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CN116492347A - Compound for activating AMPK and application thereof - Google Patents

Compound for activating AMPK and application thereof Download PDF

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Publication number
CN116492347A
CN116492347A CN202310449007.0A CN202310449007A CN116492347A CN 116492347 A CN116492347 A CN 116492347A CN 202310449007 A CN202310449007 A CN 202310449007A CN 116492347 A CN116492347 A CN 116492347A
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China
Prior art keywords
purine
ampk
group
hydroxy
compound
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CN202310449007.0A
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Chinese (zh)
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
Publication of CN116492347A publication Critical patent/CN116492347A/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 present invention relates to a compound for activating AMPK and its use in the preparation of a medicament for preventing or treating diseases or physiological conditions, including pre-diabetes, insulin resistance, type ii diabetes, X-syndrome, metabolic syndrome and obesity, which can be ameliorated by AMPK activators. The compound provided by the invention can reduce the amount of plasma glucose by more than 30wt%, reduce the amount of triglyceride by more than 35wt%, and reduce the weight by more than 15%.

Description

Compound for activating AMPK and application thereof
The present application is a divisional application of application No. 201810366456.8, application date 2013, 09, 18, and application name "a compound for activating AMPK and use thereof".
Technical Field
The present invention relates to compounds, and more particularly, to a compound for activating AMPK (AMP-activated protein kinase) and its use in the preparation of a medicament for preventing or treating diseases or physiological conditions including pre-diabetes, insulin resistance, type ii diabetes, syndrome X, metabolic syndrome and obesity, which can be ameliorated by AMPK activators.
Background
AMPK is clearly the sensor of cellular energy and the responder to energy demand. AMPK is an abnormal triad consisting of catalytic alpha subunits, regulatory beta and gamma subunits, all of which are highly conserved in eukaryotes. AMPK activation is mediated by its upstream kinases such as LKB1, calcium ion/calcitonin dependent protein phosphokinase (Ca 2+ Calmodulin dependent kinase) and TAK1 phosphorylating alpha subunit residues 172 th threonine, high AMP/ATP ratios due to physiological or pathological stress also activate AMPK. AMPK activation promotes catabolic pathways and inhibits anabolism, and restores cellular energy balance by reducing ATP consumption and promoting ATP production.
AMPK is considered as a potential drug target for metabolic syndrome including type ii diabetes, cardiovascular disease, fatty liver, etc., as an energy metabolism balance regulator. Many metabolic syndromes are associated with insulin resistance. Insulin resistance is a pathological condition in which cells fail to respond to insulin, and thus excess glucose in the blood cannot be removed to skeletal muscle or adipose tissue. In muscle cells, AMPK activation increases the expression level of glucose transporter (GLUT 4) through transcriptional regulation in a non-insulin dependent manner, and induces GLUT4 to migrate to the cell membrane resulting in an increase in the glucose uptake rate by the cell. AMPK activation also inhibits fatty acid and cholesterol synthesis by inhibiting acetyl-CoA carboxylase (acetyl-CoA carboxylase) and hydroxymethylglutarate monoacyl-CoA reductase (HMG-CoA reductase), respectively. In addition, AMPK activation results in inhibition of multiple transcription factors, including sterol regulatory element binding protein (SREBP-1 c), carbohydrate response element binding protein transcription factor (ChREBP) and liver nuclear factor 4a (HNF-4 a), and down-regulation of protein expression of enzymes involved in fatty acid synthesis and glycogenesis. The studies mentioned above have found that AMPK is supported as a therapeutic target for metabolic syndrome, especially diabetes.
AMP is a natural AMPK activator, however, AMP is an unstable compound, and extracellular administration of AMP triggers signaling (potentially leading to apoptosis, etc.) conveyed by purinergic receptors (purinergic receptor). Therefore, many researchers have been devoted to the development of AMPK activators. It is currently known that high concentrations of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and meldrum (metaformin) compounds activate AMPK in organisms. Wherein metformin has been used to treat pre-diabetes, insulin resistance, syndrome X, type ii diabetes. However, such AMPK activators have side effects including lactic acidosis, especially when the patient has renal insufficiency. There is therefore an urgent need to develop novel AMPK activators with lower effective concentrations and fewer side effects.
Disclosure of Invention
Accordingly, it is an object of the present invention to provide a compound for activating AMPK and its use in preparing a medicament for preventing or treating diseases or physiological conditions including pre-diabetes, type ii diabetes, X-syndrome, metabolic syndrome and obesity, which can be ameliorated by AMPK activators.
To achieve the above object, the present invention provides compounds of formula (1) and formula (2) and tautomers thereof:
and pharmaceutically acceptable salts thereof, wherein R2 represents a hydrogen atom, a halogen atom, a hydroxyl group, an amine group, a substituent of one or two up to ten carbons, a mercapto group, a carboxyl group, a nitro group, a sulfo group, an alkyl group, an alkylamino group, an alkylthio group, an alkoxy group, a cycloalkyl group, a substituted alkyl group, a substituted alkenyl group, a substituted alkynyl group, an acyl group, an aromatic hydrocarbon group, a substituted aromatic hydrocarbon group, an aryloxy group; r6 represents hydroxy, amino, mercapto, -NHR (monosubstituted amino) wherein R represents halogen atom, hydroxy, amino, amine base, one or two substituents up to ten carbon atoms, mercapto, carboxyl, nitro, sulfo, alkyl, alkylamino, alkylthio, alkoxy, cycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, acyl, aralkyl, substituted aralkyl, aryloxy; r3 represents a hydrogen atom or an alkyl group having at most ten carbon atoms; or a tautomer thereof or a pharmaceutically acceptable salt thereof, and an AMPK activator comprising the purine and pyrimidine and derivatives thereof or pharmaceutically acceptable salts thereof as an active compound.
