CN100357281C

CN100357281C - Bicyclic compounds, process for their preparation and pharmaceutical composition containing them

Info

Publication number: CN100357281C
Application number: CNB988116618A
Authority: CN
Inventors: B·B·罗雷; V·B·罗雷; A·C·巴吉; S·卡尔萨; R·拉马努加; R·萨克拉巴提
Original assignee: Dr Reddys Research Foundation
Current assignee: Dr Reddys Research Foundation
Priority date: 1998-05-27
Filing date: 1998-10-26
Publication date: 2007-12-26
Anticipated expiration: 2018-10-26
Also published as: EP1082313A1; WO1999020614A1; PL341795A1; CN1281443A; NZ504106A; JP2002507543A

Abstract

The present invention relates to novel antiobesity and hypocholesterolemic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel .beta.-aryl-.alpha.-oxysubstituted alkylcarboxylic acids of general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.

Description

Dicyclic compound, its preparation method and comprise their pharmaceutical composition

Invention field

The present invention relates to the compound of new anti-obesity and reducing cholesterol blood, and derivative, its analogue, its tautomer, its steric isomer, its polymorphic form, its pharmacologically acceptable salt, its acceptable solvent thing and comprise their pharmaceutical composition.More particularly, the present invention relates to alkyl carboxylic acid, its derivative, its analogue, its tautomer, its steric isomer, its polymorphic form, its pharmacologically acceptable salt, its acceptable solvent thing that the beta-aromatic-α of new following general formula (I)-oxygen replaces and the pharmaceutical composition that comprises them.

The present invention also relates to a kind of method for preparing above-mentioned new compound, its derivative, its analogue, its tautomer, its steric isomer, its polymorphic form, its pharmacologically acceptable salt, its acceptable solvent thing, new intermediate and comprise their pharmaceutical composition.

But compound reducing total cholesterol of the present invention (TC); Increase high-density lipoprotein (HDL) (HDL) and reduce low-density lipoprotein (LDL), have useful effect for coronary heart disease and atherosclerosis.

The compound of general formula (I) can be used for losing weight, treating and/or preventing following disease: hypertension, coronary heart disease, atherosclerosis, apoplexy, peripheral vascular disease and relevant disease.These compounds can be used for treating familial hypercholesteremia, hypertriglyceridemia, reduce atherogenic lipoprotein, VLDL (vldl) and LDL.Compound of the present invention can be used for treating some ephrosis, comprising: glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy and ephrosis.The compound of general formula (I) can be used for also treating and/or preventing that insulin resistance (type ii diabetes), leptine (leptin) resistance, glucose tolerance reduce, hyperlipemia, the disease relevant with X syndrome is as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorder.These compounds also can be used as aldose reductase inhibitor, be used to improve dull-witted cognitive function, treatment diabetic complication, the disease relevant with activated endothelial cell, psoriasis, polycystic ovary syndrome (PCOS), inflammatory bowel disease, osteoporosis, myotonia atrophica, pancreatitis, arteriosclerosis, vitiligoidea and be used for the treatment of cancer.Compound of the present invention and one or more HMG CoA reductase inhibitors and/or reducing blood-fat medicament/reducing blood fat protein medicament such as fibril acid (fibric acid) derivative, nicotinic acid, QUESTRAN, cholestipol or probucol unite/are used for the treatment of jointly and/or prevent above-mentioned disease.

Background of invention

Atherosclerosis and other peripheral vascular disease are the major causes that influences hundreds of millions of Chinese people's quality of life.Thereby people are for the nosetiology of understanding hypercholesteremia and hyperlipemia and develop effective therapeutic strategy and given enough concerns.

Hypercholesteremia now has been defined as the value that cholesterol level in the blood plasma has surpassed any definition that is called " normally " level.In recent years, cholesterol " ideal " blood plasma level that can be hard to bear is higher than " the best " (or " ideal ") value far below " normally " level of cholesterol in general crowd along with cholesterol levels rises to, and the danger of suffering from coronary artery disease (CAD) also can strengthen.Between hypercholesteremia and CAD, exist clear and definite cause-effect relationship, particularly to having the individual all the more so of multiple Hazard Factor.Most cholesterol is to exist with the form with various lipoprotein esterifications, as low-density lipoprotein (LDL), intermediate density lipoprotein (IDL), high-density lipoprotein (HDL) (HDL) and part vldl (VLDL).Result of study clearly illustrates that, between CAD and atherosclerosis and serum hdl-cholesterol concentration, exist inverse relation (Stampfer etc., New England Journal of Medicine, 325(1991), 373-381), along with LDL and VLDL level increase, the danger of CAD also increases.

In CAD, can find usually in carotid artery, coronary artery and cerebral arteries " fat bar " that they mainly are the cholesterol of free and esterification.Miller etc. (BMJ, 282(1981), show 1741-1744) that the increase of HDL-particle can be reduced in the quantity in narrow site in the human body coronary artery, high-caliber HDL-cholesterol can prevent atherosclerotic generation.Picardo etc. (atherosclerosis, 6(1986) 434-441) confirmed that by experiment in vitro HDL can remove de-cholesterol from cell.They propose, HDL can reduce free cholesterol excessive in the tissue and they are transferred in the liver (Macikinnon etc., journal of biological chemistry, 261(1986), 2548-2552).Thereby the reagent that can increase the HDL cholesterol will have the treatment meaning to treatment hypercholesteremia and coronary heart disease (CHD).

Obesity is a kind of disease very common in affluent society and developing country, and it is morbidity and main causes of death.Obesity is the result of body fat excessive buildup.Fat reason is also unclear.It is believed that fat reason from heredity, or facilitate by the interaction between genotype and environment.With the origin cause of formation irrelevant be since energy intake pay with energy between imbalance cause fatty deposits.The fat part method of treatment be go on a diet, motion and depress appetite.Because obesity may cause coronary heart disease, diabetes, apoplexy, hyperlipemia, gout, osteoarthritis, Fertility to reduce and a lot of other psychology and social concern, therefore, need be to the effective treatment means of this disease.

Diabetes and insulin resistance are the diseases that another kind has a strong impact on most of in the world crowd's qualities of life.Insulin resistance is meant that Regular Insulin brings into play the ability of its biological action and reduce under wide range of concentrations.For insulin resistance, health is understood a large amount of Regular Insulin of abnormal secretion to compensate this defective; Plasma glucose concentration raises inevitably and causes diabetes if not like this.In developed country, diabetes are a kind of Universal Problems, itself and multiple relevant unusually (Journal of Clinical Investigation, (1985) 75:809-817 of comprising obesity, hypertension and hyperlipemia; New England Journal of Medicine (1987) 317:350-357; Secrete in clinical and learn and the metabolism magazine (1988) 66:580-583; Journal of Clinical Investigation, (1975) 68:957-969), and relevant with other kidney complication (referring to patent application WO 95/21608).At present, people recognize that day by day insulin resistance bears major responsibility with relevant hyperinsulinemia to obesity, hypertension, atherosclerosis and type ii diabetes.Insulin resistance is described to have the syndrome-X syndrome of insulin resistance as the pathogenic key (link) in center with obesity, hypertension and anginal cognation.

Hyperlipidemia is the major cause of cardiovascular disorder (CVD) and other peripheral vascular disease.The high risk of CVD is relevant with VLDL (vldl) with the high LDL (low-density lipoprotein) seen in the hyperlipemia.Also have the patient of glucose intolerance/insulin resistance except that hyperlipemia, the danger of CVD is higher.Studies show that in a large number in the past reduced triglyceride level and total cholesterol, particularly LDL and VLDL in the blood plasma, and increase HDL cholesterol will help to prevent cardiovascular disorder.

Peroxysome proliferant agent activated receptors (PPAR) is the member in the nuclear receptor superfamily.Found the differentiation (incretology of γ isoform (PPAR γ) the adjusting adipocyte of PPAR, 135:798-800) and the homeostasis (cell of energy (1994), (1995) 83:803-812), and the α isoform of PPAR (PPAR α) is regulated Fatty Acid Oxidation (Trend.Endocrin.Metab., (1993) 4:291-296), thus cause in the blood plasma free lipid acid round-robin to reduce (Current Biol. (1995) 5:618-621).Have found that the PPAR alfa agonists can be used for treatment fat (WO 97/36579).Also finding in recent years, be that the molecule of PPAR α and PPAR gamma agonist exists and acts synergistically simultaneously, and demonstrates and can be used for treating X syndrome (WO97/25042).Also observe similar synergy between insulin sensitiser thing (PPAR gamma agonist) and HMG CoA reductase inhibitor, it can be used for treating atherosclerosis and vitiligoidea (EP 0,753 298).

Known PPAR γ in the differentiation of adipocyte, play an important role (cell, (1996) 87,377-389).The part of PPAR activates will be enough to cause terminal completely the differentiation (cell, (1994) 79,1147-1156), comprise shrinking back of cell cycle.PPAR γ consistence in some cell is expressed, will stimulate the end differentiation of adipocyte precursor to the activation of this nuclear receptor with the PPAR gamma agonist, and cause more differentiation and still less morphology and molecule variation characteristic (Molecular Cell (1998), the 465-470 of malignant state; Carcinogenesis (Carcinogenesis), (1998), 1949-53; Institute of NAS newspaper, (1997) 94,237-241) with prostate cancer tissue expression inhibiting (cancer research (1998) 58:3344-3352).It will be used for treating the cancer of the expression PPAR γ of some type, and the chemotherapy of totally nontoxic can be provided.

The leptine resistance is a kind of disease that can not reply the leptine signal because of target cell.This will cause obesity owing to excessive ingestion of food and energy expenditure reduces, and cause that glucose tolerance reduces, type ii diabetes, complication that cardiovascular disorder is relevant with other.(institute of NAS newspaper (1996) 93 5793-5796) has been reported the insulin sensitizer that possibility is expressed owing to the PRAR agonist to Kallen etc., thereby can reduce the leptine concentration in the blood plasma.But, find that recently the compound with insulin sensitizing agent also has leptine sensitization activity.They can be replied the target cell of leptine by improvement and reduce circulating plasma leptine concentration (WO/98/02159).

According to reports, some-aryl-hydroxy-propionic acid and its derivative and analogue can be used to treat hyperglycemia and hypercholesteremia.Below this compounds of some of Miao Shuing is listed in the prior art:

I) U.S.5,306,726, WO 91/19702 described several 3-aryl-2-hydoxy-propionic acid derivatives, its general formula is (IIa) and (IIb), they can be used as reducing blood-fat and hypoglycemic medicament.

These examples for compounds be shown in following formula (IIc) and (IId) in

Ii) International Patent Application WO 95/03038 and WO 96/04260 have described the compound of general formula (IIe),

Wherein, R ^aRepresent 2-benzoxazol base or 2-pyridyl, R ^bRepresent CF ₃, CH ₂OCH ₃Or CH ₃

Its representative instance is (S)-3-[4-[2-[N-(2-benzoxazol base)-N-methylamino] oxyethyl group] phenyl]-2-(2,2, the 2-trifluoro ethoxy) propionic acid (IIf).

Iii) International Patent Application WO 94/13650, WO 94/01420 and WO 95/17394 have described the compound of general formula (IIg)

A ¹-X-(CH ₂) _n-O-A ²-A ³-Y.R ² (IIg)

A wherein ¹Represent aromatic heterocycle, A ²The phenyl ring that representative replaces, A ³Representative formula (CH ₂) _m-CH-(OR ¹), R wherein ¹Represent alkyl, m is an integer; The X representative replaces or unsubstituted N; Y represents C=O or C=S; R ²Represent OR ³, R wherein ³Can be alkyl, aralkyl or aryl; N represents the integer of 2-6.These examples for compounds are shown in following formula (IIh).

Summary of the invention

The compound that the objective of the invention is to develop new reducing cholesterol and reduce body weight, and has beneficial effect treating and/or preventing following disease method: increase diseases associated with lipid level, atherosclerosis, coronary heart disease, X-syndrome, glucose tolerance reduces, insulin resistance, the insulin resistance that causes type ii diabetes and diabetic complication, being used for the treatment of wherein, insulin resistance is the disease of physiopathology mechanism, be used for the treatment of hypertension, atherosclerosis and coronary artery disease, has better effect, render a service and hypotoxicity, we are devoted to study and develop the new compound of the above-mentioned disease of effective treatment.The compound that causes developing general formula (I) in the effort that this side up.

Thereby, main purpose of the present invention provide a kind of new-alkyl carboxylic acid, its derivative, its analogue, its tautomer, its steric isomer, its polymorphic form, its pharmacologically acceptable salt, its acceptable solvent thing that aryl-oxygen replaces and comprise them or the pharmaceutical composition of its mixture.

Alkyl carboxylic acid, its derivative, its analogue, its tautomer, its steric isomer, its polymorphic form, its pharmacologically acceptable salt, its acceptable solvent thing that another object of the present invention provides new-aryl-oxygen replaces and comprise them or the pharmaceutical composition of its mixture, described compound has agonist activity to PPAR α and/or PPAR γ, and randomly can also suppress HMG CoA reductase enzyme except that PPAR α and/or PPAR gamma excitomotor activity.

Alkyl carboxylic acid, its derivative, its analogue, its tautomer, its steric isomer, its polymorphic form, its pharmacologically acceptable salt, its acceptable solvent thing that another object of the present invention provides new-aryl-oxygen replaces and comprise them or have the pharmaceutical composition of its mixture of enhanced activity, nontoxicity or toxic action reduce.

Another object of the present invention is the preparation method of new general formula (I)-aryl-oxygen alkyl carboxylic acid, its derivative, its analogue, its tautomer, its steric isomer, its polymorphic form, its pharmacologically acceptable salt and the acceptable solvent thing thereof that replace.

Another object of the present invention provides pharmaceutical composition, and it comprises general formula (I) compound, its analogue, its derivative, its tautomer, its steric isomer, its polymorphic form, its salt, its solvate or its mixture and suitable carrier, solvent, thinner and other medium commonly used in this based composition of preparation.

Another object of the present invention provides new intermediate, its preparation method and this intermediate purposes in the production process of alkyl carboxylic acid, its derivative, its analogue, its tautomer, its steric isomer, its polymorphic form, English salt and the solvate thereof of beta-aromatic-α-oxygen replacement of general formula (I).

Detailed Description Of The Invention

The propionic acid that oxygen of the present invention replaces and its derivative and analogue have following general formula (I)

Radicals R wherein ¹, R ², R ³, R ⁴And the radicals R that links to each other with carbon atom ⁵And R ⁶Can be identical or different, represent hydrogen, halogen, hydroxyl, nitro, cyano group, formyl radical or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclic radical, heteroaryl, heteroaralkyl, heteroaryloxy, assorted aralkoxy, acyl group, acyloxy, hydroxyalkyl, amino, amido, alkylamino, arylamino, aryl alkyl amino, aminoalkyl group, carbalkoxy, aryloxy carbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxy alkyl, sweet-smelling alkoxy alkyl, alkylthio, alkylthio, alkoxycarbonyl amido, aryloxy carbonyl amino, aralkoxycarbonyl amino, carboxylic acid or derivatives thereof, or sulfonic acid or derivatives thereof; When they link to each other with carbon atom, R ⁵And R ⁶One of or both also can represent oxo group; When they link to each other with nitrogen-atoms, R ⁵And R ⁶Represent hydrogen, hydroxyl, formyl radical or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroaralkyl, acyl group, acyloxy, hydroxyalkyl, amino, amido, alkylamino, arylamino, aryl alkyl amino, aminoalkyl group, aryloxy, aralkoxy, heteroaryloxy, assorted aralkoxy, carbalkoxy, aryloxy carbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxy alkyl, sweet-smelling alkoxy alkyl, alkylthio, alkylthio, carboxylic acid derivative or sulfonic acid; The X representative is selected from oxygen, sulphur or NR ¹¹Heteroatoms, R wherein ¹¹Be selected from hydrogen or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, acyl group, carbalkoxy, aryloxy carbonyl or aralkoxycarbonyl; The Ar representative replaces or unsubstituted divalence list or fused aromatic group or heterocyclic group; R ⁷Represent hydrogen atom, hydroxyl, alkoxyl group, halogen, low alkyl group, replacement or unsubstituted aralkyl or with adjacent radicals R ⁸Form a key together; R ⁸Represent hydrogen, hydroxyl, alkoxyl group, halogen, low alkyl group, acyl group or replacement or unsubstituted aralkyl or R ⁸With R ⁷Form a key together; R ⁹Represent hydrogen or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, carbalkoxy, aryloxy carbonyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, acyl group, heterocyclic radical, heteroaryl or heteroaralkyl; R ¹⁰Represent hydrogen or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, heterocyclic radical, heteroaryl or heteroaralkyl; Y represents oxygen or NR ¹², R wherein ¹²Represent hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclic radical, heteroaryl or heteroaralkyl; R ¹⁰And R ¹²Can form the ring texture of 5 or 6 yuan of carbon atoms together, it randomly comprises one or more heteroatomss that are selected from oxygen, sulphur or nitrogen; By-(CH ₂) _n-(O) _mThe linking group of-expression can link to each other by nitrogen-atoms or carbon atom; N is that integer 1-4 and m are integer 0 or 1.

R ⁵And R ⁶One of or both also can represent oxo group.

When by R ¹-R ⁴The group and the R that links to each other with carbon atom of expression ⁵And R ⁶When group is substituted; substituting group can be selected from: halogen, hydroxyl or nitro, or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aralkoxy, aryl, aralkyl, sweet-smelling alkoxy alkyl, heterocyclic radical, heteroaryl, heteroaralkyl, acyl group, acyloxy, hydroxyalkyl, amino, amido, arylamino, aminoalkyl group, aryloxy, carbalkoxy, alkylamino, alkoxyalkyl, alkylthio, alkylthio, carboxylic acid or derivatives thereof or sulfonic acid or derivatives thereof.

Preferably at R ¹-R ⁶On substituting group be halogen atom, as fluorine, chlorine, bromine; Alkyl is as methyl, ethyl, sec.-propyl, n-propyl, normal-butyl; Cycloalkyl is as cyclopropyl; Aryl is as phenyl; Aralkyl is as benzyl; (C ₁-C ₃) alkoxyl group, benzyloxy, hydroxyl, acyl group or acyloxy.

The suitable R that links to each other with nitrogen-atoms ⁵And R ⁶Be selected from hydrogen, hydroxyl, formyl radical; Replace or unsubstituted (C ₁-C ₁₂) (the C of alkyl, particularly straight or branched ₁-C ₆) alkyl, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, hexyl etc.; Ring (C ₃-C ₆) alkyl, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.Cycloalkyl can be substituted; Ring (C ₃-C ₆) alkoxyl group, as ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc., cycloalkyloxy can be substituted; Aryl, as phenyl, naphthyl etc., aryl can be substituted; Aralkyl is as benzyl or styroyl, C ₆H ₅CH ₂CH ₂CH ₂, naphthyl methyl etc., aralkyl can be substituted; , the aralkyl of replacement for example is CH ₃C ₆H ₄CH ₂, Hal-C ₆H ₄CH ₂, CH ₃OC ₆H ₄CH ₂, CH ₃OC ₆H ₄CH ₂CH ₂Deng; Heteroaryl, as pyridyl, thienyl, furyl, pyrryl,  azoles base, thiazolyl, imidazolyl,  di azoly, tetrazyl, benzopyranyl, benzofuryl etc., heteroaryl can be substituted; Heterocyclic radical, as aziridinyl, pyrrolidyl, morpholinyl, piperidyl, piperazinyl etc., heterocyclic radical can be substituted; Aralkoxy, as benzyloxy, phenyl ethoxy, naphthyl methoxyl group, phenyl propoxy-etc., aralkoxy can be substituted; Heteroaralkyl, as furfuryl, picolyl,  azoles methyl,  azoles ethyl etc., heteroaralkyl can be substituted; Aryl alkyl amino is as C ₆H ₅CH ₂NH, C ₆H ₅CH ₂CH ₂NH, C ₆H ₅CH ₂NCH ₃Deng, it can be substituted; Carbalkoxy, as methoxycarbonyl, ethoxycarbonyl etc., it can be substituted; Aryloxy carbonyl is as replacing or unsubstituted carbobenzoxy, naphthalene oxygen carbonyl etc.; Aralkoxycarbonyl, as carbobenzoxy-(Cbz), benzene ethoxycarbonyl, naphthalene methoxycarbonyl etc., it can be substituted; (C ₁-C ₆) alkylamino, as NHCH ₃, N (CH ₃) ₂, NCH ₃(C ₂H ₅), NHC ₂H ₅, NHC ₃H ₇, NHC ₆H ₁₃Deng, it can be substituted; Alkoxyalkyl, as methoxymethyl, ethoxyl methyl, methoxy ethyl, ethoxyethyl group etc., it can be substituted; Aryloxy alkyl is as C ₆H ₅OCH ₂, C ₆H ₅OCH ₂CH ₂, naphthyloxy methyl etc., it can be substituted; Sweet-smelling alkoxy alkyl is as C ₆H ₅CH ₂OCH ₂, C ₆H ₅CH ₂OCH ₂CH ₂Deng, it can be substituted; Heteroaryloxy and assorted aralkoxy, wherein heteroaryl moieties such as preceding definition and can be substituted; Aryloxy, as phenoxy group, naphthyloxy etc., aryloxy can be substituted; Arylamino is as HNC ₆H ₅, NCH ₃(C ₆H ₅), NHC ₆H ₄CH ₃, NHC ₆H ₄-Hal etc., it can be substituted; Can substituted amino; Amino (C ₁-C ₆) alkyl, it can be substituted; Hydroxyl (C ₁-C ₆) alkyl, it can be substituted; (C ₁-C ₆) alkoxyl group, as methoxyl group, oxyethyl group, propoxy-, butoxy, isopropoxy etc., it can be substituted; Sulfo-(C ₁-C ₆) alkyl, it can be substituted; (C ₁-C ₆) alkylthio, it can be substituted; Acyl group, as ethanoyl, propionyl, benzoyl etc., acyl group can be substituted; Amido is as NHCOCH ₃, NHCOC ₂H ₅, NHCOC ₃H ₇, NHCOC ₆H ₅Deng, it can be substituted; Carboxylic acid derivative, as acid amides, CONH for example ₂, CONHMe, CONMe ₂, CONHEt, CONEt ₂, CONHPh etc., carboxylic acid derivative can be substituted; Acyloxy, as OOCMe, OOCEt, OOCPh etc., it can be substituted; Sulfonic acid is as SO ₂NH ₂, SO ₂NHMe, SO ₂NMe ₂, SO ₂NHCF ₃Deng, sulfonic acid can be substituted.

