in, the elderly.
Sodium dependent glucose transport protein (SGLTs) by sodium electrochemical potentials ion by extracellular glucose actively
It is transported into cytoplasm.SGLT2 is low-affinity, and the special transhipment of high power capacity is located at the glucose on renal epithelial cell surface, and
SGLT1 is not only in renal expression, but also in the intestine and its hetero-organization also has expression.Filtered glucose about 90% is logical
SGLT2 is crossed at proximal convoluted tubule proximal end (S1 and S2 sections) by reabsorption, remaining be by SGLT1 proximal tubule distal end (S3 sections) again
It absorbs.In the presence of no SGLT2, SGLT1 is the glucose that can absorb and filter about 70%.SGLT2 inhibitor can be close in kidney
Distal convoluted tubule reduces the reabsorption of glucose, and the excretion that glucose is urinated by increase reaches the negative balance of an energy.Due to such
Inhibitor can be used for any stage of diabetes de-velopment independent of insulin action, even if in β cell deteriorations and pancreas islet
Element resist in the case of can continuous and effective reduction blood glucose, this allow for SGLT2 inhibitor as treating diabetes it is unique
Selection.
SGLT2 inhibitor is broadly divided into oxygen glycoside, carbon glycoside class, nitrogen glycoside and non-glycoside SGLT2 and inhibits
Agent.Because oxygen glycoside is very sensitive to glycosidase, facile hydrolysis, and pharmacokinetic trial is poor, the development of final oxygen glucosides
It has been stopped that, the design research and development that research direction is turned to C- glycoside drugs by people come up, and C- glycoside drugs will be in glycosidic bond
O directly changes C into, and hydrolytic stability is greatly enhanced while not influencing drug effect, medicine for property, is a kind of very promising
Drug.And more a kind of sodium glucose transporter 2 inhibitor is listed and studied at present.Several compounds are just below
It is avoided to glycosidase sensitive question by removing different head glucosides oxygen.
But there is also some shortcomings while increase drug effect, enhancing stability for existing compound, if plasma half-life is short,
The hypoglycemic effect time is not grown, and has vomiting, the areas for improvement such as diarrhea side effect.
Invention content
The present invention on the basis of existing technology, is transformed related group, is found surprisingly that, chemical combination of the present invention
Object hypoglycemic effect is stronger, extended durations of action, and side effect reduces.
The invention discloses a kind of C- glycoside SGLT2 inhibitor compounds with general formula (I),
Wherein,
N=0,1,2 or 3；
X is selected from C3~C6 alkyl, C3~C6 alkenyls, C3~C6 alkynyls, or the substituted-phenyl as shown in formula (II),
Or replace adamantyl as shown in formula (III),
Wherein, R1、R2、R3It is independent to be selected from-H ,-CH3、-CH2CH3、-CH2CH2CH3、-OCH3、-OCH2CH3、-OH、-
CH2OH、-CH2CH2OH；
Wherein, R4、R5、R6It is independent to be selected from-H ,-CH3、-CH2CH3、-OCH3、-OCH2CH3、-OH、-CH2OH、-NH2、-
NHCOCH3；
Preferably, the C- glycoside SGLT2 inhibitor compounds of general formula (I) of the present invention, wherein
N=0,1 or 2；
X is selected from the substituted-phenyl as shown in formula (II),
Or replace adamantyl as shown in formula (III),
Wherein,
R1、R2、R3It is independent to be selected from-H ,-CH3、-CH2CH3、-CH2CH2CH3；
R4、R5、R6It is independent to be selected from-H ,-CH3、-CH2CH3；
It is furthermore preferred that the C- glycoside SGLT2 inhibitor compounds of the present invention are following particular compound：
It is further preferred that the C- glycoside SGLT2 inhibitor compounds of the present invention are following particular compound：
Most preferably, C- glycoside SGLT2 inhibitor compounds of the invention are following particular compound：
The present invention further provides the preparation method of the compounds of this invention, following route may be used in the preparation method：
Using the bromo- 2- chlorobenzoic acids of 5- as starting material, through acylation, condensation, reduction reaction, the chloro- 4 '-first of the bromo- 2- of 5- is obtained
Oxygroup diphenyl-methane 4, compound 4 protect phenolic hydroxyl group to obtain 6, compound 6 after Boron tribromide acts on removing ether methyl
It is reacted through condensation, anomeric carbon etherification of hydroxyl groups, demethoxylation with glucolactone (9), obtains the chloro- 4- of key intermediate 1- (β-D-
Glucopyranose -1- bases) -2- (4- Hydroxy-benzvls)-benzene 10.