The present application provides a compound that activates AMPK in an amount effective to administer to a mammal in need of such treatment at least one compound of formula (1) and/or a pharmaceutically or nutritionally acceptable salt thereof, wherein the compound of formula (1) is defined as follows:
(1) Wherein R2 represents a hydrogen atom, a halogen atom, a hydroxyl group, an amine group, an alkyl group or-NHR (monosubstituted amine group); wherein R represents alkyl, cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, wherein: the substituted phenyl group represents a phenyl group having a substituent group including 1 to 5 hydroxyl groups and alkoxy groups, 1 to 5 hydroxyl groups and halogen atom groups, 1 to 5 hydroxyl groups and alkyl groups; the substituted benzyl represents benzyl containing substituents including 1 to 5 hydroxyl and alkoxy groups, 1 to 5 hydroxyl and halogen atom groups, 1 to 5 hydroxyl and alkyl groups; wherein R6 represents hydroxy, amino, mercapto, or-NHR (monosubstituted amino); wherein R represents an alkyl group, a cycloalkyl group, a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group, wherein the substituted phenyl group represents a phenyl group having a substituent group including 1 to 5 hydroxyl groups and alkoxy groups, 1 to 5 hydroxyl groups and halogen atom groups, 1 to 5 hydroxyl groups and alkyl groups; the substituted benzyl represents benzyl containing substituents including 1 to 5 hydroxyl and alkoxy groups, 1 to 5 hydroxyl and halogen atom groups, 1 to 5 hydroxyl and alkyl groups; the general substituents have the same meaning as defined above, wherein the hydroxy group represents a hydroxy-OH group; the halogen atom represents fluorine, chlorine, bromine and iodine; said amine group represents —nh2; said thio group represents-SH; the alkyl group represents a linear or branched saturated group having at most six carbon atoms; the alkoxy represents-OR, wherein R is alkyl; the cycloalkyl represents a single or multiple cyclized alkyl groups containing 3 to 6 carbon atoms; and tautomers, racemates, optical isomers or pharmaceutically or nutritionally acceptable salts thereof, including pharmaceutical carriers.
The present application also provides a compound that activates AMPK, which is at least one compound of formula (2) and/or a pharmaceutically or nutraceutically acceptable salt thereof, in an amount effective to administer to a mammal in need of such treatment, wherein the compound of formula (2) is defined as follows:
(2) Wherein R6 represents a hydroxyl group, an amine group, wherein R3 represents a hydrogen atom, a hydroxyl group, a halogen atom and a methyl group, wherein R2 represents a hydrogen atom and a hydroxyl group, and the general substituents have the same meanings as defined above, wherein the hydroxyl group represents a hydroxyl-OH group; the halogen atom represents fluorine, chlorine, bromine and iodine; and tautomers, racemates, optical isomers or pharmaceutically or nutritionally acceptable salts thereof, including pharmaceutical carriers.
General substituents have the meaning as defined above, where
The hydroxyl represents hydroxyl-OH;
the halogen atom represents fluorine, chlorine, bromine and iodine;
the amine group representing-NH 2 ；
Said hydrosulfur group represents-SH;
the carboxyl represents-C (O) OR, wherein R is defined herein as hydrogen atom, alkyl group, substituted alkyl group, aromatic hydrocarbon group, substituted aromatic hydrocarbon group;
said nitro group represents-NO 2 ；
The sulfo group represents-SO 3 R is R; wherein R is defined herein as hydrogen, alkyl, substituted alkyl;
the alkyl group represents a straight chain or branched chain containing up to ten carbon atoms, wherein the saturated or unsaturated groups include methyl, propyl, isopropyl, butyl, ethoxy, vinyl, ethynyl, propynyl, 2-acetylenic hexyl and other groups as defined;
the substituted alkyl group means that the alkyl group includes 1 to 7 substituents such as hydroxyl, alkylthio, alkylamino, alkylthio, halogen, alkoxy, acyloxy, amino, carboxyl, sulfo, acyl and others, so that these groups can be attached to the carbon of any alkyl moiety;
the alkylamino represents-NRR ', wherein R and R' independently represent a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, as defined herein;
said alkylthio represents-SR, wherein R refers to alkyl, substituted alkyl, aryl, substituted aryl as defined herein;
