CN102382036A - Phenoxyacetic acid compound, preparation method thereof and drug application - Google Patents
Phenoxyacetic acid compound, preparation method thereof and drug application Download PDFInfo
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- CN102382036A CN102382036A CN2010102713861A CN201010271386A CN102382036A CN 102382036 A CN102382036 A CN 102382036A CN 2010102713861 A CN2010102713861 A CN 2010102713861A CN 201010271386 A CN201010271386 A CN 201010271386A CN 102382036 A CN102382036 A CN 102382036A
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- 0 CC(CC(C(O)=O)Oc1ccc(CN(C*)[Al])cc1)=CC=* Chemical compound CC(CC(C(O)=O)Oc1ccc(CN(C*)[Al])cc1)=CC=* 0.000 description 1
- OGLWUJJSDRYIQP-UHFFFAOYSA-N Cc1cc(-[n]2c3ccccc3c3c2cccc3)ccc1OC(Cc1ccccc1)C(O)=O Chemical compound Cc1cc(-[n]2c3ccccc3c3c2cccc3)ccc1OC(Cc1ccccc1)C(O)=O OGLWUJJSDRYIQP-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses novel phenoxyacetic acid compound as shown in compound of a formula 1. The phenoxyacetic acid compound comprises optical isomer, racemic mixture, physiological acceptable salt, solvate and a crystalline form, and a preparation method of the compound includes pharmaceutical preparation containing the compound and treatment application and relevant insulin resistance clinical application of the compound.
Description
Technical field
The present invention relates to the new phenoxy acetic acid compounds of general formula I, and their steric isomer and physiologically acceptable salt.These compounds with the syndromic therapeutic processes of metabolism such as mellitus in purposes, also relate to the method that it is used to treat, and the pharmaceutical composition that contains said compound.
Background technology
Mellitus are a kind of common metabolism disorder property diseases, and in recent years, the sickness rate of mellitus is in rising trend in the world, and human life's health has been constituted serious threat.Mellitus mainly are divided into amphitypy, type 1 diabetes and diabetes B.(insulin-dependent diabetes mellitus is to cause the low hyperglycemia that causes of insulin secretion level owing to the beta Cell of islet function is impaired IDDM) to type 1 diabetes, accounts for diabetics's 10%.Diabetes B (non insulin dependent diabetes; NIDDM) in the diabetic subject, account for about 90%; It is because peripheral tissues's (liver, muscle and fatty tissue) produces opposing to Regular Insulin, causes the generation of hyperglycemia level, and then causes cardiovascular disordeies such as blood fat disorder, hypertension.Improve body and can treat diabetes B the medicine of insulin sensitivity.
(Protein tyrosine phosphatase, PTP) 1B is the novel targets of treatment diabetes B to Protein-tyrosine-phosphatase.Suppress PTP 1B and not only produce significant insulin-sensitizing effect, and increase susceptibility, can regulate body weight and metabolism of fat leptin protein.Therefore, suppress PTP1B metabolism syndromes such as diabetes B are had combined therapy effect, possibly have the potential advantages (Zhang S and Zhang Z-Y, Drug Discov.Today, 2007,12,373) that are superior to existing treatment means.
The research of small molecules PTP 1B suppressor factor is one of focus of current anti-diabetes B new drug development.Because blood sugar reducing function reaches and optionally realizes becoming the critical bottleneck that restriction PTP 1B suppressor factor develops into antidiabetic medicine in the positive polarity and the structure conservative property characteristic of PTP 1B enzyme binding cavity, body.Many aromatic rings-monocarboxylic acid class suppressor factor the Ertiprotafib of Wyeth company development has got into clinical trial; Though, prove that the rational and effective molecular designing is to obtain novel safely and efficiently PTP 1B suppressor factor, and then research and develop feasible way (the Liu G of anti-diabetes B original new drug owing to liver toxicity stops; Curr.Med.Chem.; 2003,10,1407).
The present invention is intended to design synthetic novel PTP 1B suppressor factor with antidiabetic effect.According to the interaction pattern of known PTP 1B suppressor factor and enzyme, the pharmacophore that sums up suppressor factor should comprise two aryl and a carboxyl at least.In view of the above, adopt pharmacophore to move the layout strategy that combines more, make up virtual compound library with skeleton; Through AutoDock program virtual screening; From virtual data base, optimize and imitate the bonded compound in theory by force, and these compounds are synthesized, estimate its activity.
Summary of the invention
The object of the present invention is to provide the novel phenoxy acetic acid compounds shown in a kind of formula I.
Another object of the present invention is to provide a kind of phenoxy acetic acid compounds shown in the formula I and method of analogue thereof of preparing.
Another purpose of the present invention is to provide the purposes of the compound shown in the formula I in arrestin tyrosine-phosphatase 1B (PTP 1B), and the purposes in treatment and the PTP 1B diseases associated.
In order to accomplish the object of the invention, the present invention adopts following technical scheme:
The present invention relates to have novel phenoxy acetic acid compounds and the steric isomer and the physiologically acceptable salt of general formula I,
Wherein, Ar
1, Ar
2Independently be selected from and replace or unsubstituted phenyl;
M
1, M
2Be independently selected from methylene radical-CH
2-or saturated covalent linkage, work as M
1, M
2When being saturated covalent linkage, Ar
1With Ar
2Isolated each other or connect into ring through covalent linkage at the substituted ortho position of N-;
X is selected from-(CH
2)
n-or phenyl (C
6H
4-), wherein n is 0,1 or 2;
R
1Be selected from and replace or unsubstituted C
1-6Straight or branched alkyl, C
3-6Naphthenic base ,-CH
2-R, R are selected from and replace or unsubstituted phenyl, replacement or unsubstituted indyl, replacement or unsubstituted benzofuryl, replacement or unsubstituted naphthyl;
R
2, R
3Be independently selected from hydrogen, halogen, C
1-6Alkyl, C
1-6Alkoxyl group;
Substituting group is selected from hydroxyl, amino, halogen, C
1-6Straight or branched alkyl, C
3-6Naphthenic base, C
1-6Alkoxyl group, phenyl, phenoxy, methylene-dioxy.
Preferred Ar
1, Ar
2Be substituted phenyl;
Preferred L
1And M
2Be saturated covalent linkage;
Preferred X is a phenyl;
Preferred R
1Be substituted phenyl, substituted indyl, substituted naphthyl;
Preferred R
2, R
3Be hydrogen.
Preferred formula (I) compound comprises but is not limited to compound shown in the general formula (IA) and steric isomer thereof and physiologically acceptable salt:
Wherein, R is selected from and replaces or unsubstituted phenyl, replacement or unsubstituted indyl, replacement or unsubstituted benzofuryl, replacement or unsubstituted naphthyl;
R
2, R
3Be independently selected from hydrogen, halogen, C
1-6Alkyl, C
1-6Alkoxyl group;
Substituting group is selected from hydroxyl, amino, halogen, C
1-6Straight or branched alkyl, C
3-6Naphthenic base, C
1-6Alkoxyl group, phenyl, phenoxy, methylene-dioxy.
