CN101417988B - Biguanide piperazines dipeptidyl peptidase IV inhibitor - Google Patents
Biguanide piperazines dipeptidyl peptidase IV inhibitor Download PDFInfo
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Abstract
The invention belongs to the technical field of medicine, and in particular relates to a biguanide piperazines dipeptidyl peptidase IV inhibitor as shown in a general formula (I), and a pharmaceutically acceptable salt or an isomer thereof, wherein Ar, R<1>, R<2> and R<3> are as defined in the introduction. 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 medicine for treating and/or preventing diabetes, non-insulin-dependent diabetes, high blood sugar, and insulin resistance.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to biguanide piperazines dipeptidyl peptidase IV inhibitor, its pharmacy acceptable salt or its isomer, 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; Treatment for type ii diabetes, main medicine is an oral antidiabetic drug, roughly be divided into sulfourea, biguanides, Chinese medicine preparation, other antidiabetic drugs and adjuvant drug, though it has good curative effect, but effective methods of treatment of the type ii diabetes that does not become has substantially admitted that it arrives the limit for many years, wherein two the most significant greatly problems be exactly medicine reduce can not keep aspect the hyperglycemia long-term efficacy with can not be at the cause of disease and effective mitigate the disease, and the side effect of hypoglycemia or weight increase is arranged.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 main reason 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.
Dipeptidyl peptidase-IV (DPP-IV) is a kind of cell surface protein that relates to the various biological function.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.At present first inhibitor of listing is Xi Lietating, by Merck ﹠ Co., Inc.'s exploitation, in listing in 2006, security preferably and tolerance is arranged, and finds also that at present the patient who uses has weight increase or potential to lose weight and symptom such as oedema.Its structural formula is as follows.
Yet this class pharmaceutical activity a little less than, can not meet clinical needs, 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
The objective of the invention is further improvement and optimize the DPP-IV inhibitor, the inventor provides the inhibitor derivates of the new DPP-IV of a class through great deal of experimental.
Another object of the present invention is to improve the activity of N1,N1-Dimethylbiguanide, reduces its untoward reaction.
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 represents by 1～5 R
4Replace or unsubstituted phenyl, wherein, R
4Be independently selected from:
(1) halogen,
(2) straight or branched is replaced or unsubstituted C by 1～5 halogen atom
1-6Alkyl,
(3) straight or branched is replaced or unsubstituted C by 1～5 halogen atom
1-6Alkoxyl group,
(4) CN, or
(5) hydroxyl;
R
1, R
2And R
3Independently be selected from hydrogen atom or C
1-6Alkyl.
Another embodiment of the present invention comprises the compound shown in the formula (II), its pharmacy acceptable salt or its isomer:
Wherein, Ar, R
1, R
2And R
3As defined herein.
Preferred compound is:
Wherein: Ar represents by 1～5 R
4Replace or unsubstituted phenyl, wherein, R
4Be independently selected from:
(1) fluorine atom,
(2) chlorine atom,
(3) bromine atoms,
(4) CF
3, or
(5)CN；
R
1, R
2And R
3Independently be selected from hydrogen atom or C
1-4Alkyl.
Further preferred compound is:
Wherein, Ar is selected from:
(1) phenyl,
(2) 2,4 difluorobenzene base,
(3) 2,5-difluorophenyls,
(4) 2,4, the 5-trifluorophenyl,
(5) 2-fluoro-4-(trifluoromethyl) phenyl,
(6) 2,4 dichloro benzene base, or
(7) 2-cyano group-4, the 5-difluorophenyl;
R
1, R
2And R
3Independently be selected from hydrogen atom or methyl.
" halogen atom " of the present invention is fluorine atom, chlorine atom, bromine atoms or iodine atom.