said alkoxy represents-OR, wherein R refers to alkyl, substituted alkyl, aryl, substituted aryl as defined herein;
the cycloalkyl represents a single or multiple cyclized alkyl groups containing 3 to 15 carbon atoms;
the acyl represents-C (O) R, wherein R represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, as defined herein;
the aromatic hydrocarbon group represents an aromatic cyclized carbon group;
the substituted aromatic hydrocarbon represents that the aromatic hydrocarbon contains substituent groups including halogen atoms, hydroxyl groups, amino groups, hydrosulfide groups, alkoxy groups, sulfo groups, carboxyl groups and alkyl groups as defined herein;
the aryloxy group represents-OAr, wherein Ar refers to an aromatic hydrocarbon group, and the substituted aromatic hydrocarbon group is defined herein;
preferred AMPK activators therefore include: adenine, 2-amino-6-methylaminopurine, 2-amino-6-ethylamino-purine, 2-amino-6-isobutylamino-purine, 2-amino-6-propylamino-purine, 2-amino-6-isopentylamino-purine, 2-amino-6-hexylamino-purine, 2-amino-6-cyclopropylamino-purine, 2-amino-6-cyclobutylamino-purine, 2-amino-6-cyclopentylamino-purine, 2-amino-6-cyclohexylamino-purine, 2-amino-6-anilinopurine, 2-amino-amineAmino-6- (2-chloroanilino) purine, 2-amino-6- (3-chloroanilino) purine, 2-amino-6- (4-chloroanilino) purine, 2-amino-6- (2-bromoanilino) purine, 2-amino-6- (3-bromoanilino) purine, 2-amino-6- (4-bromoanilino) purine, 2-amino-6- (2-fluoroanilino) purine, 2-amino-6- (3-fluorobutynilino) purine, 2-amino-6- (4-fluoroanilino) purine, 2-amino-6-benzylanilino) purine, 2-amino-6- (2-methylbenznilino) purine, 2-amino-6- (3-methylbenznilino) purine, 2-amino-6- (4-methylbenznilino) purine, 2-amino-6- (2-chlorobenzylamino) purine, 2-amino-6- (3-chlorobenzylamino) purine, 2-amino-6- (4-chlorobenzylamino) purine, 2-amino-6- (2-fluorobenzylamino) purine, 2-fluoro-6- (3-methylbenzylamino) purine, 2-amino-6- (4-fluorobenzylamino) purine, 2-amino-6- (3-iodobenzylamino) purine, 2-amino-6- (4-hydroxybenzylamino) purine, 2-amino-6- (2, 3-dihydroxybenzylamino) purine, 2-amino-6- (3, 4-dihydroxybenzylamino) purine, 2-amino-6- (2-methoxybenzylamino) purine, 2-amino-6- (2, 3-dimethoxybenzylamino) purine, 2-amino-6- (3, 5-dimethoxybenzylamino) purine, 2-amino-6- (2, 4, 5-trimethoxybenzylamino) purine, 2-amino-6- (3, 4, 5-trimethoxybenzylamino) purine, 6-methylaminopurine, 6-ethylamino purine, 6-isobutylamino purine, 6-isopentylamino purine, 6-hexosamino purine, 6-cyclopropylamino purine, 6- (6-cyclohexylamino) purine, 6- (6-chloroaniline) purine, 6-chloroaniline, 6- (3-chloroaniline) purine, 6- (2-bromoanilino) purine, 6- (3-bromoanilino) purine, 6- (4-bromoanilino) purine, 6- (2-fluoroanilino) purine, 6- (3-fluoroanilino) purine, 6- (4-fluoroanilino) purine, 6-benzylaminopurine, 6- (2-methylbenzylamino) purine, 6- (3-methylbenzylamino) purine, 6- (4-methylbenzylamino) purine, 6- (2-chlorobenzylamino) purine, 6- (3-chlorobenzylamino) purine, 6- (4-chlorobenzylamino) purine, 6- (2-fluorobenzylamino) purine, 6- (3-fluorobenzylamino) purine, 6- (4-fluorobenzylamino) purine, 6- (3-iodobenzylamino) purine, 6- (4-hydroxybenzylamino) purine, 6- (2, 3-dihydroxybenzyl) purineMethylamino) purine, 6- (3, 4-dihydroxybenzylamino) purine, 6- (2-methoxybenzylamino) purine, 6- (2, 3-dimethoxybenzylamino) purine, 6- (3, 5-dimethoxybenzylamino) purine, 6- (2, 4, 5-trimethoxybenzylamino) purine, 6- (3, 4, 5-trimethoxybenzylamino) purine, 2-hydroxy-6-methylaminopurine, 2-hydroxy-6-ethylamino purine, 2-hydroxy-6-isobutylamino purine, 2-hydroxy-6-propylamino purine, 2-hydroxy-6-isopentylamino purine, 2-hydroxy-6-hexylamino purine, 2-hydroxy-6-cyclopropylamino purine, 2-hydroxy-6-cyclobutylamino purine, 2-hydroxy-6-cyclopentylamino purine, 2-hydroxy-6-anilino purine, 2-hydroxy-6- (2-hydroxy-6-chloroanilino) purine, 2-hydroxy-6- (2-chlorobenzylamino) purine, 2-hydroxy-6- (2-hydroxy-chloroanilino) purine, 2-hydroxy-6- (3-bromoanilino) purine, 2-hydroxy-6- (4-bromoanilino) purine, 2-hydroxy-6- (2-fluoroanilino) purine, 2-hydroxy-6- (3-fluorobenzanilino) purine, 2-hydroxy-6- (4-fluoroanilino) purine, 2-hydroxy-6- (2-methylbenzanilino) purine, 2-hydroxy-6- (3-methylbenzanilino) purine, 2-hydroxy-6- (4-methylbenzanilino) purine, 2-hydroxy-6- (2-chlorobenzylamino) purine, 2-hydroxy-6- (3-chlorobenzylamino) purine, 2-hydroxy-6- (4-chlorobenzylamino) purine, 2-hydroxy-6- (2-fluorobenzylamino) purine, 