CN104478957A - Derivative containing nitrile-based benzene and bis-O-glucoside, preparation method thereof and application - Google Patents
Derivative containing nitrile-based benzene and bis-O-glucoside, preparation method thereof and application Download PDFInfo
- Publication number
- CN104478957A CN104478957A CN201510019642.0A CN201510019642A CN104478957A CN 104478957 A CN104478957 A CN 104478957A CN 201510019642 A CN201510019642 A CN 201510019642A CN 104478957 A CN104478957 A CN 104478957A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- glucoside
- application
- meoh
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 C[C@@]1OC(CO)C(*)C(*)C1C* Chemical compound C[C@@]1OC(CO)C(*)C(*)C1C* 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of medicine related to diabetes, in particular to an SGLT2 inhibitor shown in the specification and containing a nitrile-based benzene and bis-O-glucoside structure, a preparation method of the inhibitor and application of the inhibitor in the diabetes medicine preparation process.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes B.Specifically, the present invention relates to a kind of 2 type sodium dependent glucoses to the medicative nitrile group-containing benzene of diabetes B and two O-glucoside structure and transport son (SGLT2) inhibitor, preparation method and the purposes in pharmacy.
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 a kind of nitrile group-containing benzene and two O-glucoside analog derivative 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 formula I and pharmaceutically can accept prodrug ester.
Another object of the present invention is to provide preparation and has the compound of formula I and the method for pharmaceutically acceptable prodrug ester thereof.
Another object of the present invention is to provide the compound containing 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 formula I has following structural formula:
Formula of the present invention (I) compound is synthesized by following route:
Compound II per and III react in the presence of a base and obtain IV, and the ratio of III and II is 2:1-10:1; Compound IV deacetylate obtains I; Described alkali is selected from mineral alkali; Described deacetylated condition is selected from: 1) NH
3/ MeOH; 2) NaOH/MeOH/H
2o; 3) KOH/MeOH/H
2o; 4) MeONa/MeOH.
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.
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 formula I of the present invention is verified by receptor binding assays.
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 formula I 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.
The preparation of embodiment 1 Compound I
1.35g (10mmol) Compound II per and 8.22g (20mmol) compound III are dissolved in 10mL methylene dichloride, stirred at ambient temperature, add the solution configured by 0.8g (20mmol) NaOH and 3mL water, add 0.5g tetra-n-butyl ammonium bromide again, vigorous stirring 48 hours under room temperature.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, white solid, ESI-MS, m/z=796 ([M+H]
+).
4.98g (5mmol) compound IV is dissolved in the 20mlMeOH containing 0.31g (5mmol) MeONa, stirred at ambient temperature 3 hours, and now TLC display reaction completes.Add 3g storng-acid cation exchange resin in the reactive mixture, room temperature for overnight, pH value of solution=7.Suction filtration removing resin, filtrate boils off solvent on a rotary evaporator, and the resistates obtained is dry in vacuum oil pump, obtains I, white solid, ESI-MS, m/z=460 ([M+H]
+).
The preparation of embodiment 2 Compound I
1.35g (10mmol) Compound II per and 41.11g (100mmol) compound III are dissolved in 10mL methylene dichloride, stirred at ambient temperature, add the solution configured by 0.8g (20mmol) NaOH and 3mL water, add 0.5g tetra-n-butyl ammonium bromide again, vigorous stirring 48 hours under room temperature.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, white solid, ESI-MS, m/z=796 ([M+H]
+).
4.98g (5mmol) compound IV is dissolved in the 20mlMeOH containing 0.31g (5mmol) MeONa, stirred at ambient temperature 3 hours, and now TLC display reaction completes.Add 3g storng-acid cation exchange resin in the reactive mixture, room temperature for overnight, pH value of solution=7.Suction filtration removing resin, filtrate boils off solvent on a rotary evaporator, and the resistates obtained is dry in vacuum oil pump, obtains I, white solid, ESI-MS, m/z=460 ([M+H]
+).
The preparation of embodiment 3 reference compound D1
In order to further illustrate the drug effect of the compounds of this invention, this invention describes not yet open and being all the Compound D-1 of the applicant's design.
Its preparation method is as follows:
1.10g (10mmol) Compound II per-3 and 20.55g (50mmol) compound III are dissolved in 10mL methylene dichloride, stirred at ambient temperature, add the solution configured by 0.8g (20mmol) NaOH and 3mL water, add 0.5g tetra-n-butyl ammonium bromide again, vigorous stirring 48 hours under room temperature.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-3, white solid, ESI-MS, m/z=771 ([M+H]
+).
3.85g (5mmol) compound IV-3 is dissolved in the 20mlMeOH containing 0.31g (5mmol) MeONa, stirred at ambient temperature 3 hours, and now TLC display reaction completes.Add 3g storng-acid cation exchange resin in the reactive mixture, room temperature for overnight, pH value of solution=7.Suction filtration removing resin, filtrate boils off solvent on a rotary evaporator, and the resistates obtained is dry in vacuum oil pump, obtains D-1, white solid, ESI-MS, m/z=435 ([M+H]
+).
The IC that embodiment 6 compound suppresses SGLT2
50
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 | 2.1 |
| Reference compound D-1 | 10.4 |
Above-mentioned IC
50measurement result show, compound of the present invention is strong SGLT2 inhibitor.