Preferred formula (IA) compound comprises but is not limited to compound shown in the general formula (IAa) and steric isomer thereof and physiologically acceptable salt:
Wherein, R is selected from and replaces or unsubstituted phenyl, replacement or unsubstituted indyl, replacement or unsubstituted benzofuryl, replacement or unsubstituted naphthyl;
Substituting group is selected from hydroxyl, amino, halogen, C
1-6Straight or branched alkyl, C
3-6Naphthenic base, C
1-6Alkoxyl group, phenyl, phenoxy, methylene-dioxy.
Preferred formula (IA) compound comprises but is not limited to compound shown in the general formula (IAb) and steric isomer thereof and physiologically acceptable salt:
R
2, R
3Be independently selected from hydrogen, halogen, C
1-6Alkyl, C
1-6Alkoxyl group.
Preferred formula (I) compound comprises but is not limited to compound shown in the general formula (IB) and steric isomer thereof and physiologically acceptable salt:
Wherein, R is selected from and replaces or unsubstituted phenyl, replacement or unsubstituted indyl, replacement or unsubstituted benzofuryl, replacement or unsubstituted naphthyl;
Substituting group is selected from hydroxyl, amino, halogen, C
1-6Straight or branched alkyl, C
3-6Naphthenic base, C
1-6Alkoxyl group, phenyl, phenoxy, methylene-dioxy.
Preferred formula (I) compound comprises but is not limited to compound shown in the general formula (IC) and steric isomer thereof and physiologically acceptable salt:
Wherein, Ar
1, Ar
2Be independently selected from and replace or unsubstituted phenyl; Substituting group is selected from hydroxyl, amino, halogen, C
1-6Straight or branched alkyl, C
3-6Naphthenic base, C
1-6Alkoxyl group, phenyl, phenoxy, methylene-dioxy.
Most preferred is selected from following group:
The invention also discloses the method for preparing The compounds of this invention, may further comprise the steps:
Formula II compound and formula III compound reaction production IV compound, production V compound behind the formula IV compound alkylation removal, the latter and formula VI compound reaction production VII compound generate compound shown in the general formula I behind the formula VII compound hydrolysis:
Wherein, Ar
1, Ar
2, M
1, M
2, X, R
1, R
2And R
3Definition the same, R ' and R
5Be independently selected from C
1-4The straight or branched alkyl; W representes-Br ,-CH
2Br ,-CH
2CH
2Br or-C
6H
4Br; R
4Expression hydroxyl or halogen.
According to the present invention, the form that The compounds of this invention can isomer exists, and described usually " The compounds of this invention " comprises the isomer of this compound.
Can there be the cis-trans-isomer of two keys in The compounds of this invention, and asymmetric center has S configuration or R configuration, the present invention includes all possible steric isomer and two or more mixture of isomers.If there is suitable/trans isomer, the present invention relates to the mixture of cis form and trans forms and these forms, single if desired foreign body object can separate according to conventional methods or prepare through three-dimensional selection is synthetic.
In order to process medicament; Can compound of Formula I be pressed currently known methods mixes with known method with suitable pharmacy carrier substance, perfume compound, seasonings and pigment; And be made into the tablet of tablet or dressing, perhaps itself and other additional substances is suspended or be dissolved in water or the oil.
The invention still further relates to a kind of pharmaceutical composition that contains medicine effective dose like described compound of general formula I and pharmaceutically acceptable carrier.
Pharmaceutical research shows that compound of Formula I of the present invention has the activity that suppresses PTP 1B, and for the diabetes B that causes because of insulin resistant, this compound can improve body to insulin sensitivity, thereby reaches the purpose of treatment.
In addition; Along with further research; Find PTP 1B suppressor factor to tumour, especially disease such as mammary cancer also has treatment, therefore; PTP 1B suppressor factor can be treated other disease relevant with PTP 1B, for example malignant tumour such as metabolism syndrome disease such as mellitus, hypertension, obesity, hyperlipidemia and mammary cancer.
Further aspect of the present invention also relates to the pharmaceutical composition of The compounds of this invention as active ingredient.This pharmaceutical composition can be according to method preparation well known in the art.Can be through the pharmaceutically acceptable solid of The compounds of this invention and one or more or liquid excipient and/or assistant agent being combined, process to be suitable for any formulation of human or animal's use.The content of The compounds of this invention in its pharmaceutical composition is generally 0.1-95 weight %.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration; Route of administration can be enteron aisle or non-enteron aisle, like oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be processed ordinary preparation, also process is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For The compounds of this invention is processed tablet, the various vehicle well known in the art that can be widely used comprises thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, lime carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, TKK 021, vinyl resin, carbomer, Vinylpyrrolidone polymer, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, Sodium Croscarmellose, sodium starch glycolate, sodium hydrogencarbonate and Citric Acid, polyoxyethylene sorbitol fatty ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Can also tablet further be processed coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet.For capsule is processed in the administration unit, can the effective constituent The compounds of this invention be mixed with thinner, glidant, mixture is directly placed hard capsule or soft capsule.Also can the effective constituent The compounds of this invention be processed particle or micropill with thinner, tamanori, disintegrating agent earlier, place hard capsule or soft capsule again.Each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind that are used to prepare the The compounds of this invention tablet also can be used for preparing the capsule of The compounds of this invention.
For The compounds of this invention is processed injection, can water, ethanol, Virahol, Ucar 35 or their mixture as solvent and add an amount of this area solubilizing agent commonly used, solubility promoter, pH and adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be Prist, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.
In addition, like needs, also can in pharmaceutical prepn, add tinting material, sanitas, spices, correctives or other additive.
For reaching the medication purpose, enhancing treatment effect, medicine of the present invention or pharmaceutical composition can be used any known medication administration.
The dosage of The compounds of this invention pharmaceutical composition according to prevent or treat the character and the severity of disease, the individual instances of patient or animal, route of administration and formulation etc. can have large-scale variation.In general, the appropriate dose scope of the every day of The compounds of this invention is the 0.01-300mg/Kg body weight, is preferably the 0.1-200mg/Kg body weight, and more preferably the 10-150mg/Kg body weight most preferably is the 25-100mg/Kg body weight.Above-mentioned dosage can a dose unit or is divided into several dose unit administrations, and this depends on doctor's clinical experience and comprises the dosage regimen of using other treatment means.
Compound of the present invention or compsn can be taken separately, or merge use with other treatment medicine or symptomatic drugs.When compound of the present invention and other medicine existence synergy, should adjust its dosage according to practical situation.
Description of drawings
Fig. 1. compound ZSE-2-4 to IR mouse glucose load after the influence of glucose level
(n＝8.###，p＜0.001vs?Con；*，**，***，p＜0.05，0.01，0.001vs?IR.)
Fig. 2. compound ZSF-2-4 to IR mouse glucose load after the influence of area under blood sugar-time curve
(n＝8.###，p＜0.001vs?Con；**，***，p＜0.01，0.001vs?IR.)
Fig. 3. compound ZSE-2-4 is to the influence of the plain load of IR mouse islets back change of blood sugar
(n＝8.###，p＜0.001vs?Con；**，***，p＜0.01，0.001vs?IR.)
Fig. 4 compound ZSF-2-4 is to influence (n=8.###, the p＜0.001vs Con of area under the blood sugar-time curve of the plain load of I R mouse islets back; * *, p＜, 0.001vs IR.)
