CN104926757A - Diacyl benzylamine AMPK activator containing alcoxyl phenyl group, and preparation method and purpose of diacyl benzylamine AMPK activator - Google Patents
Diacyl benzylamine AMPK activator containing alcoxyl phenyl group, and preparation method and purpose of diacyl benzylamine AMPK activator Download PDFInfo
- Publication number
- CN104926757A CN104926757A CN201510353896.6A CN201510353896A CN104926757A CN 104926757 A CN104926757 A CN 104926757A CN 201510353896 A CN201510353896 A CN 201510353896A CN 104926757 A CN104926757 A CN 104926757A
- Authority
- CN
- China
- Prior art keywords
- compound
- benzylamine
- diacyl
- ampk activator
- ampk
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Abstract
The invention relates to the field of medicine related to type 2 diabetes, in particular to a diacyl benzylamine xanthic acid AMPK activator containing an alcoxyl phenyl group, a preparation method of the activator, and application of the activator in the preparation of the medicine for the type 2 diabetes. The formula is showed as follow, wherein R is alkyl selected from C1-C3.
Description
Technical field
The present invention relates to the pharmaceutical field of diabetes B treatment.More particularly, the present invention relates to two acyl benzylamine AMPK activator, the Its Preparation Method And Use of the medicative class of diabetes B tool containing alkoxyphenyl radical.
Background technology
Diabetes are the lysis caused by multi-pathogenesis, have influence on the population in the whole world 6%.Expect 2025, number of patients can double again and reach 300,000,000.The most important clinical pathologic characteristic of diabetes is that plasma glucose (blood sugar) concentration increases.It is the major cause leading diabetogenic various clinical symptom that blood sugar concentration increases.Unsteered hyperglycemia causes many diabetic complications, as increased capillary blood vessel and macrovascular diseases risk, comprises ephrosis, neuropathy, retinopathy, hypertension, cerebral ischemia and coronary heart disease etc.Therefore, the key that blood sugar is treatment and prevent diabetes and complication thereof is reduced.
The protein kinase (AMPK) that AMP (adenylic acid) activates participates in multiple metabolic process as a kind of important protein kinase.AMPK plays master switch effect in the balance of adjuster body energy metabolism.In muscle and liver, the activation of AMPK enhances the picked-up of glucose, fatty acid oxidation and insulin sensitivity, and decreases the generation of glucose, cholesterol and triglyceride level.Therefore, AMPK and signal path thereof are diabetes B active drug action target spots.In fact, the biguanides of widespread use clinically at present, controlling as N1,N1-Dimethylbiguanide, phenformin and buformin is exactly AMPK activator.Wherein N1,N1-Dimethylbiguanide is a current most widely used line antidiabetic medicine clinically, be not only first-selected Remedies for diabetes and also on euglycemia without impact.This shows that AMPK is the keying action target spot of type ii diabetes pharmacological agent.But a severe side effect of these widely used biguanides AMPK activator clinically to cause lactic acidosis at present.Lactic acidosis is the metabolism class disease that a class is serious, once occur threat to life.Just because of causing lactic acidosis, the biguanides AMPK activator such as phenformin are terminated clinical application in states such as America and Europes.Although N1,N1-Dimethylbiguanide causes the probability of lactic acidosis, comparatively phenformin is low, but in oral antidiabetic drug, it causes serious toxic side effects and causes dead clinical report number maximum, therefore, research and develop novel, non-biguanides AMPK activator to have and important clinical meaning as the medicine of diabetes.
The invention discloses the two acyl benzylamine AMPK activator of a class containing alkoxyphenyl radical, these compounds can be used for the medicine preparing treatment diabetes B.
Summary of the invention
An object of the present invention is to provide a kind of AMPK agonist with the excellent activity of general formula I.Another object of the present invention is to provide the method that preparation has the compound of general formula I.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 C
1-C
3alkyl.