Alkane, alkene, cycloalkane, alkynes and aromatic hydrocarbons alcohol reacted respectively with paratoluensulfonyl chloride, obtain pair of correspondent alcohol
Tosyl ester 12, compound 12 are reacted with intermediate 10, obtain each target compound.It is as follows to synthesize general line.
Formula (I) compound of the present invention can also form stable salt as needed, ester, the derivatives such as solvate,
Can such as obtain pharmaceutically acceptable atoxic pharmaceutical salts, including with inorganic acid, as hydrochloric acid, sulfuric acid are formed
Salt, and organic acid, such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, flat
The salt and amino acid that peach acid, ascorbic acid or malic acid are formed, the salt formed such as alanine, aspartic acid, lysine or with
Sulfonic acid, the salt formed such as methanesulfonic acid, p-methyl benzenesulfonic acid.
Or as needed, pharmaceutical salts can be formed with alkaline matter, such as form alkali metal salt, alkali salt, silver salt, barium
Salt etc..
The present invention formula (I) compound can also solvate (such as hydrate) form exist, therefore, these solvations
Object (such as hydrate) is also included within the compound of the present invention.
The present invention also provides the drop blood containing formula as defined above (I) compound or its pharmaceutical salts as active constituent
Sugared pharmaceutical composition.The weight ratio of the active constituent of pharmaceutical composition Zhang Hanyou in the composition is 0.1~99.9%, and drug can
The weight ratio of the carrier of receiving in the composition is 0.1~99.9%.Pharmaceutical composition is to be suitble to medicinal dosage form to exist.
Medicinal preparation is preferably such as：Tablet, sugar coated tablet, film coated tablet, enteric coated tablet, sustained-release tablet, capsule, hard capsule
Agent, soft capsule, Duracaps, powder.
The pharmaceutical composition of the present invention, as dosage form, the effective quantity of the compounds of this invention contained in every dose is 0.1
~1000mg, described every dose refers to each preparation unit, such as every of tablet, every of capsule, also can refer to each taking agent
Amount, such as each taking 100mg.
The pharmaceutical composition of the present invention is in the solid for being prepared into pulvis, tablet, dispersible pulvis, capsule, cachet form
When pharmaceutical preparation, solid carrier can be used.Workable solid carrier is preferably selected from diluent, flavoring agent, solubilizer, lubrication
One or more substances in agent, suspending agent, adhesive, swelling agent etc., or can be encapsulating substance.Suitable solid carrier includes
Magnesium carbonate, magnesium stearate, talcum powder, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, carboxymethyl cellulose
Sodium, cocoa butter etc..Since they are easy to be administered, tablet, pulvis and capsule are most suitable oral solid formulations.
Those skilled in the art can determine the preferred dose suitable for certain situation according to a conventional method.Generally, start treatment
Amount is then gradually increased dosage, until reaching optimum therapeuticing effect less than the optimal dose of active constituent.It rises for convenience
See, total daily dose can be divided into several parts, score time administration.
It is this present invention further provides using SGLT2 inhibitor shown in formula (I) of the present invention to treat diabetes B
Invention further provides for SGLT2 inhibitor and its pharmaceutical composition shown in formula (I) of the present invention and is preparing treatment diabetes B
Application in drug can improve glycemic control in the adult for having diabetes B as auxiliary diet and movement.
The beneficial effects of the present invention are find to compare with existing similar compound, change of the invention by contrast experiment
Conjunction object especially compound 13h, compound 13i, 13j, have hypoglycemic effect stronger, extended durations of action, and side effect is low
Feature.
