CN102786517A - Pyrimidine thiazole amine derivative having GK (glucokinase) and PPAR (peroxidase proliferator-activated receptor) dual agonist activities - Google Patents
Pyrimidine thiazole amine derivative having GK (glucokinase) and PPAR (peroxidase proliferator-activated receptor) dual agonist activities Download PDFInfo
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Abstract
The invention discloses a new pyrimidine thiazole amine derivative, its preparation method, its medicinal composition and its uses, and concretely relates to a pyrimidine thiazole amine derivative with the structure represented by general formula I, its medicinal salt, its preparation method, a composition containing one or more of the compounds, and uses of the compound in the treatment of diseases associated with the GK and the PPAR, such as diabetes and obesity.
Description
Invention field
The present invention relates to the pyrimidine thiazole amines verivate shown in general formula I and the II; Its pharmacologically acceptable salt; The precursor of its same biological function or verivate; And preparation method thereof, contain one or more these compound compositions and this compounds purposes at treatment and gk and px vegetation activated receptor diseases associated such as aspects such as mellitus, obesity.
Background of invention
Sugar is organism important energy and carbon source.The sugar decomposition generate energy can be supplied with the needs of organism vital movement, and glycometabolic intermediate product can be transformed into other carbon compound again, like amino acid, lipid acid, nucleosides etc.Carbohydrate metabolism can be divided into the decomposition of sugar and synthetic two aspects of sugar.Catabolism of carbohydrate comprises glycolysis-, i.e. the common decomposition approach of sugar; And tricarboxylic acid cycle, the i.e. last oxidative pathway of sugar.Glycolysis is that enzyme becomes pyruvic acid with glucose degradation and is accompanied by the process that generates ATP.It is the energy-producing common metabolic approach of breakdown of glucose in animal, plant, the microorganism cells.In the oxygen consumption organism, the pyruvic acid that glycolysis generates gets into plastosome, is become CO through tricarboxylic acid cycle by exhaustive oxidation
2And water; The NADH that glycolysis generates produces ATP and water through the respiratory chain oxidation.So glycolysis is the prelude of oxidative phosphorylation and tricarboxylic acid cycle.Gk (GK) is one of four kinds of HKs finding on one's body Mammals corridor Cofowick, S.P.The Enzymes, Vol.9 (P.Boyer ' ed.) Academic Press; New York, N bifurcation .1-48 page or leaf, 1973]; It is first key enzyme in the glycolytic pathway; It can become the 6-glucose 1-phosphate1-with glucose phosphorylation under the condition that ATP exists, get into the metabolic process in downstream.Therefore, this step is first rate-limiting step of whole carbohydrate metabolism process, and GK is first rate-limiting enzyme in the carbohydrate metabolism process, plays important biological action.
The cell distribution of GK is limited, is mainly seen in pancreas beta cell and hepatic tissue cell.In addition, GK is playing the part of important role in controlling blood sugar balance and metabolism, regulates on the one hand the glycogen metabolism, and when on an empty stomach or blood sugar when low, GK is active low, and glycogen output increases, to guarantee the energy supply of vitals; After the meal or blood sugar when high, the GK increased activity, thus promote liver starch synthetic, suppress the liver glyconeogenesis, to keep glycaemic homeostasis.Regulate and control secretion of insulin as the susceptor of glucose on the other hand.When blood sugar concentration was higher than normal value in the body, the glucose in the blood got into beta Cell of islet by glucose transporter 2 (GLUT2) transhipment, and phosphorylation generates the 6-glucose 1-phosphate1-under the GK effect.The glycolysis of glucose, oxidative metabolism increase ATP/ADP ratio; The K+ ionic channel is closed, film depolarize, voltage susceptibility Ca2+ channel opener; Stream in the Ca2+; Regular Insulin storage vesica and plasma membrane merge, and make Regular Insulin discharge into blood, and get into the adjusting that liver, fat and muscle cell are participated in blood sugar with blood circulation.Glucose in liver phosphoric acid under the effect of GK turns to-6 glucose 1-phosphate1-s, then synthetic liver starch under insulin action.At fat and muscle cell, Regular Insulin triggers glucose transporter 4 (GLUT4) and in cell, stores picked-up and the metabolism that vesica migrates to plasma membrane promotion glucose.GK discharges and glycogen metabolism double action mechanism lowering blood glucose through regulating Regular Insulin, and [Al-Hasani H plays a significant role in keeping the glycaemic homeostasis process; Tschopl M H.Mol Interv, 2003,3 (7), 367-370].[Chipkin, S.R., Kelly, K.L. and Ruderrnam, N.B. are shown in Joslin ' Diabetes (C.R.Khan and G.C.Wier compile), Lea and Febiger, Philadelphia, PA, 97-115 page or leaf, 1994].
It is to be caused by afunction after the GK transgenation that young type is early sent out mellitus (MODY), shows that GK also plays glucose sensor Liang in human body, Y, Kesavan, P., Wang, people such as L., Biochem.J.309,167-173,1995).Except that MODY, also ubiquity GK is active in the general diabetic individual descends.Pathogenesis to diabetes B discovers that further the active reduction of liver GK possibly participated in insulin resistant mechanism, causes blood sugar increasing, and islet function is impaired to be increased the weight of with insulin resistant.Can increase the active medicine of GK to stop or to delay advancing of disease so seek, might open up a new way for early prevention and treatment mellitus.
