WO2015039292A1 - Ampk-activating compound, and use thereof - Google Patents

Abstract

Disclosed are an AMPK-activating compound, and use thereof in the preparation of drugs for preventing or treating physiological conditions or diseases capable of being improved by an AMPK activator, including pre-diabetes, insulin resistance, type II diabetes, X-syndrome, metabolism syndrome and obesity. The compound of the present invention reduces plasma glucose more than 30 wt%, and reduces triglyceride more than 35 wt%, and also reduces weight more than 15%.

Description

 Compound for activating AMPK and use thereof

Technical field

 The invention relates to an activated sputum (ΑΜΡ-activated protein catalyzed and its preparation for the treatment or treatment of sputum or physiological conditions for the treatment of sputum activators, including beach urinary tract disease, islet mites Use in drugs for type 2 diabetes, X syndrome, and metabolic syndrome.

Background technique

ΑΜΡΚ is clearly the sensor of cellular energy and the responder of energy demand. ΑΜΡΚ is a heterotrimer composed of catalytic α-subunits, regulatory β, and Υ-units, and all sub-units are highly retained in *†海生物. AMPK is activated by upstream kinases such as calcium L BL / ^^ Pigment protein phosphorylation (Ca ²⁺ / Calmodulin dependent kinase) phosphorylation and ΊΆΚ1 α subunit with retention of body 172 SU amine resulting in high pressure by a physiological or pathological The ΑΜΡ/ΑΓΡ ratio also activates AMPK. AMPK live te^f earns 3⁄44 lines of metabolism and inhibits anabolism, and eliminates the energy balance of the cells.

 As an energy metabolizer, AMPK is considered to be a potential drug target for the second type of sugar cane, cardiovascular surface, fatty liver, etc. Many metabolic syndromes are associated with insulin resistance. Insulin resistance is a pathological condition in which the fine-grained response to insulin is due to excessive glucose in J«^3⁄4 being unable to be removed to the bone path «fatty tissue. In several meat cells, AMPK activation is in a non-insulin-producing manner, and the amount of glucose transporting protein (GLUT4) is regulated by transcriptional transduction, and the induction of GLUT4 transfer to the fines leads to an increase in the rate of glucose uptake by the cells. AMPK activation also inhibits the synthesis of fatty acid steroids by using acetyl-CoA caAoxylase and hydroxymethylglutaminase A enzyme (HMG € aA reductase). Inhibition of pro-AMPK activation guides, including sterol regulatory element whitening (SREBP-lc), shed element whitening transcription factor (ChREBP) and hepatic nuclear factor 4a (HF, and down-regulating fatty acid complexes The protein expression of the enzymes involved in the nascent nascent action supports AMPK as a therapeutic target for metabolic syndrome.

 AMP is a natural AMPK activator. However, AMP is a destabilizing method and extracellular ^3⁄4 AMP triggers the transmission of a message conveyed by a purinetgic receptor (which may lead to apoptosis). Therefore, many researches have been carried out on the development of AMPK activators. It is currently known that high-grade 3⁄43⁄4 of 5- 13⁄4 唾 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲Insulin resistance, X syndrome, type 2 sugar vine. However, AMPK activator finely deletes including lactic acidosis, especially when patients have 'do not earn.' Because J« ^ cuts need to be novel and less effective and less Side effects of AMPK activators.

Summary of the invention

 In view of the above, the object of the present invention is to prepare a method for the treatment of AMPK activators which can be improved or treated by AMPK activators, including pre-diabetes and type 2 diabetes. , X-group, metabolic syndrome, and use in menopause drugs.

 For the purpose of 3⁄4^^, the invention #ί共式 (1) and (2) and its mutual $

 (2)

 And a pharmaceutically acceptable salt thereof, wherein R2 represents a subunit, a pertinyl atom, a 3⁄4*, an amine group, a JS* band with one or two of the longest ten«, a hydrogen carboxyl group, a nitrosulfo group, a slit, a base,垸 Hydrogen entanglement, ring sulcus, taken ί leg, taken 働 base is taken from the base, 芳 缝, substituted aryam, aryl 6 indicates guanamine, hydrogen one leg (single where R represents a halogen atom) , 3⁄4*, JS*, JS* with one or two of the longest ten «, ^, hydrogen «, several groups, nitrosulfo, slit, fiber base, hydrogen hydride, entanglement, ring seam, a ί leg, a substituted alkenyl group, a substituted alkynyl group, an acyl aryl group 3⁄4*, a substituted aryl group 3⁄4*, an aromatic «; R3 represents a sub- or a maximum of ten carbons or a pharmaceutically acceptable salt thereof, And a hydrazine activator comprises the hydrazine and a pyrimidine or a pharmaceutically acceptable salt thereof as an activation

3⁄4]3⁄4 takes ^*^ meaning and is the same, where

 Hydrogen exchange ~OH;

 The prime atoms represent fluorine, chlorine, desert, and hydrazine;

 Filament ^" 3⁄4;

 The hydrogen «t^"SH;

 ^ ^-Qp R, where R^u/ti, sub, taken aryl, substituted aryl; 3⁄4 said nitrane ^"N(3⁄4;

 The sulphur is shown as "S(3⁄4; where R^U/ti, sub, ^ is taken

 Straight or branched as shown, wherein the radicals include methyl, propyl, isopropyl butyl, 3⁄4), ethynylpropynyl 2-alkyn 3⁄4 and others Group

 The skin is taken from 1 to 7 such as 3⁄4*, such as 3⁄4*, hydrogen«, m*, hydrazine halogen atom, entanglement, acyltransfer, JS*, carboxyl, sulfo, β and others, so that the group can be Fiber to bribe ^ electricity

 An NR ' is shown, wherein R and R ±« are ti, sub, aryl, and substituted arene;

 «Hydrogen « ^ shows ^ "SR, where R 3⁄4*, taken aryl ^, substituted aryl; IS * as in this 亓; shown ^" OR, where R 3⁄4*, taken fang 3⁄4*, substituted fang 3⁄4*如本亓; the ring ^ 3⁄4t shows a single or multiple rings with 3-15

 The indication "C(0)R, wherein R refers to a record, ^ is taken to be an aromatic ^, is substituted for an aromatic; IS* is as defined herein;

 Aromatic cyclized carbon

 The substituted aryl group is suspected to be a halogen atom, 纮 JS*, hydrogen, 垸, Xinjiang, carboxyl, and sew;

^"OAr, where Ar refers to the aryl is replaced by aryl 3⁄4* as this 亓; 因 活 活 : :

2-胺基 3-m¾s* 2-胺基 、 2-胺基 2-漠繊基) P 、 2-胺基 3-漠 基 、 2-胺基 漠纖基 、 2-胺基 · <2-Λ¾¾基) ^p 、 2-胺基 3- 氟漠 2-胺基 2-腿 4苯甲胺基 、 2-胺基 · <2-甲基苯甲胺 、 2-胺基 · <3-甲基苯甲胺基票呤、 2-胺基 · <~甲基苯甲胺基 ) 、 2-胺基 · <2-«甲胺基票呤、 2-胺基 -tt甲胺基 ) 、 2-胺基 · <·«甲胺基 ) 、 2-胺基 · <2-Λ¾甲胺基 ) 、 2-胺基 · <3-Λ¾甲 腿 2-胺基 甲胺 、 2-胺基 膽胺 、 2-胺基 甲腿 Bismuth, 2-amino group, 2-leg base P, 2-JS3⁄4^hex, 2-amino group 43⁄4», 2-