When by the R that links to each other with nitrogen ⁵And R ⁶When the group of expression was substituted, preferred substituted can be selected from halogen, as fluorine, chlorine; Hydroxyl, acyl group, acyloxy or amino.

Suitable X comprises oxygen, sulphur or as the group NR of preceding definition ¹¹, preferred oxygen and sulphur.Aptly, R ¹¹Represent hydrogen, (C ₁-C ₆) alkyl, (C ₃-C ₆) cycloalkyl, aryl such as phenyl or naphthyl, aralkyl such as benzyl or styroyl; Acyl group is as ethanoyl, propionyl, butyryl radicals, benzoyl etc.; (C ₁-C ₆) carbalkoxy; Aryloxy carbonyl is as carbobenzoxy, CH ₃OC ₆H ₄OCO, Hal-C ₆H ₄OCO, CH ₃C ₆H ₄OCO, naphthalene oxygen carbonyl etc.; Aralkoxycarbonyl is as carbobenzoxy-(Cbz), benzene ethoxycarbonyl etc.; By R ¹¹The group of expression can be substituted or not be substituted.When by R ¹¹When the group of expression was substituted, substituting group can be selected from halogen, halo or not halogenated low alkyl group, hydroxyl and halo or not halogenated (C ₁-C ₃) alkoxyl group.

Preferably the group of being represented by Ar is to replace or unsubstitutedly be selected from following group: divalence phenylene, naphthylidene, pyridyl, quinolyl, benzofuryl, dihydro benzo furyl, benzopyranyl, dihydrobenzopyrans base, indyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazol base etc.Substituting group on the group of being represented by Ar can be selected from the halo of straight or branched or not halogenated (C ₁-C ₆) alkyl, halo or not halogenated (C ₁-C ₃) alkoxyl group, halogen, acyl group, amino, amido, sulfenyl or carboxylic acid or sulfonic acid and its derivative.

More preferably, the Ar representative replaces or unsubstituted divalence phenylene, naphthylidene, benzofuryl, indyl, indolinyl, quinolyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazol base.

Further preferably, Ar represents divalence phenylene or benzofuryl, and it does not replace or by methyl, halogenated methyl, methoxyl group or halogenated methoxy.

Suitable R ⁷Comprise hydrogen, low alkyl group, as methyl, ethyl or propyl group; Hydroxyl, (C ₁-C ₃) alkoxyl group; Halogen atom is as fluorine, chlorine, bromine, iodine; Aralkyl, as benzyl, styroyl, it can be substituted or not be substituted, perhaps R ⁷With R ⁸Represent a key together.

Suitable R ⁸Can be hydrogen; Low alkyl group is as methyl, ethyl or propyl group; Hydroxyl, (C ₁-C ₃) alkoxyl group; Halogen atom is as fluorine, chlorine, bromine, iodine; Acyl group is as (the C of straight or branched ₂-C ₁₀) acyl group, as ethanoyl, propionyl, butyryl radicals, pentanoyl, benzoyl etc.; Aralkyl, as benzyl, styroyl, it can be substituted or not be substituted, perhaps with R ⁷Form a key together.

By R ⁹The suitable group of expression can be selected from (the C of hydrogen, straight or branched ₁-C ₁₆) alkyl, preferred (C ₁-C ₁₂) alkyl, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, amyl group, hexyl, octyl group etc.; (C ₃-C ₇) cycloalkyl, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc., cycloalkyl can be substituted; Aryl, as phenyl, naphthyl, aryl can be substituted; Heteroaryl, as pyridyl, thienyl, furyl etc., heteroaryl can be substituted; Heteroaralkyl, as furfuryl, picolyl,  azoles methyl,  azoles ethyl etc., heteroaralkyl can be substituted; Aralkyl, as benzyl, styroyl etc., wherein moieties can comprise C ₁-C ₆Atom, wherein aryl moiety can be substituted; Heterocyclic radical, as aziridinyl, pyrrolidyl, piperidyl etc., heterocyclic radical can be substituted; (C ₁-C ₆) alkoxyl group (C ₁-C ₆) alkyl, as methoxymethyl, ethoxyl methyl, methoxy ethyl, ethoxycarbonyl propyl etc., alkoxyalkyl can be substituted; (the C of straight or branched ₂-C ₁₆) acyl group, as ethanoyl, propionyl, butyryl radicals, benzoyl, capryloyl, decanoyl etc., it can be substituted; (C ₁-C ₆) carbalkoxy, alkyl can be substituted; Aryloxy carbonyl, as carbobenzoxy, naphthalene oxygen carbonyl etc., aryl can be substituted; (C ₁-C ₆) alkyl amino-carbonyl, alkyl can be substituted; Aromatic yl aminocarbonyl, as PhNHCO, naphthyl aminocarboxyl etc., aryl moiety can be substituted.Substituting group can be selected from halogen, hydroxyl or nitro or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aryl, aralkyl, sweet-smelling alkoxy alkyl, heterocyclic radical, heteroaryl, heteroaralkyl, acyl group, acyloxy, hydroxyalkyl, amino, amido, arylamino, aminoalkyl group, aryloxy, carbalkoxy, alkylamino, alkoxyalkyl, alkylthio, alkylthio, carboxylic acid or derivatives thereof or sulfonic acid or derivatives thereof.

Suitable to R ¹⁰The group of expression can be selected from (the C of hydrogen, straight or branched ₁-C ₁₆) alkyl, preferred (C ₁-C ₁₂) alkyl, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, amyl group, hexyl, octyl group etc.; (C ₃-C ₇) cycloalkyl, as cyclopropyl, cyclopentyl, cyclohexyl etc., cycloalkyl can be substituted; Aryl, as phenyl, naphthyl etc., aryl can be substituted; Heteroaryl, as pyridyl, thienyl, furyl etc., heteroaryl can be substituted; Heteroaralkyl, as furfuryl, picolyl,  azoles methyl,  azoles ethyl etc., heteroaralkyl can be substituted; Aralkyl, as benzyl and styroyl etc., aralkyl can be substituted; Heterocyclic radical, as aziridinyl, pyrrolidyl, piperidyl etc., heterocyclic radical can be substituted.R ¹⁰On substituting group can be selected from R ¹-R ⁶Identical group.

Suitable to R ¹²The group of expression can be selected from (the C of hydrogen, straight or branched ₁-C ₁₆) alkyl, preferred (C ₁-C ₁₂) alkyl; Hydroxyl (C ₁-C ₆) alkyl; Aryl is as phenyl, naphthyl etc.; Aralkyl is as benzyl, styroyl etc.; Heterocyclic radical is as aziridinyl, pyrrolidyl, piperidyl etc.; Heteroaryl is as pyridyl, thienyl, furyl etc.; Heteroaralkyl is as furfuryl, picolyl,  azoles methyl,  azoles ethyl etc.

Suitable to R ¹⁰And R ¹²The ring structure of Xing Chenging can be selected from pyrrolidyl, piperidyl, morpholinyl, piperazinyl etc. together.

Suitable m is the integer of 0-1.Preferably when m=0, Ar represents divalence benzofuryl, benzoxazol base, benzothiazolyl, indyl, indolinyl, dihydro benzo furyl or dihydrobenzopyrans base and when m=1, and the Ar representative replaces or unsubstitutedly is selected from following group: divalence phenylene, naphthylidene, pyridyl, quinolyl, benzofuryl, dihydro benzo furyl, benzopyranyl, dihydrobenzopyrans base, indyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazol base etc.

Suitable n is the integer of 1-4.Preferred n is integer 1 or 2.

During preferred m=1, n is 2.

During also preferred m=0, n is 1.

The pharmacologically acceptable salt that constitutes a part of the present invention comprises the salt of carboxylic moiety, as an alkali metal salt such as Li, Na and K salt, alkaline earth salt such as Ca and Mg salt, the salt of organic bases such as Methionin, arginine, guanidine, diethanolamine, choline etc., the ammonium salt of ammonium or replacement, aluminium salt.Salt can comprise acid salt, suitable salt be vitriol, nitrate, phosphoric acid salt, perchlorate, borate, halogen acid salt, acetate, tartrate, maleate, Citrate trianion, succinate, palmitate, mesylate, benzoate, salicylate, Hydroxynaphthoate, benzene sulfonate, ascorbate salt, glycerophosphate, ketoglutarate etc.The acceptable solvent thing can be hydrate or comprises other recrystallisation solvent such as alcohol.

The useful especially compound of the present invention comprises:

(E/Z)-and 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-the 2-ethoxy ethyl acrylate;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(-) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(E/Z)-3-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) methyl cumarone-5-yl]-the 2-ethoxy ethyl acrylate;

(E/Z)-and 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-the 2-ethoxy ethyl acrylate;

(±) 3-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) methyl cumarone-5-yl]-2-ethoxy-propionic acid methyl esters;

(+) 3-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) methyl cumarone-5-yl]-2-ethoxy-propionic acid methyl esters;

(-) 3-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) methyl cumarone-5-yl]-2-ethoxy-propionic acid methyl esters;

(±)-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(-) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(±) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(+) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(-) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(±) 2-(2-luorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(+) 2-(2-luorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(-) 2-(2-luorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(E/Z)-and 3-[4-[2-(3-oxo-2H-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-the 2-ethoxy ethyl acrylate;

(±) 3-[4-[2-(3-oxo-2H-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(+) 3-[4-[2-(3-oxo-2H-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(-) 3-[4-[2-(3-oxo-2H-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(E/Z)-and 3-[6-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthyl]-the 2-ethoxy ethyl acrylate;

(±) 3-[6-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthyl]-2-ethoxy-propionic acid methyl esters;

(+) 3-[6-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthyl]-2-ethoxy-propionic acid methyl esters;

(-) 3-[6-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthyl)-2-ethoxy-propionic acid methyl esters;

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-the 2 hydroxy propanoic acid ethyl ester;

3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-the 2 hydroxy propanoic acid ethyl ester;

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-benzyloxy ethyl propionate;

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-butoxy ethyl propionate;

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-hexyloxy ethyl propionate;

(E/Z)-and 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy group ethyl propenoate;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters;

(-) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters;

(E/Z)-and 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy group ethyl propenoate;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters;

(-) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters;

(E/Z)-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-the 2-ethoxy ethyl acrylate;

(±) 3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid methyl esters;

(+) 3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid methyl esters;

(-) 3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid methyl esters;

(E/Z)-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-the 2-ethoxy ethyl acrylate;

(±) 3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid methyl esters;

(+) 3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid methyl esters;

(-) 3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid methyl esters;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid and its salt;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid and its salt;

(-) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid and its salt;

(±) 3-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) methyl cumarone-5-yl]-2-ethoxy-propionic acid and its salt;

(+) 3-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) methyl cumarone-5-yl]-2-ethoxy-propionic acid and its salt;

(-) 3-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) methyl cumarone-5-yl]-2-ethoxy-propionic acid and its salt;

(±) 3-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) methyl cumarone-5-yl]-2-ethoxy-propionic acid and its salt;

(+) 3-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) methyl cumarone-5-yl]-2-oxyethyl group-propionic acid and its salt;

(-) 3-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) methyl cumarone-5-yl]-2-oxyethyl group-propionic acid and its salt;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid and its salt;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid and its salt;

(-) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid and its salt;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group) phenyl]-2-ethoxy-c acid amides;

(-) 3-[4-[2-(2.3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(±) N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(+) N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(-) N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(-) 3-[4-[2-(2.3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(±) N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(+) N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(-) N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(±) N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(+) N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(-) N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(±) N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(+) N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

(-) N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-c acid amides;

2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid and its salt;

2-(2-luorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid and its salt;

(±) 3-[4-[2-(3-oxo-2H-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid and its salt;

(+) 3-[4-[2-(3-oxo-2H-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid and its salt;

(-) 3-[4-[2-(3-oxo-2H-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid and its salt;

(±) 3-[4-[2-(3-oxo-2H-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid and its salt;

(+) 3-[4-[2-(3-oxo-2H-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid and its salt;

(-) 3-[4-[2-(3-oxo-2H-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid and its salt;

(±) 3-[6-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] naphthyl]-2-ethoxy-propionic acid and its salt;

(+) 3-[6-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] naphthyl]-2-ethoxy-propionic acid and its salt;

(-) 3-[6-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] naphthyl]-2-ethoxy-propionic acid and its salt;

(±) 3-[6-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthyl]-2-ethoxy-propionic acid and its salt;

(+) 3-[6-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthyl]-2-ethoxy-propionic acid and its salt;

(-) 3-[6-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthyl]-2-ethoxy-propionic acid and its salt;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2 hydroxy propanoic acid and its salt;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2 hydroxy propanoic acid and its salt;

(-) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2 hydroxy propanoic acid and its salt;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2 hydroxy propanoic acid and its salt;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2 hydroxy propanoic acid and its salt;

(-) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2 hydroxy propanoic acid and its salt;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-benzyloxy propionic acid and its salt;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-benzyloxy propionic acid and its salt;

(-) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-benzyloxy propionic acid and its salt;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-butoxy propionic acid and its salt;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-butoxy propionic acid and its salt;

(-) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-butoxy propionic acid and its salt;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-hexyloxy propionic acid and its salt;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-hexyloxy propionic acid and its salt;

(-) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-hexyloxy propionic acid and its salt;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid and its salt;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid and its salt;

(-) 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid and its salt;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid and its salt;

(+) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid and its salt;

(-) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid and its salt;

(±) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters;

(+) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters;

(-) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters;

(±) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid and its salt;

(+) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid and its salt;

(-) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid and its salt;

(±) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters;

(+) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters;

(-) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters;

(±) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid and its salt;

(+) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid and its salt;

(-) 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid and its salt;

(±) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid 4-nitro phenyl ester;

(+) 3-[4-[2-(2,3-dihydro-1.4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid 4-nitro phenyl ester;

(-) 3-[4-[2-(2.3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid 4-nitro phenyl ester;

(±) 3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid and its salt;

(+) 3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid and its salt;

(-) 3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid and its salt;

(±) 3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid 4-nitro phenyl ester;

(+) 3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid 4-nitro phenyl ester; With

(-) 3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid 4-nitro phenyl ester.

According to a feature of the present invention, the compound of general formula (I) (R wherein ⁷And R ⁸Represent a key together, Y represention oxygen atom, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁹, R ^D, X, n, m and Ar such as preceding definition) can be according to the following path of preparing that is shown in reaction scheme I.

Reaction scheme-I

Route (1):

The compound of the compound of general formula (IIIa) (wherein all symbols such as preceding definition) and general formula (IIIb) (R wherein ⁹And R ¹⁰As preceding definition, R ¹⁴Representative (C ₁-C ₆) alkyl) reaction, the compound of generation general formula (I), wherein R ⁷With R ⁸Represent a key together, the Y represention oxygen atom, this is reflected at a kind of alkali and has solvent-free carrying out down, this alkali such as alkalimetal hydride, for example NaH or KH or organolithium compound, for example CH ₃Li, BuLi etc. or alkoxide are as NaOMe, NaOEt, K ⁺BuO ^-Or its mixture.This reaction can be carried out in the presence of solvent, as THF, two  alkane, DMF, DMSO, DME etc. or its mixture.HMPA can be used as solubility promoter.Temperature of reaction is-78 ℃ to 50 ℃.Preferably-10 ℃ to 30 ℃.Under anhydrous condition, react more effective.The compound of general formula (IIIb) can be according to the described method preparation of document (Annalen.Chemie, (1996) 53,699).

Route (2):

The compound of the compound of general formula (IIIc) (wherein all symbols such as preceding definition) and general formula (IIId) (R wherein ⁷And R ⁸Represent a key together, all symbols such as preceding definition, L ¹Be leavings group, as halogen atom, tosic acid root, methanesulfonate, trifluoromethanesulfonic acid root etc., preferred halogen atom) reaction, obtain general formula (I) compound as preceding definition, this reaction can be carried out in the presence of solvent, as DMSO, DMF, DME, THF, two  alkane, ether etc. or its mixture.Reaction can be carried out under inert atmosphere, adopts rare gas element such as N ₂, Ar or He keep inert atmosphere.Reaction can be carried out in the presence of a kind of alkali, as alkali, and for example sodium hydroxide or potassium hydroxide; Alkaline carbonate, for example yellow soda ash or salt of wormwood; Alkalimetal hydride is as sodium hydride or potassium hydride KH; Organo-metallic alkali, for example n-Butyl Lithium; Alkali metal ammonia compound, for example sodium amide or its mixture.In the amount of formula (IIIc) compound, the consumption of alkali is the 1-5 equivalent, preferred 1-3 equivalent.Can add phase-transfer catalyst as, as quaternary alkylammonium halides or tetra-alkyl ammonium hydroxide.Reaction can be carried out under 0 ℃ to 150 ℃, preferred 15 ℃ to 100 ℃.Reaction times is 0.25-48 hour, preferred 0.25-12 hour.

Route (3):

The compound of the compound of formula (IIIe) (wherein all symbols such as preceding definition) and formula (IIIf) (R wherein ⁹=R ¹⁰And as preceding definition) reaction, the compound of production (I), wherein R ⁷And R ⁸Represent a key together, this reaction can be in the presence of a kind of alkali solvent-free carrying out, this alkali such as alkalimetal hydride, for example NaH, KH or organolithium compound, for example CH ₃Li, BuLi etc. or alkoxide are as NaOMe, NaOEt, K ⁺BuO ^-Deng or its mixture.Reaction can be carried out in the presence of aprotonic solvent, as THF, two  alkane, DMF, DMSO, DME etc. or its mixture.HMPA can be used as solubility promoter.Temperature of reaction is-78 ℃ to 100 ℃, preferred-10 ℃ to 50 ℃.

Route (4):

The compound of the compound of general formula (IIIa) (wherein all other symbols such as preceding definition) and general formula (IIIg) (R wherein ⁸Represent hydrogen atom, R ⁹And R ¹⁰As preceding definition) reaction can in the presence of a kind of alkali, carry out.The character of alkali is not crucial.The alkali that any routine is used for aldol reaction all can adopt; Alkali for example is metal hydride, and as NaH or KH, metal alkoxide is as NaOMe, K ⁺BuO ^-Or NaOEt, also can adopt the metal amide, as LiNH ₂Or LiN (ipr) ₂Can adopt aprotonic solvent, as THF, ether or two  alkane.Reaction can be carried out under inert atmosphere, can adopt rare gas element such as N ₂, Ar or He keep inert atmosphere, be reflected at carry out under the anhydrous condition more effective.Temperature of reaction is-80 ℃ to 35 ℃.The beta-hydroxy product that begins to produce adopts conventional dehydration conditions to dewater, as uses such as the PTSA in benzene or the toluene equal solvent and handle.The character and the dewatering agent of solvent are unimportant.Adoptable temperature is 20 ℃ of reflux temperatures to solvent for use, preferably adopts Dean Stark water trap to react under the reflux temperature of solvent by removing to anhydrate continuously.

Route (5):

The compound of formula (IIIh) (wherein all symbols such as preceding definition, L ¹Represent leavings group,, tosic acid root, methanesulfonate, trifluoromethanesulfonic acid root etc. as halogen atom) with the compound of formula (IIIi) (R wherein ⁷And R ⁸Represent a key together, R ⁹, R ¹⁰With Ar such as preceding definition) reaction, the compound of production (I), m=1 wherein, all other symbols such as preceding definition.This reaction can be carried out in the presence of aprotonic solvent, as THF, DMF, DMSO, DME etc. or its mixture.Reaction can be carried out under inert atmosphere, can adopt rare gas element such as N ₂, Ar or He keep inert atmosphere.Reaction can be carried out in the presence of a kind of alkali, as salt of wormwood, yellow soda ash or NaH or its mixture.When yellow soda ash or salt of wormwood during, can adopt acetone as solvent as alkali.Temperature of reaction is 0 ℃ to 120 ℃, preferred 30 ℃ to 100 ℃.Reaction times is 1-24 hour, preferred 2-12 hour.The compound of formula (IIIi) can carry out Wittig Horner reaction according to the compound of the aryl aldehyde that makes hydroxyl protection such as benzyloxy aryl aldehyde and formula (IIIb), the known method of deprotection preparation subsequently.