Recognize in recent years: pancreatic beta type glucokinase is confined to the brain of rat, wherein particularly expresses in the feeding center (ventromedial nucleus of hypothalamus, VMH).The neurocyte of the about twenty percent among the VMH is known as glucose response property neurone (glucose-responsive neutrons), is considered to aspect management of body weight, play a significant role in the past.In the brain of rat, give glucose, then food ration reduces, and if analogue one glycosamine that gives glucose in the brain suppresses glucose metabolism, many foods then take place.The electrophysiology experiment shows: glucose response property neurone and physiological glucose concn change (5-20mM) and are activated accordingly, but through inhibition glucose metabolisms such as glycosamines, then its activity is suppressed.Can infer the glucose concn sensory perceptual system of VHM and the insulin secretion of pancreatic beta cell is the mechanism via glucokinase equally.Therefore, except that liver, pancreatic beta cell, the active material of glucokinase that activates VHM not only has the effect of blood sugar regulation, also possibly regulate the worried obesity of a lot of diabetes B patients.Can know by above-mentioned record; Compound with glucokinase activation can be used as treatment of diabetes medicine and/or prophylactic agent; Perhaps the chronic complicating diseases of mellitus such as retinopathy, ephrosis, neurosis, ischemic heart disease, arteriosclerosis treat and/or prevent medicine, further can be used as the fat medicine that treats and/or prevents.
It has been found that many GK small molecules acvators; Has the various structure characteristic: like substituted phenylacetamides (WO0058293WO0185706WO0208209WO0185707WO0183465WO0246173WO 2004072066WO0246173); Substituted hydantoins (WO0183478), substituted azole class (WO2006112549), substituent indole (US0067939WO031179); The substituted Propionamides of isoindoline (WO0248106); Substituted anthranilamide-based (WO03080585), substituted α phenylacryloyl amine (WO0214312) etc., wherein phenylacetamides is that research is done many one type.Though above-mentioned GK acvator research has been made very big contribution to this area, and is active for improving compound structure and GK acvator, research is still being continued in this area.
Px vegetation activated receptor (PPARs) belongs to the nuclear hormone receptor superfamily, has three kinds of hypotypes (PPAR α, PPAR γ, PPAR δ).Three kinds of acceptors are exercised the function of lipid transmitter, and important organism metabolism is regulated in the expression of coordinated regulation several genes sequence.PPARs has multiple biological effect, can promote adipocyte differentiation and steatogenesis, and enhancing body is to the susceptibility of Regular Insulin, and sugared balance in the mediation body is the drug targets of effectively treating metabolic disease (like type ii diabetes and atherosclerosis).And generation of the inflammation-inhibiting factor and inflammatory reaction, influence tumor growth, to cardiovascular generation protective effect.Research in recent years shows that PPARs also has neuroprotective, can alleviate nerve cell damage in the nerve degenerative diseases such as A Ercaimo disease, Parkinson's disease, cerebral ischemia and multiple sclerosis.
PPAR γ is different with classical nuclear receptor; After it is combined to activate by sepcific ligands; Still can not Direct Recognition combine special DNA regulating and controlling sequence, must be through (retinoid X receptor RXR) forms heterodimer with vitamin A acid x acceptor; Under the effect of many auxiliary adjustment factors (cofactors), regulate special genetic transcription.The PPAR γ part that activated gene is transcribed in early stage research calls the PPAR gamma agonist, is called suppressor factor and suppressor gene is transcribed.Latest Progress shows that PPAR γ combines the special conformation of formation with different ligands, determined the selective binding effect of PPAR γ one RXR heterodimer and special cofactor, has further determined heterogeneic alternative transcription regulating effect.Just because of this structure and interactional selectivity, make different PPAR γ parts through the selected gene transcriptional control, produce different biological effects.With regard to the complicacy of gene regulating; Same PPAR γ part is to the activation of transcribing of target gene; The inhibition that has, therefore, more and more scholars is with the unilateral definition of " regulator " replacement " agonist/suppressor factor "; And then the known selectively acting of research in some PPAR γ part of specific gene transcriptional control call " selective PPAR gamma modulators " (selective PPAR γ modulator, SPPARM).If any micromolecular compound activate PPAR γ; Then with the interaction of different cofactors; Can fatty atomization and glycolipid metabolism process be separated in the gene regulating level, promptly some promotes the not induced lipolysis differentiation of PPAR gamma agonist of glycolipid metabolism.
Research to the PPAR gamma modulators at present mainly concentrates on two problems: the one, and we need PPAR γ part to have great activation activity, activate PPAR γ to reach appropriateness, regulate the purpose that target gene is transcribed; The 2nd, can the fat differentiation be separated with insulin-sensitizing effect in the gene regulating level? The compound or the material that align under study for action should deeply be inquired into the molecular mechanism that its PPAR γ regulates, and screening existing insulin-sensitizing effect does not influence the fat differentiation again even promote lipometabolic PPAR gamma modulators.
Because PPAR α/δ participates in regulating lipid metabolism, improves hyperlipidaemia, alleviate the fat differentiation of PPAR γ activation-inducing to a certain extent; PPAR δ is also more extensive than PPAR α on tissue distribution; Research to PPAR δ in recent years also receives publicity; Many investigators are devoted to develop PPAR alpha/gamma double agonists or α/δ/γ three agonists; Expect that this type of medicine can reach the hypoglycemic effect of bringing into play regulating blood fat simultaneously, specific aim treatment obesity, insulin resistant, metabolic syndrome.Point out in the result of study of animal and clinical experiment at present; PPAR alpha/gamma double agonists or α/δ/γ three agonists really can improve insulin resistant; Improve hyperlipemia, but owing to still lack drug safety and toxicity test foundation, the application prospect of this compounds is still waiting to observe.