Description of the drawings
The MS collection of illustrative plates of Fig. 1 13c
Fig. 2 13c's1HNMR collection of illustrative plates
Fig. 3 13c's13CNMR collection of illustrative plates
The DEPT collection of illustrative plates of Fig. 4 13c
The MS collection of illustrative plates of Fig. 5 13d
Fig. 6 13d's1HNMR collection of illustrative plates
Fig. 7 13d's13CNMR collection of illustrative plates
The DEPT collection of illustrative plates of Fig. 8 13d
The MS collection of illustrative plates of Fig. 9 13e
Figure 10 13e's1HNMR collection of illustrative plates
Figure 11 13e's13CNMR collection of illustrative plates
The DEPT collection of illustrative plates of Figure 12 13e
The MS collection of illustrative plates of Figure 13 13f
Figure 14 13f's1HNMR collection of illustrative plates
Figure 15 13f's13CNMR collection of illustrative plates
The DEPT collection of illustrative plates of Figure 16 13f
The MS collection of illustrative plates of Figure 17 13g
Figure 18 13g's1HNMR collection of illustrative plates
Figure 19 13g's13CNMR collection of illustrative plates
The DEPT collection of illustrative plates of Figure 20 13g
The MS collection of illustrative plates of Figure 21 13h
Figure 22 13h's1HNMR collection of illustrative plates
Figure 23 13h's13CNMR collection of illustrative plates
The DEPT collection of illustrative plates of Figure 24 13h
The MS collection of illustrative plates of Figure 25 13i
Figure 26 13i's1HNMR collection of illustrative plates
Figure 27 13i's13CNMR collection of illustrative plates
The DEPT collection of illustrative plates of Figure 28 13i
The MS collection of illustrative plates of Figure 29 13j
Figure 30 13j's1HNMR collection of illustrative plates
Figure 31 13j's13CNMR collection of illustrative plates
The DEPT collection of illustrative plates of Figure 32 13j
HSGLT1 the and hSGLT2 inhibitory activity curve graphs of Figure 33 13c
HSGLT1 the and hSGLT2 inhibitory activity curve graphs of Figure 34 13d
HSGLT1 the and hSGLT2 inhibitory activity curve graphs of Figure 35 13e
HSGLT1 the and hSGLT2 inhibitory activity curve graphs of Figure 36 13f
HSGLT1 the and hSGLT2 inhibitory activity curve graphs of Figure 37 13g
HSGLT1 the and hSGLT2 inhibitory activity curve graphs of Figure 38 13h
HSGLT1 the and hSGLT2 inhibitory activity curve graphs of Figure 39 13i
HSGLT1 the and hSGLT2 inhibitory activity curve graphs of Figure 40 13j
HSGLT1 the and hSGLT2 inhibitory activity curve graphs of Figure 41 reference material Dapagliflozins
Specific implementation mode
It further illustrates the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
The synthesis of the bromo- 2- chlorobenzoyl chlorides (2) of 5-
The bromo- 2- chlorobenzoic acids (1) of 60.00g (0.26mol) 5- are added in the dichloromethane dried to 200mL, are added dropwise
1.5mL (5.2mol) DMF slowly drips 32mL (0.39mmol) oxalyl chloride under the conditions of ice salt bath into reaction solution in four times, it is desirable that
Between 0~5 DEG C, drop finishes reacting liquid temperature, and reaction solution is slowly increased to room temperature reaction 12h.Thin-layer chromatography TLC monitoring reactions,
Until raw material reaction finishes, solvent and oxalyl chloride are removed under reduced pressure, be used in combination dichloromethane that oxalyl chloride is evaporated off in three times, obtained after cooling
Off-white solid (2) 53.5g, yield 89.1%MS-EI (m/z):255.1[M+H]+
Embodiment 2
The synthesis of the chloro- 4'- methoxy benzophenones (3) of the bromo- 2- of 5-
34.10g (0.26mol) aluminum trichloride (anhydrous)s are added to dry 110mL dichloromethanes in three batches under condition of ice bath
In alkane, 23mL (0.22mol) methyl phenyl ethers anisole is slowly added dropwise into reaction solution after stirring 15min, control rate of addition makes reaction solution temperature
Dichloromethane (115mL) solution of intermediate 2 (66g), control drop is slowly added dropwise at 0~5 DEG C in degree into reaction solution after 30min
Acceleration makes reacting liquid temperature be maintained at 0~5 DEG C, and drop finishes, and ice bath reacts 4h.It is warmed to room temperature reaction 6h.Reaction finishes, and will react
Liquid is poured slowly into 750mL ice water, stir 45min, separate organic layer, successively use 1molL-1 sodium hydrate aqueous solutions,
2molL-1 hydrochloric acid, saturated common salt water washing, and anhydrous sodium sulfate is dried, and removes solvent under reduced pressure, residue is tied again with ethyl alcohol
It is brilliant to obtain white needle-like crystals (3) 58.11g, yield 78.4%.It is 89.3% that HPLC methods, which detect purity,.MS-EI(m/z):325.1
[M]+
Embodiment 3
The synthesis of the chloro- 4'- methoxyl groups diphenyl-methanes (4) of the bromo- 2- of 5-
3 (0.17mol) of the triethylsilane of 5mL (0.31mol) and 5.5g are added to the 1 of 20mL under stirring condition:2
Dichloromethane reacted with acetonitrile mixture, to be slowly added to 2.5mL boron trifluoride ether under the conditions of 10 DEG C molten for control temperature
Liquid is no more than 20 DEG C with the carry out controlling reaction temperature of reaction.HPLC monitoring reactions, if unreacted is complete, are stirred overnight
Reaction, adds 0.5mL triethylsilanes and reaction temperature is then risen to 50 DEG C and is stirred to react by 0.3mL boron trifluoride ether liquid
4h.Stop reaction with the KOH solution of 5mL7N after cooling, water phase extracts (2 ×) with dichloromethane, merges organic phase, uses 2N successively
KOH, saturated common salt washing (2 ×), anhydrous sodium sulfate drying, filtering, solvent is evaporated off in filtrate decompression, and residue is tied again with ethyl alcohol
Crystalline substance obtains white solid 3.1g, yield 65.0%.MS-EI(m/z):311.6[M]+,312.4[M+H]-
Embodiment 4
The synthesis of 4- (the bromo- 2- chlorobenzyls of 5-) phenol (5)
The 4 of 20.0g (64mmol) are dissolved in 80mL dichloromethane under stirring condition, 6mL (70.4mmol) is slowly added dropwise
Boron tribromide solution, 0~4 DEG C of controlling reaction temperature, drop finish, and mixed liquor is slowly increased to react after reaction 3.5h is stirred at room temperature
Liquid is cooled to -78 DEG C, is used in combination 100mL methanol solutions to stop reaction, mixed liquor is poured into 500mL ice water and is stirred to react 30min.