2-Amino 3-m3⁄4s* 2-Amino, 2-Amino 2-indiyl) P, 2-Amino 3-Mo, 2-Amino-based, 2-Amino <2- Λ3⁄43⁄4 base) ^p , 2-amino 3-ribo 2-amino 2- leg 4-benzylamino, 2-amino] <2-methylbenzylamine, 2-amino] <3-methyl Benzylamine-based, 2-amino- <~methylbenzylamino), 2-amino] <2-«methylaminophenanthrene, 2-amino-tt-methylamino), 2- Amino group · <·«methylamino), 2-amino group <2-Λ3⁄4 methylamino), 2-amino group <3-Λ3⁄4 methyl leg 2-aminomethylamine, 2-aminocholamine, 2-amino leg

2-Amino-Bisinterstylamino 2-amino-3,~2⁄4*benzylamino 2-amino 2,~2⁄4⁄4 benzylamino)^2-Amino <2-A Amino), 2-amino^23-dimethyl-3-benzylamino), 2-aminodimethyl benzophenone, 2-amino group <2Α5-trimethyl benzylamine, 2-amine Base · <3Α5-trimethyl H3⁄4 benzylamino), methylamino, & Ζ ^^ propylamino P, isobutylamino, isoamylamino, propyl leg guanidine, butylamino P, W group P, W ,6·繊基Ρ, 6<2-3⁄4» base, 6<3-«amino) Ρ, 6<Φ3⁄4» base) 、, 6<2- desert fiber base, 6<3- desert fiber, 6<Φ desert fiber base, 6<2-fluorine

6<3-*3⁄4S*)^ 6<-t3⁄4S*) ^p ^ 6·benzylamine, 6<2-methylbenzylamine, 6<3-methylmethylamino) P, 6<Φ甲Benzoylamine, 6<2 A leg 6<3- fresh leg, 6<-«¥ leg 6<2 methylamine, 6<3 methylamine 6<~ silk leg 6<3·? Bile leg

6^3⁄43⁄4 methylamino 6<2,3-di 3⁄4* benzylamine, 6<3,~2⁄4*benzamide, 6<2,~2⁄4⁄4⁄4 benzylamino) 嘌呤, 6<2-甲Benzylamino), 6(23-dimethylphenylamino) hydrazine, 6<3 dimethyl phenylamino), 6<2,4,5-trimethyl I* benzoic acid JS*) , 6<3,4, three armor, I* benzylamino), 2-3⁄43⁄4^methylamino, 2-^Ζylhydrazine, 2-diisobutylaminopurine, 2-3⁄43⁄4 propylamine P, 2-record Heterogeneous P, 2-recorded 4,

2-録 ¾¾t基 2 · <2-漠纖基 2 3-漠纖基 2 漠纖基

_2, ^ propylamino 2-3⁄43⁄4 ^ butylamino p, 2 de · hexylamino hydrazine, 2-hydroxy cellulose ρ,

2-record 3⁄43⁄4t base 2 · <2- desert fiber base 2 3- desert fiber base 2 desert fiber base

, 2 -bond 繊, 2, 2 4 benzyl, 2- 2 -methylbenzylamino), 2-3⁄43⁄4 <3-methylbenzylamino), 2-» <~methylbenzylamine Base), 2- - 2- Leg 2 - Fresh Leg 2 Fresh Methylamine, 2 2-Methylamine, 2 -Methylamino 2 Methylamino 2 3 Methylamino

 Benzylamino) hydrazine, -^^ bis-benzylamino) hydrazine, 2-» <3,~2⁄4*benzylamino) hydrazine, 2-

^<2,~2 3⁄43⁄4 benzylamine, 2-3⁄43⁄4 <2-methyl JS3⁄4), S-^^^-dimethylform JS3⁄4), ^^^Odimethylidene I* benzylamino), 2 -3⁄43⁄4 <2A5-Third Armor I*Benzylamine, 2-3⁄43⁄4 <3A5-Third Armor I* Benzylamino), 2-Methyl Amethylamino, 2-Methyl^^Jt, 2- Methyl ■ Isobutylamino, 2-methyl A propylamino 2 2-methyl phenyl P, 2-methyl 4 hexyl, 2-methyl, propyl, 2-methyl, butyl, 2-methyl Pentylamino, 2-methylhexylamino, 2-methyl-4-yl, 2-methyl·<2-3⁄4»yl), 2-methyl"<3-3⁄4», 2-methyl-2-methyl Base 2 - desert fiber, 2-methyl 3-mercapto) ^ 2-methyl desert 3⁄43⁄4) 2-, 2-methyl 2-t3⁄4, 2-methyl-fluoro-dilt, 2-methyl

, 2-methyl 4-benzoic acid test, 2-methyl 2-methylbenzylamino 2-methyl 3-methyl silk leg) P, 2-methylmethanthine leg) P, 2-methyl 2 methylamine, 2-methyl-fresh test, 2-methylmethylamino), 2-methyl·<2-Λ3⁄4 methylamino) , 2-methyl·<3-«methylamine, 2-methyl·<·«methylamine^2-methyloxime, 2-methylbenzylamine, 2-methylbenzylamine, 2 -Methyl 3,~2 3⁄4*benzylamine, 2-methyl~2⁄4⁄4 benzylamino) Ρ, 2-methyl· <2-methyl phenylamino) 嘌呤, 2-methyl^ 2 Benzylamine, 2-methyl 3,5-dimethyl benzoylamine, 2-methyl·<2Α5-trimethoxybenzo JS*), 2-methyl·<3Α5-trimethyl JS3⁄4), 2-methylamino 4-amino group,

2 -« 胺¾ ^錄 、 2<2-漠¾¾> ^錄 、 2<3-漠¾*> ^錄 、 2<~漠纖基) ^錄 、 2-苯甲胺基 ¾¾ 、 2·<2-甲基苯甲胺^ 2·<3-甲基苯甲胺^ 2·<~甲基苯甲 胺¾ ^錄 、 2·<2 甲胺基) ^錄 、 2<3 甲胺 錄 、 2 -«¥JS*>^¾* ^ 2<2-«甲胺基)^ 2<3-*¾甲胺基)^ ¾ ^票呤、 2·<~ 甲胺基)^ ¾¾P票呤、 23- 砍苯甲胺 錄 、 2·<Φ¾¾苯甲胺基) ^錄 、 二 ¾¾苯甲腿) ^錄 、 2·<2,Φ二 ¾«甲胺基) ^錄 、 2<3,~二¾«甲腿) ^錄 、 二甲 甲腿) ^錄 、 2·<2,3-二甲 «苯甲胺基)^ 嘌呤、 2<3 二甲 «苯甲胺基)^ 嘌呤、 2·<2Α5-三甲 «苯甲胺 基)^ 2·<3Α5-三甲 «苯甲胺^ ^-¥«^ 2-胺纖 Ρ 、 2-¾»^ 2-甲搬 、 2-胺基 4錄 、 2, 二錄 、 2-甲基 ·6錄 、 2-胺基 4氢德 、 2擔 4氢赫 、 2-甲基 4氢德 Ρ 、 2-氢 ¾¾» 、 2-氢德 4錄票 呤、 2,^二氢德 、 2-氢德 4甲基 、 2-氢德 、 2-氢德 丙基 、 2-i¾t嘌 呤、 2-i¾ 氢驗 、 2-^¾4甲 、