Mellitus are a kind of whole body chronic metabolic disease, and its pathological characters mainly is a hyperglycemia.It has been generally acknowledged that the main pathological change that causes hyperglycemia comprises the weakening and the metabolic imbalance of glycogen (being also referred to as three big pathological changes) of minimizing, effect of insulin secretion.The activation energy of gk (GK) promotes insulin secretion and glycogen metabolism simultaneously; The activation energy of px vegetation activated receptor (PPAR) increases the susceptibility of body cell to Regular Insulin.Therefore; Three big pathological changes to the mellitus hyperglycemia; Structure and pharmacological action based on known GK and PPAR small molecules agonist; Make up and synthetic GK and the two target spot ligand compounds of PPAR, research and develop a kind of many target spots of ' one medicine that can improve insulin secretion, glycogen metabolism and promotion peripheral tissues simultaneously the susceptibility of Regular Insulin ' medicine, will become the new way of seeking general efficacious therapy Glucovance.
Summary of the invention
The invention provides a kind of pyrimidine thiazole amines verivate that glucokinase activators can be used as the general structure I of px vegetation activated receptor agonist again that promptly can be used as:
The object of the present invention is to provide a kind of GK of having and the active new pyrimidine thiazole amines of PPAR double excitations verivate, its pharmacologically acceptable salt.
Another object of the present invention is to provide a kind of method for preparing new pyrimidine thiazole amines verivate.
A purpose more of the present invention is to provide a kind of pharmaceutical composition that contains one or more this compounds.
Another purpose of the present invention is based on GK and PPAR biological function, proposes the new ideas of many target drugs combined therapy mellitus.
Another again purpose of the present invention provides GK and two ligand compounds of PPAR and the purposes of this compounds in treatment and GK and PPAR diseases related medicine.
The present invention relates to have the pyrimidine thiazole amines verivate of following general formula I:
In the formula
R
1Be selected from hydrogen, halogen, amino, hydroxyl, the COOC1-8 alkyl, carboxyl, aminoacyl, the C1-8 alkyl replaces aminoacyl, C1-8 alkyl, carboxy-methyl mercapto-group, methylol, propyloic;
Preferred R
1Be selected from hydrogen, fluorine, chlorine, bromine, amino, the COOC1-4 alkyl, carboxyl, aminoacyl, the C1-4 alkyl replaces aminoacyl, C1-4 alkyl, carboxy-methyl mercapto-group, methylol, propyloic;
Preferred R
1Be selected from hydrogen, fluorine, chlorine, bromine, amino, methoxycarbonyl, ethoxycarbonyl, the isopropyl ester base, methoxycarbonyl, carboxyl, aminoacyl, the methylamine acyl group, the Isopropylamine acyl group encircles the third methylamine acyl group, methyl, ethyl, carboxy-methyl mercapto-group, methylol, propyloic;
Most preferred R
1Be selected from hydrogen, fluorine, chlorine, ethoxycarbonyl, the isopropyl ester base, methoxycarbonyl, carboxyl, aminoacyl, the methylamine acyl group, the Isopropylamine acyl group encircles the third methylamine acyl group, methyl, carboxy-methyl mercapto-group, methylol.
R
2Be selected from hydrogen, halogen, amino, hydroxyl, the COOC1-8 alkyl, carboxyl, aminoacyl, the C1-8 alkyl replaces aminoacyl, C1-8 alkyl, carboxy-methyl mercapto-group, methylol, propyloic;
Preferred R
2Be selected from hydrogen, fluorine, chlorine, bromine, amino, the COOC1-4 alkyl, carboxyl, aminoacyl, the C1-4 alkyl replaces aminoacyl, C1-4 alkyl, carboxy-methyl mercapto-group, methylol, propyloic;
Preferred R
2Be selected from hydrogen, fluorine, chlorine, bromine, amino, methoxycarbonyl, ethoxycarbonyl, the isopropyl ester base, methoxycarbonyl, carboxyl, aminoacyl, the methylamine acyl group, the Isopropylamine acyl group encircles the third methylamine acyl group, methyl, ethyl, carboxy-methyl mercapto-group, methylol, propyloic;
Most preferred R
2Be selected from hydrogen, fluorine, chlorine, ethoxycarbonyl, the isopropyl ester base, methoxycarbonyl, carboxyl, aminoacyl, the methylamine acyl group, the Isopropylamine acyl group encircles the third methylamine acyl group, methyl, carboxy-methyl mercapto-group, methylol.
R
3Be selected from hydrogen, halogen, the C1-8 alkylamino, virtue is amino, the C1-8 alkoxyl group, aryloxy, the C1-8 alkylthio, arylthio, nitro, cyanic acid,
Preferred R
3Be selected from hydrogen, chlorine, the C1-6 alkylamino, virtue is amino, the C1-6 alkoxyl group, aryloxy, the C1-6 alkylthio, thiophenyl, the pyridine sulfenyl, nitro, cyanic acid,
Preferred R
3Be selected from hydrogen, chlorine, methylamino-, ethylamino, isopropylamino encircles third methylamino-, phenylamino, pyridine is amino, methoxyl group, oxyethyl group, butoxy, phenoxy, the pyridine methoxyl group, methylthio group, thiophenyl, the pyridine sulfenyl, nitro, cyanic acid,
Most preferred R
3Be selected from ethylamino, isopropylamino encircles third methylamino-, phenylamino, and pyridine is amino, oxyethyl group, butoxy, the pyridine methoxyl group,
R
4Be selected from hydrogen, methyl, trifluoromethyl, fluorine or chlorine, methoxyl group, methylthio group, methylamino-.