It is used in combination the sodium hydroxide solution of 1N to adjust PH7~8, dichloromethane extraction merges organic phase, anhydrous sodium sulfate drying, and filtering subtracts
Solvent is evaporated off in pressure, and residue ethyl alcohol recrystallization obtains 5 pale solid 19.62g of compound, yield 78.0%.MS-EI(m/z):
298[M]+,321.4[M+Na]-
Embodiment 5
The synthesis of (4- (the bromo- 2- chlorobenzyls of 5-) phenoxy group) (tertiary butyl) dimethylsilane (6)
5 and 39mL (0.28mol) triethylamine of 60.00g (0.2mol) is dissolved in 125mL dichloromethane, condition of ice bath
Under be slowly added to tert-butyl chloro-silicane, finish, mixed liquor be slowly increased to room temperature, continue to be stirred to react 15h.Thin layer color
Spectrum TLC is detected to the reaction was complete, and reaction solution is poured into 200mL ice water, continues to be stirred to react 20min, there is solid precipitation, mistake
Filter, filtrate are extracted with dichloromethane, and organic phase removes solvent under reduced pressure, and residue crosses silicagel column (petroleum ether：Ethyl acetate=10:
1) milky sticky solid 6,60..12g, yield 97.7%.MS-EI (m/z), are obtained:411[M]+.
Embodiment 6
The synthesis of tetra--O- trimethyl silyl-β-D- gluconolactones (9) of 2,3,4,6-
By the 1,5- glucolactones of 14.00g (0.08mol), under conditions of -5 DEG C of the N-methylmorpholine of 80mL
It is stirred to react in 120mL tetrahydrofuran solutions, 50mL (0.48mol) trim,ethylchlorosilane is slowly dropped in mixed liquor, and
Rate of addition is controlled, reaction temperature is made to be no more than 5 DEG C, after being stirred to react 1h, temperature is increased to 35 DEG C the reaction was continued 15h, then
It is cooled to room temperature and is stirred overnight, poured into ice water after being diluted with 100mL dichloromethane, control temperature is no more than 10 DEG C, and stirring is anti-
25min is answered, separates organic phase, and successively with 10% hydrochloric acid solution, water, saturated common salt washing, anhydrous sodium sulfate dry filter, filtrate
It removes solvent under reduced pressure, obtains colourless oil liquid, residue absolute ethyl alcohol recrystallizes to obtain compound 9,140.3g, yield 92.4%.
MS-EI(m/z):465[M-H]+,466[M]+.
Embodiment 7
(3R, 4S, 5S, 6R) -2- (the chloro- 3- of 4- (4- hydroxybenzyls) phenyl) -6- (methylol) -2- methyl tetrahydrochysene -2H- pyrroles
It mutters the synthesis of -3,4,5- triols (7)
The tetrahydrofuran for being added to 300mL under nitrogen protection by the 6 of 56.36g (0.13mol) under the conditions of -78 DEG C is molten
In liquid, and hexane solution in the normal-butyl of 2.3mL (0.18mol) is slowly dropped in mixed liquor, after being stirred to react 30min,
Reaction solution is added drop-wise in the toluene solution of 3 (80.10g, 0.18mol) of -78 DEG C of precooling, is stirred to react under nitrogen protection
The methanol solution (250mL, 0.6mol/L) of methanesulfonic acid is added after 1.5h, is slowly increased to room temperature reaction 18h.65mL saturated carbons are added
Sour hydrogen sodium solution quenching reaction, ethyl acetate solution extraction merge organic phase, and anhydrous sodium sulfate is dried, and filtering, filtrate decompression is steamed
Except solvent, 7 crude products are obtained, are dissolved in hot toluene solution, are slowly added in hexane solution, yellow solid 7,47.8g, yield is precipitated
84.8%.MS-EI(m/z):412[M+H]+,410[M]+
Embodiment 8
The synthesis of the chloro- 4- of 1- (β-D- glucopyranose -1- bases) -2- (4- Hydroxy-benzvls)-benzene (10)
It is dissolved in 300mL dichloromethane acetonitrile (1 by the 7 of 45.3g (0.11mol):1) it in mixed liquor, is stirred to react, be cooled to-
It is slowly added under the conditions of 10 DEG C in 29mL (0.17mol) triethylsilane to mixed liquor, 16mL (0.13mol) is then slowly added dropwise
Boron trifluoride ether liquid reacts 5h under condition of ice bath, and the quenching reaction of 150mL saturated sodium bicarbonate solutions is added, is stirred to react
15min separates organic phase, removes solvent under reduced pressure, and residue with Ethyl acetate and water are stirred to react stratification, separate organic
Phase, water phase are extracted with ethyl acetate (2 ×), merge organic phase, use water, saturated common salt washing, organic phase anhydrous sodium sulfate successively
Dry, solvent is evaporated off in filtering, filtrate decompression, and residue absolute ethyl alcohol recrystallization obtains compound 10,36.4g, yield 87.1%.