2 butylamino, 2-propylamino 4-amino P, 2 pentyl 4, 2-hexyl, 2 propylamino 4-amino P, 2 butylamino-based P, 2-cyclopentylamino-based P, 2 hexylamino group P, amine group, 2·<2-3⁄4»amino group P, 2·<3-3⁄4» group), 2 3⁄4», 22-« amine, 23-*3⁄4S*> ^»^ 2 t3⁄4S3⁄4>^Amino P, 2<2-Moistureyl)^Amino P, 2·<3-Molybdenyl)Amineyl P, 2·<ΦMoistylamine Aminopurine, 2-Benzylamino 4-aminopurine, 2<2-methylbenzylamino)amine, 2·<3-methylbenzylamino-amine, 2·<~methylbenzylamine Amino-based noise, 2·<2-methylamino-amine-based noise, 2·<3-fresh leg), amine Ρ, 2·<Φ fresh methylamine, 2·<2 methylamine, 23-« A leg) ^Amino 2 methylamine 3⁄4 ■ ^Amino Ρ, 2·<3·? Bile leg·amine 2 3⁄43⁄4 benzylamine 2<2,3-di 3⁄4*benzylamine 2<2,~2⁄4⁄4 benzylamine A, P<2,~2⁄4«methylamine Amino group, 2·<2,3-dimethyl-3-benzylamino)amine, 2·<2,3-dimethyl-3-benzylamino)amine, -dimethyl ketone Methylamine 3⁄4^»f^, 2·<2,4,5-trimethylsulfonylbenzylamine 3⁄4^J»f^, 2·<3,4,5-trimethylsulfenylbenzamine 3⁄4^JS* 2 -Methylamine record, 2-isobutylamine base record, 2-propion leg record, 2-iso-amyl leg record, 2, C-leg record, 2 butylamine 4 record, 2, ampule record, 2, leg Record, 2-fiber base 4 record, 2·<2-3⁄4» record, 2·<3-3⁄4» base)^

2 -« amine 3⁄4 ^录, 2<2-漠3⁄43⁄4> ^录, 2<3-漠3⁄4*> ^录, 2<~漠纤基) ^, 2-benzylamino 3⁄43⁄4, 2·< 2-Methylbenzylamine^ 2·<3-methylbenzamine^ 2·<~Methylbenzylamine 3⁄4 ^, 2·<2 methylamino) ^, 2<3 methylamine, 2 - «¥JS*>^3⁄4* ^ 2<2-«methylamino)^ 2<3-*3⁄4 methylamino)^ 3⁄4 ^, 2, 2·<~ methylamino)^ 3⁄43⁄4P, 23- chopped benzylamine, 2·<Φ3⁄43⁄4 benzylamino) ^, 2 3⁄43⁄4 Benzyl leg) ^, 2·<2, Φ 2⁄4 «methylamino) ^, 2<3,~ 2⁄4«甲腿) ^录,甲甲腿) ^录,2·<2,3-dimethyl«benzylamino)^ 嘌呤, 2<3 dimethyl «benzylamino)^ 嘌呤, 2 ·<2Α5-三甲«苯甲胺基)^ 2·<3Α5-三甲«苯甲胺^ ^-¥«^ 2-amine fiber 、, 2-3⁄4»^ 2-A move, 2-amino group 4 , 2, II, 2-methyl·6, 2-amino 4-hydrogen, 2-hydrogen 4-hydrogen, 2-methyl 4-hydrogen hydrazine, 2-hydrogen 3⁄43⁄4», 2-hydrogen 4呤, 2,^ dihydrogen, 2-hydrogen 4-methyl, 2-hydrogen, 2-hydrogenpropyl, 2-i3⁄4t嘌呤, 2-i3⁄4 hydrogen, 2-^3⁄44 A,

2-雜 4丙腿嘌 呤、 2-氢 «- -2-异戊烯纖 、 2-¾^-2-异戊烯纖 、 2-丙基 - -2-异戊烯纖 、 2-苯甲 基 _₂ 戊烯搬 、 ₂ _ _₂_异戊烯搬 、 2-· 、 2-氯 4錄 、 2-氯 4氢赫票 呤、 ₂_氯 甲胺基 P 、 2-氯 丙胺基 P 、 2-氯 苯甲胺基 P 、 2-氯 4纖基嘌 呤、 2-氯- -2-异戊烯詹 、 2- 、 2-氟 4錄 、 2-氟 4氢赫 、 2-氟 甲 、 2-氟 基嘌呤、 2-氟 丙胺基嘌呤、 2-氟 苯甲胺基嘌呤、 2-氟 纖基嘌呤、 2-氟 - -2-异戊烯基 腺 P 、 2-静 、 2 錄 、 2 氢德 P 、 2 甲胺基 P 、 、 2- ^^丙胺基 Ρ 、 2 苯甲胺基 Ρ 、 2 纖基 Ρ 、 2善 -2-异戊烯搬 、 2·? 、 2 錄 、 2 氢德 、 2 甲胺基 、 2 ¾t基 、 2 丙胺基 P 、 2^ 苯甲 、 2 ¾» 、 2善 -2-异戊烯纖 Ρ 、 2-氢 、 2-丙基 -Ν⁶- 环 、 2-苯甲基 、 2 -雜 、&^ 、 2-氯 -N⁶- 环 、 2-氟- 、& ¾| 、 2善 、&^ 、 2善 、 &¾| 、 2-腿 Amino, 2-propyl 3⁄4|, 2-propyl 43⁄43⁄4, 2-propyl 4-hydrogen β, 2-propyl 4-methylamino, 2-propyl 4-ethylamino 2-propyl 4-propene, 2-leg Benzylamine P, 2-^6·Benzene, 2-propylbenzylaminopurine, 2-^3⁄4^Fiberyl P, 2-propyl 43⁄4», 2-Benzene, 2-Benzyl Base 4, 2-benzyl-4-hydrogen, 2-benzylmethylamino-2-phenylmethyl P, 2-benzylmethylpropene, 2-3⁄4»^ 2- miscellaneous 4, ₂ -di Hydrogen _P , ₂ -heteromethylamino _P ,

2-hetero 4 propylene leg 嘌 Bismuth, 2-hydrogen «- -2-isopentenyl, 2-3⁄4^-2-isopentene, 2-propyl--2-isopentenyl, 2-benzyl- ₃ -pentene , ₂ _ _ ₂ _ isoprene, 2-·, 2-chloro 4, 2-chloro 4-hydrogen, ₂ _chloromethylamino P, 2-chloropropylamino P, 2-chlorobyl Amino P, 2-chloro-4-phenylindole, 2-chloro--2-isopentenyl, 2-, 2-fluoro-4-, 2-fluoro-4-hydrogen, 2-fluoromethyl, 2-fluoroanthridine , 2-fluoropropylamino hydrazine, 2-fluorobenzylamino hydrazine, 2-fluorocellulose hydrazine, 2-fluoro--2-isopentenyl gland, 2-static, 2-record, 2-hydrogen P, 2 methylamino P, , 2-^^propylamino hydrazine, 2 benzylamino hydrazine, 2 phenyl fluorene, 2 good-2-isopentene, 2·?, 2, 2, hydrogen, 2 Amino, 2 3⁄4t, 2 propylamino P, 2^ benzo, 2 3⁄4», 2 good-2-isoprene, 2-hydrogen, 2-propyl-Ν ⁶ - ring, 2-phenyl Base, 2-hetero, &^, 2-chloro-N ⁶ - ring, 2-fluoro-, & 3⁄4|, 2 good, &^, 2 good, &3⁄4|, 2-leg