Preferred R
4Be selected from hydrogen, methyl, trifluoromethyl, fluorine or chlorine, methoxyl group, methylthio group.
Preferred R
4Be selected from hydrogen, methyl, trifluoromethyl, fluorine or chlorine, methoxyl group.
Most preferred R
4Be selected from hydrogen, methyl, trifluoromethyl.
Preferred aryl groups is selected from phenyl, pyridyl.
In order to prepare the described compound of general formula I of the present invention, according to the structure of general formula I, the present invention prepares compound of Formula I will be divided into two kinds of routes.
Article one, in the route, is raw material, under alkaline condition, reacts generation midbody compound 3 with dichloro pyrimidine verivate 2, again with R with thiazole sulfonamide derivatives 1
3Reaction obtains product 4.
In the second route, be raw material with halo thiazole derivative 5, the following and pyrimidinamine derivatives 6 reaction generation target compounds 7 of alkaline environment.
In addition, starting raw material and midbody in the above-mentioned reaction obtain easily, and each step reaction can be according to the document of having reported or can is easy to the ordinary method in the organic synthesis synthesize to those skilled in the art.The said pharmacy acceptable salt of general formula I comprises different acid salt, like following mineral acid or organic acid acid salt: hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid; Methylsulfonic acid, tosic acid, trifluoroacetic acid, matrimony vine acid, toxilic acid; Tartrate, fumaric acid, Hydrocerol A, lactic acid.The said pharmacy acceptable salt of general formula I also comprises Different Alkali metal-salt (lithium, sodium, sylvite), alkaline earth salt (calcium; Magnesium salts) and ammonium salt and the salt of physiologically acceptable cationic organic bases can be provided, like methylamine, n n dimetylaniline; Trimethylamine 99, piperidines, the salt of morpholine and three (2-hydroxyethyl) amine.All these salt within the scope of the present invention all can adopt the ordinary method preparation.
The invention still further 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 0.001-150mg/Kg body weight, is preferably the 0.01-100mg/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.
The compounds of this invention is the dual acvator of GK and PPAR or its precursor; Can discharge through regulating Regular Insulin; Tissue is to the susceptibility and the glycogen metabolism multiple action mechanism lowering blood glucose of Regular Insulin; Can be used for preventing and treat 1 type or 2 types especially diabetes B and relevant complication, or other disease relevant with GK and PPAR.
Embodiment
Below will combine embodiment that invention is described further, but not limit the scope of the invention.
Determining instrument: NMR spectrum is with Vaariaan Mercury 300 type NMRs.Mass spectrum is with ZAD-2F and VG300 mass spectrograph.
Embodiment 1:2-(4-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-is amino) phenoxy) ETHYLE ACETATE
The preparation of a:N-(6-chloro-2 methylpyrimidines-4-yl)-4-methylthiazol-2-amine:
With 2-methyl-4, and the 6-dichloro pyrimidine (16.3g, 0.1mol); (11.4g 0.1mol) joins among the DMF (250mL) 2-amino-4-methylthiazol, and ice bath stirs down; With 60%NaH (8g; 0.2mol) join in the reaction solution, room temperature reaction 6h, the back that reacts completely adds Glacial acetic acid min. 99.5 (15mL) termination reaction. in batchesIn reaction solution impouring 1L saturated sodium bicarbonate ice-water bath, there are a large amount of solids to separate out, filter, washing, dry cake, recrystallization obtain N-(6-chloro-2 methylpyrimidines-4-yl)-4-methylthiazol-2-amine 16.5 grams.
The preparation of b:2-(4-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-is amino) phenoxy) ETHYLE ACETATE:
With N-(6-chloro-2 methylpyrimidines-4-yl)-4-methylthiazol-2-amine (2.4g, 10mmol), 2-(4-amino-benzene oxygen)-ETHYLE ACETATE (1.75g, 10mmol); NaI (50mg) joins among the DMF (20mL), and 150 ℃ of reaction 36h react completely, and reduce to room temperature; The evaporated under reduced pressure solvent adds ETHYLE ACETATE (200mL), successively with washing; Saturated sodium-chloride is washed, and anhydrous sodium sulfate drying concentrates the back column chromatography and obtains white solid 1.32 grams.
1H?NMR(DMSO-d
6，300MHz)，δ(ppm)：11.15(s，1H，-NH-)，9.20(s，1H，-NH-)，7.52(d，2H，ArH)，6.99(d，2H，ArH)，6.67(d，1H，ArH)，6.23(s，1H，ArH)，4.83(s，2H，-CH
2O-)，4.27(q，2H，Me-CH
2-)，2.60(s，3H，-CH
3)，2.32(s，3H，-CH
3)，1.32(t，3H，-CH
3).MS(FAB)：400(M+1)
Embodiment 2:2-(4-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-is amino) phenoxy) acetate
2-(4-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-is amino) phenoxy) ETHYLE ACETATE (300mg) is added among methyl alcohol (10mL) and the 2.5N NaOH (15mL), and 60 ℃ are stirred 2h, reduce to room temperature; Add entry (30mL), with ether (30mL) extraction, water layer is transferred pH to 2 with concentrated hydrochloric acid; There are a large amount of white native lands to separate out; Filter, dry cake obtains white solid 255mg.
1H?NMR(DMSO-d
6，300MHz)，δ(ppm)：12.59(s，1H，COOH)，11.11(s，1H，-NH-)，9.17(s，1H，-NH-)，7.62(d，2H，ArH)，6.98(d，2H，ArH)，6.65(d，1H，ArH)，6.23(s，1H，ArH)，4.83(s，2H，-CH
2O-)，2.55(s，3H，-CH
3)，2.30(s，3H，-CH
3).MS(FAB)：372(M+1).