MS-EI(m/z):381[M+H]+,380[M]+
Embodiment 9
(3R, 4R, 5S, 6R) -2- (3- (4- n-butoxies) benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrroles
It mutters the synthesis of -3,4,5- triols (13c)
9mLN, N- bis- is added in 10 and 2.1g (6.8mmol) cesium carbonate of 1.7g (4.5mmol) under the conditions of 55 DEG C of oil baths
It is stirred to react 13min in methylformamide, the p-methyl benzenesulfonic acid N-butyl of 1.35g (5.9mmol) is added under the conditions of 60 DEG C of oil bath,
It is stirred to react 15h, saturated salt solution, ethyl acetate extraction is added, the drying of organic layer anhydrous sodium sulfate is filtered, removed under reduced pressure molten
Agent, residue cross silica gel column chromatography (dichloromethane:Methanol=20:1) 2.08g colorless viscous solid 13c, yield 80.6%. are obtained
Embodiment 10
(3R, 4R, 5S, 6R) -2- (3- (4- positive hexyloxies) benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrroles
It mutters the synthesis of -3,4,5- triols (13d)
9mLN, N- bis- is added in 10 and 2.1g (6.8mmol) cesium carbonate of 1.7g (4.5mmol) under the conditions of 55 DEG C of oil baths
It is stirred to react 13min in methylformamide, the just own ester of 1.51g (5.9mmol) p-methyl benzenesulfonic acid is added under the conditions of 60 DEG C of oil bath, stirs
Reaction 15h to be mixed, saturated salt solution, ethyl acetate extraction is added, the drying of organic layer anhydrous sodium sulfate filters, removes solvent under reduced pressure,
Residue crosses silica gel column chromatography (dichloromethane:Methanol=20:1) 2.23g colorless viscous solid 13d, yield 81.3%. are obtained
Embodiment 11
(3R, 4R, 5S, 6R) -2- (3- (4- propargyl alcoholates) benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrroles
It mutters the synthesis of -3,4,5- triols (13e)
9mLN, N- bis- is added in 10 and 2.1g (6.8mmol) cesium carbonate of 1.7g (4.5mmol) under the conditions of 55 DEG C of oil baths
It is stirred to react 13min in methylformamide, the p-methyl benzenesulfonic acid propynyl ester of 1.24g (5.9mmol) is added under the conditions of 60 DEG C of oil bath,
It is stirred to react 15h, saturated salt solution, ethyl acetate extraction is added, the drying of organic layer anhydrous sodium sulfate is filtered, removed under reduced pressure molten
Agent, residue cross silica gel column chromatography (dichloromethane:Methanol=20:1) 1.89g colorless viscous solid 13e, yield 76.4%. are obtained
Embodiment 12
(3R, 4R, 5S, 6R) -2- (3- (4- phenoxy groups) benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -
The synthesis of 3,4,5- triols (13f)
9mLN, N- bis- is added in 10 and 2.1g (6.8mmol) cesium carbonate of 1.7g (4.5mmol) under the conditions of 55 DEG C of oil baths
It is stirred to react 13min in methylformamide, the p-methyl benzenesulfonic acid phenyl ester of 1.46g (5.9mmol) is added under the conditions of 60 DEG C of oil bath, stirs
Reaction 15h to be mixed, saturated salt solution, ethyl acetate extraction is added, the drying of organic layer anhydrous sodium sulfate filters, removes solvent under reduced pressure,
Residue crosses silica gel column chromatography (dichloromethane:Methanol=20:1) 1.91g colorless viscous solid 13f, yield 70.7%. are obtained
Embodiment 13
(3R, 4R, 5S, 6R) -2- (3- (4- benzyloxies) benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrans -
The synthesis of 3,4,5- triols (13g)
Under condition of ice bath, the triethylamine of the paratoluensulfonyl chloride of 7.0g (37mmol) and 5.0mL (37mmol) are added
In the dichloromethane solution of 40mL, benzyl alcohol 2.5mL (23mmol) is slowly added into mixed liquor after 10min, controls temperature
No more than 8 DEG C, after reacting 5h, TLC detects (petroleum ether：Ethyl acetate=25：1) to the reaction was complete, 10mL dichloromethane is added,
Reaction solution is poured into ice water (10mL × 2), is stirred to react 15min, successively with 10% hydrochloric acid solution, saturated sodium bicarbonate is satisfied
It is washed with salt, the drying of organic phase anhydrous sodium sulfate, filtering, solvent is evaporated off in filtrate decompression, and residue crosses silicagel column, obtains compound
Benzyl 4- oluene sulfonic acides esters (G13) are used for the preparation of 13g.
