CN110092768A - Composition and application method comprising white 1 inhibitor of sodium glucose co-transporter 2 - Google Patents

Composition and application method comprising white 1 inhibitor of sodium glucose co-transporter 2 Download PDF

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CN110092768A
CN110092768A CN201910322150.7A CN201910322150A CN110092768A CN 110092768 A CN110092768 A CN 110092768A CN 201910322150 A CN201910322150 A CN 201910322150A CN 110092768 A CN110092768 A CN 110092768A
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姬建新
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Chengdu Institute of Biology of CAS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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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

Composition and application method comprising 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, 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:
Wherein:
R1It can be the R independently arbitrarily replaced1A、-N(R1A)(R1B)、-OR1A、-SR1A、-S(O)R1AOr-S (O)2R1A；
R1It can be and not replace, is monosubstituted or polysubstituted；
R1AIt is the C optionally replaced1-20Linear or branched alkyl group, aryl, heterocycle, amino, aminoacyl, azo, carbonyl, carboxylic Base, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, isothiocyanates, nitrile, nitro, nitroso, nitryl Base, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkenyl, alkynyl, ester, ketone, alcohol etc., and including appointing It anticipates deuterated substituent group.
R1AIncluding with flowering structure:
R1BIt is hydrogen, deuterium hydrogen or is equal to R1A；
R2The C independently arbitrarily replaced1-10Linear or branched alkyl group, C1-10Straight or branched alkoxyl, deuteroalkyl, 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., and including any deuterated substituent group；
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, deuteroalkyl, 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, phosphine oxygroup, phosphonic acid base, phosphonate group etc., and including any deuterated substituent group；
R4、R5、R6Can be independently hydrogen, deuterium hydrogen, halogen, hydroxyl, alkoxy, deuteroalkyl, single or multiple glycosyls, Heterocycle, ester group, sulfanyl, mercaptan, amino, phosphine oxygroup, phosphonic acid base, phosphonate group for arbitrarily replacing etc..
R4、R5、R6It can be equal or different, can be identical substitution or different substitutions.
X is the optional various oxides of one or more N, O, S, C, P or corresponding.
The invention further relates to the pharmaceutical composition comprising the compound disclosed herein, and treated using them or Manage cardiovascular disease, metabolic disease (especially diabetes and various complication), intestines problem, kidney trouble and certain classes The method of the cancer of type.
We test the compound to the growth inhibition effect of SGLT1, and test result discovery: such compound has pole Its significant activity for inhibiting SGLT1, the IC50 of one of compound is 26.30 ± 4.21 mcg/mls, passes through measurement Its half-inhibitory concentration is shown: the above pharmacodynamic result illustrates that compound has unexpected inhibition SGLT1 effect, thus It is expected that the compound or pharmaceutically acceptable salt thereof be contemplated as SGLT1 inhibitor medicaments especially prevent and treat type-2 diabetes mellitus namely The purposes of 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 really The originality cut.
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
(2S, 3S, 4R, 5S, 6R) -2- (3- (4- ((E) -4 methoxyl group -4- oxygen-butyl -1- alkenyl) benzyl) -4- methyl Phenyl) -6- (methylsulfany) tetrahydro -2H- pyrans -3,4,5- three base triacetate preparation (2):
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.
(2S, 3S, 4R, 5S, 6R) -2- (3- (4- (4- methoxyl group -4- oxygen-butyl) benzyl) -4- aminomethyl phenyl) -6- (first Base sulfenyl) tetrahydro -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- 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).