Embodiment 3:2-(3-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-is amino) phenoxy) ETHYLE ACETATE
Operation steps obtains white solid (585mg, 29%) with embodiment 1.
1H?NMR(DMSO-d
6，300MHz)，δ(ppm)：11.12(s，1H，-NH-)，9.33(s，1H，-NH-)，7.38(s，1H，ArH)，7.20-7.09(m，2H，ArH)，6.51(d，1H，ArH)，6.27(s，1H，ArH)，4.74(s，2H，-CH
2O-)，4.17(q，2H，Me-CH
2-)，2.43(s，3H，-CH
3)，2.22(s，3H，-CH
3)，1.20(t，3H，-CH
3).MS(FAB)：400(M+1)
Embodiment 4:2-(3-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-is amino) phenoxy) acetate
Operation steps obtains white solid (260mg, 95%) with embodiment 2.
1H?NMR(DMSO-d
6，300MHz)，δ(ppm)：11.17(s，1H，-NH-)，9.31(s，1H，-NH-)，7.33(s，1H，ArH)，7.15(t，1H，ArH)，7.07(d，1H，ArH)，6.60(s，1H，ArH)，6.49(d，1H，ArH)，6.27(s，1H，ArH)，4.55(s，2H，-CH
2O-)，2.42(s，3H，-CH
3)，2.17(s，3H，-CH
3).MS(FAB)：372(M+1).
Embodiment 5:2-methyl-2-(4-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-is amino) phenoxy) ethyl propionate
Operation steps obtains white solid 585mg with embodiment 1.
1H?NMR(DMSO-d
6，300MHz)，δ(ppm)：12.85(s，1H，COOH)，11.60(s，1H，-NH-)，9.20(s，1H，-NH-)，7.96(s，1H，ArH)，7.31(m，3H，ArH)，6.73(d，2H，ArH)，6.10(s，1H，ArH)，2.35(s，3H，-CH
3)，1.38(s，6H，-CH
3×2).MS(FAB)：414(M+1).
Embodiment 6:2-methyl-2-(4-(2-methyl-6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-is amino) phenoxy) ethyl propionate
Operation steps obtains white solid 556mg with embodiment 1.
1H?NMR(DMSO-d
6，300MHz)，δ(ppm)：11.70(s，1H，-NH-)，9.30(s，1H，-NH-)，8.03(s，1H，ArH)，7.20(d，2H，ArH)，6.79(d，2H，ArH)，6.20(s，1H，ArH)，4.33-4.16(m，4H，Me-CH
2-×2)，2.45(s，3H，-CH
3)，1.45(s，6H，-CH
3×2)，1.28(t，3H，-CH
3)，1.19(t，3H，-CH
3).MS(FAB)：486(M+1).
Embodiment 7:2-(4-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-yl) piperazine-1-yl) ethanol
The preparation of a:N-(6-chloro-2 methylpyrimidines-4-yl)-4-methylthiazol-2-amine is with embodiment 1.
B:2-(4-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-yl) piperazine-1-yl) alcoholic acid preparation:
With N-(6-chloro-2 methylpyrimidines-4-yl)-4-methylthiazol-2-amine (2.4g, 10mmol), hydroxyethyl piperazine (1.73g, 10mmol), DIPEA (1.94g, 15mmol), DMSO (5mL) joins in the dioxane (60mL), 110 ℃ the reaction 10h, react completely.In reaction solution impouring water (200mL), stir 1h, filter.Dry cake, re-crystallizing in ethyl acetate obtain white solid (1.7g, 50%).
1H NMR (DMSO-d
6, 300MHz), δ (ppm): 10.98 (s, 1H ,-NH-), 6.55 (s, 1H, ArH), 5.98 (s, 1H, ArH), 3.53-3.47 (m, 6H ,-CH
2* 3), 2.47-2.39 (m, 6H, CH
2* 3), 2.34 (s, 3H ,-CH
3), 2.21 (s, 3H ,-CH
3) .MS (FAB): 335 (M+1).
Embodiment 8:2-(4-(2-methyl-6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-yl) piperazine-1-yl) ethanol
The preparation of a:2-(6-chloro-2 methylpyrimidines-4-amido) thiazole-5-carboxylic acid ethyl ester:
With 2-methyl-4, and the 6-dichloro pyrimidine (16.3g, 0.1mol), thiazolamine-5-ethyl formate (17.2g; 0.1mol) join among the DMF (250mL), ice bath stirs down, with 60%NaH (8g; 0.2mol) join in the reaction solution, room temperature reaction 6h reacts completely. in batchesAdd Glacial acetic acid min. 99.5 (15mL) termination reaction.In reaction solution impouring 1L saturated sodium bicarbonate ice-water bath, there are a large amount of solids to separate out, filter, washing, dry cake obtains 2-(6-chloro-2-methylpyrimidine-4-amido) thiazole-5-ethyl formate (18.5g, 65%) bullion.
B:2-(4-(2-methyl-6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-yl) piperazine-1-yl) alcoholic acid preparation:
With 2-(6-chloro-2-methylpyrimidine-4-amido) thiazole-5-ethyl formate (149mg, 5mmol), hydroxyethyl piperazine (865mg, 5mmol), DIPEA (970mg, 7.5mmol), DMSO (5mL) joins in the dioxane (60mL), 110 ℃ the reaction 10h, react completely.In reaction solution impouring water (200mL), stir 1h, filter.Dry cake, re-crystallizing in ethyl acetate obtain 2-(4-(2-methyl-6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-yl) piperazine-1-yl) ethanol white solid.
