CN1242010A - Substituted benzo [1,4] dioxanes as antiobesity agents - Google Patents

Abstract

This invention relates to novel substituted 1,4-benzodioxane compounds having antidiabetic, antihyperglycemic, and antiobesity properties represented by formula (II) wherein R<1> and R<6> are independently hydrogen, C1 to C6 alkyl, trifluoromethyl, cyano, C1 to C6 alkoxy, or halogen; R<2> is hydrogen or C1 to C6 trialkylsilyl; R<3> is hydrogen or C1 to C6 alkoxycarbonyl; or R<2> and R<3> are joined to form the oxazolidinone ring (III); R<4> and R<5> are independently hydrogen or C1 to C6 alkyl; R<7> and R<8> are independently OR<9> or NR<10>R<11>; R<9> is hydrogen, C1 to C12 alkyl, C1 to C12 cycloalkyl, C1 to C12 silylalkyl, phenyl, naphthyl, phenyl C<1> to C<6> alkyl, C1 to C6 alkoxy C1 to C6 alkyl, pyridyl, thiophenyl, furanyl, imidazolyl, oxazolyl, -CHR<12>COOR<13>, -CHR<12>C(O)R<13>, -CHR<12>CONR<10>R<11>, -CHR<12>OCOOR<13>, or -CHR<12>OC(O)R<13>; R<10> and R<11> are independently hydrogen, C1 to C12 alkyl, phenyl, naphthyl, phenyl-C1 to C6 alkyl, furanylalkyl, or alkoxycarbonylalkyl; R<12> and R<13> are independently hydrogen, C1 to C12 alkyl, phenyl, naphthyl, or phenyl-C1 to C6 alkyl; and the pharmaceutically acceptable salts thereof, a salt thereof; an enantiomer thereof, the racemic mixtures thereof, and the diastereomeric mixtures thereof.

Description

Replacement benzo [1,4] diox as diet pill

The present invention relates to have anti-diabetic, the new replacement of hyperglycemia and fat-reducing character 1,4-benzodioxan compound.The invention still further relates to the medicinal compositions that contains these compounds, the preparation method of these compounds and the method for using these compounds for treating Mammals diabetes and/or hyperglycemia and/or obesity.Find that also these fat-reducing compounds can be used for reducing the lipid content of edible domestic animal.Background of the present invention

As everyone knows, can heal with medicine and suffer from the patient of diabetes, hyperglycemia and obesity.The compounds of this invention passes through as selectivity β ₃3 adrenergic receptor agonists and reach the effect of anti-diabetic, hyperglycemia and fat-reducing.Hormesis to these acceptors on white adipocyte and brown fat cell starts lipolysis (steatolysis) and consumed energy.To β ₃The selective stimulating effect of adrenergic receptor is important to chronic treatment.The hormesis of other beta-receptor can cause that side effect such as heart rate increase (β ₁Act on) and/or muscular tremor (β ₂Effect).The compounds of this invention demonstrates β ₃The high selectivity of adrenergic receptor.

Bloom etc. are at United States Patent (USP) 5,061, disclose the 5-(2-((2-aryl-2-hydroxyethyl) amino) propyl group)-1 with hyperglycemia and active general formula of fat-reducing (I), 3-benzo dioxole in 727:

R wherein ¹And R ⁴Can be one or more identical or different group, be selected from: hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, hydroxyl, halogen, trifluoromethyl, carboxyl, hydroxyalkyl, alkoxy carbonyl, C ₁-C ₄Sulfane base, alkylsulfonyl and sulfinyl; X is a divalent group, for:

Or Wherein R ' is selected from: hydrogen, C ₁-C ₄Alkyl and C ₁-C ₄Acyl group, Y are selected from carbonyl and thiocarbonyl; R ²And R ³Can be identical or different, be selected from: hydrogen and C ₁-C ₄Alkyl; R ⁵And R ⁶Be selected from: hydrogen, carboxyl, alkoxy carbonyl, methylol ,-CH ₂OCH ₂COOR ₇With-CH ₂OCH ₂CH ₂OR ₇, R wherein ⁷Be hydrogen or C ₁-C ₄Alkyl; Condition is R ⁵And R ⁶Not all be hydrogen.