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 and acrylamide react under the condition heated, and obtain III; Compound III in the presence of a base with CH
3cOCl reacts, and obtains compound IV; Compound V and compound VI generation condensation reaction, obtain compound VI I; Compound VI I uses N-bromo-succinimide (NBS) to process under light illumination, obtains compound VI II; There is substitution reaction in compound IV and compound VI II, obtains Compound I in the presence of a base; The definition of R as previously mentioned.
Compound of Formula I of the present invention has AMPK activation, can be used as effective constituent for the preparation of diabetes B medicine.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-1000mg/ 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 synthesis of embodiment 1 Compound I-1
A. the synthesis of compound III
Compound II per (0.87g, 10mmol) and acrylamide (0.71g, 10mmol) are dissolved in 10mL dimethylbenzene, and then temperature rising reflux spends the night, and TLC shows reaction to be completed.The direct pressure reducing and steaming solvent of reaction mixture, the resistates obtained uses column chromatography purification, obtains compound III, white solid.ESI-MS,m/z＝159([M+H]
+)。
B. the synthesis of compound IV-1
Diisopropylamine (1.01g, 10mmol) be dissolved in the THF of 10mL drying, be cooled to-78 DEG C in a nitrogen atmosphere, stir, in system, the hexane solution (6.25mL of the n-BuLi of 1.6M is slowly added with syringe, 10mmol), after dropwising, reaction mixture continues stirring 10 minutes at such a temperature, then will by compound III (1.11g, solution 7mmol) be made into the THF of 3mL drying is slowly added drop-wise in reaction system, and after dropwising, reaction mixture continues stirring 10 minutes at such a temperature.With syringe, the solution that the THF by Acetyl Chloride 98Min. (0.78g, 10mmol) and 1mL drying prepares slowly is added drop-wise in reaction system, dropwises rear reaction mixture and continue stirring at such a temperature 30 minutes, then at room temperature stir again and spend the night.Reaction mixture pours in 200mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound IV-1, white solid.ESI-MS,m/z＝201([M+H]
+)。
C. the synthesis of compound VI I-1
P-methyl aceto phenone V (1.34g, 10mmol) and VI-1 (1.23g, 10mmol) is dissolved in 10mL ethanol, adds Glacial acetic acid 1mL, and then reaction mixture refluxes under a nitrogen and spends the night, and TLC detection reaction completes.Reaction mixture pours in 200mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use saturated NaHCO successively
3solution and salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound VI I-1, white solid.ESI-MS,m/z＝240([M+H]
+)。
D. the synthesis of compound VI II-1
Compound VI I-1 (1.91g, 8mmol) and NBS (1.78g, 10mmol) is dissolved in 15mL CCl
4in, irradiate at 500W incandescent light and flow 3 hours next time, TLC checks and finds that reaction completes.Reaction mixture pours in 200mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use saturated NaHCO successively
3solution and salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound VI II-1, white solid.ESI-MS,m/z＝319([M+H]
+)。
E. the synthesis of Compound I-1
Diisopropylamine (0.61g, 6mmol) be dissolved in the THF of 6mL drying, be cooled to-78 DEG C in a nitrogen atmosphere, stir, in system, the hexane solution (3.75mL of the n-BuLi of 1.6M is slowly added with syringe, 6mmol), after dropwising, reaction mixture continues stirring 10 minutes at such a temperature, then will by compound IV-1 (1.00g, solution 5mmol) be made into the THF of 3mL drying is slowly added drop-wise in reaction system, and after dropwising, reaction mixture continues stirring 10 minutes at such a temperature.With syringe, the solution that the THF by VIII-1 (1.91g, 6mmol) and 5mL drying prepares slowly is added drop-wise in reaction system, dropwises rear reaction mixture and continue stirring at such a temperature 30 minutes, then at room temperature stir again and spend the night.Reaction mixture pours in 200mL frozen water, stirs, uses CH
2cl
2(60mL × 3) extract, and merge extraction phase, use salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains Compound I-1, white solid.ESI-MS,m/z＝438([M+H]
+)。
embodiment 2-4
With reference to the method for embodiment 1, synthesize compound listed in Table.