1H NMR (DMSO-d
6, 300MHz), δ (ppm): 11.60 (s, 1H ,-NH-), 8.03 (s, 1H, ArH), 7.04 (s, 1H, ArH), 4.43 (m, 1H, OH), 4.29-4.22 (q, 2H ,-CH
2), 3.51 (m, 6H, CH
2* 3), 3.32 (s, 4H ,-CH
2), 2.43 (m, 2H ,-CH
2), 2.41 (s, 3H ,-CH
3), 1.28 (t, 3H ,-CH
3) .MS (FAB): 393 (M+1).
Embodiment 9:2-(1-(2-methyl-6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-yl) piperidin-4-yl) ethanol
Operation steps obtains white solid 256mg with embodiment 8.
1H?NMR(DMSO-d
6，400MHz)，δ(ppm)：11.53(s，1H，-NH-)，8.02(s，1H，ArH)，6.04(s，1H，ArH)，4.47(t，1H，-OH)，4.25(m，4H，-CH
2×2)，3.53-3.50(m，1H，-CH)，3.25(t，2H，-CH
2)，2.84(t，2H，-CH
2)，2.49-2.45(m，2H，-CH
2)，2.39(s，3H，-CH
3)，1.73-1.70(m，2H，-CH
2)，1.27(t，3H，-CH
3)，1.11-1.02(m，2H，-CH
2).MS(FAB)：392(M+1).
Embodiment 10:2-(1-(2-methyl-6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-yl) piperidin-4-yl) acetate
Operation steps obtains white solid 356mg with embodiment 8.
1H?NMR(DMSO-d
6，400MHz)，δ(ppm)：11.53(s，1H，-NH-)，8.02(s，1H，ArH)，6.06(s，1H，ArH)，4.25(q，2H，-CH
2)，4.13(m，2H，-CH
2)，3.53-3.50(m，1H，-CH)，3.03-2.97(m，2H，-CH
2)，2.55-2.45(m，2H，-CH
2)，2.40(s，3H，-CH
3)，1.90-1.86(m，2H，-CH
2)，1.53-1.43(m，2H，-CH
2)，1.28(t，3H，-CH
3).MS(FAB)：406(M+1).
Embodiment 11:2-((1-(2-methyl-6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-yl) piperidin-4-yl) methoxyl group) acetate
Operation steps obtains white solid 342mg with embodiment 8.
1H?NMR(DMSO-d
6，300MHz)，δ(ppm)：12.16(s，1H，COOH)，11.18(s，1H，-NH-)，7.63(s，1H，ArH)，5.66(s，1H，ArH)，3.88-3.83(m，2H，-CH
2)，3.58(s，2H，-CH
2)，2.92(d，2H，-CH
2)，2.33(s，3H，-CH
3)，2.10(m，4H，-CH
2)，1.46(m，1H，-CH)，1.37-1.33(m，2H，-CH
2)，0.89(t，3H，-CH
3)，0.74-0.71(m，2H，-CH
2).MS(FAB)：436(M+1)
Embodiment 12:2-(4-(6-(different third oxygen formyl thiazole of 5--2-is amino) pyrimidine-4-yl) piperazine-1-yl) ethanol
Operation steps obtains white solid 342mg with embodiment 8.
1H?NMR(DMSO-d
6，300MHz)，δ(ppm)：11.66(s，1H，-NH-)，8.41(s，1H，ArH)，8.02(s，1H，ArH)，6.20(s，1H，ArH)，5.07(m，1H，CH)，4.44(m，1H，OH)，4.25(m，2H，-CH
2-)，3.51(m，6H，CH
2×3)，2.48(m，4H，CH
2×2)，2.42(m，2H，-CH
2)，1.28(d，6H，-CH
3×2).MS(FAB)：393(M+1)
Embodiment 13:2-(4-(6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-yl) piperazine-1-yl) ethanol
Operation steps obtains white solid 242mg with embodiment 8.
1H?NMR(DMSO-d
6，300MHz)，δ(ppm)：11.68(s，1H，-NH-)，8.41(s，1H，ArH)，8.04(s，1H，ArH)，6.21(s，1H，ArH)，4.44(m，1H，OH)，4.28-4.22(q，2H，-CH
2)，3.53-3.52(m，6H，CH
2×3)，2.50(m，4H，-CH
2)，2.44-2.40(m，2H，-CH
2)，2.42(t，2H，-CH
3).MS(FAB)：379(M+1)
Embodiment 14:2-methyl-2-(4-(2-methyl-6-(5-carboxyl thiazole-2-is amino) pyrimidine-4-is amino) phenoxy) propionic acid
Operation steps obtains white solid 223mg with embodiment 1 and embodiment 2.
1H?NMR(DMSO-d
6，300MHz)，δ(ppm)：12.88(s，2H，COOH×2)，11.62(s，1H，-NH-)，9.27(s，1H，-NH-)，7.95(s，1H，ArH)，7.40(d，2H，ArH)，6.84(d，1H，ArH)，6.19(s，1H，ArH)，2.44(s，3H，-CH
3)，1.48(s，6H，-CH
3×2).MS(FAB)：430(M+1)。
Pharmacologically active
External activity is estimated:
Activation to gk
1. reaction principle:
2. reaction system is formed:
Comprise 5mmol/l ATP in the reaction system, 0.2U/ml G6PDH, 0.2mmol/l NADP, 5mmol/lMgCl
2, 1mmol/l DTT, 25mmol/l KCl, 100mmol/l Tris-HCl, different concns glucose, 1%DMSO, different concns test-compound and recombination human source liver GK protein liquid.