9mLN, N- bis- is added in 10 and 2.1g (6.8mmol) cesium carbonate of 1.7g (4.5mmol) under the conditions of 55 DEG C of oil baths
It is stirred to react 13min in methylformamide, (G13) of 1.55g (5.9mmol) is added under the conditions of 60 DEG C of oil bath, is stirred to react
15h, is added saturated salt solution, ethyl acetate extraction, and the drying of organic layer anhydrous sodium sulfate filters, removes solvent, residue under reduced pressure
Cross silica gel column chromatography (dichloromethane:Methanol=20:1) 2.16g colorless viscous solid 13g, yield 77.9%. are obtained
Embodiment 14
(3R, 4R, 5S, 6R) -2- (3- (4- benzene ethyoxyl) benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrroles
It mutters the synthesis of -3,4,5- triols (13h)
Under condition of ice bath, the triethylamine of the paratoluensulfonyl chloride of 7.0g (37mmol) and 5.0mL (37mmol) are added
In the dichloromethane solution of 40mL, benzyl carbinol 2.35mL (23mmol) is slowly added into mixed liquor after 10min, controls temperature
No more than 8 DEG C, after reacting 5h, TLC detects (petroleum ether：Ethyl acetate=25：1) to the reaction was complete, 10mL dichloromethane is added,
Reaction solution is poured into ice water (10mL × 2), is stirred to react 15min, successively with 10% hydrochloric acid solution, saturated sodium bicarbonate is satisfied
It is washed with salt, the drying of organic phase anhydrous sodium sulfate, filtering, solvent is evaporated off in filtrate decompression, and residue crosses silicagel column, obtains compound
P-methyl benzenesulfonic acid phenethyl ester (H13) is used for the preparation of 13h.
9mLN, N- bis- is added in 10 and 2.1g (6.8mmol) cesium carbonate of 1.7g (4.5mmol) under the conditions of 55 DEG C of oil baths
It is stirred to react 13min in methylformamide, (H13) of 1.63g (5.9mmol) is added under the conditions of 60 DEG C of oil bath, is stirred to react
15h, is added saturated salt solution, ethyl acetate extraction, and the drying of organic layer anhydrous sodium sulfate filters, removes solvent, residue under reduced pressure
Cross silica gel column chromatography (dichloromethane:Methanol=20:1) 2.24g colorless viscous solid 13h, yield 78.4%. are obtained
Embodiment 15
(3R, 4R, 5S, 6R) -2- (3- (4- Buddha's warrior attendants alkoxy) benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysene -2H- pyrroles
It mutters the synthesis of -3,4,5- triols (13i)
Under condition of ice bath, the triethylamine of the paratoluensulfonyl chloride of 7.0g (37mmol) and 5.0mL (37mmol) are added
In the dichloromethane solution of 40mL, adamantanol 3.50g (23mmol) is slowly added into mixed liquor after 10min, control temperature
Degree is no more than 8 DEG C, and after reacting 5h, TLC detects (petroleum ether：Ethyl acetate=25：1) to the reaction was complete, 10mL dichloromethanes are added
Reaction solution is poured into ice water (10mL × 2), is stirred to react 15min by alkane, successively with 10% hydrochloric acid solution, saturated sodium bicarbonate,
Saturated common salt is washed, the drying of organic phase anhydrous sodium sulfate, filtering, and solvent is evaporated off in filtrate decompression, and residue crosses silicagel column, obtains chemical combination
Object p-methyl benzenesulfonic acid Buddha's warrior attendant alkyl ester (I13) is used for the preparation of 13i.
