CN102718727B - The aryl urea derivative of GK and PPAR double excitation activity - Google Patents
The aryl urea derivative of GK and PPAR double excitation activity Download PDFInfo
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- CN102718727B CN102718727B CN201110079336.8A CN201110079336A CN102718727B CN 102718727 B CN102718727 B CN 102718727B CN 201110079336 A CN201110079336 A CN 201110079336A CN 102718727 B CN102718727 B CN 102718727B
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- 0 **C(/C=C/*=CC1)=CC=C1OCC([N+]([O-])=O)=O Chemical compound **C(/C=C/*=CC1)=CC=C1OCC([N+]([O-])=O)=O 0.000 description 2
- KWQSLUADDPOZFM-UHFFFAOYSA-N CC(C)=CCN(C(Nc(nc1)ccc1C(O)=O)=O)c(cc1)ccc1OCC(O)=O Chemical compound CC(C)=CCN(C(Nc(nc1)ccc1C(O)=O)=O)c(cc1)ccc1OCC(O)=O KWQSLUADDPOZFM-UHFFFAOYSA-N 0.000 description 1
- LHYDOVHSHXGJOX-UHFFFAOYSA-N CCCCCN(C(Nc1ccc(C)cn1)=O)c(cc1)ccc1OCC(OCC)=O Chemical compound CCCCCN(C(Nc1ccc(C)cn1)=O)c(cc1)ccc1OCC(OCC)=O LHYDOVHSHXGJOX-UHFFFAOYSA-N 0.000 description 1
- ABEZMYBMPKOPAS-UHFFFAOYSA-N CCCCCN(C(Nc1ncc[s]1)=O)c(cc1)ccc1OCC(OCC)=O Chemical compound CCCCCN(C(Nc1ncc[s]1)=O)c(cc1)ccc1OCC(OCC)=O ABEZMYBMPKOPAS-UHFFFAOYSA-N 0.000 description 1
- KKEVOFIGYGDCCO-UHFFFAOYSA-N CCOC(COc(cc1)ccc1N(CC=C(C)C)C(Nc(nc1)ccc1C(OC)=O)=O)=O Chemical compound CCOC(COc(cc1)ccc1N(CC=C(C)C)C(Nc(nc1)ccc1C(OC)=O)=O)=O KKEVOFIGYGDCCO-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses the new aryl urea derivative of a class and method for making thereof and pharmaceutical composition and purposes.Specifically, relate to the aryl urea derivative shown in general formula I, its pharmacologically acceptable salt, and preparation method thereof, composition containing this compound one or more, is treating the disease relevant with glucokinase and peroxisome proliferation activated receptor-α as the purposes in diabetes, obesity etc. with this compounds.
Description
Invention field
The present invention relates to the aryl urea derivative shown in general formula I and II, its pharmacologically acceptable salt, the precursor of its same biological function or derivative, and preparation method thereof, composition containing this compound one or more, is treating the disease relevant with glucokinase and peroxisome proliferation activated receptor-α as the purposes in diabetes, obesity etc. with this compounds.
Background of invention
Sugar is the important energy of organism and carbon source.Sugar decomposition generate energy, can be used for the needs of organism vital movement, and glycometabolic intermediate product can be transformed into again other carbon compound, as amino acid, lipid acid, nucleosides etc.Carbohydrate metabolism can be divided into the decomposition of sugar and sugared synthesis two aspect.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 glucose degradation is become pyruvic acid and along with generating the process of ATP by enzyme.It is the energy-producing common metabolic approach of breakdown of glucose in animal, plant, microorganism cells.In oxygen consumption organism, the pyruvic acid that glycolysis generates enters plastosome, is become C0 through tricarboxylic acid cycle by exhaustive oxidation
2and water; The NADH that glycolysis generates produces ATP and water through respiratory chain oxidation.So glycolysis is the prelude of oxidative phosphorylation and tricarboxylic acid cycle.Glucokinase (GK) is one of the four kinds of hexokinase found with it Mammals [Cofowick, S.P.TheEnzymes, Vo1.9 (P.Boyer ' ed.) AcademicPress, NewYork, N bifurcation .1-48 page, 1973], first key enzyme in glycolytic pathway, glucose phosphorylation under ATP existent condition, can be become G6P by it, enters 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 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 plays key player in control blood glucose balance and metabolism, on the one hand regulates glycogen metabolism, when on an empty stomach or blood sugar is low time, GK hypoactivity, glycogen exports to be increased, to ensure the energy supply of vitals; After the meal or blood sugar height time, GK increased activity, thus promote liver starch synthesis, suppresses liver glyconeogenesis, to maintain glycaemic homeostasis.On the other hand as the secretion of the susceptor regulation and control Regular Insulin of glucose.When blood sugar concentration in body is higher than normal value, the glucose in blood is transported by glucose transporter 2 (GLUT2) and is entered beta Cell of islet, and under GK effect, phosphorylation generates G6P.The glycolysis of glucose, oxidative metabolism make ATP/ADP ratio increase, K+ ionic channel is closed, membrane depolarization, voltage susceptibility Ca2+ channel opener, stream in Ca2+, Regular Insulin stores vesica and plasma membrane fusion, makes insulin releasing enter blood, and enters with blood circulation the adjustment that liver, fat and muscle cell participate in blood sugar.Glucose in liver phosphoric acid under the effect of GK turns to-6 glucose 1-phosphate1-s, then under insulin action, synthesizes liver starch.At fat and muscle cell, Regular Insulin triggers glucose transporter 4 (GLUT4) in cell, stores picked-up and the metabolism that vesica migrates to plasma membrane promotion glucose.GK reduces blood sugar by regulating insulin releasing and glycogen metabolism double action mechanism, and play a significant role [A1-HasaniH in maintenance glycaemic homeostasis process; TschoplMH.MolInterv, 2003,3 (7), 367-370].[Chipkin, S.R., Kelly, K.L. and Ruderrnam, N.B. sees Joslin ' Diabetes (C.R.Khan and G.C.Wier volume), Lea and Febiger, Philadelphia, PA, 97-115 page, 1994].
Young type early onset diabetes (MODY) is caused by afunction after GK transgenation, shows that GK also plays glucose sensor Liang in human body, Y, Kesavan, P., the people such as Wang, L, Biochem.J.309,167-173,1995).Except MODY, also ubiquity GK activity decrease in general diabetic individual.Study discovery further to the pathogenesis of diabetes B, liver GK activity reduces may participate in insulin resistant mechanism, causes blood sugar increasing, and islet function is impaired to be increased the weight of with insulin resistant.So searching can increase the medicine of GK activity to stop or to delay advancing of disease, likely for early prevention and treatment diabetes open up a new way.
Recognize in recent years: pancreatic beta type glucokinase is confined to brain, the wherein particularly middle expression of feeding center (ventromedial nucleus of hypothalamus, VMH) of rat.The neurocyte of the about twenty percent in VMH is referred to as glucose response neurone (glucose-responsiveneutrons), is considered to play a significant role in control volume double recipe face in the past.In the brain of rat, give glucose, then food ration reduces, and if analogue one glycosamine giving glucose in brain to suppress glucose metabolism, then there is many foods.Electrophysiology experiment shows: glucose response neurone changes (5-20mM) and activated accordingly with physiological glucose concn, but suppresses glucose metabolism by glycosamine etc., then its activity is suppressed.Can estimate the glucose concn sensory perceptual system of VHM same with the insulin secretion of pancreatic beta cell is mechanism via glucokinase.Therefore, except liver, pancreatic beta cell, the material activating the glucokinase activity activity of VHM not only has the effect regulating blood sugar, also may regulate the obesity of a lot of diabetes B patient worries.From above-mentioned record, the compound with Glucokinase Activation effect can be used as curative and/or the prophylactic agent of diabetes, or the chronic complicating diseases of the diabetes such as retinopathy, ephrosis, neurosis, ischemic heart disease, arteriosclerosis treat and/or prevent medicine, can be used as further fat treating and/or preventing medicine.
It has been found that the agent of many GK activation of small molecules, there is different constitutional featuress: as the phenylacetamides (WO0058293WO0185706WO0208209WO0185707WO0183465WO0246173WO 2004072066WO0246173) replaced, the hydantoins (WO0183478) replaced, substituted azole class (WO2006112549), substituent indole (US0067939WO031179), the Propionamides (WO0248106) that isoindoline replaces, anthranilamide-based (WO03080585) that replace, the α phenylacryloyl amine (WO0214312) etc. replaced, wherein phenylacetamides is that many classes are done in research.Although above-mentioned GK activator research has made very large contribution to this area, for improving compound structure and GK activator activity, this area is still in continuation research.
Peroxisome proliferation activated receptor-α (PPARs) belongs to nuclear hormone receptor superfamily, has three kinds of hypotypes (PPAR α, PPAR γ, PPAR δ).Three kinds of acceptors exercise the function of lipid sensor, and the expression of coordinated regulation several genes sequence, regulates important organism metabolism.PPARs has multiple biological effect, Adipocyte Differentiation and steatogenesis can be promoted, enhancing body is to the susceptibility of Regular Insulin, and in mediation body, sugar balance, is the drug targets of effectively treating metabolic disease (as type ii diabetes and atherosclerosis).And the inflammation-inhibiting factor generates and inflammatory reaction, affects tumor growth, to cardiovascular generation protective effect.Research in recent years shows, PPARs also has neuroprotective, can alleviate the damage of neurocyte in the nerve degenerative diseases such as alzheimers disease, Parkinson's disease, cerebral ischemia and multiple sclerosis.
