Abstract:
The present invention relates to a method for treating disease or condition susceptible to amelioration by AMPK activators and compounds of formula which are useful to activate AMP-activated protein kinase (AMPK) and the use of the compounds in the prevention or treatment of disease, including pre-diabetes, type 2 diabetes, syndrome X, metabolic syndrome and obesity.

Description:
BACKGROUND OF THE INVENTION 
       [0001]    1. Technical Field 
         [0002]    The present invention relates to a method for treating disease or condition susceptible to amelioration by AMPK activators and compounds of formula which are useful to activate AMP-activated protein kinase (AMPK) and the use of the compounds in the prevention or treatment of disease, including pre-diabetes, type 2 diabetes, syndrome X, metabolic syndrome and obesity. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0003]    2. Description of Related Art 
         [0004]    Adenosine 5′-monophosphate-activated protein kinase (AMPK) is a cellular energy sensor and a responder to energy demand. AMPK is a heterotrimer composed of catalytic α subunit and regulatory β, γ subunits. All these subunits are highly conserved in eukaryotes. The activation of AMPK is through phosphorylation on the conserved 172 th -threonine residue of α subunit by upstream kinasessuch as LKB1, Ca 2+ /Calmodulin dependent kinase, and TAK1. High AMP/ATP ratio caused by physiological or pathological stress activates AMPK. Upon activation, AMPK activates catabolic pathway and inhibits anabolism which in term restores cellular energy balance by decreasing ATP consumption and promoting ATP generation. 
         [0005]    As a regulator of energy homeostasis, AMPK has been suggested to be a potential drug target for metabolic syndromes including type II diabetes, cardio-vascular disease, and fatty liver disease. Many of the metabolic syndromes are linked to insulin resistance. Insulin resistance is a pathological condition in which cells fail to respond to insulin thus excess glucose in the blood stream cannot be removed into skeletal muscle or fat tissue. The activation of AMPK increases protein level of GLUT4, a glucose transporter, via transcriptional regulation and induces GLUT4 translocation to the plasma membrane in muscle cells in an insulin independent manner resulting in increases in the rate of cellular glucose uptake. Activation of AMPK also inhibits fatty acids and cholesterol synthesis via suppressing acetyl-CoA carboxylase and HMG-CoA reductase, respectively. In addition, activation of AMPK leads to inhibition of several transcription factors, including SREBP-1c, ChREBP and HNF-4a, and down-regulates the expression of enzymes which are mainly involved in fatty acid synthesis and gluconeogenesis. These findings support the idea that AMPK is a target of choice in the treatment of metabolic syndrome, in particular, diabetes. 
         [0006]    AMP is the natural activator of AMPK in cells. However, it&#39;s an unstable compound and extracellular application of AMP might trigger purinergic receptor-mediated signaling (that might lead to apoptosis etc). As a result, many researchers have been devoted to AMPK activator development. Compounds such as 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) and metformin can activate AMPK at high concentration in vivo. Metformin has been used to treat pre-diabetes, insulin resistance, syndrome X and type 2 diabetes. However, its side effects include lactic acidosis, especially when patients have renal insufficiency. Developing novel AMPK activators with lower effective concentration and fewer side effects is therefore urgent. 
       BRIEF SUMMARY OF THE INVENTION 
       [0007]    The present invention is direct to compounds of formulae I and II and the tautomer 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    , wherein R2 is hydrogen, halogen, hydroxy group, amino group or amino group with mono or di-substituted with hydrocarbon group at most 10 carbon, mercapto, carboxyl, nitro, sulfo, alkyl, alkylamino, alkylmercapto, alkoxy, cycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, acyl, aryl, substituted aryl, aryloxy;
 
R6 is hydroxy group, amino group, mercapto group, —NHR group, where R is halogen, hydroxy group, amino group or amino group with mono or di-substituted with hydrocarbon group at most 10 carbon, mercapto, carboxyl, nitro, sulfo, alkyl, alkylamino, alkylmercapto, alkoxy, cycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, acyl, aryl, substituted aryl, aryloxy;
 
R3 is hydrogen or alkyl group at most 10 carbon; or its tautomer or pharmaceutically acceptable salts thereof, and an AMPK activator which comprises said purine and pyrimidine derivatives or pharmaceutical acceptable salts thereof as an active compound.
 