(R, R)-5-[2-[[2-(3-chloro-phenyl-)-2-hydroxyethyl] amino] propyl group]-1,3-benzo dioxole-2, synthetic, the antidiabetic effect of 2-dicarboxylic acid esters and antiobesity action by Bloom etc. at United States Patent (USP) 5, open in 061,727, and at Bloom etc., J.Med.Chem., 1992,35,3081 and Largis etc., Drug Dev.Res., 1994,32,69 and Bloom etc., Drugs of the Future, describe in detail in 1994,19,23.

The compounds of this invention contains 1,4-benzodioxan ring, and the compound in the United States Patent (USP) 5,061,727 of Bloom etc. contains 1,3-benzo dioxole.They are possessed β ₃The highly selective of acceptor demonstrates the much higher fat-reducing and the activity of hyperglycemia in animal model.Therefore when The compounds of this invention was made medicinal compositions, it can be used for treating diabetes, hyperglycemia and the obesity of humans and animals, and demonstrated minimum side effect such as heart rate increase and/or muscular tremor.The people that have health perception now are just by taking exercise and low-fat diet effort reduction body fat.The compounds of this invention can help people to reduce fat, and by handling edible domestic animal, as ox, pig, sheep, goat, turkey and chicken, and provides lean meat for people consume.

The present invention's general introduction

The invention provides new formula (II) compound and pharmacy acceptable salt thereof, its esters; Its enantiomorph, its racemic mixture, with and non-enantiomer mixture:

R wherein ¹And R ⁶Independently be hydrogen, C ₁-C ₆Alkyl, trifluoromethyl, cyano group, C ₁-C ₆Alkoxy or halogen;

R ²Be hydrogen or C ₁-C ₆Trialkylsilkl; R ³Be hydrogen or C ₁-C ₆Alkoxy carbonyl; Or

R ²And R ³Xing Cheng oxazolidone ring links to each other;

R ⁴And R ⁵Independently be hydrogen or C ₁-C ₆Alkyl;

R ⁷And R ⁸Independently be OR ⁹Or NR ¹⁰R ¹¹

R ⁹Be hydrogen, C ₁-C ₁₂Alkyl, C ₁-C ₁₂Cycloalkyl, C ₁-C ₁₂Silyl alkyl, phenyl,

Naphthyl, phenyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy C ₁-C ₆Alkyl, pyridyl, thiophene

Base, furyl, imidazolyl, oxazolyl ,-CHR ¹²COOR ¹³,-CHR ¹²C (O) R ¹³,

-CHR ¹²CONR ¹⁰R ¹¹,-CHR ¹²OCOOR ¹³Or-CHR ¹²OC (O) R ¹³

R ¹⁰And R ¹¹Independently be hydrogen, C ₁-C ₁₂Alkyl, phenyl, naphthyl, phenyl-C ₁-C ₆Alkyl,

Furyl alkyl or alkoxy carbonyl alkyl;

R ¹²And R ¹³Independently be hydrogen, C ₁-C ₁₂Alkyl, phenyl, naphthyl or phenyl-C ₁-C ₆Alkyl.

R ¹Preferably halogen is more preferably chlorine, and preferably on position between phenyl ring.R ²And R ³Independent separately preferably hydrogen or continuous Xing Cheng oxazolidone ring.R ⁴And R ⁵Independent separately preferably hydrogen or C ₁-C ₆Alkyl; Be more preferably hydrogen or methyl.In particularly preferred embodiments, R ⁴And R ⁵One of them is a hydrogen and another is a methyl.R ⁶Hydrogen preferably.R ⁹Preferably hydrogen, C ₁-C ₁₂Alkyl, C ₁-C ₁₂Cycloalkyl, phenyl, phenyl C ₁-C ₆Alkyl or C ₁-C ₆Alkoxy C ₁-C ₆Alkyl; Be more preferably hydrogen, methyl, ethyl, sec.-propyl, isobutyl-, octyl group, cyclopropyl, cyclohexyl, benzyl or 2-ethoxyethyl group.

