CN110117300A - Medicinal usage comprising white 1 inhibitor of sodium glucose co-transporter 2 - Google Patents
Medicinal usage comprising white 1 inhibitor of sodium glucose co-transporter 2 Download PDFInfo
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Abstract
The present invention relates to a kind of white 1 (SGLT1) inhibitor of sodium glucose co-transporter 2 include their compositions pharmaceutical synthesis method and they treatment metabolism class disease especially diabetes B purposes.
Description
Technical field
The present invention relates to a kind of sodium glucose co-transporter 2 white 1 (SGLT1) inhibitor, the medicine comprising their compositions
Object synthetic 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 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 in delay intestines by SGLT-1 sugar is shown in activity in vivo test.Inhibitor shows low systemic exposure
Characteristic.
Part of the present invention is related to the application method of the compound comprising following formula and its officinal salt and they:
Or its officinal salt, in which:
R1It can be the R independently optionally 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、R6It can be independently halogen, hydroxyl, the alkyl of any carbochain or alkoxy, naphthenic base, single or multiple
Glycosyl, the heterocycle arbitrarily replaced, ester group, sulfanyl, mercaptan, amino etc..
R4、R5、R6It can be equal or different, can be identical substitution or different substitutions.
X1、X2、X3It is the optional various oxides of one or more N, O, S, C, P or corresponding.
X4It is C, NH, O or corresponding oxide.
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: such compound has pole
Its significant activity for inhibiting SGLT1 shows that the IC50 of one of compound is 18.87 by measuring its half-inhibitory concentration
± 3.27 mcg/mls thus it can be expected that the compound or pharmaceutically acceptable salt thereof is contemplated as SGLT1 inhibitor medicaments especially
It is the purposes for preventing and treating 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 SGLT1 effect aspect is inhibited to grind
The novelty studied carefully, and uncommon low systemic exposure is had found in pharmacokinetics test, it is expected to become inhibition
SGLT1 and the drug candidate for treating diabetes.Compound inhibition potent for SGLT1 belongs to unexpected discovery, has
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 of compound 2:
2- methyl -4- bromobenzoic acid (1,100g, 465mmol) is dissolved in 500mL methylene chloride, grass is added at room temperature
Acyl chlorides (52mL, 605mmol) stirs 10 minutes.The n,N-Dimethylformamide (DMF, 3mL) of catalytic amount is added dropwise, connects tail
Aspiration receiving apparatus, and reaction is stirred at room temperature until reaction solution becomes homogeneous in reaction.Vacuum distillation removes volatile solutes,
Then mixture is dissolved in the methylene chloride of 1000mL, and N is added, O- dimethyl hydroxyl amine hydrochlorate (92g,
930mmol).Reaction solution is cooled to 0 DEG C and is slowly added to triethylamine (215mL, 1.533mol) hereinafter, being then vigorously stirred down.
After triethylamine adds, reaction is to slowly warm up to room temperature and is stirred overnight.TCL contact plate, after the reaction was completed with saturation chlorination
Ammonium salt solution is quenched.Water layer be extracted with dichloromethane it is secondary three times, merge organic layer, washed twice with saturated salt solution, in anhydrous sulphur
It is dry on sour sodium.Solvent is distilled off in filtering, vacuum decompression.Obtained Weinreb amide (110g, 97% yield) does not need pure
Change for reacting in next step.
It is prepared by compound 3:
The Weinreb amide (110g, 451mmol) is transferred in 500mL anhydrous tetrahydro furan (THF), is cooled to 0
℃.It is added under ice bath 4- chlorophenylmagnesium bromide (1M, in THF, 677mL, 677mmol), is transferred to room temperature after addition and stirs
Mix reaction 3 hours.The monitoring reaction of TCL contact plate, is quenched with saturated aqueous ammonium chloride after the reaction was completed, ethyl acetate extraction three
It is secondary.Merge organic phase, saturated salt solution washes twice, and anhydrous magnesium sulfate dries, filters and solvent is distilled off in vacuum decompression.?
(the bromo- 2- aminomethyl phenyl of 5-) (4- chlorphenyl) ketone (139g, 99% yield) arrived does not need to be further purified in next step
Reaction.