         [0008]    The generic substitutes have meanings identical with definition, wherein 
         [0009]    “hydroxy” refers to the group —OH; 
         [0010]    “halogen” refers to F, Cl, Br, I; 
         [0011]    “amino” refers to the group —NH 2 ; 
         [0012]    “mercapto” refers to the group —SH; 
         [0013]    “carboxyl” refers to the group —C(O)OR, where R is hydrogen, alkyl, substituted alkyl, acryl, substitute acryl s defined herein; 
         [0014]    “nitro” refers to the group —NO 2 ; 
         [0015]    “sulfo” refers to the group —SO 3 R, whereas R is hydrogen, alkyl, or substituted alkyl as defined herein; 
         [0016]    “alkyl” refers to linear or branched chain at most 10 carbons which is saturated or unsaturated being selected from the group such as methyl, propyl, isopropyl, butyl, allyl, vinyl, ethinyl, propargyl, hexen-2-yl and the like exemplifying this term; 
         [0017]    “substituted alkyl” refers to alkyl including one to seven substituents such as hydroxy, mercapto, alkylamino, alkylmercapto, halogen, alkoxy, acyloxy, amino, carboxy, sulfo, acyl, and the like, whereby these group may be attach to any carbon of the alkyl moiety; 
         [0018]    “alkylamino” refers to the group —NRR′, where R and R′ are independently hydrogen, alkyl, substituted alkyl, acryl, substituted acryl as defined herein; 
         [0019]    “alkylmercapto” refers to the group —SR, where R is alkyl, substituted alkyl, acryl, substituted acryl as defined herein; 
         [0020]    “alkoxy” refers to the group —OR, where R is alkyl, substituted alkyl, acryl, substituted acryl as defined herein; 
         [0021]    “cycloalkyl′ refers to a cyclic or polycyclic alky group containing 3 to 15 carbon. 
         [0022]    “acyl” refers to the group —C(O)R, where R is hydrogen, alkyl, substituted alkyl, acryl, substituted acryl as defined herein; 
         [0023]    “aryl” refers to an aromatic carbocyclic group; 
         [0024]    “substituted aryl” refers to aryl group containing substituents such as halogen, hydroxy, amino, mercapto, alkoxy, sulfo, carboxy, alkyl as defined herein; 
         [0025]    “aryloxy” refers to the group —OAr, where Ar is aryl, substitute aryl as defined herein; 
         [0026]    Therefore, particularly preferred AMPK activating compounds include adenine, 2-amino-6-methylaminopurine, 2-amino-6-ethylaminopurine, 2-amino-6-isobutylaminopurine, 2-amino-6-propylaminopurine, 2-amino-6-isopentylaminopurine, 2-amino-6-hexylaminopurine, 2-amino-6-cyclopropylaminopurine, 2-amino-6-cyclobutylaminopurine, 2-amino-6-cyclopentylaminopurine, 2-amino-6-cyclohexylaminopurine, 2-amino-6-anilinopurine, 2-amino-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-fluoroanilino)purine, 2-amino-6-(4-fluoroanilino)purine, 2-amino-6-benzylaminopurine, 2-amino-6-(2-methylbenzylamino)purine, 2-amino-6-(3-methylbenzylamino)purine, 2-amino-6-(4-methylbenzylamino)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-amino-6-(3-fluorobenzylamino)purine, 2-amino-6-(4-fluorobenzylamino)purine, 2-amino-6-(3-iodobenzylamino)purine, 2-amino-6-(4-hydroxybenzylamin)purine, 2-amino-6-(2,3-dihydroxybenzylamino)purine, 2-amino-6-(3,4-dihydroxybenzylamino)purine, 2-amino-6-(2,4-dihydroxybenzylamino)purine, 2-amino-6-(2-methoxylbenzylamino)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-ethylaminopurine, 6-propylaminopurine, 6-Isobutylaminopurine, 6-Isopentylaminopurine, 6-hexylaminopurine, 6-cyclopropylaminopurine, 6-cyclobutylaminopurine, 6-cyclopantylaminopurine, 6-cyclohexylaminopurine, 6-anilinopurine, 6-(2-chloroanilino)purine, 6-(3-chloroanilino)purine, 6-(4-chloroanilino)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-dihydroxybenzylamino)purine, 6-(3,4-dihydroxybenzylamino)purine, 6-(2,4-dihydroxybenzylamino)purine, 6-(2-methoxylbenzylamino)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-ethylaminopurine, 2-hydroxy-6-isobutylaminopurine, 2-hydroxy-6-propylaminopurine, 2-hydroxy-6-isopentylaminopurine, 2-hydroxy-6-hexylaminopurine, 2-hydroxy-6-cyclopropylaminopurine, 2-hydroxy-6-cyclobutylaminopurine, 2-hydroxy-6-cyclopentylaminopurine, 2-hydroxy-6-cyclohexylaminopurine, 2-hydroxy-6-anilinopurine, 2-hydroxy-6-(2-chloroanilino)purine, 2-hydroxy-6-(3-chloroanilino)purine, 2-hydroxy-6-(4-chloroanilino)purine, 2-hydroxy-6-(2-bromoanilino)purine, 2-hydroxy-6-(3-bromoanilino)purine, 2-hydroxy-6-(4-bromoanilino)purine, 2-hydroxy-6-(2-fluoroanilino)purine, 2-hydroxy-6-(3-fluoroanilino)purine, 2-hydroxy-6-(4-fluoroanilino)purine, 2-hydroxy-6-benzylaminopurine, 2-hydroxy-6-(2-methylbenzylamino)purine, 2-hydroxy-6-(3-methylbenzylamino)purine, 2-hydroxy-6-(4-methylbenzylamino)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-fluorobenzylamino)purine, 2-hydroxy-6-(3-iodobenzylamino)purine, 2-hydroxy-6-(4-hydroxybenzylamin)purine, 2-hydroxy-6-(2,3-dihydroxybenzylamino)purine, 2-hydroxy-6-(3,4-dihydroxybenzylamino)purine, 2-hydroxy-6-(2,4-dihydroxybenzylamino)purine, 2-hydroxy-6-(2-methoxylbenzylamino)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-ethylaminopurine, 2-methyl-6-isobutylaminopurine, 2-methyl-6-propylaminopurine, 2-methyl-6-isopentylaminopurine, 2-methyl-6-hexylaminopurine, 2-methyl-6-cyclopropylaminopurine, 2-methyl-6-cyclobutylaminopurine, 2-methyl-6-cyclopentylaminopurine, 2-methyl-6-cyclohexylaminopurine, 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-fluoroanilino)purine, 2-methyl-6-(4-fluoroanilino)purine, 2-methyl-6-benzylaminopurine, 2-methyl-6-(2-methylbenzylamino)purine, 2-methyl-6-(3-methylbenzylamino)purine, 2-methyl-6-(4-methylbenzylamino)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-hydroxybenzylamin)purine, 2-methyl-6-(2,3-dihydroxybenzylamino)purine, 2-methyl-6-(3,4-dihydroxybenzylamino)purine, 2-methyl-6-(2,4-dihydroxybenzylamino)purine, 2-methyl-6-(2-methoxylbenzylamino)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-methyami no-6-aminopurine, 2-ethylamino-6-aminopurine, 2-isobutylamino-6-aminopurine, 2-propylamino-6-aminopurine, 2-isopentylamino-6-aminopurine, 2-hexylamino-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-(2-chloroanilino)-6-aminopurine, 2-(3-chloroanilino)-6-aminopurine, 2-(4-chloroanilino)-6-aminopurine, 2-(2-bromoanilino)-6-aminopurine, 2-(3-bromoanilino)-6-aminopurine, 2-(4-bromoanilino)-6-aminopurine, 2-(2-fluoroanilino)-6-aminopurine, 2-(3-fluoroanilino)-6-aminopurine, 2-(4-fluoroanilino)-6-aminopurine, 2-benzylamino-6-aminopurine, 2-(2-methylbenzylamino)-6-aminopurine, 2-(3-methylbenzylamino)-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-(3,4-dihydroxybenzylamino)-6-aminopurine, 2-(2,4-dihydroxybenzylamino)-6-aminopurine, 2-(2-methoxylbenzylamino)-6-aminopurine, 2-(2,3-dimethoxybenzylamino)-6-aminopurine, 2-(3,5-dimethoxybenzylamino)-6-aminopurine, 2-(2,4,5-trimethoxybenzylamino)-6-aminopurine, 2-(3,4,5-trimethoxybenzylamino)-6-aminopurine, 2-methyamino-6-hydroxypurine, 2-ethylamino-6-hydroxypurine, 2-isobutylamino-6-hydroxypurine, 2-propylamino-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-(2-chloroanilino)-6-hydroxypurine, 2-(3-chloroanilino)-6-hydroxypurine, 2-(4-chloroanilino)-6-hydroxypurine, 2-(2-bromoanilino)-6-hydroxypurine, 2-(3-bromoanilino)-6-hydroxypurine, 2-(4-bromoanilino)-6-hydroxypurine, 2-(2-fluoroanilino)-6-hydroxypurine, 2-(3-fluoroanilino)-6-hydroxypurine, 2-(4-fluoroanilino)-6-hydroxypurine, 2-benzylamino-6-hydroxypurine, 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-(3,4-dihydroxybenzylamino)-6-hydroxypurine, 2-(2,4-dihydroxybenzylamino)-6-hydroxypurine, 2-(2-methoxylbenzylamino)-6-hydroxypurine, 2-(2,3-dimethoxybenzylamino)-6-hydroxypurine, 2-(3,5-dimethoxybenzylamino)-6-hydroxypurine, 2-(2,4,5-trimethoxybenzylamino)-6-hydroxypurine, 2-(3,4,5-trimethoxybenzylamino)-6-hydroxypurine, 6-hydroxypurine, 6-mercaptopurine, 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-dimercaptopurine, 2-mercapto-6-methylaminopurine, 2-mercapto-6-ethylaminopurine, 2-mercapto-6-propylpurine, 2-ethyladenine, 2-ethyl-6-hydroxypurine, 2-ethyl-6-mercaptopurine, 2-ethyl-6-methylaminopurine, 2-ethyl-6-ethylaminopurine, 2-ethyl-6-propylaminopurine, 2-propyadenine, 2-propyl-6-hydroxypurine, 2-propyl-6-mercaptopurine, 2-propyl-6-methylaminopurine, 2-propyl-6-ethylaminopurine, 2-propyl-6-propylaminopurine, 2-amino-6-benzylaminopurine, 2-ethyl-6-benzylaminopurine, 2-propyl-6-benzylaminopurine, 2-ethyl-6-anilinopurine, 2-propyl-6-anilinopurine, 2-benzyl-adenine, 2-benzyl-6-hydroxypurine, 2-benzyl-6-mercaptopurine, 2-benzyl-6-methyaminopurine, 2-benzyl-6-ethylaminopurine, 2-benzyl-6-propylaminopurine, 2-phenyl-adenine, 2-phenyl-6-hydroxypurine, 2-phenyl-6-mercaptopurine, 2-phenyl-6-methyaminopurine, 2-phenyl-6-ethylaminopurine, 2-phenyl-6-propylaminopurine, 2-mercapto-N 6 -2-isopentenyladenine, 2-ethyl-N 6 -2-isopentenyladenine, 2-propyl-N 6 -2-isopentenyladenine, 2-benzyl-N 6 -2-isopentenyladenine, 2-phenyl-N 6 -2-isopentenyladenine, 2-chloroadenine, 2-chloro-6-hydroxypurine, 2-chloro-6-mercaptopurine, 2-chloro-6-methyaminopurine, 2-chloro-6-ethylpurine, 2-chloro-6-propylaminopurine, 2-chloro-6-benzylaminopurine, 2-chloro-6-anilinopurine, 2-chloro-N 6 -2-isopentenyladenine, 2-fluoroadenine, 2-fluoro-6-hydroxypurine, 2-fluoro-6-mercaptopurine, 2-fluoro-6-methyaminopurine, 2-fluoro-6-ethylpurine, 2-fluoro-6-propylaminopurine, 2-fluoro-6-benzylaminopurine, 2-fluoro-6-anilinopurine, 2-fluro-N 6 -2-isopentenyladenine, 2-bromoadenine, 2-bromo-6-hydroxypurine, 2-bromo-6-mercaptopurine, 2-bromo-6-methyaminopurine, 2-bromo-6-ethylpurine, 2-bromo-6-propylaminopurine, 2-bromo-6-benzylaminopurine, 2-bromo-6-anilinopurine, 2-bromo-N 6 -2-isopentenyladenine, 2-iodoadenine, 2-iodo-6-hydroxypurine, 2-iodo-6-mercaptopurine, 2-iodo-6-methyaminopurine, 2-iodo-6-ethylpurine, 2-iodo-6-propylaminopurine, 2-iodo-6-benzylaminopurine, 2-iodo-6-anilinopurine, 2-iodo-N 6 -2-isopentenyladenine, 2-mercapto-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-methylbut-2-enylamino)purine, 2-hydroxy-6-(4-Hydroxy-3-methylbut-2-enylamino)purine, 2-mercapto-6-(4-Hydroxy-3-methylbut-2-enylamino)purine, 2-methyl-6-(4-Hydroxy-3-methylbut-2-enylamino)purine, 2-ethyl-6-(4-Hydroxy-3-methylbut-2-enylamino)purine, 2-propyl-6-(4-Hydroxy-3-methylbut-2-enylamino)purine, 2-benzyl-6-(4-Hydroxy-3-methylbut-2-enylamino)purine, 2-phenyl-6-(4-Hydroxy-3-methylbut-2-enylamino)purine, 2-chloro-6-(4-Hydroxy-3-methylbut-2-enylamino)purine, 2-fluoro-6-(4-Hydroxy-3-methylbut-2-enylamino)purine, 2-bromo-6-(4-Hydroxy-3-methylbut-2-enylamino)purine, 2-iodo-6-(4-Hydroxy-3-methylbut-2-enylamino)purine, 2-cyclohexyl-6-(4-Hydroxy-3-methylbut-2-enylamino)purine, 2-amino-6-Furfurylaminopurine, 2-hydroxy-6-Furfurylaminopurine, 2-mercapto-6-Furfurylaminopurine, 2-methyl-6-Furfurylaminopurine, 2-ethyl-6-Furfurylaminopurine, 2-propyl-6-Furfurylaminopurine, 2-benzyl-6-Furfurylaminopurine, 2-phenyl-6-Furfurylaminopurine, 2-chloro-6-Furfurylaminopurine, 2-fluoro-6-Furfurylaminopurine, 2-bromo-6-Furfurylaminopurine, 2-iodo-6-Furfurylaminopurine, 2-cyclohexyl-6-Furfurylaminopurine, 2-amino-6-acetylaminopurine, 2-hydroxy-6-acetylaminopurine, 2-mercapto-6-acetylaminopurine, 2-methyl-6-acetylaminopurine, 2-ethyl-6-acetylaminopurine, 2-propyl-6-acetylaminopurine, 2-benzyl-6-acetylaminopurine, 2-phenyl-6-acetylaminopurine, 2-chloro-6-acetylaminopurine, 2-fluoro-6-acetylaminopurine, 2-bromo-6-acetylaminopurine, 2-iodo-6-acetylaminopurine, 2-cyclohexyl-6-acetylaminopurine, 2-dimethylamino-6-hydroxypurine, guanine, xanthine, hypoxanthine, 6-thioguanine, 5-methylcytosine, 5,6-dihydrouracil, thymine, cytosine, uracil, 5-fluorouracil, floxuridine, 6-azauracil, each of which may be present as a salt, a hydrate, in form as a prodrug or as a metabolite. 
         [0027]    According to one embodiment of the present invention there is provided a method of treating disease regulated by activation of AMPK which are useful for the prevention or treatment of pre-diabetes administrating a therapeutically effective amount of a compound of formula (I) in a mammal. 
         [0028]    According to one embodiment of the present invention there is provided a method of treating disease regulated by activation of AMPK which are useful for the prevention or treatment of pre-diabetes administrating a therapeutically effective amount of a compound of formula (II) in a mammal. 
         [0029]    According to one embodiment of the present invention there is provided a method of treating disease regulated by activation of AMPK which are useful for the prevention or treatment of insulin resistance administrating a therapeutically effective amount of a compound of formula (I) in a mammal. 
         [0030]    According to one embodiment of the present invention there is provided a method of treating disease regulated by activation of AMPK which are useful for the prevention or treatment of insulin resistance administrating a therapeutically effective amount of a compound of formula (II) in a mammal. 
         [0031]    According to one embodiment of the present invention there is provided a method of treating disease regulated by activation of AMPK which are useful for the prevention or treatment of type 2 diabetes administrating a therapeutically effective amount of a compound of formula (I) in a mammal. 
         [0032]    According to one embodiment of the present invention there is provided a method of treating disease regulated by activation of AMPK which are useful for the prevention or treatment of type 2 diabetes administrating a therapeutically effective amount of a compound of formula (II) in a mammal. 
         [0033]    According to one embodiment of the present invention there is provided a method of treating disease regulated by activation of AMPK which are useful for the prevention or treatment of syndrome X administrating a therapeutically effective amount of a compound of formula (I) in a mammal. 
         [0034]    According to one embodiment of the present invention there is provided a method of treating disease regulated by activation of AMPK which are useful for the prevention or treatment of syndrome X administrating a therapeutically effective amount of a compound of formula (II) in a mammal. 
         [0035]    According to one embodiment of the present invention there is provided a method of treating disease regulated by activation of AMPK which are useful for the prevention or treatment of metabolic syndrome administrating a therapeutically effective amount of a compound of formula (I) in a mammal. 
         [0036]    According to one embodiment of the present invention there is provided a method of treating disease regulated by activation of AMPK which are useful for the prevention or treatment of metabolic syndrome administrating a therapeutically effective amount of a compound of formula (II) in a mammal. 
         [0037]    According to one embodiment of the present invention there is provided a method of treating disease regulated by activation of AMPK which are useful for the prevention or treatment of obesity administrating a therapeutically effective amount of a compound of formula (I) in a mammal. 
         [0038]    According to one embodiment of the present invention there is provided a method of treating disease regulated by activation of AMPK which are useful for the prevention or treatment of obesity administrating a therapeutically effective amount of a compound of formula (II) in a mammal. 
         [0039]    According to one embodiment of the present invention there is provided a pharmaceutical composition comprising a therapeutically effect amount of a compound of formula (I) in combination with pharmaceutically suitable carrier. 
         [0040]    According to one embodiment of the present invention there is provided a pharmaceutical composition comprising a therapeutically effect amount of a compound of formula (II) in combination with pharmaceutically suitable carrier. 
         [0041]    According to one embodiment of the present invention, the pharmaceutically composition may additionally including second pharmaceutical agent for treatment of pre-diabetes, insulin resistance, type 2 diabetes, syndrome X, metabolic syndrome. The suitable second pharmaceutical agents include various biguanides, thiazolidinediones, thienopyridones, and other AMPK activators. 
         [0042]    As set forth herein, the present invention includes administering pharmaceutically effect amount of any compounds of formula (I) and (II) and the salts and prodrugs thereof to a mammal. Preferably, the present invention also includes administering pharmaceutically effect amount of any compounds of formula (I) and (II) to a human and more preferable to a human in need of treatment for any disorders set forth herein. 
       BRIEF DESCRIPTION OF THE DRAWINGS 
       [0043]    NO DRAWING 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Definition 
       [0000]    
       