The alkyl group that comprises straight chain and side chain herein as the term " alkyl " of definition or part definition is as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, amyl group and hexyl.Term " halogen " as definition or part definition comprises chlorine, bromine, fluorine and iodine herein.Term " cycloalkyl " as definition or part definition comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl herein.

Exist the acid salt of the The compounds of this invention of basic nitrogen can be with pharmaceutically acceptable inorganic or organic acid preparation, as, but be not limited thereto hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetate, fumaric acid, toxilic acid, succsinic acid, phenylformic acid, methylsulfonic acid or tosic acid.Base addition salt with The compounds of this invention of hydroxy-acid group can be by the oxide compound or the oxyhydroxide preparation of alkali-metal oxide compound or oxyhydroxide or alkaline-earth metal, as NaOH, KOH, Ca (OH) ₂

β of the present invention ₃Alternative cpd is used for the treatment of diabetes, hyperglycemia and the obesity of mammiferous non-insulin-depending type.Beta-3 adrenergic receptor can be divided into β ₁, β ₂And β ₃Hypotype.β ₁The activation of acceptor is accelerated heart rate, and β ₂Therefore glycogenolysis in the receptor for stimulating muscle suppresses the synthetic of glycogen.β ₃The activation of acceptor stimulates the triglyceride level steatolysis of brown adipose tissue or decomposes generation glycerine and free fatty acids, thereby promotes the loss of fatty substance.Stimulate β ₃The compound of acceptor has antiobesity action.Brown adipose tissue also works on the glucose homeostasis, so β ₃2-adrenergic agonist components also has lowering blood glucose or antidiabetic activity.

Remove to provide and stimulate β ₃Outside the compound of acceptor, the present invention also provides the method and the medicinal compositions of treatment Mammals obesity, hyperglycemia and diabetes.Except that being the treatment of obesity of human body health benefit, The compounds of this invention also can be consumed fat in institute domesticated animal such as ox, poultry, pig, sheep, the Goral mutton by reducing for people, and provides more health benefit for people.The present invention describes in detail

The compounds of this invention can prepare according to one of following listed logical method.

By shown in the scheme I, pyrocatechol 1 usefulness alkali and dibromosuccinic acid ester 2 are handled De Dao oxazolidone 3, its hydrolysis is obtained 1,4-benzodioxan dioctyl phthalate 4, wherein R ¹, R ⁴, R ⁵And R ⁶Define the same.Synthesizing of starting raw material pyrocatechol 1 at United States Patent (USP) 5,061, explanation in 727 and 5,420,291.

Scheme I

By shown in the following scheme II, carboxylic acid disodium 4 is changed into the disilver salt of carboxylic acid, obtain diester compound 6, wherein R with iodo derivative 5 processing again ¹, R ⁴, R ⁵, R ⁶, R ¹²And R ¹³Define the same.

Scheme II

The other method of following scheme III explanation preparation diester is wherein with the pure R of dicarboxylic acid 4 ⁹OH and an acidic catalyst are handled and are obtained diester compound 7, wherein R ¹, R ⁴, R ⁵, R ⁶And R ⁹Define the same.

Scheme III

Shown in following scheme IV, diester compound 7 is hydrolyzed into monoesters 8a and/or 8b, wherein R under alkaline condition ¹, R ⁴, R ⁵, R ⁶And R ⁹Define the same.Regional isomer 8a and 8b one or both of can be prepared by hydrolysis reaction.

Scheme IV

Shown in following plan V, make diester compound 7 and amine HNR ¹⁰R ¹¹Reaction obtains diamide compound 9, wherein R ¹, R ⁴, R ⁵, R ⁶, R ⁹, R ¹⁰And R ¹¹Define the same.

Plan V

Shown in following plan V I, monoester compound 8a or 8b suitably can be changed into monoesters/single acyl halide derivative, as change into the oxalyl chloride that corresponding acyl chlorides can be used in dimethyl formamide and the methylene dichloride and finish easily.This monoesters/single acyl halide derivative 10a or 10b can be changed into monoesters/monoamide of corresponding formula II then, as by with formula HNR ¹⁰R ¹¹Amine reaction.

