CN104530153A - One category of phenyl S-glucoside derivatives, preparation method of phenyl-class S-glucoside derivatives and application of phenyl-class S-glucoside derivatives in medicament - Google Patents
One category of phenyl S-glucoside derivatives, preparation method of phenyl-class S-glucoside derivatives and application of phenyl-class S-glucoside derivatives in medicament Download PDFInfo
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- CN104530153A CN104530153A CN201510021101.1A CN201510021101A CN104530153A CN 104530153 A CN104530153 A CN 104530153A CN 201510021101 A CN201510021101 A CN 201510021101A CN 104530153 A CN104530153 A CN 104530153A
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- compound
- phenyl
- class
- glucoside derivatives
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- 0 CSC(*)=C(C#N)C#N Chemical compound CSC(*)=C(C#N)C#N 0.000 description 3
- JURPTAYVJIIEPZ-UHFFFAOYSA-N Cc(cc(cc1)NC(SC)=C(C#N)C#N)c1SC(C(C1O)O)OC(CO)C1O Chemical compound Cc(cc(cc1)NC(SC)=C(C#N)C#N)c1SC(C(C1O)O)OC(CO)C1O JURPTAYVJIIEPZ-UHFFFAOYSA-N 0.000 description 1
- RESJHCCPSZNMBZ-UHFFFAOYSA-N Cc1cc(N)ccc1S Chemical compound Cc1cc(N)ccc1S RESJHCCPSZNMBZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- 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 associated with diabetes, in particular to a category of phenyl S-glucoside structure 2-type sodium-dependent glucose transporter (SGLT2) inhibitors, a preparation method of the SGLT2 inhibitors, and application of the SGLT2 inhibitors in preparation of the drugs for treating the diabetes. Please see the formula in the specification, wherein R is selected from H, C1-C5 alkyl groups and C3-C6 naphthenic bases.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes B.Specifically, the present invention relates to 2 type sodium dependent glucose transhipment (SGLT2) inhibitor, the Preparation method and uses to the medicative class phenyl S-glucoside structure of diabetes B.。
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.
The invention discloses a class phenyl S-glucoside analog derivative 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 the compound containing general formula I and and is treating the application in diabetes.Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula I has following structural formula:
Wherein, R is selected from H, C
1-C
5alkyl and C
3-C
6cycloalkyl.
The compound of preferred formula I has following structure,
Compound of Formula I of the present invention is synthesized by following route:
Compound II per is according to literature method synthesis (SCI, 1996,17,236).Compound II per and compound III are obtained by reacting IV; Compound IV and V are obtained by reacting VI in the presence of a base; VI deacetylate obtains I; Described alkali is selected from various mineral alkali and organic bases; The reagent of described deacetylation is selected from NH
3, mineral alkali and sodium alkoxide; 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-700mg/ 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.
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.
The preparation of embodiment 1 I-1
3.41g (20mmol) Compound II per and 2.50g (20mmol) compound III-1 are dissolved in the toluene of 30mL drying, and under stirring in nitrogen atmosphere, temperature rising reflux spends the night, and TLC shows reaction to be completed.Be poured into after reaction mixture is slightly cold in 200mL frozen water, stir, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, resistates column chromatography purification obtains IV-1, white solid, ESI-MS, m/z=248 [M+H]
+.
2.47g (10mmol) compound IV-1 and 6.17g (15mmol) compound V are dissolved in 30mL chloroform, stir, add 3.18g (30mmol) solid Na
2cO
3, 1mL water and 0.5g benzyl triethyl ammonium bromide, vigorous stirring overnight under room temperature.TLC shows reaction to be completed.Reaction mixture is poured in 200mL frozen water, and stir, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, resistates column chromatography purification obtains VI-1, white solid, ESI-MS, m/z=578 [M+H]
+.
2.89g (5mmol) compound VI-1 is dissolved in the methyl alcohol containing 0.3g MeONa, stirred at ambient temperature 5 hours, and TLC shows reaction to be completed.Add 5g storng-acid cation exchange resin in reaction system, stir until the pH=7 of system.Suction filtration, filtrate is evaporate to dryness on a rotary evaporator, and residue vacuum is dry, obtains I-1, white solid, ESI-MS, m/z=410 [M+H]
+.
The preparation of embodiment 2 I-2
3.41g (20mmol) Compound II per and 2.78g (20mmol) compound III-2 are dissolved in the toluene of 30mL drying, and under stirring in nitrogen atmosphere, temperature rising reflux spends the night, and TLC shows reaction to be completed.Be poured into after reaction mixture is slightly cold in 200mL frozen water, stir, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, resistates column chromatography purification obtains IV-2, white solid, ESI-MS, m/z=262 [M+H]
+.
