CN104447746A - AMPK activating compound and its use - Google Patents

AMPK activating compound and its use Download PDF

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Publication number
CN104447746A
CN104447746A CN201310430034.XA CN201310430034A CN104447746A CN 104447746 A CN104447746 A CN 104447746A CN 201310430034 A CN201310430034 A CN 201310430034A CN 104447746 A CN104447746 A CN 104447746A
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Prior art keywords
purine
amido
base
methyl
hydroxyl
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CN201310430034.XA
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Inventor
邱壬乙
陈翰民
郭正宜
林俊材
黄纯芳
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HUAAN MEDICAL Co Ltd
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HUAAN MEDICAL Co Ltd
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Priority to CN202310449007.0A priority Critical patent/CN116492347A/en
Priority to CN201310430034.XA priority patent/CN104447746A/en
Priority to CN201810366456.8A priority patent/CN108703970A/en
Publication of CN104447746A publication Critical patent/CN104447746A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

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

Abstract

The invention relates to an AMPK activating compound and its use in the preparation of drugs for preventing or treating diseases or physiological states which can be improved by an AMPK activator and comprise pre-diabetes, insulin resistance, type II diabetes, X-syndromes, metabolism syndromes and obesity. The compound reduces the blood plasma glucose amount by above 30wt%, reduces the triglyceride amount by above 35wt% and reduces the body weight by above 15%.

Description

A kind of compound activating AMPK and uses thereof
Technical field
The present invention is about compound, espespecially one activates the compound of AMPK (AMP-activated protein kinase) and prevents or disease therapy in the disease can improved by AMPK activator for the preparation for the treatment of or physiological situation, comprises the purposes in the medicine of pre-diabetes, insulin resistant, Second-Type diabetes, X-syndrome, metabolic syndrome and obesity.
Background technology
AMPK is clearly the inductor block of cellular energy and the respondent of energy requirement.AMPK is that different triplet is made up of catalytic α sub-cell body, modulability β, γ sub-cell body, and all sub-cell bodies are tool height retention in eukaryote.AMPK activates by its upstream kinases as LKB1, calcium ion/take the plain protein phosphokinase (Ca relied on of calcium 2+/ Calmodulindependent kinase) and the 172nd Soviet Union's amino acid residue of TAK1 phosphorylation α sub-cell body tool retention, cause high AMP/ATP ratio also to activate AMPK by physiology or pathology pressure.Can promote that katabolism path is carried out and suppresses anabolism after AMPK activation, consume by reducing ATP and promote ATP to generate and then recover the energy balance of cell.
As a kind of energy metabolism balance attemperator, AMPK is considered to metabolic syndrome, comprises the medicine target of tool potentiality of Second-Type diabetes, cardiovascular disorder, fatty liver etc.Many metabolic syndromes are all relevant with insulin resistant.Insulin resistant is a pathological state, and cell cannot respond Regular Insulin in this situation, and therefore too much in blood glucose cannot remove to skeletal muscle or fatty tissue.In muscle cell, AMPK activation, in non-insulin-dependent mode, is increased the performance amount of glucose transport protein (GLUT4), and induces GLUT4 to be transferred on cytolemma to cause cellular uptake glucose speed to increase by transcriptional control.AMPK activation also suppresses the synthesis of lipid acid and cholesterol respectively by suppression acetyl-CoA carboxylase (acetyl-CoA carboxylase) and Hydroxymethylglutaryl list acyl coenzyme A reductase enzyme (HMG-CoA reductase).In addition, AMPK activation causes the suppression of multiple transcription factor, comprise Sterol regulatory element binding protein (SREBP-1c), carbohydrate response element binding protein transcription factor (ChREBP) and hepatocyte nuclear factor 4a (HNF-4a), the protein performance of ferment and the synthesis of the adjustment lipid acid that declines and gluconeogenesis effect are correlated with.The above-mentioned research mentioned finds, all supports that AMPK is as the treatment target of metabolic syndrome especially diabetes.
AMP is natural A MPK activator, but AMP is a unstable compound, and uses AMP in extracellular and can cause the message transmission (may cause apoptosis etc.) that purinoceptor (purinergic receptor) passes on.Therefore, many researchists are devoted to the exploitation of AMPK activator.5-aminoimidazole-4-carbozamide-1-β-D-RIBOSE the glycosides (AICAR) of current known high density and Mei Fuming (metformin) compound can activate the AMPK in organism.Wherein metformin has been used for the treatment of pre-diabetes, insulin resistant, X-syndrome, Second-Type diabetes.But this kind of AMPK activator has side effect and comprise lactic acidosis, especially when patient has the situation of renal insufficiency.Therefore in the urgent need to developing novelty and the AMPK activator of the lower effective concentration of tool and less side effect.
Summary of the invention
In view of this, the object of the present invention is to provide the compound of a kind of AMPK of activation and for the preparation for the treatment of the disease or physiological situation prevention or disease therapy that can be improved by AMPK activator, comprise the purposes in the medicine of pre-diabetes, Second-Type diabetes, X-syndrome, metabolic syndrome and obesity.
For achieving the above object, the invention provides formula (1) and formula (2) compound and tautomer thereof:
And pharmaceutically acceptable salt, wherein R2 represent hydrogen atom, halogen atom, hydroxyl, amido, amido band one or two the longest ten carbon substituting group, thiohydroxy, carboxyl, nitro, sulfo group, alkyl, alkylamino radical, alkane thiohydroxy, alkoxyl group, cycloalkyl, be substituted alkyl, be substituted thiazolinyl, be substituted alkynyl, acyl group, aryl, be substituted aryl, aryloxy; R6 represent hydroxyl, amido, thiohydroxy ,-NHR (monosubstituted amido) wherein R represent halogen atom, hydroxyl, amido, amido band one or two the longest ten carbon substituting group, thiohydroxy, carboxyl, nitro, sulfo group, alkyl, alkylamino radical, alkane thiohydroxy, alkoxyl group, cycloalkyl, be substituted alkyl, be substituted thiazolinyl, be substituted alkynyl, acyl group, aryl, be substituted aryl, aryloxy; R3 represents the alkyl of hydrogen atom or maximum ten carbon; Or its tautomer or its pharmaceutically acceptable salt, and an AMPK activator comprises described purine and pyrimidine and derivative or its pharmaceutically acceptable salt thereof using as an active compound.