Plan V I

The specific embodiment that below comprises is used to illustrate the preparation method, present disclosure is not imposed any restrictions.Agents useful for same and intermediate or can be provided by commerce perhaps can easily be prepared according to the normative document method by those persons skilled in the art of organic synthesis field.Those persons skilled in the art of this area also have other to prepare the method for The compounds of this invention as can be known.Embodiment 16-{ (2R)-2-[(5R)-5-(3-chloro-phenyl)-2-oxo-oxazolidines-3-yl]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate dimethyl ester

Will (R, R)-(±)-5-(3-chloro-phenyl-)-3-(2-(3, the 4-dihydroxy phenyl)-1-(methylethyl)-2-azolactone (3.47g, 10mmol), meso 1,2-dibromosuccinic acid dimethyl ester (3.06g, 10mmol) and anhydrous K ₂CO ₃Mixture in acetone, refluxed 6 hours.Filtering reaction mixed solution then, the residue washing with acetone.The acetone filtrate that merges is concentrated, and the crude product that obtains is through purification by silica gel column chromatography, and with 3: 1 hexanes: eluent ethyl acetate obtained light yellow liquid.Output 2.8g (57%) M ⁺H.Embodiment 26-{2-[5-(3-chloro-phenyl)-2-oxo-oxazolidines-3-yl]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate 3-methyl esters

6-{ (2R)-2-[(5R)-5-(3-chloro-the phenyl)-2-oxo-oxazolidines-3-yl that is stirring]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate dimethyl ester (2.4g, add in ethanolic soln 5mmol) sodium hydroxide (1.0g, 25mmol).To stir 8 hours under the reaction mixture room temperature.Concentration response mixed solution then, water (100ml) dissolving.Add concentrated hydrochloric acid, use the chloroform extraction isolated compound; The water thorough washing is used anhydrous magnesium sulfate drying; Filter, concentrate.Product through purification by silica gel column chromatography, is used the chloroform wash-out.Output: 2.0g solid; 198 ℃ of mp; M ⁺H 476.Embodiment 3 (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate

With 6-{ (2R)-2-[(5R)-5-(3-chloro-phenyl)-2-oxo-oxazolidines-3-yl]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate dimethyl ester (2.4g, 5mmol) and sodium hydroxide (1.0g, 25mmol) at ethanol: water (9: 1, refluxed 72 hours in 50ml).The concentration response mixed solution dissolves residue water (50ml).With 1N HCl neutralization, filter the solid of separating out; The water thorough washing, dry air.Its purity is enough to further transform.Output: 2.0g; 220 ℃; M ⁺H 436.Embodiment 4 (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] dioxs-2,3-dioctyl phthalate diisopropyl ester embodiment 5 (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] dioxs-2,3-dioctyl phthalate 3-isopropyl ester

Hydrogen chloride gas fed in 0 ℃ the Virahol (100ml) 15 minutes, and added (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] dioxs-2, and the 3-dioctyl phthalate (2.15g, 5mmol).Reaction mixture was refluxed 24 hours, concentrate.The residue that obtains is neutralized with sodium hydrogen carbonate solution, use chloroform extraction.Use anhydrous sodium sulfate drying; Filter, concentrate.The product that obtains is passed through purification by silica gel column chromatography, use chloroform again with chloroform earlier: methyl alcohol (9: 1) wash-out.Elder generation's wash-out goes out diester, is monoesters then.(2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate diisopropyl ester amorphous; Output 850mg (32%); M ⁺H 520.(2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate-3-isopropyl ester amorphous; Output 700mg (29%); M ⁺H 478.Preparation (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2, the logical method of 3-dioctyl phthalate alkyl ester and cycloalkyl ester

Hydrogen chloride gas fed in 0 ℃ the suitable alcohol (100ml) 15 minutes, and added (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] dioxs-2, and the 3-dioctyl phthalate (2.15g, 5mmol).With reaction mixture be heated to 100 ℃ 48 hours.Then, excessive alcohol is removed in decompression, and residue neutralizes with sodium hydrogen carbonate solution.With the product chloroform extraction that obtains; The water thorough washing; Use anhydrous magnesium sulfate drying; Filter, concentrate.The product that obtains is passed through purification by silica gel column chromatography.Post is used chloroform again with chloroform earlier: methyl alcohol (9: 1) wash-out.Embodiment 6 (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dibutyl carboxylic acid