Route (6):

The compound of the compound of general formula (IIIj) (wherein all symbols such as preceding definition) and general formula (IIIi) (R wherein ⁷And R ⁸Represent a key together, R ⁹, R ¹⁰With Ar such as preceding definition), the compound of production (I), m=1 wherein, all other symbols such as preceding definition.This reacts available suitable coupler and carries out, and for example adopts dicyclohexylurea (DCU), triaryl phosphine/dialkyl group azepine dicarboxylic ester, as PPh ₃/ DEAD etc.Reaction can be carried out in the presence of solvent, as THF, DME, methylene dichloride, chloroform, toluene, acetonitrile, tetracol phenixin etc.Can adopt rare gas element such as N ₂, Ar or He keep inert atmosphere.Reaction can be carried out in the presence of DMAP, HOBT, and its consumption is the 0.05-2 equivalent, preferred 0.25-1 equivalent.Temperature of reaction is 0 ℃ to 100 ℃, preferred 20 ℃ to 80 ℃.Reaction times is 0.5-24 hour, preferred 6-12 hour.

In another embodiment of the invention, can prepare the compound of general formula (I) by one or more methods shown in the following scheme II, wherein R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁹, R ¹⁰, X, n, m as defined above, R ⁷Represent hydrogen atom, hydroxyl, alkoxyl group, halogen, low alkyl group, replacement or unsubstituted aralkyl, R ⁸Represent hydrogen, hydroxyl, alkoxyl group, halogen, low alkyl group, acyl group or replacement or unsubstituted aralkyl, Ar such as preceding definition, Y represents oxygen:

Reaction scheme-II

Route 7:

Formula (IVa) compound (representative formula (I) compound, wherein R of will be as mentioned above obtaining in (reaction scheme I) ⁷And R ⁸Represent a key together, Y represention oxygen atom, all other symbols such as preceding definition) reduce, obtain the compound of general formula (I), wherein R ⁷And R ⁸Represent hydrogen atom respectively, all symbols such as preceding definition, this reaction can be carried out in the presence of hydrogen and catalyzer, and catalyzer for example is Pd/C, Rh/C, Pt/C etc.Can adopt mixture of catalysts.Reaction also can be carried out in the presence of solvent, as two  alkane, acetate, ethyl acetate etc.Can adopt the pressure of normal atmosphere to 80psi.Catalyzer is preferably 5-10%Pd/C, and its consumption is 50-300%w/w.Reaction also can be adopted the metal solvent reduction, as magnesium in alcohol or the sodium amalgam in alcohol, particular methanol.Hydrogenation process can carry out comprising in the presence of the metal catalyst of chiral ligand, obtains formula (I) compound of optically active form.Metal catalyst can comprise rhodium, ruthenium, indium etc.The preferred chirality phosphine of chiral ligand is as (2S, 3S)-two (phenylbenzene-phosphino-) butane, 1, two (diphenylphosphino) ethane, 1 of 2-, two (the 2-p-methoxy-phenyl phenyl phosphino-) ethane of 2-, (-)-2,3-isopropylidene-2,3-dihydroxyl-1, two (phenylbenzene-phosphino-) butane of 4-etc.Can adopt the suitable chiral catalyst (referring to the asymmetric synthesis principle, Tet.Org.Chem.Series, 14 volumes, the 311-316 page or leaf, Baldwin J.E. edits) of any product that can provide required polarimetry purity (I).

Route 8:

The compound of formula (IVb) (wherein all symbols such as preceding definition, L ²Be leavings group, as halogen atom) with the alcohol of general formula (IVc) (R wherein ⁹As preceding definition) reaction, the formula of generation (I) compound such as preceding definition, this reaction can be carried out in the presence of solvent, as THF, DMF, DMSO, DME etc. or its mixture.Reaction can be carried out under inert atmosphere, can adopt rare gas element such as N ₂, Ar or He keep inert atmosphere.Reaction can be carried out in the presence of a kind of alkali, as KOH, NaOH, NaOMe, NaOEt, K ⁺BuO ^-Or NaH or its mixture.Can add phase-transfer catalyst, as quaternary alkylammonium halides or tetra-alkyl ammonium hydroxide.Reaction can be carried out under 20 ℃ to 120 ℃, preferred 30 ℃ to 100 ℃.Reaction times is 1-12 hour, preferred 2-6 hour.General formula (IVb) compound and its preparation method are stated in common unsettled U. S. application 08/982,910.

Route 9:

As the compound of the formula (IIIh) of preceding definition and compound (wherein all symbols such as the preceding definition) reaction of formula (IIIi), the compound of production (I), m=1 wherein, all other symbols such as preceding definition, this reaction can be carried out in the presence of solvent, as THF, DMF, DMSO, DME etc. or its mixture.Reaction can be carried out under inert atmosphere, can adopt rare gas element such as N ₂, Ar or He keep inert atmosphere.Reaction can be carried out in the presence of a kind of alkali, as salt of wormwood, yellow soda ash, NaH or its mixture.When salt of wormwood or yellow soda ash during as alkali, available acetone is made solvent.Temperature of reaction is 20 ℃ to 120 ℃, preferred 30 ℃ to 80 ℃.Reaction times is 1-24 hour, preferred 2-12 hour.The compound of formula (IIIi) can carry out Wittig Horner reaction according to the compound of hydroxyaryl aldehyde that makes protection and formula (IIIb), the known method preparation of two keys of reduction subsequently and deprotection.Perhaps, formula (IIIi) compound can be according to WO 94/01420 described method preparation.

Route 10:

Compound (wherein all symbols such as preceding definition) reaction as the compound and the general formula (IIIi) of the general formula (IIIj) of preceding definition, the compound of production (I), m=1 wherein, all other symbols such as preceding definition, this reaction can be carried out in the presence of suitable coupler, for example adopt dicyclohexylurea (DCU), triaryl phosphine/dialkyl group azepine dicarboxylic ester, as PPh ₃/ DEAD etc.Reaction can be carried out in the presence of solvent, as THF, DME, methylene dichloride, chloroform, toluene, acetonitrile, tetracol phenixin etc.Can adopt rare gas element such as N ₂, Ar or He keep inert atmosphere.Reaction can be carried out in the presence of DMAP, HOBT, and its consumption is the 0.05-2 equivalent, preferred 0.25-1 equivalent.Temperature of reaction is 0 ℃ to 100 ℃, preferred 20 ℃ to 80 ℃.Reaction times is 0.5-24 hour, preferred 6-12 hour.

Route 11:

The compound of formula (IVd) (compound of its representative formula (I), wherein R ⁹Represent hydrogen atom, all other symbols such as preceding definition) with the compound of formula (IVe) (R wherein ⁹As preceding definition, L ²Be leavings group, as halogen atom) reaction can in the presence of solvent, carry out, as THF, DMF, DMSO, DME etc.Can adopt rare gas element such as N ₂, Ar or He keep inert atmosphere.Reaction can be carried out in the presence of a kind of alkali, as KOH, NaOH, NaOMe, K ⁺BuO ^-, NaH etc.Can add phase-transfer catalyst as, as quaternary alkylammonium halides or tetra-alkyl ammonium hydroxide.Temperature of reaction is 20 ℃ to 150 ℃, preferred 30 ℃ to 100 ℃.Reaction times is 1-24 hour, preferred 2-6 hour.

Route 12:

As general formula (IIIa) compound of preceding definition and the compound of formula (IIIg) (R wherein ⁸, R ⁹And R ¹⁰As preceding definition) reaction can under normal condition, carry out.Alkali is not crucial.Any alkali that routine is used for aldol reaction all can adopt, and comprises metal hydride, as NaH or KH; Metal alkoxide is as NaOMe, K ^tBuO ^-Or NaOEt; The metal amide is as LiNH ₂Or LiN (ipr) ₂Can use aprotonic solvent, as THF.Inert atmosphere can adopt for example argon, be reflected at carry out under the anhydrous condition more effective.Temperature of reaction is-80 ℃ to 25 ℃.Beta-hydroxy aldol product can adopt ordinary method to carry out decarboxylation reaction, is advantageously undertaken by the ion hydrogenation technology, for example handles in the presence of as trifluoroacetic acid in acid with trialkyl silane.Can adopt solvent such as methylene dichloride.Preferred reaction is carried out under 25 ℃.If react slower, can adopt higher temperature.

Route 13:

The compound of the compound of general formula (IIIc) (wherein all symbols such as preceding definition) and general formula (IIId) (L wherein ¹Be leavings group, as halogen atom, tosic acid root, methanesulfonate, trifluoromethanesulfonic acid root etc., preferred L ¹Be halogen atom, all other symbols such as preceding definition) reaction, the compound of generation general formula (I).This reaction can be carried out in the presence of solvent, as DMSO, DMF, DME, THF, two  alkane, ether etc. or its mixture.Reaction can be carried out under inert atmosphere, can adopt rare gas element such as N ₂, Ar or He keep inert atmosphere.Reaction can be carried out in the presence of a kind of alkali, as alkali, and for example sodium hydroxide or potassium hydroxide, alkaline carbonate, for example yellow soda ash or salt of wormwood; Alkalimetal hydride is as sodium hydride or potassium hydride KH; Organo-metallic alkali, n-Butyl Lithium for example, alkali metal ammonia compound, for example sodium amide or its mixture.In the amount of formula (IIIc) compound, the consumption of alkali is the 1-5 equivalent, preferred 1-3 equivalent.Reaction can be carried out under 0 ℃ to 150 ℃, preferred 15 ℃ to 100 ℃.Reaction times is 0.25-24 hour, preferred 0.25-12 hour.

Route 14:

The compound of formula (IVf) can carry out in the presence of alkali or acid to formula (I) conversion of compounds process, and the selection of alkali or acid is not crucial.Routine is used for nitrile and all can adopts to acid-hydrolyzed any alkali, as the metallic hydrogen ammonium oxide, as NaOH in water-containing solvent or KOH, perhaps routine is used for nitrile and all can adopts to esterolytic any acid, as the dried HCl in alcohol excess such as methyl alcohol, ethanol, propyl alcohol etc.Reaction can be carried out to the reflux temperature of solvent at 0 ℃, preferred 25 ℃ of reflux temperatures to solvent.Reaction times is 0.25-48 hour.

Route 15:

The compound of the compound of formula (IVg) (wherein all symbols such as preceding definition) and formula (IVc) (R wherein ⁹As preceding definition) reaction, the compound of production (I) (by the insertion reaction of rhodium carbenoid adjusting), this reaction can be at rhodium (II) salt, as carrying out under rhodium acetate (II) existence.Reaction can be carried out in the presence of solvent, as benzene, toluene, two  alkane, ether, THF etc. or its mixture, perhaps works as at R ⁹OH exists down as solvent and carries out, and reacts under the temperature of any suitable speed that the required product of formation is provided, and carries out at elevated temperatures usually, as the reflux temperature of solvent.Can adopt rare gas element such as N ₂, Ar or He keep inert atmosphere.Reaction times is 0.5-24 hour, preferred 0.5-6 hour.

(wherein Y represents oxygen and R to the compound of general formula (I) ¹⁰As preceding definition) can by with formula NHR ¹⁰R ¹²The reaction of suitable amine change into the compound of another kind of formula (I) (wherein Y represent NR ¹²), R wherein ¹⁰And R ¹²As preceding definition.Aptly, the compound of formula (I) (YR wherein ¹⁰Represent OH) can change into sour halogen, preferred YR ¹⁰=Cl adopts suitable reagent, as oxalyl chloride, thionyl chloride etc., handles with amine subsequently.Perhaps, mixed acid anhydride can be by the compound of formula (I) (YR wherein ¹⁰Represent OH, all other symbols such as preceding definition) by preparing with processing such as carboxylic acid halides such as Acetyl Chloride 98Min., acetyl bromide, pivalyl chloride, dichlorobenzoyl chlorides.Reaction can be carried out in the presence of suitable alkali, as pyridine, triethylamine, diisopropyl ethyl amine etc.Can adopt solvent, as halohydrocarbon, for example chloroform or methylene dichloride; Hydrocarbon is as benzene,toluene,xylene etc.Reaction can be carried out under-40 ℃ to 40 ℃, preferred 0 ℃ to 20 ℃.Prepared carboxylic acid halides or mixed acid anhydride can further be handled with suitable amine.

In another embodiment of the invention, provide new intermediate and its preparation method and the purposes in the hydroxyl alkane acid of preparation beta-aromatic-alpha-substitution thereof of following formula (IVf)

Radicals R wherein ¹, R ², R ³, R ⁴With the radicals R that links to each other with carbon atom ⁵And R ⁶Can be identical or different, represent hydrogen, halogen, hydroxyl, nitro, cyano group, formyl radical or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclic radical, heteroaryl, heteroaralkyl, heteroaryloxy, assorted aralkoxy, acyl group, acyloxy, hydroxyalkyl, amino, amido, alkylamino, arylamino, aryl alkyl amino, aminoalkyl group, carbalkoxy, aryloxy carbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxy alkyl, sweet-smelling alkoxy alkyl, alkylthio, alkylthio, alkoxycarbonyl amido, aryloxy carbonyl amino, aralkoxycarbonyl amino, carboxylic acid or derivatives thereof or sulfonic acid or derivatives thereof; The radicals R that links to each other with nitrogen-atoms ⁵And R ⁶Represent hydrogen, hydroxyl, formyl radical or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroaralkyl, acyl group, acyloxy, hydroxyalkyl, amino, amido, alkylamino, arylamino, aryl alkyl amino, aminoalkyl group, aryloxy, aralkoxy, heteroaryloxy, assorted aralkoxy, carbalkoxy, aryloxy carbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxy alkyl, sweet-smelling alkoxy alkyl, alkylthio, alkylthio, carboxylic acid derivative or sulfonic acid; When linking to each other with carbon atom, R ⁵And R ⁶One of or both also can represent oxo group; The X representative is selected from oxygen, sulphur or NR ¹¹Heteroatoms, R wherein ¹¹Be selected from hydrogen or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, acyl group, carbalkoxy, aryloxy carbonyl or aralkoxycarbonyl; The Ar representative replaces or unsubstituted divalence list or fused aromatic group or heterocyclic group; R ⁷Represent hydrogen atom, hydroxyl, alkoxyl group, halogen, low alkyl group or replacement or unsubstituted aralkyl; R ⁸Represent hydrogen, hydroxyl, alkoxyl group, halogen, low alkyl group, acyl group, replacement or unsubstituted aralkyl; R ⁹Represent hydrogen or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, carbalkoxy, aryloxy carbonyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, acyl group, heterocyclic radical, heteroaryl or heteroaralkyl; By-(CH ₂) _n-(O) _mThe linking group of-expression can link to each other by nitrogen-atoms or carbon atom; N is that integer 1-4 and m are integer 0 or 1.

The compound of formula (IVf) (R wherein ⁷And R ⁸All represent hydrogen atom, all other symbols such as preceding definition) according to the listed method preparation of reaction scheme-III.

Scheme II I

The compound of the compound of formula (IIIa) (wherein all symbols such as preceding definition) and formula (IVh) (R wherein ⁹As preceding definition, Hal represents halogen atom, as Cl, Br or I) reaction can under normal condition, in the presence of a kind of alkali, carry out.Alkali is not crucial.Can adopt routine to be used for any alkali of Wittig reaction, comprise metal hydride, as NaH or KH; Metal alkoxide is as NaOMe, K ^tBuO ^-Or NaOEt; Or the metal amide, as LiNH ₂Or LiN (ipr) ₂Can adopt aprotonic solvent, as THF, DMSO, two  alkane, DME etc.Can use the mixture of solvent.Can use HMPA to make solubility promoter.Can adopt inert atmosphere, as argon atmospher, be reflected at carry out under the anhydrous condition more effective.Temperature of reaction can be-80 ℃ to 100 ℃.

The compound of formula (IVi) (wherein all symbols such as preceding definition) can by with alcohol under anhydrous condition and in the presence of strong anhydrous acid such as tosic acid, handle the compound (R wherein of a conversion accepted way of doing sth (IVj) ⁷And R ⁸Represent hydrogen atom, all other symbols such as preceding definition).

Handle the compound (R wherein of back production (IVf) with trialkylsilkl prussiate such as trimethylsilyl cyanide as the compound of the formula (IVj) of preceding definition ⁷And R ⁸Represent hydrogen atom, all other symbols such as preceding definition).

In another embodiment of the invention, provide new intermediate and its preparation method and the purposes in the hydroxyl alkane acid of preparation beta-aromatic-alpha-substitution thereof of following formula (IVg)

Radicals R wherein ¹, R ², R ³, R ⁴With the radicals R that links to each other with carbon atom ⁵And R ⁶Can be identical or different, represent hydrogen, halogen, hydroxyl, nitro, cyano group, formyl radical or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclic radical, heteroaryl, heteroaralkyl, heteroaryloxy, assorted aralkoxy, acyl group, acyloxy, hydroxyalkyl, amino, amido, alkylamino, arylamino, aryl alkyl amino, aminoalkyl group, carbalkoxy, aryloxy carbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxy alkyl, sweet-smelling alkoxy alkyl, alkylthio, alkylthio, alkoxycarbonyl amido, aryloxy carbonyl amino, aralkoxycarbonyl amino, carboxylic acid or derivatives thereof or sulfonic acid or derivatives thereof; When linking to each other with carbon atom, R ⁵And R ⁶One of or both also can represent oxo group; The radicals R that links to each other with nitrogen-atoms ⁵And R ⁶Represent hydrogen, hydroxyl, formyl radical or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroaralkyl, acyl group, acyloxy, hydroxyalkyl, amino, amido, alkylamino, arylamino, aryl alkyl amino, aminoalkyl group, aryloxy, aralkoxy, heteroaryloxy, assorted aralkoxy, carbalkoxy, aryloxy carbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxy alkyl, sweet-smelling alkoxy alkyl, alkylthio, alkylthio, carboxylic acid derivative or sulfonic acid; The X representative is selected from oxygen, sulphur or NR ¹¹Heteroatoms, R wherein ¹¹Be selected from hydrogen or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, acyl group, carbalkoxy, aryloxy carbonyl or aralkoxycarbonyl; The Ar representative replaces or unsubstituted divalence list or fused aromatic group or heterocyclic group; R ⁷Represent hydrogen atom, hydroxyl, alkoxyl group, halogen, low alkyl group or replacement or unsubstituted aralkyl; R ¹⁰Represent hydrogen or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, heterocyclic radical, heteroaryl or heteroaralkyl; Y represents oxygen; By-(CH ₂) _n-(O) _mThe linking group of-expression can link to each other by nitrogen-atoms or carbon atom; N is that integer 1-4 and m are integer 0 or 1.

The compound of formula (IVg) (wherein all other symbols such as preceding definition) but compound and a kind of suitable diazo reagent prepared in reaction of through type (IVk)

R wherein ⁸Be hydrogen atom, all other symbols such as preceding definition.

Diazotization reaction can be carried out under normal condition.Suitable diazo reagent is an alkyl nitrile, as the isopentyl nitrile.Reaction can be carried out in the presence of solvent, as THF, two  alkane, ether, benzene etc. or its mixture.Temperature of reaction is-50 ℃ to 80 ℃.Reaction can be carried out under inert atmosphere, can adopt rare gas element such as N ₂, Ar or He keep inert atmosphere.Reaction times is 1-24 hour, preferred 1-12 hour.

The compound of formula (IVk) also can be by making formula (IIIh) the compound prepared in reaction of compound (wherein all symbols such as preceding definition) and formula (IVl)

R wherein ⁸Be hydrogen atom, all other symbols such as preceding definition.

The compound of formula (IIIh) (wherein all symbols such as preceding definition) can carry out in the presence of solvent with the reaction of the compound (wherein all symbols such as preceding definition) of formula (IVl), as THF, DMF, DMSO, DME etc. or its mixture.Reaction can be carried out under inert atmosphere, can adopt rare gas element such as N ₂, Ar or He keep inert atmosphere.Reaction can be carried out in the presence of a kind of alkali, as salt of wormwood, yellow soda ash or NaH or its mixture.When salt of wormwood or yellow soda ash during, can adopt acetone as solvent as alkali.Temperature of reaction is 20 ℃ to 120 ℃, preferred 30 ℃ to 80 ℃.Reaction times is 1-24 hour, preferred 2-12 hour.

The term that is adopted " solvent-free (neat) " is meant and is reflected at without carrying out under the condition of solvent in this application.Pharmacologically acceptable salt can be by making formula (I) compound and the normal alkali of 1-4 prepared in reaction in solvent such as ether, THF, methyl alcohol, the trimethyl carbinol, two  alkane, Virahol, ethanol etc., described alkali for example is sodium hydroxide, sodium methylate, sodium hydride, potassium tert.-butoxide, calcium hydroxide, magnesium hydroxide etc.Can adopt the mixture of solvent.Also can adopt organic bases, for example Methionin, arginine, diethanolamine, choline, guanidine and derivative thereof etc.Perhaps, when the acid salt possibility, this salt can be by with acid treatment preparation, and described acid for example is the spirit of salt, Hydrogen bromide, sulfuric acid, phosphoric acid, tosic acid, methylsulfonic acid, acetate, citric acid, toxilic acid, Whitfield's ointment, hydroxynaphthoic acid, xitix, palmitinic acid, succsinic acid, phenylformic acid, Phenylsulfonic acid, tartrate in solvent such as ethyl acetate, ether, alcohol, acetone, THF, two  alkane etc. etc.Also can adopt the mixture of solvent.