3. operating process:
Preparation reaction mixture (ATP, G6PDH, NADP, MgCl
2, DTT, KCl, glucose Tris-HCl) → add test-compound → addings reorganization GK protein liquid → room temperature measuring 340nm absorbance, and is designated as initial value (0min) → 37 ℃ incubation, every at a distance from 10 minutes 340nm readings once till the 60min → calculation result.
4. method of calculation:
Activate multiple=(OD
t-OD
0)
Sample hose/ (OD
t-OD
0)
Reaction tubes
Annotate: sample hose is to add test-compound in the system, and reaction tubes shines for the reaction pair that does not add test-compound.Activate multiple＞1.5 and be regarded as the positive.
The active result of part embodiment
Activation to px vegetation activated receptor
1. principle:
PPAR γ combines the back to activate with its part, insert in the nucleus, forms heterodimer with another nuclear receptor RXR, can specific recognition dna sequence dna PPRE (PPAR responsive element), and the latter regulates and control the expression of series of genes.Set up the luciferase reporter gene of PPRE regulation and control, make the expression level reaction PPAR activated level of reporter gene.
2. method:
1) PPAR γ is expressed in construction, the plasmid vector of RXR, and PPAR γ, the luciferase reporter gene plasmid vector of the response element PPRE regulation and control of RXR.
2) with the method for liposome transfection (Lipofectamine2000, invitrogen), cotransfection PPAR, RXR, PPRE-luciferase expression plasmid advance mammal cell line 293E cell.
3) the 293E cell transfecting was used trysinization after 24 hours, was divided into some parts behind the counting cells; Mix with the substratum that adds sample respectively; In suitable culture plate, cultivated 24 hours, this step must be set up negative control (adding DMSO), positive control (like Rosiglitazone); Each sample is set up parallel-group. and sample concentration can be provided with some gradients as required, and for example 10
-9～10
-5M.
4) after dosing 24-48 hour, with the abundant lysing cell of cell pyrolysis liquid, collect each porocyte lysate in the culture plate, (Luciferase Assay System Promega), measures the fluorescence reading with chemiluminescence detector immediately to add the luciferase reaction substrate.
3. Compound P PAR screening active ingredients:
With the luciferase reporter gene method of above-mentioned foundation, the PPAR γ of comparative compound activates active.Calculate the relative reactivity of SCREENED COMPOUND: the fluorescent value reading of compound is compared with the fluorescent value reading of positive control rosiglitazone, and the activity of establishing rosiglitazone is 100%, and the activity of other compounds is expressed as relative reactivity, that is:
The relative reactivity of SCREENED COMPOUND=sample reading/positive control reading * 100%
The active result of part embodiment
Claims (13)
1. pyrimidine thiazole amines compound and the pharmacologically acceptable salt thereof shown in general formula I,
In the formula
R
1Be selected from hydrogen, halogen, amino, hydroxyl, the COOC1-8 alkyl, carboxyl, aminoacyl, the C1-8 alkyl replaces aminoacyl, C1-8 alkyl, carboxy-methyl mercapto-group, methylol, propyloic;
R
2Be selected from hydrogen, halogen, amino, hydroxyl, the COOC1-8 alkyl, carboxyl, aminoacyl, the C1-8 alkyl replaces aminoacyl, C1-8 alkyl, carboxy-methyl mercapto-group, methylol, propyloic;
R
3Be selected from hydrogen, halogen, the C1-8 alkylamino, virtue is amino, the C1-8 alkoxyl group, aryloxy, the C1-8 alkylthio, arylthio, nitro, cyanic acid,
R
4Be selected from hydrogen, methyl, trifluoromethyl, fluorine or chlorine, methoxyl group, methylthio group, methylamino-.
2. according to the compound and the pharmacologically acceptable salt thereof of claim 1, it is characterized in that,
R
1Be selected from hydrogen, fluorine, chlorine, bromine, amino, the COOC1-4 alkyl, carboxyl, aminoacyl, the C1-4 alkyl replaces aminoacyl, C1-4 alkyl, carboxy-methyl mercapto-group, methylol, propyloic;
R
2Be selected from hydrogen, fluorine, chlorine, bromine, amino, the COOC1-4 alkyl, carboxyl, aminoacyl, the C1-4 alkyl replaces aminoacyl, C1-4 alkyl, carboxy-methyl mercapto-group, methylol, propyloic;
R
3Be selected from hydrogen, chlorine, the C1-6 alkylamino, virtue is amino, the C1-6 alkoxyl group, aryloxy, the C1-6 alkylthio, thiophenyl, the pyridine sulfenyl, nitro, cyanic acid,
R
4Be selected from hydrogen, methyl, trifluoromethyl, fluorine or chlorine, methoxyl group, methylthio group.