General substituting group implication is identical with definition, wherein
Described hydroxyl represents hydroxy-OH;
Described halogen atom represents fluorine, chlorine, bromine, iodine;
Described amido represents-NH 2;
Described thiohydroxy represents-SH;
Described carboxyl represents-C (O) OR, and wherein R is defined as hydrogen atom, alkyl, is substituted alkyl, aryl, is substituted aryl herein;
Described nitro represents-NO 2;
Described sulfo group represents-SO 3r; Wherein R is defined as hydrogen atom, alkyl, is substituted alkyl herein;
Described Alkyl means straight or side chain at the most containing ten carbon atoms, wherein saturated or unsaturated group comprise methyl, propyl group, sec.-propyl, butyl, oxyethyl group, vinyl, ethynyl, proyl, 2-alkynes hexyl and other meet the group of definition;
Described be substituted alkyl represent alkyl comprise 1 to 7 substituting group as hydroxyl, thiohydroxy, alkylamino radical, alkane thiohydroxy, halogen atom, alkoxyl group, acyloxy, amido, carboxyl, sulfo group, acyl group and other, thus make these groups can be connected to the carbon of any moieties;
Described alkylamino radical represents-NRR', and wherein R and R' represents hydrogen atom, alkyl independently, is substituted alkyl, aryl, is substituted aryl as defined herein;
Described alkane thiohydroxy represents-SR, and wherein R refers to alkyl, is substituted alkyl, aryl, is substituted aryl as defined herein;
Described alkoxyl group represents-OR, and wherein R refers to alkyl, is substituted alkyl, aryl, is substituted aryl as defined herein;
Described cycloalkyl represents the single or multiple cyclisation alkyl containing 3-15 carbon atom;
Described acyl group represents-C (O) R, and wherein R refers to hydrogen atom, alkyl, is substituted alkyl, aryl, is substituted aryl as defined herein;
Described aryl represents aromatic series cyclisation carbon back;
The described aryl that is substituted represents that aryl contains substituting group and comprises halogen atom, hydroxyl, amido, thiohydroxy, alkoxyl group, sulfo group, carboxyl, alkyl as defined herein;
Described aryloxy represents-OAr, and wherein Ar refers to aryl, is substituted aryl as defined herein;
Therefore preferably AMPK activation base comprises: adenine, 2-amido-6-methylaminopurine, 2-amido-6-ethylamino-purine, 2-amido-6-isobutyl amine purine, 2-amido-6-Propylamino purine, 2-amido-6-isoamyl amido purine, 2-amido-6-hexylamine base purine, 2-amido-6-cyclopropyl amino purine, 2-amido-6-ring butylamine base purine, 2-amido-6-cyclopentamine base purine, 2-amido-6-cyclohexylamino purine, 2-amido-6-anilino-purine, 2-amido-6-(2-chloroanilino) purine, 2-amido-6-(3-chloroanilino) purine, 2-amido-6-(4-chloroanilino) purine, 2-amido-6-(2-bromobenzene amido) purine, 2-amido-6-(3-bromobenzene amido) purine, 2-amido-6-(4-bromobenzene amido) purine, 2-amido-6-(2-fluoroanilino) purine, 2-amido-6-(3-bromofluorobenzene amido) purine, 2-amido-6-(4-fluoroanilino) purine, 2-amido-6-benzene methanamine base purine, 2-amido-6-(2-methyl benzene methanamine base) purine, 2-amido-6-(3-methyl benzene methanamine base) purine, 2-amido-6-(4-methyl benzene methanamine base) purine, 2-amido-6-(2-Histol base) purine, 2-amido-6-(3-Histol base) purine, 2-amido-6-(4-Histol base) purine, 2-amido-6-(2-fluorobenzene methylamino) purine, 2-amido-6-(3-fluorobenzene methylamino) purine, 2-amido-6-(4-fluorobenzene methylamino) purine, 2-amido-6-(3-iodobenzene methylamino) purine, 2-amido-6-(4-Hydrobenzylamine base) purine, 2-amido-6-(2,3-dihydroxy benzenes methylamino) purine, 2-amido-6-(3,4-dihydroxy benzenes methylamino) purine, 2-amido-6-(2,4-dihydroxy benzenes methylamino) purine, 2-amido-6-(2-methoxybenzylamine base) purine, 2-amido-6-(2,3-dimethoxybenzylamine base) purine, 2-amido-6-(3,5-dimethoxybenzylamine base) purine, 2-amido-6-(2,4,5-trimethoxy-benzene methylamino) purine, 2-amido-6-(3,4,5-trimethoxy-benzene methylamino) purine, 6-methylaminopurine, 6-ethylamino-purine, 6-Propylamino purine, 6-isobutyl amine purine, 6-isoamyl amido purine, 6-hexylamine base purine, 6-cyclopropyl amino purine, 6-ring butylamine base purine, 6-cyclopentamine base purine, 6-cyclohexylamino purine, 6-anilino-purine, 6-(2-chloroanilino) purine, 6-(3-chloroanilino) purine, 6-(4-chloroanilino) purine, 6-(2-bromobenzene amido) purine, 6-(3-bromobenzene amido) purine, 6-(4-bromobenzene amido) purine, 6-(2-fluoroanilino) purine, 6-(3-fluoroanilino) purine, 6-(4-fluoroanilino) purine, 6-benzene methanamine base purine, 6-(2-methyl benzene methanamine base) purine, 6-(3-methyl benzene methanamine base) purine,6-(4-methyl benzene methanamine base) purine, 6-(2-Histol base) purine, 6-(3-Histol base) purine, 6-(4-Histol base) purine, 6-(2-fluorobenzene methylamino) purine, 6-(3-fluorobenzene methylamino) purine, 6-(4-fluorobenzene methylamino) purine, 6-(3-iodobenzene methylamino) purine, 6-(4-Hydrobenzylamine base) purine, 6-(2,3-dihydroxy benzenes methylamino) purine, 6-(3,4-dihydroxy benzenes methylamino) purine, 6-(2,4-dihydroxy benzenes methylamino) purine, 6-(2-methoxybenzylamine base) purine, 6-(2,3-dimethoxybenzylamine base) purine, 6-(3,5-dimethoxybenzylamine base) purine, 6-(2,4,5-trimethoxy-benzene methylamino) purine, 6-(3,4,5-trimethoxy-benzene methylamino) purine, 2-hydroxyl-6-methylaminopurine, 2-hydroxyl-6-ethylamino-purine, 2-hydroxyl-6-isobutyl amine purine, 2-hydroxyl-6-Propylamino purine, 2-hydroxyl-6-isoamyl amido purine, 2-hydroxyl-6-hexylamine base purine, 2-hydroxyl-6-cyclopropyl amino purine, 2-hydroxyl-6-ring butylamine base purine, 2-hydroxyl-6-cyclopentamine base purine, 2-hydroxyl-6-cyclohexylamino purine, 2-hydroxyl-6-anilino-purine, 2-hydroxyl-6-(2-chloroanilino) purine, 2-hydroxyl-6-(3-chloroanilino) purine, 2-hydroxyl-6-(4-chloroanilino) purine, 2-hydroxyl-6-(2-bromobenzene amido) purine, 2-hydroxyl-6-(3-bromobenzene amido) purine, 2-hydroxyl-6-(4-bromobenzene amido) purine, 2-hydroxyl-6-(2-fluoroanilino) purine, 2-hydroxyl-6-(3-bromofluorobenzene amido) purine, 2-hydroxyl-6-(4-fluoroanilino) purine, 2-hydroxyl-6-benzene methanamine base purine, 2-hydroxyl-6-(2-methyl benzene methanamine base) purine, 2-hydroxyl-6-(3-methyl benzene methanamine base) purine, 2-hydroxyl-6-(4-methyl benzene methanamine base) purine, 2-hydroxyl-6-(2-Histol base) purine, 2-hydroxyl-6-(3-Histol base) purine, 2-hydroxyl-6-(4-Histol base) purine, 2-hydroxyl-6-(2-fluorobenzene methylamino) purine, 2-hydroxyl-6-(3-fluorobenzene methylamino) purine, 2-hydroxyl-6-(4-fluorobenzene methylamino) purine, 2-hydroxyl-6-(3-iodobenzene methylamino) purine, 2-hydroxyl-6-(4-Hydrobenzylamine base) purine, 2-hydroxyl-6-(2,3-dihydroxy benzenes methylamino) purine, 2-hydroxyl-6-(3,4-dihydroxy benzenes methylamino) purine, 2-hydroxyl-6-(2,4-dihydroxy benzenes methylamino) purine, 2-hydroxyl-6-(2-methoxybenzylamine base) purine, 2-hydroxyl-6-(2,3-dimethoxybenzylamine base) purine, 2-hydroxyl-6-(3,5-dimethoxybenzylamine base) purine, 2-hydroxyl-6-(2,4,5-trimethoxy-benzene methylamino) purine,2-hydroxyl-6-(3,4,5-trimethoxy-benzene methylamino) purine, 2-methyl-6-methylaminopurine, 2-methyl-6-ethylamino-purine, 2-methyl-6-isobutyl amine purine, 2-methyl-6-Propylamino purine, 2-methyl-6-isoamyl amido purine, 2-methyl-6-hexylamine base purine, 2-methyl-6-cyclopropyl amino purine, 2-methyl-6-ring butylamine base purine, 2-methyl-6-cyclopentamine base purine, 2-methyl-6-cyclohexylamino purine, 2-methyl-6-anilino-purine, 2-methyl-6-(2-chloroanilino) purine, 