According to above logical method, by (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] dioxs-2, (2.15g 5mmol) prepares title compound with propyl carbinol and obtains brown oil: 1.1g (40%) the 3-dioctyl phthalate; M ⁺H 548.Embodiment 7 (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate two-(2-oxyethyl group-ethyl) ester

By (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2, [1,4] diox-2, (2.15g 5mmol) prepares title compound with cellosolvo to the 3-dioctyl phthalate to 3-dihydro-benzo.Obtain two diastereomers, be amorphous solid: enantiomorph 1: output 800mg (33%) M ⁺H 480.Enantiomorph 2: output 600mg (25%) M ⁺H 480.Embodiment 8 (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dicarboxylate

According to above logical method, by (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] dioxs-2, (2.15g 5mmol) obtains brown oil with the ethanol preparation title compound: 600mg (24%) to the 3-dioctyl phthalate; M ⁺H 492.Embodiment 9 (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate dicyclohexyl ester

According to above logical method, by (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] dioxs-2, (2.15g 5mmol) prepares title compound with hexalin and obtains brown foam: 750mg (40%) the 3-dioctyl phthalate; M ⁺H 600.Embodiment 10 (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate two cyclopentyl esters

According to above logical method, by (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] dioxs-2, (2.15g 5mmol) prepares title compound with cyclopentanol and obtains amorphous solid: 1.4g (49%) the 3-dioctyl phthalate; M ⁺H 572.Embodiment 11 (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate dioctyl ester

According to above logical method, by (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] dioxs-2, (2.15g 5mmol) prepares title compound with the 1-octanol and obtains brown foam: 1.3g (39%) the 3-dioctyl phthalate; M ⁺H 660.Embodiment 12 (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate dibenzyl ester

According to above logical method, by (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] dioxs-2, (2.15g 5mmol) prepares title compound with benzylalcohol and obtains brown oil: 1.0g (32%) the 3-dioctyl phthalate; M ⁺H 616.The selectivity of people's Beta-3 adrenergic receptor

The β of the activity of testing compound on people's B-adrenergic receptor through the people ₃, β ₂, or β ₁The Chinese hamster ovary of adrenergic receptor transfection (CHO) raji cell assay Raji.The preparation of these cells is at Emorine, L.J., Marullo, S., Briend-Sutren, M., Patey, G., Tate, K., Delavier-Klutchko, C., Strosberg, the molecular characterization Science 1989,245 (8) of A.D. people's β3-Shen Shangxiansunengshouti, 1118-1121 and at Muzzin, P., Revelli, J.-P., Kuhne, F., Gocayne, J.D., McCombie, W.R., Venter, J.C., Giacobino, J.-P., Fraser, C.M. fatty tissue-special β3-Shen Shangxiansunengshouti, the molecular cloning of obesity and decrement are regulated J.Biol.Chem.1991, and 226, illustrate among the 24053-24058.The activity of agonist is represented by the increase of cAMP level in the Chinese hamster ovary celI.Testing compound is for β ₃The selectivity of acceptor by with β ₂And β ₁The result's of adrenergic receptor transfectional cell contrast and estimating.Method: 1). use by people's β in the experiment ₃, β ₂Or β ₁The Chinese hamster ovary of adrenergic receptor transfection (CHO) cell.2). cell is cultivated the fusion state in 24 hole flat boards.3). medicine is dissolved among the DMSO, and concentration is 10 μ M.4). cell and medicine under the concentration of 10nM, were cultivated 10 minutes in 37 ℃., measure under the maximum 10 μ M concentration that improve of cAMP in making all 3 kinds of cells as n-compound with isoproterenol (standard 1).5). (Chicago, measure by scintillation proximity assay IL) with Amersham company for cell cAMP concentration.6). the activity of testing compound is represented with the percentage ratio of isoproterenol response.

Influence to the rat free fatty acid levels

Rat is by β on the response adipocyte plasma membrane ₃The increase of the blood plasma free fatty acid of receptor for stimulating (FFA) shows the β to list-oral dosage ₃The reaction of antagonist.With 5-{2-[2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-benzo [1,3] dioxole-2,2-dioctyl phthalate diisopropyl ester (standard 2) is as n-compound.All testing compounds are with the 0.1mg/kg dosed administration, with the response contrast of standard 2.

