CN101418000A - DPP-IV inhibitor derivates containing benzofuran sulfonyl ureas - Google Patents

DPP-IV inhibitor derivates containing benzofuran sulfonyl ureas Download PDF

Info

Publication number
CN101418000A
CN101418000A CN 200810166085 CN200810166085A CN101418000A CN 101418000 A CN101418000 A CN 101418000A CN 200810166085 CN200810166085 CN 200810166085 CN 200810166085 A CN200810166085 A CN 200810166085A CN 101418000 A CN101418000 A CN 101418000A
Authority
CN
China
Prior art keywords
acid
hydrogen atom
compound
isomer
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN 200810166085
Other languages
Chinese (zh)
Other versions
CN101418000B (en
Inventor
黄振华
赵红宇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Ao He Research Institute Co Ltd
Original Assignee
Shandong Xuanzhu Pharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong Xuanzhu Pharma Co Ltd filed Critical Shandong Xuanzhu Pharma Co Ltd
Priority to CN2008101660855A priority Critical patent/CN101418000B/en
Publication of CN101418000A publication Critical patent/CN101418000A/en
Application granted granted Critical
Publication of CN101418000B publication Critical patent/CN101418000B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

The invention belongs to the technical field of medicine, and in particular relates to a DPP-IV inhibitor derivative which is as shown in a general formula (I) and contains benzofuran sulfonylurea, and a pharmaceutically acceptable salt or an isomer thereof, wherein R<1>, R<2>, R<3>, R<4>, A, X, and Y are as defined in the instruction. The invention also relates to a method for preparing the compounds, a pharmaceutical composition containing the compounds, as well as application of the compounds in the preparation of medicines for treating and/or preventing diabetes, non-insulin-dependent diabetes, high blood sugar, and insulin resistance.