2-methyl-6-(3-chloroanilino) purine, 2-methyl-6-(4-chloroanilino) purine, 2-methyl-6-(2-bromobenzene amido) purine, 2-methyl-6-(3-bromobenzene amido) purine, 2-methyl-6-(4-bromobenzene amido) purine, 2-methyl-6-(2-fluoroanilino) purine, 2-methyl-6-(3-bromofluorobenzene amido) purine, 2-methyl-6-(4-fluoroanilino) purine, 2-methyl-6-benzene methanamine base purine, 2-methyl-6-(2-methyl benzene methanamine base) purine, 2-methyl-6-(3-methyl benzene methanamine base) purine, 2-methyl-6-(4-methyl benzene methanamine base) purine, 2-methyl-6-(2-Histol base) purine, 2-methyl-6-(3-Histol base) purine, 2-methyl-6-(4-Histol base) purine, 2-methyl-6-(2-fluorobenzene methylamino) purine, 2-methyl-6-(3-fluorobenzene methylamino) purine, 2-methyl-6-(4-fluorobenzene methylamino) purine, 2-methyl-6-(3-iodobenzene methylamino) purine, 2-methyl-6-(4-Hydrobenzylamine base) purine, 2-methyl-6-(2,3-dihydroxy benzenes methylamino) purine, 2-methyl-6-(3,4-dihydroxy benzenes methylamino) purine, 2-methyl-6-(2,4-dihydroxy benzenes methylamino) purine, 2-methyl-6-(2-methoxybenzylamine base) purine, 2-methyl-6-(2,3-dimethoxybenzylamine base) purine, 2-methyl-6-(3,5-dimethoxybenzylamine base) purine, 2-methyl-6-(2,4,5-trimethoxy-benzene methylamino) purine, 2-methyl-6-(3,4,5-trimethoxy-benzene methylamino) purine, 2-methylamino-6-amido purine, 2-ethylamino--6-amido purine, 2-isobutyl amine-6-amido purine, 2-Propylamino-6-amido purine, 2-isoamyl amido-6-amido purine, 2-hexylamine base-6-amido purine, 2-cyclopropyl amino-6-amido purine, 2-ring butylamine base-6-amido purine, 2-cyclopentamine base-6-amido purine, 2-cyclohexylamino-6-amido purine, 2-anilino--6-amido purine, 2-(2-chloroanilino)-6-amido purine, 2-(3-chloroanilino)-6-amido purine, 2-(4-chloroanilino)-6-amido purine, 2-(2-fluoroanilino)-6-amido purine, 2-(3-fluoroanilino)-6-amido purine,2-(4-fluoroanilino)-6-amido purine, 2-(2-bromobenzene amido)-6-amido purine, 2-(3-bromobenzene amido)-6-amido purine, 2-(4-bromobenzene amido)-6-amido purine, 2-benzene methanamine base-6-amido purine, 2-(2-methyl benzene methanamine base)-6-amido purine, 2-(3-methyl benzene methanamine base)-6-amido purine, 2-(4-methyl benzene methanamine base)-6-amido purine, 2-(2-Histol base)-6-amido purine, 2-(3-Histol base)-6-amido purine, 2-(4-Histol base)-6-amido purine, 2-(2-fluorobenzene methylamino)-6-amido purine, 2-(3-fluorobenzene methylamino)-6-amido purine, 2-(4-fluorobenzene methylamino)-6-amido purine, 2-(3-iodobenzene methylamino)-6-amido purine, 2-(4-Hydrobenzylamine base)-6-amido purine, 2-(2,3-dihydroxy benzenes methylamino)-6-amido purine, 2-(2,4-dihydroxy benzenes methylamino)-6-amido purine, 2-(3,4-dihydroxy benzenes methylamino)-6-amido purine, 2-(2,3-dimethoxybenzylamine base)-6-amido purine, 2-(2,3-dimethoxybenzylamine base)-6-amido purine, 2-(3,5-dimethoxybenzylamine base)-6-amido purine, 2-(2,4,5-trimethoxy-benzene methylamino)-6-amido purine, 2-(3,4,5-trimethoxy-benzene methylamino)-6-amido purine, 2-methylamino-hypoxanthine, 2-ethylamino--hypoxanthine, 2-isobutyl amine-hypoxanthine, 2-Propylamino-hypoxanthine, 2-isoamyl amido-hypoxanthine, 2-hexylamine base-hypoxanthine, 2-cyclopropyl amino-hypoxanthine, 2-ring butylamine base-hypoxanthine, 2-cyclopentamine base-hypoxanthine, 2-cyclohexylamino-hypoxanthine, 2-anilino--hypoxanthine, 2-(2-chloroanilino)-hypoxanthine, 2-(3-chloroanilino)-hypoxanthine, 2-(4-chloroanilino)-hypoxanthine, 2-(2-fluoroanilino)-hypoxanthine, 2-(3-fluoroanilino)-hypoxanthine, 2-(4-fluoroanilino)-hypoxanthine, 2-(2-bromobenzene amido)-hypoxanthine, 2-(3-bromobenzene amido)-hypoxanthine, 2-(4-bromobenzene amido)-hypoxanthine, 2-benzene methanamine base-hypoxanthine, 2-(2-methyl benzene methanamine base)-hypoxanthine, 2-(3-methyl benzene methanamine base)-hypoxanthine, 2-(4-methyl benzene methanamine base)-hypoxanthine, 2-(2-Histol base)-hypoxanthine, 2-(3-Histol base)-hypoxanthine, 2-(4-Histol base)-hypoxanthine, 2-(2-fluorobenzene methylamino)-hypoxanthine, 2-(3-fluorobenzene methylamino)-hypoxanthine, 2-(4-fluorobenzene methylamino)-hypoxanthine,2-(3-iodobenzene methylamino)-hypoxanthine, 2-(4-Hydrobenzylamine base)-hypoxanthine, 2-(2, 3-dihydroxy benzenes methylamino)-hypoxanthine, 2-(2, 4-dihydroxy benzenes methylamino)-hypoxanthine, 2-(3, 4-dihydroxy benzenes methylamino)-hypoxanthine, 2-(2, 3-dimethoxybenzylamine base)-hypoxanthine, 2-(2, 3-dimethoxybenzylamine base)-hypoxanthine, 2-(3, 5-dimethoxybenzylamine base)-hypoxanthine, 2-(2, 4, 5-trimethoxy-benzene methylamino)-hypoxanthine, 2-(3, 4, 5-trimethoxy-benzene methylamino)-hypoxanthine, hypoxanthine, 6-sulfhydryl purine, N 6-methyl adenine, 2-amido adenine, 2-hydroxyadenine, 2-methyl adenine, 2-amido-hypoxanthine, 2,6-xanthine, 2-methyl-6 oxipurinol, 2-amido-6-sulfhydryl purine, 2-hydroxyl-6-sulfhydryl purine, 2-methyl-6-sulfhydryl purine, 2-sulfhydryl adenine, 2-sulfhydryl-hypoxanthine, 2,6-sulfuryl purine, 2-sulfhydryl-6-methyl purine, 2-sulfhydryl-6-ethyl purine, 2-sulfhydryl-6-propyl group purine, 2-ethyl adenine, 2-ethyl-hypoxanthine, 2-ethyl-6-sulfhydryl purine, 2-ethyl-6-methylaminopurine, 2-ethyl-6-ethylamino-purine, 2-ethyl-6-Propylamino purine, 2-propyl group adenine, 2-propyl group-hypoxanthine, 2-propyl group-6-sulfhydryl purine, 2-propyl group-6-methylaminopurine, 2-propyl group-6-ethylamino-purine, 2-propyl group-6-Propylamino purine, 2-amido-6-benzene methanamine base purine, 2-ethyl-6-benzene methanamine base purine, 2-propyl group-6-benzene methanamine base purine, 2-ethyl-6-anilino-purine, 2-propyl group-6-anilino-purine, 2-benzyl adenine, 2-benzyl-hypoxanthine, 2-benzyl-6-sulfhydryl purine, 2-benzyl-6-methylaminopurine, 2-benzyl-6-ethylamino-purine, 2-benzyl-6-Propylamino purine, 2-phenyl adenine, 2-phenyl-hypoxanthine, 2-phenyl-6-sulfhydryl purine, 2-phenyl-6-methylaminopurine, 2-phenyl-6-ethylamino-purine, 2-phenyl-6-Propylamino purine, 2-sulfhydryl-N 6-2-isopentenyl gland purine, 2-ethyl-N 6-2-isopentenyl gland purine, 2-propyl group-N 6-2-isopentenyl gland purine, 2-benzyl-N 6-2-isopentenyl gland purine,2-phenyl-N 6-2-isopentenyl gland purine, 2-chloroadenine, the chloro-hypoxanthine of 2-, 2-chloro-6-sulfhydryl purine, 2-chloro-6-methylaminopurine, 2-chloro-6-ethylamino-purine, 2-chloro-6-Propylamino purine, 2-chloro-6-benzene methanamine base purine, 2-chloro-6-anilino-purine, the chloro-N of 2- 6-2-isopentenyl gland purine, 2-fluoroadenine, the fluoro-hypoxanthine of 2-, 2-fluoro-6-sulfhydryl purine, 2-fluoro-6-methylaminopurine, 2-fluoro-6-ethylamino-purine, 2-fluoro-6-Propylamino purine, 2-fluoro-6-benzene methanamine base purine, 2-fluoro-6-anilino-purine, the fluoro-N of 2- 6-2-isopentenyl gland purine, 2-bromine adenine, the bromo-hypoxanthine of 2-, 2-bromo-6-sulfhydryl purine, 2-bromo-6-methylaminopurine, 2-bromo-6-ethylamino-purine, 2-bromo-6-Propylamino purine, 2-bromo-6-benzene methanamine base purine, 2-bromo-6-anilino-purine, the bromo-N of 2- 6-2-isopentenyl gland purine, 2-iodine adenine, the iodo-hypoxanthine of 2-, 2-iodo-6-sulfhydryl purine, 2-iodo-6-methylaminopurine, 2-iodo-6-ethylamino-purine, 2-iodo-6-Propylamino purine, 2-iodo-6-benzene methanamine base purine, 2-iodo-6-anilino-purine, the iodo-N of 2- 6-2-isopentenyl gland purine, 2-sulfhydryl-N 6-cyclohexyl adenine, 2-propyl group-N 6-cyclohexyl adenine, 2-ethyl-N 6-cyclohexyl adenine, 2-benzyl-N 6-cyclohexyl adenine, 2-phenyl-N 6The chloro-N of-cyclohexyl adenine, 2- 6The fluoro-N of-cyclohexyl adenine, 2- 6The bromo-N of-cyclohexyl adenine, 2- 6The iodo-N of-cyclohexyl adenine, 2- 6-cyclohexyl