Fig. 5. compound ZSE-2-4 is to the influence of GIR value in the experiment of the positive sugar pincers of IR mouse
(n＝8.###，p＜0.001vs?Con；＊＊＊，p＜0.001vsIR.)
Fig. 6. compound ZSE-2-4 is to the influence of IR mouse blood cholesterol levels
(n＝8.###，p＜0.001vsCon；＊＊＊，p＜0.001vsI?R.)
Embodiment
Below in conjunction with embodiment invention is further described, but these embodiment do not limit the scope of the invention.
The structure of compound is confirmed through nucleus magnetic resonance (NMR) or mass spectrum (MS) or high resolution mass spectrum (HRMS).NMR displacement (δ) provides with 1,000,000/(ppm) unit.M.p. be that temperature is correction up not with a ℃ fusing point that provides.Column chromatography generally uses 200～300 order silica gel to be carrier.It is to use INOVA-500 that NMR measures, and the mensuration solvent is CDCl
3, DMSO-D
6, in be designated as TMS, chemical shift is to provide as unit with ppm.The mensuration of MS is with VG-ZAB-2F 200C mass spectrograph.
Abbreviation:
TLC: thin-layer chromatography;
DMSO: DMSO 99.8MIN.;
CDCl3: deuterochloroform;
DMF:N, dinethylformamide;
Min: minute;
H: hour.
Embodiment 1: the final product structural formula is following, is numbered ZSE-1-42
a)
With the 9H-carbazole (2505mg 15mmol) is dissolved in the 20mL oil of mirbane with 4-bromoanisole (18mmol), add the Cu powder (30mg, 3.6mmol) and anhydrous K
2CO
3(2760mg 20mol), stirs reflux 24h down, filters, and most oil of mirbane are removed in underpressure distillation, and ethyl alcohol recrystallization gets brown solid a, yield 87.1%.
b)
A (5mmol) is dissolved in the 10mL acetonitrile, and (750mg is 5mmol) with (CH to add NaI
3)
3SiCl, the nitrogen gas stream protection is reflux 24h down, and stopped reaction adds 10mL water, with ether (10mL*3) extraction, merges organic phase, uses saturated Na
2S
2O
3(6mL) clean, organic phase is used anhydrous Na
2SO
4Drying, column chromatography for separation gets cured shape solid b, yield 31.9%.
c)
(180mg 1mmol) is dissolved among the 5mL THF, adds Ph in order with b (1mmol) and 2-hydroxyl-3-methyl phenylpropionate
3P (1mmol) and DEAD (1mmol) stir reflux 14h down, and column chromatography for separation gets colourless thick thing c, yield 52.2%.
d)
C (0.5mmol) is dissolved in the 10mL ethanol, and adding 1mL water and NaOH (40mg, 1mmol), stirring at room 6h, the TLC monitoring, raw material point disappears.Steam except that ethanol, add 8mL water and make it dissolving, regulate pH to 3-4, filter with 5% Hydrogen chloride, drying, column chromatography for separation gets white solid, yield 91%.
1H?NMR(300Hz，CD
3COCD
3)δppm?8.19-8.16(m，2H，ArH)，7.49-7.17(m，15H，ArH)，5.14-5.08(m，1H，CH)，3.42-3.28(m，2H，CH
2).
FAB-MS(positive，m/z)：408(M+H
+)
Embodiment 2: the final product structural formula is following, is numbered ZSE-1-49
a)
With the 9H-carbazole (2505mg 15mmol) is dissolved in the 20mL oil of mirbane with 2-methyl-4-bromo-methyl-phenoxide (18mmol), add the Cu powder (230mg, 3.6mmol) and anhydrous K
2CO
3(2760mg 20mmol), stirs reflux 24h down, filters, and most oil of mirbane are removed in underpressure distillation, and ethyl alcohol recrystallization gets brown solid a, yield 79.3%.
b)
A (5mmol) is dissolved in the 10mL acetonitrile, and (750mg is 5mmol) with (CH to add NaI
3)
3SiCl, the nitrogen gas stream protection is reflux 24h down, and stopped reaction adds 10mL water, with ether (10mL*3) extraction, merges organic phase, uses saturated Na
2S
2O
3(6mL) clean, organic phase is used anhydrous Na
2SO
4Drying, column chromatography for separation gets cured shape solid b, yield 16.9%.
c)
(180mg 1mmol) is dissolved among the 5mLTHF, adds Ph in order with b (1mmol) and 2-hydroxyl-3-methyl phenylpropionate
3P (1mmol) and DEAD (1mmol) stir reflux 14h down, and column chromatography for separation gets colourless thick thing c, yield 48.9%.
d)
C (0.5mmol) is dissolved in the 10mL ethanol, and adding 1mL water and NaOH (40mg, 1mmol), stirring at room 6h, the TLC monitoring, raw material point disappears.Steam except that ethanol, add 8mL water and make it dissolving, regulate pH to 3-4, filter with 5% Hydrogen chloride, drying, column chromatography for separation gets white solid.Yield 85.6%.
1H?NMR(300Hz，CD
3COCD
3)δppm?8.18-8.18(m，2H，ArH)，7.47-7.03(m，14H，ArH)，5.11(dd，1H，J＝5.4Hz，J＝8.1Hz，CH)，3.46-3.40(dd，1H，J＝4.2Hz，J＝13.8Hz，CH
2)，3.37-3.30(dd，1H，J＝8.4Hz，J＝14.1Hz，CH
2)，2.31(s，3H，CH
3).FAB-MS(positive，m/z)：421(M+H
+)
Embodiment 3: the final product structural formula is following, is numbered LJZ-3-24
a)
With 1.67g (10mmol) card azoles, 2.58g (12mmol) 2; 6-dimethyl--4-bromo-methyl-phenoxide, 191mg (1mmol) cuprous iodide, 3.45g (25mmol) salt of wormwood, 230mg (2mmol) L-proline(Pro) are dissolved in/are suspended among the 25mL DMSO; Nitrogen protection is stirred 36h down in 90 ℃.Stopped reaction, put cold, thin up, ethyl acetate extraction, drying; Concentrate column chromatography for separation (sherwood oil: ETHYLE ACETATE=30: 1), get light yellow oil, add 2mL ethanol, hold over night; Separate out a large amount of white needle-like crystals, filter, drying gets white crystal 1.6g, yield=53%.
b)
9-(4-methoxyl group-3,5-dimethyl-)-9H-card azoles 1.42g (4.7mmol) is dissolved in the 20mL methylene dichloride, and cryosel is bathed and is dripped BBr down
3Dichloromethane solution, drip to finish, stirred overnight at room temperature, the raw material primitive reaction is complete.Add the less water cancellation, ethyl acetate extraction, drying concentrates, column chromatography for separation (sherwood oil: ETHYLE ACETATE=15: 1), get white solid 1.18g, yield=87%.
c)
With 632mg (2.1mmol) 2,6-dimethyl--4-(9H-card azoles base)-phenol, 756mg (4.2mmol) Alpha-hydroxy methyl phenylpropionate, 1.1g (4.2mmol) triphenylphosphine are dissolved in the 30mL benzene, place ice bath; The benzole soln (0.63mL DEAD is dissolved in 6mL benzene) that dropwise adds diethyl azodiformate drips and finishes stirring at room 30min; In reaction solution impouring water, ethyl acetate extraction, drying; Concentrate; Column chromatography for separation (sherwood oil: ETHYLE ACETATE=30: 1), get white oily matter 640mg, yield=68%.
d)
640mg (1.43mmol) 2-(2,6-dimethyl--4-(9-(9H-card azoles base)))-phenoxy-3-phenylpropionic acid methyl esters is dissolved in the 20mL ethanol, adds the aqueous solution of 112mg (2mmol) Pottasium Hydroxide, stirring at room; Reaction 4h, stopped reaction is divided exactly ethanol; Hydrogen chloride regulator solution pH value is about 2-3, ethyl acetate extraction, drying; Concentrate, get white powder 610mg, yield=98%.