4- (4- (2- methyl -5- ((2S, 3R, 4R, 5S, 6R) -3,4,5- trihydroxy -6- (methylsulfany) tetrahydro -2H- pyrrole Mutter -2- base) benzyl) phenyl) and butyric acid preparation (4):
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 5:
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 (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 ester (HATU, 1g, 2.6mmol), DIPEA (0.77mL, 4.4mmol) and 2- ammonia Base-2- methyl-1-(pyrrolidin-1-yl) propane-1- ketone (406mg, 2.6mmol).It is stirred to react at room temperature 3 hours.TCL point Plate is quenched with saturated sodium bicarbonate after the reaction was completed, and ethyl acetate extracts 3 times, merging organic phase, and saturated common salt water washing 3 times. Anhydrous sodium sulfate dries, filters concentration, and crude product is by 100-200 mesh silica gel column purification, and methylene chloride: methanol=20:1 is eluted, Concentrated solvent obtains foamy white solid target compound (600mg, 47% yield).1H NMR(400MHz,CDCl3)δ 7.24-7.15 (m, 2H), 7.15-7.03 (m, 5H), 4.41 (d, J=9.5Hz, 1H), 4.17 (d, J=9.3Hz, 1H), 3.95 (s, 2H), 3.67 (t, J=8.8Hz, 1H), 3.61-3.47 (m, 6H), 2.62 (t, J=7.2Hz, 2H), 2.26 (d, J= 11.6Hz, 3H), 2.19 (s, 3H), 2.17-2.12 (m, 2H), 1.94 (d, J=7.4Hz, 4H), 1.84 (s, 3H), 1.63 (d, J =15.5Hz, 6H)
It is prepared by compound 6:
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, sequentially add HATU (125mg, 0.33mmol), DIPEA (77 μ L, 0.44mmol) and 2- amino-2-methyl -1- (4- (2- oxygen -2 (pyrrolidin-1-yl) ethyl) Piperazine -1- base) propane -1- ketone (74mg, 0.26mmol).It is stirred to react at room temperature 3 hours.TCL contact plate, after the reaction was completed with full It being quenched with sodium bicarbonate, ethyl acetate extracts 3 times, merging organic phase, and saturated common salt water washing 3 times.Anhydrous sodium sulfate is dry, mistake Filter concentration, crude product is by 100-200 mesh silica gel column purification, and methylene chloride: methanol=10:1 elution, concentrated solvent obtain foam Shape white solid target compound (68mg, 44% yield).1H NMR(400MHz,MeOD)δ8.28(s,1H),7.50–7.41 (m, 1H), 7.23-7.14 (m, 4H), 7.10 (q, J=8.1Hz, 4H), 4.41 (d, J=9.4Hz, 1H), 4.15 (d, J= 9.1Hz,1H),3.98(s,2H),3.78(s,3H),3.52–3.39(m,9H),3.37(s,2H),2.77(s,3H),2.62(t, J=7.4Hz, 2H), 2.21 (d, J=12.9Hz, 5H), 2.16 (s, 4H), 2.01-1.83 (m, 6H), 1.45 (s, 6H)
It is prepared by compound 7:
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 2mL DMF, sequentially add HATU (125mg, 0.33mmol), DIPEA (77 μ L, 0.44mmol) and 2,2,6,6- tetramethyl piperidine -4- amine (41mg, 0.26mmol).At room temperature It is stirred to react 3 hours.TCL contact plate, is quenched with saturated sodium bicarbonate after the reaction was completed, and ethyl acetate extracts 3 times, is merged organic Phase, saturated common salt water washing 3 times.Anhydrous sodium sulfate dries, filters concentration, crude product 100-200 mesh silica gel column purification, dichloromethane Alkane: methanol=30:1 elution, concentrated solvent obtain foamy white solid target compound (80mg, 62% yield).1H NMR (400MHz, MeOD) δ 7.21-7.14 (m, 4H), 7.12-7.06 (m, 4H), 4.41 (dd, J=9.5,2.4Hz, 1H), 4.29 (dd, J=9.8,6.0Hz, 1H), 4.17-4.12 (m, 1H), 3.98 (s, 2H), 3.52-3.39 (m, 4H), 3.37 (s, 3H), 2.61 (t, J=7.6Hz, 2H), 2.22 (d, J=4.8Hz, 5H), 2.16 (s, 3H), 2.05 (dd, J=14.0,3.6Hz, 2H), 1.92 (dd, J=15.1,7.7Hz, 2H), 1.57 (s, 2H), 1.53 (s, 6H), 1.46 (s, 6H)
It is prepared by compound 8:
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 2mL DMF, sequentially add HATU (125mg, 0.33mmol), DIPEA (77 μ L, 0.44mmol) and 2- amino-2-methyl-N- (2- (methylamino) ethyl) propionamide (41mg, 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, ethyl acetate extraction It takes 3 times, merging organic phase, saturated common 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=30:1 elution, concentrated solvent obtain foamy white solid target compound (31mg, 24% yield).1H NMR(400MHz,MeOD)δ7.21-7.15(m,4H),7.11-7.06(m,3H),5.50(s, 1H), 4.41 (d, J=9.4Hz, 1H), 4.15 (d, J=9.1Hz, 1H), 3.95 (d, J=15.6Hz, 3H), 3.55-3.40 (m, 6H),3.35(s,3H),3.09-2.92(m,2H),2.96–2.72(m,2H),2.67–2.60(m,2H),2.44–2.31(m, 2H), 2.22 (s, 3H), 2.16 (s, 3H), 1.90 (dd, J=9.4,5.5Hz, 2H), 1.30 (s, 6H)
It is prepared by compound 9:
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 DMF, sequentially add HATU (125mg, 0.33mmol), DIPEA (77 μ L, 0.44mmol) and (1- amino-cyclopropane) (octahydro -2H- iso-indoles -2- base) ketone (54mg, 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, ethyl acetate extraction It takes 3 times, merging organic phase, saturated common 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=40:1 elution, concentrated solvent obtain foamy white solid target compound (71mg, 49%).1H NMR (400MHz, MeOD) δ 7.17 (dd, J=20.8,7.0Hz, 4H), 7.11-7.04 (m, 4H), 4.41 (d, J=9.4Hz, 1H), 4.15 (d, J=9.1Hz, 1H), 3.96 (s, 2H), 3.61-3.40 (m, 5H), 3.38 (s, 1H), 3.33 (dd, J=3.3,1.6Hz, 2H), 2.60 (t, J=7.6Hz, 2H), 2.29-2.18 (m, 6H), 2.16 (s, 4H), 1.94-1.85 (m, 2H), 1.59 (dd, J=15.3,7.1Hz, 2H), 1.53-1.30 (m, 9H), 0.93 (dd, J=5.8, 3.4Hz,2H).
It is prepared by compound 10:
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 DMF, sequentially add HATU (125mg, 0.33mmol), DIPEA (77 μ L, 0.44mmol) and (2R) -2- amino-Isosorbide-5-Nitrae-two (octahydro -2H- iso-indoles -2- base) positive fourth Alkane-Isosorbide-5-Nitrae-diketone (91mg, 0.26mmol).It is stirred to react at room temperature 3 hours.TCL contact plate uses unsaturated carbonate hydrogen after the reaction was completed Sodium is quenched, and ethyl acetate extracts 3 times, merging organic phase, and saturated common salt water washing 3 times.Anhydrous sodium sulfate dries, filters concentration, Crude product is by 100-200 mesh silica gel column purification, and methylene chloride: it is solid to obtain foamy white for methanol=30:1 elution, concentrated solvent Body target compound (47mg, 27% yield).1H NMR (400MHz, MeOD) δ 7.23-7.03 (m, 7H), 5.09 (dd, J= 8.2,6.3Hz, 1H), 4.41 (d, J=9.5Hz, 1H), 4.15 (d, J=9.2Hz, 1H), 3.96 (s, 2H), 3.83-3.59 (m, 2H),3.58–3.25(m,10H),3.05–2.84(m,1H),2.65–2.53(m,2H),2.37–2.26(m,2H),2.26– 2.17 (m, 7H), 2.15 (s, 3H), 1.90 (dd, J=14.2,6.8Hz, 2H), 1.70-1.33 (m, 17H) .HRMS (ESI) calcd for C44H61N3O7S[M+H]+:776.4264；found:776.4259.
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 the compounds of this invention SGLT1 inhibitory activity < 150nM.

Claims (18)

1. a kind of compound such as following formula:
Or its officinal salt, in which:
R1It can be the R independently arbitrarily replaced1A、-N(R1A)(R1B)、-OR1A、-SR1A、-S(O)R1AOr-S (O)2R1A；
R1It can be and not replace, is monosubstituted or polysubstituted；
R1AIt is the C optionally replaced1-20Linear or branched alkyl group, aryl, heterocycle, amino, aminoacyl, azo, carbonyl, carboxyl, Cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, isothiocyanates, nitrile, nitro, nitroso, nitroxyl, Oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea alkenyl, alkynyl, ester, ketone, alcohol etc., and including any Deuterated substituent group, R1AIncluding with flowering structure:
R1BIt is hydrogen, deuterium hydrogen or is equal to R1A；
R2The C independently arbitrarily replaced1-10Linear or branched alkyl group, C1-10It is straight or branched alkoxyl, deuteroalkyl, aryl, miscellaneous It is ring group, amino, aminoacyl, azo, carbonyl, carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, different Thiocyanates, nitrile, nitro, nitroso, nitroxyl, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea Alkenyl, alkynyl, ester, ketone, alcohol etc., and including any deuterated substituent group；
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, C1-10It is straight or branched alkoxyl, deuteroalkyl, aryl, miscellaneous It is ring group, amino, aminoacyl, azo, carbonyl, carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, imido acyl group, imino group, different Thiocyanates, nitrile, nitro, nitroso, nitroxyl, oxygroup, sulfanyl, sulfonyl, thioaldehydes, thiocyanates, thioketones, thiocarbamide, urea Alkenyl, alkynyl, ester, ketone, alcohol, phosphine oxygroup, phosphonic acid base, phosphonate group etc., and including any deuterated substituent group；
R4、R5、R6It can be independently hydrogen, deuterium hydrogen, halogen, hydroxyl, alkoxy, deuteroalkyl, single or multiple glycosyls, any Substituted heterocycle, ester group, sulfanyl, mercaptan, amino, phosphine oxygroup, phosphonic acid base, phosphonate group etc.,
R4、R5、R6It can be equal or different, can be identical substitution or different substitutions；
X is the optional various oxides of one or more N, O, S, C, P or corresponding.