adenine, 2-amido-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-hydroxyl-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine,2-sulfhydryl-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-methyl-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-ethyl-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-propyl group-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-benzyl-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-phenyl-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-chloro-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, the fluoro-6-of 2-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, the bromo-6-of 2-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, the iodo-6-of 2-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-cyclohexyl-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-amido-6-furfuryl alcohol amido purine, 2-hydroxyl-6-furfuryl alcohol amido purine, 2-sulfhydryl-6-furfuryl alcohol amido purine, 2-methyl-6-furfuryl alcohol amido purine, 2-ethyl-6-furfuryl alcohol amido purine, 2-propyl group-6-furfuryl alcohol amido purine, 2-benzyl-6-furfuryl alcohol amido purine, 2-phenyl-6-furfuryl alcohol amido purine, 2-chloro-6-furfuryl alcohol amido purine, 2-fluoro-6-furfuryl alcohol amido purine, 2-bromo-6-furfuryl alcohol amido purine, 2-iodo-6-furfuryl alcohol amido purine, 2-cyclohexyl-6-furfuryl alcohol amido purine, 2-amido-6-acetamido purine, 2-hydroxyl-6-acetamido purine, 2-sulfhydryl-6-acetamido purine, 2-methyl-6-acetamido purine, 2-ethyl-6-acetamido purine, 2-propyl group-6-acetamido purine, 2-benzyl-6-acetamido purine, 2-phenyl-6-acetamido purine, the chloro-6-acetamido purine of 2-, the bromo-6-acetamido purine of 2-, the iodo-6-acetamido purine of 2-, 2-cyclohexyl-6-acetamido purine, 2-dimethyl amido-hypoxanthine, Guanine, xanthine, hypoxanthine, 6-sulfydryl Guanine, 5-methylcytosine, 5,6-dihydro urinates close pyridine, thymidine, cytimidine, urinate close pyridine, 5 FU 5 fluorouracil, floxuridine, wherein each can be used as salt to 6-azauracil, hydrate, as precursor medicine, or the form as a kind of metabolin exists.
Further, its Chinese style (1) compound is AMPK activator.
Further, its Chinese style (2) compound is AMPK activator.
The present invention also provides the compound of a kind of AMPK of activation for the preparation of the purposes for the treatment of in the medicine of the disease that can be improved by AMPK activator or physiological situation, the compound of wherein said activation AMPK is the compound of at least one effective dose, it is selected from claim 1 or 2 and/or its acceptable salt pharmaceutically and in trophology, the Mammals treated to need this.
The present invention also provides the compound of a kind of AMPK of activation being selected from by the physiological situation of the following group formed or disease for the preparation of prevention or treatment: the purposes in the medicine of pre-diabetes, insulin resistant, Second-Type diabetes, X-syndrome, metabolic syndrome, the compound of wherein said activation AMPK is the compound of at least one effective dose, it is selected from formula (1) compound and/or its acceptable salt pharmaceutically and in trophology, the Mammals treated to need this, thus increase grape cell sugar.
The present invention also provides the compound of a kind of AMPK of activation being selected from by the physiological situation of the following group formed or disease for the preparation of prevention or treatment: the purposes in the medicine of pre-diabetes, insulin resistant, Second-Type diabetes, X-syndrome, metabolic syndrome, wherein said compound is the compound of at least one effective dose, it is selected from formula (2) compound and/or its acceptable salt pharmaceutically and in trophology, the Mammals treated to need this, thus increase grape cell sugar.
The present invention also provides a kind of purposes of compound in the medicine for the preparation of prevention or treatment obesity activating AMPK, the compound of wherein said activation AMPK is the compound of at least one effective dose, it is selected from formula (1) compound and/or its acceptable salt pharmaceutically and in trophology, the Mammals treated to need this, thus reduce mammiferous blood plasma triglyceride and reduce body weight.
The present invention also provides a kind of purposes of compound in the medicine for the preparation of prevention or treatment obesity activating AMPK, the compound of wherein said activation AMPK is the compound of at least one effective dose, it is selected from formula (2) compound and/or its acceptable salt pharmaceutically and in trophology, the Mammals treated to need this, thus reduce mammiferous blood plasma triglyceride and reduce body weight.
Invention further provides a medicine, this pharmaceutical pack combines with pharmaceutically suitable carrier containing formula (1) compound of effective dose.
Invention further provides a medicine, this pharmaceutical pack combines with pharmaceutically suitable carrier containing formula (2) compound of effective dose.
The present invention can contain the second medicine for the medicine for the treatment of pre-diabetes, insulin resistant, Second-Type diabetes, X-syndrome, metabolic syndrome.Suitable the second medicament comprises various biguanides, thiazolidinedione, Thienopyridinone and other AMPK activator.
As described herein, the present invention includes and the formula (1) of pharmaceutical effective dose and any compound of formula (2) and its salt and prodrug are used to mammals.More suitably, the present invention also comprises the mankind needing to treat any disease as herein described to the mankind especially preference, uses the formula (1) of pharmaceutical effective dose and any compound of formula (2).
Term used herein " AMPK " refers to AMP activated protein kinase.
Term used herein " pre-diabetes " refers to a physiological situation, it is characterized by fasting plasma glucose higher than 100 milligrams/deciliter but lower than 140 milligrams/deciliter.
Term used herein " insulin resistant " refers to a physiological situation, and wherein whole body or tissue comprise liver, skeletal muscle, fatty tissue cannot to insulin response.
Term used herein " Second-Type diabetes " also refers to non insulin dependent diabetes or Adult Onset's patients with type Ⅰ DM; Refer to the insulin production deficiency that Metabolic disorder causes or insulin resistant, its feature is generally fasting plasma glucose higher than 140 milligrams/deciliter.
Term used herein " X-syndrome " refers to a physiological situation, and its feature has less than two symptoms at least: hyperglycemia (non insulin dependent diabetes), hypertension, high triglyceride, low hdl cholesterol.
Compound provided by the present invention can reduce plasma glucose amount and be greater than 30wt%, reduces triglyceride amount and is greater than 35wt%, and reduce body weight more than 15%.
Embodiment
Embodiment 1
2-amido-6-(3-Histol base) purine
After 4 mmole 2-amido-6-chloropurines are dissolved in the butanols of 20 milliliters, add the 3-Histol of 5 mmoles and the triethylamine of 6 mmoles.Mixture was in 90 DEG C of reactions 4 hours.After cooling, filter after obtaining product and clean with water and butanols and obtain crystallization from dimethyl formamide or ethanol.HPLC: purity is greater than 98%.Productive rate 95%, the results are shown in Table 1.