Method: 1). medicine is dissolved among the DMSO concentration 10mg/mL.2). 20 μ l DMSO-drug solutions are joined the 10mL methylcellulose gum: tween-80 (0.5%: 0.1%), ultimate density are 20 μ g/mL.3). with methylcellulose gum: the tween-80 drug suspension is by gavage (1mL/200g body weight; Or 0.1mg/kg) takes to rat, collect blood after 50 minutes.4). (Brentwood, the free fatty acids of the test kit analysed for plasma that N.Y.) provides by Biochemical Diagnostics Inc. are provided.5). the response of medicine is calculated by following formula.

Influence to the mouse hyperglycemia

In first day morning (baseline), 35 mouse are (male, db/db (C57BL/KsJ), Jackson Laboratories, 2-7 month is big, 35-60g) fasting is 4 hours, weigh, non-narcotic down from the tail point collection baseline blood sample of every mouse, be placed directly in the test tube of fluoride, mix, preserve in the ice.Recover feed to mouse then.Separated plasma is with the level of glucose in the Abbot VP analysis-e/or determining blood plasma.Because the volatility of db/db mice plasma glucose level, therefore remove 5 mouse with extreme value (as maximum or minimum) plasma glucose levels, 30 mouse of residue are divided into 7 groups of (solvent contrasts that plasma glucose levels mean value equates at random, Ciglitazone (standard 3), 5 testing compound groups).In first and second and three day afternoon, take (P.O.) solvent (2% tween 80 of 0.2mL/salt solution w/v) or testing compound for the mouse of random feeding.The 4th day morning, food was taken out from cage 3 hours, collect blood sample, take testing compound or solvent the 4th time for then mouse.Take behind the testing compound and to regather blood sample in 2 and 4 hours.Measure plasma glucose levels.Be evaluation testing compound activity, animal is determined by following to the percentage ratio that the 4th day (2 and 4 hours mean values) plasma glucose levels changes from taking (first day baseline sample) before the testing compound: Hyperglycemia db/db mice plasma glucose level reduces 50-60% and represents glucose level normalizing.Table I

Compound (embodiment)	β 2 a	β 3 a	The rat free fatty acids b
				?4	?9％	4％	32％
?5	?11％	50％	6％
				?6	?16％	51％	0％
?7	?33％	40％	7％
				?8	??-	?-	19％
?9	?1％	3％	3％
				?10	?4％	3％	20％
?11	?38％	97％	5％
				?12	?11％	27％	11％

^aPeople's beta receptor of expressing in the Chinese hamster ovary cell, the testing compound of 10nM is expressed as the result of the % of isoproterenol activity under the 10 μ M (increase on cAMP). ^bThe rising of rat plasma free fatty acids, 0.1mg/kg testing compound, be expressed as 5-{2-[2-under the 0.1mg/kg (3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-benzo [1,3] dioxole-2, the result of the % of 2-dioctyl phthalate diisopropyl ester response (78% increases).

Medicinal compositions

Can give required its patient separately or with pharmaceutical carrier with The compounds of this invention.Pharmaceutical carrier can be solid or liquid.

Used solid carrier can comprise one or more materials, and it also can be used as flavouring agent, lubricant, solubilizing agent, suspension agent, weighting agent, glidant, compressing tablet auxiliary, tackiness agent or tablet disintegrant or packs capsule material.In the powder agent, carrier is to disperse sufficient solid, and it mixes with disperseing sufficient active ingredient.In the tablet, active ingredient is mixed with the carrier of the necessary compacting character of having of suitable proportion, compresses by desired shape and size.Powder agent and tablet preferably contain the active ingredient up to 99%.Suitable solid carrier comprises, as, calcium phosphate, Magnesium Stearate, talcum powder, sucrose, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidine, low melt wax and ion exchange resin.

