CN101486688B - DPP-IV inhibitors having a sulfonamide amidoalkylpiperazine structure - Google Patents

Abstract

The present invention belongs to the technical field of medicine, and in particular relates to a DPP-IV inhibitor having a sulfonamide amidoalkylpiperazine structure represented by general formula (I), a pharmaceutically acceptable salt thereof or an isomer thereof: wherein Ar, Ar', R ¹ and n are as defined in the description; the present invention also relates to the preparation method of these compounds, the pharmaceutical composition containing these compounds, and the preparation of these compounds in the treatment and/or prevention of diabetes, non-insulin-dependent diabetes, high Drug application in blood sugar and insulin resistance.

Description

DPP-IV inhibitor with sulfonyl amine acyl alkyl piperazine structure

1, technical field

The invention belongs to medical technical field; be specifically related to have DPP-IV inhibitor, its pharmacy acceptable salt or its isomer of sulfonyl amine acyl alkyl piperazine structure; the preparation method of these compounds; the pharmaceutical composition that contains these compounds, and these compounds treat and/or prevent application in the medicine of diabetes, non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia, insulin resistance in preparation.

2, background technology

Diabetes are a kind of whole body chronic metabolic disease that normal level causes that exceed owing to blood sugar is out of control.Substantially be divided into four classes, comprise: I type (insulin-dependent), II type (non-insulin-depending type), other type and gestational diabetes.I type and type ii diabetes belong to primary diabetes mellitus, are modal two kinds of forms, are caused by the h and E factor interaction.The cause of disease of diabetes is very complicated, but is because Regular Insulin is absolute or relative the shortage after all, or insulin resistant.Its characteristics are because the absolute or relative deficiency of Regular Insulin and target cell to the susceptibility reduction of Regular Insulin, cause the metabolism disorder of carbohydrate, protein, fat, ionogen and water.

In recent years, because the rhythm of life that the change of growth in the living standard, dietary structure, day are becoming tight and few moving mode of life of sitting etc. all multifactor more, whole world onset diabetes rate increases rapidly, and diabetes have become the chronic disease of the third-largest serious threat human health after tumour, cardiovascular pathological changes.Present global diabetic subject has surpassed 1.2 hundred million people, China patient people the second in the world of living in groups.According to statistics, the diabetic subject that made a definite diagnosis of China reaches more than 4,000 ten thousand, and with annual 1000000 speed increase.Wherein, the type i diabetes patient accounts for 10%, and the type ii diabetes patient accounts for 90%.Diabetes have become the public health problem of people's growing interests.

The type i diabetes medicine mainly is insulin preparation and surrogate thereof at present; For the treatment of type ii diabetes, main medicine is an oral antidiabetic drug, roughly is divided into sulfourea, biguanides, Chinese medicine preparation, other antidiabetic drugs and adjuvant drug.Though it has good curative effect, medicine can not kept long-term efficacy aspect the hyperglycemia reducing, can not be at the cause of disease and effective mitigate the disease.Many antidiabetic medicines at first can fine controlling blood sugar, but along with the continuity of medication treatment then can not keep curative effect, Here it is, and people adopt conjoint therapy or use one of principal element of other different classes of medicines instead, and existing antidiabetic medicine to lack permanently effective major cause is because their mechanism of action is to increase target tissue to the susceptibility of insulin action or improve the activity that pancreas produces Regular Insulin, but the decay basic cause of disease of these diabetes of pancreatic beta cell function is lacked targeting.

Dipeptidase-IV (DPP-IV) extensively exists in vivo, it is a kind of cell surface protein that relates to the various biological function, the interior various active enzyme of the body of can degrading, as glucagon-like-peptide-1 (glucagons-like peptide 1, GLP-1), glucose pancreotropic hormone polypeptide (glucose-dependent insulinotropic polypeptide, GIP), neuropeptide, P material and chemokine etc.And the shortage of GLP-1, GIP all is the major cause of type ii diabetes (being non insulin dependent diabetes).The DPP-IV inhibitor is the medicine of a new generation's treatment diabetes.It has protected the activity of GLP-1 and GIP etc. by suppressing the DPP-IV activity, promotes insulin secretion, has the effect of protection β cell function in the time of lowering blood glucose, and can not cause side effects such as hypoglycemia and weight increase.

Tolazamide is a first-generation sulfonylurea Drugs Promoting Insulin Secretion, but lowering blood glucose, obviously reduces HbA _1c, the side effect of hypoglycemia, anaphylaxis, weight increase, dosage correlation gastrointestinal reaction is still arranged.The inhibitor sitagliptin phosphoric acid salt of the DPP-IV of another listing has security preferably and tolerance, finds also that at present the patient who uses has weight increase or potential to lose weight and symptom such as oedema.

The structural formula of tolazamide and sitagliptin is as follows:

The tolazamide sitagliptin

Yet the types of drugs for the treatment of diabetes at present is limited, can not meet clinical needs.In order to solve diabetics's misery, the Regular Insulin of himself is able to " resurrection " and play one's part to the full, blood sugar can be absorbed by the body tissue cell and utilize again, blood sugar is descended, reach steady in a long-term and the purpose of controlling blood sugar all sidedly, the medicine of being badly in need of the inhibitor of the more DPP-IV of exploitation satisfies clinical application.

3, summary of the invention

In order to address the above problem, further improve and optimize the DPP-IV inhibitor, the inventor provides a class new DPP-IV inhibitor through great deal of experimental.

