CN104478967A - O-galactoside derivative with nitrile group benzene thiazolyl and preparation method and application thereof - Google Patents
O-galactoside derivative with nitrile group benzene thiazolyl and preparation method and application thereof Download PDFInfo
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- CN104478967A CN104478967A CN201510019506.1A CN201510019506A CN104478967A CN 104478967 A CN104478967 A CN 104478967A CN 201510019506 A CN201510019506 A CN 201510019506A CN 104478967 A CN104478967 A CN 104478967A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The invention relates to the field of drugs relevant to diabetes, in particular to a sodium glucose co-transporter 2 (SGLT2) inhibitor of an O-galactoside structure with nitrile group benzene thiazolyl and a preparation method and application of the inhibitor in diabetic drug preparation. Please see the general formula I in the specification.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes.Specifically, the present invention relates to 2 type sodium dependent glucoses transhipment (SGLT2) inhibitor to the O-galactoside structure of diabetes B medicative nitrile group-containing benzene thiazolyl, preparation method and in purposes pharmaceutically.
Background technology
Whole world diabetic subject presents the trend increased gradually, and wherein about the overwhelming majority is diabetes B patient.Sulfonylurea, N1,N1-Dimethylbiguanide class, thiazolidinediones, alpha-glucosidase inhibitor class, dipeptidyl peptidase-iv inhibitor class and trypsin class medicine is mainly contained at present at the antidiabetic medicine of Clinical practice.These medicines have good therapeutic action, but long-term treatment exists comparatively severe side effect, and owing to there is resistance, in some cases in time drug combination be all difficult to the blood sugar controlling patient.
2 type sodium dependent glucoses transhipment (SGLT2) are the novel targets of the treatment diabetes of discovered in recent years.SGLT2 is mainly distributed in renal proximal tubules, and its effect absorbs the glucose in urine, and returns it in blood, therefore suppresses that SGLT2's just can reduce the concentration of glucose in blood.When SGLT2 function is suppressed, more glucose will be secreted from urine, this glucose level that will contribute to diabetic subject and keep correct.
Chinese patent CN200610093189.9 discloses the compound of having structure as SGLT2 inhibitor:
Wherein, A is O, S, NH, (CH
2)
n, n=0-3.
Chinese patent CN200380110040.1 discloses the compound of having structure as SGLT2 inhibitor:
Wherein, A is covalent linkage, O, S, NH, (CH
2)
n, n=1-3.
Chinese patent CN200480006761.2 discloses the compound of having structure as SGLT2 inhibitor:
Wherein, X is covalent linkage or low-grade alkylidene.
The invention discloses the O-galactoside analog derivative of a class nitrile group-containing benzene thiazolyl as novel SGLT2 inhibitor, these compounds can be used for the medicine preparing treatment diabetes particularly diabetes B.
Summary of the invention
An object of the present invention is the shortcoming and defect overcoming prior art, provide one to have excellent activity, there is the compound of general formula I and pharmaceutically can accept prodrug ester.
Another object of the present invention is to provide preparation and has the compound of general formula I and the method for pharmaceutically acceptable prodrug ester thereof.
Another object of the present invention is to provide compound containing general formula I and the pharmaceutically application of acceptable prodrug ester in treatment diabetes thereof.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The present invention has the compound of general formula I:
Be selected from following compound further,
Compound of Formula I of the present invention is synthesized by following route:
There is Wittig and react in Compound II per and compound III, obtains IV; IV catalytic hydrogenation obtains V; V continues reduction and obtains VI; VI and S is obtained by reacting VII under an acidic catalyst catalysis; VII urges at alkali and obtains I at lower deacetylate; The catalyzer of described catalytic hydrogenation is selected from Pd/C, Pd (OH)
2with Raney nickel; Described an acidic catalyst is selected from TfOH and TMSOTf.The definition of R as previously mentioned.
The pharmaceutically acceptable prodrug ester of formula I of the present invention, comprises the ester that any one or more hydroxyl in molecule and ethanoyl, pivaloyl group, various phosphoryl, formamyl, alkoxyl formyl etc. are formed.
Compound of Formula I of the present invention has the restraining effect of SGLT2, can be used as the medicine of effective constituent for the preparation of diabetes aspect.The activity of compound of Formula I of the present invention is verified by receptor binding assays.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-300mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
Embodiment 1
The nitrogen protection in the THF of 20mL drying of 2.14g (10mmol) II-1 and 3.48g (10mmol) compound III flows through night next time.TLC shows reaction to be completed.Compound of reaction pours in 100mL frozen water, stir, with the dichloromethane extraction of 50mL × 3, merge extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, the resistates column chromatography purification obtained after evaporate to dryness on a rotary evaporator, obtains product IV-1, white solid, ESI-MS, m/z=285 ([M+H]
+).
