CN104478964A - Benzene O-glucoside derivative with acrylonitrile structure and preparation method and application thereof - Google Patents
Benzene O-glucoside derivative with acrylonitrile structure and preparation method and application thereof Download PDFInfo
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- CN104478964A CN104478964A CN201510020812.7A CN201510020812A CN104478964A CN 104478964 A CN104478964 A CN 104478964A CN 201510020812 A CN201510020812 A CN 201510020812A CN 104478964 A CN104478964 A CN 104478964A
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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
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
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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 a phenyl group O-glucoside structure with an acrylonitrile structure and a preparation method and application of the inhibitor in diabetic drug preparation. According to the general formula I (please see the specification), R is selected from an alkyl group of H, an alkyl group of C1-C8 and a naphthenic base of C3-C8.
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 glucoses transhipment (SGLT2) inhibitor to the medicative phenyl O-glucoside structure containing vinyl cyanide structure of diabetes B, Preparation method and use.。
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 containing the phenyl O-glucoside analog derivative of vinyl cyanide structure as novel SGLT2 inhibitor, these compounds can be used for preparing the medicine for the treatment of 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 the application in treatment diabetes thereof.
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
8alkyl and C
3-C
8cycloalkyl.
Preferred following general formula (I) compound,
Wherein, R is selected from H, C
1-C
5alkyl and C
3-C
6cycloalkyl.
More preferably the compound of general formula (I) has following structure,
General formula of the present invention (I) compound is synthesized by following route:
Compound II per CH
3oCH
2group (MOM) is protected, and obtains III; Compound III changes corresponding acyl chlorides IV into; Compound V with after NaH process and IV react, finally use Me
2sO
4be obtained by reacting VI; VI acid treatment obtains VII; VII and VIII is obtained by reacting IX; IX deacetylate obtains I; The described reagent being converted into acyl chlorides comprises SOCl
2, PCl
3, PCl
5(COCl)
2; Described acid is selected from mineral acid and following organic acid, methylsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichoroacetic acid(TCA).Wherein R base 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
13.8g (100mmol) Compound II per-1 and 12.08g (150mmol) CH
3oCH
2cl (MOMCl) is dissolved in the DMF of 250mL drying, stirs, adds 55.28g (400mmol) solid K
2cO
3, then at N
2lower stirring is spent the night, and TLC detection reaction completes.Be poured into after reaction mixture is slightly cold in 1000mL frozen water, under stirring, pH=2 is regulated, 200mL × 3 dichloromethane extraction, brine It with concentrated hydrochloric acid, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is III-1, faint yellow solid, ESI-MS, m/z=181 [M-H]
-, for next step reaction.
Above-mentioned III-1 is dissolved in the methylene dichloride of 100mL drying, and ice-water bath cooling is lower stirs, and slowly drips 12.69g (100mmol) SOCl
2, at a low price, drip DMF, then a room temperature for overnight.Reaction mixture is evaporate to dryness on a rotary evaporator, and the resistates obtained is IV-1, white solid, for next step reaction.
3.30g (50mmol) the third two eyeball (V) is dissolved in the THF of 100mL drying, ice-water bath cooling is lower stirs, slowly add 4.80g (120mmol, 60%) NaH, after adding, more slowly add 10.03g (50mmol) IV-1 and be dissolved in the solution that 10mL THF makes.Dropwise rear continuation stirring 1 hour, then drip 7.57g (60mmol) methyl-sulfate, dropwise rear room temperature for overnight.Reaction mixture is poured in 500mL frozen water, under stirring, regulates pH=5 with concentrated hydrochloric acid, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is VI-1, column chromatography purification, obtains sterling VI-1, white solid, ESI-MS, m/z=245 [M+H]
+.
7.32g (30mmol) compound VI-1 is dissolved in 100mL MeOH, and ice-water bath cooling is lower stirs, and slowly drip 0.5mL concentrated hydrochloric acid, stirred at ambient temperature 3 hours, reaction completes.Reaction mixture is poured in 500mL frozen water, stirs, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is VII-1, column chromatography purification, obtain sterling VII-1, white solid, ESI-MS, m/z=201 [M+H]
+.
4.00g (20mmol) compound VI I-1 and 12.34g (30mmol) compound VI II is dissolved in 50mL methylene dichloride, stir, slowly add the solution be made up of 0.80g (20mmol) NaOH and 10mL water, then add 1g tetra-n-butyl ammonium bromide again.Room temperature for overnight.TLC checks that reaction completes.Reaction mixture is poured in 500mL frozen water, stirs, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is IX-1, column chromatography purification, obtain sterling IX-1, white solid, ESI-MS, m/z=531 [M+H]
+.
5.30g (10mmol) Compound I X-1 is dissolved in the 30mL MeOH containing 0.6g MeONa, then stirred at ambient temperature 3 hours, and reaction completes.Then add the storng-acid cation exchange resin of 5g drying, room temperature for overnight.Suction filtration, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained is positive empty dry, obtains I-1, white solid, ESI-MS, m/z=363 [M+H]
+.