-3-methylbutane-2-enyl), 2-3⁄43⁄4 < ~3⁄43⁄4-3-methylbutane-2-enamine, 2-hydrogen»^<~3⁄4*-3-methylbut-2-enamine 3⁄4, 2 -Methyl 3⁄43⁄4-3-methylbutane-2-enamine, 2-3⁄4 < ~3⁄43⁄4-3-methylbut-2-enamine, 2-propyl 3⁄43⁄4-3-methylbutene-2-phenylmethyl · < ·3⁄43⁄4-3-methyl-butane 2 enamine, 2-3⁄43⁄4 < ~3⁄43⁄4-3-methylbutene 2 JS*yf^, 2-m3⁄4 < ~3⁄43⁄4-3-methylbutene 2S3⁄4 ), 2-fluoro·<·3⁄43⁄4-3-methylbutane-2-enamine, 2-^ < ~ slit _3-methylbutene 2 enamine, 2- <4-3⁄43⁄4-3-¥-*-Τ 2 olefinic leg 2 & 3⁄4 3⁄43⁄4-3-methylbutan-2-enylamino-aminoxanyl hydrazine, 2-3⁄43⁄4 ^ guanylamino P, 2-hydroquinone P, 2-methyl sterol, 2- 3⁄4 ^, 2-propyl 4 Xialamine P, 2-Benzyl 4 Xi, 2-organoamino 2-chlorine, 2-fluoro 4 Xia, 2 Xia, 2-ring 3⁄4 ^ , 2-leg 4 B earn base p, 2-methyl 4 B β base, 2- ^ ^ B « base ^ ticket 呤, 2- propyl 4 ethyl « base ^ ticket 呤, 2- phenylmethyl 4 乙 « Base^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ -Dimethyl 3⁄4«^3⁄43⁄4 , bird droppings, yellow, yellow, ^m ^

Pyrimidine, 5 di-bromopyridine, thymine, cytosine, uridine, 5-pyrimidine, glucoside, and pyrimidine, each of which can be used as a prodrug as a salt or water, or as a decorative form .

 Further, wherein the formula (1) is an AMPK activator.

 Further, wherein the formula (2) is an AMPK activator.

 The invention relates to the use of activating AMPK for the preparation of a medicament for the treatment of a drapes or physiological condition which is ameliorated by an AMPK activator, wherein the activation of AMPK is at least one of Claim 1 or 2 to destroy a pharmaceutically acceptable nutritionally acceptable salt thereof for use in a mammal in need of such treatment.

 The invention discloses a method for activating AMPK in the preparation of a medicament for preventing or treating a disease selected from the group consisting of: pre-diabetes, insulin resistance, type 2 diabetes, X syndrome, metabolic syndrome Use of the activated oxime to at least one of the following elements: which is selected from the group consisting of formula (1), or a pharmaceutically acceptable salt thereof, to be treated Mammals, thereby increasing cellular glucose.

The invention discloses a method for activating AMPK in the preparation of a medicament for preventing or treating a disease selected from the group consisting of: pre-diabetes, insulin resistance, type 2 diabetes, X syndrome, metabolic syndrome Use of the compound, wherein the compound is at least one selected from the group consisting of the formula (2) or a pharmaceutically acceptable salt thereof, for the mammal in need of such treatment, thereby increasing the cell glucose. The invention relates to a method for activating ΑΜΡκ in the preparation of a medicament for preventing or treating ω, wherein the activation

The sputum is at least one type of sulphate, which is selected from the formula (1), or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment, thereby The blood acid is derived from ester and body weight.

 The invention relates to the use of activating sputum in the preparation of a medicament for preventing or treating ω, wherein the activation

The sputum is at least one type of sulphate, which is selected from the formula (2), or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment, thereby The blood acid is derived from ester and body weight.

 The present invention further comprises a drug, which comprises a combination of a formula (1) and a pharmaceutically acceptable carrier. The present invention further relates to a drug, which comprises a combination of formula (2) and a pharmaceutically suitable carrier. The medicament for treating pre-diabetes, insulin resistance, type 2 diabetes, x-m metabolic syndrome may comprise a second medicament. Suitable second agents include various classes, thiasodione, thienopyridin, and other AMPK activators.

 As described herein, the present invention encompasses the administration of a pharmaceutically effective amount of any of the compounds of formula (2) and salts and prodrugs thereof. More suitably, the present invention also includes a human being, which has a preference for treating the human body of the present invention, has a pharmacy amount of 3⁄4 ^

53⁄41) and 53⁄42)

 The fine term "AMPK" refers to the agonist-activated protein kinase.

 The term "lingual urinary tract disease" refers to a physiological condition, and the lake is positive for blood sugar higher than recommended.

3⁄4S The term "insulin resistance" refers to a physiological condition in which the whole body or tissue including the liver, skeletal muscle, and adipose tissue is incapable of insulin.

 Brain terminology "Type 2 diabetes, also refers to non-insulin type diabetes or A «diabetes; refers to insulin production caused by metabolic disorders. Island *3⁄4 resistance, «often fasting blood glucose is higher than 10 0 3⁄4 ^.

 The term 3⁄4S Syndrome refers to a physiological condition that has at least two of the following symptoms: fasting and high blood! 3⁄4 non-insulin-dependent sugar cane high blood pressure GROHE triester low high density protein cholesterol.

 The withdrawal of the present invention can result in a grape body greater than 30% by weight, a triglyceride amount greater than 35 wt%, and a body weight of more than 15%.

 detailed description

 Example 1

 2-aminomethylamine

 After dissolving 4 mmol of 2-amino-4-chloroindole in 20 liters of butanol, 5 mmol of 3-3⁄4⁄4 methylamine and 6 mmol of triethylamine were added. Mix 3⁄4 at 90°01⁄2 4 hours. After cooling, it considers the product after 3⁄47 and butanol «and crystallization from dimethylmethyl or acetyl. HPLC: ^ at 98%. The yield was 95%. The result is recorded in 1.

 Table 1 produced by the method of Example 1

环丙胺基 49.9/50.5 5.5/5.3 44.6/44.2 191

Cyclopropylamine 49.9/50.5 5.5/5.3 44.6/44.2 191

 Cyclobutylamino group 53.0/52.9 6.1/5.9 40.9/41.1 205

 Cyclopentylamine 54.5/55.0 6.3/6.5 39.2/38.5 219

 Cyclohexylamine 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-Moline aniline 42.5/43.3 3.3/3.0 27.1/27.5 306

 3- Desert aniline 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

 Benzylamine 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-chlorobenzylamine 51.1/52.5 4.3/4.0 31.1/30.6 276

 3-chlorobenzylamine 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-iodobenzylamine 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-methoxybenzylamino 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-trimethoxybenzylamino 54.1/54.5 5.0/5.5 25.6/25.4 331

 3,4, benzylaminoamine 54.1/54.5 5.6/5.5 25.8/25.4 331

6<3 methylamine

After ₄ mmol of the chlorine _P was cold-dissolved in ₂₀ ml of butanol, 5 mmol of 3-t3⁄4 methylamine and 6 mmol of triethylamine were added. Mixed in 90°Q1⁄2 4 hours. After cooling, the product was considered to be washed with water and butanol and crystallized from dimethylmethylcellulose or ethanol. HPLC: 97%. The yield was 94%. result

 Table 2 is produced by the method of Embodiment 2

环戊胺基 59.2/59.1 6.6/6.4 34.2/34.5 204 环己胺基 60.5/60.8 7.1/7.0 32.4/32.2 218

Cyclopentylamine 59.2/59.1 6.6/6.4 34.2/34.5 204 Cyclohexylamine 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

 Benzylamine 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-methylbenzylamine 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-iodobenzylamine 41.1/41.0 3.2/2.9 20.1/19.9 352

 4-hydroxybenzylamine 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-methoxybenzylamino 60.6/61.2 4.5/5.1 28.1/27.4 256

 2,3-Dimethoxybenzylamino group 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 chlorine

 4 3⁄4 ^ er 2-amino 4 chloro was dissolved in 35 liters of 50 wt% sulfur, and 5 3⁄4 hr of sodium nitrate was added. Mix at -10 hours and then at 50°Q1⁄2 for 1 hour. After cooling, the product is considered to be crystallized from water and butanol «and from dimethylmethylcellulose or ethanol. HPLC: at 98%. The yield was 86%. MS (ESI) nVe 170.88 (M+H^); lHNM MSQ 36): 8.01 (s,

1H, =CH-N), 1326 (s, 2H, OH and NH).