The steric isomer that constitutes a part of the present invention can be by adopting the reactant preparation of its single enantiomer form in the possible course of processing, perhaps, perhaps split by the mixture of ordinary method with steric isomer by in the presence of the reagent of single enantiomer form or catalyzer, reacting.Some preferable methods comprise uses the microorganism Split Method, the diastereoisomeric salt that fractionation forms with chiral acid, described chiral acid for example is amygdalic acid, camphorsulfonic acid, tartrate, lactic acid etc., or the diastereoisomeric salt that forms with chiral base, described chiral base such as brucine, cinchona alkaloid and derivative thereof etc.The conventional method that adopts is stated in following document: Jaques etc., " enantiomorph, racemic modification and fractionation " (Wiley Interscience, 1981).More specifically, the compound of formula (I) (YR wherein ¹⁰Represent OH) can handle 1: 1 mixture that changes into non-mapping acid amides by the amino alcohol that obtains with Chiral Amine, amino acid, by amino acid; Can adopt the conventional reaction conditions that acid is changed into acid amides; Diastereomer can separate by fractional crystallization or chromatography, and the steric isomer of formula (I) compound can make by pure non-mapping acid amides is hydrolyzed.

The various polymorphic forms that constitute general formula (I) compound of a part of the present invention can make by under different condition formula (I) compound being carried out crystallization.For example, adopt conventional different solvents or its mixture that adopts to carry out recrystallize; Under differing temps, carry out crystallization; Adopt the various types of cooling, be included in the crystallisation process from very fast extremely very slow cool down.Polymorphic form also can obtain by compound being heated or melting to cool off gradually or cool off fast.The existence of polymorphic form can be passed through solid probe NMR spectrum, IR spectrum, dsc, powder x-ray diffraction or other technical measurement.

The compound of general formula (I) can be used for treating and/or preventing that insulin resistance (type ii diabetes), leptine resistance, glucose tolerance reduce, hyperlipemia, with the X syndrome diseases associated, as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorder.These compounds also can be used as aldose reductase inhibitor, are used for improving dull-witted cognitive function, the treatment diabetic complication, the disease relevant with activated endothelial cell, psoriasis, polycystic ovary syndrome (PCOS), inflammatory bowel disease, osteoporosis and be used for the treatment of cancer.Compound of the present invention can be united with one or more HMG CoA reductase inhibitors, reducing blood-fat medicament/reducing blood fat protein medicament such as nerve fiber acid derivative, nicotinic acid, QUESTRAN, cholestipol or probucol and is used for the treatment of and/or prevention of arterial sclerosis and/or vitiligoidea.Compound of the present invention can administration or administration in certain synergistic cycle with the combination of HMG CoA reductase inhibitor and/or reducing blood-fat/reducing blood fat protein medicament.HMG CoA reductase inhibitor is optional from the medicine that is used to treat or prevent hyperlipidemia, as lovastatin, general Liprevil, simvastatin, fluvastatin, Chinese mugwort Liprevil (atorvastatin), simvastatin and its analogue.Suitable nerve fiber acid derivative can be gemfibrozil, chlorine Bei Te, fenofibrate, Win-35833, bezafibrate and its analogue.

The present invention also provides pharmaceutical composition, it comprises general formula (I) compound, its derivative, its analogue, its tautomer, its steric isomer, its polymorphic form, its pharmacologically acceptable salt or its acceptable solvent thing as mentioned above, also comprises conventional pharmaceutically acceptable carrier, thinner etc.

Pharmaceutical composition can be the conventional formulation that adopts, as tablet, capsule, pulvis, syrup, solution, suspension etc., can comprise correctives, sweeting agent etc., in suitable solid or liquid vehicle or thinner, or in suitable sterile media, to form Injectable solution or suspension.Described composition comprises 1-20% usually, the active compound of preferred 1-10wt%, and the rest part of composition is pharmaceutically acceptable carrier, thinner or solvent.

Aforesaid formula (I) compound can deliver medicine to Mammals clinically, comprises the people, and administration can be adopted oral or the administered parenterally approach.The preferred oral administration, oral administration is more convenient, and can avoid injecting the pain and the stimulation that may cause.But, when the patient can not swallow medicine, when perhaps the oral administration post-absorption is impaired, and because disease or other abnormal conditions, it also is necessary adopting administered parenterally.No matter adopt which kind of administering mode, the scope of dosage or multiple dosing dosage is about 0.01-50mg/kg body weight once a day, preferably about 0.01-30mg/kg body weight.But for the individual patient for the treatment of, best dosage is to be determined by the doctor who is responsible for treating, and begins to adopt less dosage usually, increases dosage later on to determine optimal dosage.

Suitable pharmaceutically acceptable carrier comprises solid weighting agent or thinner, aseptic aqueous solution or organic solution.The amount of active compound in this pharmaceutical composition should be enough to the aforesaid dosage that provides required.Therefore, for oral administration, compound can make up with suitable solid, liquid vehicle or thinner and form capsule, tablet, pulvis, syrup, solution, suspension etc.If necessary, pharmaceutical composition can comprise other component, as correctives, sweeting agent, vehicle etc.For administered parenterally, compound can be combined to form injectable solution or suspension with sterile aqueous media or organic medium.For example, can adopt the solution in sesame oil or peanut oil, aqueous propylene glycol etc., and the aqueous solution of water-soluble pharmaceutically acceptable acid additive salt or the salt that forms with the alkali of compound.Zhi Bei Injectable solution can pass through intravenously, intraperitoneal, subcutaneous or intramuscularly by this way, and human body preferably adopts intramuscularly.

Describe the present invention in detail by the following embodiment that provides, but these embodiment are not limiting the scope of the invention.

Preparation example 1

4-[2-(3-oxo-2H-1,4-benzoxazine-4-yl) oxyethyl group] phenyl aldehyde

With 2H-1,4-benzoxazine-3-(4H)-ketone (1.6g, 10.7mmol), 4-(2-bromine oxethyl) phenyl aldehyde (2.95g, 12.8mmol) and salt of wormwood (5.93g, 42.97mmol) mixture in anhydrous dimethyl formamide (30mL) stirred 10 hours down at 80 ℃.Add entry (100mL), with ethyl acetate extraction (2 * 75mL).Dried over sodium sulfate is used in organic layer water (50mL) after the merging and salt solution (50mL) washing, filters, and steams solvent.Resistates carries out chromatography with silica gel, adopts the mixture (2: 8) of ethyl acetate and sherwood oil, obtains title compound (2.9g, 91%), is colorless solid.mp：75-78℃。

¹H NMR (CDCl ₃, 200MHz): 4.37 (s, 4H), 4.62 (s, 2H), 6.96-7.26 (complicated peak (complex), 6H), 7.82 (d, J=8.4Hz, 2H), 9.89 (s, 1H).

Preparation example 2

6-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] the cyano group naphthalene

With methylsulfonic acid 2-(2,3-dihydro-1,4-benzothiazine-4-yl) ethyl ester (0.49g, 1.82mmol), 2-hydroxyl-6-cyano group naphthalene (0.28g, 1.65mmol) and salt of wormwood (1.15g, 8.28mmol) mixture in anhydrous dimethyl formamide (15mL) stirred 12 hours down at 80 ℃.Add entry (50mL), with ethyl acetate extraction (2 * 25mL).Dried over sodium sulfate is used in ethyl acetate layer water (25mL) after the merging and salt solution (20mL) washing, filters, and decompression steams solvent.Resistates carries out chromatography with silica gel, adopts the mixture of ethyl acetate and sherwood oil, obtains title compound (0.41g, 72%), is light yellow solid.mp：94-96℃。

¹H NMR (CDCl ₃, 200MHz): 3.05 (t, J=5.21Hz, 2H), 3.79-3.85 (complicated peak, 4H), 4.31 (t, J=5.82Hz, 2H), 6.64-6.78 (complicated peak, 2H), 6.97-7.25 (complicated peak, 4H), 7.53-7.80 (complicated peak, 3H), 8.13 (s, 1H).

Preparation example 3

6-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthaldehyde

Under-70 ℃, in 1 hour, the 6-[2-(2 that makes to preparation example 2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] (8g adds diisobutyl aluminium hydride (93mL, 20% toluene dispersion liquid) to the cyano group naphthalene in anhydrous tetrahydro furan 22.9mmol) (15mL) solution.After adding, reaction mixture was stirred 16 hours down at 25 ℃.At last, add ethyl formate (20mL) and stirred 1 hour down at 25 ℃.Add saturated ammonium chloride solution (15mL).With reaction mixture 10% sulfuric acid acidation, with ethyl acetate extraction (2 * 75mL).Ethyl acetate layer water after the merging (2 * 50mL) and salt solution (50mL) washing, use dried over sodium sulfate.Filter, decompression steams solvent.Resistates carries out chromatography with silica gel, adopts the mixture (10: 90) of ethyl acetate and sherwood oil, obtains title compound (4.5g, 56%), is light yellow solid.mp：100-102℃。

¹H NMR (CDCl ₃, 200MHz): 3.06 (t, J=5.2Hz, 2H), 3.72-3.86 (complicated peak, 4H), 4.33 (t, J=5.67Hz, 2H), 6.60-6.79 (complicated peak, 2H), 6.97-7.25 (complicated peak, 4H), 7.74-7.93 (complicated peak, 3H), 8.25 (s, 1H), 10.09 (s, 1H).

Preparation example 4

4-[4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl] methoxybenzaldehyde

Under nitrogen atmosphere, under 25 ℃, to 4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2-methyl alcohol (6.0g, add in methylene dichloride 33.51mmol) (20mL) solution triethylamine (10.15g, 100.5mmol).Under 0 ℃, in above-mentioned reaction mixture, add methylsulfonyl chloride (5.75g, 50.25mmol), 25 ℃ of following restir 10 hours.Add entry (50mL), with chloroform extraction (2 * 25mL).Dried over sodium sulfate is used in organic extract liquid water (50mL) washing after the merging, filters, and decompression steams solvent.Resistates carries out chromatography with silica gel, adopts the mixture (2: 8) of ethyl acetate and hexane, obtains methylsulfonic acid (4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) methyl esters (3.7g, 43%), is a kind of slurries.

¹H NMR (CDCl ₃, 200MHz): 2.88 (s, 3H), 3.07 (s, 3H), 3.13-3.31 (complicated peak, 2H), 4.41 (d, J=5.2 Hz, 2H), 4.53-4.55 (complicated peak, 1H), 6.81-6.89 (complicated peak, 4H).

With methylsulfonic acid (4-methyl-3,4-dihydro-2H-1,4-benzoxazine-4-yl) methyl esters (3.7g, 14.39mmol), 4-hydroxy benzaldehyde (2.6g, 21.29mmol) and salt of wormwood (5.9g, 42.7mmol) mixture in anhydrous dimethyl formamide (30mL) stirred 10 hours down at 80 ℃.Add entry (100mL), with ethyl acetate extraction (2 * 70mL).Dried over sodium sulfate is used in organic layer water (50mL) after the merging and salt solution (50mL) washing, filters, and decompression steams solvent.Resistates carries out chromatography with silica gel, adopts mixture (2: the 8) wash-out of ethyl acetate and sherwood oil, obtains title compound (1.3g, 32%), is a kind of heavy-gravity liquid.

¹H NMR (CDCl ₃, 200MHz): 2.93 (s, 3H), 3.24-3.46 (complicated peak, 2H), 4.14-4.37 (complicated peak, 2H), 4.68-4.71 (complicated peak, 1H), 6.72-7.10 (complicated peak, 6H), 7.86 (d, J=8.8Hz, 2H), 9.92 (s, 1H).

Preparation example 5

4-[4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) methoxybenzaldehyde

According to preparation example 4 similar methods, by 4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-methyl alcohol (4.0g, 15.68mmol) preparation title compound (3.2g, 80%), be light yellow solid.mp：92-94℃。

¹H NMR (CDCl ₃, 200MHz): 3.38-3.43 (complicated peak, 2H), 4.14-4.32 (complicated peak, 2H), 4.46 (d, J=7.8Hz, 2H), 4.60-4.65 (complicated peak, 1H), 6.65-6.89 (complicated peak, 4H), 7.00 (d, J=8.8Hz, 2H), 7.32 (5,5H), 7.83 (d, J=8.8Hz, 2H), 9.90 (s, 1H).

Embodiment 1

(E/Z)-and 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-second Oxygen base ethyl propenoate

Under nitrogen atmosphere, with 2-oxyethyl group phosphine acyl acetic acid three ethyl (W.Grell and H.Machleidt, Annalen Chemie, 1960, 699,53) and ((1.39g is in the ice-cold suspension of anhydrous tetrahydro furan 29.1mmol) (5mL) for 7.8g, anhydrous tetrahydro furan 29.1mmol) (15mL) the solution sodium hydride (60%, oily dispersion liquid) under adding to lentamente and stirring.Mixture was stirred 30 minutes down at 0 ℃, add 4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group again] phenyl aldehyde (7.5g, 26.5mmol) anhydrous tetrahydro furan (20mL) solution of (according to the disclosed preparation example 1 described method preparation of U.S. Patent application 08/982,910).Mixture is warming up to 25 ℃, restir 20 hours.Steam solvent, resistates is suspended in (100mL), with ethyl acetate extraction (2 * 75mL).Dried over sodium sulfate is used in ethyl acetate layer water (75mL) after the merging and salt solution (50mL) washing, filters, and decompression steams solvent.Resistates carries out chromatography with silica gel, and the mixture (2: 8) that adopts ethyl acetate and sherwood oil obtains title compound (8.0g as elutriant, 75%), being a kind of jelly, is 65: 35 Z: the mixture of E geometrical isomer (R.A.Aitken and G.L.Thom, synthetic 1989, 958).

¹H NMR (CDCl ₃, 200MHz): 1.18 and 1.36 (compound 6H, isomery OEt, triplet signals), 3.51 (t, J=4.48Hz, 2H), 3.71 (t, J=5.39Hz, 2H), 3.89-4.03 (complicated peak, 2H), 4.10-4.34 (complicated peak, 6H), 6.07 (s, 0.35H, E olefinic proton), and 6.63-7.14 (complicated peak, 6.65H), 7.73 (d, J=8.72Hz, 2H).

Embodiment 2

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-the 2-ethoxy-propionic acid Methyl esters

(E/Z)-3-[4-[2-(2 with embodiment 1 acquisition, 3-dihydro-1,4-benzoxazine 4-yl) oxyethyl group] phenyl]-the 2-ethoxy ethyl acrylate (8.0g, 20.0mmol) and magnesium chips (9.64g, 396.7mmol) mixture in anhydrous methanol (50mL) stirred 20 hours down in 25 ℃.After this, add entry (50mL), regulate pH to about 7.0 with 10% aqueous hydrochloric acid, solution is with ethyl acetate extraction (2 * 10mL).Dried over sodium sulfate is used in organic extract liquid water (75mL) after the merging and salt solution (75mL) washing, filters removal of solvent under reduced pressure.Resistates carries out chromatography with silica gel, adopts the mixture (2: 8) of ethyl acetate and sherwood oil to make elutriant, obtains title compound (5.0g, 64%), is colloidal liquid.

¹H NMR (CDCl ₃, 200MHz): 1.15 (t, J=7.0Hz, 3H), 2.93 (d, J=6.64Hz, 2H), 3.23-3.38 (complicated peak, 1H), 3.43-3.72 (complicated peak, 8H), 3.97 (t, J=6.9Hz, 1H), 4.14 (t, J=5.81Hz, 2H), 4.19 (t, J=4.2Hz, 2H), 6.55-6.83 (complicated peak, 6H), 7.13 (d, J=8.39Hz, 2H).

Embodiment 3

(E/Z)-3-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) methyl cumarone-5-yl)-2- Ethoxy ethyl acrylate

According to method similar to Example 1, (1.0g 3.41mmol) makes title compound (0.8g, 58%), is gelatinoid by 5-formyl radical-2-(2,3-dihydro-1,4-benzoxazine-4-yl) methyl cumarone.

¹H NMR (CDCl ₃, 200MHz): 1.06 and 1.38 (6H, OCH ₂CH ₃And OCH ₂CH ₃, the triplet signal), 3.48 (t, J=4.98Hz, 2H), 3.89-4.18 (complicated peak, 2H), 4.28-4.40 (complicated peak, 4H), 4.54 and 4.56 (compound, 2H ,-NCH ₂-signal), 6.20 (0.5H, E olefinic proton isomer), 6.52 and 6.59 (compound, 1H), 6.65-6.83 (complicated peak, 2.5H), 7.08-7.11 (complicated peak, 1H), 7.32-7.44 (complicated peak, 2H), 7.69 (d, J=8.3Hz, 1H), 7.99 (s, 1H).

Embodiment 4

(E/Z)-and 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-second Oxygen base ethyl propenoate

According to being similar to embodiment 1 described method, by according to patent application 08/982, the 4-[2-(2 that 910 disclosed preparation example 2 described methods make, 3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl aldehyde (3.3g, 11.03mmol) prepare gluey title compound (3.2g, 71%), its be 38: 62 geometrical isomers (according to ¹H NMR records).

¹H NMR (CDCl ₃, 200MHz): 1.14 and 1.35 (compound, 6H, isomery OCH ₂CH ₃The triplet signal), 3.02 (t, J=4.9Hz, 2H), 3.69-3.88 (complicated peak, 4H), 3.92-4.03 (complicated peak, 2H), 4.12-4.33 (complicated peak, 4H), 6.06 (s, 0.38H, E olefinic proton), 6.61-7.14 (complicated peak, 6.62H), 7.73 (d, J=8.81Hz, 2H).

Embodiment 5

3-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) methyl cumarone-5-yl]-the 2-oxyethyl group Methyl propionate

According to being similar to embodiment 2 described methods, and (the E/Z)-3-[2-that obtains by embodiment 3 (2,3-dihydro-1,4-benzoxazine-4-yl) methyl cumarone-5-yl]-2-ethoxy ethyl acrylate (0.8g, 1.96mmol) make title compound (0.6g, 78%), for-kind of jelly.

¹H NMR (CDCl ₃, 200MHz): 1.15 (t, J=7.0Hz, 3H), 3.07 (d, J=5.8Hz, 2H), 3.28-3.67 (complicated peak, 4H), 3.70 (s, 3H), 4.03 (t, J=6.0Hz, 1H), 4.28 (t, J=4.47Hz, 2H), 4.54 (s, 2H), 6.52 (s, 1H), and 6.62-6.89 (complicated peak, 4H), 7.10 (d, J=7.05Hz, 1H), 7.35 (complicated peak, 2H).

Embodiment 6

3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-the 2-ethoxy-c The acid methyl esters

According to being similar to embodiment 2 described methods, and (the E/Z)-3-[4-[2-that obtains by embodiment 4 (2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy ethyl acrylate (3.1g, 7.50mmol) make title compound (2.3g, 76%), be a kind of colloidal liquid.

¹H NMR (CDCl ₃, 200MHz): 1.15 (t, J=7.01Hz, 3H), 2.93 (d, J=6.65Hz, 2H), 3.03 (t, J=5.21Hz, 2H), 3.23-3.41 (complicated peak, 1H), 3.52-3.80 (complicated peak, 8H), 3.97 (t, J=7.01Hz, 1H), 4.14 (t, J=5.81Hz, 2H), and 6.61-6.82 (complicated peak, 4H), 6.92-7.05 (complicated peak, 2H), 7.13 (d, J=8.53Hz, 2H).

Embodiment 7

2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-second Oxygen base methyl propionate

Under-78 ℃, the 3-[4-[2-(2 that in embodiment 2, obtains, 3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters (0.6g, 1.5mmol) anhydrous tetrahydro furan (5mL) solution in add di-isopropyl lithamide (5.25L, the THF/ hexane solution of 0.5mL).-78 ℃ down stir 1 hour after, add methyl-iodide (0.75mL), reaction mixture is warming up to room temperature (about 25 ℃), and under this temperature restir 20 hours.Add entry (20mL), use the 1N hcl acidifying, with ethyl acetate extraction (2 * 25mL).Dried over sodium sulfate is used in ethyl acetate layer water (25mL) after the merging and salt solution (25mL) washing, filters, and decompression steams solvent, obtains title compound (0.5g, 80%), is a kind of oil.

¹H NMR (CDCl ₃, 200MHz): 1.21 (t, J=6.97Hz, 3H), 1.31 (s, 3H), 2.95 (s, 2H), 3.32-3.58 (complicated peak, 4H), 3.62-3.84 (complicated peak, 5H), 4.14 (t, J=5.81Hz, 2H), 4.22 (t, J=4.25Hz, 2H), 6.55-6.88 (complicated peak, 6H), 7.08 (d, J=8.63Hz, 2H).