Description

The DPP-IV inhibitor derivates that contains benzofuran sulfonyl ureas
1, technical field
The invention belongs to medical technical field, be specifically related to contain DPP-IV inhibitor derivates, its pharmacy acceptable salt or its isomer of benzofuran sulfonyl ureas, 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 peptide1, 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 diabetes B (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.
The inhibitor gliclazide of the DPP-IV of listing is the oral sulfonylureas drugs for diabetes of the s-generation at present, its hypoglycemic activity is 3～30 times of tolbutamide (first-generation sulfonylureas drugs for diabetes), be mainly used in slight, moderate diabetes B that the treatment islet function remains, its blood sugar reducing function is stronger, but serious delay hypoglycemia and hepatic renal dysfunction are arranged clinically.The inhibitor sitagliptin phosphate of another DPP-IV 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.Yet pharmaceutical activity is relatively poor, can not meet clinical needs.Therefore, the inhibitor medicaments of being badly in need of the more anti-type ii diabetes of exploitation satisfies clinical application.
The structural formula of gliclazide and sitagliptin is as follows:
Figure A200810166085D00061
?
Figure A200810166085D00062
Gliclazide sitagliptin
3, summary of the invention
In order to address the above problem, further improve and optimize the inhibitor of DPP-IV, the inventor provides the inhibitor of the new DPP-IV of a class 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:
Figure A200810166085D00063
Wherein, R 1, R 2Independently represent hydrogen atom respectively, halogen atom, cyano group, hydroxyl is replaced or unsubstituted C by 1-5 halogen atom 1-6Alkyl or C 1-6Alkoxyl group;
R 3, R 4Independently represent hydrogen atom or C respectively 1-6Alkyl;
X represents N or C-R 5, R wherein 5Be selected from hydrogen atom, cyano group, replaced or unsubstituted C by 1-5 halogen atom 1-6Alkyl or C 1-6Alkoxyl group;
Y represents N or C-R 6, R wherein 6Be selected from hydrogen atom, cyano group, replaced or unsubstituted C by 1-5 halogen atom 1-6Alkyl or C 1-6Alkoxyl group;
A represents group shown in the following formula:
Figure A200810166085D00071
Perhaps
Figure A200810166085D00072
Another embodiment of the present invention comprises the described compound of formula II, its pharmacy acceptable salt or its isomer:
Figure A200810166085D00073
Wherein, R 1, R 2Independently represent hydrogen atom respectively, fluorine atom, bromine atoms, trifluoromethyl or cyano group;
R 3, R 4Independently represent hydrogen atom respectively, methyl or ethyl;
X represents N or C-R 5, R wherein 5Be selected from hydrogen atom, replaced or unsubstituted C by 1-5 halogen atom 1-4Alkyl;
Y represents N or C-R 6, R wherein 6Be selected from hydrogen atom, replaced or unsubstituted C by 1-5 halogen atom 1-4Alkyl;
A represents group shown in the following formula:
Figure A200810166085D00074
Perhaps
Figure A200810166085D00075
Further preferred compound is:
Wherein, R 1, R 2Independently represent hydrogen atom respectively, fluorine atom, trifluoromethyl or cyano group;
R 3, R 4Independently represent hydrogen atom or methyl respectively;
X represents N or C-R 5, R wherein 5Be selected from hydrogen atom, methyl, ethyl, trifluoromethyl, CH 2CF 3Perhaps CF 2CF 3
Y represents N or C-R 6, R wherein 6Be selected from hydrogen atom, methyl, ethyl, trifluoromethyl, CH 2CF 3Perhaps CF 2CF 3
A represents group shown in the following formula:
Figure A200810166085D00076
Perhaps
Figure A200810166085D00077
Further preferred compound is:
Wherein, R 1, R 2Independently represent hydrogen atom or fluorine atom respectively;
R 3, R 4Independently represent hydrogen atom respectively;
X represents N;
Y represents C-R 6, R 6Be selected from methyl or trifluoromethyl;
A represents group shown in the following formula:
Figure A200810166085D00081
Perhaps
Figure A200810166085D00082
" 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 alkyl of the direct-connected or side chain of 1-6 carbon atom; 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, isohexyl, 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-methyl-2-methyl-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, different 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-methyl-2-methyl propoxy-, the ring propoxy-, cyclobutoxy group, 1-methyl cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
Particularly preferred compound is as follows:
Chemical name: 7-[(R)-N-3-amino-4-[2-(N-butylamine formyl radical) amido alkylsulfonyl-4,7-two fluorine-based cumarone-5-yls] butyryl radicals]-3-(trifluoromethyl)-5,6,7; 8-tetrahydrochysene-[1,2,4] triazolo [4; 3-a] pyrazine, be called for short compound 1, structural formula is as follows:
Figure A200810166085D00083
Chemical name: 7-[(R)-N-3-amino-4-[2-[N-(cyclopentyl is [c] tetramethyleneimine also) amido formyl radical] amido alkylsulfonyl-4; 7-two fluorine-based cumarone-5-yls] butyryl radicals]-3-(trifluoromethyl)-5; 6; 7,8-tetrahydrochysene-[1,2; 4] triazolo [4; 3-a] pyrazine, be called for short compound 2, structural formula is as follows:
Figure A200810166085D00091
Chemical name: 7-[(R)-N-3-amino-4-[2-[N-(cyclohexyl is [c] tetramethyleneimine also) amido formyl radical] amido alkylsulfonyl-4; 7-two fluorine-based cumarone-5-yls] butyryl radicals]-3-(trifluoromethyl)-5; 6; 7,8-tetrahydrochysene-[1,2; 4] triazolo [4; 3-a] pyrazine, be called for short compound 3, structural formula is as follows:
Figure A200810166085D00092
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:
Figure A200810166085D00101
The preparation of compound shown in the step 1 formula A
In reaction flask, add the tetrahydrofuran solution of raw material 1, under low temperature, be added dropwise to n-Butyl Lithium/hexane solution then, insulated and stirred.Be added dropwise to the tetrahydrofuran (THF) cold soln of raw material 2 then, stirring reaction.Add the shrend reaction of going out, reaction solution concentrates, residuum adds ethyl acetate and 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) promptly gets compound shown in the formula A.
The preparation of compound shown in the step 2 formula B
To go up that compound is dissolved in the acetonitrile shown in the step gained formula A, dripping hydrochloric acid then, reaction solution stirring at room.Add methyl alcohol, be concentrated into driedly, this operates triplicate.And then repeat once with toluene, solid.This solid slowly adds the triethylamine of 50g with methylene dichloride dissolving back, and then slowly is added dropwise to (Boc) 2O.The 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, promptly get compound shown in the formula B.
The preparation of compound shown in the step 3 formula C
To go up in reaction flask in the tetrahydrofuran (THF) of compound adding shown in the step gained formula B, ice bath cools off, and is added dropwise to the aqueous solution of lithium hydroxide then, the reaction solution stirring at room.Concentrating under reduced pressure, residuum acetic acid ethyl dissolution, saturated sodium bicarbonate and salt solution washing, anhydrous magnesium sulfate drying.Steaming desolventizes, and promptly gets compound shown in the formula C.
The preparation of compound shown in the step 4 formula D
In reaction flask, add and go up compound and ether shown in the step gained formula C, then in adding triethylamine and isopropyl chlorocarbonate, finish, stirring reaction, add the ethyl acetate solution that contains diazomethane then, add an amount of 1-methyl-3-nitro-1-nitrosoguanidine that is 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 driedly, promptly get compound shown in the formula D.
The preparation of compound shown in the step 5 formula E
In reaction flask, add to go up the methanol solution of compound shown in the step gained formula D, the cooling back add diisopropyl ethyl amine and silver benzoate.Reaction solution heats up and stirs.Reaction is finished, and removes methyl alcohol under reduced pressure, and residuum dissolves with methylene dichloride, filtering insoluble solid thing, and filtrate concentrates, and the silicagel column purifying obtains solid.This solid is dissolved in the tetrahydrofuran (THF), add then contain lithium hydroxide water in, reaction solution stirring at room 16h.With the ethyl acetate dilution, anhydrous magnesium sulfate drying is used in saturated sodium bicarbonate and salt washing, concentrates, and promptly gets compound shown in the formula E behind the concentration of reaction solution.
The preparation of compound shown in the step 6 formula F
Add under room temperature and go up compound shown in the step gained formula E, HOBT (1-hydroxy benzo triazole) and DMF add 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, add raw material 3 (its preparation method is referring to J.Med.Chem.2005,48,141-151), heat up and stir, reaction is finished, and adds 300ml water, separates out solid, with methyl alcohol and ethyl acetate mixed solution recrystallization, promptly get compound shown in the formula F.
The preparation of compound shown in the step 7 formula G
In the exsiccant reaction flask, add compound shown in methylene dichloride and the last step gained formula F, reduce temperature after the stirring and dissolving.Slowly drip the dichloromethane solution of chloromethane sulphonyl under the vigorous stirring, drip and finish, heat up stirring reaction.Reaction is finished, and feeds exsiccant raw material 4 under the vigorous stirring, regulates the pH value, stops ventilation, stirring reaction.Add entry, saturated sodium-chloride washing respectively, anhydrous magnesium sulfate drying removes solvent under reduced pressure, and the residuum recrystallizing methanol promptly gets compound shown in the formula G.
The preparation of compound shown in the step 8 formula H
Compound shown in the step gained formula G after the methylene dichloride dissolving, reduces temperature on adding in reaction flask.Slowly drip raw material 5, elevated temperature, stirring reaction.Be warming up to backflow again, be added dropwise to hydrochloric acid under the vigorous stirring, behind the reaction 1h, reduce to room temperature, tell organic layer, water layer is transferred pH with sig water under ice bath, separates out solid filtering, successively water, ethyl acetate washing, get crude product, use ethyl alcohol recrystallization, promptly get compound shown in the formula H.