 Example 4

 2d methylamine

 After dissolving 3 3⁄4 Å 2-3⁄4⁄4 ^ of the chlorine obtained in Example 3 in 20 liters of butanol, 4 3⁄4^ of 3-3⁄43⁄4 methylamine and 6 tt of 3⁄4f were added. Mix 3⁄4 at 90°01⁄2 4 hours. After cooling, the product was considered to be washed with water and butanol and crystallized from dimethylformamide or ethanol. HPLC: at 97%. The yield was 93%. Result 3.

 Table 3 is produced by the method of Example 4;

乙胺基 47.2/46.9 5.2/5.1 38.7/39.1 180

Ethylamine 47.2/46.9 5.2/5.1 38.7/39.1 180

Alanine 49.8/49.7 5.3/5.7 36.5/36.2 194

Isobutylamine 52.4/52.2 6.5/6.3 33.5/33.8 208

Isoamylamine 54.1/54.3 6.9/6.8 31.9/31.7 222

Hexylamine 56.7/56.2 7.1/7.3 29.9/29.8 236

Cyclopropylamine 50.1/50.3 4.9/4.7 36.7/36.6 192

Cyclobutylamine 52.9/52.7 5.5/5.4 39.6/34.1 206

Cyclopentylamine 54.9/54.8 6.2/6.0 31.5/31.9 220

Cyclohexylamine 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-nonylaniline 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

Benzylamine 60.3/59.7 4.4/4.6 28.7/29.0 242

 2-methylbenzylamine 61.4/61.2 5.8/5.1 27.1/27.4 256

 3-methylbenzylamine 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-iodobenzylamine 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-methoxybenzylamino 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-Trimethoxybenzylamine 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 chloride

 After dissolving 3 3⁄4^l of 2 chlorine in 20 ml of butanol, 4 rpm of methyl manganese chloride was added. Mixed with palladium catalyzed at 80 1 ^ 24 hours. After cooling, 3⁄4i of the product was obtained, washed with butanol and crystallized from dimethylmethane or ethanol. HPLC: ^^ at 97%. The yield was 91%.

 Example 6

₂ —Methyl _ <3 Methylamine

After the 3 2-methyl 4 chloro group obtained in Example 5 was dissolved in 20 liters of butanol, 4 3⁄4^ of 3-«methylamine and 6 3⁄4» of 3⁄4f were added. Mixed at 90 °01⁄24 hours. After cooling, the product was considered to be crystallized from water and butanol and from dimethylformene or ethanol. HPLC: 98%. The yield was 93%. Result 4. Table 4 is produced by the method of Example 6

 Example 7

 2·<3 methylamine

 After dissolving 4 Torr in 20 ml of butanol, 5 liters of 3-fresh methylamine and 6 rpm of triethylamine were added. Mix at 90 ° C for 4 hours. After cooling, itH obtained the product and then butanol and crystallized from dimethyl ketone or ethanol. HPLC: at 95%. The yield was 92%. Result 5.

Table 5 is produced by the method of Example 7 Compound substituents produced by the method of Example 7 % C % H % N ESI-MS

"M+H ⁺ 1

 Methylamino 44.4/43.9 4.8/4.9 50.8/51.2 165

 Ethylamine 47.1/47.2 5.9/5.7 47.0/47.2 179

 Isobutylamine 52.8/52.4 6.9/6.8 40.3/40.7 207

 Alanine 49.4/50.0 6.6/6.3 44.0/43.7 193

 Isoamylamine 55.1/54.5 7.1/7.3 37.8/38.2 221

 Hexylamine 55.2/56.4 7.9/7.7 36.9/35.9 235

 Cyclopropylamine 50.6/50.5 5.4/5.3 44.0/44.2 191

 Cyclobutylamine 52.7/52.9 6.2/5.9 41.1/41.1 205

 Cyclopentylamine 55.4/55.0 6.5/6.5 38.1/38.5 219

 Cyclohexylamine 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-Moline aniline 44.0/43.3 3.1/3.0 26.8/27.5 306

 3- Desert aniline 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

 Benzylamine 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-chlorobenzylamine 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-iodobenzylamine 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-methoxybenzylamino 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 After dissolving 4 rpm of 2-chloro 3⁄4 ^ in 20 liters of butanol, 5 Torr of 3-fresh methylamine and 6 rpm of triethylamine were added. Mixing; at 90 ° Ο 1⁄2 4 hours. After cooling, itH gives the product 3⁄4 and butanol and earns from dimethyl ketone or acetamidine to crystallize. HPLC: 3⁄4λ at 91%. The yield was 88%. Result 6.

Table 6 is produced by the method of Example 8.

 AMPK activity analysis

In the small ίί meat cell C ₂ C1 ₂ , mouse fibrin 3T3-L1 and human cancer cell HepG2 target the impact of AMPK activation of the cells with glucomannan DMEM fine recording liquid containing 10wt% fetal cattle gift (EBS ), 4 mM; fe--gluten (L-glutamine), 2 mM sodium pyruvate and 1 wt% penicillin I slreptomycin (Lake Life Technology, hvito n) at 37 V, 5 Culture in %(v/V)03⁄4 environment. 3xltf cells were seeded in ^veil disks, and cells were treated with the indicated compounds for 30 hours after 24 hours, followed by dissolution of the cells and analysis by Western blotting. Equal amounts of protein were separated by electrophoresis with 12^*sodium sulphate polypropyleneamineamine followed by transfer to a polyvinylidene fluoride membrane. The transferred polyvinylidene fluoride membrane was immersed in 3 wt% of cattle dissolved in PBS buffer. After serum albumin 60, they were added with MAPK (T3⁄4rl72) antibody (12000, Cell signaling), anti-AMPK antibody (1:2000 (vv), Cell signaling), anti-glucose transport protein. 4 antibodies (l: 1000 (vv), Millipore pore) or a few protein antibodies (l: 5000 ( _V v); Merck) at 4 ° C. After the 16 hours, the secondary antibody was added for 1 hour at room temperature. The 3⁄4⁄2 band is protected by cold light and the signal is recorded in the negative. The resulting signal was scanned and analyzed by image analysis software (TotalLab Quant).

The effect of various modifications on AMPK activation is summarized in Table 7. Most of the tests were performed in biliary, aliquots of several meat cells, QC1 ₂ mouse, and the AMPK in human hepatoma cells Hep G2 cells.