PPAR γ is different from classical nuclear receptor, after it is combined activation by sepcific ligands, still can not Direct Recognition in conjunction with special DNA regulating and controlling sequence, must by with vitamin A acid x acceptor (retinoidXreceptor, RXR) heterodimer is formed, under the effect of many auxiliary adjustment factors (cofactors), regulate special genetic transcription.Early stage research calls PPAR gamma agonist the PPAR γ part that activated gene is transcribed, and suppressor gene is transcribed is called inhibitor.Latest Progress shows, PPAR γ is combined the particular conformation formed with different ligands, determines the selective binding effect of PPAR γ mono-RXR heterodimer and special cofactor, determines further heterogeneic alternative transcription regulating effect.Just because of this structure and interactional selectivity, make different PPAR γ parts by 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, some suppression, therefore, increasing scholar uses the unilateral definition of " conditioning agent " replacement " agonist/inhibitor ", and then the known selectively acting of research is called " selective PPARγ modulator " (selectivePPAR γ modulator, SPPARM) in some PPAR γ part of specific gene transcriptional control.If any micromolecular compound activate PPAR γ, then from the interaction of different cofactor, Adipose Differentiation process and glycolipid metabolism process can be separated in gene regulating level, namely some promotes the PPAR gamma agonist not induced lipolysis differentiation of glycolipid metabolism.
At present mainly two problems is concentrated on to the research of PPAR gamma modulators: one is that we need PPAR γ part to have great Activation Activity, activate PPAR γ to reach appropriateness, regulate the object that target gene is transcribed; Does is two Adipose Differentiation can be separated with insulin-sensitizing effect in gene regulating level? align the molecular mechanism that compound under study for action or material answer its PPAR γ of further investigated to regulate, screening existing insulin-sensitizing effect does not affect again Adipose Differentiation and even promotes lipometabolic PPAR gamma modulators.
Because PPAR α/δ participates in regulating lipid metabolism, improve hyperlipidaemia, alleviate the Adipose Differentiation of PPAR γ activation-inducing to a certain extent; In tissue distribution, PPAR δ is also more extensive than PPAR α, in recent years the research of PPAR δ is also received publicity, many investigators are devoted to exploitation PPAR alpha/gamma double agonists or α/δ/γ tri-agonist, expect that this type of medicine can reach the hypoglycemic effect simultaneously playing adjusting blood lipid, immunotherapy targeted autoantibody 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 tri-agonist really can improve insulin resistant, improve hyperlipemia, but owing to still lacking drug safety and toxicity test foundation, the application prospect of this compounds need to observe.
Diabetes are a kind of whole body chronic metabolic disease, its pathological characters mainly hyperglycemia.It has been generally acknowledged that cause the main pathological change of hyperglycemia comprise the minimizing of insulin secretion, effect weaken with liver glycometabolic imbalance (also referred to as three large pathological changes).The activation energy of glucokinase (GK) promotes insulin secretion and glycogen metabolism simultaneously; The activation energy of peroxisome proliferation activated receptor-α (PPAR) increases body cell to the susceptibility of Regular Insulin.Therefore, for three large pathological changes of diabetes hyperglycemia, based on structure and the pharmacological action of known GK and PPAR small molecule agonist, build and the two target spot ligand compound of synthesis GK and PPAR, research and develop a kind of insulin secretion, glycogen metabolism and promotion peripheral tissues of can simultaneously improving to ' one medicine Mutiple Targets of the susceptibility of Regular Insulin ' medicine, the new way finding general effective treatment Glucovance will be become.
Summary of the invention
The invention provides a kind of aryl urea derivative of general structure I that not only can be used as glucokinase activators but also can be used as peroxisome proliferation activated receptor-α agonist:
The object of the present invention is to provide a kind of new aryl carbamide derivative with GK and PPAR double excitation activity, its pharmacologically acceptable salt, its solvate, its prodrug, its polycrystalline or eutectic.
Another object of the present invention is to provide a kind of method preparing new aryl carbamide derivative.
Another object of the present invention is to provide a kind of pharmaceutical composition containing one or more this compound.
Another object of the present invention is based on GK and PPAR biological function, proposes the new ideas of Mutiple Targets combinational drug therapy diabetes.
Another object more of the present invention is to provide the two ligand compound of GK and PPAR, and the purposes of this compounds in treatment with GK and PPAR diseases related medicine.
The present invention relates to the aryl urea derivative with following general formula I:
In formula
R1 elects C1-8 alkyl as, C2-8 alkoxyalkyl, C1-8 haloalkyl, C2-8 haloalkoxy alkyl, C3-8 alcoxyl alkoxyalkyl, C3-8 carbalkoxyl alkyl, C3-8 cycloalkyl, C3-8 cycloalkylalkyl, C3-8 cycloalkanes oxyalkyl, C3-8 Heterocyclylalkyl, C5-8 aralkyl, C5-8 heteroaralkyl, the allyl group that C1-8 alkyl replaces, C3-8 heterocycle alkoxyalkyl, C6-8 mixes n-alkyl aryl oxygen, C6-8 n-alkyl aryl oxygen, the allyl oxyalkyl that C1-8 alkyl replaces.Wherein cycloalkyl, heterocyclic radical, aryl, heteroaryl can have atom or group to replace.
R2 is selected from-C (0) NHCH
3,-C (NH) CH
3,-C (NH) NHCH
3,-C (S) NHCH
3the hetero-aromatic ring be connected with through ring carbon atom, it contains 5-6 annular atoms, wherein have 1-4 to be selected from nitrogen, the heteroatoms of sulphur or oxygen, and one of them nitrogen-atoms is positioned at the ortho position connecting carbon; Or it contains 9-10 annular atoms, form by condensing with the hetero-aromatic ring containing 5-6 annular atoms containing the aromatic ring of 6 annular atomses or hetero-aromatic ring, and have the individual heteroatoms being selected from nitrogen, oxygen or sulphur of 1-5 in ring, one of them nitrogen-atoms is positioned at the ortho position of connection carbon; Described aromatic ring or hetero-aromatic ring be without replace, monosubstituted or polysubstituted.As:
R′R″＝HCH
2OH，CH
2COOHCH
3CH
2CH
3FClCOOHSCH
2COOHSCH
2COOEt
OPhCOOHCH
2PhFCH
2PhCOOCH
3COOEtCOOi-PrCOOt-BuCH
2COOEt
R3 is selected from hydrogen, C1-6 straight or branched alkyl, metal ion.
R4 is selected from hydrogen, fluorine or chlorine, C1-6 straight or branched alkyl, part fluoro or chloro C1-6 alkyl, C1-6 alkylamino, nitro, cyano group.
In the preferred example of aryl urea derivative of general formula I:
R1 elects C2-6 alkyl as, C2-6 alkoxyalkyl, C1-6 haloalkyl, C2-6 haloalkoxy alkyl, C3-6 alcoxyl alkoxyalkyl, C3-6 carbalkoxyl alkyl, C3-6 cycloalkyl, C3-8 cycloalkylalkyl, C3-6 cycloalkanes oxyalkyl, C3-6 Heterocyclylalkyl, C5-8 aralkyl, C2-8 heteroaralkyl, the allyl group that C1-6 alkyl replaces, C3-6 heterocycle alkoxyalkyl, C2-8 mixes n-alkyl aryl oxygen, C6-8 n-alkyl aryl oxygen, the allyl oxyalkyl that C1-6 alkyl replaces.Wherein cycloalkyl, heterocyclic radical, aryl, heteroaryl can have atom or group to replace.
R2 is selected from-C (O) NHCH
3,-C (NH) CH
3,-C (NH) NHCH
3,-C (S) NHCH
3the hetero-aromatic ring be connected with through ring carbon atom, as:
R′R″＝HCH
2OH，CH
2COOHCH
3CH
2CH
3FClCOOHSCH
2COOHSCH
2COOEt
OPhCOOHCH
2PhFCH
2PhCOOCH
3COOEtCOOi-PrCOOt-BuCH
2COOEt
R3 is selected from hydrogen, C1-4 straight or branched alkyl, potassium or sodium or calcium ion.
R4 is selected from hydrogen, fluorine or chlorine, C1-4 straight or branched alkyl, part fluoro or chloro C1-4 alkyl, C1-4 alkylamino, nitro, cyano group.
In the preferred example of aryl urea derivative of general formula I:
R1 elects ethyl as, n-propyl, normal-butyl, n-pentyl, 3-methyl butyl, ethoxypropyl, methoxycarbonyl propyl, ethoxyethyl, methoxyethyl, methoxy (ethoxy) ethyl, isopropoxyethyl, tertiary fourth oxygen ethyl, 3-trifluoromethylpropyl, trifluoromethylphenoxy ethyl, two (trifluoromethyl) methoxy ethyl, ethoxyethoxy ethyl, ethoxycarbonyl ethyl, 3-Cyclopropylpropyl, 2-cyclopropylethyl, Cvclopropvlmethvl, cyclopropyl, 3-cyclopentylpropyi, 2-cyclopentyl ethyl, cyclopentyl-methyl, cyclopentyl, 3-Cyclohexylpropyl, 2-cyclohexyl-ethyl, cyclohexyl methyl, cyclohexyl, furans-2-methyl, thiophene-2-methyl, thiazole-2-methyl, pyridine-3-methyl, tetrahydrofuran (THF)-2-methyl, tetramethylene sulfide-2-methyl, thiazolidine-2-methyl, piperidines-3-methyl, ring third methoxyethyl, morpholine propyl group, piperidines propyl group, piperazinyl-propyl, halogen substiuted or without substituted benzene propyl group, pyrrole presses against propyl group, morpholine ethyl, piperidinoethyl, piperazine ethyl, halogen substiuted or without substituted benzene ethyl, pyrrole presses against ethyl, morpholine methyl, piperidine methyl, piperazine methyl, halogen substiuted or without substituted benzene methyl, pyrrole presses against methyl, allyl group, 3-methylene propyl group, 3, 3-dimethylallyl, 3-oxocyclopentyl methyl, cyclopentenes propyl group, piperidines methoxycarbonyl propyl, piperidines methoxyethyl, furans methoxyethyl, furans methoxycarbonyl propyl, piperazine ethoxyethyl, benzyloxyethyl, between fluorine benzyloxyethyl, pyridine-3-methoxyethyl, allyl oxygen ethyl, 3-methylene third oxygen ethyl, 3, 3-diformazan allyl oxygen ethyl.