2-hydroxy-6- (3-fluorobenzylamino) purine, 2-hydroxy-6- (4-fluorobenzenylmethylamino) purine, 2-hydroxy-6- (3-iodobenzyl) purine, 2-hydroxy-6- (4-hydroxybenzenylmethylamino) purine, 2-hydroxy-6- (2, 3-dihydroxybenzylamino) purine, 2-hydroxy-6- (3, 4-dihydroxybenzylamino) purine, 2-hydroxy-6- (2-methoxybenzylamino) purine, 2-hydroxy-6- (2, 3-dimethoxybenzylamino) purine, 2-hydroxy-6- (3, 5-dimethoxybenzylamino) purine, 2-hydroxy-6- (2, 4, 5-trimethoxybenzylamino) purine, 2-hydroxy-6- (3, 4, 5-trimethoxybenzylamino) purine, 2-methyl-6-methylaminopurine, 2-methyl-6-ethylamino purine, 2-methyl-6-isobutylamino purine, 2-methyl-6-propylamino purine, 2-methyl-6-isopentylamino purine, 2-methyl-6-hexylamino purine, 2-methyl-6-cyclopropylamino purine, 2-methyl-6-methylamino purine-cyclobutylamino purine, 2-methyl-6-cyclopentylamino purine, 2-methyl-6-cyclohexylamino purine, 2-methyl-6-anilinopurine, 2-methyl-6- (2-chloroanilino) purine, 2-methyl-6- (3-chloroanilino) purine, 2-methyl-6- (4-chloroanilino) purine, 2-methyl-6- (2-bromoanilino) purine, 2-methyl-6- (3-bromoanilino) purine, 2-methyl-6- (4-bromoanilino) purine, 2-methyl-6- (2-fluoroanilino) purine, 2-methyl-6- (3-fluorobnilino) purine, 2-methyl-6- (4-fluoroanilino) purine, 2-methyl-6-benzylanilino) purine, 2-methyl-6- (2-methylbenznilino) purine, 2-methyl-6- (3-methylbenznilino) purine, 2-methyl-6- (4-methylbenznilino) purine, 2-methyl-6- (2-chlorobenzylamino) purine, 2-methyl-6- (3-chlorobenzylamino) purine, 2-methyl-6- (4-chlorobenzylamino) purine, 2-methyl-6- (2-fluorobenzylamino) purine, 2-methyl-6- (3-fluorobenzylamino) purine, 2-methyl-6- (4-fluorobenzylamino) purine, 2-methyl-6- (3-iodobenzylamino) purine, 2-methyl-6- (4-hydroxybenzylamino) purine, 2-methyl-6- (2, 3-dihydroxybenzylamino) purine, 2-methyl-6- (3, 4-dihydroxybenzylamino) purine, 2-methyl-6- (2-methoxybenzylamino) purine, 2-methyl-6- (2, 3-dimethoxybenzylamino) purine, 2-methyl-6- (3, 5-dimethoxybenzylamino) purine, 2-methyl-6- (2, 4, 5-trimethoxybenzylamino) purine, 2-methyl-6- (3, 4, 5-trimethoxybenzylamino) purine, 2-methyl-6- (2-methoxybenzylamino) purine, 2-methylamino-6-butylamine, 2-amino-2-butylamine-purine, 2-isopentyl-6-aminopurine, 2-hexosamini-6-aminopurine, 2-cyclopropylamino-6-aminopurine, 2-cyclobutylamino-6-aminopurine, 2-cyclopentylamino-6-aminopurine, 2-cyclohexylamino-6-aminopurine, 2-anilino-6-aminopurine, 2- (2-chloroanilino) -6-aminopurine, 2- (3-chloroanilino) -6-aminopurine, 2- (4-chloroanilino) -6-aminopurine, 2- (2-fluoroanilino) -6-aminopurine, 2- (3-fluoroanilino) -6-aminopurine, 2- (4-fluoroanilino) -6-aminopurine, 2- (2-bromoanilino) -6-aminopurine, 2- (3-bromoanilino) -6-aminopurine, 2- (2-methylbenzanilino) -6-aminopurine, 2- (3-methylamino) -6-aminopurineAn aminobenzylamino) -6-aminopurine, 2- (4-methylbenzylamino) -6-aminopurine, 2- (2-chlorobenzylamino) -6-aminopurine, 2- (3-chlorobenzylamino) -6-aminopurine, 2- (4-chlorobenzylamino) -6-aminopurine, 2- (2-fluorobenzylamino) -6-aminopurine, 2- (3-fluorobenzylamino) -6-aminopurine, 2- (4-fluorobenzylamino) -6-aminopurine, 2- (3-iodobenzylamino) -6-aminopurine, 2- (4-hydroxybenzylamino) -6-aminopurine, 2- (2, 3-dihydroxybenzylamino) -6-aminopurine, 2- (2, 4-dihydroxybenzylamino) -6-aminopurine, 2- (3, 4-dihydroxybenzylamino) -6-aminopurine, 2- (2, 3-dimethoxybenzylamino) -6-aminopurine, 2- (3, 5-dimethoxybenzylamino) -6-aminopurine, 2- (2, 4-dimethoxybenzylamino) -6-aminopurine, 2- (3, 4, 5-trimethoxy-benzylaminoyl) -6-aminopurine, 2-methylamino-6-hydroxypurine, 2-ethylamino-6-hydroxypurine, 2-isobutylamino-6-hydroxypurine, 2-propylamine-6-hydroxypurine, 2-isopentylamino-6-hydroxypurine, 2-hexylamino-6-hydroxypurine, 2-cyclopropylamino-6-hydroxypurine, 2-cyclobutylamino-6-hydroxypurine, 2-cyclopentylamino-6-hydroxypurine, 2-cyclohexylamino-6-hydroxypurine, 2-anilino-6-hydroxypurine, 2- (2-chloroanilino) -6-hydroxypurine, 2- (3-chloroanilino) -6-hydroxypurine, 2- (4-chloroanilino) -6-hydroxypurine, 2- (2-fluoroanilino) -6-hydroxypurine, 2- (3-fluoroanilino) -6-hydroxypurine, 2- (4-fluoroanilino) -6-hydroxypurine, 2- (2-bromoanilino) -6-hydroxypurine, 2- (3-bromoanilino) -6-hydroxypurine, 2- (4-bromoanilino) -6-hydroxypurines, 2-bromoanilino) -6-hydroxypurines, 2- (2-methylbenzylamino) -6-hydroxypurine, 2- (3-methylbenzylamino) -6-hydroxypurine, 2- (4-methylbenzylamino) -6-hydroxypurine, 2- (2-chlorobenzylamino) -6-hydroxypurine, 2- (3-chlorobenzylamino) -6-hydroxypurine, 