         “AMPK” used herein refers to adenosine 5′-monophosphate-activated protein kinase. 
         “pre-diabetes” used herein refers to a physiological condition characterized by a fasting blood sugar higher than 100 mg/dL but below than 140 mg/dL. 
         “insulin resistance” used herein refers to a physiological condition in which whole body or tissues including liver, skeletal muscle, adipose tissue fail to response to insulin. 
         “type 2 diabetes” used herein also known as noninsulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes. It refers to a metabolic disorder caused by insufficient insulin production or insulin resistance which often manifested by a fasting glucose higher than 140 mg/dL. 
         “syndrome X” used herein refers to a condition characterized by symptoms of at least two of the following: Fasting hyperglycemia (non-insulin dependent diabetes), high blood pressure, high triglycerides, low HDL cholesterol. 
       
     
       Example 1 
     2-amino-6-(3-chlorobenzylamino)purine 
       [0049]    4 mmol of 2-amino-6-chloropurine were dissolved in 20 mL of butanol and then 5 mmol of 3-chlorobenzylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90° C. for 4 hr. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity&gt;98%. Yield 95%. 
         [0050]    Table 1 compound prepared by the method of example 1 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 Compounds prepared by the method of example 1 
               
             
          
           
               
                   
                 CHN analysis 
                   
               
               
                   
                 Found/Calculated 
                 ESI-MS 
               
             
          
           
               
                 R 6  substitution 
                 % C 
                 % H 
                 % N 
                 [M + H + ] 
               
               
                   
               
               
                 methylamino 
                 43.5/43.9 
                 5.1/4.9 
                 51.4/51.2 
                 165 
               
               
                 ethylamino 
                 47.0/47.2 
                 5.5/5.7 
                 47.5/47.2 
                 179 
               
               
                 isobutylamino 
                 52.5/52.4 
                 6.2/6.8 
                 41.3/40.7 
                 207 
               
               
                 propylamino 
                 50.3/50.0 
                 6.2/6.3 
                 43.5/43.7 
                 193 
               
               
                 isopentylamino 
                 54.4/54.5 
                 7.3/7.3 
                 38.3/38.2 
                 221 
               
               
                 hexylamino 
                 56.0/56.4 
                 7.6/7.7 
                 36.4/35.9 
                 235 
               
               
                 cyclopropylamino 
                 49.9/50.5 
                 5.5/5.3 
                 44.6/44.2 
                 191 
               
               
                 cyclobutylamino 
                 53.0/52.9 
                 6.1/5.9 
                 40.9/41.1 
                 205 
               
               
                 cyclopentylamino 
                 54.5/55.0 
                 6.3/6.5 
                 39.2/38.5 
                 219 
               
               
                 cyclohexylamino 
                 56.8/56.9 
                 6.8/6.9 
                 36.4/36.2 
                 233 
               
               
                 anilino 
                 58.5/58.4 
                 4.6/4.5 
                 36.9/37.1 
                 227 
               
               
                 2-chloroanilino 
                 51.0/50.7 
                 3.4/3.5 
                 32.3/32.2 
                 261 
               
               
                 3-chloroanilino 
                 50.2/50.7 
                 3.7/3.5 
                 32.8/32.2 
                 261 
               
               
                 4-chloroanilino 
                 50.6/50.7 
                 3.7/3.5 
                 32.5/32.2 
                 261 
               
               
                 2-bromoanilino 
                 42.5/43.3 
                 3.3/3.0 
                 27.1/27.5 
                 306 
               
               
                 3-bromoanilino 
                 42.2/43.3 
                 3.5/3.0 
                 27.6/27.5 
                 306 
               
               
                 4-bromoanilino 
                 43.1/43.3 
                 2.9/3.0 
                 27.7/27.5 
                 306 
               
               
                 2-fluoroanilino 
                 54.0/54.1 
                 3.5/3.7 
                 34.6/34.4 
                 245 
               
               
                 3-fluoroanilino 
                 54.4/54.1 
                 3.8/3.7 
                 34.1/34.4 
                 245 
               
               
                 4-fluoroanilino 
                 54.7/54.1 
                 3.6/3.7 
                 34.5/34.4 
                 245 
               
               
                 benzylamino 
                 59.6/60.0 
                 5.2/5.0 
                 35.2/35.0 
                 241 
               
               
                 2-methylbenzylamino 
                 61.1/61.4 
                 5.4/5.5 
                 33.5/33.0 
                 255 
               
               
                 3-methylbenzylamino 
                 61.5/61.4 
                 5.3/5.5 
                 33.2/33.0 
                 255 
               
               
                 4-methylbenzylamino 
                 61.8/61.4 
                 5.7/5.5 
                 32.5/33.0 
                 255 
               
               
                 2-chlorobenzylamino 
                 51.1/52.5 
                 4.3/4.0 
                 31.1/30.6 
                 276 
               
               
                 3-chlorobenzylamino 
                 52.1/52.5 
                 3.9/4.0 
                 31.5/30.6 
                 276 
               
               
                 4-chlorobenzylamino 
                 52.6/52.5 
                 3.8/4.0 
                 30.4/30.6 
                 276 
               
               
                 2-fluorobenzylamino 
                 55.2/55.8 
                 4.2/4.3 
                 32.9/32.5 
                 259 
               
               
                 3-fluorobenzylamino 
                 56.1/55.8 
                 4.0/4.3 
                 32.6/32.5 
                 259 
               
               
                 4-fluorobenzylamino 
                 55.3/55.8 
                 4.5/4.3 
                 32.6/32.5 
                 259 
               
               
                 3-iodobenzylamino 
                 40.1/39.4 
                 2.7/3.0 
                 23.5/23.0 
                 367 
               
               
                 4-hydroxybenzylamino 
                 56.1/56.2 
                 4.8/4.7 
                 33.0/32.8 
                 257 
               
               
                 2,3-dihydroxybenzylamino 
                 53.1/52.9 
                 4.0/4.4 
                 30.5/30.9 
                 273 
               
               
                 3,4-dihydroxybenzylamino 
                 53.2/52.9 
                 4.5/4.4 
                 30.1/30.9 
                 273 
               
               
                 2,4-dihydroxybenzylamino 
                 53.6/52.9 
                 4.3/4.4 
                 30.8/30.9 
                 273 
               
               
                 2-methoxylbenzylamino 
                 57.1/57.8 
                 5.5/5.2 
                 31.3/31.1 
                 271 
               
               
                 2,3-dimethoxybenzylamino 
                 56.4/56.0 
                 5.8/5.4 
                 27.1/28.0 
                 301 
               
               
                 3,5-dimethoxybenzylamino 
                 56.7/56.0 
                 5.1/5.4 
                 27.8/28.0 
                 301 
               
               
                 2,4,5- 
                 54.1/54.5 
                 5.0/5.5 
                 25.6/25.4 
                 331 
               
               
                 trimethoxybenzylamino 
               
               
                 3,4,5- 
                 54.1/54.5 
                 5.6/5.5 
                 25.8/25.4 
                 331 
               