R2 is selected from-C (O) NHCH
3,-C (NH) CH
3,-C (NH) NHCH
3,-C (S) NHCH
3the hetero-aromatic ring be connected with through ring carbon atom, as:
R3 is selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, potassium or sodium or calcium ion.
R4 is selected from hydrogen, fluorine or chlorine, methyl, ethyl, propyl group, a methyl fluoride or difluoromethyl, a chloromethyl or dichloro-methyl, methylamino-or dimethylamino, nitro, cyano group.
In the aryl urea derivative embodiment particularly preferably of general formula I:
R1 is selected from ethyl, n-propyl, normal-butyl, n-pentyl, 3-methyl butyl, ethoxypropyl, methoxycarbonyl propyl, ethoxyethyl, methoxyethyl, methoxy (ethoxy) ethyl, isopropoxyethyl, tertiary fourth oxygen ethyl, 3-trifluoromethylpropyl, trifluoromethylphenoxy ethyl, two (trifluoromethyl) methoxy ethyl, ethoxyethoxy ethyl, ethoxycarbonyl ethyl, 3-Cyclopropylpropyl, 2-cyclopropylethyl, Cvclopropvlmethvl, cyclopropyl, 3-cyclopentylpropyi, 2-cyclopentyl ethyl, cyclopentyl-methyl, cyclopentyl, 3-Cyclohexylpropyl, 2-cyclohexyl-ethyl, cyclohexyl methyl, cyclohexyl, furans-2-methyl, thiophene-2-methyl, thiazole-2-methyl, pyridine-3-methyl, tetrahydrofuran (THF)-2-methyl, tetramethylene sulfide-2-methyl, thiazolidine-2-methyl, piperidines-3-methyl, ring third methoxyethyl, morpholine propyl group, piperidines propyl group, piperazinyl-propyl, hydrocinnamyl or a fluorobenzene propyl group, pyrrole presses against propyl group, morpholine ethyl, piperidinoethyl, piperazine ethyl, fluorobenzene ethyl between styroyl, pyrrole presses against ethyl, morpholine methyl, piperidine methyl, piperazine methyl, benzyl between phenmethyl, pyrrole presses against methyl, allyl group, 3-methylene propyl group, 3, 3-dimethylallyl, 3-oxocyclopentyl methyl, cyclopentenes propyl group, piperidines methoxycarbonyl propyl, piperidines methoxyethyl, furans methoxyethyl, furans methoxycarbonyl propyl, piperazine ethoxyethyl, benzyloxyethyl, between fluorine benzyloxyethyl, pyridine-3-methoxyethyl, allyl oxygen ethyl, 3-methylene third oxygen ethyl, 3, 3-diformazan allyl oxygen ethyl.
R2 is selected from-C (O) NHCH
3,-C (NH) CH
3,-C (NH) NHCH
3,-C (S) NHCH
3the hetero-aromatic ring be connected with through ring carbon atom, as:
R3 is selected from hydrogen, methyl, ethyl, sec.-propyl, the tertiary butyl, potassium or sodium or calcium ion.
R4 is selected from hydrogen, fluorine or chlorine, methyl, methylamino-or dimethylamino, nitro, cyano group.
In the aryl urea derivative most preferred embodiment of general formula I:
R1 is selected from ethyl, n-propyl, normal-butyl, n-pentyl, 3-methyl butyl, ethoxypropyl, methoxycarbonyl propyl, ethoxyethyl, methoxyethyl, isopropoxyethyl, tertiary fourth oxygen ethyl, 3-trifluoromethylpropyl, two (trifluoromethyl) methoxy ethyl, ethoxyethoxy ethyl, ethoxycarbonyl ethyl, 3-Cyclopropylpropyl, 2-cyclopropylethyl, Cvclopropvlmethvl, cyclopropyl, 3-cyclopentylpropyi, 2-cyclopentyl ethyl, cyclopentyl-methyl, cyclopentyl, 3-Cyclohexylpropyl, 2-cyclohexyl-ethyl, cyclohexyl methyl, cyclohexyl, furans-2-methyl, thiophene-2-methyl, thiazole-2-methyl, pyridine-3-methyl, tetrahydrofuran (THF)-2-methyl, tetramethylene sulfide-2-methyl, thiazolidine-2-methyl, piperidines-3-methyl, ring third methoxyethyl, morpholine propyl group, piperidines propyl group, piperazinyl-propyl, hydrocinnamyl or a fluorobenzene propyl group, morpholine ethyl, piperidinoethyl, piperazine ethyl, styroyl, between fluorobenzene ethyl, pyrrole presses against ethyl, morpholine methyl, piperidine methyl, piperazine methyl, phenmethyl, between benzyl, pyrrole presses against methyl, allyl group, 3-methylene propyl group, 3, 3-dimethylallyl, 3-oxocyclopentyl methyl, cyclopentenes propyl group, piperidines methoxyethyl, furans methoxyethyl, piperazine ethoxyethyl, benzyloxyethyl, between fluorine benzyloxyethyl, pyridine-3-methoxyethyl, 3, 3-diformazan allyl oxygen ethyl.
R2 is selected from-C (O) NHCH
3,-C (NH) CH
3,-C (NH) NHCH
3,-C (S) NHCH
3the hetero-aromatic ring be connected with through ring carbon atom, as:
R3 is selected from hydrogen, methyl, ethyl, potassium or sodium or calcium ion.
R4 is selected from hydrogen, fluorine or chlorine, methyl, dimethylamino.
In order to prepare the compound described in 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 four steps.The preparation of the first step starting compound substituted aniline 1; Second step is the preparation of intermediate 2; 3rd step is the preparation of compound 3; It is finally the preparation of compound 4.
The first step: be basic raw material with P-aminophenol derivatives, reacts with α halogenated acid (ester) under alkaline condition and generates ether compound 1; Or with p-nitrophenyl amphyl for basic raw material, react with α halogenated acid (ester) under first alkaline condition, the nitro that then reduces generates ether compound 1; Or be dehydrated into ether compound 1 between αhydroxycarboxylicacid's ester and p-aminophenol or p-NP derivative molecular.
Second step: with anils 1 for raw material, reacts with haloalkane under alkaline environment and generates secondary amine compound 2.
Or anils 1 first reacts with aldehydes or ketones, then reduction generates secondary amine compound 2.
3rd step: a kind of mode is secondary amine compound 2 and primary amine R
2nH
2the carbamide compounds 3 replaced is generated by CDI reaction.
Another kind of mode is primary amine R
2nH
2first be converted into isocyanic ester (as by phosgene or surpalite), and then react with secondary amine compound 2 carbamide compounds 3 generating and replace.
Another mode is by p-nitrophenyl oxygen base formyl chloride, primary amine R
2nH
2the carbamide compounds 3 generating and replace is reacted with secondary amine compound 2.
4th step: the hydrolysis of ester group in the carbamide compounds 3 replaced can be generated the carbamide compounds 4 containing carboxyl.
In addition, the starting raw material in above-mentioned reaction and intermediate easily obtain, and each step reaction according to the document reported or can be easy to synthesis to those skilled in the art by the ordinary method in organic synthesis.Compound described in general formula I can the form of solvate or non-solvent compound exist, and utilizes different solvents to carry out crystallization and may obtain different solvates.Pharmacy acceptable salt described in general formula I comprises different acid salt, as 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, citric acid, lactic acid.Pharmacy acceptable salt described in general formula I also comprises Different Alkali metal-salt (lithium, sodium, sylvite), alkaline earth salt (calcium, magnesium salts) and ammonium salt, with the salt that can provide physiologically acceptable cationic organic bases, as methylamine, dimethylamine, 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 ordinary method to prepare.In the preparation process of described compound of Formula I and solvate thereof and its salt, may there is polycrystalline or eutectic in different crystallization condition.
The invention still further relates to the pharmaceutical composition using the compounds of this invention as active ingredient.This pharmaceutical composition can be prepared according to method well known in the art.By pharmaceutically acceptable to the compounds of this invention and one or more solid or liquid excipient and/or assistant agent being combined, make any formulation being suitable for human or animal and using.The content of the compounds of this invention in its pharmaceutical composition is generally 0.1-95 % by weight.
The compounds of this invention or the pharmaceutical composition containing it can administrations in a unit, route of administration can be enteron aisle or non-bowel, as 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 made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
In order to the compounds of this invention is made tablet, various vehicle well known in the art can be widely used, comprise 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, calcium 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, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet can also be made coating tablet further, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
In order to administration unit is made capsule, effective constituent the compounds of this invention can be mixed with thinner, glidant, mixture is directly placed in hard capsule or soft capsule.Also effective constituent the compounds of this invention first particle or micropill be can be made with thinner, tamanori, disintegrating agent, then hard capsule or soft capsule are placed in.Also the capsule preparing the compounds of this invention is can be used for for the preparation of each thinner of the compounds of this invention tablet, tamanori, wetting agent, disintegrating agent, glidant kind.