Claims (3)
1. there is compound and the pharmaceutically acceptable prodrug ester thereof of formula I structure,
2. synthesize the method for compound described in claim 1:
Compound II per and III react in the presence of a base and obtain IV, and the ratio of III and II is 2:1-10:1; Compound IV deacetylate obtains I; Described alkali is selected from mineral alkali; Described deacetylated condition is selected from: 1) NH
3/ MeOH; 2) NaOH/MeOH/H
2o; 3) KOH/MeOH/H
2o; 4) MeONa/MeOH.
3. compound described in claim 1 and pharmaceutically acceptable salt and the application of prodrug ester in preparation treatment diabetes medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510019642.0A CN104478957A (en) | 2015-01-14 | 2015-01-14 | Derivative containing nitrile-based benzene and bis-O-glucoside, preparation method thereof and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510019642.0A CN104478957A (en) | 2015-01-14 | 2015-01-14 | Derivative containing nitrile-based benzene and bis-O-glucoside, preparation method thereof and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104478957A true CN104478957A (en) | 2015-04-01 |
Family
ID=52753578
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510019642.0A Pending CN104478957A (en) | 2015-01-14 | 2015-01-14 | Derivative containing nitrile-based benzene and bis-O-glucoside, preparation method thereof and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104478957A (en) |
Citations (5)
| 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 | β-glucosidase, method for producing the same, and method for producing β-type glycoside using the same |
| WO2014151030A1 (en) * | 2013-03-15 | 2014-09-25 | Novartis Ag | Cell proliferation inhibitors and conjugates thereof |
| CN104230866A (en) * | 2002-05-20 | 2014-12-24 | 阿斯利康有限公司 | C-aryl glucoside sglt2 inhibitors and method |
-
2015
- 2015-01-14 CN CN201510019642.0A patent/CN104478957A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230866A (en) * | 2002-05-20 | 2014-12-24 | 阿斯利康有限公司 | C-aryl glucoside sglt2 inhibitors and method |
| 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 | β-glucosidase, method for producing the same, and method for producing β-type glycoside using the same |
| WO2014151030A1 (en) * | 2013-03-15 | 2014-09-25 | Novartis Ag | Cell proliferation inhibitors and conjugates thereof |
Non-Patent Citations (2)
| Title |
|---|
| HANS GUNTER THOMAS ET AL.: "Oxidatively induced glycosylation starting from hydroquinone glycosides", 《TETRAHEDRON》 * |
| VANESSA PARMENOPOULOU ER 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》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108350014A (en) | Aminoglycoside derivative and its application in treating hereditary conditions | |
| Das et al. | Versatile thiosugars in medicinal chemistry | |
| CN104530149A (en) | Halogen-substituted phenyl group double-O-glucoside derivant, and preparation method and application thereof | |
| CN104478957A (en) | Derivative containing nitrile-based benzene and bis-O-glucoside, preparation method thereof and application | |
| EP2621273A2 (en) | Polyphosphate and pyrophosphate derivative of saccharides | |
| CN104447905A (en) | Derivative containing nitrobenzene and bis-O-glucoside and preparation method and application of derivative | |
| CN104478959A (en) | Compound with nitrile group biphenyl double-glucoside structure and preparation method and application thereof | |
| CN104530150A (en) | Compound with amino benzene and diosgenin-diglucoside structure and preparation method and application thereof | |
| CN104530152A (en) | Compound containing acrylonitrile base and trifluoro methoxyphenyl O-galactoside structure and application | |
| CN104447907A (en) | Compound containing nitro biphenyl diosgenin-diglucoside structure and preparation method and application thereof | |
| CN104478956A (en) | Phenyl double O-glucoside derivative and preparation method and application thereof | |
| CN104447906A (en) | Alcoxyl phenyl group diosgenin-diglucoside derivative and preparation method and application thereof | |
| CN104478958A (en) | Compound with halogenated biphenyl double-glucoside structure and preparation method and application thereof | |
| CN104478963A (en) | Compound containing nitrile-based benzene S-glucoside structure and application of compound | |
| CN104497072A (en) | Derivative containing acrylonitrile and benzene halide O-glucoside structures and preparation method and application thereof | |
| CN104497070A (en) | Compound with trifluoromethyl-S-glucoside and application | |
| CN104497068A (en) | Compound with trifluoromethoxybenzene-S-glucoside structure and application thereof | |
| CN104530151A (en) | Compound containing nitrobenzene S-glucoside structure and application thereof | |
| CN104478960A (en) | Compound containing acrylonitrile-based and benzotrifluoride-based O-glucoside structure and application | |
| CN104497074A (en) | Compound with acrylonitrile group and nitrobenzene-O-glucoside structure and application | |
| CN104497071A (en) | Compound with acrylonitrile group and cyanobenzene-O-glucoside structure and application | |
| CN104497069A (en) | Amido phenyl S-glucoside derivative, preparation method and use thereof | |
| CN104478969A (en) | O-galactoside derivative with alcoxyl phenyl group thiazolyl and preparation method and application thereof | |
| CN104530155A (en) | O-galactoside derivative with halogenated phenyl thiazolyl and preparation method and application thereof | |
| CN104530153A (en) | 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 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150401 |