Technical scheme of the present invention is as follows:

The invention provides the compound shown in the general formula (I), its pharmacy acceptable salt or its isomer:

Wherein: Ar, Ar ' independently represent respectively by 1～5 R ²Replace or unsubstituted phenyl, wherein, R ²Be selected from:

(1) halogen atom,

(2) straight or branched is replaced by halogen atom or unsubstituted C _1-6Alkyl or alkoxyl group,

(3) cyano group, or

(4) hydroxyl;

R ¹Represent hydrogen atom, by halogen atom, hydroxyl, carboxyl or amino the replacement or unsubstituted C _1-6Alkyl;

N represents 1～6 integer.

Another technical scheme of the present invention comprises the compound shown in the general formula (II), its pharmacy acceptable salt or its isomer:

Wherein, Ar, Ar ', R ¹Define by claim 1 with n.

Preferred compound is:

Wherein: Ar, Ar ' independently represent respectively by 1～5 R ²Replace or unsubstituted phenyl, wherein, R ²Be selected from:

(1) fluorine atom, chlorine atom or bromine atoms,

(2) methyl, ethyl or trifluoromethyl, or

(3) cyano group;

R ¹Represent hydrogen atom, methyl, ethyl, trifluoromethyl, methylol, hydroxyethyl, carboxymethyl, propyloic, aminomethyl or aminoethyl;

N represents 1～3 integer.

Further preferred compound is:

Wherein, Ar, Ar ' independently are selected from respectively:

(1) phenyl,

(2) 2-fluoro phenyl,

(3) 4-chlorophenyl,

(4) 4-aminomethyl phenyl,

(5) 3,4-difluorophenyls,

(6) 2,5-difluorophenyls,

(7) 2,4, the 5-trifluorophenyl,

(8) 2-fluoro-4-(trifluoromethyl) phenyl,

(9) the 4-bromo-2, the 5-difluorophenyl,

(10) 2-cyano group-4, the 5-difluorophenyl,

(11) 4-cyano group-2, the 5-difluorophenyl, or

(12) 5-cyano group-2,4 difluorobenzene base;

R ¹Represent hydrogen atom, methyl or trifluoromethyl;

N represents 1 or 2.

" halogen atom " of the present invention is fluorine atom, chlorine atom, bromine atoms or iodine atom.

" C of the present invention _1-6Alkyl " be the straight chain of 1-6 carbon atom or the alkyl of side chain; comprise methyl; ethyl; n-propyl; sec.-propyl; normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, the 2-methyl butyl, neo-pentyl, the 3-amyl group, n-hexyl, the 4-methyl amyl, the 3-methyl amyl, the 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, the 2-ethyl-butyl, 1, the 2-dimethyl propyl, cyclopropyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl etc.

" C of the present invention _1-6Alkoxyl group " be the straight chain of 1-6 carbon atom or the alkoxyl group of side chain; comprise methoxyl group; oxyethyl group; positive propoxy; isopropoxy; n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, 2-methyl butoxy, neopentyl oxygen, the 3-pentyloxy, positive hexyloxy, 4-methyl pentyloxy, 3-methyl pentyloxy, 2-methyl pentyloxy, 1-methyl pentyloxy, 3,3-dimethyl butoxy, 2,2-dimethyl butoxy, 1,1-dimethyl butoxy, 1,2-dimethyl butoxy, 1,3-dimethyl butoxy, 2,3-dimethyl butoxy, 2-ethyl butoxy, 1,2-dimethyl propoxy-, the ring propoxy-, cyclobutoxy group, 1-methyl cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.

Further preferred compound is as follows:

Chemical name: N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl]-N '-[(to the Methyl benzenesulfonyl amido) acetyl-2-yl] piperazine, be called for short compound 1, structural formula is as follows:

Chemical name: N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl]-N '-[(p-chloro benzenesulfonamide) acetyl-2-yl] piperazine, be called for short compound 2, structural formula is as follows:

The present invention also provides the preparation method of above-claimed cpd, and reaction equation is as follows, but is not limited only to following method:

Reactions steps:

The preparation of step 1 compd A

With (2S)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (being raw material 1) is dissolved in the tetrahydrofuran (THF), splash into n-Butyl Lithium/hexane solution, insulated and stirred splashes into the tetrahydrofuran (THF) cold soln of raw material 2, stirring reaction then, add the shrend reaction of going out, reaction solution concentrates, and residuum adds ethyl acetate and hydrochloric acid, divides water-yielding stratum, with ethyl acetate extraction three times, merge organic layer, salt is washed, anhydrous magnesium sulfate drying, concentrating under reduced pressure, silicagel column purifying (eluent is the mixed solution of ethyl acetate and hexanaphthene) gets compd A.

The preparation of step 2 compd B

Compd A is dissolved in the acetonitrile, dripping hydrochloric acid, the reaction solution stirring at room adds methyl alcohol, be concentrated into driedly, this operates triplicate, and then repeats once with toluene, solid, this solid slowly adds triethylamine with methylene dichloride dissolving back, and then slowly is added dropwise to (Boc) ₂O reaction solution stirring at room, the solid that the filtering reaction generates, filtrate is diluted with methylene dichloride, respectively with HCl solution and saturated brine washing, anhydrous magnesium sulfate drying, silicagel column purifying, eluent are the mixed solution of acetonitrile and sherwood oil, get compd B.