1H?NMR(300MHz，acetone-d6)δppm?8.19-7.20(m，15H)，4.90(t，1H)，3.37(d，2H)，2.36(s，6H)
ESI-TOF-MS(positive，m/z)：435.5(M+H
+)
Embodiment 4: the final product structural formula is following, is numbered ZSE-2-7
a)
Piperonylaldehyde (10mmol) and 4-fluoroaniline (10mmol) are dissolved in the 25mmol ethanol, and reflux 5h is cooled to room temperature, adds NaBH
4(10mmol), continue to stir 4h.Revolve dried ethanol, add 20mL water, with ether (20mL*3) extraction, merge organic phase, saturated aqueous common salt cleans, and anhydrous sodium sulfate drying filters, and revolves dry diethyl ether, and 95% ethyl alcohol recrystallization gets a, yield 83%.
b)
A (6mmol) and 4-brooethyl methyl-phenoxide are mixed, add K
2CO
3(993mg, 7.2mmol) with 20mL DMF, stirring at room 15h adds 20mL water, with ether (20mL*3) extraction, merges organic phase, the saturated common salt washing, anhydrous sodium sulfate drying, column chromatography for separation gets colourless thick thing b, yield 70%.
c)
(160mg 4mmol) is dissolved in the 20mL water, adds b (2mmol), and stirring at room 5h regulates the pH value to 3-4 with Hydrogen chloride, adds the saturated NaHCO of 5mL with NaOH
3Solution, ether (20mL*3) extraction merges organic phase, the saturated common salt washing, anhydrous sodium sulfate drying filters, and revolves dried solvent, gets white solid c, yield 92%.
d)
With c (2mmol), 2-hydroxyl-3-phenylpropionic acid methyl esters (360mg, 2mmol) and triphenylphosphine (384mg 2mmol) mixes; Splash into 0.2mLTHF, the ultrasonic mixing that makes it, dropping DEAD (524mg, 2mmol); Continue ultrasonic 1h, column chromatography for separation gets colourless thick thing d, yield 41%.
e)
(40mg 1mmol) is dissolved in the 15mL water, adds d, stirring at room 5h with NaOH; 5% Hydrogen chloride is regulated pH to 3-4, and ether (10mL*3) extraction merges organic phase, the saturated common salt washing; Anhydrous sodium sulfate drying revolves dried solvent, gets thick product; PE: EA=4: 1 mixed solvent recrystallization gets white crystal, yield 69.3%.
1H?NMR(300Hz，CD
3COCD
3)δppm?7.38-6.69(m，16H，ArH)，5.94(s，2H，OCH
2)，4.95-4.88(dd，1H，J＝7.8Hz，J＝15.6Hz，CH)，4.53(s，2H，NCH
2)，4.51(s，2H，NCH
2)，3.32-3.25(dd，1H，J＝4.8Hz，J＝14.7Hz，CH
2)，3.24-3.16(dd，1H，J＝8.7Hz，J＝13.5Hz，CH
2).
FAB-MS(positive，m/z)：500(M+H
+)
Embodiment 5: the final product structural formula is following, is numbered ZSE-2-42
a)
Piperonylaldehyde (10mmol) and aniline (10mmol) are dissolved in the 25mL ethanol, and reflux 5h is cooled to room temperature, adds NaBH
4(10mmol), continue to stir 4h.Revolve dried ethanol, add 20mL water, with ether (20mL*3) extraction, merge organic phase, saturated aqueous common salt cleans, and anhydrous sodium sulfate drying filters, and revolves dry diethyl ether, and 95% ethyl alcohol recrystallization gets a, yield 79%.
b)
A (6mmol) and 4-brooethyl methyl-phenoxide are mixed, add K
2CO
3(993mg, 7.2mmol) with 20mL DMF, stirring at room 15h adds 20mL water, with ether (20mL*3) extraction, merges organic phase, the saturated common salt washing, anhydrous sodium sulfate drying, column chromatography for separation gets colourless thick thing b, yield 71%.
c)
(160mg 4mmol) is dissolved in the 20mL water, adds b (2mmol), and stirring at room 5h regulates the pH value to 3-4 with Hydrogen chloride, adds the saturated NaHCO of 5mL with NaOH
3Solution, ether (20mL*3) extraction merges organic phase, the saturated common salt washing, anhydrous sodium sulfate drying filters, and revolves dried solvent, gets white solid c, yield 91%.
d)
With c (2mmol), 2-hydroxyl-3-phenylpropionic acid methyl esters (360mg, 2mmol) and triphenylphosphine (384mg 2mmol) mixes; Splash into 0.2mLTHF, the ultrasonic mixing that makes it, dropping DEAD (524mg, 2mmol); Continue ultrasonic 1h, column chromatography for separation gets colourless thick thing d, yield 43%.
e)
(40mg 1mmol) is dissolved in the 15mL water, adds d, stirring at room 5h with NaOH; 5% Hydrogen chloride is regulated pH to 3-4, and ether (10mL*3) extraction merges organic phase, the saturated common salt washing; Anhydrous sodium sulfate drying revolves dried solvent, gets thick product; PE: EA=4: 1 mixed solvent recrystallization gets white crystal, yield 77.1%.
1H?NMR(300Hz，CD
3COCD
3)δppm?11.35(br.s，1H，COOH)，7.38-6.56(m，17H，ArH)，5.94(s，2H，OCH
2)，4.91(dd，1H，J＝4.8Hz，J＝8.1Hz，OCHCOOH)，4.57(s，2H，NCH
2)，4.55(s，2H，NCH
2)，3.31-3.25(dd，1H，J＝4.8Hz，J＝14.1Hz，CH
2)，3.24-3.17(dd，1H，J＝8.4Hz，J＝14.4Hz，CH
2).