2- (4-chlorobenzylamino) -6-hydroxypurine, 2- (2-fluorobenzylamino) -6-hydroxypurine, 2- (3-fluorobenzylamino) -6-hydroxypurine, 2- (4-fluorobenzylamino) -6-hydroxypurine, 2- (3-iodobenzylamino) -6-hydroxypurine, 2- (4-hydroxybenzylamino) -6-hydroxypurine, 2- (2, 3-dihydroxybenzylamino) -6-hydroxypurine, 2- (2, 4-dihydroxybenzylamino) -6-hydroxypurine, 2- (3, 4-dihydroxybenzylamino) -6-hydroxypurineAminopurine, 2- (2, 3-dimethoxy benzylamino) -6-hydroxypurine, 2- (3, 5-dimethoxy benzylamino) -6-hydroxypurine, 2- (2, 4, 5-trimethoxy benzylamino) -6-hydroxypurine, 2- (3, 4, 5-trimethoxy benzylamino) -6-hydroxypurine, 6-mercapto purine, N 6 -methyladenine, 2-aminoadenine, 2-hydroxyadenine, 2-methyladenine, 2-amino-6-hydroxypurine, 2, 6-dihydroxypurine, 2-methyl-6-hydroxypurine, 2-amino-6-mercaptopurine, 2-hydroxy-6-mercaptopurine, 2-methyl-6-mercaptopurine, 2-mercaptoadenine, 2-mercapto-6-hydroxypurine, 2, 6-dihydromercaptopurine, 2-mercapto-6-methylpurine, 2-mercapto-6-ethylpurine, 2-mercapto-6-propylpurine, 2-ethyladenine, 2-ethyl-6-hydroxypurine, 2-ethyl-6-mercaptopurine, 2-methylaminopurine, 2-ethyl-6-ethylamino-purine, 2-ethyl-6-propylaminopurine, 2-propyl-6-hydroxypurine, 2-propyl-6-propyl-aminopurine, 2-propyl-6-mercaptopurine, 2-propyl-methylaminopurine, 2-amino-6-aminopurine, 2-ethyl-6-aminopropylamine, 2-ethyl-6-aminopurine, 2-propyl-6-anilinopurine, 2-benzyl adenine, 2-benzyl-6-hydroxypurine, 2-benzyl-6-mercaptopurine, 2-benzyl-6-methylaminopurine, 2-benzyl-6-ethylaminopurine, 2-benzyl-6-propylaminopurine, 2-phenyladenine, 2-phenyl-6-hydroxypurine, 2-phenyl-6-mercaptopurine, 2-phenyl-6-methylaminopurine, 2-phenyl-6-ethylaminopurine, 2-phenyl-6-propylaminopurine, 2-mercaptoN 6 -2-isopentenyl adenine, 2-ethyl-N 6 -2-isopentenyl adenine, 2-propyl-N 6 -2-isopentenyl adenine, 2-benzyl-N 6 -2-isopentenyl adenine, 2-phenyl-N 6 -2-isopentenyl adenine, 2-chloroadenine, 2-chloro-6-hydroxy purine, 2-chloro-6-mercapto purine, 2-chloro-6-methylaminopurine, 2-chloro-6-ethylamino purine, 2-chloro-6-propylamine purine, 2-chloro-6-benzylaminopurine, 2-chloro-6-anilinopurine, 2-chloro-N 6 -2-isopentenyl adenine, 2-fluoroadenine2-fluoro-6-hydroxy-purine, 2-fluoro-6-mercapto-purine, 2-fluoro-6-methylamino-purine, 2-fluoro-6-ethylamino-purine, 2-fluoro-6-propylamino-purine, 2-fluoro-6-benzylaminopurine, 2-fluoro-6-anilinopurine, 2-fluoro-N 6 -2-isopentenyl adenine, 2-bromoadenine, 2-bromo-6-hydroxy purine, 2-bromo-6-hydrothiopurine, 2-bromo-6-methylaminopurine, 2-bromo-6-ethylamino purine, 2-bromo-6-propylamine purine, 2-bromo-6-benzylaminopurine, 2-bromo-6-anilinopurine, 2-bromo-N 6 -2-isopentenyl adenine, 2-iodoadenine, 2-iodo-6-hydroxy purine, 2-iodo-6-hydrothiopurine, 2-iodo-6-methylaminopurine, 2-iodo-6-ethylamino purine, 2-iodo-6-propylamine purine, 2-iodo-6-benzylaminopurine, 2-iodo-6-anilinopurine, 2-iodo-N 6 -2-isopentenyl adenine, 2-hydrosulfanyl-N 6 -cyclohexyladenine, 2-propyl-N 6 -cyclohexyladenine, 2-ethyl-N 6 -cyclohexyladenine, 2-benzyl-N 6 -cyclohexyladenine, 2-phenyl-N 6 -cyclohexyladenine, 2-chloro-N 6 -cyclohexyladenine, 2-fluoro-N 6 -cyclohexyladenine, 2-bromo-N 6 -cyclohexyladenine, 2-iodo-N 6 -cyclohexyladenine, 2-amino-6- (4-hydroxy-3-methyl-buta-2-enamine) purine, 2-hydroxy-6- (4-hydroxy-3-methyl-buta-2-enamine) purine, 2-mercapto-6- (4-hydroxy-3-methyl-buta-2-enamine) purine, 2-methyl-6- (4-hydroxy-3-methyl-buta-2-enamine) purine, 2-ethyl-6- (4-hydroxy-3-methyl-buta-2-enamine) purine, 2-propyl-6- (4-hydroxy-3-methyl-buta-2-enamine) purine, 2-benzyl-6- (4-hydroxy-3-methyl-buta-2-enamine) purine, 2-phenyl-6- (4-hydroxy-3-methyl-buta-2-enamine) purine, 2-chloro-6- (4-hydroxy-3-methyl-buta-2-enamine) purine, 2-bromo-6- (4-hydroxy-3-methyl-buta-2-enamine) purine, 2-iodo-6- (4-hydroxy-3-methyl-buta-2-enamine) purine, 2-cyclohexyl-6- (4-hydroxy-3-methyl-buta-2-enamine) purine, 2-amino-6-furfuryl amino purine, 2-hydroxy-6-furfuryl amino purine, 2-mercapto-6-furfuryl amino purine, 2-methyl-6-furfuryl amino purine, 2-ethyl-6-furfuryl amino purine, 2-propyl-6-furfuryl amino purine, 2-benzyl-6-furfuryl amino purine, 2-phenyl-6-furfuryl amino amineThe metabolizable form of the pharmaceutical composition may be 2-chloro-6-furfuryl amino purine, 2-fluoro-6-furfuryl amino purine, 2-bromo-6-furfuryl amino purine, 2-iodo-6-furfuryl amino purine, 2-cyclohexyl-6-furfuryl amino purine, 2-amino-6-acetaminopurine, 2-hydroxy-6-acetaminopurine, 2-hydrosulfo-6-acetaminopurine, 2-methyl-6-acetaminopurine, 2-ethyl-6-acetaminopurine, 2-propyl-6-acetaminopurine, 2-benzyl-6-acetaminopurine, 2-phenyl-6-acetaminopurine, 2-chloro-6-acetaminopurine, 2-bromo-6-acetaminopurine, 2-iodo-6-acetaminopurine, 2-cyclohexyl-6-acetaminopurine, 2-dimethylamino-6-hydroxy purine, guanosine, xanthine, hypoxanthine, 6-sulfhydryl guanosine, 5-methylcytosine, 5, 6-dihydrouracil, thymine, uracil, 5-fluorouracil, uridine, or a prodrug form thereof.