The preparation of step 3 Compound C

Add tetrahydrofuran (THF) to compd B, ice bath cools off, and drips the aqueous solution of lithium hydroxide then, the reaction solution stirring at room, concentrating under reduced pressure, residuum acetic acid ethyl dissolution, the washing of saturated sodium bicarbonate and salt solution, anhydrous magnesium sulfate drying, steam desolventize Compound C.

The preparation of step 4 Compound D

Add Compound C, ether, triethylamine and isopropyl chlorocarbonate, finish, stirring reaction adds the ethyl acetate solution that contains diazomethane then, add an amount of 1-methyl-3-nitro-1-nitrosoguanidine and be dissolved in ether and sodium hydroxide mixing solutions, the reaction solution stirring reaction, the organic layer drying, mixed solution dilutes with ethyl acetate, saturated sodium bicarbonate and salt water washing, anhydrous magnesium sulfate drying, be evaporated to dried, Compound D.

The preparation of step 5 compd E

Compound D is dissolved in the methyl alcohol, cooling adds diisopropyl ethyl amine and silver benzoate, reaction solution rises to stirring at room, reaction is finished, remove methyl alcohol under reduced pressure, residuum dissolves with methylene dichloride, filtering insoluble solid thing, and filtrate concentrates, the silicagel column purifying obtains solid, this solid is dissolved in the tetrahydrofuran (THF), adds then and contain in the water of lithium hydroxide the reaction solution stirring at room, dilute with ethyl acetate behind the concentration of reaction solution, anhydrous magnesium sulfate drying use in the washing of saturated sodium bicarbonate and salt, concentrated compd E.

The preparation of step 6 compound F 17-hydroxy-corticosterone

Under room temperature, throw compd E, HOBT (1-hydroxy benzo triazole), DMF, add DCC (dicyclohexyl charcoal imide) then, the stirring at room reaction is crossed and is filtered out the solid that reaction generates, filtrate continuation adds in the reaction flask, add piperazine, the 60 ℃ of stirrings that heat up, reaction is finished, add entry, separate out solid,, get compound F 17-hydroxy-corticosterone with methyl alcohol and ethyl acetate mixed solution recrystallization.

The preparation of step 7 compound G

In reaction flask, add compound F 17-hydroxy-corticosterone, after the methylene dichloride dissolving, cooling, slowly drip raw material 3, heat up stirring reaction, be warming up to backflow again, be added dropwise to hydrochloric acid under the vigorous stirring, after the reaction, reduce to room temperature, tell organic layer, water layer is transferred pH with sig water under ice bath, separate out solid filtering, water, ethyl acetate washing get crude product successively, get compound G with ethyl alcohol recrystallization.

Ar in the above reaction equation, Ar ', R ¹With n as mentioned before.Compound G is the compound shown in the general formula (I).

The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention is meant by the salt of pharmaceutically acceptable, non-toxic bases or acid preparation, comprises organic acid salt, inorganic acid salt, organic alkali salt, inorganic base salts.Organic acid comprises formic acid, acetate, Phenylsulfonic acid, phenylformic acid, tosic acid, butene dioic acid, (2R, 3R)-2,3-dyhydrobutanedioic acid, camphorsulfonic acid, citric acid, methylsulfonic acid, ethyl sulfonic acid, propanesulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, glactaric acid, pamoic acid, pantothenic acid, succsinic acid, tartrate etc., preferred especially Phenylsulfonic acid, tosic acid, citric acid, toxilic acid, fumaric acid, tartrate.Mineral acid comprises Hydrogen bromide, spirit of salt, nitric acid, sulfuric acid, phosphoric acid etc., preferred especially Hydrogen bromide, spirit of salt, sulfuric acid, phosphoric acid.Organic bases comprises primary, the second month in a season and tertiary amine, be substituted amine and comprise naturally occurring replacement amine, cyclammonium and basic ion exchange resin, be selected from arginine, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylin ethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, Histidine, Hai Baming, isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, the polyamides resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.Mineral alkali comprises the basic cpd of ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminium, iron, copper, ferrous, manganese, bivalent manganese etc., the basic cpd of preferred especially ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium.

The compounds of this invention contains one or more asymmetric centers, thereby can be used as racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.The compounds of this invention has asymmetric center, and each will independently produce two optical isomers this class asymmetric center, and scope of the present invention comprises all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.The present invention includes all isomeric forms of these compounds.Part of compounds of the present invention can exist with tautomeric forms, and it has the tie point of different hydrogen by one or more double-bond shifts.For example, ketone and its enol form are the keto-enol tautomerism bodies.Each tautomer and composition thereof all is included in the compound of the present invention.

Compound of the present invention can be united with one or more other medicines, and is more safer or more effective than single medicine.Can be with these other medicines and formula (I) compound simultaneously or in succession by a kind of approach and with its usual amounts administration.During administration simultaneously, be preferably the medicinal compositions of the unit dosage form that contains described other medicines and formula (I) compound.Can with formula (I) compound drug combination or respectively administration or in same medicinal compositions other activeconstituents of administration include, but are not limited to:

(a) other pepx IV inhibitor;

(b) insulin sensitisers comprises: (i) PPAR gamma agonist, as glitazones (as troglitazone, pioglitazone, englitazone, MCC-555, Rosiglitazone etc.) and other PPAR part, comprise PPAR α/γ economic benefits and social benefits agonist, as KRP-297 and PPAR alfa agonists such as Fenofibric Acid derivative (gemfibrozil, clofibrate, fenofibrate and bezafibrate); (ii) biguanides is as N1,N1-Dimethylbiguanide and phenformin; (iii) albumen network propylhomoserin phosphoesterase-1B (PTP-1B) inhibitor;