               
                 trimethoxybenzylamino 
               
               
                   
               
             
          
         
       
     
       Example 2 
     6-(3-chlorobenzylamino)purine 
       [0051]    4 mmol of 6-chloropurine were dissolved in 20 mL of butanol and then 5 mmol of 3-chlorobenzylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90° C. for 4 hr. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity&gt;97%. Yield 94%. 
         [0052]    Table 2 compound prepared by the method of example 2 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 Compounds prepared by the method of example 2 
               
             
          
           
               
                   
                 CHN analysis 
                 ESI-MS 
               
               
                   
                 Found/Calculated 
                 [M + 
               
             
          
           
               
                 R 6  substitution 
                 % C 
                 % H 
                 % N 
                 H + ] 
               
               
                   
               
               
                 methylamino 
                 48.1/48.3 
                 4.9/4.7 
                 47.0/47.0 
                 150 
               
               
                 ethylamino 
                 51.8/51.5 
                 5.7/5.6 
                 42.5/42.9 
                 164 
               
               
                 propylamino 
                 54.0/54.2 
                 6.4/6.3 
                 39.6/39.5 
                 178 
               
               
                 Isobutylamino 
                 56.7/56.5 
                 7.1/6.9 
                 36.2/36.6 
                 192 
               
               
                 Isopentylamino 
                 58.8/58.5 
                 7.5/7.4 
                 37.7/34.1 
                 206 
               
               
                 hexylamino 
                 60.1/60.2 
                 7.9/7.8 
                 32.0/31.9 
                 220 
               
               
                 cyclopropylamino 
                 54.4/54.8 
                 5.5/5.2 
                 40.1/40.0 
                 176 
               
               
                 cyclobutylamino 
                 56.2/57.1 
                 6.2/5.9 
                 37.6/37.0 
                 190 
               
               
                 cyclopantylamino 
                 59.2/59.1 
                 6.6/6.4 
                 34.2/34.5 
                 204 
               
               
                 cyclohexylamino 
                 60.5/60.8 
                 7.1/7.0 
                 32.4/32.2 
                 218 
               
               
                 anilino 
                 62.6/62.5 
                 4.5/4.3 
                 32.9/33.2 
                 212 
               
               
                 2-chloroanilino 
                 53.5/53.8 
                 3.4/3.3 
                 28.8/28.5 
                 247 
               
               
                 3-chloroanilino 
                 53.2/53.8 
                 3.4/3.3 
                 28.7/28.5 
                 247 
               
               
                 4-chloroanilino 
                 53.6/53.8 
                 3.1/3.3 
                 28.9/28.5 
                 247 
               
               
                 2-bromoanilino 
                 44.9/45.5 
                 3.1/2.8 
                 24.4/24.1 
                 291 
               
               
                 3-bromoanilino 
                 45.9/45.5 
                 3.1/2.8 
                 25.0/24.1 
                 291 
               
               
                 4-bromoanilino 
                 44.9/45.5 
                 3.4/2.8 
                 24.2/24.1 
                 291 
               
               
                 2-fluoroanilino 
                 57.5/57.6 
                 3.3/3.5 
                 30.9/30.6 
                 230 
               
               
                 3-fluoroanilino 
                 57.9/57.6 
                 3.4/3.5 
                 30.5/30.6 
                 230 
               
               
                 4-fluoroanilino 
                 57.5/57.6 
                 3.7/3.5 
                 30.3/30.6 
                 230 
               
               
                 benzylamino 
                 64.2/64.0 
                 5.1/4.9 
                 30.7/31.1 
                 226 
               
               
                 2-methylbenzylamino 
                 65.0/65.3 
                 5.6/5.5 
                 29.4/29.3 
                 240 
               
               
                 3-methylbenzylamino 
                 65.1/65.3 
                 5.8/5.5 
                 29.1/29.3 
                 240 
               
               
                 4-methylbenzylamino 
                 65.8/65.3 
                 5.1/5.5 
                 29.1/29.3 
                 240 
               
               
                 2-chlorobenzylamino 
                 55.2/55.5 
                 3.8/3.9 
                 27.1/27.0 
                 261 
               
               
                 3-chlorobenzylamino 
                 55.9/55.5 
                 3.7/3.9 
                 27.4/27.0 
                 261 
               
               
                 4-chlorobenzylamino 
                 55.6/55.5 
                 3.6/3.9 
                 27.8/27.0 
                 261 
               
               
                 2-fluorobenzylamino 
                 58.9/59.3 
                 4.5/4.1 
                 29.1/28.8 
                 244 
               
               
                 3-fluorobenzylamino 
                 59.1/59.3 
                 4.2/4.1 
                 28.7/28.8 
                 244 
               
               
                 4-fluorobenzylamino 
                 59.8/59.3 
                 3.9/4.1 
                 28.5/28.8 
                 244 
               
               
                 3-iodobenzylamino 
                 41.1/41.0 
                 3.2/2.9 
                 20.1/19.9 
                 352 
               
               
                 4-hydroxybenzylamino 
                 58.9/59.7 
                 4.8/4.6 
                 29.3/29.0 
                 242 
               
               
                 2,3-dihydroxybenzylamino 
                 56.9/56.0 
                 4.1/4.3 
                 26.4/27.2 
                 258 
               
               
                 3,4-dihydroxybenzylamino 
                 56.5/56.0 
                 4.4/4.3 
                 27.5/27.2 
                 258 
               
               
                 2,4-dihydroxybenzylamino 
                 56.7/56.0 
                 4.1/4.3 
                 26.9/27.2 
                 258 
               
               
                 2-methoxylbenzylamino 
                 60.6/61.2 
                 4.5/5.1 
                 28.1/27.4 
                 256 
               
               
                 2,3-dimethoxybenzylamino 
                 59.3/58.9 
                 5.2/5.3 
                 24.2/24.5 
                 286 
               
               
                 3,5-dimethoxybenzylamino 
                 59.2/58.9 
                 5.6/5.3 
                 24.1/24.5 
                 286 
               
               
                 2,4,5-trimethoxybenzylamino 
                 57.5/57.1 
                 5.9/5.4 
                 21.5/22.2 
                 316 
               
               
                 3,4,5-trimethoxybenzylamino 
                 57.4/57.1 
                 5.5/5.4 
                 21.6/22.2 
                 316 
               
               
                   
               
             
          
         
       
     
       Example 3 
     2-hydroxy-6-chloropurine 
       [0053]    4 mmol of 2-amino-6-chloropurine were dissolved in 35 mL of 50% H 2 SO 4  and then 5 mmol of sodium nitrate was added. The mixture was reacted at −10° C. for 2 hr and then 50° C. for another 1 hr. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity&gt;98%. Yield 86%. MS (ESI) m/e 170.88 (M+H + );  1 H NMR (DMSO-d 6 ): 8.01 (s, 1H, ═CH—N), 13.26 (s, 2H, OH and NH). 
       Example 4 
     2-hydroxy-6-(3-chlorobenzylamino)purine 
       [0054]    3 mmol of 2-hydroxy-6-chloropurine from example 3 were dissolved in 20 mL of butanol and then 4 mmol of 3-chlorobenzylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90° C. for 4 hr. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity&gt;97%. Yield 93%. 
         [0055]    Table 3 compound prepared by the method of example 4 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 Compounds prepared by the method of example 4 
               
             
          
           
               
                   
                 CHN analysis 
                 ESI-MS 
               
               
                   
                 Found/Calculated 
                 [M + 
               
             
          
           
               
                 R 6  substitution 
                 % C 
                 % H 
                 % N 
                 H + ] 
               
               
                   
               
               
                 methylamino 
                 43.8/43.6 
                 4.5/4.3 
                 42.0/42.4 
                 166 
               
               
                 ethylamino 
                 47.2/46.9 
                 5.2/5.1 
                 38.7/39.1 
                 180 
               
               
                 propylamino 
                 49.8/49.7 
                 5.3/5.7 
                 36.5/36.2 
                 194 
               
               
                 Isobutylamino 
                 52.4/52.2 
                 6.5/6.3 
                 33.5/33.8 
                 208 
               
               
                 Isopentylamino 
                 54.1/54.3 
                 6.9/6.8 
                 31.9/31.7 
                 222 
               
               
                 hexylamino 
                 56.7/56.2 
                 7.1/7.3 
                 29.9/29.8 
                 236 
               
               
                 cyclopropylamino 
                 50.1/50.3 
                 4.9/4.7 
                 36.7/36.6 
                 192 
               
               
                 cyclobutylamino 
                 52.9/52.7 
                 5.5/5.4 
                 39.6/34.1 
                 206 
               
               
                 cyclopantylamino 
                 54.9/54.8 
                 6.2/6.0 
                 31.5/31.9 
                 220 
               
               
                 cyclohexylamino 
                 57.8/56.6 
                 6.1/6.5 
                 29.5/30.0 
                 234 
               
               
                 anilino 
                 57.9/58.1 
                 4.1/4.0 
                 30.9/30.8 
                 228 
               
               
                 2-chloroanilino 
                 50.1/50.5 
                 3.3/3.1 
                 27.1/26.8 
                 263 
               
               
                 3-chloroanilino 
                 50.3/50.5 
                 3.6/3.1 
                 26.6/26.8 
                 263 
               
               
                 4-chloroanilino 
                 49.8/50.5 
                 3.5/3.1 
                 27.3/26.8 
                 263 
               
               
                 2-bromoanilino 
                 43.5/43.2 
                 2.9/2.6 
                 22.1/22.9 
                 307 
               
               
                 3-bromoanilino 
                 43.1/43.2 
                 2.1/2.6 
                 23.6/22.9 
                 307 
               
               
                 4-bromoanilino 
                 43.5/43.2 
                 2.4/2.6 
                 23.1/22.9 
                 307 
               
               
                 2-fluoroanilino 
                 54.1/53.9 
                 3.7/3.3 
                 28.1/28.6 
                 246 
               
               
                 3-fluoroanilino 
                 54.6/53.9 
                 3.5/3.3 
                 27.9/28.6 
                 246 
               
               
                 4-fluoroanilino 
                 53.3/53.9 
                 3.1/3.3 
                 29.4/28.6 
                 246 
               