2. the compound of claim 1, wherein R3It is the C optionally replaced1-10Alkyl, hydrogen, deuterium hydrogen, deuteroalkyl, phosphine oxygroup, phosphine Acidic group, phosphonate group；Especially methyl, ethyl.
3. the compound of claim 1, wherein R4、R5、R6It can be hydrogen, deuterium hydrogen, deuteroalkyl, deuterated alkoxy, halogen, hydroxyl Base, deuterium hydroxyl, the alkyl of any carbochain or alkoxy, single or multiple glycosyls, the heterocycle arbitrarily replaced, ester group, sulfanyl, sulphur Alcohol, amino；Especially hydroxyl, deuterium hydroxyl, ester group, deuterated ester group.
4. the compound of claim 1, wherein R2It is the C optionally replaced1-4Linear or branched alkyl group；Especially methyl, ethyl or Its deuterated object.
5. the compound of claim 1, wherein R2It is halogen, alkoxy, deuteroalkyl.
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, alkoxy, deuterated alkoxy, deuterated amide, 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, thiocyanates, thioketones, thiocarbamide, urea alkenyl, alkynyl, Ester, ketone, alcohol etc., and including any deuterated above-mentioned substituent group；
X1It is the optional various oxides of one or more N, O, S, C, P or corresponding；
R2It is independently hydrogen, deuterium hydrogen, halogen, hydroxyl, deuterated hydroxyl or the C optionally replaced1-10Linear or branched alkyl group, C1-10Directly Chain or branched alkoxy, deuteroalkyl, deuterated alkoxy, the optional 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., and including any deuterated above-mentioned substituent group.
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 with one or more R7AReplace；
Each R7AIt is independently any substituted C1-20Linear or branched alkyl group, alkoxy, deuterated alkoxy, deuterated amide, virtue Base, heterocycle, amino, aminoacyl, deuterated aminoacyl, azo, carbonyl, carboxyl, cyano, formoxyl, guanidine radicals, halogen, hydroxyl, Asia Aminoacyl, imino group, isothiocyanates, nitrile, nitro, nitroso, nitroxyl, oxygroup, sulfanyl, sulfonyl, thiocyanates, sulphur Ketone, thiocarbamide, urea alkenyl, alkynyl, ester, ketone, alcohol etc., and including any deuterated above-mentioned substituent group.
12. the compound of claim 11, wherein R7It is the C optionally replaced1-20Linear or branched alkyl group, substituted-amino.
13. the compound of claim 11, wherein R7AIt is five yuan or hexa-member heterocycle, deuterated heterocycle, deuterated amide, especially tetrahydro Pyrrole 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. treating and improving the application in cardiovascular disease and metabolic disease patient in claim 1-14.
16. treating and improving the application in diabetic in claim 1-14.
17. treating and improving the application in diabetic's complication, including microvascular complication meeting in claim 1-14 Caused retinopathy, nephrosis and the nervous system disease.And cardiovascular disease caused by big vascular syndrome.
18. wherein the patient had taken or had just taken at present other therapeutic drug, including blood pressure lowering to claim 15-18 Medicine, hypolipidemic, antidiabetic, hypoglycemic agent, slimming drugs or appetite inhibitor.
CN201910322150.7A 2018-04-23 2019-04-22 Composition and application method comprising white 1 inhibitor of sodium glucose co-transporter 2 Pending CN110092768A (en)

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