" C of the present invention
1-6Alkyl " be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methyl butyl, neo-pentyl, 3-amyl group, n-hexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2; 2-dimethylbutyl, 1; 1-dimethylbutyl, 1; 2-dimethylbutyl, 1; 3-dimethylbutyl, 2,3-dimethylbutyl, 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 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-methyl-2-methyl propoxy-, the ring propoxy-, cyclobutoxy group, 1-methyl cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
Particularly preferred compound is as follows:
Chemical name: N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl]-N '-(N, N-dimethyl guanidine radicals) formimino piperazine, be called for short compound 1, 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
Raw material 1 is dissolved in the tetrahydrofuran (THF), drips an amount of n-Butyl Lithium/hexane solution then, insulated and stirred.Drip raw material 2 then in tetrahydrofuran (THF) cold soln, stirring reaction.Add the shrend reaction of going out, reaction solution is concentrated, residuum adds ethyl acetate and 1N hydrochloric acid, the branch 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, drips the hydrochloric acid of 1N then, the 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 triethylamine with methylene dichloride dissolving back; and then slowly be added dropwise to amino protecting agent; the reaction solution stirring at room; the solid that the filtering reaction generates, filtrate is diluted with methylene dichloride, and HCl solution and the saturated brine with 1N washs respectively; 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) in 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, saturated sodium bicarbonate and salt solution washing, anhydrous magnesium sulfate drying.Steaming desolventize Compound C.
The preparation of step 4 Compound D
Add Compound C, ether adds triethylamine and isobutyl chlorocarbonate then, finish, stirring reaction adds the ethyl acetate solution that contains diazomethane then, adds an amount of 1-methyl-3-nitro-1-nitrosoguanidine down in 0 ℃ and is dissolved in ether and 40% sodium hydroxide mixing solutions, 0 ℃ of following stirring reaction of reaction solution, the organic layer drying, mixed solution dilutes with ethyl acetate, saturated sodium bicarbonate and salt water washing, anhydrous magnesium sulfate drying is evaporated to dried Compound D.
The preparation of step 5 compd E
Compound D is dissolved in the methyl alcohol, is cooled to, add diisopropyl ethyl amine and silver benzoate.Reaction solution rises to stirring at room, and 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), adds then and contain in the water of lithium hydroxide the reaction solution stirring at room.With ethyl acetate dilution, anhydrous magnesium sulfate drying use in saturated sodium bicarbonate and salt washing behind the concentration of reaction solution, concentrated compd E.
The preparation of step 6 compound F 17-hydroxy-corticosterone
Under room temperature, throw compd E, HOBT, DMF adds DCC (dicyclohexylcarbodiimide) then, the stirring at room reaction.Cross to filter out and react the solid that generates, filtrate continuation adds in the reaction flask, adds piperazine, the 60 ℃ of stirrings that heat up, and reaction finishes, and adds entry, separates out solid, with methyl alcohol and ethyl acetate mixed solution recrystallization, gets compound F 17-hydroxy-corticosterone.
The preparation of step 7 Compound I
Add 10% HCl-ethanol in reaction flask, raw material 3 in stirring at room, adds dissolve with ethanol after removing solvent under reduced pressure again, slowly adds compound F 17-hydroxy-corticosterone then in batches, refluxes to stir and spends the night.With after the methylene dichloride dissolving, be warming up to backflow after reaction solution is decompressed to and does, be added dropwise to 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, separate out solid filtering, water, ethyl acetate washing promptly get Compound I successively.
Ar in the above reaction equation, R
1, R
2And R
3The group of representative as mentioned before.
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 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, 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, ketone, ferrous, manganese, bivalent manganese etc., the basic cpd of preferred especially ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium.
Compound I contains one or more asymmetric centers, thereby can be used as racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.Compound I 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 and or administration or include, but are not limited to respectively at other activeconstituents of the secondary administration of same medicinal compositions;
(a) other dipeptidyl peptidase IV inhibitors;
(b) insulin sensitisers comprises (i) PPAR gamma agonist for example glitazones (for example troglitazone, pioglitazone, englitazone, MCC-555, Rosiglitazone etc.) and other PPAR part, comprise PPAR α/γ economic benefits and social benefits agonist, KRP-297 for example, with PPAR alfa agonists Fenofibric Acid derivative (gemfibrozil, clofibrate, fenofibrate and bezafibrate) for example, (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, KRP-297 for example, (vi) cholesterol absorption inhibitor, for example β-Gu Zaichun and ezetimibe, (vii) ethanoyl CoA, chole-sterol acyltransferase inhibitor, for example avasimibe, (viii) antioxidant, for example probucol;
(k) PPAR delta agonists;
(1) 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 Compound I 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 Compound I and other medicines generally arrives between about 1:200 at 200:1, is preferably about 20:1 and arrives between about 1:20.The drug combination of Compound I 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.Wherein contain the compound 10mg～10g shown in the general formula (I) of physiology significant quantity, preferred 20mg～5g can be 0.025g, 0.05g, 0.075g, 0.125g, 0.25g, 0.5g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g etc.Can be by 1～4 time arrangement every day, give described compound 1～2 time preferred every day.