 Table 7

10 122 119 124

10 122 119 124

 100 228 251 209

200 284 277 261-hydroxy-6-hydroxythio hydrazine 1 104 118 105

 10 109 122 108

100 198 210 204

200 251 277 222-amino -6-methylamino hydrazine 1 119 109 114

 10 187 135 139

100 215 220 230

200 351 332 348-hydroxy-6-methylamino hydrazine 1 118 113 115

 10 151 162 148

100 255 271 266

200 361 382 354-Hetthio adenine 1 105 112 118

 10 115 128 119

100 221 204 195

200 289 297 308-Hexylthio-6-hydroxyindole 1 109 115 113

 10 148 147 132

100 251 220 209

200 333 308 315,6-dihydrothio hydrazine 1 104 102 110

 10 117 98 133

100 215 178 244

200 298 260 366-chloroadenine 1 110 118 116

 10 155 143 139

100 284 271 220

200 326 311 314-Chloro-6-hydroxyindole 1 109 108 110

 10 156 145 163

100 277 243 249

200 331 356 375-fluorourea 嘌呤 1 102 114 117

 10 112 165 180

100 213 291 259

200 303 323 315-bromourea 嘌呤 1 116 119 113

 10 172 188 190

100 263 277 253

200 349 361 354-iodine adenine 1 114 116 115

 10 143 179 151

100 214 237 227

200 311 358 341-Bromo-hypoxanthine 1 108 111 110

 10 142 176 160

100 214 245 242

200 321 357 359-methylamino hydrazine 1 103 107 116

 10 108 129 141

100 213 241 259

200 328 347 363 6-hexylaminopyrene 1 109 108 112

 10 123 111 148

100 248 170 280

200 359 265 317

6-cyclohexylamino hydrazine 1 107 107 111

 10 110 152 132

100 248 269 261

200 322 333 354

₆ -(4-methylbenzylamino) 嘌呤1 112 110 106

 10 158 163 121

100 270 259 245

200 358 347 348

6-(3-chloroanilino) 嘌呤 1 108 116 106

 10 118 130 109

100 186 217 212

200 307 301 319

2-amino-6-isoamylamino 嘌呤 1 104 110 117

 10 114 169 174

100 238 271 250

200 305 361 341

2-amino-6-(2,3-dimethoxybenzylamine 1 106 118 115 base)嘌呤

 10 144 156 127

100 263 250 229

200 334 347 318

2-hydroxy-6-propylamino hydrazine 1 114 109 110

 10 122 129 133

100 201 233 270

200 324 361 339

2-hydroxy-6-benzylamino hydrazine 1 108 115 109

 10 135 126 137

100 244 230 261

200 356 309 338

2-methyl-cyclopentylamino hydrazine 1 105 114 117

 10 128 140 140

100 280 241 240

200 342 350 301

2-methyl-6-(3,4,5-trimethoxybenzylamine 1 106 115 112 base) 嘌呤 10 117 141 168

 100 211 254 270

200 361 346 359

2-Benzylamino-6-amino hydrazine 1 110 119 105

 10 128 147 116

100 259 217 235

200 312 308 364

2-cyclohexylamino-6-hydroxyindole 1 108 118 111

 10 118 172 137

100 209 283 248

200 321 375 351 Chest uracil 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-hydroxyuracil 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 Fluorouridine 1 117 116 117

 10 144 141 147

 100 231 222 206

 200 312 343 308

 6-nitrouracil 1 109 109 108

 10 109 115 124

 100 197 185 199

 200 284 288 273

 AICA 1200 335 340 319

 Glucose uptake - organism eve

The side glucose analogs (2-NBDQMolecular Probes) were analyzed for the effects of biochemical luminal glucose uptake in muscle cells C ₂ C1 ₂ . QC1 ₂ cells were treated with a new AMPK activator at 37 ° C for 30 minutes. After adding 500 glucose analogs, the cells were cultured at room temperature for 5 times, and the cells were buffered with phosphorus β three times and 70% (ν ν ) Ethanol fixed. The intracellular glucose analogs are deleted.

The effect of ministry on glucose uptake is summarized in Table 8. The chromatograms of most of the a^ic ₂ ci ₂ cells are shown as the average of three independent experiments.

 Table 8

 Reagent concentration (microM) glucose uptake (%, as opposed to

 Control group

 6-hydroxyindole 1 109±2.2

 10 242±23.7

 100 289±21.4

 600 318±21.2

₆ -(4-methylbenzylamino) 嘌呤1 114±9.2

 10 205±14.6

 100 281±11.5

 600 309±9.1

 2-cyclohexylamino-6-hydroxyindole 1 108±2.1

 10 195±11.9

 100 251±16.2

 600 311±10.7

 Thymouracil 1 110±3.2

 10 167±15.1

 100 215±18.2

600 283±22.3 AICA 1200 264±19.2

 Health»inner

In order to increase the effect of Hf^^ compounds on the regulation of plasma glucose levels, N, rats were fed as high-fat diets, and mice were used as second-type sugar animals. 3⁄4 C57BI76J mice were housed at 22 ° C for 12 hours/day cycle. Feed high-fat diet 60%// with unlimited diet. Fat feet or normal feed. 0.1-50 亳 kilograms of the ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ Should be empty injection of high fat feeding ^ ¹ fear, rat two days ^ ^ ό天, « -1 hour after the administration of plasma, and measured plasma glucose and triacids.

 With the application of physiological food 3⁄47 fiber fat feeding, the parent-to-be-produced « ^ of the profitable grape grain is greater than 30wt%, the triglyceride is more than 35wt%, and ^ 15% or more.

 The description of J f is only a preferred embodiment of the present invention, and is not intended to cover the scope of protection of the present invention, and other equivalent changes made by the spirit of the present invention should be the same as that of the present invention. protected range.

Claims

1. A compound that activates AMPK, wherein the compound that activates AMPK is an effective amount of at least one of its pharmaceutically nutritionally acceptable salts, to a mammal in need of such treatment , which is described as follows:

(1) Among them, R2 represents ti, ion, halogen atom, ¾*, amine group, ^¾*^-NH (m -, where R represents ^¾*, ring gap, hetero, fiber taken, benzyl group taken methyl , in: The substituted means containing substitutions include 1 to 5 hydroxyl groups and alkoxy groups, 1 to 5 hydroxyl groups and halogen atom groups, and 1 to 5 hydroxyl groups. The substituted benzyl group represents a group containing substitutions including 1 to 5 hydroxyl groups, 1 to 5 hydroxyl groups and halogen atoms, 1 to 5 wherein R6 represents hydrogen, hydrogen or alkyl (single hydroxyl); wherein 1 Table ¾*, ring gap, heterogeneous, taken ^ m benzyl is taken methyl, in The obtained values include 1 to 5 halogen atoms, 1 to 5 hydroxyl groups, and 1 to 5 hydroxyl groups. The substituted benzyl group means a substituted group including 1 to 5 hydroxyl groups, 1 to 5 hydroxyl and halogen atom groups, and 1 to 5 mm atoms. ¾^ takes ^½ and has the same meaning as , where The hydrogen shown is ~OH; The element atom represents fluorine, chlorine, bromine, and phosphorus; The filaments are shown as ¾; The ¾¾^"SH; The linear or branched chains shown mostly contain six ^^ subgroups; Shown is ^"OR, where R is ^¾ The ring ^ represents a single or multiple rings containing ^ 6 «sub-elements and its tautomers^, racemates, optical isomers^ or its pharmaceutically nutritionally acceptable salts, including pharmaceutical 2. A compound that activates AMPK, which is characterized in that the compound that activates AMPK is at least one effective amount of formula (2) and its pharmaceutically nutritionally acceptable salt, in order to require this treatment A mammal, wherein said 5H2) is defined as follows:

