CN104945370A - Xanthate compound containing halothiophene and nitrobenzene hexamethylbenzene structure, preparation method and application - Google Patents

Xanthate compound containing halothiophene and nitrobenzene hexamethylbenzene structure, preparation method and application Download PDF

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Publication number
CN104945370A
CN104945370A CN201510355282.1A CN201510355282A CN104945370A CN 104945370 A CN104945370 A CN 104945370A CN 201510355282 A CN201510355282 A CN 201510355282A CN 104945370 A CN104945370 A CN 104945370A
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compound
reaction mixture
preparation
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10mmol
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邓润卿
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Foshan Saiweisi Pharmaceutical Technology Co Ltd
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Foshan Saiweisi Pharmaceutical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/18—Radicals substituted by singly bound hetero atoms other than halogen by sulfur atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to pharmaceutical field related to 2-diabetes mellitus, in particular to a xanthate activating agent containing containing halothiophene and nitrobenzene hexamethylbenzene structure and a preparation method and the application in the preparation process for 2-diabetes mellitus drugs. R is selected from halogen substituent group.

Description

Containing xanthate compounds, the Preparation method and use of halogenated thiophene and nitre benzene mellitene structure
Technical field
The present invention relates to the pharmaceutical field of diabetes B treatment.More particularly, the present invention relates to the xanthate class AMPK activator, its preparation method that the medicative class of diabetes B tool are contained to halogenated thiophene and nitre benzene mellitene structure, and the purposes in pharmacy.
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 xanthate class AMPK activator containing halogenated thiophene and nitre benzene mellitene structure, 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.
The compound that another object of the present invention is to provide containing general formula I is treating the application in diabetes B as effective constituent.
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 halogenic substituent.
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 reacts with compound III under Louis acid catalysis, obtains compound IV; Compound IV is through BX 3process the methyl sloughed on methoxyl group, obtain VI; Compound VI by first in the presence of a base with CS 2reaction, obtains corresponding xanthogenate, the latter again with after the compound VI I that adds there is substitution reaction, obtain Compound I; Wherein, the definition of X=Br or Cl, 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 IV-1
Compound II per (1.48g, 10mmol) and compound III-1 (2.01g, 10mmol) are dissolved in the CH of 20mL drying 2cl 2in, stirred at ambient temperature, adds anhydrous AlCl 3(1.33g, 10mmol), then reaction mixture at room temperature stirs and spends the night, and TLC shows reaction to be completed.Reaction mixture pours in 200mL frozen water, stirs, uses CH 2cl 2(60mL × 3) extract, and merge extraction phase, use 1% dilute hydrochloric acid and salt water washing successively, 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＝314([M+H] +)。
B. the synthesis of compound V-1
Compound IV-1 (1.88g, 6mmol) is dissolved in the CH of 15mL drying 2cl 2in, be cooled to-50 DEG C under nitrogen protection, stir, slowly drip the BCl of 1.0M with syringe 3the CH of (10mL, 10mmol) 2cl 2solution, after dropwising, reaction mixture is warmed up to room temperature gradually, and at room temperature stirs 1 hour, and TLC shows reaction to be completed.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 V-1, white solid.ESI-MS,m/z＝300([M+H] +)。
The synthesis of C.VI-1
Compound V-1 (1.20g, 4mmol) be dissolved in 10mL THF, stirred at ambient temperature, add NaOH (0.40g, 10mmol), stirred at ambient temperature 30 minutes, then add (R)-propylene oxide (0.29g, 5mmol), gained reaction mixture then temperature rising reflux 12 hours, TLC shows reaction to be completed.Reaction mixture pours in 100mL 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 VI-1, white solid.ESI-MS,m/z＝358([M+H] +)。
D. the synthesis of Compound I-1
Compound VI-1 (0.71g, 2mmol) is dissolved in the THF of 10mL drying, and stirred at ambient temperature adds 60%NaH (0.40g, 10mmol), continues stirring 30 minutes, then adds dry CS 2(0.23g, 3mmol), continue stirring 30 minutes, finally add compound VI I-1 (0.50g, 3mmol), reaction mixture at room temperature stirs 5 hours, and TLC follows the tracks of and finds that reaction completes.Reaction mixture pours in 100mL 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＝565([M+H] +)。
the synthesis of embodiment 2 Compound I-2
A. the synthesis of compound IV-1
Compound II per (1.48g, 10mmol) and compound III-1 (2.01g, 10mmol) are dissolved in the CH of 20mL drying 2cl 2in, stirred at ambient temperature, adds anhydrous AlCl 3(1.33g, 10mmol), then reaction mixture at room temperature stirs and spends the night, and TLC shows reaction to be completed.Reaction mixture pours in 200mL frozen water, stirs, uses CH 2cl 2(60mL × 3) extract, and merge extraction phase, use 1% dilute hydrochloric acid and salt water washing successively, 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＝314([M+H] +)。
B. the synthesis of compound V-1