Embodiment 8

2-(2-luorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] benzene Base]-the 2-ethoxy-propionic acid

According to being similar to embodiment 7 described methods, and the 3-[4-[2-that obtains by embodiment 2 (2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters (0.6g, 1.5mmol) make title compound (0.6g, 78%), be a kind of brown liquid.

¹H NMR(CDCl ₃，200MHz)：1.22(t，J＝6.96Hz，3H)。3.03-3.18 (complicated peak, 4H), 3.51 (t, J=4.2Hz, 2H), 3.59-3.71 (complicated peak, 7H), 4.14 (t, J=5.81Hz, 2H), 4.22 (t, J=4.24Hz, 2H), 6.42-6.85 (complicated peak, 6H), 6.90-7.32 (complicated peak, 6H).

Embodiment 9

(E/Z)-and 3-[4-[2-(3-oxo-2H-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-second Oxygen base ethyl propenoate

According to being similar to embodiment 1 described method, by 4-[2-(3-oxo-2H-1, the 4-benzoxazine-4-yl) oxyethyl group of preparation example 1 acquisition] phenyl aldehyde (2.9g, 9.7mmol) make title compound (3.9g, 97%), be 32: 68 E: Z isomer is a kind of white solid.mp：92-95℃。

¹H NMR (CDCl ₃, 200MHz): 1.13-1.43 (complicated peak, 6H), 3.88-4.02 (complicated peak, 2H), 4.07-4.40 (complicated peak, 6H), 4.60 (s, 2H), 6.05 (s, 0.32H, E olefinic protons), 6.76-7.32 (complicated peak, 6.68H), 7.71 (d, J=8.72Hz, 2H).

Embodiment 10

3-[4-[2-(3-oxo-2H-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-the 2-ethoxy-c The acid methyl esters

According to being similar to embodiment 2 described methods, (E/Z)-3-[4-[2-(3-oxo-2H-1,4-benzoxazine-4-yl) oxyethyl group by embodiment 9 acquisitions] phenyl]-(2.0g 4.8mmol) makes title compound (1.0g to the 2-ethoxy ethyl acrylate, 51%), is a kind of colourless soup compound.

¹H NMR(CDCl ₃，200MHz)：1.14(t，J＝7.0Hz，3H)。2.92 (d, J=6.6Hz, 2H), 3.25-3.41 (complicated peak, 1H), 3.53-3.61 (complicated peak, 1H), 3.68 (s, 3H), 3.96 (t, J=7.0Hz, 1H), 4.21-4.32 (complicated peak, 4H), 4.68 (s, 2H), 6.77 (d, J=8.63Hz, 2H), 6.98-7.33 (complicated peak, 6H).

Embodiment 11

(E/Z)-and 3-[6-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthyl]-2-second Oxygen base ethyl propenoate

According to being similar to embodiment 1 described method, and the 6-[2-that obtains by preparation example 3 (2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] (1.5g 4.29mmol) makes title compound (1.74g, 87%) to naphthaldehyde, be 1: the 1E/Z mixture of isomers is a kind of brown soup compound.

¹H NMR (CDCl ₃, 200MHz): 0.99-1.47 (complicated peak, 6H), 3.06 (t, J=4.98Hz, 2H), 3.79-3.95 (complicated peak, 4H), 3.99-4.18 (complicated peak, 2H), 4.25-4.37 (complicated peak, 4H), (6.23 s, 0.5H, E olefinic proton), 6.59-6.79 (complicated peak, 2H), and 6.97-7.29 (complicated peak, 4.5H), 7.57-7.95 (complicated peak, 3H), 8.14 (s, 1H).

Embodiment 12

3-[6-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthyl]-the 2-ethoxy-c The acid methyl esters

According to being similar to embodiment 2 described methods, (E/Z)-3-[6-[2-(2 by embodiment 11 acquisitions, 3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthyl]-2-ethoxy ethyl acrylate (1.7g, 3.67mmol) make title compound (1.25g, 75%), is a kind of colourless soup compound.

¹H NMR (CDCl ₃, 200MHz): 1.14 (t, J=7.06Hz, 3H), 3.06 (t, J=5.21Hz, 2H), 3.13 (d, J=7.15Hz, 2H), 3.29-3.37 (complicated peak, 1H), 3.57-3.64 (complicated peak, 1H), 3.70 (s, 3H), and 3.77-3.83 (complicated peak, 4H), 4.09 (t, J=7.2Hz, 1H), 4.25 (t, J=5.81Hz, 2H), 6.62-6.79 (complicated peak, 2H), and 6.96-7.36 (complicated peak, 5H), 7.60-7.70 (complicated peak, 3H).

Embodiment 13

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2 hydroxy propanoic acid second Ester

Employing is similar to preparation example 2 described conditions, by methylsulfonic acid 2-(2,3 dihydros-1,4-benzoxazine-4-yl) ethyl ester (0.36g, 1.42mmol), salt of wormwood (0.80g, 5.8mmol) and 2-hydroxyl-3-(4-hydroxy phenyl) ethyl propionate (0.3g, 1.42mmol) make title compound (0.14g, 32%), be a kind of colloidal liquid.

¹H NMR (CDCl ₃, 200MHz): 1.24 (t, J=7.15Hz, 3H), 2.71 (d, J=6.23Hz, 1H, D ₂O is commutative), 2.84-3.10 (complicated peak, 2H), 3.50 (t, J=4.47Hz, 2H), 3.67 (t, J=5.48Hz, 2H), 4.11-4.26 (complicated peak, 6H), 4.37-4.39 (complicated peak, 1H), 6.61-6.86 (complicated peak, 6H), 7.11 (d, J=8.62Hz, 2H).

Embodiment 14

3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2 hydroxy-propionic acid second Ester

Employing is similar to preparation example 2 described conditions, by methylsulfonic acid 2-(2,3 dihydros-1,4-benzothiazine-4-yl) ethyl ester (8.2g, 30.0mmol), salt of wormwood (20.7g, 150mmol) with 2-hydroxyl-3-(4-hydroxy phenyl) ethyl propionate (6.3g, 30.0mmol) make title compound (1.9g, 17%), be a kind of colloidal liquid.

¹H NMR (CDCl ₃, 200MHz): 1.29 (t, J=7.11Hz, 3H), 2.70-2.80 (bs, 1H, D ₂O is commutative), and 2.82-3.15 (complicated peak, 4H), 3.65-3.82 (complicated peak, 4H), 4.10-4.30 (complicated peak, 4H), 4.28-4.40 (complicated peak, 1H), 6.62-6.89 (complicated peak, 4H), 6.92-7.18 (complicated peak, 4H).

Embodiment 15

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-benzyloxy propionic acid Ethyl ester

Under nitrogen atmosphere, 3-[4-[2-(2 with embodiment 13 acquisitions, 3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2 hydroxy propanoic acid ethyl ester (0.5g, 1.34mmol) anhydrous dimethyl formamide (5mL) solution add to stir and ice-cooled under sodium hydride (60%, the oil dispersion liquid) (0.08g is in anhydrous dimethyl formamide 1.66mmol) (3mL) suspension.Reaction mixture was stirred 30 minutes down at 0 ℃, add again bromotoluene (0.46g, 2.69mmol).Mixture is warming up to 25 ℃, restir 18 hours.Add entry (25mL), with ethyl acetate extraction (2 * 50mL).Organic layer water (50mL) after the merging and salt solution (50mL) washing, use dried over sodium sulfate, to filter. decompression steams solvent, resistates carries out chromatography with silica gel, adopt the mixture (2: 8) of ethyl acetate and sherwood oil to make elutriant, obtain title compound (0.3g) and 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-benzyloxy benzyl propionate.This mixture (1: 1) is used for embodiment 47 without separation.

¹H NMR (CDCl ₃, 200MHz): 1.23 (t, J=7.05Hz, 1.5H), 2.99 (d, J=7.06Hz, 4H), 3.0-3.72 (complicated peak, 8H), 4.05-4.30 (complicated peak, 12H), and 4.32-4.71 (complicated peak, 4H), 5.13 (s, 2H), 6.55-6.89 (complicated peak, 12H), and 7.05-7.36 (complicated peak, 19H).

Embodiment 16

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-butoxy propionic acid Ethyl ester

Adopt similar preparation example 2 described conditions, by methylsulfonic acid 2-(2,3 dihydros-1,4-benzoxazine-4-yl) ethyl ester (0.46g, 1.78mmol), salt of wormwood (0.98g, 7.12mmol) and 2-butoxy-3-(4-hydroxy phenyl) ethyl propionate (0.47g, 1.78mmol) make title compound (0.4g, 52%), be a kind of colloidal liquid.

¹H NMR (CDCl ₃, 200MHz): 0.84 (t, J=7.53Hz, 3H), 1.19-1.34 (complicated peak, 5H), and 1.43-1.55 (complicated peak, 2H), 2.92 (d, J=6.32Hz, 2H), and 3.22-3.36 (complicated peak, 1H), 3.48-3.59 (complicated peak, 3H), 3.68 (t, J=5.82Hz, 2H), 3.93 (t, J=6.2Hz, 1H), and 4.11-4.24 (complicated peak, 6H), 6.61-6.86 (complicated peak, 6H), 7.13 (d, J=8.3Hz, 2H).

Embodiment 17

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-hexyloxy propionic acid Ethyl ester

Adopt similar preparation example 2 described conditions, by methylsulfonic acid 2-(2,3 dihydros-1,4-benzoxazine-4-yl) ethyl ester (0.35g, 1.3mmol), salt of wormwood (0.75g, 5.4mmol) and 2-hexyloxy-3-(4-hydroxy phenyl) ethyl propionate (0.4g, 1.3mmol) make title compound (0.31g, 50%), be a kind of colourless soup compound.

¹H NMR (CDCl ₃, 200MHz): 0.85 (t, J=5.72Hz, 3H), 1.20-1.34 (complicated peak, 7H), and 1.40-1.66 (complicated peak, 4H), 2.93 (d, J=6.0Hz, 2H), and 3.21-3.31 (complicated peak, 1H), 3.49-3.60 (complicated peak, 3H), 3.68 (t, J=5.72Hz, 2H), 3.93 (t, J=5.81Hz, 1H), 4.11-4.24 (complicated peak, 6H), 6.62-6.81 (complicated peak, 5H), 7.09-7.16 (complicated peak, 3H).

Embodiment 18

(E/Z)-and 3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-benzene Oxygen base ethyl propenoate

According to being similar to embodiment 1 described method, by 4-[2-(2,3-dihydro-1; 4-benzoxazine-4-yl) oxyethyl group] phenyl aldehyde (1.0g; 3.0mmol) and 2-phenoxy group phosphine acyl acetic acid three ethyl (A.G.Schultz etc., organic chemistry magazine, 1983; 48; 3408) (1.3g 4.0mmol) makes title compound (0.92g, 58%); it is E: the mixture of Z isomer (40: 60) is a kind of paste liquid.

¹H NMR (CDCl ₃, 200MHz): 1.06 and 1.18 (compound 3H, isomery OCH ₂CH ₃, the triplet signal), and 3.43-3.57 (complicated peak, 2H), 3.64-3.75 (complicated peak, 2H), 4.06-4.28 (complicated peak, 6H), 6.60-6.90 (complicated peak, 8H), 6.94-7.12 (complicated peak, 2H), 7.22-7.45 (complicated peak, 3H), 7.64 (d, J=8.72Hz, 1H).

Embodiment 19

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-the 2-phenoxy propionic acid Methyl esters

According to being similar to embodiment 2 described methods, and (the E/Z)-3-[4-[2-that obtains by embodiment 18 (2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy group ethyl propenoate (0.9g, 2.0mmol) make title compound (0.49g, 57%), be a kind of gelatinoid.

¹H NMR (CDCl ₃, 200MHz): 3.17 (d, J=6.2Hz, 2H), 3.50 (t, J=4.3Hz, 2H), 3.65-3.70 (complicated peak, 5H), 4.14 (t, J=5.76Hz, 2H), 4.21 (t, J=4.15Hz, 2H), 4.75 (t, J=6.4Hz, 1H), 6.61-6.98 (complicated peak, 9H), and 7.17-7.27 (complicated peak, 4H).

Embodiment 20

(E/Z)-and 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-benzene Oxygen base ethyl propenoate

According to being similar to embodiment 1 described method, by 4-[2-(2,3-dihydro-1; 4-benzothiazine-4-yl] oxyethyl group] phenyl aldehyde (4.0g; 13.0mmol) and 2-phenoxy group phosphine acyl acetic acid three ethyl (A.G.Schultz etc., organic chemistry magazine, 1983; 48; 3408) (5.07g 16.0mmol) makes title compound (3.7g, 60%); be E: the mixture of Z isomer (35: 65) is a kind of gelatinoid.

¹H NMR (CDCl ₃, 200MHz): 1.05-1.36 (complicated peak, 3H), 3.00-3.11 (complicated peak, 2H), 3.64-3.85 (complicated peak, 4H), and 4.09-4.30 (complicated peak, 4H), 6.58-7.13 (complicated peak, 8H), 7.20-7.46 (complicated peak, 4H), 7.65 (d, J=8.7Hz, 2H).

Embodiment 21

3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy group third The acid methyl esters

According to being similar to embodiment 2 described methods, and (the E/Z)-3-[4-[2-that obtains by embodiment 20 (2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid ethyl ester (3.7g, 8.0mmol) make title compound (2.3g, 64%), be a kind of gelatinoid.

¹H NMR (CDCl ₃, 200MHz): 2.99 (t, J=5.439Hz, 2H), 3.15 (d, J=5.99Hz, 2H), 3.60-3.78 (complicated peak, 7H), 4.13 (t, J=5.4Hz, 2H), 4.74 (t, J=6.23Hz, 1H), 6.58-6.89 (complicated peak, 6H), 6.90-7.06 (complicated peak, 2H), and 7.11-7.30 (complicated peak, 5H).

Embodiment 22

(E/Z)-3-[4-(4-methyl-2,3-dihydro-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2- Ethoxy ethyl acrylate

According to being similar to embodiment 1 described method, 4-(4-methyl-3 by preparation example 4 acquisitions, 4-dihydro-2H-1,4-benzoxazine-2-yl) methoxybenzaldehyde (1.2g, 4.24mmol) make title compound (0.4g, 25%), be E: the mixture of Z isomer (1: 1) is a kind of brown liquid.

¹H NMR (CDCl ₃, 200MHz): 1.36 (t, J=7.1Hz, 6H), 2.90 (s, 3H), 3.26-3.45 (complicated peak, 2H), 3.99 (q, J=7.2Hz, 2H), 4.10-4.38 (complicated peak, 4H), and 4.50-4.60 (complicated peak, 1H), 6.70 (d, J=7.47Hz, 2H), 6.81-6.90 (complicated peak, 5H), 7.75 (d, J=8.8Hz, 2H).

Embodiment 23

3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-the 2-ethoxy The base methyl propionate

According to being similar to embodiment 2 described methods, (E/Z)-3-[4-(4-methyl-3 by embodiment 22 acquisitions, 4-dihydro-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy ethyl acrylate (0.4g, 1.0mmol) make title compound (0.25g, 65%), is a kind of thick liquid.

¹H NMR (CDCl ₃, 200MHz): 1.16 (t, J=7.0Hz, 3H), 2.89 (s, 3H), 2.95 (d, J=6.2Hz, 2H), and 3.19-3.41 (complicated peak, 3H), 3.55-3.66 (complicated peak, 1H), 3.70 (s, 3H), 3.95-4.24 (complicated peak, 3H), and 4.60-4.64 (complicated peak, 1H), 6.64-7.08 (complicated peak, 6H), 7.15 (d, J=8.4Hz, 2H).

Embodiment 24

(E/Z)-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]- The 2-ethoxy ethyl acrylate

According to being similar to embodiment 1 described method, 4-[4-benzyl-3 by preparation example 5 acquisitions, 4-dihydro-2H-1,4-benzoxazine-2-yl) methoxybenzaldehyde (3.0g, 8.35mmol) make title compound (3.0g, 76%), be E: the mixture of Z isomer (1: 1) is a kind of paste liquid.

¹H NMR (CDCl ₃, 200MHz): 1.33-1.40 (complicated peak, 6H), 3.39-3.44 (complicated peak, 2H), 3.99 (q, J=7.0Hz, 2H), 4.11-4.38 (complicated peak, 4H), 4.46 (d, J=5.0Hz, 2H), and 4.52-4.66 (complicated peak, 1H), 6.60-6.97 (complicated peak, 7H), 7.28 (s, 5H), 7.75 (d, J=8.8Hz, 2H).

Embodiment 25

3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-the 2-ethoxy The base methyl propionate

According to being similar to embodiment 2 described methods, (E/Z)-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl by embodiment 24 acquisitions]-2-ethoxy ethyl acrylate (1.5g, 3.17mmol) make title compound (1.5g, 100%).

¹H NMR (CDCl ₃, 200MHz): 1.17 (t, J=7.0Hz, 3H), 2.96 (d, J=6.6Hz, 2H), 3.31-3.57 (complicated peak, 3H), 3.60-3.70 (complicated peak, 1H), 3.71 (s, 3H), 3.97-4.26 (complicated peak, 3H), 4.47 (d, J=4.0Hz, 2H), 4.56-4.61 (complicated peak, 1H), and 6.68-6.90 (complicated peak, 6H), 7.15 (d, J=8.5Hz, 2H), 7.29 (s, 5H).

Embodiment 26

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl)-the 2-ethoxy-propionic acid

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group to embodiment 2 acquisitions] phenyl]-(4.7g adds 10% aqueous sodium hydroxide solution (28mL) to 2-ethoxy-propionic acid methyl esters in methyl alcohol 12.2mmol) (50mL) solution.Mixture was stirred 3 hours down at 25 ℃.Removal of solvent under reduced pressure, resistates 2N hcl acidifying is with ethyl acetate extraction (2 * 100mL).Dried over sodium sulfate is used in ethyl acetate layer water (75mL) after the merging and salt solution (50mL) washing, filters, decompression steams solvent, and resistates carries out chromatography with silica gel, adopts eluent ethyl acetate, obtain title compound (3.0g, 66%), be a kind of paste liquid.

¹H NMR (CDCl ₃, 200MHz): 1.17 (t, J=6.96Hz, 3H), 2.85-3.12 (complicated peak, 2H), 3.40-3.61 (complicated peak, 4H), 3.69 (t, J=5.72 Hz, 2H), 4.04 (dd, J=7.38 and 4.27Hz, 1H), 4.10-4.28 (complicated peak, 4H), 6.52-6.85 (complicated peak, 6H), 7.14 (d, J=8.6Hz, 2H), the COOH proton is too wide and can not observe.

Embodiment 27

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-the 2-ethoxy-propionic acid, Sodium salt

3-[4-[2-(2,3-dihydro-1, the 4-benzoxazine-4-yl) oxyethyl group that embodiment 26 is obtained] phenyl]-the 2-ethoxy-propionic acid (0.15g, 0.4mmol) and the mixture of the sodium methylate (23.4mg) in the methyl alcohol (5mL) 25 ℃ of stirrings 2 hours down.Remove and desolvate, resistates develops (3 * 10mL) with anhydrous diethyl ether.Leach the solid that is settled out, (2 * 5mL) washings by the P2O5 drying, obtain title compound (0.12g, 75%) under vacuum, be colourless water absorbability solid with anhydrous diethyl ether.

¹H NMR (DMSO-d ₆, 200MHz): δ 0.98 (t, J=6.83Hz, 3H), 2.60-2.69 (complicated peak, 1H), 2.78-2.92 (complicated peak, 1H), and 3.05-3.21 (complicated peak, 2H), 3.41-3.75 (complicated peak, 5H), 4.08-4.21 (complicated peak, 4H), and 6.49-6.85 (complicated peak, 61-:1), 7.12 (d, J=8.3Hz, 2H).

Embodiment 28

3-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) methyl cumarone-5-yl]-the 2-oxyethyl group Propionic acid

According to being similar to embodiment 26 described methods, and the 3-[2-that obtains by embodiment 5 (2,3-dihydro-1,4-benzoxazine-4-yl) methyl cumarone-5-yl]-2-ethoxy-propionic acid methyl esters (0.6g, 1.51mmol) make title compound (0.5g, 87%), be a kind of gelatinoid.

¹H NMR (CDCl ₃, 200MHz) δ: 1.26 (t, J=7.06 Hz, 3H), 3.05-3.28 (complicated peak, 2H), and 3.40-3.68 (complicated peak, 4H), 4.09 (dd, J=7.47 and 4.24 Hz, 1H), 4.28 (t, J=4.15 Hz, 2H), 4.53 (s, 2H), 6.52 (s, 1H), 6.60-6.90 (complicated peak, 4H), 7.13 (d, J=8.7Hz, 1H), (complicated peak, 2H), the COOH proton is too wide and can not observe for 7.32-7.36.

Embodiment 29

3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-the 2-ethoxy-c Acid

According to being similar to embodiment 26 described methods, and the 3-[4-[2-that obtains by embodiment 6 (2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters (2.3g, 5.73mmol) make title compound (1.4g, 63%), be a kind of gelatinoid.