X in the above reaction equation, Y, R 1, R 2, R 3, R 4, A representative group as mentioned before, i.e. 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 or inorganic base salts.Organic acid comprises acetate, Phenylsulfonic acid, phenylformic acid, tosic acid, butene dioic acid, (2R, 3R)-2,3-dyhydrobutanedioic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, pamoic acid, pantothenic acid, succsinic acid, tartrate etc., preferred especially Phenylsulfonic acid, tosic acid, butene dioic 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, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, meglumine, glucosamine, Histidine, Hai Baming, isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, 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, ketone, 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, 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 (for example troglitazone, pioglitazone, englitazone, MCC-555, Rosiglitazone etc.) and other PPAR part, comprise PPAR α/γ economic benefits and social benefits agonist, as KRP-297, with PPAR alfa agonists such as Fenofibric Acid derivative (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (ii) biguanides, for example N1,N1-Dimethylbiguanide and phenformin and (iii) albumen network propylhomoserin phosphoesterase-1B (PTP-1B) inhibitor;
(c) Regular Insulin or insulin-mimickers;
(d) sulfonylurea and other Regular Insulin succagoga, for example tolbutamide and Glipizide, meglitinide and related drugs;
(e) alpha-glucosidase inhibitor (for example 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, (i) HMG-CoA reductase inhibitor (lovastatin for example, 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, Fenofibric Acid derivative (gemfibrozil for example, clofibrate, fenofibrate and bezafibrate), (v) PPAR α/γ economic benefits and social benefits agonist, for example KRP-297; (vi) cholesterol absorption inhibitor, for example β-Gu Zaichun and ezetimibe, (vii) ethanoyl CoA, chole-sterol acyltransferase inhibitor, for example avasimibe and (viii) antioxidant, for example 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 2 are selected 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 arrives between about 1:200 at about 200:1, is preferably about 20:1 and arrives between 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 derivates that contains benzofuran sulfonyl ureas 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 or 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, (21) ephrosis, (22) neuropathy, (23) X syndromes, the hyperandrogenism (polycystic ovary syndrome) of (24) 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 derivates that contains benzofuran sulfonyl ureas of the present invention is compared with immediate prior art, has the following advantages:
(1) the DPP-IV inhibitor derivates that contains benzofuran sulfonyl ureas of the present invention can suppress the activity of DPP-IV (being responsible for the enzyme of degraded GLP-1) preferably, makes the interior GLP-1 level of body more stable;
(2) the DPP-IV inhibitor derivates that contains benzofuran sulfonyl ureas of the present invention has good security and tolerance in vivo, and incidence rate of adverse reaction reduces more;
(3) the DPP-IV inhibitor derivates that contains benzofuran sulfonyl ureas of the present invention has the advantage of DPP-IV inhibitor and sulfonylurea, has double effects.
(4) the DPP-IV inhibitor derivates preparation technology who contains benzofuran sulfonyl ureas of the present invention is simple, 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 1～3, self-control, its chemical name and structural formula are as mentioned before;
Reference substance: sitagliptin phosphate: self-control, its chemical name and structural formula are as mentioned before;
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 l100 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 (pH5.5) 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 (pH8.0) 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 (pH7.4) of 100mM 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 omited than sitagliptin phosphate, selectivity and sitagliptin phosphate to DPP-7, DPP-8, DPP-9 are suitable, the activity of 3 couples of DPP-IV of compound is slightly poor than sitagliptin, selectivity to DPP-8 is also relatively poor, and 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 1～3, self-control, its chemical name and structural formula are as mentioned before;
Reference substance: gliclazide: commercial;
Experimental technique:
1, modeling: choose 100 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 90 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, 46 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 5 groups at random by body weight and glucose level with 46, 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), compound 3 medication groups (are called for short 3 groups of compounds, 9), gliclazide medication group (is called for short the gliclazide group, 9), pathology control group (be called for short pathologic group, 10).