ESI-TOF-MS(positive，m/z)：m/z?482(M+H
+)
Embodiment 6: the final product structural formula is following, is numbered ZSE-2-43
a)
Piperonylaldehyde (10mmol) and 4-monomethylaniline (10mmol) are dissolved in the 25mL ethanol, and reflux 5h is cooled to room temperature, adds NaBH
4(10mmol), continue to stir 4h.Revolve dried ethanol, add 20mL water, with ether (20mL*3) extraction, merge organic phase, saturated aqueous common salt cleans, and anhydrous sodium sulfate drying filters, and revolves dry diethyl ether, and 95% ethyl alcohol recrystallization gets a, yield 74%.
b)
A (6mmol) and 4-brooethyl methyl-phenoxide are mixed, add K
2CO
3(993mg, 7.2mmol) with 20mL DMF, stirring at room 15h adds 20mL water, with ether (20mL*3) extraction, merges organic phase, the saturated common salt washing, anhydrous sodium sulfate drying, column chromatography for separation gets colourless thick thing b, yield 73%.
c)
(160mg 4mmol) is dissolved in the 20mL water, adds b (2mmol), and stirring at room 5h regulates the pH value to 3-4 with Hydrogen chloride, adds the saturated Na HCO of 5mL with NaOH
3Solution, ether (20mL*3) extraction merges organic phase, the saturated common salt washing, anhydrous sodium sulfate drying filters, and revolves dried solvent, gets white solid c, yield 93%.
d)
With c (2mmol), 2-hydroxyl-3-phenylpropionic acid methyl esters (360mg, 2mmol) and triphenylphosphine (384mg 2mmol) mixes; Splash into 0.2mL THF, the ultrasonic mixing that makes it, dropping DEAD (524mg, 2mmol); Continue ultrasonic 1h, column chromatography for separation gets colourless thick thing d, yield 42%.
e)
(40mg 1mmol) is dissolved in the 15mL water, adds d, stirring at room 5h with NaOH; 5% Hydrogen chloride is regulated pH to 3-4, and ether (10mL*3) extraction merges organic phase, and saturated aqueous common salt cleans; Anhydrous sodium sulfate drying revolves dried solvent, gets thick product; PE: EA=4: 1 mixed solvent recrystallization gets white crystal, yield 67%.
1H?NMR(300Hz，CD
3COCD
3)δppm?11.40(br.s，1H，COOH)，7.35-6.62(m，16H，ArH)，5.93(s，2H，OCH
2)，4.9(m，1H，OCHCOOH)，4.52(s，2H，NCH
2)，4.49(s，2H，NCH
2)，3.31-3.16(m，2H，CH
2)，2.31(s，3H，CH
3).
ESI-TOF-MS(positive，m/z)：m/z?496(M+H
+)
Embodiment 7: the final product structural formula is following, is numbered ZSE-2-48
a)
Piperonylaldehyde (10mmol) and 4-anisidine (10mmol) are dissolved in the 25mL ethanol, and reflux 5h is cooled to room temperature, adds NaBH
4(10mmol), continue to stir 4h.Revolve dried ethanol, add 20mL water,, merge organic phase with ether (20mL*3) extraction, the saturated common salt washing, anhydrous sodium sulfate drying filters, and revolves dry diethyl ether, and 95% ethyl alcohol recrystallization gets a, yield 78%.
b)
A (6mmol) and 4-brooethyl methyl-phenoxide are mixed, add K
2CO
3(993mg, 7.2mmol) with 20mL DMF, stirring at room 15h adds 20mL water, with ether (20mL*3) extraction, merges organic phase, the saturated common salt washing, anhydrous sodium sulfate drying, column chromatography for separation gets colourless thick thing b, yield 78%.
c)
(160mg 4mmol) is dissolved in the 20mL water, adds b (2mmol), and stirring at room 5h regulates the pH value to 3-4 with Hydrogen chloride, adds the saturated NaHCO of 5mL with NaOH
3Solution, ether (20mL*3) extraction merges organic phase, the saturated common salt washing, anhydrous sodium sulfate drying filters, and revolves dried solvent, gets white solid c, yield 81%.
d)
With c (2mmol), 2-hydroxyl-3-phenylpropionic acid methyl esters (360mg, 2mmol) and triphenylphosphine (384mg 2mmol) mixes; Splash into 0.2mLTHF, the ultrasonic mixing that makes it, dropping DEAD (524mg, 2mmol); Continue ultrasonic 1h, column chromatography for separation gets colourless thick thing d, yield 47%.
e)
(40mg 1mmol) is dissolved in the 15mL water, adds d, stirring at room 5h with NaOH; 5% Hydrogen chloride is regulated pH to 3-4, and ether (10mL*3) extraction merges organic phase, the saturated common salt washing; Anhydrous sodium sulfate drying revolves dried solvent, gets thick product; PE: EA=4: 1 mixed solvent recrystallization gets white crystal, yield 58.2%.
1H?NMR(300Hz，CD
3COCD
3)δppm?7.38-6.71(m，16H，ArH)，5.92(s，2H，OCH
2)，4.90(dd，1H，J＝4.2Hz，J＝7.8Hz，OCHCOOH)，4.43(s，2H，NCH
2)，4.41(s，2H，NCH
2)，3.64(s，3H，CH
3)，3.31-3.25(dd，1H，J＝4.5Hz，J＝14.8Hz，CH
2)，3.24-3.16(dd，1H，J＝8.4Hz，J＝14.4Hz，CH
2).
ESI-TOF-MS(positive，m/z)：512(M+H
+)
Embodiment 8: the final product structural formula is following, is numbered LJZ-3-43
a)
With 1.67g (10mmol) kappa azoles, 2.58g (12mmol) 2; 6-dimethyl--4-bromo-methyl-phenoxide, 191mg (1mmol) cuprous iodide, 3.45g (25mmol) salt of wormwood, 230mg (2mmol) L-proline(Pro) are dissolved in/are suspended among the 25mL DMSO; Nitrogen protection is stirred 36h down in 90 ℃.Stopped reaction, put cold, thin up, ethyl acetate extraction, drying; Concentrate column chromatography for separation (sherwood oil: ETHYLE ACETATE=30: 1), get light yellow oil, add 2mL ethanol, hold over night; Separate out a large amount of white needle-like crystals, filter, drying gets white crystal 1.6g, yield=53%.
b)
9-(4-methoxyl group-3,5-dimethyl-)-9H-card azoles 1.42g (4.7mmol) is dissolved in the 20mL methylene dichloride, and cryosel is bathed the dichloromethane solution that drips BBr3 down, and drip and finish, stirred overnight at room temperature, the raw material primitive reaction is complete.Add the less water cancellation, ethyl acetate extraction, drying concentrates, column chromatography for separation (sherwood oil: ETHYLE ACETATE=15: 1), get white solid 1.18g.
c)
With 144mg (0.5mmol) 2,6-dimethyl--4-(9-(9H-card azoles base))-phenol, 230mg (1mmol) 2-hydroxyl-3-(2-naphthyl) methyl propionate, 262mg (1mmol) triphenylphosphine are dissolved in the 20mL benzene, place ice bath; The benzole soln (0.16mL DEAD is dissolved in 6mL benzene) that dropwise adds diethyl azodiformate drips and finishes stirring at room 30min; In reaction solution impouring water, ethyl acetate extraction, drying; Concentrate; Column chromatography for separation (sherwood oil: ETHYLE ACETATE=30: 1), get colorless oil 95mg, yield=38%.
d)
95mg 2-(2,6-dimethyl--4-(9-(9H-card azoles base))) phenoxy-3-(2-naphthyl)-methyl propionate is dissolved in the 10mL ethanol, adds the aqueous solution of 56mg (1mmol) Pottasium Hydroxide, stirring at room; Reaction 4h, stopped reaction steams and removes ethanol; Hydrogen chloride regulator solution pH value is about 2-3, ethyl acetate extraction, drying; Concentrate, get white powder 85mg, yield=92%.