Further, wherein the compound of formula (1) is an AMPK activator.
Further, wherein the compound of formula (2) is an AMPK activator.
The present invention also provides the use of a compound that activates AMPK in the manufacture of a medicament for the treatment of a disease or physiological condition ameliorated by an AMPK activator, wherein the compound that activates AMPK is at least one effective dose of a compound selected from the group consisting of compounds of formulae (1) and (2) and/or pharmaceutically and nutritionally acceptable salts thereof, for administration to a mammal in need of such treatment.
The present invention also provides a compound for activating AMPK for use in the preparation of a medicament for preventing or treating a physiological condition or disease selected from the group consisting of: use of a pre-diabetes, insulin resistance, type ii diabetes, syndrome X, metabolic syndrome in the manufacture of a medicament, wherein the compound that activates AMPK is at least one effective dose of a compound selected from the group consisting of a compound of formula (1) and/or a pharmaceutically and nutritionally acceptable salt thereof, for administration to a mammal in need of such treatment, thereby increasing cellular glucose.
The present invention also provides the use of a compound which activates AMPK in the manufacture of a medicament for the treatment of a disease or physiological condition ameliorated by an AMPK activator, characterised in that the compound which activates AMPK is at least one effective dose of a compound selected from the compounds described herein above and/or pharmaceutically and nutritionally acceptable salts thereof, for administration to a mammal in need of such treatment.
The present application also provides a compound that activates AMPK for use in the preparation of a medicament for preventing or treating a physiological condition or disease selected from the group consisting of: use of a compound for activating AMPK in the manufacture of a medicament for pre-diabetes, insulin resistance, type ii diabetes, syndrome X, metabolic syndrome, characterized in that said compound is at least one compound selected from the group consisting of the compounds described herein and/or pharmaceutically and nutritionally acceptable salts thereof, for administration to a mammal in need of such treatment, thereby increasing cellular glucose uptake and decreasing blood glucose concentration.
The present invention also provides a compound for activating AMPK for use in the preparation of a medicament for preventing or treating a physiological condition or disease selected from the group consisting of: use of a pre-diabetes, insulin resistance, type ii diabetes, syndrome X, metabolic syndrome in the manufacture of a medicament, wherein said compound is at least one compound selected from the group consisting of compounds of formula (2) and/or pharmaceutically and nutritionally acceptable salts thereof, in an amount effective to increase cellular glucose in a mammal in need of such treatment.
The present invention also provides a method for preventing or treating obesity, comprising administering to a mammal in need of such treatment an AMPK-activating compound, wherein the AMPK-activating compound is at least one effective amount of a compound selected from the group consisting of a compound of formula (1) and pharmaceutically and nutritionally acceptable salts thereof, to reduce plasma triglycerides and reduce body weight in the mammal.
Use of an AMPK activating compound in the manufacture of a medicament for the prevention or treatment of obesity, wherein the AMPK activating compound is at least one compound selected from the group consisting of the compounds described herein above and/or pharmaceutically and nutritionally acceptable salts thereof, in an amount effective to administer to a mammal in need of such treatment, thereby reducing plasma triglycerides and reducing body weight in the mammal.