It is prepared by compound 4:
By (the bromo- 2- aminomethyl phenyl of 5-) (4- chlorphenyl) ketone (139g, 449mmol) and triethylsilane (285mL,
It 1.796mol) is dissolved in 800mL acetonitrile, and is cooled to 0 DEG C.It is added boron trifluoride ether (340mL, 2.694mol), and will
Reaction is heated to 60 DEG C and reacts 2 hours.Reaction solution is poured slowly into the ice water of saturated sodium bicarbonate after the reaction was completed by TCL contact plate
In be quenched.Water phase is extracted with ethyl acetate three times, merges organic phase, and saturated salt solution washes twice, and anhydrous sodium sulfate is dry, mistake
It filters and solvent is distilled off in vacuum decompression.Crude product 100-200 mesh silica gel column chromatography, petroleum ether elution.Eluent is concentrated to get
The target compound (120g, 87% yield) of white solid.
It is prepared by compound 5:
It will ((3aS, 5R, 6S, 6aS) -6- hydroxyl -2,2- dimethyl-tetrahydrofuran simultaneously dioxane between [2,3-d] [1,3]
Amylene -5- base) (morpholinyl) ketone (46g, 169mmol) is dissolved in 300mL THF, it is cooled to 0 DEG C.Uncle is added under nitrogen protection
Butylmagnesium chloride (1M, in THF, 200mL, 200mmol), and kept for 0 DEG C and be stirred to react 30 minutes, it is denoted as solution A.Meanwhile
The bromo- 2- of 4- (4- chlorophenylmethyl) -1- methylbenzene (60g, 203mmol) is taken to be dissolved in 300mL THF under nitrogen protection, be cooled to -
78℃.N-BuLi (2.5M, in hexane, 88mL, 220mmol) is added dropwise and stirs 20 minutes by dropping funel and is denoted as
Solution B.Solution A is transferred in solution B by intubation at -78 DEG C, and is kept for -78 DEG C stir 1 hour, is then transferred to room temperature
It is stirred to react 2 hours.TCL contact plate, is quenched with saturated aqueous ammonium chloride after the reaction was completed, and ethyl acetate extracts three times, is merged
Organic phase is simultaneously washed twice by saturated salt solution, and anhydrous magnesium sulfate dries, filters, concentration.Crude product 30% ethyl acetate/petroleum
Ether mashing purifying.It filters white depositions and title compound (50g, 73% yield) is provided.
It is prepared by compound 6:
By (3- (4- rate benzyl) -4- aminomethyl phenyl) ((3aS, 5S, 6R, 6aS) -6- hydroxyl -2,2- dimethyl tetrahydro furan
Mutter simultaneously [2,3-d] [1,3] dioxole -5- base) ketone (50g, 124mmol) and cerium chloride seven-hydrate (55.5g,
It 149mmol) is suspended in 500mL methanol.Being slowly added to sodium borohydride, (1.9g, 49.6mmol are dissolved in 20mL 1N NaOH water
In solution), reaction 30 minutes is stirred at room temperature after addition.TCL contact plate is quenched with 500mL saturated ammonium chloride after the reaction was completed,
Vacuum distillation removes most of methanol, and residual object is diluted with water.Water phase is extracted with ethyl acetate three times, and salt water washes twice,
Anhydrous magnesium sulfate is dry.Filtering is concentrated under reduced pressure.Crude product does not need to be further purified for (48g, 95% yield) in next step.
It is prepared by compound 7:
By (3aS, 5S, 6R, 6aS) -5- ((S)-(4- chlorophenylmethyl) -4- aminomethyl phenyl) (hydroxyl)-methyl) -2,2- two
Methyltetrahydrofuran simultaneously [2,3-d] [1,3] dioxole -6- alcohol (48g, 119mmol) be suspended in 200mL water and
In 200mL glacial acetic acid.Reaction is heated to 100 DEG C of reactions overnight, solvent, residue toluene azeotropic distillation three is removed under reduced pressure
It is secondary, then solvent is drained under high vacuum.Crude product does not need to be further purified for reacting in next step.
Above-mentioned crude product is dissolved in 500mL acetonitrile, be added triethylamine (107mL, 774mmol) and acetic anhydride (73mL,
774mmol), the DMAP (300mg) of catalysis equivalent is added.Reaction 3 hours is stirred at room temperature in reaction mixture.TCL contact plate, reaction
After be removed under reduced pressure solvent, residue 1000mL ethyl acetate dilution, organic phase is washed twice with saturation sodium bisulfate.It is acid
Aqueous solution uses the back extraction of 500mL ethyl acetate twice again.Merging organic phase, saturated salt solution washes twice, and anhydrous sodium sulfate is dry,
Be concentrated under reduced pressure, toluene azeotropic obtain twice be easy transfer brown solid title compound (55g, 87% yield), do not need into
The purifying of one step for reacting in next step.