embodiment 5 Compound ira vitro is to the activation of AMPK
To recombinate AMPK enzyme reactivating with LKBl in vitro before enzyme assay expression in escherichia coli people.Use two kinds of technology for detection AMPK enzymic activitys based on fluorescence (α-screening and Delfia) and (comprise 25mM Tris/HCl damping fluid, pH7.5, Hepes damping fluid containing 100 μMs of ATP/50mM respectively at microwell plate, 25mM Tris/HCl damping fluid, pH7.4, containing 125 μMs of ATP) on synthesis skin substrate (AMARAASAAALARRR, i.e. " AMARAA " skin) and serial dilution activator existence under carry out.By adding AMPK (50-100ng) initiation reaction.After mixing, plank is at room temperature hatched 30 minutes.Enzymic activity is detected to measure the phosphoric acid amount of mixing in AMARAA by using the antibody of anti-phosphorylate serine.Activity represents with the percentage (%) contrasting (Basal activity is expressed as 100).
Test result sees the following form.
| Compound | α-screening | Delfia |
| I-1 | 185 | 191 |
| I-2 | 158 | 179 |
| I-3 | 161 | 176 |
| I-4 | 143 | 152 |
As can be seen from upper table result, compound of the present invention has very strong activation to AMPK, can as preparation treatment diabetes B medicine.
Claims (4)
1. there is the compound of general formula I,
Wherein, R is selected from C
1-C
3alkyl.
2. the compound of Formula I that defines of claim 1, is selected from:
3. synthesize arbitrary the defined method belonging to the compound of general formula I of claim 1-2:
Compound II per and acrylamide react under the condition heated, and obtain III; Compound III in the presence of a base with CH
3cOCl reacts, and obtains compound IV; Compound V and compound VI generation condensation reaction, obtain compound VI I; Compound VI I uses the process of N-bromo-succinimide under light illumination, obtains compound VI II; There is substitution reaction in compound IV and compound VI II, obtains Compound I in the presence of a base; As described in the definition of R is as arbitrary in claim 1-2.
4. the compound of Formula I that one of claim 1-2 defines is preparing the application in treatment diabetes B medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510353896.6A CN104926757A (en) | 2015-06-24 | 2015-06-24 | Diacyl benzylamine AMPK activator containing alcoxyl phenyl group, and preparation method and purpose of diacyl benzylamine AMPK activator |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510353896.6A CN104926757A (en) | 2015-06-24 | 2015-06-24 | Diacyl benzylamine AMPK activator containing alcoxyl phenyl group, and preparation method and purpose of diacyl benzylamine AMPK activator |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104926757A true CN104926757A (en) | 2015-09-23 |
Family
ID=54114212
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510353896.6A Pending CN104926757A (en) | 2015-06-24 | 2015-06-24 | Diacyl benzylamine AMPK activator containing alcoxyl phenyl group, and preparation method and purpose of diacyl benzylamine AMPK activator |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104926757A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101998853A (en) * | 2008-04-11 | 2011-03-30 | 默克专利有限公司 | Thienopyridone derivatives as AMP-activated protein kinase (AMPK) activators |
| CN104395319A (en) * | 2012-06-29 | 2015-03-04 | 普克塞尔公司 | Thienopyridone derivatives useful as activators of ampk |
-
2015
- 2015-06-24 CN CN201510353896.6A patent/CN104926757A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101998853A (en) * | 2008-04-11 | 2011-03-30 | 默克专利有限公司 | Thienopyridone derivatives as AMP-activated protein kinase (AMPK) activators |
| CN104395319A (en) * | 2012-06-29 | 2015-03-04 | 普克塞尔公司 | Thienopyridone derivatives useful as activators of ampk |
Non-Patent Citations (3)
| Title |
|---|