The present invention also provides a method for preventing or treating obesity, comprising administering to a mammal in need of such treatment an AMPK-activating compound, wherein the AMPK-activating compound is at least one effective amount of a compound selected from the group consisting of a compound of formula (2) and pharmaceutically and nutritionally acceptable salts thereof, to reduce plasma triglycerides and reduce body weight in the mammal.
The invention further provides a medicament comprising an effective amount of a compound of formula (1) in association with a pharmaceutically suitable carrier.
The invention further provides a medicament comprising an effective amount of a compound of formula (2) in association with a pharmaceutically suitable carrier.
The present invention provides a use of an AMPK activating compound in the manufacture of a medicament for the prevention or treatment of obesity, wherein the AMPK activating compound is at least one compound selected from the group consisting of compounds of formula (2) and/or pharmaceutically and nutritionally acceptable salts thereof, for administration to a mammal in need of such treatment, thereby reducing plasma triglycerides and reducing body weight in the mammal.
The invention can contain a second medicine for treating pre-diabetes, insulin resistance, type II diabetes, X-syndrome and metabolic syndrome. Suitable second agents include various biguanides, thiazolidinediones, thienopyridinones and other AMPK activators.
As described herein, the invention includes administering to a mammal a pharmaceutically effective dose of any of the compounds of formulas (1) and (2), and salts and prodrugs thereof. More suitably, the invention also includes the administration of a pharmaceutically effective dose of any of the compounds of formula (1) and formula (2) to a human in particular preference for treating any of the diseases described herein.
The term "AMPK" as used herein refers to adenosine monophosphate activated protein kinase.
The term "prediabetes" as used herein refers to a physiological condition characterized by fasting blood glucose above 100 mg/dl but below 140 mg/dl.
The term "insulin resistance" as used herein refers to a physiological condition in which the whole body or tissues, including liver, skeletal muscle, adipose tissue, are not responsive to insulin.
The term "type II diabetes" as used herein also refers to non-insulin dependent diabetes mellitus or adult-onset diabetes mellitus; refers to insulin production deficiency or insulin resistance caused by metabolic disorders and is generally characterized by fasting blood glucose above 140 mg/dl.
The term "X-syndrome" as used herein refers to a physiological condition characterized by at least two of the following symptoms: fasting hyperglycemia (non-insulin dependent diabetes mellitus), hypertension, high triglycerides, low high density lipoprotein cholesterol.
The compound provided by the invention can reduce the amount of plasma glucose by more than 30wt%, reduce the amount of triglyceride by more than 35wt%, and reduce the weight by more than 15%.
Detailed Description
Example 1
2-amino-6- (3-chlorobenzylamino) purines
After 4 mmol of 2-amino-6-chloropurine was dissolved in 20 ml of butanol, 5 mmol of 3-chlorobenzenemethylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90℃for 4 hours. After cooling, the product is filtered off, washed with water and butanol and crystallized from dimethylformamide or ethanol. HPLC: the purity is more than 98 percent. The yield was 95%.
Table (1) Compounds produced in the manner of example 1
Example 2
6- (3-Chloroanilino) purine
After 4 mmol of 6-chloropurine was dissolved in 20 ml of butanol, 5 mmol of 3-chlorobenzenemethylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90℃for 4 hours. After cooling, the product is filtered off, washed with water and butanol and crystallized from dimethylformamide or ethanol. HPLC: the purity is more than 97 percent. The yield was 94%.
Table (2) Compounds produced in the manner of example 2
Example 3
2-hydroxy-6-chloropurine
After 4 mmol of 2-amino-6-chloropurine was dissolved in 35 ml of 50wt% sulfuric acid, 5 mmol of sodium nitrate was added. The mixture was reacted at-10℃for 2 hours and then at 50℃for 1 hour. After cooling, the product is filtered off, washed with water and butanol and crystallized from dimethylformamide or ethanol. HPLC: the purity is more than 98 percent. The yield was 86%. MS (ESI) M/e 170.88 (M+H) + )；1H NMR(DMSO-d6):8.01(s,1H,＝CH-N),13.26(s,2H,OH and NH).
Example 4
2-hydroxy-6- (3-chlorobenzylamino) purine
After dissolving 3 mmol of 2-hydroxy-6-chloropurine obtained in example 3 in 20 ml of butanol, 4 mmol of 3-chlorobenzenemethylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90℃for 4 hours. After cooling, the product is filtered off, washed with water and butanol and crystallized from dimethylformamide or ethanol. HPLC: the purity is more than 97 percent. The yield thereof was found to be 93%.
Table (3) Compounds produced in the manner of example 4
Example 5
2-methyl-6-chloropurine
After 3 mmol of 2-iodo-6-chloropurine was dissolved in 20 ml of butanol, 4 mmol of methylmanganese chloride was added. The mixture was reacted at 80℃for 24 hours under palladium catalysis. After cooling, the product is filtered off, washed with water and butanol and crystallized from dimethylformamide or ethanol. HPLC: the purity is more than 97 percent. The yield was 91%.
Example 6
2-methyl-6- (3-chlorobenzylamino) purine
After 3 mmol of 2-methyl-6-chloropurine obtained in example 5 was dissolved in 20 ml of butanol, 4 mmol of 3-chlorobenzenemethylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90℃for 4 hours. After cooling, the product is filtered off, washed with water and butanol and crystallized from dimethylformamide or ethanol. HPLC: the purity is more than 98 percent. The yield thereof was found to be 93%.