(2) Among them, R6 means Hong legs, Among them, R3 represents bighead, Lu, halogen atom and methyl group, Where R2 represents bighead^ ¾^ takes ^½ and has the same meaning as , where The hydrogen shown is ~OH; The element atom represents fluorine, chlorine, bromine, and phosphorus; Its tautomeric racemates, optical compounds and pharmaceutically and nutritionally acceptable salts thereof, including pharmaceutical compositions. 3. The chemical composition for activating AMPK as claimed in claim 1 is that, the chemical for activating AMPK is Chemically selected from the following groups: adenophosphate, 2-aminobutylamine, 2-aminobutylamine, 2-aminopropanol, 2-aminopropanol, 2-aminopropanol, 2-amino group, propyl group, 2-amino group, butyl group, 2-amino group, pentyl group, 2-amino group, 2-amino group, 2-amino group, 2-amino group, 2-amino group, 2-amino group, 2-amino group, 2-amino group Amino 2-amino 2-amino 2-bromyl 2-amino-bromyl 2-amino bromyl, 2-JS¾- <2-t¾S*)^ 2-amino 3-fluoro Bromofiber, 2-amino, benzylamine P, 2-amino·<2-methylbenzoyl 2-methylbenzylamine, 2-aminomethylbenzylamine), 2 -Amino group <2-methylamino group), 2-amino group 3-¾methylamino group, 2-amino group methylamino group), 2-amino group ^<2-*¾methylamino group), 2 -Amino group·<3-Λ¾methylamino group), 2-Amino group·<·Λ¾methylamino group), Benzylamine 2-aminobenzylamine, 2-amino 3-dihydrobenzylamine, 2-amino, ), 2-amino·<2-methyl«benzylamine), 2-amino^23-dimethyl! ^A JS¾), S-JS*^ Dimethyl «benzylamine, 2-amino ^2,4,5-trimethylH¾benzylamine, 2-Amino group · <3Α5-trimethyl|¾benzylamine group, methylamino group, & ^^ propylamine group, isobutylamine group, 6^ base P, , W, propyl, butylamine base P, W, pentyl, W, hexyl, 6. fiber base P, 6<2-¾» base) P, 6<3-¾¾S¾)P,

6<2-bromofiberyl, &{3-bromofiberyl, 6<Φbromofiberyl, 6<2-t¾tyl) ^p , 6<3-t¾tyl, 6<*«base, &■ benzylamine group , 6<2-methylmethylamine 6<3-methylmethylamino), 6<Φmethylbenzylamine, 6<2-¾¾methylamine 6<3 methylamine, 6<~methylmethylamine 6 <2-Silk Armor Legs 6<3-Silk Armor Legs 6< methylamine, 6<3·? 6<~Benzenemethylamine, Benzylamine, & {3,4-Dihydrobenzylamine), 6<2,~Dihydrobenzylamine), 6<2-Methyl«benzyl amino group), 6<2,3-dimethylbenzylamine, 6<3 dimethylbenzylamine), 6<2,4,5-trimethylbenzylamine, 6<3Α5-trimethylmethylamine )Purine, 2-¾¾^methylamino,

2-isopentyl, 2-¾hexane, 2-¾s^, propylamino 2-¾¾^butylamine p, Amino P, 2-hexylamine group, 2-fiberyl P, 2-hexylamine group Leg), 2 Dan, 2 Dan · <2-Moxian, 2 Dan Moxian, 2 Dan Mo Xianji

2 de-fluorobromofiber base 2 t¾ base _2- methylbenzylamine, 2-methylbenzylamine, 2-methylbenzylamine, 2-methylbenzylamine , 2 fresh methylamine ^ 2 · <2 methylamine, 2-methylamine, 2-methylamine, 2-ethylbenzylamine, 2-ethylbenzylamine, 2-¾¾-<3,4 - ^{Dihydrobenzene} , 2-» Methylbenzylamine, Ζ-»^-dimethylH¾benzylamine, 2-¾<2,4,5-trimethylbenzylamine)^ 2-¾<3A5-trimethylmethylJS¾), 2-methylmethylamino, 2-methylamino, 2-methylbutanyl, 2-methylpropylamino, 2-methylisopentyl, 2-methylethyl 2-methylpropylamine Purine, 2-methyl, butyl, 2-methyl, 2-methylhexyl, 2-methyl·6¾¾, 2-methyl·<2-¾», 2-methyl3-¾ «* 2-methyl, 2-methyl 2-bromyl) p, 2-methyl 3-bromyl, 2-methyl bromyl, 2-methyl·<2-Λ¾¾ base) ^p , 2 -Methyl 3-fluorobromide 2-methyl 2-methyl 4 benzyl amino, 2-methyl · <2-methyl benzyl amine, 2-methyl 3-methyl benzyl amino) purine, 2-methylmethylbenzylamine, 2-methyl2methylamino)purine, 2-methyl-ttmethylamino), 2-methyl·<·«methylamino), 2-methyl · <2-Λ¾methylamino), 2-methyl·<3-Λ¾methylamine) Ρ, 2-methylmethylamine, 2-methylbenzylamine, 2-methylmethylmethyl) Ρ, ₂ _Methyl _2?3 -Dibenzylamine ₂ _Methyl ₃ ,_Dibenzobenzylamine 2-Methyl 2,~Dibenzobenzylamine) ^ 2-Methyl·<2-Methyl Methylamine), 2-methyl(dimethylbenzylamine), 2-methyldimethylbenzylamine, 2-methyl2A5-trimethylbenzylamine, 2-methyl3A5- Trimethyl(H2benzylamine), 2-methylamino(4-amino), 2-isobutyl(amino)(4-amino), 2-propyl, 2-isoamino(4-amino)

2. Ding leg, 2. Wu leg, 2-¾»^amine group, 2·<2-¾»yl)^amine group P, 23-¾¾S*>^»^ 2·<Φ¾¾«>^amine group P, 2·<2-*«base) ^Amino group P, 2·<3-*«yl)^amine group, 2*¾«>^amine group P, 2·<2-bromoyl)^amine group, 2<3-bromofiber, 2 bromide ¾¾>^Amino group, 2-benzylamine group, 2·<2-methylbenzylamine group)^amine group, 2·<3-methylbenzylamine group·amino group, 2·<~ Methyl benzylamine)^amine P, 2·<2 methylamine amino P, 2·<3 methylamine, 2 methylamine amino P, 22-methylbenzyl)^amine P, 2·< 3 methylaminoamine)^, 2 methylaminoamine P, 2·<3·?cholamineamine 2¾«methylaminoamineP, benzylamine)^, 2<2,~dihydrobenzylamine )^amine group, 2<3,~dimethylbenzylamine^amine group, 2·<2,3-dimethyl«benzylamine¾^J»f^, 2<2,3-dimethyl«benzene Methylamino)^aminopurine, 2<3,5-dimethylamine*benzylamine)^aminopurine, 2·<2Α5-trimethylamino*benzylamine)^aminopurine, 2 ·<3,4,5-trimethylbenzylamine, 2-methylamino, 2-isobutylamine ^ 2-propylamine, 2-pentylamine, 2-hexylamine, 2-propylamine, 2-cyclobutylamine, 2-methyl, 2-fiberyl, 22-«amine record,