For the compounds of this invention is made injection, can with water, ethanol, Virahol, propylene glycol or their mixture as solvent and add the conventional solubilizing agent in appropriate this area, solubility promoter, pH adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, 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 prepared lyophilized injectable powder, N.F,USP MANNITOL, glucose etc. also can be added as propping agent.
In addition, as needs, also tinting material, sanitas, spices, correctives or other additive can be added in pharmaceutical preparation.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can with any known medication administrations.
The dosage of the compounds of this invention pharmaceutical composition is according to preventing or the character of disease therapy and severity, and the individual instances of patient or animal, route of administration and formulation etc. can have large-scale change.In general, the Suitable dosage ranges of the every day of the compounds of this invention is 0.001-150mg/Kg body weight, is preferably 0.01-100mg/Kg body weight.Above-mentioned dosage can a dose unit or be divided into several dosage unit administration, and this depends on the clinical experience of doctor and comprises the dosage regimen using other treatment means.
Compound of the present invention or composition can be taken separately, or merge with other treatment medicine or symptomatic drugs and use.When compound of the present invention and other medicine exist act synergistically time, its dosage should be adjusted according to practical situation.
The compounds of this invention is the dual activator of GK and PPAR or its precursor, by regulating insulin releasing, organize the susceptibility to Regular Insulin and glycogen metabolism multiple action mechanism reduction blood sugar, can be used for prevention and therapy 1 type or 2 types especially diabetes B and relevant complication, or the Other diseases relevant with GK and PPAR.
Embodiment
Below with reference to embodiment, invention is described further, but does not limit the scope of the invention.
Determining instrument: NMR (Nuclear Magnetic Resonance) spectrum VaariaanMercury300 type nuclear magnetic resonance analyser.Mass spectrum ZAD-2F and VG300 mass spectrograph.
Embodiment 1:2-{4-[1-n-pentyl-3-(pyridine-2-base) urea groups] phenoxy group } ethyl acetate
2-(4-nitrophenoxy) Synthesis Diethyl ether:
4-nitrophenols (200mg, 1.4mmol) is dissolved in 40mlDMF, adds Anhydrous potassium carbonate (198.7mg, 1.4mmol), 2-ethyl bromoacetate (0.133ml, 1.2mmol) is added under stirring, heat 80 DEG C of reactions, TLC monitors, and after 8 hours, raw material disappears, evaporated under reduced pressure DMF, adds 50mlEA, washing, saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, solvent evaporated obtains faint yellow solid 240mg, yield 89%.
The synthesis of 2-(4-amino-benzene oxygen) ethyl acetate:
2-(4-nitrophenoxy) ethyl acetate 446mg is dissolved in methyl alcohol (15ml), adds Pd/C in right amount, normal temperature and pressure catalysis hydrogenation, after 5h, TLC detection reaction is complete, filters, and uses methyl alcohol repetitive scrubbing, concentrating under reduced pressure obtains brown solid 433mg, yield 97%.
The synthesis of 2-(4-n-amylamine phenoxyl) ethyl acetate:
By 2-(4-amino-benzene oxygen) ethyl acetate (850mg, 3.8mmol) be dissolved in dry DMF (20ml), Anhydrous potassium carbonate (263mg is added under stirring, 1.9mmol), then bromo pentane (576mg is added, 3.8mmol), stirring reaction at 80 DEG C, TLC detection disappears to raw material, evaporate to dryness DMF after stopped reaction, add ethyl acetate (30ml), use water and saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrated, column chromatography (moving phase PE: EA=20: 1), obtains pale yellow oil 900mg, yield 66%.
2-{4-[1-n-pentyl-3-(pyridine-2-base) urea groups] phenoxy group } synthesis of ethyl acetate:
Room temperature, by CDI (535mg, 3.3mmol), be dissolved in dry methylene chloride (8ml), under stirring, add PA (282mg, 3mmol), then catalytic amount DMAP is added, after reflux 3h, TLC detection reaction is complete, and ice-water bath is cooled to 0 DEG C, drips 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, dichloromethane solution 1mmol), finish and rise to room temperature reaction gradually, TLC detection reaction is complete, about 12h.Stopped reaction, adds methylene dichloride (50ml), fully stirs, and then uses water and saturated common salt water washing successively, anhydrous sodium sulfate drying.Concentrated, column chromatography (moving phase PE: EA=4: 1), obtains colorless viscous thing 379mg, yield 98.4%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：8.07(m，1H，ArH)，7.94(d，1H，ArH)，7.64-7.73(m，1H，ArH)，7.32(d，2H，ArH)，7.05(m，2H，ArH)，7.06(s，1H，-CONH-)6.93-6.97(m，1H，ArH)，4.84(s，2H，-COCH
2-)，4.19(t，2H，-CH
2-)，3.60(t，2H，-CH
2-)，1.40-1.45(m，2H，-CH
2)，1.21-1.40(m，4H，-CH
2×2)，1.19-1.32(m，3H，-CH
3)，0.83(t，3H，-CH
3).
MS(FAB)：386(M+1)
Embodiment 2:2-{4-[1-n-pentyl-3-(pyridine-2-base) urea groups] phenoxy group } acetic acid
By 2-{4-[1-n-pentyl-3-(pyridine-2-base) urea groups] phenoxy group } ethyl acetate (343mg, 0.89mmol), be dissolved in methyl alcohol (20ml), salt of wormwood (245mg is dripped under stirring, 1.78mmol) and the solution of water (4ml), reflux is complete to TLC detection reaction, add water (8ml) stopped reaction, remove methanol solvate under reduced pressure, adjust about pH=5 with 1N hydrochloric acid under ice-water bath, occur white casse, extraction into ethyl acetate, use water and saturated common salt water washing successively, anhydrous sodium sulfate drying.Concentrated, Diethyl ether recrystallization obtains white solid 270mg, yield 93%.
1HNMR(DMSO-d6，300MHz)，δ(ppm)：8.07(m，1H，ArH)，7.94(d，1H，ArH)，7.67-7.72(m，1H，ArH)，7.29(d，2H，ArH)，6.98(s，1H，-CONH-)，6.92-7.02(m，3H，ArH)，4.57(s，2H，-COCH
2-)，3.59(t，2H，-CH
2-)，1.43(m，2H，-CH
2)，1.23-1.25(m，4H，-CH
2×2)，0.83(t，3H，-CH
3).
MS(FAB)：358(M+1).
Embodiment 3:2-{4-[1-n-pentyl-3-(thiazol-2-yl) urea groups] phenoxy group } ethyl acetate
Operation is with embodiment 1, difference is to feed intake into CDI (535mg, 3.3mmol), and solvent is 1,2-ethylene dichloride (15ml), thiazolamine (300mg, 3mmol), DMAP catalytic amount, 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, 1mmol), obtain faint yellow solid 367mg, yield 86%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：9.81(s，1H，CONH-)，7.25(d，1H，ArH)，7.20(d，2H，ArH)，7.95-7.98(m，3H，ArH)，4.80(s，2H，-COCH
2-)，4.18(q，2H，-CH
2-)，3.62(t，2H，-CH
2-)，1.40-1.45(m，2H，-CH
2)，1.20-1.24(m，7H，-CH
2×2，-CH
3)，0.83(t，3H，-CH
3).
MS(FAB)：392(M+1).
Embodiment 4:2-{4-[1-n-pentyl-3-(thiazol-2-yl) urea groups] phenoxy group } acetic acid
Operation is with embodiment 2, difference is to feed intake as 2-{4-[1-n-pentyl-3-(thiazol-2-yl) urea groups] phenoxy group } ethyl acetate (505mg, 1.29mmol), methyl alcohol (15ml), water (3ml), salt of wormwood (356mg, 2.58mmol), 50 DEG C of reaction 3h, aftertreatment Diethyl ether recrystallization obtains white solid 416mg, yield 88.7%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：7.25(d，1H，ArH)，7.20(d，2H，ArH)，6.94-6.98(m，3H，ArH)，4.70(s，2H，-COCH
2-)，3.62(t，2H，-CH
2-)，1.42(m，2H，-CH
2)，1.21-1.24(m，4H，-CH
2×2)，0.82(t，3H，-CH
3).
MS(FAB)：364(M+1).
Embodiment 5:2-{4-[1-n-pentyl-3-(5-chlorine thiazol-2-yl) urea groups] phenoxy group } ethyl acetate
Operation is with embodiment 1, difference is to feed intake into CDI (535mg, 3.3mmol), and solvent is 1,2-ethylene dichloride (15ml), 2-amino-5-diuril azoles (404mg, 3mmol), DMAP catalytic amount, 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, 1mmol), obtain faint yellow solid 373mg, yield 87.6%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：10.34(s，1H，CONH-)，7.40(s，1H，ArH)，7.20(d，2H，ArH)，6.81(d，2H，ArH)，4.80(s，2H，-COCH
2-)，4.17(q，2H，-CH
2-)，3.60(t，2H，-CH
2-)，1.40-1.50(m，2H，-CH
2)，1.24-1.33(m，7H，-CH
2×2，-CH
3)，0.80-0.84(t，3H，-CH
3)
MS(FAB)：427(M+1).