The compound that table 1 manufactures with embodiment 1 method
Embodiment 2
6-(3-Histol base) purine
After 4 mmole 6-chloropurines are dissolved in the butanols of 20 milliliters, add the 3-Histol of 5 mmoles and the triethylamine of 6 mmoles.Mixture was in 90 DEG C of reactions 4 hours.After cooling, filter after obtaining product and clean with water and butanols and obtain crystallization from dimethyl formamide or ethanol.HPLC: purity is greater than 97%.Productive rate 94%, the results are shown in Table 2.
The compound that table 2 manufactures with embodiment 2 method
Embodiment 3
2-hydroxyl-6-chloropurine
After 4 mmole 2-amido-6-chloropurines are dissolved in 35 milliliters of 50wt% sulfuric acid, add the SODIUMNITRATE of 5 mmoles.Mixture reacts 1 hour in 50 DEG C after 2 hours in-10 DEG C of reactions again.After cooling, filter after obtaining product and clean with water and butanols and obtain crystallization from dimethyl formamide or ethanol.HPLC: purity is greater than 98%.Productive rate 86%.MS (ESI) m/e170.88 (M+H +); 1H NMR (DMSO-d6): 8.01 (s, 1H ,=CH-N), 13.26 (s, 2H, OH and NH).
Embodiment 4
2-hydroxyl-6-(3-Histol base) purine
After 3 mmole 2-hydroxyl-6-chloropurines from embodiment 3 gained are dissolved in the butanols of 20 milliliters, add the 3-Histol of 4 mmoles and the triethylamine of 6 mmoles.Mixture was in 90 DEG C of reactions 4 hours.After cooling, filter after obtaining product and clean with water and butanols and obtain crystallization from dimethyl formamide or ethanol.HPLC: purity is greater than 97%.Productive rate 93%, the results are shown in Table 3.
The compound that table 3 manufactures with embodiment 4 method
Embodiment 5
2-methyl-6-chloropurine
After the iodo-6-chloropurine of 3 mmole 2-is dissolved in 20 milliliters of butanols, add the methyl chloride manganese of 4 mmoles.Mixture reacts 24 hours in 80 DEG C under palladium chtalyst.After cooling, filter after obtaining product and clean with water and butanols and obtain crystallization from dimethyl formamide or ethanol.HPLC: purity is greater than 97%.Productive rate 91%.
Embodiment 6
2-methyl-6-(3-Histol base) purine
After 3 mmole 2-methyl-6-chloropurines from embodiment 5 gained are dissolved in the butanols of 20 milliliters, add the 3-Histol of 4 mmoles and the triethylamine of 6 mmoles.Mixture was in 90 DEG C of reactions 4 hours.After cooling, filter after obtaining product and clean with water and butanols and obtain crystallization from dimethyl formamide or ethanol.HPLC: purity is greater than 98%.Productive rate 93%, the results are shown in Table 4.
The compound that table 4 manufactures with embodiment 6 method
Embodiment 7
2-(3-Histol base)-6-amido purine
After 4 mmole 2-chloro-6-amido purine is dissolved in the butanols of 20 milliliters, add the 3-Histol of 5 mmoles and the triethylamine of 6 mmoles.Mixture was in 90 DEG C of reactions 4 hours.After cooling, filter after obtaining product and clean with water and butanols and obtain crystallization from dimethyl formamide or ethanol.HPLC: purity is greater than 95%.Productive rate 92%, the results are shown in Table 5.
The compound that table 5 manufactures with embodiment 7 method
Embodiment 8
2-(3-Histol base)-hypoxanthine
After the chloro-hypoxanthine of 4 mmole 2-is dissolved in the butanols of 20 milliliters, add the 3-Histol of 5 mmoles and the triethylamine of 6 mmoles.Mixture was in 90 DEG C of reactions 4 hours.After cooling, filter after obtaining product and clean with water and butanols and obtain crystallization from dimethyl formamide or ethanol.HPLC: purity is greater than 91%.Productive rate 88%, the results are shown in Table 6.
The compound that table 6 manufactures with embodiment 8 method
AMPK activation analysis
In mouse muscle cell C 2c1 2, mouse fibrocyte 3T3-L1 and human hepatocarcinoma cells Hep G2 carries out the analysis of target compound to AMPK activating influence.Cell contains 10wt% foetal calf serum (FBS) with high glucose DMEM cell culture fluid, 4mM is left-handed-bran vinegar amino acid (L-glutamine), 2mM Sodium.alpha.-ketopropionate (sodium pyruvate) and 1wt% penicillin/streptomycin (penicillin/streptomycin) (the rich Life Science of Lay, Invitrogen) are in 37 DEG C, 5% (v/v) CO 2cultivate under environment.3 × 10 5cell is inoculated in 6-well dish, with appointed compound process cell 30 minutes after 24 hours, and then dissolved cell analyzing with Western blot.Equal protein matter is separated with SDS-PAGE, is then transferred to polyvinylidene fluoride film.Polyvinylidene fluoride film after transfer printing is dipped to the 3wt% bovine serum albumin after 60 minutes being dissolved in PBS damping fluid; add anti-phosphorylation AMPK (Thr172) antibody (1:2000 (v/v) respectively; cell science and technology Cellsignaling); anti-AMPK antibody (1:2000 (v/v); cell science and technology Cell signaling); anti-glucose transport protein-4 antibody (1:1000, Mi Libo Millipore) or anti-a-Actin antibody (1:5000 (v/v); Merck) in 4 DEG C of effects.Add corresponding two after 16 hours to resist and react 1 hour under room temperature.Tool immune response belt is detected by matter with cold light, and with egative film record signal.Analyze with image analysing computer quantitation software (TotalLab Quant) after the signal scanning of gained.
Various compound is added up in table 7 impact that AMPK activates.The compound of major part test all significantly activates mouse muscle cell C 2c1 2, AMPK in mouse fibrocyte 3T3-L1 and human hepatocarcinoma cells Hep G2 cell.
Table 7
Glucose uptake-in vitro analysis
Use fluorescent glucose analogue (2-NBDG, Molecular Probes) in muscle cell C 2c1 2analyze representative compound to the impact of glucose uptake.C 2c1 2cell adds 500 μMs of fluorescent glucose analogues after processing 30 minutes with selected new A MPK activator at 37 DEG C, and cultivate after 5 minutes under room temperature, cell cleans three times with phosphate buffer soln, and fixes with 70% (v/v) ethanol.The fluorescence of glucose inside cells analogue is detected with fluorophotometer.
The impact of the selected compounds on glucose picked-up of part is added up in table 8.The compound of major part test all significantly promotes C 2c1 2the glucose uptake of cell.Data are expressed as the mean+SD of three independent experiments.
Table 8
Organism build-in test
In order to assess the impact that representational compound regulates plasma glucose levels further, feeding mouse using high fat diet and testing as Second-Type diabetes animal model.C57BL/6J Mouse feeder in 22 DEG C, 12 little time/circulation at night feed high fat diet (60% kilocalorie of % fat) or chow diet in not dietary restriction mode.The selected compound of 0.1-50 mg/kg awards mouse in 24 week age in abdominal injection mode, 1 and 3 hour measuring blood value after injection.Abdominal injection high fat diet is fed mouse one day twice and is continued 6 days, and last dispensing, after 1 hour, is collected blood plasma and measures plasma glucose and triglyceride content.
Compared with feeding mouse with the high fat diet of injection normal saline solution, find that selected compound reduces plasma glucose amount and is greater than 30wt%, reduce triglyceride amount and be greater than 35wt%, and reduce body weight more than 15%.
The above, be only preferred embodiment of the present invention, and be not used to limit scope of patent protection of the present invention, other equivalence change of using patent of the present invention spirit to do, and all should in like manner belong to scope of patent protection of the present invention.