Grouping of table 1 animal and administration
Figure A200810166085D00181
6 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: as shown in table 2, 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 1～3 curer's glucose level is significantly less than the gliclazide group, prompting compound 1～3 can obviously reduce diabetes B rat blood sugar level, improves the diabetes B carbohydrate metabolism disturbance.
Table 2 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;
Conclusion: the effect of 1～3 pair of type ii diabetes of The compounds of this invention is better than sitagliptin phosphate and gliclazide, 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-[(4,7-two fluorine-based cumarone-5-yls) methyl]-5-sec.-propyl pyrrole The preparation of piperazine
In reaction flask, throw 9.2g (50mmol) (2S)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine is dissolved in the 300ml tetrahydrofuran solution, is added dropwise to 24ml (60mmol then in-78 ℃, 30min, 2.5N) n-Butyl Lithium/hexane solution, insulated and stirred 30min.Be added dropwise to the 5-chloromethyl-4 of 11.1g (55mmol) then, the 50ml tetrahydrofuran (THF) cold soln of 7-two fluorine-based cumarones ,-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 11.8g solid chemical compound, yield: 67.2%.
Embodiment 2 (R The preparation of)-N-2-(tertbutyloxycarbonyl) amido-3-(4,7-two fluorine-based cumarone-5-yls) alanine methyl ester
(2R, 5S)-2,5-dihydro-3,6-dimethoxy-2-[(4,7-two fluorine-based cumarone-5-yls) methyl with 17.5g (50mmol)]-the 5-isopropylpyrazine is dissolved in the 100ml acetonitrile, drips the hydrochloric acid of 100mllN then, reaction solution stirring at room 24h.Add methyl alcohol, be concentrated into driedly, this operate triplicate. and then repeat once with toluene, must 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 anhydrous magnesium sulfate drying, silicagel column purifying respectively, eluent is the mixed solution of acetonitrile and sherwood oil, obtains 10.9g solid target compound.Yield: 61.2%.
Embodiment 3 (R The preparation of)-N-2-(tertbutyloxycarbonyl) amido-3-(4,7-two fluorine-based cumarone-5-yls) L-Ala
In reaction flask with (R)-N-2-(tertbutyloxycarbonyl) amido-3-(4 of 10.7g (30mmol), 7-two fluorine-based cumarone-5-yls) add the 200ml tetrahydrofuran (THF) in the alanine methyl ester, the ice bath cooling, be added dropwise to the 200ml aqueous solution of 2.15g (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.Steaming desolventize the 7.3g solid, yield: 71.0%.
Embodiment 4 (R )-3-[(tertbutyloxycarbonyl) amido]-system of 1-diazonium-4-(4,7-two fluorine-based cumarone-5-yls) butyl 2-ketone Be equipped with
(R)-N-2-(tertbutyloxycarbonyl) amido-3-(4 that in reaction flask, adds 8.5g (25mmol), 7-two fluorine-based cumarone-5-yls) 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, 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 7.5g solid target compound, yield: 82.1%.
Embodiment 5 (R)-3-[(tertbutyloxycarbonyl) amido]-the butyro-preparation of 4-(4,7-two fluorine-based cumarone-5-yls)
In reaction flask, add 14.6g (40mmol) (R)-the 3-[(tertbutyloxycarbonyl) amido]-1-diazonium-4-(4,7-two fluorine-based cumarone-5-yls) butyl-2-ketone is dissolved in the 300ml methyl alcohol, is cooled to-30 ℃ of silver benzoates that add 18.9g (120mmol) diisopropyl ethyl amine and 4.6g (20mmol). and reaction solution rises to stirring at room 3h.Reaction is finished, and removes methyl alcohol under reduced pressure, and residuum dissolves with the 200ml methylene dichloride, filtering insoluble solid thing, and filtrate concentrates, and the silicagel column purifying obtains solid.This solid is dissolved in the 100ml tetrahydrofuran (THF), adds in the water of the 100ml that contains 1.8g (75mmol) lithium hydroxide reaction solution stirring at room 16h then.With ethyl acetate dilution, anhydrous magnesium sulfate drying use in saturated sodium bicarbonate and salt washing behind the concentration of reaction solution, concentrated 7.1g white solid compound, yield: 49.8%.
Embodiment 6 7-[(R)-N-3-(tertbutyloxycarbonyl) amido-4-(4,7-two fluorine-based cumarone-5-yls) butyryl radicals]-3-(fluoroform Base)-5,6,7, the preparation of 8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine
Under room temperature, throw (R)-3-[(tertbutyloxycarbonyl of 17.8g (50mmol)) amido]-4-(4,7-two fluorine-based cumarone-5-yls) butyric acid, 6.8g (50mmol) HOBT (1-hydroxy benzo triazole), DMF100ml, add 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) 3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] (its preparation method is referring to J.Med.Chem.2005 for pyrazine for triazolo [4,3-a], 48,141-151), heat up 60 ℃ and stir 3h, reaction is finished, and adds 300ml water, separates out solid, with methyl alcohol and ethyl acetate mixed solution recrystallization, get product 18.1g, yield: 68.4%.