Liquid vehicle can be used in preparation solution, suspensoid, emulsion, syrup and the elixir.Can with solubilization of active ingredient of the present invention or be suspended in pharmaceutically acceptable liquid vehicle such as water, organic solvent, the two mixture or pharmaceutically acceptable oils or grease in.Liquid vehicle can contain other suitable medicinal additive such as solubilizing agent, emulsifying agent, buffer reagent, preservatives, sweeting agent, flavouring agent, suspensoid, thickening material, tinting material, viscosity modifier, stablizer or osmotic pressure regulator.The example of the suitable liquid vehicle of oral and parenterai administration comprises that water (especially contains above additive, as derivatived cellulose, the preferably carboxymethyl cellulose sodium solution), alcohols (comprising monohydroxy-alcohol and polyvalent alcohol) and its derivative and oils (as the Oleum Cocois and the peanut oil of rectifying) as dibasic alcohol.For parenterai administration, its carrier also can be grease such as ethyl oleate and isopropyl myristate.Sterile liquid carrier can be used in the composition of sterile liquid form of parenterai administration.

The liquid pharmaceutical composition that can be utilized as sterile solution or suspension carries out as intramuscular, intraperitoneal or subcutaneous injection.Also available sterile solution carries out intravenous administration.Oral administration can be used the form of liquid or solid composition.

Compound of the present invention also can be with suppository form rectal administration commonly used.For sucking in nasal cavity or the segmental bronchus or being blown into administration, The compounds of this invention can be made water or partially aqueous solution, use with the form of aerosol then.Also The compounds of this invention can be contained the percutaneous plaster transdermal administration of active compound and carrier by utilization, this carrier is inertia to active compound, and is nontoxic to skin, and can medicament be transported into blood by skin and absorb for whole body.This carrier can adopt various forms such as missible oil and ointment, paste, gelifying agent and occlusive devices.Missible oil and ointment can be the viscous liquid or the semi-solid emulsion of oil-in-water or water-in-oil type.Also be fit to by being dispersed in the paste that the oil that contains active ingredient or the absorption powder in the hydrophilic petroleum form.Available various occlusive devices is released into active ingredient in the blood flow, as be covered with semi-permeable membranes contain active ingredient and carrier or carrier free bank, or contain the matrix of active ingredient.Other occlusive devices is known in the literature.In addition, The compounds of this invention can be admixed in the controlled release hypodermic implant and in for some time, discharge gradually, avoid frequently taking medicine.Also fat-reducing compound of the present invention can be admixed in the animal-feed, be used for domestic animal as a kind of oral mode.

The used dosage of concrete patient that treatment suffers from obesity and/or diabetes and/or hyperglycemia must determine by the doctor in charge is subjective.Variable factor comprises seriousness, stature, age, the reactive mode of patient's dysfunction.Treatment is general from the low dose less than this compound dose,optimum.Increase dosage then until reaching best effect.The accurate dosage of administration will be decided according to experience and standard medical principle to the individuality of being treated by the doctor in charge in oral, non-enteron aisle, nasal cavity or the segmental bronchus.

Medicinal compositions preferred unit dosage form is as tablet or capsule.In these forms, composition is subdivided into the unit dosage form that contains an amount of active ingredient again; This unit dosage form can be packaged into composition, as the syringe of powder, the glass tube vial of packing, ampoule, prefilled or contain the sachet of liquid.Unit dosage form can be, as capsule or tablet itself, or the packaged form of any of these composition of proper amt.

Claims (8)

1. the compound and pharmacy acceptable salt, its enantiomorph or the diastereomer that have following formula, or its pharmacy acceptable salt:

R wherein ¹And R ⁶Independently be hydrogen, C ₁-C ₆Alkyl, trifluoromethyl, cyano group, C ₁-C ₆Alkoxyl group or halogen; R ²Be hydrogen or C ₁-C ₆Trialkylsilkl; R ³Be hydrogen or C ₁-C ₆Alkoxy carbonyl; Or R ²And R ³Xing Cheng oxazolidone ring links to each other; R ⁴And R ⁵Independently be hydrogen or C ₁-C ₆Alkyl; R ⁷And R ⁸Independently be OR ⁹Or NR ¹⁰R ¹¹R ⁹Be hydrogen, C ₁-C ₁₂Alkyl, C ₁-C ₁₂Cycloalkyl, C ₁-C ₁₂Silyl alkyl, phenyl, naphthyl, phenyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy C ₁-C ₆Alkyl, pyridyl, thienyl, furyl, imidazolyl, oxazolyl ,-CHR ¹²COOR ¹³,-CHR ¹²C (O) R ¹³,-CHR ¹²CONR ¹⁰R ¹¹,-CHR ¹²OCOOR ¹³Or-CHR ¹²OC (O) R ¹³R ¹⁰And R ¹¹Independently be hydrogen, C ₁-C ₁₂Alkyl, phenyl, naphthyl, phenyl-C ₁-C ₆Alkyl, furyl alkyl or alkoxycarbonyl alkyl; R ¹²And R ¹³Independently be hydrogen, C ₁-C ₁₂Alkyl, phenyl, naphthyl or phenyl-C ₁-C ₆Alkyl.

2. according to the compound and the pharmacy acceptable salt thereof of claim 1, it is selected from: 6-{ (2R)-2-[(5R)-5-(3-chloro-phenyl)-2-oxo-oxazolidines-3-yl]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate dimethyl ester; 6-{2-[5-(3-chloro-phenyl)-2-oxo-oxazolidines-3-yl]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate 3-methyl esters; (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate; (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate diisopropyl ester; (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate 3-isopropyl ester; (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dibutyl carboxylic acid; (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate two-(2-oxyethyl group-ethyl) ester; (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dicarboxylate; (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate dicyclohexyl ester; (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate two cyclopentyl esters; (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate dioctyl ester; (2,3-is suitable)-6-{ (2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxyl-ethylamino]-propyl group }-2,3-dihydro-benzo [1,4] diox-2,3-dioctyl phthalate dibenzyl ester.

3. the method for the mammiferous obesity of treatment obesity or the mammiferous diabetes that treatment suffers from diabetes or hyperglycemia and/or the method for hyperglycemia, it comprises the compound according to claim 1 or 2 that gives this Mammals treatment significant quantity.

4. increase the method for the cutability of the domestic animal of being raised for people's consumption, it comprises the compound according to claim 1 or 2 that gives this edible animal significant quantity.

5. medicinal compositions, it comprises the compound according to claim 1 or 2 of pharmaceutically acceptable carrier and treatment significant quantity.

6. according to the compound of claim 1 or 2 purposes as medicine.

7. be used for the treatment of purposes in the medicine of mammiferous diabetes that fat mammiferous obesity or treatment suffer from diabetes or hyperglycemia and/or hyperglycemia according to the compound of claim 1 or 2 in preparation.

8. preparation is according to the method for the compound of claim 1 or 2, and it comprises: the pyrocatechol that a) makes formula 1 Bromosuccinic acid ester reaction with formula 2

R wherein ¹⁴Be C ₁-C ₁₂Alkyl obtains wherein R of formula II compound ⁷And R ⁸All be OR ⁹, R ⁹Be C ₁-C ₁₂Alkyl; B) with formula II compound hydrolysis, wherein R ⁷And R ⁸All be OR ⁹And R ⁹Be C ₁-C ₁₂Alkyl obtains formula II compound, wherein R ⁷And R ⁸All be OR ⁹And R ⁹Be hydrogen; C) make described suitable dicarboxylic acid or its salt and formula R ⁹The alcohol reaction of OH, wherein R ⁹As definition in the claim 1, obtain wherein R of formula II compound ⁷And R ⁸All be OR ⁹D) with formula II compound hydrolysis, wherein R ⁷And R ⁸All be OR ⁹, obtain regional isomer 8a or 8b one of them or both E) make wherein R of formula II compound ⁷And R ⁸All be OR ⁹With formula NR ¹¹R ¹²Amine reaction, R wherein ¹¹And R ¹²As definition in the claim 1, obtain wherein R of formula II compound ⁷And R ⁸All be NR ¹⁰R ¹¹Or g) makes the carboxylic acid halides of formula 10a or 10b

Wherein X is a halogen, with formula HNR ¹⁰R ¹¹Amine reaction obtain formula II compound, wherein R ⁷And R ⁸One of be OR ⁹, another is-NR ¹⁰R ¹¹