3. according to the compound and the pharmacologically acceptable salt thereof of claim 2, it is characterized in that,
R
1Be selected from hydrogen, fluorine, chlorine, bromine, amino, methoxycarbonyl, ethoxycarbonyl, the isopropyl ester base, methoxycarbonyl, carboxyl, aminoacyl, the methylamine acyl group, the Isopropylamine acyl group encircles the third methylamine acyl group, methyl, ethyl, carboxy-methyl mercapto-group, methylol, propyloic;
R
2Be selected from hydrogen, fluorine, chlorine, bromine, amino, methoxycarbonyl, ethoxycarbonyl, the isopropyl ester base, methoxycarbonyl, carboxyl, aminoacyl, the methylamine acyl group, the Isopropylamine acyl group encircles the third methylamine acyl group, methyl, ethyl, carboxy-methyl mercapto-group, methylol, propyloic;
R
3Be selected from hydrogen, chlorine, methylamino-, ethylamino, isopropylamino encircles third methylamino-, phenylamino, pyridine is amino, methoxyl group, oxyethyl group, butoxy, phenoxy, the pyridine methoxyl group, methylthio group, thiophenyl, the pyridine sulfenyl, nitro, cyanic acid,
R
4Be selected from hydrogen, methyl, trifluoromethyl, fluorine or chlorine, methoxyl group.
4. according to the compound and the pharmacologically acceptable salt thereof of claim 3, it is characterized in that,
R
1Be selected from hydrogen, fluorine, chlorine, ethoxycarbonyl, the isopropyl ester base, methoxycarbonyl, carboxyl, aminoacyl, the methylamine acyl group, the Isopropylamine acyl group encircles the third methylamine acyl group, methyl, carboxy-methyl mercapto-group, methylol.
R
2Be selected from hydrogen, fluorine, chlorine, ethoxycarbonyl, the isopropyl ester base, methoxycarbonyl, carboxyl, aminoacyl, the methylamine acyl group, the Isopropylamine acyl group encircles the third methylamine acyl group, methyl, carboxy-methyl mercapto-group, methylol.
R
3Be selected from ethylamino, isopropylamino encircles third methylamino-, phenylamino, and pyridine is amino, oxyethyl group, butoxy, the pyridine methoxyl group,
R
4Be selected from hydrogen, methyl, trifluoromethyl.
5. according to each compound and pharmacologically acceptable salt thereof of claim 1-4, described compound is selected from:
2-(4-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-is amino) phenoxy) ETHYLE ACETATE
2-(4-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-is amino) phenoxy) acetate
2-methyl-2-(4-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-is amino) phenoxy) ethyl propionate
2-methyl-2-(4-(2-methyl-6-(thiazole-2-is amino) pyrimidine-4-is amino) phenoxy) propionic acid
2-methyl-2-(4-(2-methyl-6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-is amino) phenoxy) propionic acid
2-methyl-2-(4-(2-methyl-6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-is amino) phenoxy) ethyl propionate
2-(3-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-is amino) phenoxy) ETHYLE ACETATE
2-(3-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-is amino) phenoxy) acetate
2-methyl-2-(3-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-is amino) phenoxy) ethyl propionate
2-methyl-2-(3-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-is amino) phenoxy) propionic acid
2-(4-(2-methyl-6-(4-methylthiazol-2-is amino) pyrimidine-4-yl) piperazine-1-yl) ethanol
2-(4-(2-methyl-6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-yl) piperazine-1-yl) ethanol
2-(1-(2-methyl-6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-yl) piperidin-4-yl) ethanol
2-(1-(2-methyl-6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-yl) piperidin-4-yl) acetate
2-((1-(2-methyl-6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-yl) piperidin-4-yl) methoxyl group) acetate
2-(4-(6-(different third oxygen formyl thiazole of 5--2-is amino) pyrimidine-4-yl) piperazine-1-yl) ethanol
2-(4-(6-(5-ethoxycarbonyl thiazole-2-is amino) pyrimidine-4-yl) piperazine-1-yl) ethanol
6. according to the compound of claim 1-5, it is characterized in that described medicinal salt comprises with mineral acid, organic acid, alkalimetal ion, alkaline earth metal ion maybe can provide physiologically acceptable cationic organic bases to combine salt and the ammonium salt that forms.
7. according to the compound of claim 6, it is characterized in that described mineral acid is selected from hydrochloric acid, Hydrogen bromide, phosphoric acid or sulfuric acid; Described organic acid is selected from methylsulfonic acid, tosic acid, trifluoroacetic acid, matrimony vine acid, toxilic acid tartrate, fumaric acid, Hydrocerol A or lactic acid; Described alkalimetal ion is selected from lithium ion, sodium ion, potassium ion; Described alkaline earth metal ion comprises calcium ion, mg ion; Describedly can provide physiologically acceptable cationic organic bases to be selected from methylamine, n n dimetylaniline, Trimethylamine 99, piperidines, morpholine or three (2-hydroxyethyl) amine.
8. prepare the method for each said compound of claim 1-7, comprise the steps:
With thiazole sulfonamide derivatives 1 is raw material, reacts under alkaline condition with dichloro pyrimidine verivate 2 to generate midbody compound 3, obtains product 4 with the R3 reaction again;
9. prepare the method for each said compound of claim 1-7, comprise the steps:
With halo thiazole derivative 5 is raw material, the following and pyrimidinamine derivatives 6 reaction generation target compounds 7 of alkaline environment;
10. pharmaceutical composition comprises as carrier commonly used on each described compound of claim 1-7 of effective constituent or its pharmaceutically useful salt and the pharmacopedics.
11. each described compound of claim 1-7 and pharmacologically acceptable salt thereof the preparation prevention with or the medicine of treatment and gk and px vegetation activated receptor diseases associated in application.
12., it is characterized in that described and gk and px vegetation activated receptor diseases associated are selected from the chronic complicating diseases and the obesity of mellitus, mellitus according to the application of claim 11.
13., it is characterized in that described mellitus are selected from type 1 diabetes or diabetes B according to the application of claim 12; The chronic complicating diseases of described mellitus is selected from retinopathy, ephrosis, neurosis, ischemic heart disease or arteriosclerosis.
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