¹H NMR (CDCl ₃, 200MHz) δ: 1.18 (t, J=7.0Hz, 3H), 2.82-3.15 (complicated peak, 4H), and 3.40-3.68 (complicated peak, 2H), 3.70-3.81 (complicated peak, 4H), 4.05 (dd, J=7.29,4.33 Hz, 1H), 4.16 (t, J=5.72 Hz, 2H), 6.68-6.74 (complicated peak, 2H), 6.81 (d, J=8.5Hz, 2H), 6.94-7.06 (complicated peak, 2H), 7.14 (d, J=8.5Hz, 2H).The COOH proton is too wide and can not observe.

Embodiment 30

3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-the 2-ethoxy-c Acid, sodium salt

According to being similar to embodiment 27 described methods, and the 3-[4-[2-that obtains by embodiment 29 (2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid (0.5g, 1.30mmol) make title compound (0.42g, 81%), be colorless solid.

¹H NMR (CDCl ₃, 200 MHz): δ 0.98 (t, J=7.0Hz, 3H), 2.72-3.25 (complicated peak, 5H), 3.30-3.51 (complicated peak, 1H), 3.61-3.73 (complicated peak, 4H), 3.82-3.91 (complicated peak, 1H), 4.04 (t, J=5.72Hz, 2H), 6.52-6.79 (complicated peak, 4H), and 6.91-7.03 (complicated peak, 2H), 7.10 (d, J=8.4Hz, 2H).

Embodiment 31

3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-the 2-ethoxy-c Acid amides

With oxalyl chloride (0.28mL, 3.1mmol) and 3-[4-[2-(2,3-dihydro-1, the 4-benzothiazine-4-yl) oxyethyl group that obtains of embodiment 29] phenyl]-(0.6g, anhydrous methylene chloride 1.55mmol) (10mL) solution refluxed 2 hours the 2-ethoxy-propionic acid.Removal of solvent under reduced pressure and excessive oxalyl chloride.Resistates is dissolved in the methylene dichloride, and stirred 30 minutes with ammoniacal liquor (5mL).Reaction mixture chloroform extraction (2 * 25mL).Dried over sodium sulfate is used in chloroform layer water (25mL) washing after the merging, filters, and decompression steams solvent.Resistates carries out chromatography with silica gel, adopts the mixture (7: 3) of ethyl acetate and sherwood oil to make elutriant, obtains title compound (0.32g, 54%), is a kind of colorless solid.mp：120-122℃。

¹H NMR (CDCl ₃, 200MHz): δ 1.15 (t, J=6.96Hz, 3H), 2.81-3.20 (complicated peak, 4H), 3.38-3.58 (complicated peak, 2H), 3.71-3.90 (complicated peak, 4H), 3.91 (dd, J=7.38 and 3.73 Hz, 1H), 4.16 (t, J=5.58Hz, 2H), 5.54 (bs, D ₂O is commutative, 1H), and 6.44 (bs, D ₂O is commutative, 1H), 6.59-6.84 (complicated peak, 4H), 6.92-7.19 (complicated peak, 4H).

Embodiment 32

N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) methoxyl group] phenyl]-2-second Oxygen base propionic acid amide

The 3-[4-[2-(2 that embodiment 29 under ice-cooled obtains, 3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid (0.3g, 0.78mmol) and triethylamine (0.162g, 1.6mmol) anhydrous methyl chloride (10mL) solution in add pivalyl chloride (0.10g, 0.86mmol), and under 0 ℃, stirred 30 minutes.Under 25 ℃, in above-mentioned reaction mixture, add methylamine (40% solution) (0.124mL), continue to stir 1 hour down at 25 ℃.Add entry (20mL), with ethyl acetate extraction (2 * 20mL).Dried over sodium sulfate is used in organic extract liquid water (10mL) after the merging and salt solution (10mL) washing, filters, and decompression steams solvent.Resistates carries out chromatography with silica gel, adopts mixture (1: the 1) wash-out of ethyl acetate and sherwood oil, obtains title compound, is colorless solid.mp：80-82℃。

¹H NMR (CDCl ₃, 200MHz): δ 1.11 (t, J=7.0Hz, 3H), 2.76 (d, J=4.89Hz, 3H), 2.81-2.88 (complicated peak, 1H), 3.01-3.12 (complicated peak, 3H), and 3.39-3.52 (complicated peak, 2H), 3.70-3.81 (complicated peak, 4H), and 3.86-3.91 (complicated peak, 1H), 4.14 (t, J=5.81Hz, 2H), 6.48 (bs, 1H), 6.61-6.81 (complicated peak, 4H), 6.94-7.14 (complicated peak, 4H).

Embodiment 33

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-the 2-oxyethyl group Propionic acid amide

According to being similar to embodiment 31 described methods, by 3-[4-[2-(2,3 dihydros-1 of embodiment 26 acquisitions, 4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid (0.25g, 0.67mmol) and ammoniacal liquor (4mL) make title compound (0.2g, 80%), be a kind of white solid.mp：107-109℃。

¹H NMR (CDCl ₃, 200MHz): δ 1.13 (t, J=6.96Hz 3H), 2.81-2.93 (complicated peak, 1H), and 3.03-3.19 (complicated peak, 1H), 3.34-3.59 (complicated peak, 4H), 3.69 (t, J=5.53Hz, 2H), 3.88 (dd, J=7.43 and 3.7Hz, 1H), 4.15 (t, J=5.58Hz, 2H), 4.28 (t, J=4.24Hz, 2H), 5.49 (bs, 1H, D ₂O is commutative), 6.43 (bs, 1H, D ₂O is commutative), 6.68-6.87 (complicated peak, 6H), 7.15 (d, J=8.49Hz, 2H).

Embodiment 34

N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-second Oxygen base propionic acid amide

According to being similar to embodiment 32 described methods, 3-[4-[2-(2 by embodiment 26 acquisitions, 3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid (0.3g, 0.8mmol) and methylamine (40% solution) (2mL) make title compound (0.23g, 74%), is a kind of white solid.mp：97-99℃。

¹H NMR (CDCl ₃, 200MHz): δ 1.14 (t, J=7.0Hz, 3H), 2.76 (d, J=4.98Hz, 3H), and 4.80-4.90 (complicated peak, 1H), 3.02-3.14 (complicated peak, 1H), 3.35-3.45 (complicated peak, 2H), 3.52 (t, J=4.57Hz, 2H), 3.68 (t, J=5.81Hz, 2H), 7.88 (dd, J=7.06 and 3.74Hz, 1H), 4.14 (t, J=5.72Hz, 2H), 4.22 (t, J=4.15Hz, 2H), 6.50 (bs, 1H), 6.55-6.89 (complicated peak, 6H), 7.11 (d, J=8.3Hz, 2H).

Embodiment 35

N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-second Oxygen base propionic acid amide

According to being similar to embodiment 32 described methods, 3-[4-[2-(2 by embodiment 26 acquisitions, 3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid (0.3g, 0.8mmol) and benzyl amine (0.095g, 0.88mmol) make title compound (0.25g, 67%), be a kind of white solid.mp：94-96℃。

¹H NMR (CDCl ₃, 200MHz): δ 1.11 (t, J=7.0Hz, 3H), 2.82-3.18 (complicated peak, 2H), and 3.40-3.55 (complicated peak, 4H), 3.70 (t, J=5.49Hz, 2H), 3.94-3.98 (complicated peak, 1H), 4.14 (t, J=5.72Hz, 2H), 4.23 (t, J=4.24Hz, 2H), 4.28-4.52 (complicated peak, 2H), 6.60-6.87 (complicated peak, 6H), 7.06-7.32 (complicated peak, 7H).The CONH proton is too wide and can not observe.

Embodiment 36

N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-second Oxygen base propionic acid amide

According to being similar to embodiment 32 described methods, 3-[4-[2-(2 by embodiment 29 acquisitions, 3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid (0.25g, 0.65mmol) and benzyl amine (0.076g, 0.71mmol) make title compound (0.22g, 74%), be a kind of white solid.mp：92-93℃。

¹H NMR (CDCl ₃, 200MHz): δ 1.15 (t, J=7.0Hz, 3H), 2.88-3.20 (complicated peak, 4H), 3.42-3.60 (complicated peak, 2H), 3.73-3.87 (complicated peak, 4H), 3.98-4.06 (complicated peak, 1H), 4.18 (t, J=5.72Hz, 2H), 4.30-4.56 (complicated peak, 2H), and 6.61-6.90 (complicated peak, 4H), 7.00-7.43 (complicated peak, 9H), the CONH proton is too wide and can not observe.

Embodiment 37

2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-second Oxygen base propionic acid

According to being similar to embodiment 26 described methods, and the 2-methyl-3-[4-[2-that obtains by embodiment 7 (2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters (0.5g, 1.2mmol) make title compound (0.3g, 62%), be a kind of colloidal liquid.

¹H NMR (CDCl ₃, 200MHz): δ 1.24 (complicated peak, 6H), 2.98, (3.04 each 1H, 2d, each J=14.1Hz), 3.51 (t, J=4.25Hz, 2H), 3.49-3.71 (complicated peak, 4H), 4.15 (t, J=5.63Hz, 2H), 4.22 (t, J=4.48Hz, 2H), 6.60-6.87 (complicated peak, 6H), 7.07 (2H), the COOH proton is too wide and can not observe for d, J=8.67Hz.

Embodiment 38

2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-second Oxygen base propionic acid, sodium salt

According to being similar to embodiment 27 described methods, and the 2-methyl-3-[4-[2-that obtains by embodiment 37 (2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid (0.22g, 0.57mmol) make title compound (0.12g, 51%), be a kind of white solid.

¹H NMR (DMSO-d ₆, 200MHz) δ: 0.96-1.08 (complicated peak, 6H), 2.79 (s, 2H), 3.28-3.52 (complicated peak, 4H), 3.64 (t, J=5.3 Hz, 2H), 4.05-4.19 (complicated peak, 4H), 6.48-6.59 (complicated peak, 1H), 6.62-6.86 (complicated peak, 4H), 7.03-7.28 (complicated peak, 3H).

Embodiment 39

According to being similar to embodiment 26 described methods, by embodiment 8 obtain 2-(2-luorobenzyl)-(2-(2 for 3-[4-, 3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters (0.6g, 1.2mmol) make title compound (0.25g, 42%), is a kind of colloidal liquid.

¹H NMR (CDCl ₃, 200MHz): δ 1.12 (t, J=6.82Hz, 3H), 1.65 (bs, 1H, D ₂O is commutative), and 3.11-3.42 (complicated peak, 4H), 3.50 (t, J=4.34Hz, 2H), 3.68 (t, J=5.67Hz, 2H), and 3.70-3.89 (complicated peak, 2H), 4.14 (t, J=5.67Hz, 2H), 4.21 (t, J=4.15Hz, 2H), and 6.62-6.86 (complicated peak, 6H), 7.03-7.12 (complicated peak, 4H), and 7.18-7.30 (complicated peak, 2H).

Embodiment 40

2-(2-luorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] benzene Base]-the 2-ethoxy-propionic acid, sodium salt

According to being similar to embodiment 27 described methods, 2-(2-luorobenzyl)-3-[4-[2-(2 by embodiment 39 acquisitions, 3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid (0.22g, 0.45mmol) make title compound (0.11g, 48%), is a kind of white solid.

¹H NMR (CDCl ₃, 200MHz): δ 1.02 (t, J=6.65 Hz, 3H), and 2.75-2.92 (complicated peak, 4H), 3.39-3.58 (complicated peak, 4H), 3.62 (bs, 2H), and 4.04-4.20 (complicated peak, 4H), 6.49-6.82 (complicated peak, 5H), 6.90-7.28 (complicated peak, 6H), and 7.49-7.13 (complicated peak, 1H).

Embodiment 41

3-[4-[2-(3-oxo-2H-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-the 2-ethoxy-c Acid

According to being similar to embodiment 26 described methods, the 3-[4-[2-that obtains by embodiment 10 (3-oxo-2H-1,4-benzoxazine-4-yl] oxyethyl group] phenyl]-(1.0g 2.5mmol) makes title compound (0.75g to 2-ethoxy-propionic acid methyl esters, 77%), is a kind of white solid.mp：90-03℃。

¹H NMR (CDCl ₃, 200MHz): δ 1.18 (t, J=6.96Hz, 3H), 2.88-3.13 (complicated peak, 2H), 3.41-3.63 (complicated peak, 2H), 4.06 (dd, J=7.43 and 4.33Hz, 1H), 4.25-4.52 (complicated peak, 4H), 4.61 (s, 2H), 6.80 (d, J=8.62Hz, 2H), and 7.00-7.34 (complicated peak, 6H).The COOH proton is too wide and can not observe.

Embodiment 42

3-[4-[2-(3-oxo-2H-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-the 2-ethoxy-c Acid, sodium salt

According to being similar to embodiment 27 described methods, 3-[4-[2-(3-oxo-2H-1,4-benzoxazine-4-yl) oxyethyl group by embodiment 41 acquisitions] phenyl]-(0.2g 0.51mmol) makes title compound (0.12g to the 2-ethoxy-propionic acid, 56%), is white solid.

¹H NMR (CDCl ₃, 200MHz): δ 0.99 (t, J=6.97Hz, 3H), 2.61-2.80 (complicated peak, 2H), and 3.32-3.57 (complicated peak, 1H), 3.60-3.72 (complicated peak, 1H), 3.65-3.70 (complicated peak, 1H), 4.18 (bs, 2H), 4.30 (bs, 2H), 4.68 (s, 2H), 6.78 (d, J=8.4 Hz, 2H), 7.03-7.14 (complicated peak, 5H), 7.42 (d, J=7.06Hz, 1H).

Embodiment 43

3-[6-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthyl]-the 2-ethoxy-c Acid

According to being similar to embodiment 26 described methods, and the 3-[6-[2-that obtains by embodiment 12 (2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthyl]-2-ethoxy-propionic acid methyl esters (1.2g, 2.66mmol) make title compound (0.8g, 69%), be a kind of white solid.mp：102-104℃。

¹H NMR (CDCl ₃, 200MHz): δ 1.15 (t, J=7.01Hz, 3H), 3.06 (t, J=4.98Hz, 2H), 3.08-3.63 (complicated peak, 4H), and 3.77-3.83 (complicated peak, 4H), 4.15 (dd, J=4.15 and 4.18Hz, 1H), 4.28 (t, J=5.95Hz, 2H), and 6.59-6.79 (complicated peak, 2H), 6.96-7.36 (complicated peak, 5H), and 7.61-7.79 (complicated peak, 3H).The COOH proton is too wide and can not observe.

Embodiment 44

3-[6-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthyl]-the 2-ethoxy-c Acid, sodium salt

According to being similar to embodiment 27 described methods, and the 3-[6-[2-that obtains by embodiment 43 (2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] naphthyl]-2-ethoxy-propionic acid (0.2g, 0.457mmol) make title compound (0.16g, 76%), be a kind of white solid.mp：138-140℃。

¹H NMR (DMSO-d ₆, 200MHz): δ 0.98 (t, J=7.06Hz, 3H), 2.72-2.90 (complicated peak, 1H), and 2.92-3.21 (complicated peak, 3H), 3.32-3.54 (complicated peak, 2H), 3.61-3.91 (complicated peak, 5H), 4.28 (bs, 2H), 6.56 (t, J=7.00Hz, 1H), 6.73-7.00 (complicated peak, 3H), and 7.05-7.30 (complicated peak, 2H), 7.38 (d, J=8.3 Hz, 1H), 7.60-7.82 (complicated peak, 3H).

Embodiment 45

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2 hydroxy propanoic acid

According to being similar to embodiment 26 described methods, and the 3-[4-[2-that obtains by embodiment 13 (2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2 hydroxy propanoic acid ethyl ester (0.15g, 0.40mmol) make title compound (0.06g, 43%), be a kind of brown paste liquid.

¹H NMR (CDCl ₃, 200MHz): δ 2.85-3.19 (complicated peak, 2H), 3.43 (t, J=4.15 Hz, 2H), 3.61 (t, J=5.49Hz, 2H), 4.07 (t, J=5.40Hz, 2H), 4.16 (t, J=4.48Hz, 2H), 4.45 (bs, 1H), and 6.50-6.82 (complicated peak, 6H), 7.08 (d, J=7.88Hz, 2H).COOH and OH proton are too wide and can not observe.

Embodiment 46

3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2 hydroxy propanoic acid

According to being similar to embodiment 26 described methods, and the 3-[4-[2-that obtains by embodiment 14 (2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2 hydroxy propanoic acid ethyl ester (1.7g, 4.39mmol) make title compound (0.7g, 46%), be a kind of white solid.mp：74-76℃。

¹H NMR (CDCl ₃, 200MHz): δ 2.88-3.18 (complicated peak, 4H), 3.69-3.79 (complicated peak, 4H), 4.15 (t, J=5.72Hz, 2H), 4.45 (dd, J=6.73 and 4.79Hz, 1H), 4.51-4.97 (bs, D ₂O is commutative, and 1H), (complicated peak, 4H), (complicated peak, 4H), the COOH proton is too wide and can not observe for 6.94-7.17 for 6.65-6.89.

Embodiment 47

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-benzyloxy propionic acid

According to being similar to embodiment 26 described methods, and the 3-[4-[2-that obtains by embodiment 15 (2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-benzyloxy ethyl propionate (0.24g, 0.52mmol) make title compound (0.15g, 67%), be a kind of thick liquid.

¹H NMR (CDCl ₃, 200MHz): δ 1.40-2.80 (br, 1H, D ₂O is commutative), 2.993.18 (complicated peak, 2H), 3.51 (t, J=4.34Hz, 2H), 3.70 (t, J=5.82Hz, 2H), 4.13-4.24 (complicated peak, 5H), 4.51 (d, J=17.0Hz, 2H), 6.60-6.89 (complicated peak, 6H), 7.10-7.37 (complicated peak, 7H).

Embodiment 48

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-benzyloxy propionic acid, Sodium salt

According to being similar to embodiment 27 described methods, and the 3-[4-[2-that obtains by embodiment 47 (2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-benzyloxy propionic acid (0.13g, 0.30mmol) make title compound (0.1g, 73%), be a kind of milky water absorbability solid.

¹H NMR (DMSO-d ₆, 200MHz): δ 2.62-2.74 (complicated peak, 1H), 2.89-2.98 (complicated peak, 1H), 3.48 (t, J=4.2Hz, 2H), 3.67 (t, J=5.48Hz, 2H), 4.12-4.26 (complicated peak, 5H), 4.65 (d, J=12.45Hz, 2H), 6.45-6.84 (complicated peak, 6H), and 7.12-7.25 (complicated peak, 7H).

Embodiment 49

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-butoxy propionic acid

According to being similar to embodiment 26 described methods, and the 3-[4-[2-that obtains by embodiment 16 (2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-butoxy ethyl propionate (0.4g, 0.93mmol) make title compound (0.25g, 67%), be a kind of paste liquid.

¹H NMR (CDCl ₃, 200MHz): δ 0.87 (t, J=7.15Hz, 3H), 1.25-1.40 (complicated peak, 2H), and 1.49-1.66 (complicated peak, 2H), 2.95-3.15 (complicated peak, 2H), 3.43-3.53 (complicated peak, 4H), 3.68 (t, J=5.49Hz, 2H), 4.00-4.12 (complicated peak, 1H), 4.14 (t, J=5.65Hz, 2H), 4.22 (t, J=4.25Hz, 2H), 6.60-6.89 (complicated peak, 6H), 7.12 (2H) the .COOH proton is too wide and can not observe for d, J=8.39Hz.

Embodiment 50

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-butoxy propionic acid, Sodium salt

According to being similar to embodiment 27 described methods, and the 3-[4-[2-that obtains by embodiment 49 (2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-butoxy propionic acid (0.2g, 0.5mmol) make title compound (0.12g, 57%), for-kind of water absorbability Off-white solid.

¹H NMR (DMSO-d ₆, 200MHz): δ 0.78 (t, J=7.06Hz, 3H), 1.16-1.56 (complicated peak, 4H), 2.52-2.64 (complicated peak, 1H), 2.79-2.87 (complicated peak, 1H), 2.99-3.18 (complicated peak, 2H), 3.40 (bs, 2H), 3.66 (t, J=5.31Hz, 2H), and 4.10-4.25 (complicated peak, 5H), 6.52-6.90 (complicated peak, 6H), 7.12 (d, J=8.3Hz, 2H).

Embodiment 51

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-hexyloxy propionic acid

According to being similar to embodiment 26 described methods, and the 3-[4-[2-that obtains by embodiment 17 (2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-hexyloxy ethyl propionate (0.3g, 0.65mmoI) make title compound (0.17g, 60%), be a kind of green liquid.

¹H NMR (CDCl ₃, 200MHz): δ 0.86 (t, J=5.72Hz, 3H), 1.25-1.33 (complicated peak, 4H), and 1.41-1.75 (complicated peak, 4H), 2.94-3.06 (complicated peak, 2H), 3.36-3.58 (complicated peak, 4H), 3.68 (t, J=5.49Hz, 2H), 4.01-4.06 (complicated peak, 1H), 4.14 (t, J=5.7Hz, 2H), 4.22 (t, J=4.15Hz, 2H), 6.71-7.08 (complicated peak, 6H), 7.12 (d, J=8.4Hz, 2H).The COOH proton is too wide and can not observe.