               
                 benzylamino 
                 60.3/59.7 
                 4.4/4.6 
                 28.7/29.0 
                 242 
               
               
                 2-methylbenzylamino 
                 61.4/61.2 
                 5.8/5.1 
                 27.1/27.4 
                 256 
               
               
                 3-methylbenzylamino 
                 60.8/61.2 
                 5.2/5.1 
                 27.7/27.4 
                 256 
               
               
                 4-methylbenzylamino 
                 62.0/61.2 
                 4.8/5.1 
                 27.2/27.4 
                 256 
               
               
                 2-chlorobenzylamino 
                 52.5/52.3 
                 3.5/3.7 
                 25.8/25.4 
                 277 
               
               
                 3-chlorobenzylamino 
                 52.4/52.3 
                 3.4/3.7 
                 25.9/25.4 
                 277 
               
               
                 4-chlorobenzylamino 
                 52.1/52.3 
                 3.9/3.7 
                 25.5/25.4 
                 277 
               
               
                 2-fluorobenzylamino 
                 55.7/55.6 
                 4.1/3.9 
                 26.9/27.0 
                 260 
               
               
                 3-fluorobenzylamino 
                 55.2/55.6 
                 4.2/3.9 
                 27.3/27.0 
                 260 
               
               
                 4-fluorobenzylamino 
                 55.9/55.6 
                 3.4/3.9 
                 27.7/27.0 
                 260 
               
               
                 3-iodobenzylamino 
                 39.5/39.3 
                 2.8/2.7 
                 18.6/19.1 
                 368 
               
               
                 4-hydroxybenzylamino 
                 55.4/56.0 
                 4.5/4.3 
                 27.7/27.2 
                 258 
               
               
                 2,3-dihydroxybenzylamino 
                 52.9/52.7 
                 3.8/4.1 
                 25.4/25.6 
                 274 
               
               
                 3,4-dihydroxybenzylamino 
                 52.1/52.7 
                 4.4/4.1 
                 25.7/25.6 
                 274 
               
               
                 2,4-dihydroxybenzylamino 
                 52.9/52.7 
                 4.6/4.1 
                 24.8/25.6 
                 274 
               
               
                 2-methoxylbenzylamino 
                 57.1/57.6 
                 4.2/4.8 
                 26.7/25.8 
                 272 
               
               
                 2,3-dimethoxybenzylamino 
                 54.9/55.8 
                 5.5/5.0 
                 23.4/23.2 
                 302 
               
               
                 3,5-dimethoxybenzylamino 
                 56.1/55.8 
                 4.8/5.0 
                 23.4/23.2 
                 302 
               
               
                 2,4,5-trimethoxybenzylamino 
                 54.0/54.4 
                 5.6/5.2 
                 21.5/21.1 
                 332 
               
               
                 3,4,5-trimethoxybenzylamino 
                 54.5/54.4 
                 5.3/5.2 
                 21.3/21.1 
                 332 
               
               
                   
               
             
          
         
       
     
       Example 5 
     2-methyl-6-chloropurine 
       [0056]    3 mmol of 2-Iodo-6-chloropurine was dissolved in 20 mL of butanol and then 4 mmol of MeMgCl was added. The mixture was reacted at 80° C. for 24 hr under Pd-catalysis. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity&gt;97%. Yield 91%. 
       Example 6 
     2-methy-6-(3-chlorobenzylamino)purine 
       [0057]    3 mmol of 2-methyl-6-chloropurine from example 5 were dissolved in 20 mL of butanol and then 4 mmol of 3-chlorobenzylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90° C. for 4 hr. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity&gt;98%. Yield 93%. 
         [0058]    Table 4 compound prepared by the method of example 6 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 Compounds prepared by the method of example 6 
               
             
          
           
               
                   
                 CHN analysis 
                 ESI-MS 
               
               
                   
                 Found/Calculated 
                 [M + 
               
             
          
           
               
                 R 6  substitution 
                 % C 
                 % H 
                 % N 
                 H + ] 
               
               
                   
               
               
                 methylamino 
                 51.4/51.5 
                 5.9/5.6 
                 42.7/42.9 
                 164 
               
               
                 ethylamino 
                 54.5/54.2 
                 6.4/6.3 
                 39.1/39.5 
                 178 
               
               
                 propylamino 
                 56.1/56.5 
                 6.7/6.9 
                 37.2/36.6 
                 192 
               
               
                 Isobutylamino 
                 58.9/58.5 
                 7.5/7.4 
                 33.6/34.1 
                 206 
               
               
                 Isopentylamino 
                 60.3/60.2 
                 7.4/7.8 
                 32.3/31.9 
                 220 
               
               
                 hexylamino 
                 62.2/61.8 
                 8.1/8.2 
                 29.7/30.0 
                 234 
               
               
                 cyclopropylamino 
                 57.5/57.1 
                 6.3/5.9 
                 36.2/37.0 
                 190 
               
               
                 cyclobutylamino 
                 58.9/59.1 
                 6.2/6.4 
                 34.9/34.5 
                 204 
               
               
                 cyclopantylamino 
                 60.7/60.8 
                 7.3/7.0 
                 32.0/32.2 
                 218 
               
               
                 cyclohexylamino 
                 62.1/62.3 
                 7.7/7.4 
                 30.2/30.3 
                 232 
               
               
                 anilino 
                 64.4/64.0 
                 4.8/4.9 
                 30.8/31.1 
                 226 
               
               
                 2-chloroanilino 
                 55.4/55.5 
                 3.6/3.9 
                 27.5/27.0 
                 261 
               
               
                 3-chloroanilino 
                 55.2/55.5 
                 3.8/3.9 
                 27.4/27.0 
                 261 
               
               
                 4-chloroanilino 
                 55.1/55.5 
                 4.1/3.9 
                 27.3/27.0 
                 261 
               
               
                 2-bromoanilino 
                 47.7/47.4 
                 3.1/3.3 
                 23.1/23.0 
                 305 
               
               
                 3-bromoanilino 
                 48.1/47.4 
                 3.0/3.3 
                 22.7/23.0 
                 305 
               
               
                 4-bromoanilino 
                 47.2/47.4 
                 3.2/3.3 
                 23.5/23.0 
                 305 
               
               
                 2-fluoroanilino 
                 59.5/59.3 
                 4.4/4.1 
                 28.2/28.8 
                 244 
               
               
                 3-fluoroanilino 
                 59.8/59.3 
                 4.0/4.1 
                 28.4/28.8 
                 244 
               
               
                 4-fluoroanilino 
                 59.1/59.3 
                 3.7/4.1 
                 29.4/28.8 
                 244 
               
               
                 benzylamino 
                 65.5/65.3 
                 5.7/5.5 
                 28.8/29.3 
                 240 
               
               
                 2-methylbenzylamino 
                 66.8/66.4 
                 5.9/6.0 
                 27.3/27.6 
                 254 
               
               
                 3-methylbenzylamino 
                 66.9/66.4 
                 5.4/6.0 
                 27.7/27.6 
                 254 
               
               
                 4-methylbenzylamino 
                 65.9/66.4 
                 6.2/6.0 
                 27.9/27.6 
                 254 
               
               
                 2-chlorobenzylamino 
                 57.8/57.0 
                 4.3/4.4 
                 25.4/25.6 
                 275 
               
               
                 3-chlorobenzylamino 
                 57.2/57.0 
                 4.8/4.4 
                 25.1/25.6 
                 275 
               
               
                 4-chlorobenzylamino 
                 56.4/57.0 
                 3.7/4.4 
                 26.7/25.6 
                 275 
               
               
                 2-fluorobenzylamino 
                 61.1/60.7 
                 4.9/4.7 
                 27.0/27.2 
                 258 
               
               
                 3-fluorobenzylamino 
                 60.8/60.7 
                 4.1/4.7 
                 27.3/27.2 
                 258 
               
               
                 4-fluorobenzylamino 
                 60.9/60.7 
                 4.8/4.7 
                 27.4/27.2 
                 258 
               
               
                 3-iodobenzylamino 
                 43.3/42.8 
                 3.3/3.3 
                 18.9/19.2 
                 366 
               
               
                 4-hydroxybenzylamino 
                 61.1/61.2 
                 4.1/5.1 
                 28.2/27.4 
                 256 
               
               
                 2,3-dihydroxybenzylamino 
                 57.8/57.6 
                 4.4/4.8 
                 26.1/25.8 
                 272 
               
               
                 3,4-dihydroxybenzylamino 
                 57.3/57.6 
                 5.2/4.8 
                 25.6/25.8 
                 272 
               
               
                 2,4-dihydroxybenzylamino 
                 57.9/57.6 
                 4.6/4.8 
                 25.9/25.8 
                 272 
               
               
                 2-methoxylbenzylamino 
                 63.0/62.4 
                 5.1/5.6 
                 26.2/26.0 
                 270 
               
               
                 2,3-dimethoxybenzylamino 
                 59.7/60.2 
                 5.5/5.7 
                 23.8/23.4 
                 300 
               
               
                 3,5-dimethoxybenzylamino 
                 60.3/60.2 
                 5.9/5.7 
                 23.5/23.4 
                 300 
               
               
                 2,4,5-trimethoxybenzylamino 
                 58.8/58.3 
                 5.4/5.8 
                 21.5/21.3 
                 330 
               
               
                 3,4,5-trimethoxybenzylamino 
                 58.4/58.3 
                 5.5/5.8 
                 21.5/21.3 
                 330 
               
               
                   
               
             
          
         
       
     
       Example 7 
     2-(3-chlorobenzylamino)-6-aminopurine 
       [0059]    4 mmol of 2-chloro-6-aminopurine were dissolved in 20 mL of butanol and then 5 mmol of 3-chlorobenzylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90° C. for 4 hr. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity&gt;95%. Yield 92%. 
         [0060]    Table 5 compound prepared by the method of example 7 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 Compounds prepared by the method of example 7 
               
             
          
           
               
                   
                 CHN analysis 
                 ESI-MS 
               
               
                   
                 Found/Calculated 
                 [M + 
               
             
          
           
               
                 R 2  substitution 
                 % C 
                 % H 
                 % N 
                 H + ] 
               
               
                   
               
               
                 methylamino 
                 44.4/43.9 
                 4.8/4.9 
                 50.8/51.2 
                 165 
               