Embodiment 6:2-{4-[1-n-pentyl-3-(5-chlorine thiazol-2-yl) urea groups] phenoxy group } acetic acid
Operation is with embodiment 2, difference is to feed intake as 2-{4-[1-n-pentyl-3-(5-chlorine thiazol-2-yl) urea groups] phenoxy group } ethyl acetate (549mg, 1.29mmol), methyl alcohol (15ml), water (3ml), salt of wormwood (356mg, 2.58mmol), 50 DEG C of reaction 3h, aftertreatment Diethyl ether recrystallization obtains white solid 465mg, yield 90.6%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：10.35(s，1H，CONH-)，7.32(s，1H，ArH)，7.20(d，2H，ArH)，6.94(d，2H，ArH)，4.69(s，2H，-COCH
2-)，3.60(t，2H，-CH
2-)，1.42(m，2H，-CH
2)，1.24-1.23(m，4H，-CH
2×2)，0.80-0.84(t，3H，-CH
3).
MS(FAB)：399(M+1).
Embodiment 7:2-{4-[1-n-pentyl-3-(4-ethoxy acetyl thiazol-2-yl) urea groups] phenoxy group } ethyl acetate
Operation is with embodiment 1, and difference is to feed intake into CDI (535mg, 3.3mmol), solvent is 1,2-ethylene dichloride (15ml), 2-amino-1,3-thiazoles-4-ethyl formate (516mg, 3mmol), DMAP catalytic amount, 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, 1mmol), obtain faint yellow solid 371mg, yield 80.0%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：10.54(s，1H，CONH-)，7.85(s，1H，ArH)，7.20(d，2H，ArH)，6.97(d，2H，ArH)，4.80(s，2H，-COCH
2-)，4.14-4.26(m，4H，-CH
2×2)，3.61(t，2H，-CH
2-)，1.42(m，2H，-CH
2)，1.14-1.30(m，10H，-CH
2×2，-CH
3×2)，0.80-0.84(t，3H，-CH
3).
MS(FAB)：464(M+1).
Embodiment 8:2-{4-[1-n-pentyl-3-(4-carboxyl thiazol-2-yl) urea groups] phenoxy group } acetic acid
Operation is with embodiment 2; difference is to feed intake as 2-{4-[1-n-pentyl-3-(4-ethoxy acetyl thiazol-2-yl) urea groups] phenoxy group } ethyl acetate (598mg; 1.29mmol); methyl alcohol (15ml), water (3ml), salt of wormwood (712mg; 5.16mmol); 50 DEG C of reaction 6h, aftertreatment Diethyl ether recrystallization obtains white solid 476mg, yield 90.5%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：12.84(s，2H，-COOH×2)，10.38(s，1H，CONH-)，7.82(s，1H，ArH)，7.20(d，2H，ArH)，6.95(d，2H，ArH)，4.69(s，2H，-COCH
2-)，3.63(t，2H，-CH
2-)，1.43(m，2H，-CH
2)，1.14-1.28(m，4H，-CH
2×2)，0.80-0.84(t，3H，-CH
3).
MS(FAB)：408(M+1).
Embodiment 9:2-{4-[1-n-pentyl-3-(4-methylthiazol-2-base) urea groups] phenoxy group } ethyl acetate
Operation is with embodiment 1, difference is to feed intake into CDI (535mg, 3.3mmol), solvent is ethylene dichloride (15ml), 2-amino-4-methylthiazol (343mg, 3mmol), DMAP catalytic amount, 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, 1mmol), obtain faint yellow solid 361mg, yield 89%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：9.63(s，1H，CONH-)，7.18(d，2H，ArH)，6.95(d，2H，ArH)，6.48(s，1H，ArH)，4.79(s，2H，-COCH
2-)，4.17(q，2H，-CH
2-)，3.61(t，2H，-CH
2-)，2.12(s，3H，-CH
3)，1.40-1.50(m，2H，-CH
2)，1.24-1.14(m，7H，-CH
2×2，-CH
3)，0.80-0.84(t，3H，-CH
3).
MS(FAB)：406(M+1).
Embodiment 10:2-{4-[1-n-pentyl-3-(4-methylthiazol-2-base) urea groups] phenoxy group } acetic acid
Operation is with embodiment 2, difference is to feed intake as 2-{4-[1-n-pentyl-3-(4-methylthiazol-2-base) urea groups] phenoxy group } ethyl acetate (523mg, 1.29mmol), methyl alcohol (15ml), water (3ml), salt of wormwood (356mg, 2.58mmol), 50 DEG C of reaction 3h, aftertreatment Diethyl ether recrystallization obtains white solid 463mg, yield 95%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：7.18(d，2H，ArH)，6.93(d，2H，ArH)，6.48(s，1H，ArH)，4.69(s，2H，-COCH
2-)，3.60(t，2H，-CH
2-)，2.12(s，3H，-CH
3)，1.42(m，2H，-CH
2)，1.23-1.21(m，4H，-CH
2×2)，0.82(t，3H，-CH
3).
MS(FAB)：378(M+1).
Embodiment 11:2-{4-[1-n-pentyl-3-(3-methoxy methyl acyl pyridine-6-base) urea groups] phenoxy group } ethyl acetate
Operation is with embodiment 1, difference is to feed intake into CDI (535mg, 3.3mmol), solvent is ethylene dichloride (15ml), 6-amino-acidum nicotinicum methyl esters (456mg, 3mmol), DMAP catalytic amount, 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, 1mmol), obtain faint yellow solid 388.5mg, yield 87.6%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：8.63(d，1H，ArH)，8.18-8.22(dd，1H，ArH)，8.06(d，1H，ArH)，7.60(s，1H，-CONH-)，7.32(d，2H，ArH)，7.05(d，2H，ArH)，4.84(s，2H，-COCH
2-)，4.14-4.21(q，2H，-CH
2-)，3.81(s，3H，-OCH
3)，3.62(t，2H，-CH
2-)，1.41-1.46(m，2H，-CH
2)，1.14-1.26(m，7H，-CH
2×2，CH
3)，0.83(t，3H，-CH
3).
MS(FAB)：444(M+1).
Embodiment 12:2-{4-[1-n-pentyl-3-(3-pyridinecarboxylic acid-6-base) urea groups] phenoxy group } acetic acid
Operation is with embodiment 2; difference is to feed intake as 2-{4-[1-n-pentyl-3-(3-methoxy methyl acyl pyridine-6-base) urea groups] phenoxy group } ethyl acetate (572.1mg; 1.29mmol); methyl alcohol (15ml), water (3ml), salt of wormwood (712mg; 5.16mmol); 50 DEG C of reaction 6h, aftertreatment Diethyl ether recrystallization obtains white solid 472mg, yield 91.2%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：8.64(d，1H，ArH)，8.20(m，1H，ArH)，8.05(d，1H，ArH)，7.52(s，1H，-CONH-)，7.32(d，2H，ArH)，7.03(d，2H，ArH)，4.74(s，2H，-COCH
2-)，3.62(t，2H，-CH
2-)，1.44(m，2H，-CH
2)，1.24(m，4H，-CH
2×2)，0.83(t，3H，-CH
3).
MS(FAB)：402(M+1).
Embodiment 13:2-{4-[1-n-pentyl-3-(6-methoxybenzothiazole-2-base) urea groups] phenoxy group } ethyl acetate
Operation is with embodiment 1, difference is to feed intake into CDI (535mg, 3.3mmol), solvent is ethylene dichloride (15ml), 2-amino-6-methoxybenzothiazole (541mg, 3mmol), DMAP catalytic amount, 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, 1mmol), obtain pale yellow oil 398mg, yield 84.3%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：10.05(s，1H，CONH-)，7.43(s，1H，ArH)，7.33(m，1H，ArH)，7.21(d，2H，ArH)，6.90-6.98(m，3H，ArH)，4.80(s，2H，-COCH
2-)，4.15-4.22(q，2H，-CH
2-)，3.76(s，3H，-OCH
3)，3.65(t，2H，-CH
2-)，1.44(m，2H，-CH
2)，1.16-1.25(m，7H，-CH
2×2，CH
3)，0.83(t，3H，-CH
3).
MS(FAB)：472(M+1).
Embodiment 14:2-{4-[1-n-pentyl-3-(6-methoxybenzothiazole-2-base) urea groups] phenoxy group } acetic acid
Operation is with embodiment 2, difference is to feed intake as 2-{4-[1-n-pentyl-3-(6-methoxybenzothiazole-2-base) urea groups] phenoxy group } ethyl acetate (608mg, 1.29mmol), methyl alcohol (15ml), water (3ml), salt of wormwood (356mg, 2.58mmol), 50 DEG C of reaction 8h aftertreatment, Diethyl ether recrystallization obtains white solid 511mg, yield 89.3%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：7.42(s，1H，ArH)，7.34(m，1H，ArH)，7.21(d，2H，ArH)，6.90-6.96(m，3H，ArH)，4.70(s，2H，-COCH
2-)，3.76(s，3H，-OCH
3)，3.65(t，2H，-CH
2-)，1.44(m，2H，-CH
2)，1.24-1.25(m，4H，-CH
2×2)，0.83(t，3H，-CH
3).
MS(FAB)：444(M+1).