The hydrate of the arbitrary compound of the present invention, its pharmacy acceptable salt, its isomer, its hydrate or its salt, 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.
Dipeptidyl peptidase-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.
Therefore, described compound can be used in the method for the prevention of following disease, illness and symptom and treatment:
1, type ii diabetes and relative disease, now full confirmation GLP-1 and GIP can be by DPP-IV quick inactivatings in vivo.To DPP-IV
(-/-)Studies show that of defective mouse: the DPP-IV restraining effect can increase the stable state concentration of GLP-1 and GIP, thereby has improved the glucose tolerance.Similar with GLP-1 and GIP, other hyperglycemic-glycogenolytic factor series peptide that relates to the glucose adjusting also can be by DPP-IV (for example PACAP) deactivation.These peptides also can be played a role aspect the glucose homeostasis by the DPP-IV deactivation.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.
2, 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 Crohn's disease and ulcerative colitis, (16) other inflammation, (17) pancreatitis, (18) abdominal fatness, (19) neuropathy, (20) 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.
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 biguanide piperazines dipeptidyl peptidase IV inhibitor to be used for the treatment of and/or to prevent purposes in the medicine of following one or more diseases in preparation: diabetes, non-insulin-dependent diabetes mellitus (NIDDM) (type ii diabetes), hyperglycemia, obesity, unusual lipidemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL level, the low dextrose tolerance, insulin resistance, matter fat illness, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, atherosclerosis and sequela thereof, vascular restenosis, the easy basic syndrome of intestines, enteritis, other inflammation, pancreatitis, abdominal fatness, neuropathy, retinopathy, ephrosis, neuropathy, X syndrome, ovarian hyperandrogenism (polycystic ovary syndrome) and other have the disease of insulin resistance, and described method comprises to the described compound of administration general formula (I).
Biguanide piperazines dipeptidyl peptidase IV inhibitor of the present invention is compared with immediate prior art, has the following advantages:
(1) the new DPP-IV inhibitor compound of the present invention can promote secretion of insulin preferably, and can not cause side effects such as hypoglycemia and weight increase;
(2) biguanide piperazines dipeptidyl peptidase IV inhibitor of the present invention has good security and tolerance in vivo, and incidence rate of adverse reaction reduces more;
(3) The compounds of this invention has the advantage of DPP-IV inhibitor and biguanides concurrently, has double effects;
(4) The compounds of this invention preparation technology 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, 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 couple of DPP-IV of The compounds of this invention is omited than sitagliptin phosphate, and is suitable to selectivity and the sitagliptin phosphate of DPP-7, DPP-8, DPP-9, and therefore, compound 1 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, self-control, its chemical name and structural formula are as mentioned before;
Reference substance: N1,N1-Dimethylbiguanide: commercial;
Experimental technique:
1, modeling: choose 60 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 50 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, 28 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 3 groups at random by body weight and glucose level with 28, compound 1 medication group (is called for short 1 group of compound, 9), N1,N1-Dimethylbiguanide medication group (be called for short N1,N1-Dimethylbiguanide group, 9), pathology control group (being called for short pathologic group, 10).
Grouping of table 2 animal and administration
4 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 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, and compound 1 curer's glucose level is significantly less than the N1,N1-Dimethylbiguanide group, and prompting compound 1 can obviously reduce type ii diabetes rat blood sugar level, improves the type ii diabetes carbohydrate metabolism disturbance.