Claims (9)

1. one kind activates the compound of AMPK, it is characterized in that, the compound of described activation AMPK is formula (1) compound of at least one effective dose and/or its acceptable salt pharmaceutically or in nutrition, the Mammals treated to need this, wherein said formula (1) compound is defined as follows:
(1)
Wherein, R2 represents hydrogen atom, halogen atom, hydroxyl, amido, alkyl or-NHR (monosubstituted amido); Wherein R represents alkyl, cycloalkyl, phenyl, is substituted phenyl, phenmethyl, is substituted phenmethyl,
Wherein:
The described phenyl that is substituted represents the phenyl comprising 1 to 5 hydroxyl and alkoxyl group, 1 to 5 hydroxyl and halogen atom base, 1 to 5 hydroxyl and alkyl containing substituting group;
The described phenmethyl that is substituted represents the phenmethyl comprising 1 to 5 hydroxyl and alkoxyl group, 1 to 5 hydroxyl and halogen atom base, 1 to 5 hydroxyl and alkyl containing substituting group;
Wherein R6 represents hydroxyl, amido, thiohydroxy or-NHR (monosubstituted amido); Wherein R represents alkyl, cycloalkyl, phenyl, is substituted phenyl, phenmethyl, is substituted phenmethyl,
Wherein
The described phenyl that is substituted represents the phenyl comprising 1 to 5 hydroxyl and alkoxyl group, 1 to 5 hydroxyl and halogen atom base, 1 to 5 hydroxyl and alkyl containing substituting group;
The described phenmethyl that is substituted represents the phenmethyl comprising 1 to 5 hydroxyl and alkoxyl group, 1 to 5 hydroxyl and halogen atom base, 1 to 5 hydroxyl and alkyl containing substituting group;
General substituting group implication is identical with definition, wherein
Described hydroxyl represents hydroxy-OH;
Described halogen atom represents fluorine, chlorine, bromine, iodine;
Described amido represents-NH 2;
Described sulfenyl represents-SH;
Described Alkyl means straight or side chain are at the most containing the saturated group of six carbon atom;
Described alkoxyl group represents-OR, and wherein R is alkyl;
Described cycloalkyl represents the single or multiple cyclisation alkyl containing 3-6 carbon atom;
And tautomer, racemic modification, optical isomer or its acceptable salt pharmaceutically or in nutrition, comprise pharmaceutical carrier.
2. one kind activates the compound of AMPK, it is characterized in that, the compound of described activation AMPK is formula (2) compound of at least one effective dose and/or its acceptable salt pharmaceutically or in trophology, the Mammals treated to need this, wherein said formula (2) compound is defined as follows:
(2)
Wherein R6 represents hydroxyl, amido,
Wherein R3 represents hydrogen atom, hydroxyl, halogen atom and methyl,
Wherein R2 represents hydrogen atom and hydroxyl,
General substituting group implication is identical with definition, wherein
Described hydroxyl represents hydroxy-OH;
Described halogen atom represents fluorine, chlorine, bromine, iodine;
And tautomer, racemic modification, optical isomer or its acceptable salt pharmaceutically or in trophology, comprise pharmaceutical carrier.
3. activate the compound of AMPK as claimed in claim 1, it is characterised in that, the compound of described activation AMPK is selected from by the following group formed: adenine, 2-amido-6-ethylamino-purine, 2-amido-6-isobutyl amine purine, 2-amido-6-Propylamino purine, 2-amido-6-isoamyl amido purine, 2-amido-6-hexylamine base purine, 2-amido-6-cyclopropyl amino purine, 2-amido-6-ring butylamine base purine, 2-amido-6-cyclopentamine base purine, 2-amido-6-cyclohexylamino purine, 2-amido-6-anilino-purine, 2-amido-6-(2-chloroanilino) purine, 2-amido-6-(3-chloroanilino) purine, 2-amido-6-(4-chloroanilino) purine, 2-amido-6-(2-bromobenzene amido) purine, 2-amido-6-(3-bromobenzene amido) purine, 2-amido-6-(4-bromobenzene amido) purine, 2-amido-6-(2-fluoroanilino) purine, 2-amido-6-(3-bromofluorobenzene amido) purine, 2-amido-6-(4-fluoroanilino) purine, 2-amido-6-benzene methanamine base purine, 2-amido-6-(2-methyl benzene methanamine base) purine, 2-amido-6-(3-methyl benzene methanamine base) purine, 2-amido-6-(4-methyl benzene methanamine base) purine, 2-amido-6-(2-Histol base) purine, 2-amido-6-(3-Histol base) purine, 2-amido-6-(4-Histol base) purine, 2-amido-6-(2-fluorobenzene methylamino) purine, 2-amido-6-(3-fluorobenzene methylamino) purine, 2-amido-6-(4-fluorobenzene methylamino) purine, 2-amido-6-(3-iodobenzene methylamino) purine, 2-amido-6-(4-Hydrobenzylamine base) purine, 2-amido-6-(2,3-dihydroxy benzenes methylamino) purine, 2-amido-6-(3,4-dihydroxy benzenes methylamino) purine, 2-amido-6-(2,4-dihydroxy benzenes methylamino) purine, 2-amido-6-(2-methoxybenzylamine base) purine, 2-amido-6-(2,3-dimethoxybenzylamine base) purine, 2-amido-6-(3,5-dimethoxybenzylamine base) purine, 2-amido-6-(2,4,5-trimethoxy-benzene methylamino) purine, 2-amido-6-(3,4,5-trimethoxy-benzene methylamino) purine, 6-methylaminopurine, 6-ethylamino-purine, 6-Propylamino purine, 6-isobutyl amine purine, 6-isoamyl amido purine, 6-hexylamine base purine, 6-cyclopropyl amino purine, 6-ring butylamine base purine, 6-cyclopentamine base purine, 6-cyclohexylamino purine, 6-anilino-purine, 6-(2-chloroanilino) purine, 6-(3-chloroanilino) purine, 6-(4-chloroanilino) purine, 6-(2-bromobenzene amido) purine, 6-(3-bromobenzene amido) purine, 6-(4-bromobenzene amido) purine, 6-(2-fluoroanilino) purine, 6-(3-fluoroanilino) purine, 6-(4-fluoroanilino) purine, 6-benzene methanamine base purine,6-(2-methyl benzene methanamine base) purine, 6-(3-methyl benzene methanamine base) purine, 6-(4-methyl benzene methanamine base) purine, 6-(2-Histol base) purine, 6-(3-Histol base) purine, 6-(4-Histol base) purine, 6-(2-fluorobenzene methylamino) purine, 6-(3-fluorobenzene methylamino) purine, 6-(4-fluorobenzene methylamino) purine, 6-(3-iodobenzene methylamino) purine, 6-(4-Hydrobenzylamine base) purine, 6-(2,3-dihydroxy benzenes methylamino) purine, 6-(3,4-dihydroxy benzenes methylamino) purine, 6-(2,4-dihydroxy benzenes methylamino) purine, 6-(2-methoxybenzylamine base) purine, 6-(2,3-dimethoxybenzylamine base) purine, 6-(3,5-dimethoxybenzylamine base) purine, 6-(2,4,5-trimethoxy-benzene methylamino) purine, 6-(3,4,5-trimethoxy-benzene methylamino) purine, 2-hydroxyl-6-methylaminopurine, 2-hydroxyl-6-ethylamino-purine, 2-hydroxyl-6-isobutyl amine purine, 2-hydroxyl-6-Propylamino purine, 2-hydroxyl-6-isoamyl amido purine, 2-hydroxyl-6-hexylamine base purine, 2-hydroxyl-6-cyclopropyl amino purine, 2-hydroxyl-6-ring butylamine base purine, 2-hydroxyl-6-cyclopentamine base purine, 2-hydroxyl-6-cyclohexylamino purine, 2-hydroxyl-6-anilino-purine, 2-hydroxyl-6-(2-chloroanilino) purine, 2-hydroxyl-6-(3-chloroanilino) purine, 2-hydroxyl-6-(4-chloroanilino) purine, 2-hydroxyl-6-(2-bromobenzene amido) purine, 2-hydroxyl-6-(3-bromobenzene amido) purine, 2-hydroxyl-6-(4-bromobenzene amido) purine, 2-hydroxyl-6-(2-fluoroanilino) purine, 