2.61g (10mmol) compound IV-2 and 6.17g (15mmol) compound V are dissolved in 30mL chloroform, stir, add 3.18g (30mmol) solid Na
2cO
3, 1mL water and 0.5g benzyl triethyl ammonium bromide, vigorous stirring overnight under room temperature.TLC shows reaction to be completed.Reaction mixture is poured in 200mL frozen water, and stir, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, resistates column chromatography purification obtains VI-2, white solid, ESI-MS, m/z=592 [M+H]
+.
2.96g (5mmol) compound VI-2 is dissolved in the methyl alcohol containing 0.3g MeONa, stirred at ambient temperature 5 hours, and TLC shows reaction to be completed.Add 5g storng-acid cation exchange resin in reaction system, stir until the pH=7 of system.Suction filtration, filtrate is evaporate to dryness on a rotary evaporator, and residue vacuum is dry, obtains I-2, white solid, ESI-MS, m/z=424 [M+H]
+.
Embodiment 3-9
With reference to embodiment 1,2 operation steps, prepare compound listed in Table.
Embodiment 10
The IC that compound of the present invention and related compound suppress SGLT2
50be worth the similar method recorded according to document and measure (Meng, W.et al, J.Med.Chem., 2008,51,1145-1149).
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) |
| Embodiment 1 compound | 18.5 |
| Embodiment 2 compound | 6.8 |
| Embodiment 3 compound | 9.2 |
| Embodiment 4 compound | 23.6 |
| Embodiment 5 compound | 17.3 |
| Embodiment 6 compound | 12.4 |
| Embodiment 7 compound | 15.1 |
| Embodiment 8 compound | 30.2 |
| Embodiment 9 compound | 26.9 |
Above-mentioned IC
50measurement result show, compound of the present invention is strong SGLT2 inhibitor, can be used for prepare treatment diabetes B medicine.
Claims (4)
1. there is compound and the pharmaceutically acceptable prodrug ester thereof of general formula I,
Wherein, R is selected from H, C
1-C
5alkyl and C
3-C
6cycloalkyl.
2. the compound of Formula I that defines of claim 1, is selected from following compounds,
3. synthesize arbitrary the defined method belonging to the compound of general formula I of claim 1-2:
Compound II per and compound III are obtained by reacting IV; Compound IV and V are obtained by reacting VI in the presence of a base; VI deacetylate obtains I; Described alkali is selected from various mineral alkali and organic bases; The reagent of described deacetylation is selected from NH
3, mineral alkali, sodium alkoxide; As described in the definition of R is as arbitrary in claim 1-2.
4. the compound of Formula I that defines of one of claim 1-2 and pharmaceutically acceptable salt and the application of prodrug ester in preparation treatment diabetes medicament.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510021101.1A CN104530153A (en) | 2015-01-15 | 2015-01-15 | One category of phenyl S-glucoside derivatives, preparation method of phenyl-class S-glucoside derivatives and application of phenyl-class S-glucoside derivatives in medicament |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510021101.1A CN104530153A (en) | 2015-01-15 | 2015-01-15 | One category of phenyl S-glucoside derivatives, preparation method of phenyl-class S-glucoside derivatives and application of phenyl-class S-glucoside derivatives in medicament |
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| Publication Number | Publication Date |
|---|---|
| CN104530153A true CN104530153A (en) | 2015-04-22 |
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ID=52845818
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1259119A (en) * | 1997-05-07 | 2000-07-05 | 诺沃挪第克公司 | Substituted 3,3-diamino-2-propenenitriles their preparation and 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 |
| CN101917999A (en) * | 2007-11-07 | 2010-12-15 | 弗尔德里克斯制药股份有限公司 | Modulation of protein trafficking |
| WO2014152518A2 (en) * | 2013-03-14 | 2014-09-25 | Celtaxsys, Inc. | Inhibitors of leukotriene a4 hydrolase |
-
2015
- 2015-01-15 CN CN201510021101.1A patent/CN104530153A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1259119A (en) * | 1997-05-07 | 2000-07-05 | 诺沃挪第克公司 | Substituted 3,3-diamino-2-propenenitriles their preparation and use |
| CN101917999A (en) * | 2007-11-07 | 2010-12-15 | 弗尔德里克斯制药股份有限公司 | Modulation of protein trafficking |
| 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 |
| WO2014152518A2 (en) * | 2013-03-14 | 2014-09-25 | Celtaxsys, Inc. | Inhibitors of leukotriene a4 hydrolase |
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Application publication date: 20150422 |