CN104926755A - Nitrobenzene di-acyl benzylamine AMPK (adenosine monophosphate activated protein kinase) activator, method for manufacturing same and application of nitrobenzene di-acyl benzylamine AMPK activator - Google Patents
Nitrobenzene di-acyl benzylamine AMPK (adenosine monophosphate activated protein kinase) activator, method for manufacturing same and application of nitrobenzene di-acyl benzylamine AMPK activator Download PDFInfo
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- CN104926755A CN104926755A CN201510353013.1A CN201510353013A CN104926755A CN 104926755 A CN104926755 A CN 104926755A CN 201510353013 A CN201510353013 A CN 201510353013A CN 104926755 A CN104926755 A CN 104926755A
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- 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
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Abstract
The invention relates to the field of medicine related to type-2 diabetes mellitus, in particular to a xanthic acid AMPK (adenosine monophosphate activated protein kinase) activator with nitrobenzene di-acyl benzylamine, a method for manufacturing the xanthic acid AMPK activator and application thereof. The xanthic acid AMPK activator, the method and the application have the advantages that the xanthic acid AMPK activator can be applied to manufacturing the medicine for the type-2 diabetes mellitus.
Description
Technical field
The present invention relates to the pharmaceutical field of diabetes B treatment.More particularly, the present invention relates to the medicative class of diabetes B tool containing nitre benzene two acyl benzylamine AMPK activator, Its Preparation Method And Use.
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 a class containing the two acyl benzylamine AMPK activator of nitre benzene, 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:
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.
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 (1.38g, 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=255([M+H]
+)。
D. the synthesis of compound VI II-1
Compound VI I-1 (2.03g, 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=334([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 (2.00g, 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=453([M+H]
+)。
embodiment 2-3
With reference to the method for embodiment 1, synthesize compound listed in Table.
embodiment 4 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 | 239 | 205 |
I-2 | 214 | 197 |
I-3 | 182 | 176 |
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,
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.
4. the compound of Formula I that one of claim 1-2 defines is preparing the application in treatment diabetes B medicine.
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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 |
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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 (2)
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》 * |
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