               
                 ethylamino 
                 47.1/47.2 
                 5.9/5.7 
                 47.0/47.2 
                 179 
               
               
                 isobutylamino 
                 52.8/52.4 
                 6.9/6.8 
                 40.3/40.7 
                 207 
               
               
                 propylamino 
                 49.4/50.0 
                 6.6/6.3 
                 44.0/43.7 
                 193 
               
               
                 isopentylamino 
                 55.1/54.5 
                 7.1/7.3 
                 37.8/38.2 
                 221 
               
               
                 hexylamino 
                 55.2/56.4 
                 7.9/7.7 
                 36.9/35.9 
                 235 
               
               
                 Cyclopropylamino 
                 50.6/50.5 
                 5.4/5.3 
                 44.0/44.2 
                 191 
               
               
                 Cyclobutylamino 
                 52.7/52.9 
                 6.2/5.9 
                 41.1/41.1 
                 205 
               
               
                 cyclopentylamino 
                 55.4/55.0 
                 6.5/6.5 
                 38.1/38.5 
                 219 
               
               
                 cyclohexylamino 
                 57.1/56.9 
                 7.0/6.9 
                 35.9/36.2 
                 233 
               
               
                 anilino 
                 57.9/58.4 
                 4.8/4.5 
                 37.3/37.1 
                 227 
               
               
                 2-chloroanilino 
                 50.8/50.7 
                 3.4/3.5 
                 32.4/32.2 
                 261 
               
               
                 3-chloroanilino 
                 50.9/50.7 
                 3.6/3.5 
                 32.0/32.2 
                 261 
               
               
                 4-chloroanilino 
                 51.4/50.7 
                 3.3/3.5 
                 31.8/32.2 
                 261 
               
               
                 2-bromoanilino 
                 44.0/43.3 
                 3.1/3.0 
                 26.8/27.5 
                 306 
               
               
                 3-bromoanilino 
                 43.1/43.3 
                 3.2/3.0 
                 27.6/27.5 
                 306 
               
               
                 4-bromoanilino 
                 43.6/43.3 
                 2.9/3.0 
                 27.2/27.5 
                 306 
               
               
                 2-fluoroanilino 
                 54.2/54.1 
                 3.8/3.7 
                 34.5/34.4 
                 245 
               
               
                 3-fluoroanilino 
                 54.3/54.1 
                 3.6/3.7 
                 34.1/34.4 
                 245 
               
               
                 4-fluoroanilino 
                 54.5/54.1 
                 3.6/3.7 
                 34.1/34.4 
                 245 
               
               
                 benzylamino 
                 59.1/60.0 
                 5.4/5.0 
                 35.5/35.0 
                 241 
               
               
                 2-methylbenzylamino 
                 60.9/61.4 
                 5.7/5.5 
                 33.4/33.0 
                 255 
               
               
                 3-methylbenzylamino 
                 61.5/61.4 
                 5.2/5.5 
                 33.3/33.0 
                 255 
               
               
                 4-methylbenzylamino 
                 61.8/61.4 
                 5.6/5.5 
                 32.6/33.0 
                 255 
               
               
                 2-chlorobenzylamino 
                 51.9/52.5 
                 4.2/4.0 
                 30.7/30.6 
                 276 
               
               
                 3-chlorobenzylamino 
                 52.8/52.5 
                 3.9/4.0 
                 30.5/30.6 
                 276 
               
               
                 4-chlorobenzylamino 
                 52.9/52.5 
                 3.9/4.0 
                 30.3/30.6 
                 276 
               
               
                 2-fluorobenzylamino 
                 55.9/55.8 
                 4.5/4.3 
                 32.7/32.5 
                 259 
               
               
                 3-fluorobenzylamino 
                 55.2/55.8 
                 4.5/4.3 
                 32.8/32.5 
                 259 
               
               
                 4-fluorobenzylamino 
                 56.1/55.8 
                 4.2/4.3 
                 32.1/32.5 
                 259 
               
               
                 3-iodobenzylamino 
                 39.0/39.4 
                 3.0/3.0 
                 23.1/23.0 
                 367 
               
               
                 4-hydroxybenzylamino 
                 56.8/56.2 
                 4.5/4.7 
                 32.5/32.8 
                 257 
               
               
                 2,3-dihydroxybenzylamino 
                 52.7/52.9 
                 4.5/4.4 
                 31.1/30.9 
                 273 
               
               
                 3,4-dihydroxybenzylamino 
                 52.6/52.9 
                 4.3/4.4 
                 31.2/30.9 
                 273 
               
               
                 2,4-dihydroxybenzylamino 
                 53.2/52.9 
                 4.2/4.4 
                 30.6/30.5 
                 273 
               
               
                 2-methoxylbenzylamino 
                 58.1/57.8 
                 5.1/5.2 
                 30.8/31.1 
                 271 
               
               
                 2,3-dimethoxybenzylamino 
                 55.7/56.0 
                 5.3/5.4 
                 28.4/28.0 
                 301 
               
               
                 3,5-dimethoxybenzylamino 
                 56.2/56.0 
                 5.5/5.4 
                 27.4/28.0 
                 301 
               
               
                 2,4,5-trimethoxybenzylamino 
                 53.8/54.5 
                 5.6/5.5 
                 25.7/25.4 
                 331 
               
               
                 3,4,5-trimethoxybenzylamino 
                 54.2/54.5 
                 5.4/5.5 
                 25.7/25.4 
                 331 
               
               
                   
               
             
          
         
       
     
       Example 8 
     2-(3-chlorobenzylamino)-6-hydroxypurine 
       [0061]    4 mmol of 2-chloro-6-hydroxypurine were dissolved in 20 mL of butanol and then 5 mmol of 3-chlorobenzylamine and 6 mmol of triethylamine were added. The mixture was reacted at 90° C. for 4 hr. After cooling, the product was filter out and washed with water and butanol and crystallized from dimethyformamide or ethanol. HPLC: purity&gt;91%. Yield 88%. 
         [0062]    Table 6 compound prepared by the method of example 8 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 Compounds prepared by the method of example 8 
               
             
          
           
               
                   
                 CHN analysis 
                 ESI-MS 
               
               
                   
                 Found/Calculated 
                 [M + 
               
             
          
           
               
                 R 2  substitution 
                 % C 
                 % H 
                 % N 
                 H + ] 
               
               
                   
               
               
                 methylamino 
                 44.1/43.6 
                 4.2/4.3 
                 42.5/42.4 
                 166 
               
               
                 ethylamino 
                 46.7/46.9 
                 5.2/5.1 
                 39.0/39.1 
                 180 
               
               
                 propylamine 
                 49.5/49.7 
                 5.6/5.7 
                 36.5/36.2 
                 194 
               
               
                 Isobutylamino 
                 52.1/52.2 
                 6.4/6.3 
                 33.7/33.8 
                 208 
               
               
                 Isopentylamino 
                 54.2/54.3 
                 6.6/6.8 
                 31.9/31.7 
                 222 
               
               
                 hexylamino 
                 55.8/56.2 
                 7.4/7.3 
                 30.0/29.8 
                 236 
               
               
                 cyclopropylamino 
                 50.7/50.3 
                 4.6/4.7 
                 36.9/36.6 
                 192 
               
               
                 cyclobutylamino 
                 52.1/52.7 
                 5.5/5.4 
                 34.4/34.1 
                 206 
               
               
                 cyclopantylamino 
                 54.1/54.8 
                 6.2/6.0 
                 32.4/31.9 
                 220 
               
               
                 cyclohexylamino 
                 56.1/56.6 
                 6.7/6.5 
                 29.6/30.0 
                 234 
               
               
                 anilino 
                 57.4/58.1 
                 4.2/4.0 
                 31.1/30.8 
                 228 
               
               
                 2-chloroanilino 
                 50.2/50.5 
                 3.2/3.1 
                 26.9/26.8 
                 263 
               
               
                 3-chloroanilino 
                 49.8/50.5 
                 3.2/3.1 
                 27.4/26.8 
                 263 
               
               
                 4-chloroanilino 
                 50.9/50.5 
                 3.2/3.1 
                 26.4/26.8 
                 263 
               
               
                 2-bromoanilino 
                 43.6/43.2 
                 2.4/2.6 
                 22.6/22.9 
                 307 
               
               
                 3-bromoanilino 
                 43.5/43.2 
                 2.7/2.6 
                 22.6/22.9 
                 307 
               
               
                 4-bromoanilino 
                 43.1/43.2 
                 2.7/2.6 
                 23.1/22.9 
                 307 
               
               
                 2-fluoroanilino 
                 53.5/53.9 
                 3.4/3.3 
                 28.9/28.6 
                 246 
               
               
                 3-fluoroanilino 
                 54.1/53.9 
                 3.4/3.3 
                 28.3/28.6 
                 246 
               
               
                 4-fluoroanilino 
                 54.2/53.9 
                 3.2/3.3 
                 28.8/28.6 
                 246 
               
               
                 benzylamino 
                 60.1/59.7 
                 4.4/4.6 
                 28.7/29.0 
                 242 
               
               
                 2-methylbenzylamino 
                 61.5/61.2 
                 5.2/5.1 
                 27.1/27.4 
                 256 
               
               
                 3-methylbenzylamino 
                 61.7/61.2 
                 4.9/5.1 
                 27.2/27.4 
                 256 
               
               
                 4-methylbenzylamino 
                 61.4/61.2 
                 5.0/5.1 
                 27.3/27.4 
                 256 
               
               
                 2-chlorobenzylamino 
                 51.7/52.3 
                 3.9/3.7 
                 25.8/25.4 
                 277 
               
               
                 3-chlorobenzylamino 
                 52.9/52.3 
                 3.4/3.7 
                 25.2/25.4 
                 277 
               
               
                 4-chlorobenzylamino 
                 52.5/52.3 
                 3.8/3.7 
                 25.3/25.4 
                 277 
               
               
                 2-fluorobenzylamino 
                 55.9/55.6 
                 3.6/3.9 
                 27.1/27.0 
                 260 
               
               
                 3-fluorobenzylamino 
                 55.1/55.6 
                 4.1/3.9 
                 27.2/27.0 
                 260 
               