2-hydroxyl-6-(3-bromofluorobenzene amido) purine, 2-hydroxyl-6-(4-fluoroanilino) purine, 2-hydroxyl-6-benzene methanamine base purine, 2-hydroxyl-6-(2-methyl benzene methanamine base) purine, 2-hydroxyl-6-(3-methyl benzene methanamine base) purine, 2-hydroxyl-6-(4-methyl benzene methanamine base) purine, 2-hydroxyl-6-(2-Histol base) purine, 2-hydroxyl-6-(3-Histol base) purine, 2-hydroxyl-6-(4-Histol base) purine, 2-hydroxyl-6-(2-fluorobenzene methylamino) purine, 2-hydroxyl-6-(3-fluorobenzene methylamino) purine, 2-hydroxyl-6-(4-fluorobenzene methylamino) purine, 2-hydroxyl-6-(3-iodobenzene methylamino) purine, 2-hydroxyl-6-(4-Hydrobenzylamine base) purine, 2-hydroxyl-6-(2,3-dihydroxy benzenes methylamino) purine, 2-hydroxyl-6-(3,4-dihydroxy benzenes methylamino) purine, 2-hydroxyl-6-(2,4-dihydroxy benzenes methylamino) purine, 2-hydroxyl-6-(2-methoxybenzylamine base) purine, 2-hydroxyl-6-(2,3-dimethoxybenzylamine base) purine, 2-hydroxyl-6-(3,5-dimethoxybenzylamine base) purine,2-hydroxyl-6-(2,4,5-trimethoxy-benzene methylamino) purine, 2-hydroxyl-6-(3,4,5-trimethoxy-benzene methylamino) purine, 2-methyl-6-methylaminopurine, 2-methyl-6-ethylamino-purine, 2-methyl-6-isobutyl amine purine, 2-methyl-6-Propylamino purine, 2-methyl-6-isoamyl amido purine, 2-methyl-6-hexylamine base purine, 2-methyl-6-cyclopropyl amino purine, 2-methyl-6-ring butylamine base purine, 2-methyl-6-cyclopentamine base purine, 2-methyl-6-cyclohexylamino purine, 2-methyl-6-anilino-purine, 2-methyl-6-(2-chloroanilino) purine, 2-methyl-6-(3-chloroanilino) purine, 2-methyl-6-(4-chloroanilino) purine, 2-methyl-6-(2-bromobenzene amido) purine, 2-methyl-6-(3-bromobenzene amido) purine, 2-methyl-6-(4-bromobenzene amido) purine, 2-methyl-6-(2-fluoroanilino) purine, 2-methyl-6-(3-bromofluorobenzene amido) purine, 2-methyl-6-(4-fluoroanilino) purine, 2-methyl-6-benzene methanamine base purine, 2-methyl-6-(2-methyl benzene methanamine base) purine, 2-methyl-6-(3-methyl benzene methanamine base) purine, 2-methyl-6-(4-methyl benzene methanamine base) purine, 2-methyl-6-(2-Histol base) purine, 2-methyl-6-(3-Histol base) purine, 2-methyl-6-(4-Histol base) purine, 2-methyl-6-(2-fluorobenzene methylamino) purine, 2-methyl-6-(3-fluorobenzene methylamino) purine, 2-methyl-6-(4-fluorobenzene methylamino) purine, 2-methyl-6-(3-iodobenzene methylamino) purine, 2-methyl-6-(4-Hydrobenzylamine base) purine, 2-methyl-6-(2,3-dihydroxy benzenes methylamino) purine, 2-methyl-6-(3,4-dihydroxy benzenes methylamino) purine, 2-methyl-6-(2,4-dihydroxy benzenes methylamino) purine, 2-methyl-6-(2-methoxybenzylamine base) purine, 2-methyl-6-(2,3-dimethoxybenzylamine base) purine, 2-methyl-6-(3,5-dimethoxybenzylamine base) purine, 2-methyl-6-(2,4,5-trimethoxy-benzene methylamino) purine, 2-methyl-6-(3,4,5-trimethoxy-benzene methylamino) purine, 2-methylamino-6-amido purine, 2-ethylamino--6-amido purine, 2-isobutyl amine-6-amido purine, 2-Propylamino-6-amido purine, 2-isoamyl amido-6-amido purine, 2-hexylamine base-6-amido purine, 2-cyclopropyl amino-6-amido purine, 2-ring butylamine base-6-amido purine, 2-cyclopentamine base-6-amido purine, 2-cyclohexylamino-6-amido purine, 2-anilino--6-amido purine, 2-(2-chloroanilino)-6-amido purine, 2-(3-chloroanilino)-6-amido purine, 2-(4-chloroanilino)-6-amido purine,2-(2-fluoroanilino)-6-amido purine, 2-(3-fluoroanilino)-6-amido purine, 2-(4-fluoroanilino)-6-amido purine, 2-(2-bromobenzene amido)-6-amido purine, 2-(3-bromobenzene amido)-6-amido purine, 2-(4-bromobenzene amido)-6-amido purine, 2-benzene methanamine base-6-amido purine, 2-(2-methyl benzene methanamine base)-6-amido purine, 2-(3-methyl benzene methanamine base)-6-amido purine, 2-(4-methyl benzene methanamine base)-6-amido purine, 2-(2-Histol base)-6-amido purine, 2-(3-Histol base)-6-amido purine, 2-(4-Histol base)-6-amido purine, 2-(2-fluorobenzene methylamino)-6-amido purine, 2-(3-fluorobenzene methylamino)-6-amido purine, 2-(4-fluorobenzene methylamino)-6-amido purine, 2-(3-iodobenzene methylamino)-6-amido purine, 2-(4-Hydrobenzylamine base)-6-amido purine, 2-(2,3-dihydroxy benzenes methylamino)-6-amido purine, 2-(2,4-dihydroxy benzenes methylamino)-6-amido purine, 2-(3,4-dihydroxy benzenes methylamino)-6-amido purine, 2-(2,3-dimethoxybenzylamine base)-6-amido purine, 2-(2,3-dimethoxybenzylamine base)-6-amido purine, 2-(3,5-dimethoxybenzylamine base)-6-amido purine, 2-(2,4,5-trimethoxy-benzene methylamino)-6-amido purine, 2-(3,4,5-trimethoxy-benzene methylamino)-6-amido purine, 2-methylamino-hypoxanthine, 2-ethylamino--hypoxanthine, 2-isobutyl amine-hypoxanthine, 2-Propylamino-hypoxanthine, 2-isoamyl amido-hypoxanthine, 2-hexylamine base-hypoxanthine, 2-cyclopropyl amino-hypoxanthine, 2-ring butylamine base-hypoxanthine, 2-cyclopentamine base-hypoxanthine, 2-cyclohexylamino-hypoxanthine, 2-anilino--hypoxanthine, 2-(2-chloroanilino)-hypoxanthine, 2-(3-chloroanilino)-hypoxanthine, 2-(4-chloroanilino)-hypoxanthine, 2-(2-fluoroanilino)-hypoxanthine, 2-(3-fluoroanilino)-hypoxanthine, 2-(4-fluoroanilino)-hypoxanthine, 2-(2-bromobenzene amido)-hypoxanthine, 2-(3-bromobenzene amido)-hypoxanthine, 2-(4-bromobenzene amido)-hypoxanthine, 2-benzene methanamine base-hypoxanthine, 2-(2-methyl benzene methanamine base)-hypoxanthine, 2-(3-methyl benzene methanamine base)-hypoxanthine, 2-(4-methyl benzene methanamine base)-hypoxanthine, 2-(2-Histol base)-hypoxanthine, 2-(3-Histol base)-hypoxanthine, 2-(4-Histol base)-hypoxanthine, 2-(2-fluorobenzene methylamino)-hypoxanthine,2-(3-fluorobenzene methylamino)-hypoxanthine, 2-(4-fluorobenzene methylamino)-hypoxanthine, 2-(3-iodobenzene methylamino)-hypoxanthine, 2-(4-Hydrobenzylamine base)-hypoxanthine, 2-(2, 3-dihydroxy benzenes methylamino)-hypoxanthine, 2-(2, 4-dihydroxy benzenes methylamino)-hypoxanthine, 2-(3, 4-dihydroxy benzenes methylamino)-hypoxanthine, 2-(2, 3-dimethoxybenzylamine base)-hypoxanthine, 2-(2, 3-dimethoxybenzylamine base)-hypoxanthine, 2-(3, 5-dimethoxybenzylamine base)-hypoxanthine, 2-(2, 4, 5-trimethoxy-benzene methylamino)-hypoxanthine, 2-(3, 4, 5-trimethoxy-benzene methylamino)-hypoxanthine, hypoxanthine, 6-sulfhydryl purine, N 6-methyl adenine, 2-amido adenine, 2-hydroxyadenine, 2-methyl adenine, 2-amido-hypoxanthine, 2,6-xanthine, 2-methyl-6 oxipurinol, 2-amido-6-sulfhydryl purine, 2-hydroxyl-6-sulfhydryl purine, 2-methyl-6-sulfhydryl purine, 2-sulfhydryl adenine, 2-sulfhydryl-hypoxanthine, 2,6-sulfuryl purine, 2-sulfhydryl-6-methyl purine, 2-sulfhydryl-6-ethyl purine, 2-sulfhydryl-6-propyl group purine, 2-ethyl adenine, 2-ethyl-hypoxanthine, 2-ethyl-6-sulfhydryl purine, 2-ethyl-6-methylaminopurine, 2-ethyl-6-ethylamino-purine, 2-ethyl-6-Propylamino purine, 2-propyl group adenine, 2-propyl group-hypoxanthine, 2-propyl group-6-sulfhydryl purine, 2-propyl group-6-methylaminopurine, 2-propyl group-6-ethylamino-purine, 2-propyl group-6-Propylamino purine, 2-amido-6-benzene methanamine base purine, 2-ethyl-6-benzene methanamine