1H?NMR(300Hz，CD
3COCD
3)δppm?8.24-7.20(m，17H)，5.04(t，1H)，3.56(2，2H)，2.39(s，6H)
HRMS(m/z，positive)：calc.for?C33H28NO3+486.2051，found?486.2064(-2.61ppm).
Embodiment 9: the final product structural formula is following, is numbered LJZ-3-47
With the 9H-carbazole (2505mg 15mmol) is dissolved in the 20mL oil of mirbane with 2-methyl-4-bromo-methyl-phenoxide (18mmol), add the Cu powder (230mg, 3.6mmol) and anhydrous K
2CO
3(2760mg 20mmol), stirs reflux 24h down, filters, and most oil of mirbane are removed in underpressure distillation, and ethyl alcohol recrystallization gets brown solid, yield 79.3%.
b)
9-(4-methoxyl group-3-aminomethyl phenyl)-9H-carbazole 463mg (1.6mmol) is dissolved in the 10mL methylene dichloride, and cryosel is bathed the dichloromethane solution that drips boron tribromide (2.4mmol) down, drips and finishes; Stirring at room 2h adds 10mL water, the evaporate to dryness organic solvent; ETHYLE ACETATE (10mL * 3) extraction; Merge organic phase, use the saturated common salt water washing, organic phase is used anhydrous Na
2SO
4Drying, column chromatography for separation gets colorless oil 280mg, yield 64%.
c)
4-(9-(9H-carbazyl))-2-methylphenol 273mg (1mmol), 230mg (1mmol) 2-hydroxyl-3-(2-naphthyl)-methyl propionate, 262mg (1mmol) triphenylphosphine are dissolved in the 20mL benzene, place ice bath, dropwise add the benzole soln (0.16mL DEAD is dissolved in 6mL benzene) of diethyl azodiformate; Drip and finish, stirring at room 30min is in reaction solution impouring water; Ethyl acetate extraction; Drying concentrates column chromatography for separation (sherwood oil: ETHYLE ACETATE=30: 1); Get colorless oil 195mg, yield=40%.
d)
195mg 2-(2-dimethyl--4-(9H-kappa azoles base)) phenoxy-3-(2-naphthyl)-methyl propionate is dissolved in the 10mL ethanol, adds the aqueous solution of 56mg (1mmol) Pottasium Hydroxide, stirring at room; Reaction 4h, stopped reaction steams and removes ethanol; Hydrogen chloride regulator solution pH value is about 2-3, ethyl acetate extraction, drying; Concentrate, get white powder 150mg, yield=80%.
1H?NMR(300Hz，CD
3COCD
3)δppm?8.17-7.05(m，18H)，5.23(m，1H)，3.62(dd，1H，J＝4.2Hz，J＝15.9Hz)，3.52(dd，1H，J＝7.8Hz，J＝15.9)，2.32(s，3H)HRMS(m/z，positive)：calc.for?C32H26NO3+472.1891，found?472.1907(-3.43ppm).
Embodiment 10: the final product structural formula is following, is numbered LJZ-3-48
a)
With the 9H-carbazole (2505mg 15mmol) is dissolved in the 20mL oil of mirbane with 4-bromoanisole (18mmol), add the Cu powder (30mg, 3.6mmol) and anhydrous K
2CO
3(2760mg 20mmol), stirs reflux 24h down, filters, and most oil of mirbane are removed in underpressure distillation, and ethyl alcohol recrystallization gets brown solid, yield 87.1%.
b)
9-(4-p-methoxy-phenyl)-9H-carbazole (1.5mmol) is dissolved in the 10mL methylene dichloride, and cryosel is bathed the dichloromethane solution that drips boron tribromide (2.2mmol) down, drips and finishes; Stirring at room 2h adds 10mL water, the evaporate to dryness organic solvent; ETHYLE ACETATE (10mL * 3) extraction; Merge organic phase, use the saturated common salt water washing, organic phase is used anhydrous Na
2SO
4Drying, column chromatography for separation gets colorless oil 320mg, yield 82%.
c)
4-(9-(9H-carbazyl))-phenol 259mg (1mmol) and 2-hydroxyl-3-Phenpropionate 230mg (1mmol) 2-hydroxyl-3-(2-naphthyl)-methyl propionate, 262mg (1mmol) triphenylphosphine are dissolved in the 20mL benzene, place ice bath, dropwise add the benzole soln (0.16mLDEAD is dissolved in 6mL benzene) of diethyl azodiformate; Drip and finish, stirring at room 30min is in reaction solution impouring water; Ethyl acetate extraction; Drying concentrates column chromatography for separation (sherwood oil: ETHYLE ACETATE=30: 1); Get colorless oil 360mg, yield 76%.
d)
360mg 2-(4-(9-(9H-carbazyl)) phenoxy)-3-(2-naphthyl)-methyl propionate is dissolved in the 10mL ethanol, adds the aqueous solution of 56mg (1mmol) Pottasium Hydroxide, stirring at room; Reaction 4h, stopped reaction steams and removes ethanol; Hydrogen chloride regulator solution pH value is about 2-3, ethyl acetate extraction, drying; Concentrate, get white powder 320mg, yield=92%.
1H?NMR(300Hz，CD
3COCD
3)δppm?8.13-7.13(m，19H)，5.07(m，1H)，3.59(dd，1H)，3.39(dd，1H)
HRMS(m/z，positive)：calc.for?C31H24NO3+458.1736，found?458.1751(-3.21ppm).
Embodiment 11: the final product structural formula is following, is numbered ZSE-2-4
a)
(282mg, 1.7mmol) (371mg 1.71mmol) is dissolved in the 20ml oil of mirbane, adds K in order with 4-bromo-4 '-methoxyl biphenyl with the 9H-carbazole
2CO
3(207mg, 1.5mmol) and the Cu powder (19mg, 0.3mmol), reflux 24h under nitrogen protection, filtered while hot removes oil of mirbane under reduced pressure, the THF recrystallization, white solid (a) 410mg, yield 83.4%.
b)
(349mg 1mmol) joins in the 10ml methylene dichloride, and cryosel is bathed the dichloromethane solution 1.5ml that drips the BBr3 of 1mol/L down, finishes room temperature and continues to stir 2h, revolves dried solvent, adds 10ml water, and ether (10ml * 3) extraction merges organic phase, anhydrous Na with a
2SO
4Drying is filtered, column chromatography for separation, eluent is PE: EA=10: 1 white solid (b) 335mg, yield almost 100%.
c)
With b (335mg, 1mmol), methyl 2-hydroxyl-3-Phenpropionate (180mg, 1mmol) and triphenylphosphine (270mg; 1mmol) join in order in the 25ml single port bottle, add 0.15mlTHF, the ultrasonic mixing that makes it; (179mg 1mmol) continues ultrasonic reaction 3h, column chromatography for separation to add DEAD; Eluent is PE: EA=15: 1, get white solid (c) 233mg, yield 46.9%.
d)
(233mg 0.48mmol) is dissolved in the 10ml methyl alcohol, and (40mg, 1mmol) with 5ml water, stirring at room 5h steams and removes methyl alcohol adding NaOH, 5% Hydrogen chloride adjusting pH to 4-6, filtration, drying with c.Column chromatography for separation, eluent are PE: EA=3: 1+1%HAc, get white solid 147mg, yield 65.3%.