9mLN, N- bis- is added in 10 and 2.1g (6.8mmol) cesium carbonate of 1.7g (4.5mmol) under the conditions of 55 DEG C of oil baths
It is stirred to react 13min in methylformamide, (I13) of 1.81g (5.9mmol) is added under the conditions of 60 DEG C of oil bath, is stirred to react
15h, is added saturated salt solution, ethyl acetate extraction, and the drying of organic layer anhydrous sodium sulfate filters, removes solvent, residue under reduced pressure
Cross silica gel column chromatography (dichloromethane:Methanol=20:1) 2.20g colorless viscous solid 13i, yield 72.5%. are obtained
Embodiment 16
(3R, 4R, 5S, 6R) -2- (3- (4- adamantane ethyoxyl) benzyl) -4- chlorphenyls) -6- (methylol) tetrahydrochysenes -2H-
The synthesis of pyrans -3,4,5- triols (13j)
Under condition of ice bath, the triethylamine of the paratoluensulfonyl chloride of 7.0g (37mmol) and 5.0mL (37mmol) are added
In the dichloromethane solution of 40mL, Adamantane ethanol 4.15g (23mmol) is slowly added into mixed liquor after 10min, is controlled
Temperature is no more than 8 DEG C, and after reacting 5h, TLC detects (petroleum ether：Ethyl acetate=25：1) to the reaction was complete, 10mL dichloros are added
Reaction solution is poured into ice water (10mL × 2), is stirred to react 15min by methane, successively with 10% hydrochloric acid solution, unsaturated carbonate hydrogen
Solvent is evaporated off in sodium, saturated common salt washing, the drying of organic phase anhydrous sodium sulfate, filtering, filtrate decompression, and residue crosses silicagel column, obtains
Compound p-methyl benzenesulfonic acid Buddha's warrior attendant alkoxy ethyl methacrylate (J13) is used for the preparation of 13j.
9mLN, N- bis- is added in 10 and 2.1g (6.8mmol) cesium carbonate of 1.7g (4.5mmol) under the conditions of 55 DEG C of oil baths
It is stirred to react 13min in methylformamide, (J13) of 1.97g (5.9mmol) is added under the conditions of 60 DEG C of oil bath, is stirred to react
15h, is added saturated salt solution, ethyl acetate extraction, and the drying of organic layer anhydrous sodium sulfate filters, removes solvent, residue under reduced pressure
Cross silica gel column chromatography (dichloromethane:Methanol=20:1) 2.34g colorless viscous solid 13j, yield 73.2%. are obtained
Embodiment 17
The present invention respectively to 13c-13j this 8 target compounds carry out mass spectrums and nuclear magnetic resonance spectroscopy (1HNMR), carbon is composed
(13CNMR and13CDEPT 135) confirmation.
The hydrogen nuclear magnetic resonance modal data of 13c-13j target compounds is shown in Table 1, and mass spectrometric data is shown in Table 2, and spectrogram is shown in attached drawing 1-
32。
1 target compound hydrogen nuclear magnetic resonance modal data of table
Mass spectrum (MS) data of 2 target compound of table
19 external SGLT inhibitory activity of embodiment is screened
Experimental method
Stablize the SGLT2 and SGLT1 of expression people in Chinese hamster ovary cell (CHO), therefore is used for the Activity determination
It in experiment, is cultivated in 96 orifice plates, 37 DEG C, overnight.The activity examination that target compound inhibits SGLT1 and SGLT2 is had detected respectively
It tests.The substrate of SGLT uses radiolabeled glucalogue Alpha-Methyl-D- glucopyranosides (AMG).Inhibitor
Inhibiting the ability measurement of intake AMG is carried out in buffer solution, and buffer solution effect is the item for the low albumen for simulating glomerular filtration
Part.Each compound will measure glucose transport experiment under 8 various concentrations, and response curve is fitted to four parameter model, with
It determines the inhibitor concentration in half peak response, is denoted as 503nhibiting concentration (IC50)。
External inhibitory activity test result
From table 3 it can be seen that the derivative 13e, IC that are replaced with propargyl50Value is respectively 1.1nM, inhibits to live to SGLT2
Property than Dapagliflozin compare slightly higher (IC50=0.9nM), but it is more much higher than Dapagliflozin to the selectivity of SGLT1.Three aromatic rings
The derivative 13h that phenethyl replaces in substituted derivative (13f, 13g, 13h) is compared with Dapagliflozin to SGLT2 inhibitory activity
Identical (IC50It is 0.9nM), but selectivity is better than Dapagliflozin (being respectively 540 times and 373.4 times).Replaced with adamantane
The inhibitory activity of derivative (13i, 13j) and Dapagliflozin is not so good as to the selectivity of SGLT1.