(c) Regular Insulin or insulin-mimickers;

(d) sulfonylurea and other Regular Insulin succagoga are as tolbutamide and Glipizide, meglitinide and related drugs;

(e) alpha-glucosidase inhibitor (as acarbose)

(f) glucagon receptor antagonist;

(g) GLP-1, GLP-1 stand-in and GLP-1 receptor stimulant;

(h) GLP and GLP stand-in and GLP receptor stimulant;

(i) PACAP, PACAP stand-in and PACAP acceptor 3 agonists;

(j) cholesterol reducing agent, as (i) HMG-CoA reductase inhibitor (lovastatin, Simvastatin, Pravastatin, fluvastatin, Ah appropriate cuts down his spit of fland, rivastatin, itavastatin, superstatin and other statins), (ii) inner complex (Colestyramine, the dialkyl aminoalkyl derivative of colestipol and crosslinked dextran), (iii) nicotinic alcohol, nicotinic acid or other salt, (iv) PPAR alfa agonists, as Fenofibric Acid derivative (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPAR α/γ economic benefits and social benefits agonist is as KRP-297; (vi) cholesterol absorption inhibitor, as β-Gu Zaichun and ezetimibe, (vii) ethanoyl CoA, chole-sterol acyltransferase inhibitor is as avasimibe with (viii) antioxidant is as probucol;

(k) PPAR delta agonists;

(l) anti-obesity compound, for example Phenfluoramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y 5 inhibitor and beta 3 adrenoreceptor agonists;

(m) ileal bile acid transfer protein inhibitor; With

(n) be used for the medicine of inflammation, for example acetylsalicylic acid, non-steroidal anti-inflammatory drug, glucocorticosteroid, sulphur nitrogen sulphur pyridine and epoxidase II select inhibitor.

Above-mentioned unite comprise compound of the present invention not only with a kind of other active compound and also with the associating of two or more other active compounds.Non-limiting example comprises that the have formula compound of (I) and two or more are selected from the associating of the active compound of biguanides, sulfonylurea, HMG-CoA reductase inhibitor, PPAR agonist, PTP-1B inhibitor, other DPP-IV inhibitor and anti-obesity compound.

The weight ratio of The compounds of this invention and second kind of activeconstituents can change, and it depends on the effective dose of various compositions.In general, with the effective dose that adopts separately.Therefore for example when compound of the present invention and other medicines drug combination, the weight ratio of The compounds of this invention and other medicines generally between about 200: 1 to about 1: 200, is preferably between about 20: 1 to about 1: 20.The drug combination of The compounds of this invention and other activeconstituents generally also can be in above-mentioned scope, but under each situation, should use the effective dose of each activeconstituents.

The present invention is claimed arbitrary compound recited above, its pharmacy acceptable salt or its isomer of comprising further; pharmaceutical composition with one or more pharmaceutical carriers and/or thinner; for clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral preparations or injection.Wherein contain the compound 0.01g～10g shown in the general formula (I) of physiology significant quantity, preferred 0.02g～5g can be described activeconstituentss such as 0.025g, 0.05g, 0.075g, 0.125g, 0.25g, 0.5g, 0.6g, 0.75g, 0.8g, 0.9g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g.Can be by 1～4 time arrangement every day, give described compound 1～2 time preferred every day.

The arbitrary compound of the present invention, its pharmacy acceptable salt or its isomer, can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.

When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.

When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.

Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.

When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.

Dipeptidase-IV (DPP-IV) is a kind of cell surface protein that relates to the various biological function.It has tissue distribution (intestines, kidney, liver, pancreas, placenta, thymus gland, spleen, epithelial cell, blood vessel endothelium, lymph and myelocyte, serum) and tissue and cell type expression level widely clearly.DPP-IV is confirmed as T type cell-stimulating mark CD26, and it can be at immunoregulatory in a large number, the endocrine and neurologic peptide of external cracking.This shows that there is the effect of diving in this peptase in the various diseases process of human body or other animal.

Pharmacological evaluation proves that the DPP-IV inhibitor can significantly suppress the DPP-IV activity, and protection GLP-1 activity promotes insulin secretion, reduces hyperglycemic-glycogenolytic factor after the meal, and lowering blood glucose improves anti-sugar amount; And have the active effect of protection GIP, can improve the concentration of GIP, strengthen the effect of its insulin secretion accelerating; The DPP-IV inhibitor can also improve glycolipid metabolism, prevents weight increase.

The present invention also provides the new DPP-IV inhibitor with sulfonyl amine acyl alkyl piperazine structure to be used for the treatment of and/or to prevent purposes in the medicine of following disease in preparation.