Embodiment 2
15.2g (100mmol) Compound II per-2 and 12.08g (150mmol) CH
3oCH
2cl (MOMCl) is dissolved in the DMF of 250mL drying, stirs, adds 55.28g (400mmol) solid K
2cO
3, then at N
2lower stirring is spent the night, and TLC detection reaction completes.Be poured into after reaction mixture is slightly cold in 1000mL frozen water, under stirring, regulate pH=2 with concentrated hydrochloric acid, 200mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is III-2, white solid, ESI-MS, m/z=195 [M-H]
-, for next step reaction.
Above-mentioned III-2 is dissolved in the methylene dichloride of 100mL drying, and ice-water bath cooling is lower stirs, and slowly drips 12.69g (100mmol) SOCl
2, at a low price, drip DMF, then a room temperature for overnight.Reaction mixture is evaporate to dryness on a rotary evaporator, and the resistates obtained is IV-2, white solid, for next step reaction.
3.30g (50mmol) the third two eyeball (V) is dissolved in the THF of 100mL drying, ice-water bath cooling is lower stirs, slowly add 4.80g (120mmol, 60%) NaH, after adding, more slowly add 10.03g (50mmol) IV-2 and be dissolved in the solution that 10mL THF makes.Dropwise rear continuation stirring 1 hour, then drip 7.57g (60mmol) methyl-sulfate, dropwise rear room temperature for overnight.Reaction mixture is poured in 500mL frozen water, under stirring, regulates pH=5 with concentrated hydrochloric acid, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is VI-2, column chromatography purification, obtains sterling VI-2, white solid, ESI-MS, m/z=259 [M+H]
+.
7.74g (30mmol) compound VI-2 is dissolved in 100mL MeOH, and ice-water bath cooling is lower stirs, and slowly drip 0.5mL concentrated hydrochloric acid, stirred at ambient temperature 3 hours, reaction completes.Reaction mixture is poured in 500mL frozen water, stirs, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is VII-2, column chromatography purification, obtain sterling VII-2, white solid, ESI-MS, m/z=215 [M+H]
+.
4.28g (20mmol) compound VI I-2 and 12.34g (30mmol) compound VI II is dissolved in 50mL methylene dichloride, stir, slowly add the solution be made up of 0.80g (20mmol) NaOH and 10mL water, then add 1g tetra-n-butyl ammonium bromide again.Room temperature for overnight.TLC checks that reaction completes.Reaction mixture is poured in 500mL frozen water, stirs, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is IX-2, column chromatography purification, obtain sterling IX-2, white solid, ESI-MS, m/z=545 [M+H]
+.
5.44g (10mmol) Compound I X-2 is dissolved in the 30mL MeOH containing 0.6g MeONa, then stirred at ambient temperature 3 hours, and reaction completes.Then add the storng-acid cation exchange resin of 5g drying, room temperature for overnight.Suction filtration, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained is positive empty dry, obtains I-2, white solid, ESI-MS, m/z=377 [M+H]
+.
Embodiment 3
16.6g (100mmol) Compound II per-3 and 12.08g (150mmol) CH
3oCH
2cl (MOMCl) is dissolved in the DMF of 250mL drying, stirs, adds 55.28g (400mmol) solid K
2cO
3, then at N
2lower stirring is spent the night, and TLC detection reaction completes.Be poured into after reaction mixture is slightly cold in 1000mL frozen water, under stirring, regulate pH=2 with concentrated hydrochloric acid, 200mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is III-3, white solid, ESI-MS, m/z=199 [M-H]
-, for next step reaction.
Above-mentioned III-3 is dissolved in the methylene dichloride of 100mL drying, and ice-water bath cooling is lower stirs, and slowly drips 12.69g (100mmol) SOCl
2, at a low price, drip DMF, then a room temperature for overnight.Reaction mixture is evaporate to dryness on a rotary evaporator, and the resistates obtained is IV-3, white solid, for next step reaction.
3.30g (50mmol) the third two eyeball (V) is dissolved in the THF of 100mL drying, ice-water bath cooling is lower stirs, slowly add 4.80g (120mmol, 60%) NaH, after adding, more slowly add 10.03g (50mmol) IV-3 and be dissolved in the solution that 10mL THF makes.Dropwise rear continuation stirring 1 hour, then drip 7.57g (60mmol) methyl-sulfate, dropwise rear room temperature for overnight.Reaction mixture is poured in 500mL frozen water, under stirring, regulates pH=5 with concentrated hydrochloric acid, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is VI-3, column chromatography purification, obtains sterling VI-3, white solid, ESI-MS, m/z=273 [M+H]
+.
8.19g (30mmol) compound VI-3 is dissolved in 100mL MeOH, and ice-water bath cooling is lower stirs, and slowly drip 0.5mL concentrated hydrochloric acid, stirred at ambient temperature 3 hours, reaction completes.Reaction mixture is poured in 500mL frozen water, stirs, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is VII-3, column chromatography purification, obtain sterling VII-3, white solid, ESI-MS, m/z=229 [M+H]
+.