Embodiment 15:2-{4-[1-n-pentyl-3-(benzothiazole-2-base) urea groups] phenoxy group } ethyl acetate
Operation is with embodiment 1, difference is to feed intake into CDI (535mg, 3.3mmol), solvent is ethylene dichloride (15ml), 2-aminobenzothiazole (451mg, 3mmol), DMAP catalytic amount, 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, 1mmol), obtain pale yellow oil 349mg, yield 79%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：10.24(s，1H，CONH-)，7.78(d，1H，ArH)，7.39-7.29(m，2H，ArH)，7.22-7.15(m，3H，ArH)，6.96(d，2H，ArH)，4.80(s，2H，-COCH
2-)，4.15-4.22(q，2H，-CH
2)，3.66(t，2H，-CH
2-)，1.44(m，2H，-CH
2)，1.16-1.29(m，7H，-CH
2×2，CH
3)，0.83(t，3H，-CH
3).
MS(FAB)：442(M+1).
Embodiment 16:2-{4-[1-n-pentyl-3-(benzothiazole-2-base) urea groups] phenoxy group } acetic acid
Operation is with embodiment 2, difference is to feed intake as 2-{4-[1-n-pentyl-3-(benzothiazole-2-base) urea groups] phenoxy group } ethyl acetate (570mg, 1.29mmol), methyl alcohol (15ml), water (3ml), salt of wormwood (356mg, 2.58mmol), 50 DEG C of reaction 8h, aftertreatment Diethyl ether recrystallization obtains white solid 471mg, yield 88.3%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：7.78(d，1H，ArH)，7.39-7.29(m，2H，ArH)，7.22-7.15(m，3H，ArH)，6.96(d，2H，ArH)，4.80(s，2H，-COCH
2-)，4.15-4.20(q，2H，-CH
2-)，3.66(t，2H，-CH
2)，1.45(m，2H，-CH
2)，1.24-1.25(m，4H，-CH
2×2)，0.83(t，3H，-CH
3).
MS(FAB)：414(M+1).
Embodiment 17:2-{4-[1-n-pentyl-3-(6-methylbenzothiazole-2-base) urea groups] phenoxy group } ethyl acetate
Operation is with embodiment 1, difference is to feed intake into CDI (535mg, 3.3mmol), solvent is ethylene dichloride (15ml), 2-amino-6-methylbenzothiazole (493mg, 3mmol), DMAP catalytic amount, 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, 1mmol), obtain pale yellow oil 392mg, yield 86%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：10.08(s，1H，CONH-)，7.58(s，1H，ArH)，7.29(s，1H，ArH)，7.20(d，2H，ArH)，7.12(d，1H，ArH)，6.96(d，2H，ArH)，4.80(s，2H，-COCH
2-)，4.18(q，2H，-CH
2-)，3.65(t，2H，-CH
2-)，2.34(s，3H，-CH
3)，1.44(m，2H，-CH
2)，1.14-1.29(m，7H，-CH
2×2，CH
3)，0.83(t，3H，-CH
3).
MS(FAB)：456(M+1)
Embodiment 18:2-{4-[1-n-pentyl-3-(6-methylbenzothiazole-2-base) urea groups] phenoxy group } acetic acid
Operation is with embodiment 2, difference is to feed intake as 2-{4-[1-n-pentyl-3-(6-methylbenzothiazole-2-base) urea groups] phenoxy group } ethyl acetate (588mg, 1.29mmol), methyl alcohol (15ml), water (3ml), salt of wormwood (356mg, 2.58mmol), 50 DEG C of reaction 8h, aftertreatment Diethyl ether recrystallization obtains white solid 506mg, yield 91.7%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：7.58(s，1H，ArH)，7.27(s，1H，ArH)，7.20(d，2H，ArH)，7.12(d，1H，ArH)，6.94(d，2H，ArH)，4.70(s，2H，-COCH
2-)，3.65(t，2H，-CH
2-)，2.34(s，3H，-CH
3)，1.45(m，2H，-CH
2)，1.24-1.29(m，4H，-CH
2×2)，0.83(t，3H，-CH
3).
MS(FAB)：428(M+1).
Embodiment 19:2-{4-[1-n-pentyl-3-(5-chloropyridine-2-base) urea groups] phenoxy group } ethyl acetate
Operation is with embodiment 1, difference is to feed intake into CDI (535mg, 3.3mmol), solvent is ethylene dichloride (15ml), 2-amino-5-diuril azoles (386mg, 3mmol), DMAP catalytic amount, 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, 1mmol), obtain white oily solid 315mg, yield 75%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：8.18-8.22(dd，1H，ArH)，7.96(d，1H，ArH)，7.81(dd，1H，ArH)，7.29-7.32(m，3H，ArH，-CONH-)，7.04(d，2H，ArH)，4.83(s，2H，-COCH
2-)，4.18(q，2H，-CH
2-)，3.60(t，2H，-CH
2-)，1.40-1.44(m，2H，-CH
2)，1.25-1.18(m，7H，-CH
2×2，CH
3)，0.83(t，3H，-CH
3).
MS(FAB)：421(M+1).
Embodiment 20:2-{4-[1-n-pentyl-3-(5-chloropyridine-2-base) urea groups] phenoxy group } acetic acid
Operation is with embodiment 2, difference is to feed intake as 2-{4-[1-n-pentyl-3-(5-chloropyridine-2-base) urea groups] phenoxy group } ethyl acetate (541mg, 1.29mmol), methyl alcohol (15ml), water (3ml), salt of wormwood (356mg, 2.58mmol), 50 DEG C of reaction 8h, aftertreatment Diethyl ether recrystallization obtains white solid 485mg, yield 96%.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：13.05(s，1H，-OH)，8.13(d，1H，ArH)，7.97(d，1H，ArH)，7.82(dd，1H，ArH)，7.29-7.32(m，3H，ArH，-CONH-)，7.02(d，2H，ArH)，4.73(s，2H，-COCH
2-)，3.60(t，2H，-CH
2-)，1.43(m，2H，-CH
2)，1.24(m，4H，-CH
2×2)，0.83(t，3H，-CH
3).
MS(FAB)：393(M+1).
Embodiment 21:2-{4-[1-n-pentyl-3-(5-picoline-2-base) urea groups] phenoxy group } ethyl acetate
Operation is with embodiment 1, difference is to feed intake into CDI (535mg, 3.3mmol), solvent is methylene dichloride (15ml), 2-amino-5-methylthiazol (324mg, 3mmol), DMAP catalytic amount, 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, 1mmol), obtains white solid 265mg.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：7.90(m，1H，ArH)，7.84(d，1H，ArH)，7.52(dd，1H，ArH)，7.30(d，2H，ArH)，7.05(d，2H，ArH)，6.97(s，1H，-CONH-)，4.84(s，2H，-COCH
2-)，4.18(q，2H，-CH
2-)，3.60(t，2H，-CH
2-)，2.16(s，1H，-CH
3)，1.40-1.44(m，2H，-CH
2)，1.25-1.18(m，7H，-CH
2×2，CH
3)，0.82(t，3H，-CH
3).
MS(FAB)：400(M+1).
Embodiment 22:2-{4-[1-n-pentyl-3-(5-picoline-2-base) urea groups] phenoxy group } acetic acid
Operation is with embodiment 2, difference is to feed intake as 2-{4-[1-n-pentyl-3-(5-picoline-2-base) urea groups] phenoxy group } ethyl acetate (515mg, 1.29mmol), methyl alcohol (15ml), water (3ml), salt of wormwood (356mg, 2.58mmol), 50 DEG C of reaction 8h, aftertreatment Diethyl ether recrystallization obtains white solid 466mg.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：13.03(s，1H，-OH)，7.90(m，1H，ArH)，7.83(d，1H，ArH)，7.53(dd，1H，ArH)，7.30(d，2H，ArH)，7.01-7.04(m，3H，ArH，-CONH-)，4.73(s，2H，-COCH
2-)，3.59(t，2H，-CH
2-)，2.16(s，1H，-CH
3)，1.40-1.44(m，2H，-CH
2)，1.24(m，4H，-CH
2×2)，0.82(t，3H，-CH
3).
MS(FAB)：372(M+1).
Embodiment 23:2-{4-[1-n-pentyl-3-(5-isopropoxy formylpyridine-2-base) urea groups] phenoxy group } ethyl acetate
Operation is with embodiment 1, difference is to feed intake into CDI (535mg, 3.3mmol), solvent is methylene dichloride (15ml), PA-5-isopropyl formate (540mg, 3mmol), DMAP catalytic amount, 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, 1mmol), obtains faint yellow solid 368mg.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：8.60(d，1H，ArH)，8.16-8.20(dd，1H，ArH)，8.05(d，1H，ArH)，7.60(s，1H，-CONH-)，7.32(d，2H，ArH)，7.05(d，2H，ArH)，5.10(m，1H，CH)，4.84(s，2H，-COCH
2-)，4.14-4.21(q，2H，-CH
2-)，3.62(t，2H，-CH
2-)，1.44(m，2H，-CH
2)，1.14-1.26(m，13H，-CH
2×2，CH
3×3)，0.83(t，3H，-CH
3).
MS(FAB)：472(M+1).
Embodiment 24:2-{4-[1-n-pentyl-3-(5-nitrothiazole-2-base) urea groups] phenoxy group } ethyl acetate:
Operation is with embodiment 1, difference is to feed intake into CDI (535mg, 3.3mmol), solvent is methylene dichloride (15ml), 2-amino-5-nitrothiazole (435mg, 3mmol), DMAP catalytic amount, 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, 1mmol), obtains faint yellow oily body 377mg.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：11.60(s，1H，CONH-)，8.52(s，1H，ArH)，7.22(d，2H，ArH)，6.97(d，2H，ArH)，4.80(s，2H，-COCH
2-)，4.18(q，2H，-CH
2-)，3.64(t，2H，-CH
2-)，1.43(m，2H，-CH
2)，1.20-1.24(m，7H，-CH
2×2，-CH
3)，0.80-0.84(t，3H，-CH
3)
MS(FAB)：437(M+1).