3 external hSGLT Inhibition tests data of table
Note：Each IC of a50It is to pass through IC that value, which represents the average value b selective values measured twice,50Value SGLT1/SGLT2 meters
It calculates and obtains, take average value twice
Conclusion
8 target compound structures are confirmed by MS and 1HNMR, 13C NMR and DEPT spectrum, by target
The SGLT1 inhibitory activity experimental results of the external people of compound, which can be seen that, to be had with phenethyl substitutive derivative (13h) than reaching
Lattice arrange inhibitory activity that only will be good, and higher than Dapagliflozin to the selectivity of SGLT1, the compound replaced with n-hexyl
(13d) is more much higher than Dapagliflozin to the selectivity of SGLT2.
Claims (10)
1. a kind of 2 inhibitor of carbon glycoside class sodium glucose transporter body, the structure with general formula (I)
Wherein,
N=0,1,2 or 3；
X is selected from C3~C6 alkyl, C3~C6 alkenyls, C3~C6 alkynyls, or the substituted-phenyl as shown in formula (II),
Or replace adamantyl as shown in formula (III),
Wherein, R1、R2、R3It is independent to be selected from-H ,-CH3、-CH2CH3、-CH2CH2CH3、-OCH3、-OCH2CH3、-OH、-CH2OH、-
CH2CH2OH；
Wherein, R4、R5、R6It is independent to be selected from-H ,-CH3、-CH2CH3、-OCH3、-OCH2CH3、-OH、-CH2OH、-NH2、-
NHCOCH3。
2. 2 inhibitor of carbon glycoside class sodium glucose transporter body according to claim 1, wherein
N=0,1 or 2；
X is selected from the substituted-phenyl as shown in formula (II),
Or replace adamantyl as shown in formula (III),
Wherein,
R1、R2、R3It is independent to be selected from-H ,-CH3、-CH2CH3、-CH2CH2CH3；
R4、R5、R6It is independent to be selected from-H ,-CH3、-CH2CH3。
3. 2 inhibitor of carbon glycoside class sodium glucose transporter body according to claim 1 is selected from following compound：
4. 2 inhibitor of carbon glycoside class sodium glucose transporter body according to claim 1, as needed can be with shape
At stable salt, ester, solvate.
5. 2 inhibitor of carbon glycoside class sodium glucose transporter body according to claim 1, the salt of the stabilization is pharmacy
Upper acceptable atoxic pharmaceutical salts, including with inorganic acid, such as the salt that hydrochloric acid, sulfuric acid are formed, and organic acid, such as acetic acid, three
Fluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid
The salt and amino acid of formation, as alanine, aspartic acid, lysine formed salt or and sulfonic acid, such as methanesulfonic acid, to toluene
The salt that sulfonic acid is formed；Or as needed, pharmaceutical salts can be formed with alkaline matter, such as form alkali metal salt, alkali salt, silver
Salt, barium salt.
6. the pharmaceutical composition containing 2 inhibitor of carbon glycoside class sodium glucose transporter body described in claim 1.
7. pharmaceutical composition according to claim 6, wherein the active constituent carbon glycoside class sodium glucose transport protein contained
The weight ratio of the amount of 2 inhibitor of lean type in the composition is 0.1~99.9%, the weight of pharmaceutically acceptable carrier in the composition
Amount is than being 0.1~99.9%.
8. pharmaceutical composition according to claim 6, to be suitble to medicinal dosage form to exist, selected from tablet, capsule,
Powder.
9. the preparation method of 2 inhibitor of carbon glycoside class sodium glucose transporter body described in claim 1, steps are as follows：
Using the bromo- 2- chlorobenzoic acids of 5- as starting material, through acylation, condensation, reduction reaction, the chloro- 4 '-methoxyl groups of the bromo- 2- of 5- are obtained
Diphenyl-methane 4, compound 4 are protected to obtain 6 after Boron tribromide acts on removing ether methyl, to phenolic hydroxyl group, compound 6 and Portugal
Grape saccharic acid lactone (9) is reacted through condensation, anomeric carbon etherification of hydroxyl groups, demethoxylation, obtains the chloro- 4- of key intermediate 1- (β-D- pyrans
Glucose -1- bases) -2- (4- Hydroxy-benzvls)-benzene 10；
Alkane, alkene, cycloalkane, alkynes and aromatic hydrocarbons alcohol reacted respectively with paratoluensulfonyl chloride, obtain correspondent alcohol to toluene
Sulfonyl ester 12, compound 12 are reacted with intermediate 10, obtain target compound
10. 2 inhibitor of carbon glycoside class sodium glucose transporter body described in claim 1 is in the medicine for preparing treatment diabetes B
Application in object.
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