4.56g (20mmol) compound VI I-3 and 12.34g (30mmol) compound VI II is dissolved in 50mL methylene dichloride, stir, slowly add the solution be made up of 0.80g (20mmol) NaOH and 10mL water, then add 1g tetra-n-butyl ammonium bromide again.Room temperature for overnight.TLC checks that reaction completes.Reaction mixture is poured in 500mL frozen water, stirs, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, the resistates obtained is IX-3, column chromatography purification, obtain sterling IX-3, white solid, ESI-MS, m/z=559 [M+H]
+.
5.58g (10mmol) Compound I X-3 is dissolved in the 30mL MeOH containing 0.6g MeONa, then stirred at ambient temperature 3 hours, and reaction completes.Then add the storng-acid cation exchange resin of 5g drying, room temperature for overnight.Suction filtration, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained is positive empty dry, obtains I-3, white solid, ESI-MS, m/z=391 [M+H]
+.
Embodiment 4-12
With reference to embodiment 1-3 method, prepare compound listed in Table.
Embodiment 13
The IC that compound of the present invention and related compound suppress SGLT2
50the method that value reference literature is recorded measures (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 | 26.1 |
| Embodiment 2 compound | 9.4 |
| Embodiment 3 compound | 19.3 |
| Embodiment 4 compound | 12.1 |
| Embodiment 5 compound | 24.9 |
| Embodiment 6 compound | 15.7 |
| Embodiment 7 compound | 30.6 |
| Embodiment 8 compound | 21.5 |
| Embodiment 9 compound | 33.8 |
| Embodiment 10 compound | 37.2 |
| Embodiment 11 compound | 18.2 |
| Embodiment 12 compound | 38.4 |
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 (5)
1. there is compound and the pharmaceutically acceptable prodrug ester thereof of general formula I,
Wherein, R is selected from H, C
1-C
8alkyl and C
3-C
8cycloalkyl.
2. the compound with general formula I that claim 1 defines and pharmaceutically acceptable prodrug ester,
R is selected from H, C
1-C
5alkyl and C
3-C
6cycloalkyl.
3. the compound of Formula I that defines of claim 2, is selected from following compounds,
4. synthesize the method for the compound of arbitrary the defined general formula I of claim 1-3:
Compound II per CH
3oCH
2radical protection, obtains III; Compound III changes corresponding acyl chlorides IV into; Compound V with after NaH process and IV react, finally use Me
2sO
4be obtained by reacting VI; VI acid treatment obtains VII; VII and VIII is obtained by reacting IX; IX deacetylate obtains I; The described reagent being converted into acyl chlorides is selected from SOCl
2, PCl
3, PCl
5(COCl)
2; Described acid is selected from methylsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichoroacetic acid(TCA); Wherein R as arbitrary in claim 1-3 as described in.
5. the compound of Formula I that defines of one of claim 1-3 and pharmaceutically acceptable salt and the application of prodrug ester in preparation treatment diabetes medicament.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1802366A (en) * | 2003-03-14 | 2006-07-12 | 安斯泰来制药有限公司 | C-glycoside derivatives and salts thereof |
| CN100391963C (en) * | 2003-01-03 | 2008-06-04 | 布里斯托尔-迈尔斯斯奎布公司 | Methods of producing C-aryl glucoside SGLT2 inhibitors |
| JP2009034028A (en) * | 2007-08-01 | 2009-02-19 | Hayashibara Biochem Lab Inc | beta-GLUCOSIDASE, METHOD FOR PRODUCING THE SAME, AND METHOD FOR PRODUCING beta-TYPE GLYCOSIDE USING THE SAME |
-
2015
- 2015-01-15 CN CN201510020812.7A patent/CN104478964A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100391963C (en) * | 2003-01-03 | 2008-06-04 | 布里斯托尔-迈尔斯斯奎布公司 | Methods of producing C-aryl glucoside SGLT2 inhibitors |
| CN1802366A (en) * | 2003-03-14 | 2006-07-12 | 安斯泰来制药有限公司 | C-glycoside derivatives and salts thereof |
| JP2009034028A (en) * | 2007-08-01 | 2009-02-19 | Hayashibara Biochem Lab Inc | beta-GLUCOSIDASE, METHOD FOR PRODUCING THE SAME, AND METHOD FOR PRODUCING beta-TYPE GLYCOSIDE USING THE SAME |
Non-Patent Citations (4)
| Title |
|---|
| JASON M. CRAWFORD，ET AL.: ""Small molecule perimeter defense in entomopathogenic bacteria"", 《PNAS》 * |
| SUK YOUN KANG，ET AL.: ""Synthesis of pyridazine and thiazole analogs as SGLT2 inhibitors"", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| VANESSA PARMENOPOULOU，ET AL.: ""Structure based inhibitor design targeting glycogen phosphorylase b. Virtual screening, synthesis, biochemical and biological assessment of novel N-acyl-β-D-glucopyranosylamines"", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 万恵新，等: ""2型糖尿病治疗靶点钠-葡萄糖共转运蛋白2抑制剂研究进展"", 《药学学报》 * |
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Application publication date: 20150401 |