Type ii diabetes and relative disease, now full confirmation GLP-1 and GIP can be by DPP-IV quick inactivatings in vivo, therefore DPP-IV inhibitor of the present invention can be used for treating a large amount of illnesss that type ii diabetes and treatment and prevention are followed type ii diabetes, comprises metabolic syndrome X, reactive hypoglycemia and glycosuria sexual abnormality lipidemia.Following disease, illness is relevant with type ii diabetes with symptom, therefore can treat by the methods of treatment that adopts The compounds of this invention, control or prevention in some cases: (1) hyperglycemia, (2) low dextrose tolerance, (3) insulin resistance, (4) obesity, (5) matter fat disease, (6) unusual lipidemia, (7) hyperlipidaemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high HDL level, (12) atherosclerosis and sequela thereof, (13) vascular restenosis, (14) irritable bowel syndrome, (15) enteritis comprises crohnShi disease and ulcerative colitis, (16) retinopathy, (17) ephrosis, (18) neuropathy, (19) X syndromes, the hyperandrogenism (polycystic ovary syndrome) of (20) ovary and the disease of other tool insulin resistance; And the growth hormone deficiency disease, damage of intestines, immunosuppressive action, HIV infects, hemopoietic, neuronal disease, brain tumor is invaded and is shifted benign prostatauxe, seminal fluid motility, oulitis, osteoporosis etc.

The DPP-IV inhibitor that the present invention has a sulfonyl amine acyl alkyl piperazine structure compared with prior art has the following advantages:

(1) the DPP-IV inhibitor of the present invention with sulfonyl amine acyl alkyl piperazine structure can suppress the activity of DPP-IV preferably, makes in the body GLP-1 level more stable;

(2) the DPP-IV inhibitor of the present invention with sulfonyl amine acyl alkyl piperazine structure has good security and tolerance in vivo, and incidence rate of adverse reaction reduces more;

(3) to have the DPP-IV inhibitor preparation technology of sulfonyl amine acyl alkyl piperazine structure simple in the present invention, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.

Below further set forth the beneficial effect of The compounds of this invention by external pharmacological evaluation, but this should be interpreted as that The compounds of this invention only has following beneficial effect.

The external pharmacologically active of experimental example 1 The compounds of this invention

Trial-product: compound 1,2, self-control, its chemical name and structural formula are as mentioned before;

Reference substance: sitagliptin phosphate, commercial;

Experimental technique:

Accurately take by weighing trial-product and reference substance sitagliptin phosphate, add the DMSO dissolving, fully mixing is made into 100mM.Then with DMSO with above-mentioned mother liquor stepwise dilution to 10mM, 1mM, 100 μ M, 10 μ M.Get above-mentioned solution 4 μ l, add the damping fluid of 396 μ l, fully mixing is made into 100 μ M, 10 μ M, 1 μ M, 100nM.

1, fluorescent method detects the restraining effect to DPP-IV:

Get 5 μ l normal mouse serum, add the testing compound and the 24 μ l MgCl of 1 μ l different concns ₂Damping fluid, preincubate 5 minutes in the room temperature behind the mixing, add 10 μ l, 100 μ M reaction substrates and 20 μ l damping fluids then, carry out fluorometric assay (excitation wave 380nm/ transmitted wave 460nm) behind the lucifuge mixing, measured 1 time every 3 minutes, add 25% acetate, 40 μ l termination reactions in the time of the 20th minute, the room temperature lucifuge was placed after 5 minutes, carried out fluorometric assay once more.

2, the fluorescent method detection compound is to the restraining effect of DPP-7:

Damping fluid (pH 5.5) with the cacodylate of the BSA of 0.1mg/ml and 100mM is a reaction solution, and the Nle-Pro-AMC of 5 μ M is that substrate and 1 μ l compound are 15 minutes (exciting light and wavelength of transmitted light are respectively 360nm and 460nm) of 37 ℃ of reactions.

3, the fluorescent method detection compound is to the restraining effect of DPP-8:

With the BSA of 0.1mg/ml and the sodium phosphate buffer of 50mM (pH 8.0) is reaction solution, and the Ala-Pro-7-amino-4-trifluormethylcoumarin of 100 μ M is that substrate and 1 μ l compound react 15 minutes (exciting light and wavelength of transmitted light are respectively 400nm and 505nm) at 37 ℃.

4, the fluorescent method detection compound is to the restraining effect of DPP-9:

With the BSA of 0.1mg/ml and the Tris/HCl damping fluid of 100mM (pH 7.4) is reaction solution, and the Gly-Pro-AMC of 100 μ M is that substrate and 1 μ l compound react 30 minutes (exciting light and wavelength of transmitted light are respectively 360nm and 460nm) at 37 ℃.

Experimental result and conclusion:

Table 1 The compounds of this invention is to activity and the selectivity of DPP-IV

By table 1 as seen, compare with sitagliptin phosphate, the activity of 1,2 couples of DPP-IV of The compounds of this invention is slightly good or suitable than sitagliptin phosphate, and is suitable to selectivity and the sitagliptin phosphate of DPP-7, DPP-8, DPP-9, therefore, compound 1,2 is not only safe but also effective.

Pharmacologically active in the body of experimental example 2 The compounds of this invention

Trial-product: compound 1,2, self-control, its chemical name and structural formula are as mentioned before;

Reference substance: tolazamide, commercial;

Experimental technique:

1, modeling: choose 80 of the rats of 200g left and right sides body weight, random packet, one group of normal control group (10) gives normal diet (fatty 12%, carbohydrate 60%, protein 28%); All the other 70 give high lipid food (fatty 41%, carbohydrate 41%, protein 18%), after raising for 2 weeks, the animal fasting be can't help water and is spent the night, and presses 60mg/kg body weight abdominal injection STZ, survey animal fasting plasma glucose (fasting blood glucose after 72 hours, FBG), be stabilized in the above person of 13.5mmol/L and be modeling success, 37 of film forming.The normal control group is with isodose Trisodium Citrate-citrate buffer solution tail vein injection.