               
                 4-fluorobenzylamino 
                 54.8/55.6 
                 4.2/3.9 
                 27.5/27.0 
                 260 
               
               
                 3-iodobenzylamino 
                 38.9/39.3 
                 2.8/2.7 
                 19.3/19.1 
                 368 
               
               
                 4-hydroxybenzylamino 
                 55.8/56.0 
                 4.4/4.3 
                 27.4/27.2 
                 258 
               
               
                 2,3-dihydroxybenzylamino 
                 52.9/52.7 
                 4.3/4.1 
                 25.3/25.6 
                 274 
               
               
                 3,4-dihydroxybenzylamino 
                 52.5/52.7 
                 4.4/4.1 
                 25.8/25.6 
                 274 
               
               
                 2,4-dihydroxybenzylamino 
                 53.1/52.7 
                 4.0/4.1 
                 25.5/25.6 
                 274 
               
               
                 2-methoxylbenzylamino 
                 57.1/57.6 
                 4.9/4.8 
                 26.1/25.8 
                 272 
               
               
                 2,3-dimethoxybenzylamino 
                 56.2/55.8 
                 4.8/5.0 
                 23.1/23.2 
                 302 
               
               
                 3,5-dimethoxybenzylamino 
                 55.1/55.8 
                 5.3/5.0 
                 23.6/23.2 
                 302 
               
               
                 2,4,5-trimethoxybenzylamino 
                 54.7/54.4 
                 5.3/5.2 
                 21.0/21.1 
                 332 
               
               
                 3,4,5-trimethoxybenzylamino 
                 54.1/54.4 
                 5.4/5.2 
                 21.3/21.1 
                 332 
               
               
                   
               
             
          
         
       
     
       AMPK Activation Assay 
       [0063]    Effects of compounds on AMPK activation were analyzed in mouse muscle cell C2C12, mouse fibroblast 3T3-L1 and human hepatocyte Hep G2. Those cell lines were cultured in high-glucose Dulbecco&#39;s modified Eagle&#39;s medium (DMEM) containing 10% fetal bovine serum (FBS), 4 mM L-glutamine, 2 mM sodium pyruvate and 1% penicillin/streptomycin (Invitrogen GibcoBRL, Carlsbad, Calif., USA) at 37° C. under 5% CO2. Cells were plated at 3×10 5  per well (6-well plate). 24 h after plating, cells were treated with indicated compounds for 30 min followed by cell lysis and western blot analysis. Equal amount of protein were separated by SDS-PAGE and then electroblotted on to PVDF membranes. Membranes were blocked with 3% BSA in PBS for 60 min and incubated with anti-phospho-AMPK (Thr172) antibody (1:2,000, Cell signaling), anti-AMPK antibody (1:2,000, Cell signaling), anti-Glut4 antibody (1:1,000, Millipore) or anti-actin antibody (1:5,000; Chemicon International) at 4° C. overnight followed by the corresponding secondary antibody for 1 h at room temperature (RT). Immunoreactive bands were detected by enhanced chemiluminescence (ECL; Pierce, Rockford, Ill., USA) and recorded using Kodakfilm (Rochester, N.Y., USA). The detected signals were scanned and then quantified by using TotalLab Quant software (TotalLab). 
         [0064]    The effect of various compounds on AMPK activation is summarized in Table 7. Most of test compounds significantly activated AMPK in C2C12, 3T3-L1 and Hep G2 cells. 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 7 
               
             
             
               
                   
                   
               
               
                   
                   
                 AMPK activation (% to 
               
               
                   
                 Concentration 
                 control) 
               
             
          
           
               
                 Agent 
                 (microM) 
                 C2C12 
                 3T3-L1 
                 Hep G2 
               
               
                   
               
             
          
           
               
                 6-hydroxypurine 
                 1 
                 120 
                 118 
                 114 
               
               
                   
                 10 
                 148 
                 155 
                 146 
               
               
                   
                 100 
                 233 
                 198 
                 165 
               
               
                   
                 200 
                 341 
                 325 
                 330 
               
               
                 2,6-dihydroxypurine 
                 1 
                 105 
                 109 
                 114 
               
               
                   
                 10 
                 115 
                 132 
                 139 
               
               
                   
                 100 
                 231 
                 205 
                 198 
               
               
                   
                 200 
                 347 
                 361 
                 302 
               
               
                 Hypoxanthine 
                 1 
                 108 
                 108 
                 105 
               
               
                   
                 10 
                 121 
                 128 
                 124 
               
               
                   
                 100 
                 238 
                 231 
                 225 
               
               
                   
                 200 
                 309 
                 335 
                 341 
               
               
                 2-Dimethylamino-6-hydroxypurine 
                 1 
                 105 
                 106 
                 117 
               
               
                   
                 10 
                 111 
                 108 
                 132 
               
               
                   
                 100 
                 229 
                 205 
                 185 
               
               
                   
                 200 
                 298 
                 264 
                 218 
               
               
                 6-mercaptopurine 
                 1 
                 105 
                 114 
                 114 
               
               
                   
                 10 
                 119 
                 128 
                 122 
               
               
                   
                 100 
                 198 
                 176 
                 204 
               
               
                   
                 200 
                 289 
                 218 
                 279 
               
               
                 2,6-diaminopurine 
                 1 
                 116 
                 108 
                 113 
               
               
                   
                 10 
                 181 
                 149 
                 155 
               
               
                   
                 100 
                 281 
                 288 
                 274 
               
               
                   
                 200 
                 381 
                 335 
                 397 
               
               
                 2-hydroxyadenine 
                 1 
                 111 
                 117 
                 118 
               
               
                   
                 10 
                 166 
                 171 
                 143 
               
               
                   
                 100 
                 275 
                 264 
                 220 
               
               
                   
                 200 
                 315 
                 351 
                 338 
               
               
                 Guanine 
                 1 
                 105 
                 107 
                 119 
               
               
                   
                 10 
                 117 
                 121 
                 144 
               
               
                   
                 100 
                 241 
                 208 
                 199 
               
               
                   
                 200 
                 304 
                 312 
                 335 
               
               
                 6-thioquanine 
                 1 
                 116 
                 115 
                 116 
               
               
                   
                 10 
                 141 
                 132 
                 133 
               
               
                   
                 100 
                 215 
                 241 
                 229 
               
               
                   
                 200 
                 301 
                 289 
                 311 
               
               
                 2-methyl-6-hydroxypurine 
                 1 
                 109 
                 112 
                 116 
               
               
                   
                 10 
                 139 
                 144 
                 162 
               
               
                   
                 100 
                 241 
                 228 
                 219 
               
               
                   
                 200 
                 305 
                 338 
                 347 
               
               
                 2-amino-6-mercaptopurine 
                 1 
                 118 
                 105 
                 112 
               
               
                   
                 10 
                 122 
                 119 
                 124 
               
               
                   
                 100 
                 228 
                 251 
                 209 
               
               
                   
                 200 
                 284 
                 277 
                 261 
               
               
                 2-hydroxy-6-mercaptopurine 
                 1 
                 104 
                 118 
                 105 
               
               
                   
                 10 
                 109 
                 122 
                 108 
               
               
                   
                 100 
                 198 
                 210 
                 204 
               
               
                   
                 200 
                 251 
                 277 
                 222 
               
               
                 2-amino-6-methylaminopurine 
                 1 
                 119 
                 109 
                 114 
               
               
                   
                 10 
                 187 
                 135 
                 139 
               
               
                   
                 100 
                 215 
                 220 
                 230 
               
               
                   
                 200 
                 351 
                 332 
                 348 
               
               
                 2-hydroxy-6-methylaminopurine 
                 1 
                 118 
                 113 
                 115 
               
               
                   
                 10 
                 151 
                 162 
                 148 
               
               
                   
                 100 
                 255 
                 271 
                 266 
               
               
                   
                 200 
                 361 
                 382 
                 354 
               
               
                 2-mercaptoadenine 
                 1 
                 105 
                 112 
                 118 
               
               
                   
                 10 
                 115 
                 128 
                 119 
               
               
                   
                 100 
                 221 
                 204 
                 195 
               
               
                   
                 200 
                 289 
                 297 
                 308 
               
               
                 2-mercapto-6-hydroxypurine 
                 1 
                 109 
                 115 
                 113 
               
               
                   
                 10 
                 148 
                 147 
                 132 
               
               
                   
                 100 
                 251 
                 220 
                 209 
               
               
                   
                 200 
                 333 
                 308 
                 315 
               
               
                 2,6-dimercaptopurine 
                 1 
                 104 
                 102 
                 110 
               
               
                   
                 10 
                 117 
                 98 
                 133 
               
               
                   
                 100 
                 215 
                 178 
                 244 
               
               
                   
                 200 
                 298 
                 260 
                 366 
               
               
                 2-chloroadenine 
                 1 
                 110 
                 118 
                 116 
               
               
                   
                 10 
                 155 
                 143 
                 139 
               
               
                   
                 100 
                 284 
                 271 
                 220 
               
               
                   
                 200 
                 326 
                 311 
                 314 
               
               
                 2-chloro-6-hydroxypurine 
                 1 
                 109 
                 108 
                 110 
               
               
                   
                 10 
                 156 
                 145 
                 163 
               
               
                   
                 100 
                 277 
                 243 
                 249 
               
               
                   
                 200 
                 331 
                 356 
                 375 
               
               
                 2-fluoroadenine 
                 1 
                 102 
                 114 
                 117 
               
               
                   
                 10 
                 112 
                 165 
                 180 
               
               
                   
                 100 
                 213 
                 291 
                 259 
               
               
                   
                 200 
                 303 
                 323 
                 315 
               
               
                 2-bromoadenine 
                 1 
                 116 
                 119 
                 113 
               
               
                   
                 10 
                 172 
                 188 
                 190 
               
               
                   
                 100 
                 263 
                 277 
                 253 
               
               
                   
                 200 
                 349 
                 361 
                 354 
               
               
                 2-iodoadenine 
                 1 
                 114 
                 116 
                 115 
               
               
                   
                 10 
                 143 
                 179 
                 151 
               
               
                   
                 100 
                 214 
                 237 
                 227 
               
               
                   
                 200 
                 311 
                 358 
                 341 
               
               
                 2-bromohypoxanthine 
                 1 
                 108 
                 111 
                 110 
               