Embodiment 52

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-hexyloxy propionic acid, Sodium salt

According to being similar to embodiment 27 described methods, and the 3-[4-[2-that obtains by embodiment 51 (2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-hexyloxy propionic acid (0.18g, 0.42mmol) make title compound (0.1g, 52%), be a kind of white water absorbability solid.

¹H NMR (DMSO-d ₆, 200MHz): δ 0.82 (t, J=5.72Hz, 3H), 1.10-1.45 (complicated peak, 8H), 2.75-2.96 (complicated peak, 2H), 3.35-3.56 (complicated peak, 4H), 3.67 (t, J=5.3Hz, 2H), 4.08-4.21 (complicated peak, 5H), and 6.50-6.82 (complicated peak, 6H), 7.12 (d, J=8.0Hz, 2H).

Embodiment 53

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-the 2-phenoxy propionic acid

According to being similar to embodiment 26 described methods, and the 3-[4-[2-that obtains by embodiment 19 (2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters (0.2g, 0.461mmol) make title compound (0.1g, 53%), be a kind of colourless liquid.

¹H NMR (CDCl ₃, 200MHz): δ 2.40-2.80 (bs, 1H, D ₂O is commutative), 3.22 (d, J=5.8Hz, 2H), 3.49 (t, J=4.25Hz, 2H), 3.67 (t, J=5.81 Hz, 2H), 4.14 (t, J=5.81Hz, 2H), 4.21 (t, J=4.16Hz, 2H), 4.82 (t, J=5.9Hz, 1H), 6.61-7.02 (complicated peak, 8H), and 7.17-7.30 (complicated peak, 5H).

Embodiment 54

3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy group third Acid

According to being similar to embodiment 26 described methods, and the 3-[4-[2-that obtains by embodiment 21 (2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters (0.4g, 0.9mmol) make title compound (0.2g, 51%), be a kind of colloidal solid.

¹H NMR (CDCl ₃, 200MHz): δ 3.02 (t, J=5.0Hz, 2H), 3.22 (d, J=6.25Hz, 2H), 3.68-3.78 (complicated peak, 4H), 4.14 (t, J=5.81Hz, 2H), 4.50 (t, J=6.19Hz, 1H), 4.90-5.40 (b, 1H, D ₂O is commutative), and 6.58-6.86 (complicated peak, 7H), 6.94-7.07 (complicated peak, 2H), 7.18-7.29 (complicated peak, 4H).

Embodiment 55

3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-the 2-phenoxy propionic acid, Sodium salt

According to being similar to embodiment 27 described methods, and the 3-[4-[2-that obtains by embodiment 53 (2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid (0.1g, 0.24mmol) make title compound (0.05g, 48%), for-kind of water absorbability solid.

¹H NMR (DMSO-d ₆, 200MHz): δ 2.81-3.09 (complicated peak, 2H), 3.42 (bs, 2H), 3.65 (t, J=4.5Hz, 2H), 4.12 (bs, 4H), 4.22-4.32 (complicated peak, 1H), 6.50-6.92 (complicated peak, 8H), 7.10-7.33 (complicated peak, 5H).

Embodiment 56

2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-benzene Oxygen base methyl propionate

According to being similar to embodiment 7 described methods, and the 3-[4-[2-that obtains by embodiment 19 (2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters (0.3g, 0.69mmol) make title compound (0.27g, 87%), be a kind of paste liquid.

¹H NMR (CDCl ₃, 200MHz): δ 1.39 (s, 3H), 3.09, (3.26 each 1H, 2d, each J=13.7Hz), 3.51 (t, J=4.3Hz, 2H), 3.66-3.73 (complicated peak, 5H), 4.15 (t, J=5.5Hz, 2H), 4.22 (t, J=4.24Hz, 2H), 6.61-7.01 (complicated peak, 9H), and 7.12-7.22 (complicated peak, 4H).

Embodiment 57

2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-benzene Oxygen base propionic acid

According to being similar to embodiment 26 described methods, 2-methyl-3-[4-[2-(2 by embodiment 56 acquisitions, 3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters (0.27g, 0.60mmol) make title compound (0.13g, 50%), is a kind of lurid water absorbability solid.

¹H NMR (CDCl ₃, 200MHz): δ 1.42 (s, 3H), 3.12, (3.29 each 1H, 2d, each J=14.1 Hz), 3.50 (t, J=4.5Hz, 2H), 3.69 (t, J=5.6Hz, 2H), 4.16 (t, J=5.81Hz, 2H), 4.22 (t, J=4.5Hz, 2H), 6.62-7.17 (complicated peak, 9H), and 7.21-7.30 (complicated peak, 4H).The COOH proton is too wide and can not observe.

Embodiment 58

2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-benzene Oxygen base propionic acid, sodium salt

According to being similar to embodiment 27 described methods, 2-methyl-3-[4-[2-(2 by embodiment 57 acquisitions, 3-dihydro-1,4-benzoxazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid (0.13g, 0.28mmol) make title compound (0.055g, 46%), is a kind of water absorbability buff powder.

¹H NMR (CDCl ₃, 200MHz): δ 1.15 (s, 3H), 2.99-3.21 (complicated peak, 2H), 3.47 (bs, 2H), 3.67 (bs, 2H), 4.14 (bs, 4H), 6.53-6.9 (complicated peak, 9H), 7.08-7.30 (complicated peak, 4H).

Embodiment 59

2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-benzene Oxygen base methyl propionate

According to being similar to embodiment 7 described methods, and the 3-[4-[2-that obtains by embodiment 21 (2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters (1.0g, 2.22mmol) make title compound (0.96g, 93%), be a kind of light yellow liquid.

¹H NMR (CDCl ₃, 200MHz): δ 1.40 (s, 3H), 3.03 (t, J=4.9Hz, 2H), 3.09, (3.27 each 1H, 2d, each J=13.7Hz), and 3.70-3.85 (complicated peak, 7H), 4.16 (t, J=5.81Hz, 2H), 6.60-6.89 (complicated peak, 6H), 6.96-7.30 (complicated peak, 7H).

Embodiment 60

2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-benzene Oxygen base propionic acid

According to being similar to embodiment 26 described methods, and the 2-methyl-3-[4-[2-that obtains by embodiment 59 (2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-phenoxy propionic acid methyl esters (0.96g, 2.00mmol) make title compound (0.6g, 65%), be a kind of paste liquid.

¹H NMR (CDCl ₃, 200MHz): δ 1.42 (s, 3H), 3.03 (t, J=5.0Hz, 2H), 3.12,3.30 (each 1H, 2d, each J=13.8Hz), 3.70-3.80 (complicated peak, 4H), 4.15 (t, J=5.5Hz, 2H), and 6.58-7.08 (complicated peak, 8H), 7.18-7.30 (complicated peak, 5H), the COOH proton is too wide and can not observe.

Embodiment 61

3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-the 2-ethoxy-c Acid 4-nitro phenyl ester

According to being similar to embodiment 32 described methods, and the 3-[4-[2-that obtains by embodiment 29 (2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid (0.3g, 0.77mmol) and the 4-nitrophenols make title compound (0.15g, 38%), be a kind of yellow liquid.

¹H NMR (CDCl ₃, 200MHz): δ 1.24 (t, J=6.92Hz, 3H), 3.04 (t, J=5.16Hz, 2H), 3.12 (d, J=6.63Hz, 2H), 3.46-3.65 (complicated peak, 1H), 3.70-3.86 (complicated peak, 5H), 4.16 (t, J=5.23Hz, 2H), 4.26 (t, J=5.5Hz, 1H), 6.62-6.74 (complicated peak, 2H), 6.84 (d, J=8.62Hz, 2H), 6.94-7.22 (complicated peak, 6H), 8.23 (d, J=9.0Hz, 2H).

Embodiment 62

3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-the 2-ethoxy The base propionic acid

According to being similar to embodiment 26 described methods, by 3-[4-(4-benzyl-3, the 4-dihydro-2H-1 of embodiment 25 acquisitions, 4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid methyl esters (0.8g, 2.16mmol) make title compound (0.4g, 57%), be a kind of paste liquid.

¹H NMR (CDCl ₃, 200MHz): δ 1.17 (t, J=7.0Hz, 3H), 2.99-3.13 (complicated peak, 2H), 3.31-3.65 (complicated peak, 4H), 4.01-4.24 (complicated peak, 3H), 4.45 (d, J=3.4Hz, 2H), and 4.52-4.59 (complicated peak, 1H), 6.62-6.68 (complicated peak, 6H), 7.14 (d, J=8.6Hz, 2H), 7.27 (s, 5H), the COOH proton is too wide and can not observe.

Embodiment 63

3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-the 2-ethoxy The base propionic acid, sodium salt

According to being similar to embodiment 27 described methods, by 3-[4-(4-benzyl-3, the 4-dihydro-2H-1 of embodiment 62 acquisitions, 4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid (0.2g, 0.44mmol) make title compound (0.15g, 75%), be a kind of colourless water absorbability solid.

¹H NMR (DMSO-d ₆, 200MHz): δ 0.99 (t, J=6.97Hz, 3H), 2.60-2.90 (complicated peak, 2H), 3.30-3.65 (complicated peak, 5H), 4.16 (d, J=5.0Hz, 2H), 4.40-4.65 (complicated peak, 3H), 6.55-6.89 (complicated peak, 6H), 7.14 (d, J=8.5Hz, 2H), 7.32 (s, 5H).

Embodiment 64

3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-the 2-ethoxy Base propionic acid 4-nitro phenyl ester

According to being similar to embodiment 32 described methods, 3-[4-(4-benzyl-3 by embodiment 62 acquisitions, 4-dihydro-2H-1,4-benzoxazine-2-yl) p-methoxy-phenyl]-2-ethoxy-propionic acid (0.5g, 1.34mmol) and the 4-nitrophenols make title compound (0.6g, 100%), is a kind of burgundy liquid.

¹H NMR (CDCl ₃, 200MHz): δ 1.25 (t, J=7.0Hz, 3H), 3.14 (d, J=6.6Hz, 2H), 3.33-3.55 (complicated peak, 3H), 3.69-3.77 (complicated peak, 1H), and 4.05-4.31 (complicated peak, 3H), 4.46 (d, J=3.4Hz, 2H), and 4.55-4.61 (complicated peak, 1H), 6.63-6.68 (complicated peak, 6H), 7.11-7.28 (complicated peak, 7H), 7.52 (d, J=7.6Hz, 2H), 8.23 (d, J=9.0Hz, 2H).

Compound of the present invention can reduce glucose level, triglyceride level, total cholesterol, LDL, VLDL arbitrarily, increases HDL.Be explained by external and interior animal experiment.

The compound effect explanation:

A is external:

A) Measure the hPPAR alpha active:

In carrier for expression of eukaryon, the ligand binding domains of hPPAR α and the DNA binding domains of yeast transcription factor GAL4 are merged.Employing is as the superfect (Qiagen, Germany) of transfection reagent, and the HEK-293 cell is with this plasmid and contain the report plasmid transfection of the luciferase genes under the control of GAL4 specificity promoter.After 42 hours, add the compound and the incubated overnight of different concns in transfection.(Packard is USA) at TopCount (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis.Gene.1992,118:137-141 to adopt Packard Luclite test kit; Superfect transfection reagent handbook, in February, 1997, Qiagen, Germany) the middle luciferase activity of measuring as the PPAR α combination/activation capacity function of compound.

B) Measure the hPPAR gamma activity:

In carrier for expression of eukaryon, the ligand binding domains of hPPAR γ 1 and the DNA binding domains of yeast transcription factor GAL4 are merged. adopt lipofection amine reagent (Gibco BRL as transfection reagent, USA), the HEK-293 cell is with this plasmid with contain the report plasmid transfection of the luciferase genes under the GAL4 specificity promoter control.After 48 hours, add the compound and the incubated overnight of 1 μ M concentration in transfection.(Packard is USA) at Packard Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis.Gene.1992,118:137-141 to adopt Packard Luclite test kit; Carry out eucaryon transfection guide with cation lipoid reagent, life technology, GIBCO BRL, USA) the middle luciferase activity of measuring as the PPAR γ 1 combination/activation capacity function of medicine.

C) Measure HMG CoA reductase active

Make hepatomicrosome bonded reductase enzyme by the rat of in medium darkness circulation, raising with 2% QUESTRAN.The spectrophotometric analysis experiment is at 100mM KH ₂PO ₄, 4mM DTT, 0.2mM NADPH, 0.3mM HMG CoA and 125 μ g hepatomicrosome enzyme in carry out.The total reaction mixture volume remains on 1mL.Make the reaction beginning by adding HMG CoA.Reaction mixture was cultivated 30 minutes down at 37 ℃, be recorded in the minimizing of 340nm place absorption value.The reaction mixture of no substrate as blank (Goldstein, J.L and Brown, M.S., to the progress of ldl receptor and HMG CoA reductase enzyme, two kinds of membranins of regulating plasma cholesterols, J.Lipid Res.1984,25:1450-1461).Test compound has suppressed HMG CoA reductase enzyme.

B) In the body:

A) Effectiveness in genetic model

Sudden change in the group of laboratory animal suffers from and fat relevant with the insulin resistance non insulin dependent diabetes and the animal model of hyperlipemia with the different susceptibility of recipe being made can set up.A plurality of laboratories have been developed such as db/db and ob/ob (diabetes, (1982) 31 (1): the 1-6) genetic model of mouse and zucker fa/fa rat, understanding the physiopathology of disease, and test effect (diabetes, (1983) 32:830-838 of new antidiabetic compound; Annu.Rep.Sankyo Res.Lab. (1994), 46:1-57).The animal of isozygotying, C57 BL/KsJ-db/db mouse by the Jackson laboratory culture of the U.S., suffer from obesity, hyperglycemia, hyperinsulinemia, insulin resistance (Journal of Clinical Investigation, (1990) 85:962-967), and the animal of heterozygosis is slender and the blood sugar amount is normal.In the db/db model, with the age increase, mouse insulin secretion gradually reduces, and when glucose level can not fully be controlled, the normal observation in late period of people's type ii diabetes arrived this phenomenon.The state of pancreas and its course of disease are according to model and different.Because this model class is like type ii diabetes, the activity of having tested compound lowering blood glucose of the present invention and triglyceride level.

With body weight is the male C57BL/KsJ-db/db mouse in 8-14 age in week of 35-60 gram, and Dr.Reddy ' s WARF (DRF) Animal Lab. is fed, and is used for experiment.Provide standard food (national nutrient research institute (NIN), Hyderabad, India) and acidified water to mouse, for arbitrarily picked-up.The animal of blood glucose value greater than 350mg/dl is used for testing.Every treated animal number is 4.

Experimental compound is suspended in 0.25% carboxymethyl cellulose, and by oral every day with the dosage of 0.1mg-30mg/kg to test group by gavage administration 6 days.Control group is accepted vehicle (dosage 10ml/kg).In the time of the 6th day, 1 hour blood sample collection is used for estimating biologic activity behind medicine-feeding test compound/vehicle.

The blood of collecting from the socket of the eye venous sinus (100 μ l) is measured random blood sugar and triglyceride levels, adopt the heparinization kapillary blood sampling in the pipe that comprises EDTA, its centrifugal acquisition blood plasma.Plasma glucose and triglyceride levels pass through glucose oxidase, glycerine-3-PO respectively with spectrometry ₄Oxydase/peroxidase method measurement (Dr.Reddy ' s Lab. diagnosis branch test kit, Hyderabad, India).

Calculate the activity of the hypoglycemic and triglyceride level of test compound of the present invention according to formula.

Compound of the present invention is not all observed deleterious effects in above-mentioned experiment.

Compound	Dosage (mg/kg)	The minimizing of blood glucose levels (%)	The minimizing of triglyceride level (%)
Compound	Dosage (mg/kg)	The minimizing of blood glucose levels (%)	The minimizing of triglyceride level (%)	Embodiment 41	3	53	27
Embodiment 50	3	45	23	Embodiment 41	3	53	27
Embodiment 50	3	45	23	Embodiment 44	10	47	74

The ob/ob mouse in 5 ages in week is from Bomholtgard (Denmark), and it used when 8 ages in week.The Zucker fa/fa obese rat in 10 ages in week is from IffaCredo. (France), and it used when 13 ages in week.Animal is remained on 25 ± 1 ℃ down and in illumination in 12 hours and the dark cycle.Give the laboratory diet (NIN, Hyderabad, India) and the water of animal standard, arbitrarily absorb (Fujiwara, T., Yoshioka.S., Yoshioka, T., Ushiyama, I and Horikoshi, H., the sign of new oral antidiabetic CS-045 is to the research of KK and ob/ob mouse and Zucker obese rat, diabetes, 1988.37:1549-1558).

Test compound was with 0.1-30mg/kg/ days dosed administrations 9 days.Control animals through port gavage is accepted vehicle (0.25% carboxymethyl cellulose, dosage 10ml/kg).

At the 0th day that handles and administration in the 9th day blood sample collection under the state on the feed after 1 hour.The heparinization kapillary that employing comprises in the pipe of EDTA is collected blood sample from retro-orbital sinus.After centrifugal, the blood plasma sample is separated to estimate triglyceride level, glucose, free fatty acids, total cholesterol and Regular Insulin.Adopt commercial kit (Dr.Reddy ' s laboratory, diagnosis branch, India) to measure plasma triglyceride, glucose, total cholesterol.Blood plasma free fatty acid adopts from the commercial kit of German Boehringer Mannheim and measures.Plasma insulin adopts RIA test kit (BARC, India) to measure.The minimizing value of various parameters is calculated according to the following formula that provides in experiment.

In the experiment of ob/ob mouse oral glucose tolerance, after handling 9 days, experimentize.With mouse fasting 5 hours, and, collect blood sample to estimate plasma glucose levels in the following timed interval: 0,15,30,60 and 120 minutes with the oral attack of 3g/kg glucose.

The experimental result of db/db mouse, ob/ob mouse, Zucker fa/fa rat shows that new compound of the present invention also has prevention or regularly treats diabetes, obesity, cardiovascular disorder such as hypertension, hyperlipemia or other treatment of diseases practicality; Learn that from document these diseases are to be mutually related.

During greater than 10mg/kg, also can reduce blood glucose levels and triglyceride level at dosage.Usually, the quantity of minimizing is relevant with dosage, and is a stationary value under some dosage.

B) Plasma triglyceride in hypercholesteremic rat model and cholesterol reduce active:

Male Sprague Dawley rat (NIN raising) is fed at the DRF Animal Lab..Animal is remained on 25 ± 1 ℃ down and in illumination in 12 hours and the dark cycle.Body weight is that the rat of 180-200g is used for experimentizing.Standard laboratory food (NIN, Hyderabad, India) the 6 angel animals that are mixed with 2% cholesterol and 1% Sodium cholic acid by feed suffer from hypercholesteremia.Animal keeps identical meals (Petit, D., Bonnefis, M.T. in experimental period, Rey, C and Infante, R., Win-35833 normally and in the hyperlipemia rat influences liver lipoid and lipoprotein synthetic at blood fat, atherosclerosis, 1988,74:215-225).

Test compound was with 0.1-30mg/kg/ days dosed administrations 3 days.Control animals is only accepted vehicle (0.25% carboxymethyl cellulose, dosage 10ml/kg).

At the 0th day of compound treatment and administration in the 3rd day blood sample collection under the state on the feed after 1 hour.The heparinization kapillary that employing comprises in the pipe of EDTA is collected blood sample from retro-orbital sinus.After centrifugal, the blood plasma sample is separated to estimate total cholesterol, HDL and triglyceride level.Adopt commercial kit (Dr.Reddy ' s laboratory, diagnosis branch, India) to measure plasma triglyceride, total cholesterol and HDL.LDL and the VLDL cholesterol is calculated by the data of total cholesterol, HDL and triglyceride level.The minimizing of various experiment parameter values is calculated according to formula.

Embodiment number	Dosage mg/kg	Triglyceride level (%) ↓	Total cholesterol (%) ↓	HDL (％)↑	LDL (％)↓	VLDL (％)↓
Embodiment number	Dosage mg/kg	Triglyceride level (%) ↓	Total cholesterol (%) ↓	HDL (％)↑	LDL (％)↓	VLDL (％)↓	Embodiment 27	1	43	57	37	58	79
Embodiment 44	1	50	42	46	44	53	Embodiment 27	1	43	57	37	58	79

↓: reduce

↑: increase

C) The activity of falling plasma triglyceride and total cholesterol in Switzerland albefaction mouse and cavy

To remain in the DRF Animal House from male Switzerland albefaction mouse (SAM) and the male guinea pig of NIN.Under all animals remain on 25 ± 1 ℃ and in illumination in 12 hours and the dark cycle.Make the laboratory diet (NIN, Hyderabad, India) and the water of animals received standard, arbitrarily picked-up.Use cavy (Oliver, P., the Plancke of body weight as SAM and the 500-700g of 20-25g, M.O., Marzin, D., Clavey, V., Sauzieres, J and Fruchart, J.C., fenofibrate, gemfibrozil and nicotinic acid is to the influence of plasma lipoprotein content in normal and the hyperlipemia mouse, atherosclerosis, 1988.70:107-114).

Test compound delivers medicine to Switzerland albefaction mouse 6 days with 0.3-30mg/kg/ days oral doses.Control animals is handled (0.25% carboxymethyl cellulose, dosage 10ml/kg) with vehicle.Test compound delivered medicine to cavy 6 days with 0.3-30mg/kg/ days oral doses.Control animals is handled (0.25% carboxymethyl cellulose, dosage 5ml/kg) with vehicle.