2, test grouping and medication: become the mould rat to be divided into 4 groups at random by body weight and glucose level with 37, compound 1 medication group (is called for short 1 group of compound, 9), compound 2 medication groups (are called for short 2 groups of compounds, 9), tolazamide medication group (is called for short the tolazamide group, 9), pathology control group (be called for short pathologic group, 10).

Grouping of table 2 animal and administration

5 groups of rats are irritated stomach treatment 1 time every day, all do not limit feed and drinking-water, and treatment cycle was 8 weeks.

Rat is surveyed fasting plasma glucose (FBG) level respectively at administration fasting at the 8th weekend 12 hours from tail vein blood.

3, fasting plasma glucose (FBG) level determination: (CA USA) goes up mensuration for LifeScan, Milpitas in blood glucose meter to get tail vein.

4, statistical study: all numerical value all are expressed as mean scholar standard deviation (mean ± s).Each measurement data all adopts SPSS11.0FORWINDOWS software that data are carried out statistical treatment, a plurality of sample averages of single factor relatively use variance analysis, the multiple sample mean relatively adopts the q check in twos, before and after each group relatively with the t check of paired data.P＜0.05 o'clock is illustrated in statistics and goes up meaningful.

5, result:

Table 3 is respectively organized relatively (mean ± s) of rat FBG level

Compare with normal group, ^*P＜0.01; Compare Δ P＜0.01 with pathologic group;

As shown in table 3, pathologic group and treatment group fasting plasma glucose are all apparently higher than normal group (P＜0.01); Treatment group fasting blood glucose level significantly is lower than pathologic group (P＜0.01); Fasting blood glucose level does not have significant difference (P＞0.05) between each treatment group, compound 1, compound 2 curers' glucose level is significantly less than the tolazamide group, prompting compound 1, compound 2 can obviously reduce type ii diabetes rat blood sugar level, improve the type ii diabetes carbohydrate metabolism disturbance.

Conclusion: the effect of 1,2 pairs of type ii diabetes of The compounds of this invention is better than or is suitable with sitagliptin phosphate, but is better than tolazamide, integrates the advantage of two kinds of medicines, is applicable to the clinical development of anti-type ii diabetes.

4, embodiment

The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.

Embodiment 1 (2R, 5S)-2,5-dihydro-3,6-dimethoxy-2-[(2,4,5-trifluorophenyl) methyl]-preparation of 5-isopropylpyrazine

With 9.2g (50mmol) (2S)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine is dissolved in the 300ml tetrahydrofuran (THF), then in-78 ℃, be added dropwise to 24ml (60mmol in the 30min, 2.5N) n-Butyl Lithium/hexane solution, insulated and stirred 30min is added dropwise to 2 of 9.9g (55mmol) then, 4, the 50ml tetrahydrofuran (THF) cold soln of 5-three fluorine-based benzyl chlorides ,-78 ℃ of stirring reaction 5h ,-78 ℃ add down the 100ml shrend reaction of going out, reaction solution concentrates, residuum adds ethyl acetate and 1N hydrochloric acid, divides water-yielding stratum, uses ethyl acetate extraction three times, merge organic layer, salt is washed, anhydrous magnesium sulfate drying, concentrating under reduced pressure, silicagel column purifying (eluent is the mixed solution of ethyl acetate and hexanaphthene) gets 12g colloidal solid target compound, yield: 73.4%.

The preparation of embodiment 2 (R)-N-2-(tertbutyloxycarbonyl)-3-(2,4, the 5-trifluorophenyl) alanine methyl ester

With 16.4g (50mmol) (2R, 5S)-2,5-dihydro-3,6-dimethoxy-2-[(2,4,5-trifluorophenyl) methyl]-the 5-isopropylpyrazine is dissolved in the 100ml acetonitrile, drip the hydrochloric acid of 100ml 1N then, reaction solution stirring at room 24h adds methyl alcohol, be concentrated into dried, this operates triplicate, and then repeats once with toluene, gets solid, this solid slowly adds the triethylamine of 50g with 400ml methylene dichloride dissolving back, and then slowly is added dropwise to 24g (110mmol) (Boc) ₂O reaction solution stirring at room 8h, the solid that the filtering reaction generates, filtrate is diluted with methylene dichloride, HCl solution and saturated brine with 1N washs respectively, anhydrous magnesium sulfate drying, silicagel column purifying, eluent are the mixed solution of acetonitrile and sherwood oil, obtain 10.5g solid target compound, yield: 63.3%.

The preparation of embodiment 3 (R)-N-2-(tertbutyloxycarbonyl)-3-(2,4, the 5-trifluorophenyl) L-Ala

To (R)-N-2-of 10g (30mmol) (tertbutyloxycarbonyl)-3-(2,4,5-trifluorophenyl) adds the 200ml tetrahydrofuran (THF) in the alanine methyl ester, the ice bath cooling, drip the 200ml aqueous solution of 21.5g (90mmol) lithium hydroxide then, reaction solution stirring at room 15h, concentrating under reduced pressure, residuum acetic acid ethyl dissolution, saturated sodium bicarbonate and salt solution washing, anhydrous magnesium sulfate drying, steam desolventize the 7.7g solid, yield: 80.3%.

