CN105037322A - Xanthate compounds containing hexamethylbenzene ring and alkoxyl benzene structures, as well as preparation methods and application thereof - Google Patents
Xanthate compounds containing hexamethylbenzene ring and alkoxyl benzene structures, as well as preparation methods and application thereof Download PDFInfo
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- CN105037322A CN105037322A CN201510355298.2A CN201510355298A CN105037322A CN 105037322 A CN105037322 A CN 105037322A CN 201510355298 A CN201510355298 A CN 201510355298A CN 105037322 A CN105037322 A CN 105037322A
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- hexamethylbenzene
- alkoxyl
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- 238000002360 preparation method Methods 0.000 title abstract description 8
- ZOOODBUHSVUZEM-UHFFFAOYSA-N ethoxymethanedithioic acid Chemical class CCOC(S)=S ZOOODBUHSVUZEM-UHFFFAOYSA-N 0.000 title abstract description 6
- YUWFEBAXEOLKSG-UHFFFAOYSA-N hexamethylbenzene Chemical group CC1=C(C)C(C)=C(C)C(C)=C1C YUWFEBAXEOLKSG-UHFFFAOYSA-N 0.000 title abstract 2
- 239000003814 drug Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 39
- 206010012601 diabetes mellitus Diseases 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 7
- -1 methoxyl group Chemical group 0.000 claims description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 3
- 238000007171 acid catalysis Methods 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 abstract description 16
- 101000783681 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 Proteins 0.000 abstract description 16
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000003213 activating effect Effects 0.000 abstract 4
- 239000003795 chemical substances by application Substances 0.000 abstract 4
- 239000002253 acid Substances 0.000 abstract 2
- 239000012991 xanthate Substances 0.000 abstract 2
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- MPLLLQUZNJSVTK-UHFFFAOYSA-N 5-[3-[4-[2-(4-fluorophenyl)ethoxy]phenyl]propyl]furan-2-carboxylic acid Chemical compound O1C(C(=O)O)=CC=C1CCCC(C=C1)=CC=C1OCCC1=CC=C(F)C=C1 MPLLLQUZNJSVTK-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 0 Cc1c(C)c(C)c(CC(C(O*)=C2)=CCC2OC)c(C)c1C Chemical compound Cc1c(C)c(C)c(CC(C(O*)=C2)=CCC2OC)c(C)c1C 0.000 description 5
- 229940123208 Biguanide Drugs 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 150000004283 biguanides Chemical class 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 208000006443 lactic acidosis Diseases 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000013016 damping Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 3
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 3
- 229960003243 phenformin Drugs 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 2
- 229950006790 adenosine phosphate Drugs 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- BEZDDPMMPIDMGJ-UHFFFAOYSA-N Cc1cc(C)c(C)c(C)c1C Chemical compound Cc1cc(C)c(C)c(C)c1C BEZDDPMMPIDMGJ-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 206010054805 Macroangiopathy Diseases 0.000 description 1
- GOOHAUXETOMSMM-GSVOUGTGSA-N R-propylene oxide Chemical compound C[C@@H]1CO1 GOOHAUXETOMSMM-GSVOUGTGSA-N 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- XSEUMFJMFFMCIU-UHFFFAOYSA-N buformin Chemical compound CCCC\N=C(/N)N=C(N)N XSEUMFJMFFMCIU-UHFFFAOYSA-N 0.000 description 1
- 229960004111 buformin Drugs 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001904 diabetogenic effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 102000057593 human F8 Human genes 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 229940047431 recombinate Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of medicines related to type 2 diabetes mellitus, in particular to xanthate AMPK activating agents containing hexamethylbenzene ring and alkoxyl benzene structures, preparation methods for the xanthate AMPK activating agents, and application of the xanthic acid AMPK activating agents to preparation of medicine for treating type 2 diabetes mellitus. The general formula of the xanthic acid AMPK activating agents is as shown in the description, wherein R is selected from halogen substituent groups.
Description
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 hexamethyl phenyl ring and alcoxyl benzene 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 the xanthate class AMPK activator that a class contains hexamethyl phenyl ring and alcoxyl benzene 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 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 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 (1.86g, 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＝299([M+H]
+)。
B. the synthesis of compound V-1
Compound IV-1 (1.79g, 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＝289([M+H]
+)。
The synthesis of C.VI-1
Compound V-1 (1.15g, 4mmol) be dissolved in 10mLTHF, 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＝343([M+H]
+)。
D. the synthesis of Compound I-1
Compound VI-1 (0.68g, 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 (0.40g, 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 I-1, white solid.ESI-MS,m/z＝515([M+H]
+)。
embodiment 2-3
With reference to embodiment 1 operation steps, 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 25mMTris/HCl damping fluid, pH7.5, Hepes damping fluid containing 100 μMs of ATP/50mM respectively at microwell plate, 25mMTris/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 |
| Compound I-1 | 175 | 167 |
| Compound I-2 | 159 | 151 |
| Compound I-3 | 113 | 128 |
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 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.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510355298.2A CN105037322A (en) | 2015-06-23 | 2015-06-23 | Xanthate compounds containing hexamethylbenzene ring and alkoxyl benzene structures, as well as preparation methods and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510355298.2A CN105037322A (en) | 2015-06-23 | 2015-06-23 | Xanthate compounds containing hexamethylbenzene ring and alkoxyl benzene structures, as well as preparation methods and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105037322A true CN105037322A (en) | 2015-11-11 |
Family
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|---|---|---|---|
| CN201510355298.2A Pending CN105037322A (en) | 2015-06-23 | 2015-06-23 | Xanthate compounds containing hexamethylbenzene ring and alkoxyl benzene structures, as well as preparation methods and application thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5330696B1 (en) * | 1970-11-10 | 1978-08-29 | ||
| US5621119A (en) * | 1994-07-22 | 1997-04-15 | Heraeus Kulzer Gmbh & Co., Kg | Di(meth)acrylates having cyclic carbonate groups |
| 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 |
| US20080306084A1 (en) * | 2007-04-30 | 2008-12-11 | Gruenenthal Gmbh | Substituted Amide Compounds |
| 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 |
-
2015
- 2015-06-23 CN CN201510355298.2A patent/CN105037322A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5330696B1 (en) * | 1970-11-10 | 1978-08-29 | ||
| US5621119A (en) * | 1994-07-22 | 1997-04-15 | Heraeus Kulzer Gmbh & Co., Kg | Di(meth)acrylates having cyclic carbonate groups |
| 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 |
| US20080306084A1 (en) * | 2007-04-30 | 2008-12-11 | Gruenenthal Gmbh | Substituted Amide Compounds |
| 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 |
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