At the 0th day that handles and administration in the 6th day blood sample collection under the state on the feed after 1 hour.The heparinization kapillary that employing comprises in the pipe of EDTA is collected blood sample from retro-orbital sinus.After centrifugal, the blood plasma sample is separated to estimate triglyceride level and total cholesterol (Wieland, O. enzyme assay, Bergermeyer, H.O. volume, 1963,211-214; Trinder, P.Ann.Clin.Biochem.1969,6:24-27).Adopt commercial kit (Dr.Reddy laboratory, diagnosis branch, Hyderabad, India) to measure plasma triglyceride, total cholesterol and HDL.

Compound	Dosage (mg/kg)	Triglyceride level reduces (%)
Compound	Dosage (mg/kg)	Triglyceride level reduces (%)	Embodiment 33	3	55
Embodiment 41	10	54	Embodiment 33	3	55
Embodiment 41	10	54	Embodiment 43	3	49
Embodiment 63	3	57	Embodiment 43	3	49

C) The effect of losing weight in the hamster that cholesterol is fed:

Male Syria hamster is from NIN, Hyderabad, India.Animal is remained in the DRF Animal House.Under all animals remain on 25 ± 1 ℃ and in illumination in 12 hours and the dark cycle, make it freely obtain food and water.From treating that day, make animal keep containing the standard laboratory food (NIN) of 1% cholesterol.

Experimental compound was with oral dose administration in 1-30mg/kg/ days 15 days.Control animals is handled (Mill Q water, dosage 10ml/kg/day) with vehicle.Measured a body weight every 3 days.

Embodiment number	Dosage (mg/kg/ days)	(%) loses weight
Embodiment number	Dosage (mg/kg/ days)	(%) loses weight	Embodiment 27	10	12
Embodiment 30	10	18	Embodiment 27	10	12

Calculation formula:

1, calculate the minimizing percentage ratio of blood sugar/triglyceride level/total cholesterol/body weight according to the following equation:

Reduce percentage ratio (%)=1-(TT/OT)/(TC/OC) * 100

The 0th day contrast class value of OC=

The 0th day processing class value of OT=

The contrast class value of TC=test day

The processing class value of TT=test day

2, LDL and VLDL cholesterol value calculate according to the following equation:

LDL cholesterol value (mg/dl)=total cholesterol-HDL cholesterol-triglyceride level/5

VLDL cholesterol value (mg/dl)=total cholesterol-HDL cholesterol-LDL cholesterol

Claims

1, the compound of a kind of formula (I), its steric isomer or its pharmacologically acceptable salt

Radicals R wherein ¹, R ², R ³, R ⁴And the radicals R that links to each other with carbon atom ⁵And R ⁶Can be identical or different, represent hydrogen, halogen, hydroxyl, nitro, cyano group, formyl radical or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclic radical, heteroaryl, heteroaralkyl, heteroaryloxy, assorted aralkoxy, acyl group, acyloxy, hydroxyalkyl, amino, amido, alkylamino, arylamino, aryl alkyl amino, aminoalkyl group, carbalkoxy, aryloxy carbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxy alkyl, sweet-smelling alkoxy alkyl, alkylthio, alkylthio, alkoxycarbonyl amido, aryloxy carbonyl amino, aralkoxycarbonyl amino, carboxylic acid or derivatives thereof, or sulfonic acid or derivatives thereof; When they link to each other with carbon atom, R ⁵And R ⁶One of or both all can represent oxo group; When they link to each other with nitrogen-atoms, R ⁵And R ⁶Represent hydrogen, hydroxyl, formyl radical or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroaralkyl, acyl group, acyloxy, hydroxyalkyl, amino, amido, alkylamino, arylamino, aryl alkyl amino, aminoalkyl group, aryloxy, aralkoxy, heteroaryloxy, assorted aralkoxy, carbalkoxy, aryloxy carbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxy alkyl, sweet-smelling alkoxy alkyl, alkylthio, alkylthio, carboxylic acid derivative or sulfonic acid; The X representative is selected from oxygen, sulphur or NR ¹¹Heteroatoms, R wherein ¹¹Be selected from hydrogen or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, acyl group, carbalkoxy, aryloxy carbonyl or aralkoxycarbonyl, described substituting group are selected from halogen, the halogenated low alkyl group of selectivity, hydroxyl and the halogenated (C of selectivity ₁-C ₃) alkoxyl group; The Ar representative replaces or unsubstituted divalence list or fused aromatic group or heterocyclic group, and described substituting group is selected from the halogenated (C of straight or branched selectivity ₁-C ₆) alkyl, the halogenated (C of selectivity ₁-C ₃) alkoxyl group, halogen, acyl group, amino, amido, sulfenyl or carboxylic acid or sulfonic acid or derivatives thereof; R ⁷Represent hydrogen atom, hydroxyl, alkoxyl group, halogen, low alkyl group, aralkyl or with adjacent radicals R ⁸Form a key together; R ⁸Represent hydrogen, hydroxyl, alkoxyl group, halogen, low alkyl group, acyl group or aralkyl or R ⁸With R ⁷Form a key together; R ⁹Represent hydrogen or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, carbalkoxy, aryloxy carbonyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, acyl group, heterocyclic radical, heteroaryl or heteroaralkyl; R ¹⁰Represent hydrogen or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, heterocyclic radical, heteroaryl or heteroaralkyl; Y represents oxygen or NR ¹², R wherein ¹²Represent hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclic radical, heteroaryl or heteroaralkyl; R ¹⁰And R ¹²Can form the ring texture of 5 or 6 yuan of carbon atoms together, it can randomly comprise one or more heteroatomss that are selected from oxygen, sulphur or nitrogen; By-(CH ₂) _n-(O) _mThe linking group of-expression can link to each other by nitrogen-atoms or carbon atom; N is that integer 1-4 and m are integer 0 or 1, and condition is to link to each other and R by carbon atom when this linking group ⁵Or R ⁶When representing oxo group and X to be Sauerstoffatom, R ⁹Do not represent hydrogen atom;

Wherein work as by R ¹-R ⁴, R ⁹, R ¹⁰The group and the radicals R that links to each other with carbon atom of expression ⁵And R ⁶When being substituted, substituting group is selected from halogen, hydroxyl or nitro, or is selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aryl, aralkyl, sweet-smelling alkoxy alkyl, heterocyclic radical, heteroaryl, heteroaralkyl, acyl group, acyloxy, hydroxyalkyl, amino, amido, arylamino, aminoalkyl group, aryloxy, carbalkoxy, alkylamino, alkoxyalkyl, alkylthio, alkylthio, carboxylic acid or derivatives thereof or sulfonic acid or derivatives thereof;

And, wherein when the radicals R that links to each other with nitrogen-atoms ⁵And R ⁶When being substituted, substituting group is selected from halogen atom, hydroxyl, acyl group, acyloxy or amino.

2, according to the compound of claim 1, wherein Ar represents to replace or unsubstituted divalence phenylene, naphthylidene, pyridyl, quinolyl, benzofuryl, dihydro benzo furyl, benzopyranyl, dihydrobenzopyrans base, indyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl or benzoxazol base.

3, the method for a kind of preparation formula (I) compound

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶, n, m, Ar, X, R ⁹And R ¹⁰Such as claim 1 definition; R ⁷And R ⁸Represent a key together; Y represents oxygen; By-(CH ₂) _n-(O) _mThe linking group of-expression can link to each other by nitrogen-atoms or carbon atom, and condition is to link to each other and R by carbon atom when this linking group ⁵Or R ⁶When representing oxo group and X to be Sauerstoffatom, R ⁹Do not represent hydrogen atom;

This method comprises:

A) make the compound of formula (IIIa) and the compound reaction of formula (IIIb)

Wherein all symbols such as preceding definition

R wherein ⁹And R ¹⁰As preceding definition, R ¹⁴Representative (C ₁-C ₆) alkyl, obtain formula (I) compound as preceding definition;

B) make the compound of formula (IIIc) and the compound reaction of formula (IIId)

Wherein all symbols such as preceding definition,

R wherein ⁷And R ⁸Represent a key together, all symbols such as preceding definition, L ¹Be leavings group, produce formula (I) compound as preceding definition;

C) make the compound of formula (IIIe) and the compound reaction of formula (IIIf)

Wherein all symbols such as preceding definition,

R wherein ⁹=R ¹⁰And as preceding definition, the compound of production (I);

D) make the compound of formula (IIIa) and the compound reaction of formula (IIIg)

Wherein all other symbols such as preceding definition,

R wherein ⁸, R ⁹And R ¹⁰As preceding definition, after dehydration, produce formula (I) compound as preceding definition;

E) make the compound of formula (IIIh) and the compound reaction of formula (IIIi)

Wherein all symbols such as preceding definition, L ¹Represent leavings group,

R wherein ⁷And R ⁸Represent a key together, R ⁹, R ¹⁰With Ar such as preceding definition, the compound of production (I), wherein m represents integer 1, all other symbols such as preceding definition;

F) make the compound of formula (IIIj) and the compound reaction of formula (IIIi)

Wherein all symbols such as preceding definition

R wherein ⁷And R ⁸Represent a key together, R ⁹, R ¹⁰With Ar such as preceding definition, the compound of production (I), wherein m represents integer 1, all other symbols such as preceding definition; Randomly

Formula (I) compound that g) will obtain in above-mentioned arbitrary method changes into pharmacologically acceptable salt.

4, the method for a kind of preparation formula (I) compound

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶, n, m, Ar, X, R ⁹And R ¹⁰Such as claim 1 definition; R ⁷Represent hydrogen atom, hydroxyl, alkoxyl group, halogen, low alkyl group, replacement or unsubstituted aralkyl; R ⁸Represent hydrogen, hydroxyl, alkoxyl group, halogen, low alkyl group, acyl group or replacement or unsubstituted aralkyl; Y represents oxygen; By-(CH ₂) _n-(O) _mThe linking group of-expression can link to each other by nitrogen-atoms or carbon atom, and condition is to link to each other and R by carbon atom when this linking group ⁵Or R ⁶When representing oxo group and X to be Sauerstoffatom, R ⁹Do not represent hydrogen atom;

This method comprises:

A) make formula (IVa) compound reduction according to the preparation of either party's method of claim 3,

Formula (I) compound that this formula (IVa) compounds represented is such, wherein R ⁷And R ⁸Represent a key together, the Y represention oxygen atom, all other symbols such as preceding definition produce such formula (I) compound, wherein R ⁷And R ⁸All represent hydrogen atom, all symbols such as preceding definition;

B) make the compound of formula (IVb) and the alcohol reaction of formula (IVc)

Wherein all symbols such as preceding definition, L ²Be leavings group

R ⁹-OH (IVc)

R wherein ⁹Representative is selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, carbalkoxy, aryloxy carbonyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, acyl group, heterocyclic radical, heteroaryl or heteroaralkyl produce formula (I) compound as preceding definition;

C) make the compound of formula (IIIh) and the compound reaction of formula (IIIi)

Wherein all symbols such as preceding definition, L ¹Be leavings group

Wherein all symbols such as preceding definition produce such formula (I) compound, and wherein m represents integer

1, all other symbols such as preceding definition;

D) make the compound of formula (IIIj) and the compound reaction of formula (IIIi)

Wherein all symbols such as preceding definition

Wherein all symbols such as preceding definition produce such formula (I) compound, and wherein m represents integer 1, all other symbols such as preceding definition;

E) make the compound of formula (IVd) and the compound reaction of formula (IVe)

Formula (I) compound that this formula (IVd) compounds represented is such, wherein R ⁹Represent hydrogen atom, all other symbols such as preceding definition

R ⁹-L ² (IVe)

R wherein ⁹Representative is selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, carbalkoxy, aryloxy carbonyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, acyl group, heterocyclic radical, heteroaryl or heteroaralkyl, L ²Be halogen atom, produce formula (I) compound as preceding definition;

F) make the compound of formula (IIIa) and the compound reaction of formula (IIIg)

Wherein all symbols such as preceding definition

R wherein ⁸, R ⁹And R ¹⁰As preceding definition, behind dehydroxylation, the compound of production (I);

G) make the compound of formula (IIIc) and the compound reaction of formula (IIId)

Wherein all symbols such as preceding definition

L wherein ¹Be leavings group, all other symbols such as preceding definition produce formula (I) compound as preceding definition;

H) compound of formula (IVf) is changed into formula (I) compound as preceding definition

Wherein all symbols such as preceding definition;

I) make the compound of formula (IVg) and the compound reaction of formula (IVc)

Wherein all symbols such as preceding definition

R ⁹-OH (IVc)

R wherein ⁹Representative is selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, carbalkoxy, aryloxy carbonyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, acyl group, heterocyclic radical, heteroaryl or heteroaralkyl, the compound of production (I), randomly;

Formula (I) compound that j) will obtain in above-mentioned any method splits into its steric isomer and randomly;

K) formula (I) compound or its steric isomer that will obtain in above-mentioned any method changes into pharmacologically acceptable salt.

5, the method for a kind of preparation formula (I) compound

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶, n, m, Ar, X, R ⁷, R ⁸, R ⁹And R ¹⁰Such as claim 1 definition; Y represents NR ¹², R wherein ¹²Represent hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclic radical, heteroaryl or heteroaralkyl; R ¹⁰And R ¹²Can form the ring texture of 5 or 6 yuan of carbon atoms together, it can randomly comprise one or more heteroatomss that are selected from oxygen, sulphur or nitrogen; By-(CH ₂) _n-(O) _mThe linking group of-expression can link to each other by nitrogen-atoms or carbon atom;

This method comprises:

A) make the compound of formula (I) and R wherein ¹⁰And R ¹²Formula NHR as preceding definition ¹⁰R ¹²The reaction of suitable amine

Wherein all symbols such as preceding definition, Y represents oxygen, YR ¹⁰Represent halogen atom, or COYR ¹⁰Represent mixed acid anhydride group and randomly;

B) formula (I) compound with above-mentioned acquisition splits into steric isomer, randomly;

C) formula (I) compound with above-mentioned acquisition changes into its pharmacologically acceptable salt.

6, the compound of a kind of formula (IVf),

Radicals R wherein ¹, R ², R ³, R ⁴With the radicals R that links to each other with carbon atom ⁵And R ⁶Can be identical or different, represent hydrogen, halogen, hydroxyl, nitro, cyano group, formyl radical or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclic radical, heteroaryl, heteroaralkyl, heteroaryloxy, assorted aralkoxy, acyl group, acyloxy, hydroxyalkyl, amino, amido, alkylamino, arylamino, aryl alkyl amino, aminoalkyl group, carbalkoxy, aryloxy carbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxy alkyl, sweet-smelling alkoxy alkyl, alkylthio, alkylthio, alkoxycarbonyl amido, aryloxy carbonyl amino, aralkoxycarbonyl amino, carboxylic acid or derivatives thereof, or sulfonic acid or derivatives thereof; When linking to each other with carbon atom, R ⁵And R ⁶One of or both all can represent oxo group; When linking to each other with nitrogen-atoms, R ⁵And R ⁶Represent hydrogen, hydroxyl, formyl radical or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroaralkyl, acyl group, acyloxy, hydroxyalkyl, amino, amido, alkylamino, arylamino, aryl alkyl amino, aminoalkyl group, aryloxy, aralkoxy, heteroaryloxy, assorted aralkoxy, carbalkoxy, aryloxy carbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxy alkyl, sweet-smelling alkoxy alkyl, alkylthio, alkylthio, carboxylic acid derivative or sulfonic acid; The X representative is selected from oxygen, sulphur or NR ¹¹Heteroatoms, R wherein ¹¹Be selected from hydrogen or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, acyl group, carbalkoxy, aryloxy carbonyl or aralkoxycarbonyl; The Ar representative replaces or unsubstituted divalence list or fused aromatic group or heterocyclic group; R ⁷Represent hydrogen atom, hydroxyl, alkoxyl group, halogen, low alkyl group or replacement or unsubstituted aralkyl; R ⁸Represent hydrogen, hydroxyl, alkoxyl group, halogen, low alkyl group, acyl group, replacement or unsubstituted aralkyl; R ⁹Represent hydrogen or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, carbalkoxy, aryloxy carbonyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, acyl group, heterocyclic radical, heteroaryl or heteroaralkyl; By-(CH ₂) _n-(O) _mThe linking group of-expression can link to each other by nitrogen-atoms or carbon atom; N is that integer 1-4 and m are integer 0 or 1; Wherein when each described group was substituted, substituting group according to claim 1.

7, a kind of preparation is as the method for formula (IVf) compound as described in the claim 6, wherein R ⁷And R ⁸Represent hydrogen atom, all other symbols are as described in the claim 6, and this method comprises:

A) make the compound of formula (IIIa) and the compound reaction of formula (IVh)

Wherein all symbols such as preceding definition

R ⁹OCH ₂P ⁺PPh ₃ ^-Hal (IVh)

R wherein ⁹Representative is selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, carbalkoxy, aryloxy carbonyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, acyl group, heterocyclic radical, heteroaryl or heteroaralkyl; Hal represents halogen atom, obtains the compound of formula (IVi)

Wherein all symbols such as preceding definition,

B) make the compound and the formula R of formula (IVi) ⁹The alcohol reaction of OH, wherein R ⁹As preceding definition, obtain the compound of formula (IVj)

Wherein all symbols such as preceding definition,

C) make formula (IVj) compound that as above obtains, wherein all symbols such as preceding definition are with the reaction of trialkylsilkl prussiate, the compound of production (IVf), wherein all symbols such as preceding definition.

8, the intermediate of a kind of formula (IVg)

Radicals R wherein ¹, R ², R ³, R ⁴With the radicals R that links to each other with carbon atom ⁵And R ⁶Can be identical or different, represent hydrogen, halogen, hydroxyl, nitro, cyano group, formyl radical or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclic radical, heteroaryl, heteroaralkyl, heteroaryloxy, assorted aralkoxy, acyl group, acyloxy, hydroxyalkyl, amino, amido, alkylamino, arylamino, aryl alkyl amino, aminoalkyl group, carbalkoxy, aryloxy carbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxy alkyl, sweet-smelling alkoxy alkyl, alkylthio, alkylthio, alkoxycarbonyl amido, aryloxy carbonyl amino, aralkoxycarbonyl amino, carboxylic acid or derivatives thereof, or sulfonic acid or derivatives thereof; When linking to each other with carbon atom, R ⁵And R ⁶One of or both all can represent oxo group; When linking to each other with nitrogen-atoms, R ⁵And R ⁶Represent hydrogen, hydroxyl, formyl radical or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, alkoxyl group, cycloalkyloxy, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroaralkyl, acyl group, acyloxy, hydroxyalkyl, amino, amido, alkylamino, arylamino, aryl alkyl amino, aminoalkyl group, aryloxy, aralkoxy, heteroaryloxy, assorted aralkoxy, carbalkoxy, aryloxy carbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxy alkyl, sweet-smelling alkoxy alkyl, alkylthio, alkylthio, carboxylic acid derivative or sulfonic acid; The X representative is selected from oxygen, sulphur or NR ¹¹Heteroatoms, R wherein ¹¹Be selected from hydrogen or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, acyl group, carbalkoxy, aryloxy carbonyl or aralkoxycarbonyl; The Ar representative replaces or unsubstituted divalence list or fused aromatic group or heterocyclic group; R ⁷Represent hydrogen atom, hydroxyl, alkoxyl group, halogen, low alkyl group or replacement or unsubstituted aralkyl; R ¹⁰Represent hydrogen or be selected from following replacement or unsubstituted group: alkyl, cycloalkyl, aryl, aralkyl, heterocyclic radical, heteroaryl or heteroaralkyl; Y represents oxygen; By-(CH ₂) _n-(O) _mThe linking group of-expression can link to each other by nitrogen-atoms or carbon atom; N is that integer 1-4 and m are integer 0 or 1; Wherein when each described group was substituted, substituting group according to claim 1.

9, a kind of method for preparing the described formula of claim 8 (IVg) compound, this method comprises:

A) make the compound of formula (IIIh) and the compound reaction of formula (IV1),

L wherein ¹Be leavings group, all other symbols are as described in the claim 8

R wherein ⁸Be hydrogen atom, all other symbols are as described in the claim 8, the compound of production (IVk),

R wherein ⁸Be hydrogen atom, all other symbols such as preceding definition;

B) compound of the formula (IVk) that as above obtains and diazo reagent are reacted.

10, according to the compound of claim 1, it is selected from:

(±) 3-[4-[2-(2,3-dihydro-1,4-benzothiazine-4-yl) oxyethyl group] phenyl]-2-ethoxy-propionic acid methyl esters;

(-) 3-[4-[2-(2,3-dihydro-1,4-benzimidazole dihydrochloride-4-yl) oxyethyl group] phenyl]-2 hydroxy propanoic acid and its salt;

11, a kind of pharmaceutical composition, it comprises claim 1,2 or 10 each described formula (I) compound and pharmaceutically acceptable carrier, thinner, vehicle or solvates:

12, according to the pharmaceutical composition of claim 11, it is tablet, capsule, pulvis, syrup, solution or suspension form.