Embodiment 4 (R)-3-[(tertbutyloxycarbonyl) amino]-preparation of 1-diazonium-4-(2,4, the 5-trifluorophenyl) butyl-2-ketone

(R)-N-2-(the tertbutyloxycarbonyl)-3-(2 that adds 8g (25mmol), 4, the 5-trifluorophenyl) L-Ala, the 150ml ether, then in-30 ℃ of triethylamine and 4ml isopropyl chlorocarbonates that add 3g (30mmol) down, finish,-30 ℃ of stirring reaction 30min, add the ethyl acetate solution that contains the 5.3g diazomethane then, add an amount of 1-methyl-3-nitro-1-nitrosoguanidine down in 0 ℃ and be dissolved in ether and 40% sodium hydroxide mixing solutions, 0 ℃ of following stirring reaction 20min of reaction solution, organic layer drying, mixed solution dilutes with ethyl acetate, saturated sodium bicarbonate and salt water washing, anhydrous magnesium sulfate drying is evaporated to dried, get 7.6g solid target compound, yield: 88.2%.

Embodiment 5 (R)-3-[(tertbutyloxycarbonyl) amino]-the butyro-preparation of 4-(2,4, the 5-trifluorophenyl)

Add 13.7g (40mmol) (R)-the 3-[(tertbutyloxycarbonyl) amino]-1-diazonium-4-(2,4, the 5-trifluorophenyl) butyl-2-ketone is dissolved in the 300ml methyl alcohol, be cooled to-30 ℃ of silver benzoates that add 18.9g (120mmol) diisopropyl ethyl amine and 2.3g (10mmol), reaction solution rises to stirring at room 3h, reaction is finished, remove methyl alcohol under reduced pressure, residuum dissolves with the 200ml methylene dichloride, filtering insoluble solid thing, filtrate concentrates, the silicagel column purifying obtains solid, and this solid is dissolved in the 100ml tetrahydrofuran (THF), adds then in the water of the 100ml that contains 1.8g (75mmol) lithium hydroxide, reaction solution stirring at room 16h, with the ethyl acetate dilution, anhydrous magnesium sulfate drying is used in saturated sodium bicarbonate and salt washing behind the concentration of reaction solution, concentrate 7.2g white solid compound, yield: 54.2%.

The preparation of embodiment 6 (R)-3-(tertbutyloxycarbonyl) amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl piperazine

Under room temperature, throw (R)-3-[(tertbutyloxycarbonyl of 16.7g (50mmol)) amino]-4-(2,4, the 5-trifluorophenyl) butyric acid, 6.8g (50mmol) HOBT (1-hydroxy benzo triazole), DMF100ml adds 20g (75mmol) DCC (dicyclohexyl charcoal imide) then, stirring at room reaction 1h, cross and filter out the solid that reaction generates, filtrate continuation adds in the reaction flask, adds 19.2g (100mmol) piperazine, heats up 60 ℃ and stirs 3h, reaction is finished, add 300ml water, separate out solid, with methyl alcohol and ethyl acetate mixed solution recrystallization, get product 14.5g, yield: 72.1%.

Embodiment 7N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl]-N '-[(to the Methyl benzenesulfonyl amido) acetyl-2-yl] The preparation of piperazine

In reaction flask, add (R)-3-(tertbutyloxycarbonyl) amino-4-(2; 4; the 5-trifluorophenyl)-and 1-butyryl piperazine 12.0g (30mmol), after the dissolving of 100ml methylene dichloride, reduce temperature to 0～5 ℃; slowly drip 2-chloro-N-tolysulfonyl yl acetamide 7.4g (30mmol); elevated temperature to 40 ℃, stirring reaction 6h is warming up to backflow again; be added dropwise to 40ml 5N hydrochloric acid under the vigorous stirring; behind the reaction 1h, reduce to room temperature, tell organic layer; water layer is transferred pH 9 with sig water under ice bath; separate out solid filtering, successively water; the ethyl acetate washing gets crude product; get product 10.1g with ethyl alcohol recrystallization, yield: 65.8%.

Molecular formula: C ₂₃H ₂₇F ₃N ₄O ₄S

Molecular weight: 512.55

Ultimate analysis:

Measured value: C, 53.72%; H, 5.61%; F, 11.30%; N, 10.69%; S, 6.11%

Theoretical value: C, 53.90%; H, 5.31%; F, 11.12%; N, 10.93%; S, 6.26%

Mass spectrum (m/e): 513 (M+1)

The hydrogen spectrum: ¹H-NMR (300MHz, CD ₃OD)

δ(ppm)：7.43(m，1H)，7.29(m，1H)，7.18(m，2H)，7.09(m，2H)，4.62(s，3H)，3.91(m，1H)，3.63(m，8H)，3.60(m，2H)，2.26(s，2H)，2.83(m，2H)

Embodiment 8N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl]-N '-[(p-chloro benzenesulfonamide) acetyl-2-yl] piperazine Preparation

Preparation method's reference example 7 is thrown (R)-3-(tertbutyloxycarbonyl) amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl piperazine 12.0g (30mmol), and 2-chloro-N-gets product 11.5g, yield: 71.8% to chlorobenzene alkylsulfonyl ethanamide 8.0g (30mmol).