It is prepared by compound 8:
By (3S, 4R, 5S, 6S) -6- (3- (4- chlorophenylmethyl) -4- aminomethyl phenyl) tetrahydro -2H- pyrans -2,3,4,5- four
Base tetracetate (55g, 103mmol) is dissolved in 500mL dioxanes, then sequentially adds thiocarbamide (15.6g, 206mmol) and three
Fluorine methanesulfonic acid trimethyl silyl ester (32mL, 175mmol).Reaction is heated to 80 DEG C and reacts 4 hours, TCL monitoring reaction.Instead
Reaction solution is sufficiently cooled to room temperature after answering, iodomethane (19mL, 309mmol) is then successively slowly added to and N, N- bis- is different
Propylethylamine (DIPEA, 90mL, 515mmol).After being added dropwise, reaction 24 hours is stirred at room temperature.TCL contact plate, after the reaction was completed
600mL water quenching is slowly added to go out.Aqueous layer with ethyl acetate extracts 3 times, merges organic phase, saturated salt solution washes twice, anhydrous
Sodium sulphate dries, filters, and is concentrated under reduced pressure to give brown solid.Solid is distributed in 400mL methanol, stirring generates a large amount of whites
Solid.Filtering, solid are washed twice to obtain pure title compound (40g, 74% yield) with cold methanol.
It is prepared by compound 9:
By (2S, 3S, 4R, 5S, 6R) -2- (3- (4- chlorophenylmethyl) -4- aminomethyl phenyl) -6- (methylsulfany) tetrahydro -2H-
Pyrans -3,4, tri- base triacetate (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 (tert-butyl) tetrafluoro boric acid phosphonium salts
(2.2g, 7.6mmol), dicyclohexylmethylamine (11.1g, 57mmol) and N-Methyl pyrrolidone (100mL).Reaction flask merging
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 successively uses water, is saturated sodium bisulfate, 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 chromatography, 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 phenyl) -6- (methylsulfany) tetrahydro -2H- pyrans -3,4,5- three base triacetate recycle.
It is prepared by compound 10:
By (2S, 3S, 4R, 5S, 6R) -2- (3- (4- ((E) -4 methoxyl group -4- oxygen-butyl -1- alkenyl) benzyl) -4- first
Base phenyl) -6- (methylsulfany) tetrahydro -2H- pyrans -3,4, tri- base triacetate (3g, 5mmol) of 5- is dissolved in 1:1 (V:V)
In THF/ methanol solution, Pd/C (10% is wet, 200mg) then is added, on cover hydrogenation 3 hours at 35 DEG C of hydrogen balloon.TCL point
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).
It is prepared by compound 11:
By (2S, 3S, 4R, 5S, 6R) -2- (3- (4- (4- methoxyl group -4- oxygen-butyl) benzyl) -4- aminomethyl phenyl) -6-
(methylsulfany) tetrahydro -2H- pyrans -3,4, tri- base triacetate (3g, 5mmol) of 5- are dissolved in methanol/THF/ water (50mL, body
Product is than 2:1:2) mixed solution in, be added Lithium hydroxide monohydrate (2.1g, 50mmol), and it is small that reaction is stirred at room temperature 1
When.TCL contact plate is acidified to pH=1-2 with saturation sodium bisulfate after the reaction was completed.Acidic aqueous phase is extracted with ethyl acetate 3 times, closes
And organic phase, saturated salt solution wash twice, anhydrous magnesium sulfate dries, filters, and foaming solid crude product is concentrated under reduced pressure to obtain.Slightly
Product is dissolved with 30% sodium bicarbonate aqueous solution, and ethyl acetate is extracted twice removing impurity.Alkaline water phase saturation sodium bisulfate
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 12:
By 4- (4- (2- methyl -5- ((2S, 3R, 4R, 5S, 6R) -3,4,5- trihydroxy -6- (methylsulfany) tetrahydro -2H-
Pyrans -2- base) benzyl) phenyl) butyric acid (100mg, 0.22mmol) is dissolved in 4mL DMF, and sequentially adding 2-, (7- aoxidizes benzo
Triazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU, 125mg, 0.33mmol), DIPEA (77 μ L,
0.33mmol) and 2- amino-N- (4- leptodactyline) -2- methyl propanamide (58mg, 0.26mmol).It is stirred to react at room temperature
3 hours.TCL contact plate, is quenched with saturated sodium bicarbonate after the reaction was completed, and ethyl acetate extracts 3 times, merges organic phase, saturation food
Salt water washing 3 times.Anhydrous sodium sulfate dries, filters concentration, and crude product passes through 100-200 mesh silica gel column purification, methylene chloride: methanol
=20:1 elution, concentrated solvent obtain foamy white solid target compound (90mg, 85% yield).1H NMR
(400MHz, MeOD) δ 7.96 (s, 1H), 7.55 (t, J=5.7Hz, 1H), 7.23-7.12 (m, 5H), 7.09-7.04 (m, 4H),
6.74-6.69 (m, 2H), 4.41 (dd, J=9.4,2.7Hz, 1H), 4.15 (d, J=9.1Hz, 1H), 4.02-3.92 (m, 3H),
3.50-3.45 (m, 2H), 3.41 (dd, J=9.1,4.1Hz, 2H), 3.35-3.31 (m, 4H), 2.68 (t, J=7.3Hz, 2H),
2.60 (t, J=7.6Hz, 2H), 2.21 (d, J=4.3Hz, 3H), 2.20-2.17 (m, 2H), 2.16 (s, 3H), 1.92-1.82
(m, 2H), 1.42 (d, J=8.2Hz, 6H)
It is prepared by compound 13:
By 4- (4- (2- methyl -5- ((2S, 3R, 4R, 5S, 6R) -3,4,5- trihydroxy -6- (methylsulfany) tetrahydro -2H-
Pyrans -2- base) benzyl) phenyl) butyric acid (100mg, 0.22mmol) is dissolved in 4mL DMF, and sequentially adding 2-, (7- aoxidizes benzo
Triazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU, 125mg, 0.33mmol), DIPEA (77 μ L,
0.33mmol) and 2- amino-2-methyl-N- (pyrimidine radicals -4- methyl) propionamide (51mg, 0.26mmol).Stirring is anti-at room temperature
It answers 3 hours.TCL contact plate, is quenched with saturated sodium bicarbonate after the reaction was completed, and ethyl acetate extracts 3 times, merges organic phase, saturation
Brine It 3 times.Anhydrous sodium sulfate dries, filters concentration, and crude product passes through 100-200 mesh silica gel column purification, methylene chloride: first
Alcohol=20:1 elution, concentrated solvent obtain foamy white solid target compound (93mg, 81% yield).1H NMR
(400MHz, MeOD) δ 9.02 (d, J=1.2Hz, 1H), 8.68 (t, J=4.7Hz, 1H), 8.41 (t, J=5.9Hz, 1H),
8.21 (d, J=16.5Hz, 1H), 7.65 (d, J=5.3Hz, 1H), 7.21-7.13 (m, 4H), 7.10-7.03 (m, 4H), 5.51
(s, 1H), 4.46 (dd, J=7.2,6.2Hz, 2H), 4.43-4.39 (m, 1H), 4.15 (d, J=9.1Hz, 1H), 3.97 (s,
2H),3.52–3.36(m,5H),2.64–2.58(m,2H),2.29–2.24(m,2H),2.22(s,3H),2.15(s,3H),
1.95-1.86 (m, 2H), 1.50 (d, J=9.8Hz, 6H) .HRMS (ESI) calcd for C33H42N4O6S[M+H]+:
623.2859;found:623.2876.
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 suppression
Active testing processed.
The experimental results showed that inhibitory activity < 150nM of the SGLT1 of the compounds of this invention.
Claims (18)
1. a kind of compound such as following formula:
Or its officinal salt, in which:
R1It can be the R independently optionally 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, R1AIncluding following knot
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、R6It can be independently halogen, hydroxyl, the alkyl of any carbochain or alkoxy, naphthenic base, single or multiple sugar
Base, the heterocycle arbitrarily replaced, ester group, sulfanyl, mercaptan, amino etc.;
R4、R5、R6It can be equal or different, can be identical substitution or different substitutions;
X1、X2、X3It is the optional various oxides of one or more N, O, S, C, P or corresponding;
X4It is C, NH, O or corresponding oxide.
2. the compound of claim 1, wherein R3It is hydrogen, deuterium hydrogen, methyl, deuterated methyl, ethyl, naphthenic base, aryl.