2.27g (8mmol) compound IV-1 is dissolved in the ethanol of 20mL 95%, adds Raney nickel 0.5g, then shortening under 0.2MPa room temperature.React after 12 hours.Reaction mixture suction filtration removing catalyzer, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained is V-1, white solid, ESI-MS, m/z=287 ([M+H]
+).
1.43g (5mmol) compound V-1 is dissolved in 10mL dry toluene, and ice-water bath cooling is lower stirs, and slowly drips the toluene solution of the DIBAL-H (diisobutyl aluminium hydride) of 15mL (15mmol) 1M.After dropwising, at room temperature stir 1 hour, reaction completes.Compound of reaction pours in the 1%EDTA disodium salt solution of 100mL cooling, stir, with the dichloromethane extraction of 50mL × 3, merge extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, the resistates column chromatography purification obtained after evaporate to dryness on a rotary evaporator, obtains product VI-1, white solid, ESI-MS, m/z=245 ([M+H]
+).
0.73g (3mmol) compound VI-1 and 1.97g (4mmol) compound S are dissolved in the methylene dichloride of 20mL drying, be cooled to-30 DEG C, then slowly drip 0.89g (4mmol) TMSOTf and be dissolved into the solution made in the methylene dichloride of 2mL drying, after dropwising, continue reaction 3 hours at such a temperature.Compound of reaction pours in 100mL frozen water, stir, with the dichloromethane extraction of 50mL × 3, merge extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, the resistates column chromatography purification obtained after evaporate to dryness on a rotary evaporator, obtains product VII-1, white solid, ESI-MS, m/z=575 ([M+H]
+).
1.15g (2mmol) compound VI I-1 is dissolved in 10mL anhydrous methanol, and stirred at ambient temperature adds 0.2g MeONa, continues to stir, until reacted, and about 3 hours.Then add 2g storng-acid cation exchange resin, room temperature for overnight, until pH=7.Suction filtration removing resin, filtrate is evaporate to dryness on a rotary evaporator, then dry on oil pump, obtains product I-1, white solid, ESI-MS, m/z=407 ([M+H]
+).
Embodiment 2-3
With reference to embodiment 1 operation steps, prepare compound listed in Table:
The preparation of embodiment 4 reference compound D1
For absolutely proving the beneficial effect of the compounds of this invention, applicant describes and finds in experimentation
Following formula: compound D1 (unexposed), as drug effect reference compound.
Synthetic method is as follows:
The nitrogen protection in the THF of 20mL drying of 1.89g (10mmol) II-4 and 3.48g (10mmol) compound III flows through night next time.TLC shows reaction to be completed.Compound of reaction pours in 100mL frozen water, stir, with the dichloromethane extraction of 50mL × 3, merge extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, the resistates column chromatography purification obtained after evaporate to dryness on a rotary evaporator, obtains product IV-4, white solid, ESI-MS, m/z=260 ([M+H]
+).
2.07g (8mmol) compound IV-4 is dissolved in the ethanol of 20mL 95%, adds Raney nickel 0.5g, then shortening under 0.2MPa room temperature.React after 12 hours.Reaction mixture suction filtration removing catalyzer, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained is V-4, white solid, ESI-MS, m/z=262 ([M+H]
+).
1.31g (5mmol) compound V-4 is dissolved in 10mL dry toluene, and ice-water bath cooling is lower stirs, and slowly drips the toluene solution of the DIBAL-H (diisobutyl aluminium hydride) of 15mL (15mmol) 1M.After dropwising, at room temperature stir 1 hour, reaction completes.Compound of reaction pours in the 1%EDTA disodium salt solution of 100mL cooling, stir, with the dichloromethane extraction of 50mL × 3, merge extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, the resistates column chromatography purification obtained after evaporate to dryness on a rotary evaporator, obtains product VI-4, white-yellowish solid, ESI-MS, m/z=220 ([M+H]
+).
0.66g (3mmol) compound VI-4 and 1.97g (4mmol) compound S are dissolved in the methylene dichloride of 20mL drying, be cooled to-30 DEG C, then slowly drip 0.89g (4mmol) TMSOTf and be dissolved into the solution made in the methylene dichloride of 2mL drying, after dropwising, continue reaction 3 hours at such a temperature.Compound of reaction pours in 100mL frozen water, stir, with the dichloromethane extraction of 50mL × 3, merge extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, the resistates column chromatography purification obtained after evaporate to dryness on a rotary evaporator, obtains product VII-4, white solid, ESI-MS, m/z=550 ([M+H]
+).
1.10g (2mmol) compound VI I-4 is dissolved in 10mL anhydrous methanol, and stirred at ambient temperature adds 0.2g MeONa, continues to stir, until reacted, and about 3 hours.Then add 2g storng-acid cation exchange resin, room temperature for overnight, until pH=7.Suction filtration removing resin, filtrate is evaporate to dryness on a rotary evaporator, then dry on oil pump, obtains product D 1, white solid, ESI-MS, m/z=382 ([M+H]
+).