1H?NMR(300Hz，CD
3COCD
3)δppm?8.22-7.02(m，21H)，5.50(dd，1H，J＝5.1Hz，J＝8.1Hz)，3.39-3.33(dd，1H，J＝4.2Hz，J＝14.1Hz)，3.31-3.24(dd，1H，J＝5.1Hz，J＝14.4Hz).
FAB-MS(positive，m/z)：484(M+H
+)
Embodiment 12: the final product structural formula is following, is numbered LJZ-3-37
Compound method is synthetic with ZSE-2-4's
1H?NMR(300Hz，CD
3COCD
3)δppm?8.22-7.05(m，23H)，5.18(m，1H)，3.52-3.47(m，2H)
HRMS(m/z，positive)：calc.for?C37H26NO3+532.1913，found?525.19126(0.06ppm).
Pharmacological evaluation
Experimental example 1: compound of the present invention is to the recombinate restraining effect of PTP 1B enzyme of people
Method:
Utilize the BL21E.Coli intestinal bacteria to prepare the people PTP1B engineering bacteria of recombination, and use GST affinitive layer purification albumen, obtain PTP1B albumen.With nitro phosphoric acid salt is substrate, carries out the zymetology reaction of PTP1B, and the observation in vitro medicine is to the influence of PTP1B protein-active.
The result:
Having measured above-claimed cpd respectively is 10 at final concentration
-4M, 10
-5During M to the inhibiting rate of the people PTP1B of recombination; Measure and calculate several kinds of The compounds of this invention.The result is as shown in table 1.
Table 1. test-compound is to the restraining effect of gene recombinant human PTP1B enzyme
Experimental example 2: compound ZSE-2-4 improves the effect of insulin resistant (IR) mouse oral glucose tolerance
1. method:
Use high-sugar-fat-diet, feed C57BL mouse and form insulin resistant mouse model (IR).Animal pattern is divided into 3 groups at random, is respectively animal pattern control group (IR), rosiglitazone group and compound group, respectively oral water, positive control drug rosiglitazone (15mg/kg) and embodiment ZSE-2-4 (25mg/kg).Simultaneously, with feeding as normal control group (Con) with normal diet with batch C57BL mouse.Successive administration 7days gives animal oral glucose 2g/kg, observes behind the animal glucose load 0,30,60, changes of blood glucose during 120min, and calculates area (AUC) under blood sugar-time curve, i.e. oral glucose tolerance experiment (OGTT).
2. result:
The result shows (Fig. 1), compares with Con, and each time point blood sugar of IR treated animal all obviously raises, and demonstrates tangible glucose tolerance and lowers phenomenon.Compare with the IR treated animal; Each time point blood sugar all obviously reduces behind ZSE-2-4 group and the rosiglitazone group glucose load; And glycemic peaks obviously reduces, and area AUC obviously reduces under blood sugar-time curve, demonstrates the obvious effect (Fig. 2) that improves the oral glucose tolerance of animal; ZSE-2-4 is described to the have some improvement effect of glucose tolerance of body of the insulin resistant mouse tool of diet induced, this effect is similar with the effect of euglycemic agent rosiglitazone.
Embodiment 3. compound ZSE-2-4 improve the effect of the plain tolerance of IR mouse islets
1. method:
Use high-sugar-fat-diet, feed C57BL mouse and form insulin resistant mouse model (IR).Animal pattern is divided into 3 groups at random, is respectively animal pattern control group (IR), rosiglitazone group and ZSE-2-4 group, oral water, positive control drug rosiglitazone (15mg/kg) and embodiment ZSE-2-4 (25mg/kg) respectively.Simultaneously, with feeding as normal control group (Con) with normal diet with batch C57BL mouse.Successive administration 16days gives animal skin injected 0.4U/kg Regular Insulin, and glucose level when measuring Regular Insulin load back 0,30,60,120min is calculated area (AUC) under blood sugar-time curve; And the glucose level during with animal self 0min is as 100%, the change of blood sugar when calculating its Regular Insulin load back 30,60,120min, i.e. insulin tolerance experiment (ITT).
2. result:
The result shows (Fig. 3), and Regular Insulin load back each time point change of blood sugar amplitude of IR treated animal all is less than normal control Con group, and the AUC value increases, and demonstrates the obvious insulin resistance phenomenon.Compare with the IR animal pattern, each time point blood sugar fall of ZSE-2-4 treated animal Regular Insulin load back all obviously increases, and obviously reduction (Fig. 4) of area (AUC) under blood sugar-time curve.This effect is similar with the effect of euglycemic agent rosiglitazone, and illustrative embodiment ZSE-2-4 has the effect of certain increase insulin sensitivity to the insulin resistant IR mouse of diet induced.
Method:
Use high-sugar-fat-diet, feed C57BL mouse and form insulin resistant mouse model (IR).Animal pattern is divided into 3 groups at random, is respectively animal pattern control group (IR), rosiglitazone group and ZSE-2-4 group, oral water, positive control drug rosiglitazone 15mg/kg and embodiment ZSE-2-425mg/kg respectively.Simultaneously with feeding as normal control group (Con) with normal diet with batch C57BL mouse.Successive administration 21～24days carries out hyperinsulinism clamp (the positive sugar pincers) experiment of normal glucose level.Be animal fasting 4 hours, weigh, the anesthesia of abdominal injection vetanarcol; Be fixed in 37 ℃ of temperature-constant plates, operation separates jugular vein, intubate; Behind the input 1000U/ml anticoagulant heparin, connect microsyringe (COLE PARMER, 789100C; The U.S.) with constant speed gasing injection Regular Insulin 60pmol/kg/min and micro-peristaltic pump (ISMATEC, 78001-00, the U.S.) with variable bit rate infusion 10% glucose solution; Operation separates carotid artery, to be on the waiting list blood.Every separated 10min gets blood, with blood glucose meter (BIOSEN 5030, Germany) monitoring glucose level.Regulate glucose infusion speed according to glucose level; Make glucostasis in 95 ± 5mg/dl scope; After blood sugar was stablized 30min at least, 3 glucose infusion speed of METHOD FOR CONTINUOUS DETERMINATION were averaged as glucose infusion speed (GIR) during stable state in the positive sugar pincers experiment of animal.
The result:
In the experiment of positive sugar pincers during stable state glucose infusion speed GIR value represent the glucose disposal ability of the insulin-dependent of body, be the golden index of present generally acknowledged evaluation insulin resistant.Experimental result demonstration (Fig. 5) in the experiment of positive sugar pincers, is compared with Con, and IR treated animal GIR level obviously reduces, and explains that this animal pattern has had obvious insulin resistance.Compare with the IR animal pattern, euglycemic agent rosiglitazone and embodiment ZSE-2-4 make the GIR level improve 277.9% and 106.9% respectively.Illustrative embodiment ZSE-2-4 and rosiglitazone are similar, all have the effect of the IR mouse of obvious increase insulin resistant to the susceptibility of exogenous insulin.