Embodiment 25:2-{4-[1-n-pentyl-3-(5-nitrothiazole-2-base) urea groups] phenoxy group } acetic acid:
Operation is with embodiment 2, difference is to feed intake as 2-{4-[1-n-pentyl-3-(5-nitrothiazole-2-base) urea groups] phenoxy group } ethyl acetate (563mg, 1.29mmol), methyl alcohol (15ml), water (3ml), salt of wormwood (356mg, 2.58mmol), 50 DEG C of reaction 8h, aftertreatment Diethyl ether recrystallization obtains white solid 434mg.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：13.05(s，1H，-OH)，11.50(s，1H，CONH-)，8.52(s，1H，ArH)，7.21(d，2H，ArH)，6.95(d，2H，ArH)，4.70(s，2H，-COCH
2-)，3.64(t，2H，-CH
2)，1.44(m，2H，-CH
2)，1.23(m，4H，-CH
2×2)，0.82(t，3H，-CH
3)
MS(FAB)：409(M+1).
Embodiment 26:2-{4-[1-n-pentyl-3-(5-tert.-butoxy formylpyridine-2-base) urea groups] phenoxy group } ethyl acetate
Operation is with embodiment 1, difference is to feed intake into CDI (535mg, 3.3mmol), solvent is methylene dichloride (15ml), PA-5-t-butyl formate (583mg, 3mmol), DMAP catalytic amount, 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, 1mmol), obtains white solid 369mg.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：8.56(d，1H，ArH)，8.11-8.15(dd，1H，ArH)，8.03(d，1H，ArH)，7.55(s，1H，-CONH-)，7.32(d，2H，ArH)，7.05(d，2H，ArH)，5.10(m，1H，CH)，4.84(s，2H，-COCH
2-)，4.14-4.21(q，2H，-CH
2-)，3.62(t，2H，-CH
2-)，1.51(s，9H，-CH
3×3)，1.44(m，2H，-CH
2)，1.14-1.26(m，7H，-CH
2×2，CH
3)，0.83(t，3H，-CH
3).
MS(FAB)：486(M+1).
Embodiment 27:2-{4-[1-n-pentyl-3-(pyrazine-2-base) urea groups] phenoxy group } ethyl acetate
Operation is with embodiment 1, difference is to feed intake into CDI (535mg, 3.3mmol), solvent is methylene dichloride (15ml), 2-amino-pyrazino (285mg, 3mmol), DMAP catalytic amount, 2-(4-n-amylamine phenoxyl) ethyl acetate (265mg, 1mmol), obtains colorless oil 231mg.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：9.17(d，1H，ArH)，8.18-8.22(m，2H，ArH)，7.61(s，1H，-CONH-)，7.31(d，2H，ArH)，7.03(d，2H，ArH)，4.83(s，2H，-COCH
2-)，4.18(q，2H，-CH
2-)，3.62(t，2H，-CH
2-)，1.40-1.44(m，2H，-CH
2)，1.18-1.26(m，7H，-CH
2×2，CH
3)，0.83(t，3H，-CH
3).
MS(FAB)：387(M+1).
Embodiment 28:2-{4-[1-n-pentyl-3-(pyrazine-2-base) urea groups] phenoxy group } acetic acid
Operation is with embodiment 2, difference is to feed intake as 2-{4-[1-n-pentyl-3-(pyrazine-2-base) urea groups] phenoxy group } ethyl acetate (499mg, 1.29mmol), methyl alcohol (15ml), water (3ml), salt of wormwood (356mg, 2.58mmol), 50 DEG C of reaction 8h, aftertreatment Diethyl ether recrystallization obtains white solid 451mg.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：13.05(s，1H，-OH)，9.17(d，1H，ArH)，8.18-8.21(m，2H，ArH)，7.60(s，1H，-CONH-)，7.31(d，2H，ArH)，7.01(d，2H，ArH)，4.72(s，2H，-COCH
2-)，3.62(t，2H，-CH
2-)，1.44(m，2H，-CH
2)，1.24(m，4H，-CH
2×2)，0.83(t，3H，-CH
3).
MS(FAB)：359(M+1)
Embodiment 29:2-{4-[1-(3,3-dimethyl-allyl)-3-(5-methoxycarbonyl yl pyridines-2-base) urea groups] phenoxy group } ethyl acetate
2-(4-nitrophenoxy) Synthesis Diethyl ether.
4-nitrophenols (200mg, 1.4mmol) is dissolved in 40mlDMF, adds Anhydrous potassium carbonate (198.7mg, 1.4mmol), 2-ethyl bromoacetate (0.133ml, 1.2mmol) is added under stirring, heat 80 DEG C of reactions, TLC monitors, and after 8 hours, raw material disappears, evaporated under reduced pressure DMF, add 50mlFA, washing, saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, solvent evaporated obtains faint yellow solid 240mg.
The synthesis of 2-(4-amino-benzene oxygen) ethyl acetate:
2-(4-nitrophenoxy) ethyl acetate 446mg is dissolved in methyl alcohol (15ml), adds Pd/C in right amount, normal temperature and pressure catalysis hydrogenation, after 5h, TLC detection reaction is complete, filter, and use methyl alcohol repetitive scrubbing, concentrating under reduced pressure obtains brown solid 433mg.
The synthesis of 2-[4-(3,3-dimethallyl amido) phenoxy group] ethyl acetate:
Method is with embodiment 1, difference is: 2-(4-amino-benzene oxygen) ethyl acetate (850mg, 3.8mmol), DMF (20ml), Anhydrous potassium carbonate (263mg, 1.9mmol), add the bromo-3-methyl-2-butene of 1-(566mg, 3.8mmol), react 4 hours under room temperature, aftertreatment obtains faint yellow solid 401mg.
2-{4-[1-(3,3-dimethyl-allyl)-3-(5-methoxycarbonyl yl pyridines-2-base) urea groups] phenoxy group } synthesis of ethyl acetate:
Operation is with embodiment 1, difference is to feed intake into CDI (535mg, 3.3mmol), solvent is ethylene dichloride (15ml), PA-5-methyl-formiate (456mg, 3mmol), DMAP catalytic amount, 2-[4-(3,3-dimethallyl amido) phenoxy group] ethyl acetate (263mg, 1mmol), white solid 301.7mg is obtained.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：8.63(d，1H，ArH)，8.19-8.23(dd，1H，ArH)，8.06(d，1H，ArH)，7.64(s，1H，-CONH-)，7.28(d，2H，ArH)，7.03(d，2H，ArH)，5.22(t，1H，CH)，4.83(s，2H，-COCH
2-)，4.14-4.24(m，4H，-CH
2×2)，3.81(s，3H，-OCH
3)，1.63(s，3H，-CH
3)，1.44(s，3H，-CH
3)，1.20(t，3H，CH
3).
MS(FAB)：442(M+1)
Embodiment 30:2-{4-[1-(3,3-dimethyl-allyl)-3-(5-methoxycarbonyl yl pyridines-2-base) urea groups] phenoxy group } acetic acid
Operation is with embodiment 2; difference is to feed intake into 2-{4-[1-(3; 3-dimethyl-allyl)-3-(5-methoxycarbonyl yl pyridines-2-base) urea groups] phenoxy group } ethyl acetate (569.5mg; 1.29mmol), methyl alcohol (15ml), water (3ml); salt of wormwood (712mg; 5.16mmol), 50 DEG C of reaction 6h, aftertreatment Diethyl ether recrystallization obtains white solid 350mg.
1HNMR(DMSO-d
6，300MHz)，δ(ppm)：10.61(s，1H，-OH)，8.75(s，1H，-OH)，8.60(d，1H，ArH)，8.16-8.23(dd，1H，ArH)，8.04(d，1H，ArH)，7.55(s，1H，-CONH-)，7.28(d，2H，ArH)，7.00(d，2H，ArH)，5.22(t，1H，CH)，4.72(s，2H，-COCH
2-)，4.23(d，2H，-CH
2×2)，3.81(s，3H，-OCH
3)，1.63(s，3H，-CH
3)，1.45(s，3H，-CH
3).
MS(FAB)：400(M+1)
Pharmacologically active
External activity is evaluated:
To the activation of glucokinase
1. reaction principle:
2. reaction system composition:
Reaction system comprises 5mmol/lATP, 0.2U/mlG6PDH, 0.2mmol/lNADP, 5mmol/lMaCl
2, 1mmol/lDTT, 25mmol/lKCl, 100mmol/lTris-HCl, different 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 → add restructuring GK protein liquid → room temperature measuring 340nm absorbance, and be designated as initial value (0min)--→ 37 DEG C of incubations, every 10 minutes 340nm readings once to 60min → calculation result.
4. method of calculation:
Activate multiple=(OD
t-OD
0)
sample hose/ (OD
t-OD
0)
reaction tubes
Note: sample hose is add test-compound in system, reaction tubes is the reaction contrast not adding test-compound.Activate multiple > 1.5 and be considered as the positive.
Section Example Activity Results
To the activation of peroxisome proliferation activated receptor-α
1. principle:
Activate after PPAR γ and its ligand binding, insert in nucleus, form heterodimer with another nuclear receptor RXR, can specific recognition DNA sequence dna PPRE (PPARresponsiveelement), the latter regulates and controls the expression of series of genes.Set up the luciferase reporter gene of PPRE regulation and control, make the level that the expression level reaction PPAR of reporter gene activates.