Embodiment 7 7-[(R)-N-3-(tertbutyloxycarbonyl) amido-4-(2-amido alkylsulfonyl-4,7-two fluorine-based cumarone-5-yls) butyryl Base]-3-(trifluoromethyl)-5,6,7, the preparation of 8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine
In the exsiccant reaction flask, add methylene dichloride 100ml; 7-[(R)-N-3-(tertbutyloxycarbonyl) amido-4-(4; 7-two fluorine-based cumarone-5-yls) butyryl radicals]-3-(trifluoromethyl)-5; 6,7,8-tetrahydrochysene-[1; 2; 4] triazolo [4,3-a] pyrazine 15.9g (30mmol) reduce temperature to-15 ℃ after the stirring and dissolving.Slowly drip the 50ml dichloromethane solution of chloromethane sulphonyl 4.7g (31mmol) under the vigorous stirring, drip and finish, be warming up to 0 ℃ of stirring reaction 6h.Reaction is finished, and feeds the exsiccant ammonia under the vigorous stirring, to pH value be about 9, stop to ventilate stirring reaction 0.5h.Add 50ml water, the washing of 50ml saturated sodium-chloride respectively, anhydrous magnesium sulfate drying removes solvent under reduced pressure, and the residuum recrystallizing methanol gets off-white color solid chemical compound 9.6g, yield: 52.4%.
Embodiment 8 7-[(R)-and N-3-amino-4-[2-(N-butylamine formyl radical) amido alkylsulfonyl-4,7-two fluorine-based cumarone-5-yls] fourth Acyl group]-3-(trifluoromethyl)-5,6,7, the preparation of 8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine
In reaction flask, add 7-[(R)-N-3-(tertbutyloxycarbonyl) amido-4-(2-amido alkylsulfonyl-4; 7-two fluorine-based cumarone-5-yls) butyryl radicals]-3-(trifluoromethyl)-5; 6; 7,8-tetrahydrochysene-[1,2; 4] triazolo [4; 3-a] pyrazine 24.3g (40mmol), after the dissolving of 200ml methylene dichloride, reduce temperature to 0～5 ℃.Slowly drip n-butyl amine formyl chloride 6.1g (45mmol), elevated temperature to 50 ℃, stirring reaction 5h.Be 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 pH9 with sig water under ice bath, separates out solid filtering, successively water, ethyl acetate washing, get crude product, get product 16.3g with ethyl alcohol recrystallization, yield: 67.1%.
Molecular formula: C 23H 26F 5N 7O 5S
Molecular weight: 607.16
Ultimate analysis:
Measured value: C, 45.22%; H, 4.60%; F, 15.48%; N, 16.01%; S, 5.11%
Theoretical value: C, 45.57%; H, 4.31%; F, 15.64%; N, 16.14%; S, 5.28%
Mass spectrum (m/e): 608 (M+1)
The hydrogen spectrum: 1H-NMR (400MHz, CDCl 3) δ (ppm): 0.97 (t, 3H), 1.36 (m, 2H), 1.56 (m, 2H), 2.33 (q, 1H), 2.56 (q, 1H), 2.76 (q, 1H), 2.97 (q, 1H), 3.11 (t, 2H), 3.29 (m, 1H), 3.76 (t, 2H), 4.34 (t, 2H), 4.47 (s, 2H), 5.38 (br, 2H), 6.19 (br, 2H), 7.08 (d, 1H), 7.22 (q, 1H)
Embodiment 9 7-[(R)-and N-3-amino-4-[2-[N-(cyclopentyl is [c] tetramethyleneimine also) amido formyl radical] amido alkylsulfonyl-4,7-two Fluorine-based cumarone-5-yl] butyryl radicals]-3-(trifluoromethyl)-5,6,7, the preparation of 8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine
Preparation method's reference example 8; throw 7-[(R)-N-3-(tertbutyloxycarbonyl) amido-4-(2-amido alkylsulfonyl-4; 7-two fluorine-based cumarone-5-yls) butyryl radicals]-3-(trifluoromethyl)-5; 6,7,8-tetrahydrochysene-[1; 2; 4] triazole [4,3-a] pyrazine 24.3g (40mmol), N-(cyclopentyl is [c] tetramethyleneimine also) amine formyl chloride 8.5g (45mmol).Get product 17.3g, yield: 65.4%.
Molecular formula: C 26H 28F 5N 8O 5S
Molecular weight: 660.62
Ultimate analysis:
Measured value: C, 47.09%; H, 4.28%; F, 14.15%; N, 16.77%; S4.98%
Theoretical value: C, 47.27%; H, 4.42%; F, 14.38%; N, 16.96%; S, 4.85%
Mass spectrum (m/e): 661 (M+1)
The hydrogen spectrum: 1H-NMR (400MHz, CDCl 3) δ (ppm): 1.35 (m, 2H), 1.47 (m, 1H), 1.56 (m, 1H), 1.60 (m, 2H), 1.67 (m, 2H), 2.37 (q, 1H), 2.58 (q, 1H), 2.65 (dq, 2H), 2.75 (q, 1H), 2.87 (dq, 2H), 2.98 (q, 1H), 3.29 (m, 1H), 3.76 (t, 2H), 4.37 (t, 2H), 4.49 (s, 2H), 5.38 (br, 2H), 5.61 (br, 1H), 6.14 (br, 1H), 7.06 (d, 1H), 7.23 (q, 1H)
Embodiment 10 7-[(R)-and N-3-amino-4-[2-[N-(cyclohexyl is [c] tetramethyleneimine also) amido formyl radical] amido alkylsulfonyl-4,7-two Fluorine-based cumarone-5-yl] butyryl radicals]-3-(trifluoromethyl)-5,6,7, the preparation of 8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine
Preparation method's reference example 5; throw 7-[(R)-N-3-(tertbutyloxycarbonyl) amino-4-(2-amido alkylsulfonyl-4; 7-two fluorine-based cumarone-5-yls) butyryl radicals]-3-(trifluoromethyl)-5; 6,7,8-tetrahydrochysene-[1; 2; 4] triazole [4,3-a] pyrazine 24.3g (40mmol), N-(cyclohexyl is [c] tetramethyleneimine also) amine formyl chloride 9.1g (45mmol).Get product 16.8g, yield: 62.3%.
Molecular formula: C 27H 31F 5N 8O 5S
Molecular weight: 674.64
Ultimate analysis:
Measured value: C, 47.85%; H, 4.87%; F, 14.22%; N, 16.45%; S, 4.54%
Theoretical value: C, 48.07%; H, 4.63%; F, 14.08%; N, 16.61%; S, 4.75%
Mass spectrum (m/e): 675 (M+1)
The hydrogen spectrum: 1H-NMR (400MHz, CDCl 3) δ (ppm): 1.33 (m, 2H), 1.47 (m, 2H), 1.52～1.59 (m, 4H), 1.70 (m, 2H), 2.34 (q, 1H), 2.52 (q, 1H), 2.63 (dq, 2H), 2.75 (q, 1H), 2.84 (dq, 2H), 2.97 (q, 1H), 3.29 (m, 1H), 3.75 (t, 2H), 4.36 (t, 2H), 4.51 (s, 2H), 5.34 (br, 2H), 5.55 (br, 1H), 6.17 (br, 1H), 7.09 (d, 1H), 7.27 (q, 1H)
The preparation of embodiment 11 The compounds of this invention tablets
1, prescription:
Prescription 1:
Figure A200810166085D00221
Prescription 2:
Figure A200810166085D00231
Prescription 3:
Figure A200810166085D00232
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, the compound shown in the general formula (I), its pharmacy acceptable salt or its isomer:
Wherein, R 1, R 2Independently represent hydrogen atom respectively, halogen atom, cyano group, hydroxyl is replaced or unsubstituted C by 1-5 halogen atom 1-6Alkyl or C 1-6Alkoxyl group;
R 3, R 4Independently represent hydrogen atom or C respectively 1-6Alkyl;
X represents N or C-R 5, R wherein 5Be selected from hydrogen atom, cyano group, replaced or unsubstituted C by 1-5 halogen atom 1-6Alkyl or C 1-6Alkoxyl group;
Y represents N or C-R 6, R wherein 6Be selected from hydrogen atom, cyano group, replaced or unsubstituted C by 1-5 halogen atom 1-6Alkyl or C 1-6Alkoxyl group;
A represents group shown in the following formula:
Perhaps
2, the compound of the claim 1 shown in the general formula (II), its pharmacy acceptable salt or its isomer:
Figure A200810166085C00024
Wherein, R 1, R 2Independently represent hydrogen atom respectively, fluorine atom, bromine atoms, trifluoromethyl or cyano group;
R 3, R 4Independently represent hydrogen atom respectively, methyl or ethyl;
X represents N or C-R 5, R wherein 5Be selected from hydrogen atom, replaced or unsubstituted C by 1-5 halogen atom 1-4Alkyl;
Y represents N or C-R 6, R wherein 6Be selected from hydrogen atom, replaced or unsubstituted C by 1-5 halogen atom 1-4Alkyl;
A represents group shown in the following formula:
Figure A200810166085C00025
Perhaps
Figure A200810166085C00026
3, compound as claimed in claim 2, its pharmacy acceptable salt or its isomer:
Wherein, R 1, R 2Independently represent hydrogen atom respectively, fluorine atom, trifluoromethyl or cyano group;
R 3, R 4Independently represent hydrogen atom or methyl respectively;
X represents N or C-R 5, R wherein 5Be selected from hydrogen atom, methyl, ethyl, trifluoromethyl, CH 2CF 3Perhaps CF 2CF 3
Y represents N or C-R 6, R wherein 6Be selected from hydrogen atom, methyl, ethyl, trifluoromethyl, CH 2CF 3Perhaps CF 2CF 3
A represents group shown in the following formula:
Perhaps
Figure A200810166085C00032
4, compound as claimed in claim 3, its pharmacy acceptable salt or its isomer:
Wherein, R 1, R 2Independently represent hydrogen atom or fluorine atom respectively;
R 3, R 4Independently represent hydrogen atom respectively;
X represents N;
Y represents C-R 6, R 6Be selected from methyl or trifluoromethyl;
A represents group shown in the following formula:
Figure A200810166085C00033
Perhaps
Figure A200810166085C00034
5, compound as claimed in claim 4, for
7-[(R)-and N-3-amino-4-[2-(N-butylamine formyl radical) amido alkylsulfonyl-4,7-two fluorine-based cumarone-5-yls] butyryl radicals]-3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine,
7-[(R)-N-3-amino-4-[2-[N-(cyclopentyl is [c] tetramethyleneimine also) amido formyl radical] amido alkylsulfonyl-4,7-two fluorine-based cumarone-5-yls] butyryl radicals]-3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine and
7-[(R)-and N-3-amino-4-[2-[N-(cyclohexyl is [c] tetramethyleneimine also) amido formyl radical] amido alkylsulfonyl-4,7-two fluorine-based cumarone-5-yls] butyryl radicals]-3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine,
Its pharmacy acceptable salt or its isomer.
6, as the described compound of the arbitrary claim of claim 1～5, its pharmacy acceptable salt refers to the salt by pharmaceutically acceptable, non-toxic bases or acid preparation, comprise organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts, wherein organic acid comprises Phenylsulfonic acid, tosic acid, butene dioic acid, citric acid, toxilic acid, fumaric acid, tartrate; Mineral acid comprises Hydrogen bromide, spirit of salt, sulfuric acid, phosphoric acid; Organic bases comprises arginine, meglumine, glucosamine; Mineral alkali comprises the basic cpd of ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium.
7, the pharmaceutical composition that comprises the described compound of the arbitrary claim of claim 1～5, its pharmacy acceptable salt or its isomer and other activeconstituentss.
8, the pharmaceutical composition that comprises the described compound of the arbitrary claim of claim 1～5, its pharmacy acceptable salt or its isomer and one or more pharmaceutical carriers and/or thinner is pharmaceutically acceptable arbitrary formulation.
9, pharmaceutical composition as claimed in claim 8 contains the described compound of the arbitrary claim of claim 1～5, its pharmacy acceptable salt or its isomer 0.01g～10g as essential activeconstituents.
10, the described compound of the arbitrary claim of claim 1～5, its pharmacy acceptable salt or its isomer are in the application that is used for preparing the medicine that treats and/or prevents diabetes, non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia, insulin resistance.
CN2008101660855A 2007-10-24 2008-10-18 DPP-IV inhibitor derivates containing benzofuran sulfonyl ureas Active CN101418000B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2008101660855A CN101418000B (en) 2007-10-24 2008-10-18 DPP-IV inhibitor derivates containing benzofuran sulfonyl ureas