Compound IV-1 (1.88g, 6mmol) is dissolved in the CH of 15mL drying 2cl 2in, be cooled to-50 DEG C under nitrogen protection, stir, slowly drip the BCl of 1.0M with syringe 3the CH of (10mL, 10mmol) 2cl 2solution, after dropwising, reaction mixture is warmed up to room temperature gradually, and at room temperature stirs 1 hour, and TLC shows reaction to be completed.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 V-1, white solid.ESI-MS,m/z＝300([M+H] +)。
The synthesis of C.VI-1
Compound V-1 (1.20g, 4mmol) be dissolved in 10mL THF, stirred at ambient temperature, add NaOH (0.40g, 10mmol), stirred at ambient temperature 30 minutes, then add (R)-propylene oxide (0.29g, 5mmol), gained reaction mixture then temperature rising reflux 12 hours, TLC shows reaction to be completed.Reaction mixture pours in 100mL 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 VI-1, white solid.ESI-MS,m/z＝358([M+H] +)。
D. the synthesis of Compound I-2
Compound VI-1 (0.71g, 2mmol) is dissolved in the THF of 10mL drying, and stirred at ambient temperature adds 60%NaH (0.40g, 10mmol), continues stirring 30 minutes, then adds dry CS 2(0.23g, 3mmol), continue stirring 30 minutes, finally add compound VI I-2 (0.45g, 3mmol), reaction mixture at room temperature stirs 5 hours, and TLC follows the tracks of and finds that reaction completes.Reaction mixture pours in 100mL 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-2, white solid.ESI-MS,m/z＝548([M+H] +)。
the synthesis of embodiment 3 reference compound D-1
For further illustrating the good result of the compounds of this invention, the application describes and is all applicant's invention, not yet disclosed Compound D-1, and its structure is as follows:
Synthetic method is as follows:
A. the synthesis of compound IV-2
Compound II per (1.48g, 10mmol) and compound III-2 (1.57g, 10mmol) are dissolved in the CH of 20mL drying 2cl 2in, stirred at ambient temperature, adds anhydrous AlCl 3(1.33g, 10mmol), then reaction mixture at room temperature stirs and spends the night, and TLC shows reaction to be completed.Reaction mixture pours in 200mL frozen water, stirs, uses CH 2cl 2(60mL × 3) extract, and merge extraction phase, use 1% dilute hydrochloric acid and salt water washing successively, 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-2, white solid.ESI-MS,m/z＝269([M+H] +)。
B. the synthesis of compound V-2
Compound IV-2 (1.61g, 6mmol) is dissolved in the CH of 15mL drying 2cl 2in, be cooled to-50 DEG C under nitrogen protection, stir, slowly drip the BCl of 1.0M with syringe 3the CH of (10mL, 10mmol) 2cl 2solution, after dropwising, reaction mixture is warmed up to room temperature gradually, and at room temperature stirs 1 hour, and TLC shows reaction to be completed.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 V-2, white solid.ESI-MS,m/z＝255([M+H] +)。
The synthesis of C.VI-2
Compound V-2 (1.02g, 4mmol) be dissolved in 10mL THF, stirred at ambient temperature, add NaOH (0.40g, 10mmol), stirred at ambient temperature 30 minutes, then add (R)-propylene oxide (0.29g, 5mmol), gained reaction mixture then temperature rising reflux 12 hours, TLC shows reaction to be completed.Reaction mixture pours in 100mL 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 VI-2, white solid.ESI-MS,m/z＝313([M+H] +)。
D. the synthesis of Compound D-1
Compound VI-2 (0.62g, 2mmol) is dissolved in the THF of 10mL drying, and stirred at ambient temperature adds 60%NaH (0.40g, 10mmol), continues stirring 30 minutes, then adds dry CS 2(0.23g, 3mmol), continue stirring 30 minutes, finally add compound VI I-3 (0.40g, 3mmol), reaction mixture at room temperature stirs 5 hours, and TLC follows the tracks of and finds that reaction completes.Reaction mixture pours in 100mL 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 D-1, white solid.ESI-MS,m/z＝485([M+H] +)。
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
Reference compound D-1 135 171
Compound I-1 221 205
Compound I-2 193 174
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 halogenic substituent.
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 reacts with compound III under Louis acid catalysis, obtains compound IV; Compound IV is through BX 3process the methyl sloughed on methoxyl group, obtain VI; Compound VI by first in the presence of a base with CS 2reaction, obtains corresponding xanthogenate, the latter again with after the compound VI I that adds there is substitution reaction, obtain Compound I; Wherein, the definition of X=Br or Cl, R as arbitrary in claim 1-2 as described in.
4. the compound of Formula I that one of claim 1-2 defines is preparing the application in treatment diabetes B medicine.
CN201510355282.1A 2015-06-23 2015-06-23 Xanthate compound containing halothiophene and nitrobenzene hexamethylbenzene structure, preparation method and application Pending CN104945370A (en)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
JPS5330696A (en) * 1976-06-23 1978-03-23 Mitsui Toatsu Chem Inc Preparation of improved highly elastic urethane forms
CN1309126A (en) * 2000-11-09 2001-08-22 中国科学院兰州化学物理研究所 S-(2H-thien-2-yl) methyl alkylxanthogenate
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5330696A (en) * 1976-06-23 1978-03-23 Mitsui Toatsu Chem Inc Preparation of improved highly elastic urethane forms
CN1309126A (en) * 2000-11-09 2001-08-22 中国科学院兰州化学物理研究所 S-(2H-thien-2-yl) methyl alkylxanthogenate
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 (1)

* Cited by examiner, † Cited by third party
Title
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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