Embodiment 5
The carrier using the Chinese hamster ovary celI of stably express humanization SGLT2 to analyze as transhipment, uses the substrate that [14C]-α-D-methyl glucoside ([14C]-AMG) analyzes as transhipment.By stably express, the Chinese hamster ovary celI of humanization SGLT2 is inoculated on 96 orifice plates, and 12 hours are hatched at 37 DEG C, every hole by the KRH-Na+ washing lotion of 200 μ L (containing 120mM NaCl, 4.7mM KCl, 1.2mM MgCl2,2.2mM CaCl2,10mM HEPES and 1mM Tris (pH=7.4)) wash 3 times, then the KRH-Na+ washing lotion containing testing compound or blank is added in every hole, each testing compound arranges 10 concentration, and last each hole adds the washing lotion that 100 μ L contain [14C]-AMG (10 μ Ci/mL).96 orifice plates hatch 1 hour subsequently at 37 DEG C, then every hole adds the ice-cold stop buffer of 100 μ L (containing 120mM NaCl, 4.7mM KCl, 1.2mM MgCl2,2.2mM CaCl2,10mM HEPES, 1mM Tris and 10mM phlorizin (pH=7.4)), 5 times are washed again subsequently, each every hole 100 μ L with this stop buffer.Every Kong Zhongzai adds the ice-cold cytolysate (100mM NaOH) of 20 μ L, then shakes 5 minutes with the speed of 600rpm, and then Microscint 40 liquid adding 80 μ L in every hole dodges liquid, then shakes 5 minutes with the speed of 600rpm.Finally, this 96 orifice plate is at the upper counting of MicroBeta Trilux liquid scintillation counter (PerkinElmer).Response curve use experience four parameter model measures 503nhibiting concentration, is expressed as IC50.Shown in the following list of result.
Part of compounds of the present invention is to the IC of SGLT2
50value
| Compound | IC 50(hSGLT2,nM) |
| Compound I-1 | 2.7 |
| Compound I-2 | 4.0 |
| Compound I-3 | 3.2 |
| Reference compound D1 | 9.3 |
Above-mentioned IC
50measurement result show, compound of the present invention is strong SGLT2 inhibitor.
Claims (4)
1. there is compound and the pharmaceutically acceptable prodrug ester thereof of general formula I,
2. the compound of Formula I that defines of claim 1, is selected from following compound,
3. synthesize arbitrary the defined method belonging to the compound of general formula I of claim 1-2:
There is Wittig and react in Compound II per and compound III, obtains IV; IV catalytic hydrogenation obtains V; V continues reduction and obtains VI; VI and S is obtained by reacting VII under an acidic catalyst catalysis; VII urges at alkali and obtains I at lower deacetylate; The catalyzer of described catalytic hydrogenation is selected from Pd/C, Pd (OH)
2with Raney nickel; Described an acidic catalyst is selected from TfOH and TMSOTf, as described in the definition of R is as arbitrary in claim 1-2.
4. arbitrary the defined compound of Formula I of claim 1-2 and pharmaceutically acceptable salt and the application of prodrug ester in preparation treatment diabetes medicament.
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Citations (5)
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|---|---|---|---|---|
| CN1377363A (en) * | 1999-08-31 | 2002-10-30 | 橘生药品工业株式会社 | Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof |
| CN1437608A (en) * | 2000-03-30 | 2003-08-20 | 布里斯托尔-迈尔斯斯奎布公司 | O-aryl glucoside SGL T2 inhibitors and method |
| WO2008122014A1 (en) * | 2007-04-02 | 2008-10-09 | Theracos, Inc. | Benzylic glycoside derivatives and methods of use |
| CN101445527A (en) * | 2008-12-25 | 2009-06-03 | 天津药物研究院 | Five-membered heteroaromatics tolylene glucoside and preparation method and use thereof |
| US20110269700A1 (en) * | 2008-09-19 | 2011-11-03 | Novartis Ag | Glucoside derivatives and uses thereof |
-
2015
- 2015-01-14 CN CN201510019506.1A patent/CN104478967A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1377363A (en) * | 1999-08-31 | 2002-10-30 | 橘生药品工业株式会社 | Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof |
| CN1437608A (en) * | 2000-03-30 | 2003-08-20 | 布里斯托尔-迈尔斯斯奎布公司 | O-aryl glucoside SGL T2 inhibitors and method |
| WO2008122014A1 (en) * | 2007-04-02 | 2008-10-09 | Theracos, Inc. | Benzylic glycoside derivatives and methods of use |
| US20110269700A1 (en) * | 2008-09-19 | 2011-11-03 | Novartis Ag | Glucoside derivatives and uses thereof |
| CN101445527A (en) * | 2008-12-25 | 2009-06-03 | 天津药物研究院 | Five-membered heteroaromatics tolylene glucoside and preparation method and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| JENNIFER A. SOWINSKI，等: "Synthetic studies towards keramamide F", 《TETRAHEDRON LETTERS》 * |
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