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN200710113960.9 2007-10-24
CN200710113960 2007-10-24
CN2008101660855A CN101418000B (en) 2007-10-24 2008-10-18 DPP-IV inhibitor derivates containing benzofuran sulfonyl ureas

Publications (2)

Publication Number Publication Date
CN101418000A true CN101418000A (en) 2009-04-29
CN101418000B CN101418000B (en) 2010-12-22

Family

ID=40629018

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2008101660855A Active CN101418000B (en) 2007-10-24 2008-10-18 DPP-IV inhibitor derivates containing benzofuran sulfonyl ureas

Country Status (1)

Country Link
CN (1) CN101418000B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102260265A (en) * 2010-05-24 2011-11-30 上海阳帆医药科技有限公司 Hexahydro-pyrrole[3,4-b] pyrrole derivative, its preparation method and application
CN104039776A (en) * 2012-08-03 2014-09-10 上海恒瑞医药有限公司 Benzofuran derivatives, preparation method and medical use thereof
CN106831536A (en) * 2017-02-21 2017-06-13 山东科源制药股份有限公司 A kind of preparation method of gliclazide green synthesis process

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102260265A (en) * 2010-05-24 2011-11-30 上海阳帆医药科技有限公司 Hexahydro-pyrrole[3,4-b] pyrrole derivative, its preparation method and application
CN102260265B (en) * 2010-05-24 2015-09-02 上海阳帆医药科技有限公司 Hexahydropyrrolo [3,4-b] pyrrole derivative, Its Preparation Method And Use
CN104039776A (en) * 2012-08-03 2014-09-10 上海恒瑞医药有限公司 Benzofuran derivatives, preparation method and medical use thereof
CN106831536A (en) * 2017-02-21 2017-06-13 山东科源制药股份有限公司 A kind of preparation method of gliclazide green synthesis process
CN106831536B (en) * 2017-02-21 2020-04-03 山东科源制药股份有限公司 Preparation method of gliclazide synthesis process

Also Published As

Publication number Publication date
CN101418000B (en) 2010-12-22

Similar Documents

Publication Publication Date Title
CN110248662B (en) Combination, pharmaceutical composition and treatment method for treating prostate cancer
JP2021155415A (en) Treatment of type 2 diabetes or obesity or overweight using 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2s)-oxetan-2-ylmethyl]-1h-benzimidazole-6-carboxylic acid or pharmaceutical salt thereof
CN101357922B (en) New DPP-IV inhibitor
CN101418000B (en) DPP-IV inhibitor derivates containing benzofuran sulfonyl ureas
CN103896923B (en) A kind of Hypoglycemics, its preparation method, comprise its medical composition and its use
CN101357921B (en) New dipeptidase-IV inhibitor compound
CN101874024A (en) The pyrimidine that replaces as the 2-S-benzyl of CRTH2 antagonist
CN101418001B (en) Dipeptidase-IV inhibitor sulfonyl urea derivates
CN101357923B (en) Dipeptidase inhibitor compound
CN101357924B (en) Dipeptidase-IV inhibitor compound
CN101486688B (en) DPP-IV inhibitor with sulfonyl amine acyl alkyl piperazine structure
CN101486689B (en) DPP-IV inhibitor with sulfonamide formamide piperazine structure
CN101397300B (en) Dipeptidase-IV inhibitor derivates
CN101417987B (en) DPP-IV inhibitor with sulfonamide formyl piperazine structure
CN101417988B (en) Biguanide piperazines dipeptidyl peptidase IV inhibitor
CN101781274B (en) Acylated piperazine dipeptidyl peptidase IV inhibitor
CN102153538B (en) Benzocyclodirivative
CN101723947B (en) Dipeptidase-IV inhibitor compound
CN101781273B (en) Dipeptidylpeptidase IV inhibitor containing guanidyl
CN102408459B (en) Anomeric alkyl-containing phenyl C-glucoside derivative, preparation thereof and application
CN102234281B (en) Pyrimidine-fused cyclic derivative
CN102276627B (en) Pyridino-heterocycle derivative
CN101550139A (en) Dipeptidase-IV inhibitor containing v-triazolo [b] pyrazine
CN103304498B (en) Anti-diabetic compound, as well as preparation method and application thereof
CN111195247B (en) Alpha-glucosidase inhibitor and application thereof in hypoglycemic drugs

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
ASS Succession or assignment of patent right

Owner name: BEIJING AOHE PHARMACEUTICAL RESEARCH INSTITUTE CO.

Free format text: FORMER OWNER: SHANDONG XUANZHU MEDICAL TECHNOLOGY CO., LTD.

Effective date: 20130407

Owner name: SHANDONG XUANZHU MEDICAL TECHNOLOGY CO., LTD.

Effective date: 20130407

C41 Transfer of patent application or patent right or utility model
COR Change of bibliographic data

Free format text: CORRECT: ADDRESS; FROM: 250101 JINAN, SHANDONG PROVINCE TO: 100043 SHIJINGSHAN, BEIJING

TR01 Transfer of patent right

Effective date of registration: 20130407

Address after: 100043, A, block 33, three ancient West Street, Shijingshan District, Beijing

Patentee after: Beijing Aohe Pharmaceutical Research Institute Co., Ltd.

Patentee after: Shandong Xuanzhu Medical Technology Co., Ltd.

Address before: Tianchen Avenue in Ji'nan high tech Development Zone of Shandong province 250101 City No. 2518

Patentee before: Shandong Xuanzhu Medical Technology Co., Ltd.

DD01 Delivery of document by public notice

Addressee: Huang Xiaoxia

Document name: Notification of Passing Examination on Formalities

TR01 Transfer of patent right

Effective date of registration: 20190619

Address after: Room 301, Building 3, East of Qishanzhuang Village, Zhangjiawan Town, Tongzhou District, Beijing

Patentee after: Beijing Aohe Pharmaceutical Research Institute Co., Ltd.

Address before: 100043 Three Floors, Block A, 33 West Street, Gucheng, Shijingshan District, Beijing

Co-patentee before: Shandong Xuanzhu Medical Technology Co., Ltd.

Patentee before: Beijing Aohe Pharmaceutical Research Institute Co., Ltd.

TR01 Transfer of patent right