| CHAO WANG ET AL.: "L-Valine derived chiral N-sulfinamides as effective organocatalysts for the asymmetric hydrosilylation of N-alkyl and N-aryl protected ketimines", 《ORGANIC BIOMOLECULAR CHEMISTRY》 * |
| TAO PANG ET AL.: "Small Molecule Antagonizes Autoinhibition and Activates AMP-activated Protein Kinase in Cells", 《THE JOURNAL OF BIOLOGOCAL CHEMISTRY》 * |
| 庄静静: "AMPK及LXR通路新型天然调节剂", 《中国博士学位论文论文全文数据库》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103228668B (en) | Antidiabetic phenylpyruvic acid enol glucosides | |
| CN109689065A (en) | For treating the phosphinylidyne aminate of hepatitis type B virus | |
| CN110759908B (en) | N-benzenesulfonyl benzamide compound for inhibiting Bcl-2 protein and composition and application thereof | |
| CZ301802B6 (en) | Urea derivatives as IMPDH inhibitors and pharmaceutical compositions comprising these derivatives | |
| US11021454B2 (en) | Type of aryl benzofuran amidated derivative and medical use thereof | |
| Orr et al. | DNA chain termination activity and inhibition of human immunodeficiency virus reverse transcriptase by carbocyclic 2', 3'-didehydro-2', 3'-dideoxyguanosine triphosphate. | |
| JP2005029571A (en) | COMPOUND HAVING DNA SYNTHETASE lambda INHIBITORY ACTION AND USE OF THE SAME | |
| CN108350007B (en) | Substituted adenine compound and pharmaceutical composition thereof | |
| CN104926757A (en) | Diacyl benzylamine AMPK activator containing alcoxyl phenyl group, and preparation method and purpose of diacyl benzylamine AMPK activator | |
| CN104926756A (en) | Di-acyl benzylamine compound with cyano benzene, method for manufacturing di-acyl benzylamine compound and application thereof | |
| CN104926755A (en) | Nitrobenzene di-acyl benzylamine AMPK (adenosine monophosphate activated protein kinase) activator, method for manufacturing same and application of nitrobenzene di-acyl benzylamine AMPK activator | |
| CN105001181A (en) | Bisacyl benzylamine AMPK activator, and preparation method and application thereof | |
| CN105037296A (en) | AMPK activator containing halogenated-benzene bisamides benzylamine structures, and preparation method and application thereof | |
| CN112679409B (en) | 4-indole-substituted thiosemicarbazide derivative and preparation method and application thereof | |
| CN104945431B (en) | A kind of preparation method of the schiff bases vanadyl complex crystal for having biological activity | |
| CN104892569A (en) | Terminal-substituted nitrobenzene hexamethylbenzene xanthate compound, preparation method and application | |
| CN105037321A (en) | Xanthate AMPK activating agents comprising hexamethylbenzene ring structures, as well as preparation methods and application thereof | |
| CN104910129A (en) | Xanthate compounds containing hexamethyl benzene ring and halogeno-benzene, and preparation method and application thereof | |
| TWI344959B (en) | Treatment of hepatitis c virus infection with sesquiterpene lactones | |
| CN105037322A (en) | Xanthate compounds containing hexamethylbenzene ring and alkoxyl benzene structures, as well as preparation methods and application thereof | |
| CN104945370A (en) | Xanthate compound containing halothiophene and nitrobenzene hexamethylbenzene structure, preparation method and application | |
| CN103450163A (en) | Indazole compounds, preparation method, and pharmaceutical applications thereof | |
| CN105001194A (en) | Xanthate compound containing aminothiophene and hexamethylbenzene structures, and preparation method and application thereof | |
| CN104892568A (en) | Xanthate ester compound containing haxamethyl benzene ring and nitrile group benzene structure and preparation method and application of xanthate ester compound | |
| CN104945371A (en) | Xanthate ester compound containing nitrile thiophene and with hexamethylbenzene structure and preparation method and application thereof |
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: 20150923 |