Table (4) Compounds produced in the manner of example 6
Example 7
2- (3-Chloromethylamino) -6-aminopurine
After 4 mmol of 2-chloro-6-aminopurine was dissolved in 20 ml of butanol, 5 mmol of 3-chlorobenzenemethylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90℃for 4 hours. After cooling, the product is filtered off, washed with water and butanol and crystallized from dimethylformamide or ethanol. HPLC: the purity is more than 95 percent. The yield was 92%.
Table (5) Compounds produced in the manner of example 7
Example 8
2- (3-Chloromethylamino) -6-hydroxy-purine
After 4 mmol of 2-chloro-6-hydroxy-purine was dissolved in 20 ml of butanol, 5 mmol of 3-chlorobenzenemethylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90℃for 4 hours. After cooling, the product is filtered off, washed with water and butanol and crystallized from dimethylformamide or ethanol. HPLC: the purity is more than 91 percent. The yield was 88%.
Table (6) Compounds produced in the manner of example 8
AMPK activity assay
Analysis of the effect of the target compounds on AMPK activation was performed on mouse muscle cells C2C12, mouse fibroblasts 3T3-L1 and human hepatoma cells Hep G2. Cells in high glucose DMEM cell culture medium containing 10wt% Fetal Bovine Serum (FBS), 4mM L-glutamic acid (L-glutamine), 2mM sodium pyruvate (sodium pyruvate) and 1wt% penicillin/streptomycin (Lefu life technologies, invitrogen) at 37℃5% (v/v) CO 2 Culturing in the environment. 3X 10 5 Cells were seeded on 6-well plates for 24 hoursCells were then treated with the indicated compounds for 30 minutes, then lysed and analyzed by western blot. Equal amounts of protein were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and transferred to polyvinylidene fluoride membranes. After the transferred polyvinylidene fluoride membrane is soaked in 3wt% bovine serum albumin dissolved in PBS buffer for 60 minutes, an anti-phosphorylated AMPK (Thr 172) antibody (1:2000 (v/v), cell technology Cell signaling), an anti-AMPK antibody (1:2000 (v/v), cell technology Cell signaling), an anti-glucose transporter-4 antibody (1:1000, milbot Millipore) or an anti-motor protein antibody (1:5000 (v/v); merck) are respectively added to act at 4 ℃. After 16 hours, the corresponding secondary antibody was added and reacted at room temperature for 1 hour. The immunoreactive band is detected with a luminescent substrate and the signal is recorded with a negative film. The resulting signals were scanned and analyzed by the image analysis quantification software (Total Lab Quant) (Total Lab).
The effect of various compounds on AMPK activation is counted in table 7. Most of the tested compounds significantly activated AMPK in mouse muscle cells C2C12, mouse fibroblasts 3T3-L1 and human hepatoma cells Hep G2 cells.
Watch (7)
Glucose uptake-in vitro analysis
The effect of representative compounds on glucose uptake was analyzed on muscle cells C2C12 using fluorescent glucose analogs (2-NBDG, molecular Probes). After C2C12 cells were treated with the selected novel AMPK activator at 37℃for 30 minutes, 500. Mu.M fluorescent glucose analog was added, and after 5 minutes of incubation at room temperature, the cells were washed three times with phosphate buffer solution and fixed with 70% (v/v) ethanol. Fluorescence of intracellular glucose analogs is detected by a fluorescence photometer.
The effect of a portion of the selected compounds on glucose uptake is counted in table 8. Most of the compounds tested significantly promoted glucose uptake by C2C12 cells. Data are expressed as mean ± standard deviation of three independent experiments.
Watch (8)
In vivo testing
To further evaluate the effect of representative compounds on the modulation of plasma glucose levels, experiments were performed with high fat diet fed mice as an animal model of type ii diabetes. C57BL/6J mice were fed either high fat diet (60% kcal% fat) or normal diet at 22 ℃ for 12 hours day/night circulation. 0.1-50 mg/kg of the selected compound was administered to 24-week-old mice by intraperitoneal injection, and blood glucose levels were measured 1 and 3 hours after injection. The mice were fed with the high fat diet intraperitoneally twice a day for 6 days, and after 1 hour of the last administration, plasma was collected and the plasma glucose and triglyceride levels were measured.
The selected compounds were found to reduce plasma glucose by more than 30wt%, triglyceride by more than 35wt% and body weight by more than 15% compared to high fat diet fed mice administered normal saline.
The foregoing description is only of the preferred embodiments of the present invention and is not intended to limit the scope of the invention, and other equivalent variations using the spirit of the invention should be considered as falling within the scope of the invention.

Claims (3)

1. Use of a compound that activates AMPK and/or a pharmaceutically or nutraceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or physiological condition ameliorated by an AMPK activator, characterized in that the use consists of: administering to a mammal in need of such treatment the AMPK-activating compound and/or a pharmaceutically or nutritionally acceptable salt thereof at a dose of 0.1 mg/kg to 50 mg/kg, wherein an increase in cellular glucose uptake and a decrease in plasma triglycerides of said mammal is detected, wherein said compound is at least one selected from the group consisting of: 5-methylcytosine, thymine, cytosine, uracil and 5, 6-dihydrouracil.
2. The use of claim 1, wherein administration of at least one of the compounds and/or pharmaceutically or nutraceutically acceptable salts thereof to the mammal increases the uptake of glucose by cells of the mammal, thereby treating a physiological condition selected from the group consisting of: pre-diabetes, type II diabetes, syndrome X, and metabolic syndrome.
3. The use of claim 1, wherein administration of at least one of the compounds and/or pharmaceutically or nutraceutically acceptable salts thereof to the mammal reduces plasma triglycerides and reduces body weight of the mammal, thereby treating obesity.
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