base purine, 2-propyl group-6-benzene methanamine base purine, 2-ethyl-6-anilino-purine, 2-propyl group-6-anilino-purine, 2-benzyl adenine, 2-benzyl-hypoxanthine, 2-benzyl-6-sulfhydryl purine, 2-benzyl-6-methylaminopurine, 2-benzyl-6-ethylamino-purine, 2-benzyl-6-Propylamino purine, 2-phenyl adenine, 2-phenyl-hypoxanthine, 2-phenyl-6-sulfhydryl purine, 2-phenyl-6-methylaminopurine, 2-phenyl-6-ethylamino-purine, 2-phenyl-6-Propylamino purine, 2-sulfhydryl-N 6-2-isopentenyl gland purine, 2-ethyl-N 6-2-isopentenyl gland purine, 2-propyl group-N 6-2-isopentenyl gland purine,2-benzyl-N 6-2-isopentenyl gland purine, 2-phenyl-N 6-2-isopentenyl gland purine, 2-chloroadenine, the chloro-hypoxanthine of 2-, 2-chloro-6-sulfhydryl purine, 2-chloro-6-methylaminopurine, 2-chloro-6-ethylamino-purine, 2-chloro-6-Propylamino purine, 2-chloro-6-benzene methanamine base purine, 2-chloro-6-anilino-purine, the chloro-N of 2- 6-2-isopentenyl gland purine, 2-fluoroadenine, the fluoro-hypoxanthine of 2-, 2-fluoro-6-sulfhydryl purine, 2-fluoro-6-methylaminopurine, 2-fluoro-6-ethylamino-purine, 2-fluoro-6-Propylamino purine, 2-fluoro-6-benzene methanamine base purine, 2-fluoro-6-anilino-purine, the fluoro-N of 2- 6-2-isopentenyl gland purine, 2-bromine adenine, the bromo-hypoxanthine of 2-, 2-bromo-6-sulfhydryl purine, 2-bromo-6-methylaminopurine, 2-bromo-6-ethylamino-purine, 2-bromo-6-Propylamino purine, 2-bromo-6-benzene methanamine base purine, 2-bromo-6-anilino-purine, the bromo-N of 2- 6-2-isopentenyl gland purine, 2-iodine adenine, the iodo-hypoxanthine of 2-, 2-iodo-6-sulfhydryl purine, 2-iodo-6-methylaminopurine, 2-iodo-6-ethylamino-purine, 2-iodo-6-Propylamino purine, 2-iodo-6-benzene methanamine base purine, 2-iodo-6-anilino-purine, the iodo-N of 2- 6-2-isopentenyl gland purine, 2-sulfhydryl-N 6-cyclohexyl adenine, 2-propyl group-N 6-cyclohexyl adenine, 2-ethyl-N 6-cyclohexyl adenine, 2-benzyl-N 6-cyclohexyl adenine, 2-phenyl-N 6The chloro-N of-cyclohexyl adenine, 2- 6The fluoro-N of-cyclohexyl adenine, 2- 6The bromo-N of-cyclohexyl adenine, 2- 6The iodo-N of-cyclohexyl adenine, 2- 6-cyclohexyl adenine,2-amido-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-hydroxyl-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-sulfhydryl-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-methyl-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-ethyl-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-propyl group-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-benzyl-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-phenyl-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-chloro-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, the fluoro-6-of 2-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, the bromo-6-of 2-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, the iodo-6-of 2-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-cyclohexyl-6-(4-hydroxy-3-methyl-Ding 2 enamine base) purine, 2-amido-6-furfuryl alcohol amido purine, 2-hydroxyl-6-furfuryl alcohol amido purine, 2-sulfhydryl-6-furfuryl alcohol amido purine, 2-methyl-6-furfuryl alcohol amido purine, 2-ethyl-6-furfuryl alcohol amido purine, 2-propyl group-6-furfuryl alcohol amido purine, 2-benzyl-6-furfuryl alcohol amido purine, 2-phenyl-6-furfuryl alcohol amido purine, 2-chloro-6-furfuryl alcohol amido purine, 2-fluoro-6-furfuryl alcohol amido purine, 2-bromo-6-furfuryl alcohol amido purine, 2-iodo-6-furfuryl alcohol amido purine, 2-cyclohexyl-6-furfuryl alcohol amido purine, 2-amido-6-acetamido purine, 2-hydroxyl-6-acetamido purine, 2-sulfhydryl-6-acetamido purine, 2-methyl-6-acetamido purine, 2-ethyl-6-acetamido purine, 2-propyl group-6-acetamido purine, 2-benzyl-6-acetamido purine, 2-phenyl-6-acetamido purine, the chloro-6-acetamido purine of 2-, the bromo-6-acetamido purine of 2-, the iodo-6-acetamido purine of 2-, 2-cyclohexyl-6-acetamido purine, 2-dimethyl amido-hypoxanthine, Guanine, xanthine, hypoxanthine, 6-sulfydryl Guanine, comprises pharmaceutical carrier.
4. activate the compound of AMPK as claimed in claim 2, it is characterized in that, the compound of described activation AMPK is selected from by the following group formed: 5-methylcytosine, 5,6-dihydro urinates close pyridine, thymus pyrimidine, cytosine(Cyt), the close pyridine of urine, 5 FU 5 fluorouracil, floxuridine, 6-azauracil, and comprises pharmaceutical carrier.
5. the compound activating AMPK is for the preparation of the purposes for the treatment of in the medicine of disease or the physiological situation that can be improved by AMPK activator, it is characterized in that, the compound of described activation AMPK is the compound of at least one effective dose, it is selected from claim 1 or 2 and/or its acceptable salt pharmaceutically and in trophology, the Mammals treated to need this.
6. the compound activating AMPK is being selected from by the physiological situation of the following group formed or disease for the preparation of prevention or treatment: the purposes in the medicine of pre-diabetes, insulin resistant, Second-Type diabetes, X-syndrome, metabolic syndrome, it is characterized in that, the compound of described activation AMPK is the compound of at least one effective dose, it is selected from claim 1 and/or its acceptable salt pharmaceutically and in trophology, the Mammals treated to need this, thus increase the picked-up of grape cell sugar, reduce blood sugar concentration.
7. the compound activating AMPK is being selected from by the physiological situation of the following group formed or disease for the preparation of prevention or treatment: the purposes in the medicine of pre-diabetes, insulin resistant, Second-Type diabetes, X-syndrome, metabolic syndrome, it is characterized in that, described compound is the compound of at least one effective dose, it is selected from claim 2 and/or its acceptable salt pharmaceutically and in trophology, the Mammals treated to need this, thus increase the picked-up of grape cell sugar, reduce blood sugar concentration.
8. one kind activates the purposes of compound in the medicine for the preparation of prevention or treatment obesity of AMPK, the compound of wherein said activation AMPK is the compound of at least one effective dose, it is selected from claim 1 and/or its acceptable salt pharmaceutically and in trophology, the Mammals treated to need this, thus reduce mammiferous blood plasma triglyceride and reduce body weight.
9. one kind activates the purposes of compound in the medicine for the preparation of prevention or treatment obesity of AMPK, the compound of wherein said activation AMPK is the compound of at least one effective dose, it is selected from claim 2 and/or its acceptable salt pharmaceutically and in trophology, the Mammals treated to need this, thus reduce mammiferous blood plasma triglyceride and reduce body weight.
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