Embodiment 5. compound ZSE-2-4 are to the influence of IR mouse blood cholesterol levels
Method:
Use high-sugar-fat-diet, feed C57BL mouse and form insulin resistant mouse model (IR).Animal pattern is divided into 3 groups at random, is respectively animal pattern control group (IR), rosiglitazone group and compound group, respectively oral water, positive control drug rosiglitazone (15mg/kg) and compound ZSE-2-4 (25mg/kg).Simultaneously, with feeding as normal control group (Con) with normal diet with batch C57BL mouse.Successive administration 16days gets the hematometry blood cholesterol levels.
The result
Compare with the normal control group, the IR mouse shows tangible hypercholesterolemia.Model IR mouse is compared, and similar with the fenofibrate effect, The compounds of this invention ZSE-2-4 can obviously reduce blood total cholesterol (TC) (see figure 6).
Claims (13)
1. aryl carboxylic acid compounds and steric isomer and physiologically acceptable salt by formula (I) expression:
Wherein, Ar
1, Ar
2Independently be selected from and replace or unsubstituted phenyl;
M
1, M
2Be independently selected from methylene radical-CH
2-or saturated covalent linkage, work as M
1, M
2When being saturated covalent linkage, Ar
1With Ar
2Isolated each other or connect into ring through covalent linkage at the substituted ortho position of N-;
X is selected from-(CH
2)
n-or phenyl (C
6H
4-), wherein n is 0,1 or 2;
R
1Be selected from and replace or unsubstituted C
1-6Straight or branched alkyl, C
3-6Naphthenic base ,-CH
2-R, R are selected from and replace or unsubstituted phenyl, replacement or unsubstituted indyl, replacement or unsubstituted benzofuryl, replacement or unsubstituted naphthyl;
R
2, R
3Be independently selected from hydrogen, halogen, C
1-6Alkyl, C
1-6Alkoxyl group;
Substituting group is selected from hydroxyl, amino, halogen, C
1-6Straight or branched alkyl, C
3-6Naphthenic base, C
1-6Alkoxyl group, phenyl, phenoxy, methylene-dioxy.
2. compound according to claim 1 is characterized in that, described compound is the compound shown in the general formula (IA) and steric isomer and physiologically acceptable salt:
Wherein, R is selected from and replaces or unsubstituted phenyl, replacement or unsubstituted indyl, replacement or unsubstituted benzofuryl, replacement or unsubstituted naphthyl;
R
2, R
3Be independently selected from hydrogen, halogen, C
1-6Alkyl, C
1-6Alkoxyl group;
Substituting group is selected from hydroxyl, amino, halogen, C
1-6Straight or branched alkyl, C
3-6Naphthenic base, C
1-6Alkoxyl group, phenyl, phenoxy, methylene-dioxy.
3. compound according to claim 2 is characterized in that, described compound is the compound shown in the general formula (IAa) and steric isomer and physiologically acceptable salt:
(IAa)
Wherein, R is selected from and replaces or unsubstituted phenyl, replacement or unsubstituted indyl, replacement or unsubstituted benzofuryl, replacement or unsubstituted naphthyl;
Substituting group is selected from hydroxyl, amino, halogen, C
1-6Straight or branched alkyl, C
3-6Naphthenic base, C
1-6Alkoxyl group, phenyl, phenoxy, methylene-dioxy.
4. compound according to claim 2 is characterized in that, described compound is the compound shown in the general formula (IAb) and steric isomer and physiologically acceptable salt:
Wherein, R
2, R
3Be independently selected from hydrogen, halogen, C
1-6Alkyl, C
1-6Alkoxyl group.
5. compound according to claim 1 is characterized in that, described compound is the compound shown in the general formula (IB) and steric isomer and physiologically acceptable salt:
Wherein, R is selected from and replaces or unsubstituted phenyl, replacement or unsubstituted indyl, replacement or unsubstituted benzofuryl, replacement or unsubstituted naphthyl;
Substituting group is selected from hydroxyl, amino, halogen, C
1-6Straight or branched alkyl, C
3-6Naphthenic base, C
1-6Alkoxyl group, phenyl, phenoxy, methylene-dioxy.
6. compound according to claim 1 is characterized in that, described compound is the compound shown in the general formula (IC) and steric isomer and physiologically acceptable salt:
Wherein, Ar
1, Ar
2Be independently selected from and replace or unsubstituted phenyl; Substituting group is selected from hydroxyl, amino, halogen, C
1-6Straight or branched alkyl, C
3-6Naphthenic base, C
1-6Alkoxyl group, phenyl, phenoxy, methylene-dioxy.
7. according to each described compound in the claim 1～6, it is characterized in that described compound is selected from:
8. the preparation method of each said compound in the claim 1～7 is characterized in that, may further comprise the steps:
Formula II compound and formula III compound reaction production IV compound, production V compound behind the formula IV compound alkylation removal, the latter and formula VI compound reaction production VII compound generate compound shown in the general formula I behind the formula VII compound hydrolysis:
Wherein, Ar
1, Ar
2, M
1, M
2, X, R
1, R
2And R
3Definition with among the claim 1-7 each, R ' and R
5Be independently selected from C
1-4The straight or branched alkyl; W selection-Br ,-CH
2Br ,-CH
2CH
2Br or-C
6H
4Br; R
4Be selected from hydroxyl or halogen.
9. the compsn of a medicine, contain effective dose like each described arbitrary compound in the claim 1～7 with at pharmaceutically acceptable carrier.
10. pharmaceutical composition according to claim 9 is characterized in that, described pharmaceutical composition is selected from tablet, capsule, pill, injection, sustained release preparation, controlled release preparation or various particulate delivery system.
11. each described compound of claim 1～7 is as the purposes of protein-tyrosine phosphatase 1B inhibitor.
12. the application that each described compound of claim 1～7 is used for preparing prevention or treats the medicine of PTP 1B relative disease.
13. the application of claim 12, described disease are selected from malignant tumours such as metabolism syndrome diseases such as mellitus, hypertension, obesity, hyperlipidemia and mammary cancer.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013049661A (en) * | 2011-03-16 | 2013-03-14 | Ricoh Co Ltd | Carbazole derivative and semiconductor nanocrystal |
| WO2018219204A1 (en) * | 2017-05-27 | 2018-12-06 | 中国药科大学 | Novel phenoxuacetic acid derivative, preparation method therefor and uses of derivative as drug |
| CN109942537A (en) * | 2018-03-03 | 2019-06-28 | 中国人民解放军第二军医大学 | A kind of ALDH2 agonist, preparation method and its usage |
-
2010
- 2010-09-03 CN CN2010102713861A patent/CN102382036A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013049661A (en) * | 2011-03-16 | 2013-03-14 | Ricoh Co Ltd | Carbazole derivative and semiconductor nanocrystal |
| WO2018219204A1 (en) * | 2017-05-27 | 2018-12-06 | 中国药科大学 | Novel phenoxuacetic acid derivative, preparation method therefor and uses of derivative as drug |
| CN109942537A (en) * | 2018-03-03 | 2019-06-28 | 中国人民解放军第二军医大学 | A kind of ALDH2 agonist, preparation method and its usage |
| CN109942537B (en) * | 2018-03-03 | 2023-11-17 | 中国人民解放军第二军医大学 | ALDH2 agonist, preparation method and application thereof |
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Application publication date: 20120321 |