Molecular formula: C ₂₂H ₂₄ClF ₃N ₄O ₄S

Molecular weight: 532.96

Ultimate analysis:

Measured value: C, 49.22%; H, 4.78%; Cl, 6.24%; F, 10.15%; N, 10.82%; S, 5.80%

Theoretical value: C, 49.58%; H, 4.54%; Cl, 6.65%; F, 10.69%; N, 10.51%; S, 6.02%

Mass spectrum (m/e): 533 (M+1)

The hydrogen spectrum: ¹H-NMR (300MHz, CD ₃OD)

δ(ppm)：7.45(m，1H)，7.33(m，1H)，7.25(m，2H)，7.21(m，2H)，3.89(m，1H)，3.61(m，8H)，3.58(m，2H)，2.27(s，2H)，2.81(m，2H)

The preparation of embodiment 9 The compounds of this invention tablets

1, prescription:

Prescription 1:

Any one 125g in the compound 1-2 or derivatives thereof

Starch 200g

Hydroxypropylcellulose 40g

Microcrystalline Cellulose 45g

The 50% aqueous ethanolic solution 120g of 1%HPMC

Micropowder silica gel 3g

Magnesium Stearate 2g

Prepare 1000 altogether

Prescription 2:

Any one 50g in the compound 1-2 or derivatives thereof

Starch 200g

Hydroxypropylcellulose 50g

Microcrystalline Cellulose 55g

The 50% aqueous ethanolic solution 100g of 1%HPMC

Micropowder silica gel 3g

Magnesium Stearate 2g

Prepare 1000 altogether

Prescription 3:

Any one 25g in the compound 1-2 or derivatives thereof

Starch 225g

Hydroxypropylcellulose 50g

Microcrystalline Cellulose 55g

The 50% aqueous ethanolic solution 100g of 1%HPMC

Micropowder silica gel 3g

Magnesium Stearate 2g

Prepare 1000 altogether

2, preparation technology: take by weighing raw material and auxiliary material according to prescription, raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively; Raw material, starch, hydroxypropylcellulose and Microcrystalline Cellulose are mixed, add mixer-granulator, add 50% aqueous ethanolic solution of 1%HPMC, stirred 15 minutes, make particle; Particle is dried being lower than under 60 ℃ the condition; Dry good particle adds micropowder silica gel and Magnesium Stearate, and whole grain mixes; Sampling, the work in-process chemical examination; According to the definite sheet weight sheet of chemical examination; Finished product is examined entirely, the packing warehouse-in.

Claims (10)

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: Wherein: Ar and Ar' independently represent a phenyl group substituted or unsubstituted by 1 to 5 ^R2 , wherein ^R2 is selected from: (1) Halogen atoms, (2) straight or branched C _1-6 alkyl or alkoxy groups substituted or unsubstituted by halogen atoms, (3) cyano, or (4) Hydroxyl; R ¹ represents a hydrogen atom, a C _1-6 alkyl group substituted or unsubstituted by a halogen atom, a hydroxyl group, a carboxyl group or an amino group; n represents the integer of 1-6. 2. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, which is shown in general formula (II): Wherein, Ar, Ar', R ¹ and n are as defined in claim 1. 3. The compound or pharmaceutically acceptable salt thereof as claimed in claim 2: Wherein: Ar and Ar' independently represent a phenyl group substituted or unsubstituted by 1 to 5 R2, wherein ^R2 is selected from: (1) A fluorine atom, chlorine atom or bromine atom, (2) Methyl, ethyl or trifluoromethyl, or (3) cyano group; R ¹ represents a hydrogen atom, methyl, ethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, carboxymethyl, carboxyethyl, aminomethyl or aminoethyl; n represents the integer of 1-3. 4. The compound or pharmaceutically acceptable salt thereof as claimed in claim 3: Wherein, Ar, Ar' are independently selected from: (1) phenyl, (2) 2-fluorophenyl, (3) 4-chlorophenyl, (4) 4-methylphenyl, (5) 3,4-difluorophenyl, (6) 2,5-difluorophenyl, (7) 2,4,5-trifluorophenyl, (8) 2-fluoro-4-(trifluoromethyl)phenyl, (9) 4-bromo-2,5-difluorophenyl, (10) 2-cyano-4,5-difluorophenyl, (11) 4-cyano-2,5-difluorophenyl, or (12) 5-cyano-2,4-difluorophenyl; R ¹ represents a hydrogen atom, methyl or trifluoromethyl; n stands for 1 or 2. 5. The compound or pharmaceutically acceptable salt thereof as claimed in claim 4, which is selected from: N-[(R)-3-Amino-4-(2,4,5-trifluorophenyl)-1-butyryl]-N'-[(p-methylbenzenesulfonamido)acetyl-2-yl ] piperazine, and N-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-1-butyryl]-N'-[(p-chlorobenzenesulfonamide)acetyl-2-yl]piper Zinc. 6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein a pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid, including organic salt, inorganic acid salt, organic alkali salt or inorganic alkali salt, wherein the organic acid is benzenesulfonic acid, p-toluenesulfonic acid, citric acid, maleic acid, fumaric acid, tartaric acid; the inorganic acid is hydrobromic acid, hydrogen chloride Acid, sulfuric acid, phosphoric acid; organic bases are arginine, meglumine, glucosamine; inorganic bases are ammonium and basic compounds of lithium, sodium, potassium, calcium, magnesium, zinc, barium. 7. A pharmaceutical composition comprising the compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof and other active ingredients. 8. The pharmaceutical composition of the compound or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or diluents as claimed in any one of claims 1 to 5, which is any pharmaceutically acceptable One dose. 9. The pharmaceutical composition according to claim 8, containing 0.01 g to 10 g of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an essential active ingredient. 10. The application of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the preparation of medicines for the treatment and/or prevention of non-insulin-dependent diabetes, hyperglycemia, and insulin resistance .