               
                   
                 10 
                 142 
                 176 
                 160 
               
               
                   
                 100 
                 214 
                 245 
                 242 
               
               
                   
                 200 
                 321 
                 357 
                 359 
               
               
                 6-methylaminopurine 
                 1 
                 103 
                 107 
                 116 
               
               
                   
                 10 
                 108 
                 129 
                 141 
               
               
                   
                 100 
                 213 
                 241 
                 259 
               
               
                   
                 200 
                 328 
                 347 
                 363 
               
               
                 6-hexylaminopurine 
                 1 
                 109 
                 108 
                 112 
               
               
                   
                 10 
                 123 
                 111 
                 148 
               
               
                   
                 100 
                 248 
                 170 
                 280 
               
               
                   
                 200 
                 359 
                 265 
                 317 
               
               
                 6-cyclohexylaminopurine 
                 1 
                 107 
                 107 
                 111 
               
               
                   
                 10 
                 110 
                 152 
                 132 
               
               
                   
                 100 
                 248 
                 269 
                 261 
               
               
                   
                 200 
                 322 
                 333 
                 354 
               
               
                 6-(4-methylbenzylamino)purine 
                 1 
                 112 
                 110 
                 106 
               
               
                   
                 10 
                 158 
                 163 
                 121 
               
               
                   
                 100 
                 270 
                 259 
                 245 
               
               
                   
                 200 
                 358 
                 347 
                 348 
               
               
                 6-(3-chloroanilino)purine 
                 1 
                 108 
                 116 
                 106 
               
               
                   
                 10 
                 118 
                 130 
                 109 
               
               
                   
                 100 
                 186 
                 217 
                 212 
               
               
                   
                 200 
                 307 
                 301 
                 319 
               
               
                 2-amino-6-isopentylaminopurine 
                 1 
                 104 
                 110 
                 117 
               
               
                   
                 10 
                 114 
                 169 
                 174 
               
               
                   
                 100 
                 238 
                 271 
                 250 
               
               
                   
                 200 
                 305 
                 361 
                 341 
               
               
                 2-amino-6-(2,3-dimethoxybenzylamino)purine 
                 1 
                 106 
                 118 
                 115 
               
               
                   
                 10 
                 144 
                 156 
                 127 
               
               
                   
                 100 
                 263 
                 250 
                 229 
               
               
                   
                 200 
                 334 
                 347 
                 318 
               
               
                 2-hydroxy-6-propylaminopurine 
                 1 
                 114 
                 109 
                 110 
               
               
                   
                 10 
                 122 
                 129 
                 133 
               
               
                   
                 100 
                 201 
                 233 
                 270 
               
               
                   
                 200 
                 324 
                 361 
                 339 
               
               
                 2-hydroxy-6-benzylaminopurine 
                 1 
                 108 
                 115 
                 109 
               
               
                   
                 10 
                 135 
                 126 
                 137 
               
               
                   
                 100 
                 244 
                 230 
                 261 
               
               
                   
                 200 
                 356 
                 309 
                 338 
               
               
                 2-methyl-cyclopentylaminopurine 
                 1 
                 105 
                 114 
                 117 
               
               
                   
                 10 
                 128 
                 140 
                 140 
               
               
                   
                 100 
                 280 
                 241 
                 240 
               
               
                   
                 200 
                 342 
                 350 
                 301 
               
               
                 2-methyl-6-(3,4,5-trimethoxybenzylamino)purine 
                 1 
                 106 
                 115 
                 112 
               
               
                   
                 10 
                 117 
                 141 
                 168 
               
               
                   
                 100 
                 211 
                 254 
                 270 
               
               
                   
                 200 
                 361 
                 346 
                 359 
               
               
                 2-benzylamino-6-aminopurine 
                 1 
                 110 
                 119 
                 105 
               
               
                   
                 10 
                 128 
                 147 
                 116 
               
               
                   
                 100 
                 259 
                 217 
                 235 
               
               
                   
                 200 
                 312 
                 308 
                 364 
               
               
                 2-cyclohexylamino-6-hydroxypurine 
                 1 
                 108 
                 118 
                 111 
               
               
                   
                 10 
                 118 
                 172 
                 137 
               
               
                   
                 100 
                 209 
                 283 
                 248 
               
               
                   
                 200 
                 321 
                 375 
                 351 
               
               
                 Thymine 
                 1 
                 117 
                 109 
                 110 
               
               
                   
                 10 
                 147 
                 129 
                 113 
               
               
                   
                 100 
                 266 
                 235 
                 218 
               
               
                   
                 200 
                 354 
                 318 
                 303 
               
               
                 Cytosine 
                 1 
                 119 
                 117 
                 117 
               
               
                   
                 10 
                 158 
                 127 
                 164 
               
               
                   
                 100 
                 253 
                 2436 
                 281 
               
               
                   
                 200 
                 361 
                 310 
                 359 
               
               
                 Uracil 
                 1 
                 105 
                 114 
                 118 
               
               
                   
                 10 
                 109 
                 123 
                 144 
               
               
                   
                 100 
                 264 
                 248 
                 237 
               
               
                   
                 200 
                 358 
                 372 
                 359 
               
               
                 5-methylcytosine 
                 1 
                 116 
                 115 
                 107 
               
               
                   
                 10 
                 157 
                 161 
                 114 
               
               
                   
                 100 
                 241 
                 253 
                 218 
               
               
                   
                 200 
                 338 
                 356 
                 317 
               
               
                 5,6-dihydrouracil 
                 1 
                 108 
                 116 
                 120 
               
               
                   
                 10 
                 114 
                 159 
                 167 
               
               
                   
                 100 
                 207 
                 268 
                 274 
               
               
                   
                 200 
                 326 
                 341 
                 360 
               
               
                 5-fluorouracil 
                 1 
                 105 
                 108 
                 110 
               
               
                   
                 10 
                 105 
                 113 
                 134 
               
               
                   
                 100 
                 224 
                 248 
                 237 
               
               
                   
                 200 
                 318 
                 322 
                 319 
               
               
                 Floxuridine 
                 1 
                 117 
                 116 
                 117 
               
               
                   
                 10 
                 144 
                 141 
                 147 
               
               
                   
                 100 
                 231 
                 222 
                 206 
               
               
                   
                 200 
                 312 
                 343 
                 308 
               
               
                 6-azauracil 
                 1 
                 109 
                 109 
                 108 
               
               
                   
                 10 
                 109 
                 115 
                 124 
               
               
                   
                 100 
                 197 
                 185 
                 199 
               
               
                   
                 200 
                 284 
                 288 
                 273 
               
               
                 AICAR 
                 1200 
                 335 
                 340 
                 319 
               
               
                   
               
             
          
         
       
     
       Glucose Uptake In Vitro 
       [0065]    Effects of representative compounds on glucose uptake were analyzed in muscle cell C2C12 by using fluorescent glucose analog (2-NBDG, Molecular Probes). C2C12 were treated with selected novel AMPK activator for 30 min at 37° C. then exposed to 500 μM of fluorescent glucose analog. After 5 min incubation at room temperature, cells were washed three times with Kreb-Hepes buffered solution and fix in 70% alcohol. The fluorescence of glucose analog in cells was detected using a Fluorescence Microplate Reader System at 480-nm excitation and 530-nm emission wavelength. 
         [0066]    The effect of selected compounds on glucose uptake is summarized in Table 8 (some data not shown). Most of test compounds significantly stimulated glucose uptake in C2C12 cells. Data are presented as the mean±SEM of three independent experiments. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 8 
               
               
                   
               
               
                   
                   
                 Glucose 
               
               
                   
                   
                 uptake (% 
               
               
                   
                 Concentration 
                 to 
               
               
                 Agent 
                 (microM) 
                 control) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 6-hydroxypurine 
                 1 
                 109 ± 2.2  
               
               
                   
                 10 
                 242 ± 23.7 
               
               
                   
                 100 
                 289 ± 21.4 
               
               
                   
                 600 
                 318 ± 21.2 
               
               
                 6-(4-methylbenzylamino)purine 
                 1 
                 114 ± 9.2  
               
               
                   
                 10 
                 205 ± 14.6 
               
               
                   
                 100 
                 281 ± 11.5 
               
               
                   
                 600 
                 309 ± 9.1  
               
               
                 2-cyclohexylamino-6-hydroxypurine 
                 1 
                 108 ± 2.1  
               
               
                   
                 10 
                 195 ± 11.9 
               
               
                   
                 100 
                 251 ± 16.2 
               
               
                   
                 600 
                 311 ± 10.7 
               
               
                 Thymine 
                 1 
                 110 ± 3.2  
               
               
                   
                 10 
                 167 ± 15.1 
               
               
                   
                 100 
                 215 ± 18.2 
               
               
                   
                 600 
                 283 ± 22.3 
               
               
                 AICAR 
                 1200 
                 264 ± 19.2 
               
               
                   
               
             
          
         
       
     
       In Vivo Assay 
       [0067]    To further evaluate the effects of representative compounds on the modulation of plasma glucose level, the high-fat diet-fed mice were served as a type 2 diabetes animal model. C57BL/6J mice were maintained at 22° C. under a 12-h light/dark cycle and fed either a high fat diet (60% kcal % fat) or a normal diet ad libitum. Intraperitoneal injections of selected compounds (0.1 to 50 mg/kg) or vehicle were given to the high-fat diet-fed mice from the age of 24 weeks and glucose readings were measure at 1 and 3 hr. IP administration of the high-fat diet-fed mice continued twice a day for 6 days. On day 6, plasma was collected 1 hr after the last dosing for plasma glucose and triglycerides determined. The select compound were found to decrease plasma glucose &gt;30% and decrease plasma triacylglycerides&gt;35% and decrease body weight &gt;15% relative to control mice. 
         [0068]    Disorders such as pre-diabetes, type 2 diabetes, syndrome X, insulin resistance, metabolic syndrome, and obesity may be regulated by activation of AMPK. Thus, specific embodiments and applications of pharmaceutical composition and methods for metabolic modulation have been disclosed. It should be apparent, however, to those skilled in the art that many more modifications besides those already described are possible without departing from inventive concepts herein. 
         [0069]    The embodiments are not intended to limit the scope of the present invention. The scope of the present invention is defined only by the appended claims.