2. method:
1) construction expresses PPAR γ, the plasmid vector of RXR, and the luciferase reporter plasmid carrier that the response element PPRE of PPAR γ, RXR regulates and controls.
2) by the method (Lipofectamine2000, invitrogen) of liposome transfection, cotransfection PPAR, RXR, PPRE-luciferase expression plasmid enters mammal cell line 293E cell.
3) 293E cell transfecting is after 24 hours, with trysinization, some parts are divided into after counting cells, mix with the substratum adding sample respectively, cultivate 24 hours in suitable culture plate, this step must set up negative control (adding DMSO), positive control (as Rosiglitazone), each sample sets up parallel group. and sample concentration can arrange some gradients as required, and such as 10
-9~ 10
-5m.
4) after dosing 24-48 hour, with the abundant lysing cell of cell pyrolysis liquid, collect each porocyte lysate in culture plate, add luciferase reaction substrate (LuciferaseAssaySystem, Promega), fluorescence reading is measured immediately with chemiluminescence detector.
3. compound PPAR screening active ingredients:
By the luciferase reporter gene method of above-mentioned foundation, the PPAR γ Activation Activity of comparative compound.The relative reactivity of calculating sifting compound: by the fluorescent value reading of compound compared with the fluorescent value reading of positive control rosiglitazone, if the activity of rosiglitazone is 100%, the activity of other compounds is expressed as relative reactivity, that is:
Relative reactivity=sample readout/positive control reading × 100% of SCREENED COMPOUND
Section Example Activity Results
Claims (12)
1. the aryl urea derivative as shown in general formula I, comprises its pharmacologically acceptable salt
In formula
R1 is C2-6 alkyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, C2-6 haloalkoxy alkyl;
R2 is selected from the hetero-aromatic ring connected through ring carbon atom:
R′R″＝HCH
2OH，CH
3CH
2CH
3FClCOOCH
3COOEtCOOi-PrCOOt-Bu
R3 is selected from hydrogen, C1-4 straight or branched alkyl, potassium or sodium or calcium ion;
R4 is selected from hydrogen, fluorine or chlorine, C1-4 straight or branched alkyl.
2. the aryl urea derivative as shown in general formula I, comprises its pharmacologically acceptable salt
Wherein, R1 is selected from ethyl, n-propyl, normal-butyl, n-pentyl, 3-methyl butyl, ethoxypropyl, methoxycarbonyl propyl, ethoxyethyl, methoxyethyl, isopropoxyethyl, tertiary fourth oxygen ethyl, 3-trifluoromethylpropyl, trifluoromethylphenoxy ethyl, two (trifluoromethyl) methoxy ethyl;
R2 is selected from the hetero-aromatic ring connected through ring carbon atom:
R3 is selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, potassium or sodium or calcium ion;
R4 is selected from hydrogen, fluorine or chlorine, methyl, ethyl, propyl group.
3. compound according to claim 2, is characterized in that:
R1 is ethyl, n-propyl, normal-butyl, n-pentyl, 3-methyl butyl, ethoxypropyl, methoxycarbonyl propyl, ethoxyethyl, methoxyethyl, isopropoxyethyl, tertiary fourth oxygen ethyl, 3-trifluoromethylpropyl, trifluoromethylphenoxy ethyl, two (trifluoromethyl) methoxy ethyl;
R2 is selected from the hetero-aromatic ring connected through ring carbon atom:
R3 is selected from hydrogen, methyl, ethyl, sec.-propyl, the tertiary butyl, potassium or sodium or calcium ion;
R4 is selected from hydrogen, fluorine or chlorine, methyl.
4. compound according to claim 3, is characterized in that:
R1 is ethyl, n-propyl, normal-butyl, n-pentyl, 3-methyl butyl, ethoxypropyl, methoxycarbonyl propyl, ethoxyethyl, methoxyethyl, isopropoxyethyl, tertiary fourth oxygen ethyl, 3-trifluoromethylpropyl, two (trifluoromethyl) methoxy ethyl;
R2 is selected from the hetero-aromatic ring connected through ring carbon atom:
R3 is selected from hydrogen, methyl, ethyl, potassium or sodium or calcium ion;
R4 is selected from hydrogen, fluorine or chlorine, methyl.
5. a class aryl urea derivative, it is characterized in that, described compound is selected from:
2-(4-(1-n-pentyl-3-(pyridine-2-base) urea groups) phenoxy group) ethyl acetate
2-(4-(1-n-pentyl-3-(pyridine-2-base) urea groups) phenoxy group) acetic acid
2-(4-(1-n-pentyl-3-(5-chloropyridine-2-base) urea groups) phenoxy group) ethyl acetate
2-(4-(1-n-pentyl-3-(5-chloropyridine-2-base) urea groups) phenoxy group) acetic acid
2-(4-(1-n-pentyl-3-(5-methoxycarbonyl pyridine-2-base) urea groups) phenoxy group) ethyl acetate
2-(4-(1-n-pentyl-3-(6-methoxybenzothiazole-2-base) urea groups) phenoxy group) ethyl acetate
2-(4-(1-n-pentyl-3-(6-methoxybenzothiazole-2-base) urea groups) phenoxy group) acetic acid
2-(4-(1-n-pentyl-3-(benzothiazole-2-base) urea groups) phenoxy group) ethyl acetate
2-(4-(1-n-pentyl-3-(benzothiazole-2-base) urea groups) phenoxy group) acetic acid
2-(4-(1-n-pentyl-3-(6-methylbenzothiazole-2-base) urea groups) phenoxy group) ethyl acetate
2-(4-(1-n-pentyl-3-(6-methylbenzothiazole-2-base) urea groups) phenoxy group) acetic acid
2-{4-[1-n-pentyl-3-(5-picoline-2-base) urea groups] phenoxy group } ethyl acetate
2-{4-[1-n-pentyl-3-(5-picoline-2-base) urea groups] phenoxy group } acetic acid
2-{4-[1-n-pentyl-3-(5-isopropoxy formylpyridine-2-base) urea groups] phenoxy group } ethyl acetate
2-{4-[1-n-pentyl-3-(5-tert.-butoxy formylpyridine-2-base) urea groups] phenoxy group } ethyl acetate
2-{4-[1-n-pentyl-3-(pyrazine-2-base) urea groups] phenoxy group } ethyl acetate
2-{4-[1-n-pentyl-3-(pyrazine-2-base) urea groups] phenoxy group } acetic acid
6. compound according to claim 1, is characterized in that, described medicinal salt refers to that compound and mineral acid, Organic Acid and Base metal ion, alkaline-earth metal ions maybe can provide physiologically acceptable cationic organic bases to be combined the salt and ammonium salt formed.
7. compound according to claim 6, 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, citric acid or lactic acid; Described alkalimetal ion is selected from lithium ion, sodium ion, potassium ion; Described alkaline-earth metal ions is selected from calcium ion, magnesium ion; The described physiologically acceptable cationic organic bases that can provide is selected from methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three (2-hydroxyethyl) amine.
8. prepare the method for compound described in any one of claim 1-5, comprise following method:
In order to prepare the compound described in general formula I, according to the structure of general formula I, preparation compound of Formula I will be divided into four steps; The preparation of the first step starting compound substituted aniline 1; Second step is the preparation of intermediate 2; 3rd step is the preparation of compound 3; It is finally the preparation of compound 4;
The first step: be basic raw material with P-aminophenol derivatives, reacts with α halogenated acid or ester under alkaline condition and generates ether compound 1; Or with p-nitrophenyl amphyl for basic raw material, react with α halogenated acid or ester under first alkaline condition, the nitro that then reduces generates ether compound 1; Or be dehydrated into ether compound 1 between αhydroxycarboxylicacid's ester and p-aminophenol or p-NP derivative molecular;
Second step: with anils 1 for raw material, reacts with haloalkane under alkaline environment and generates secondary amine compound 2,
Or anils 1 first reacts with aldehydes or ketones, then reduction generates secondary amine compound 2;
3rd step: a kind of mode is secondary amine compound 2 and primary amine R
2nH
2the carbamide compounds 3 replaced is generated by CDI reaction,
Another kind of mode is primary amine R
2nH
2first be converted into isocyanic ester, and then react with secondary amine compound 2 carbamide compounds 3 generating and replace;
Another mode is by p-nitrophenyl oxygen base formyl chloride, primary amine R
2nH
2the carbamide compounds 3 generating and replace is reacted with secondary amine compound 2;
4th step: the hydrolysis of ester group in the carbamide compounds 3 replaced can be generated the carbamide compounds 4 containing carboxyl,
R
1, R
2, R
3, R
4definition identical with any one of claim 1-5.
9. a pharmaceutical composition, comprises as carrier conventional on the compound described in any one of claim 1-7 of effective constituent or its pharmaceutically useful salt and pharmacopedics.
10. the salt of the compound described in any one of claim 1-7 or its pharmaceutically acceptable acid or alkali preparation prevention and or the application for the treatment of in the medicine of the disease relevant with glucokinase and peroxisome proliferation activated receptor-α.
11. application according to claim 10, is characterized in that the described disease relevant with glucokinase and peroxisome proliferation activated receptor-α is selected from diabetes, the chronic complicating diseases of diabetes and obesity.
12. application according to claim 11, is characterized in that described diabetes are selected from type 1 diabetes or diabetes B; The chronic complicating diseases of described diabetes is selected from retinopathy, ephrosis, neurosis, ischemic heart disease or arteriosclerosis.
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