2<2-t¾t base) ^ record, 2<3-t¾t base) ^ record, 2·<Φ*¾¾ base) ^ record, 2·<2-bromofiber base) ^record, 2·<3-bromo Fiber base) hydroxyl group, ₂ bromide, 2-benzylamine, 2·<2-methylbenzylamine group), 2<3-methylbenzylamine·2·< Φnail silk nail leg)^record, 2<2 nail leg)^record, 2·<3-fresh methylamine group)^ 2·<~«methylamino)^¾¾Pine, 2·<2-«methylamino)^ 2·<3-*¾methylamino)^ 2·<~Methylamine^ 2·<3·?Benzylamine^ 2·<~¾¾BenzylJS¾>^¾¾P ^, 2<2,3-Dibenzylbenzoyl) ^Record, 2·< 2, Φ di¾¾ benzylamine record, 2<3, ~ di¾* benzylamine record, 223- dimethyl! ^AJS¾^¾¾, 2·<2, 3-Dimethyl«benzylamine^ 2·<3,5-DimethylH¾benzylamine^^ 2·<2Α5-Trimethyl«benzylamine)^ 2·<3Α5-Trimethyl«benzylamine)^ 6-Hydrogen, Ν ⁶ -methyl, 2-amino, 2-amino, 2-amino, 2-amino, 2-methyl, 2-methyl, 2-amino , 2-hydrogen, 2-methyl-4-hydrogen, 2-hydrogen 2-hydride 4 sulfide, 2^ dihydride, 2-hydride methyl, 2-hydride 4^, 2-hydride propyl P, 2-ΖΆ ^ν ^ 2-i¾ hydrogen test, 2-i¾ a Amino P, 2-

Propylamino 2-propyl, 2-propyl, 2-propyl 4-hydrogen, 2-propyl 4-methylJS*, 2-propyl, 2-propyl 4-propylamine, 2-propyl 4-methylbenzene Methylamino, 2-^¾^ Benzylamine P, 2-propylbenzylamine 2-^* Fiberyl 2-propylfiberyl P, 2-benzylmethyl, 2-phenylmethyl 4 2-benzenemethyl 4-hydrogen, 2-benzyl 4-methyl, 2-phenylmethyl-P, 2-phenylmethylpropane, 2-¾»^ 2-heterogene, 2-benzyl 4-hydride 2 4A, 2-Miscellaneous 4

2 propylamine, 2-hydrogen-2-isopentene, 2-¾-2-isopentene, 2-propyl-2-pentene fiber, 2-phenylmethyl-2- Isopentene, 2--2-isopentene, 2-·, 2-chloro4-propylamine, 2-chloro4-hydrogen, 2-chloro4-methyl, 2-chloropropylamine, 2-chloropropylamine Base P, 2-chloro-4-benzylamine base P, 2-chlorofiberyl P, 2-chloro--2-isopentene fiber P, 2-, 2-fluoro-4-methyl, 2-fluorohydrogen P, 2 -Fluoro-4-methylamino-P, 2-fluoro-4-methylamino-P, 2-fluoropropyl, 2-fluoro-4-benzyl, 2-fluoro-, -2-isopentenyl, 2-static, 2 Record, 2 hydroxyl, 2 methylamino, propylamine, benzylamine, 2-yl, 2-7^-2-isopentene, 2·?diaphragm, 2 record, 2 hydroxyl, 2 methylamine base P,

2 propylamine group, 2 benzyl, 2 fiber base, 2-benzene-2-isopentenyl, 2-hydroxysulfanyl, 2-propyl, 2-Ζ ^-^^Ά ^ν ^ 2-phenylmethyl-, &^, 2-Hetero, 2-chloro, 2-fluoro-, & 2shan, , 2shan N ⁶ - Ring 2-J» <~¾¾-3-methylbutyleneamine, 2-¾¾ <~ ¾¾-3-Methylbutenamine, 2-Hydrogen_^<4~¾¾-3-methyl-butenamine, 2-Methyl~¾¾-3-methylbutenamine, 2-¾ <-¾¾-3-methyl-but2enylamine), 2-»- <-¾*-3-methyl-but2eneJS*), 2-phenylmethyl·<·¾¾- 3-methyl-but2ene JS¾) ^ 2-¾¾ <~¾¾-3-methyl-but2ene 2-» <~¾¾-3-methylbut2ene JS¾) , 2-fluoro·<·hydroxy —3-methyl-but2eneJS¾), 2-^<Φ¾¾-3-methyl-but2eneJS¾), 2·?^<Φ¾¾-3-methyl-but2eneJS¾)2-J» <~¾¾-3-Methylbutenamine, 2-amino-4furfurylamine, 2-hydroxyfurfurylamine, 2-methyl-4furfurylamine, 2- ^¾^Antilamine-based purine, 2-propyl-4-carboxylaminopurine, 2-benzyl-4-carboxylaminopurine, ₂ -benzyl-4-pholanine-based purine, ₂ -fluoro- 2-7-ethylamine group, 2-7-ethylamine group, 2-ethylamine group, 2-aminoethyl group, 2-ethylamine group, 2-ethylamine group 4 Ethyl Ethyl P, Ethyl Ethyl 2-Propyl 4 Ethyl Ethyl P, 2-phenylmethyl 4 Ethyl Ethyl P, 2-Heterogeneous 4 Ethyl Ethyl P, 2-Chloroethyl 2 Ethyl Ethyl P, 2 B-2&¾4-ethanoyl P, 2-dimethylfiberyl-4, guano yellow P, hypoxanthine, ^m ^Includes drug content 4. The chemical that activates AMPK as claimed in claim 2 is preferably selected from the following: Group of: 5-Methylpyrimidine, 5-Methylpyrimidine, Thymine, Cytosine, Uridine, 5-pyrimidine, Glycoside, Tripyrimidine, and includes the drug contained in 5. The use of a chemical that activates AMPK in the preparation of a medicament for the treatment of a physiological or physiological condition that can be improved by an AMPK activator, preferably in that the chemical that activates AMPK is at least one chemical. It is selected from the group consisting of claims 1 or 2 or pharmaceutically and nutritionally acceptable salts thereof to satisfy mammals in need of such treatment. 6. Use of a compound that activates AMPK in the preparation of a medicament for preventing or treating a physiological condition selected from the group consisting of: diabetes, insulin resistance, type 2 diabetes, syndrome X, metabolic syndrome, period Preferably, the chemical that activates AMPK is at least one chemical in an amount selected from claim 1 or a pharmaceutically nutritionally acceptable salt thereof, for a mammal in need of such treatment, Thereby increasing cellular glucose uptake, m. 7. Use of a compound that activates AMPK in the preparation of a medicament for preventing or treating a physiological condition selected from the group consisting of: diabetes, insulin resistance, type 2 diabetes, syndrome X, metabolic syndrome, period Preferably, the chemical is at least one purified chemical selected from claim 2 or a pharmaceutically and nutritionally acceptable salt thereof, in order to treat a mammal in need of such treatment, thereby increasing cellular glucose levels. intake, fiber 8. The use of a chemical that activates AMPK in the preparation of a medicament for preventing or treating menstruation, wherein the chemical that activates AMPK is at least one purified chemical selected from claim 1 or its Pharmaceutically and nutritionally acceptable salts are administered to mammals in need of such treatment, thereby reducing blood glycerides and body weight of the mammals. 9. The use of a chemical that activates AMPK in the preparation of a medicament for preventing or treating menstruation, wherein the chemical that activates AMPK is at least one purified chemical selected from claim 2 or its Pharmaceutically and nutritionally acceptable salts are administered to mammals in need of such treatment, thereby reducing blood glycerides and body weight of the mammals.