3. the compound of claim 1, wherein R4、R5、R6Can be hydrogen, halogen, hydroxyl, the alkyl of any carbochain or alkoxy,
Single 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 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 X1、X2、X3It is O or S.
8. the compound of claim 1, wherein X4It is C, NH or S.
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:
R1It 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.;
X4It is C, NH, O or corresponding oxide;
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.;
R4、R5、R6It is hydrogen, deuterium hydrogen, methyl, alkyl, heterocycle etc.;
R4、R5、R6It can be equal or different, can be identical substitution or different substitutions.
11. the compound of claim 10, is expressed from the next:
Wherein:
R1It is the C optionally replaced1-20Linear or branched alkyl group, the optional substitution is with one or more R1AReplace;
Each R1AIt is independently any 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 R1It is the C optionally replaced1-20Linear or branched alkyl group.
13. the compound of claim 11, wherein R1AIt is substitution or amide, ester for not replacing etc..
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 16-18
Medicine, hypolipidemic, antidiabetic, hypoglycemic agent, slimming drugs or appetite inhibitor.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021227441A1 (en) * | 2020-05-15 | 2021-11-18 | 上海喆邺生物科技有限公司 | Aryl glucoside derivative and use thereof in drug |
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 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1930141A (en) * | 2004-03-16 | 2007-03-14 | 贝林格尔·英格海姆国际有限公司 | Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof |
CN101343296A (en) * | 2007-07-10 | 2009-01-14 | 莱西肯医药有限公司 | Inhibitors of sodium glucose co-transporter 2 and methods of their use |
EP1874787B1 (en) * | 2005-04-15 | 2009-12-30 | Boehringer Ingelheim International GmbH | Glucopyranosyl-substituted (heteroaryloxy-benzyl)-benzene derivatives as sglt inhibitors |
CN102414191A (en) * | 2009-02-23 | 2012-04-11 | 大正制药株式会社 | 4 -isopropylphenyl glucitol compounds as sgltl inhibitors |
CN102821764A (en) * | 2010-03-02 | 2012-12-12 | 莱西肯医药有限公司 | 6 -Benzylphenyl-2 - sulfurterahydropyran-3, 4, 5 -triol derivatives as inhibitors of sodium -glucose cotrans porters 1 and 2 for use in diabetic patients |
CN103450129A (en) * | 2004-03-16 | 2013-12-18 | 贝林格尔.英格海姆国际有限公司 | Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof |
CN104854096A (en) * | 2012-11-20 | 2015-08-19 | 莱西肯医药有限公司 | Inhibitors of sodium glucose cotransporter 1 |
-
2019
- 2019-04-22 CN CN201910322139.0A patent/CN110117300A/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1930141A (en) * | 2004-03-16 | 2007-03-14 | 贝林格尔·英格海姆国际有限公司 | Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof |
CN103450129A (en) * | 2004-03-16 | 2013-12-18 | 贝林格尔.英格海姆国际有限公司 | Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof |
EP1874787B1 (en) * | 2005-04-15 | 2009-12-30 | Boehringer Ingelheim International GmbH | Glucopyranosyl-substituted (heteroaryloxy-benzyl)-benzene derivatives as sglt inhibitors |
CN101343296A (en) * | 2007-07-10 | 2009-01-14 | 莱西肯医药有限公司 | Inhibitors of sodium glucose co-transporter 2 and methods of their use |
CN102414191A (en) * | 2009-02-23 | 2012-04-11 | 大正制药株式会社 | 4 -isopropylphenyl glucitol compounds as sgltl inhibitors |
CN102821764A (en) * | 2010-03-02 | 2012-12-12 | 莱西肯医药有限公司 | 6 -Benzylphenyl-2 - sulfurterahydropyran-3, 4, 5 -triol derivatives as inhibitors of sodium -glucose cotrans porters 1 and 2 for use in diabetic patients |
CN104854096A (en) * | 2012-11-20 | 2015-08-19 | 莱西肯医药有限公司 | Inhibitors of sodium glucose cotransporter 1 |
Non-Patent Citations (1)
Title |
---|
GOODWIN, NC ET AL.: "Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1(SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021227441A1 (en) * | 2020-05-15 | 2021-11-18 | 上海喆邺生物科技有限公司 | Aryl glucoside derivative and use thereof in drug |
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 |
CN115003661A (en) * | 2020-05-15 | 2022-09-02 | 上海喆邺生物科技有限公司 | Aryl glucoside derivatives and their use in medicine |
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