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;
Conclusion: the effect of 1 pair of type ii diabetes of The compounds of this invention is better than sitagliptin phosphate and N1,N1-Dimethylbiguanide, 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 (2S)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine 9.2g (50mmol) is dissolved among the tetrahydrofuran (THF) 300ml, in-78 ℃, 30min, be added dropwise to then n-Butyl Lithium/hexane solution 24ml (60mmol, 2.5N), insulated and stirred 30min.Be added dropwise to 2,4 of 9.9g (55mmol) then, 5-three fluorine-based benzyl chloride tetrahydrofuran (THF) cold soln 50ml ,-78 ℃ of stirring reaction 5h.Add entry 100ml cancellation reaction under-78 ℃, 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
Will (2R, 5S)-2,5-dihydro-3,6-dimethoxy-2-[(2,4,5-trifluorophenyl) methyl]-5-isopropylpyrazine 16.4g (50mmol) is dissolved among the acetonitrile 100ml, drips the hydrochloric acid 100ml of 1N then, reaction solution stirring at room 24h.Add methyl alcohol, be concentrated into driedly, this operates triplicate.And then repeat once with toluene, solid.This solid slowly adds triethylamine 50g with methylene dichloride 400ml dissolving back, and then slowly is added dropwise to (Boc)
2O24g (110mmol).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-(tertbutyloxycarbonyl)-3-(2,4, the 5-trifluorophenyl)-the middle tetrahydrofuran (THF) 200ml that adds of alanine methyl ester 10g (30mmol), the ice bath cooling, be added dropwise to the aqueous solution 200ml 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 7.7g solid, yield: 80.3%.
Embodiment 4 (R)-3-[(tertbutyloxycarbonyl) amino]-preparation of 1-diazonium-4-(2,4, the 5-trifluorophenyl) butyl-2-ketone
Add (R)-N-2-(tertbutyloxycarbonyl)-3-(2,4, the 5-trifluorophenyl)-L-Ala 8g (25mmol), ether 150ml, add triethylamine 3g (30mmol) and isopropyl chlorocarbonate 4ml down in-30 ℃ then, 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 is evaporated to dried solid target compound 7.6g, yield: 88.2%.
Embodiment 5 (R)-3-[(tertbutyloxycarbonyl) amino]-the butyro-preparation of 4-(2,4, the 5-trifluorophenyl)
With (R)-3-[(tertbutyloxycarbonyl) amino]-1-diazonium-4-(2,4, the 5-trifluorophenyl) butyl-2-ketone 13.7g (40mmol) is dissolved among the methyl alcohol 300ml, is cooled to-30 ℃, adds diisopropyl ethyl amine 18.9g (120mmol) and silver benzoate 2.3g (10mmol).Reaction solution rises to stirring at room 3h, and reaction is finished, and removes methyl alcohol under reduced pressure, and residuum dissolves with methylene dichloride 200ml, filtering insoluble solid thing, and filtrate concentrates, and the silicagel column purifying obtains solid.This solid is dissolved among the tetrahydrofuran (THF) 100ml, adds then and contain among the water 100ml of 1.8g (75mmol) lithium hydroxide reaction solution stirring at room 16h.With ethyl acetate dilution, anhydrous magnesium sulfate drying use in saturated sodium bicarbonate and salt washing behind the concentration of reaction solution, concentrated 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) amino]-4-(2,4, the 5-trifluorophenyl) butyric acid 16.7g (50mmol), HOBT (1-hydroxy benzo triazole) 6.8g (50mmol), DMF100ml, add DCC (dicyclohexyl carbimide) 20g (75mmol) then, stirring at room reaction 1h.Cross and filter out the solid that reaction generates, filtrate continuation adds in the reaction flask, adds piperazine 8.6g (100mmol), heats up 60 ℃ and stirs 3h, reaction is finished, and adds 300ml water, separates out solid, with methyl alcohol and ethyl acetate mixed solution recrystallization, get product 14.5g, yield: 72.1%.
Embodiment 7 N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl]-N '-(N, N-dimethyl guanidine radicals) formimino piperazine
Preparation
The HCl-ethanol 50ml of adding 10% in reaction flask, cyano group dimethylguanidine 5.6g (50mmol), in stirring at room 2h, add ethanol 100ml dissolving again after removing solvent under reduced pressure, slowly add (R)-3-(tertbutyloxycarbonyl) amino-5-(2 then in batches, 4, the 5-trifluorophenyl)-1-butyryl piperazine 18.1g (45mmol), reflux to stir and spend the night.Reaction solution is decompressed to dried back with after the methylene dichloride 100ml dissolving, be warming up to backflow, be added dropwise to 5N hydrochloric acid 40ml 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, water, ethyl acetate washing successively, get crude product, get product 10.2g with ethyl alcohol recrystallization, yield: 54.6%.
Molecular formula: C
18H
26F
3N
7O
Molecular weight: 413.44
Ultimate analysis: measured value: C, 52.11%; H, 6.56%; F, 13.48; N, 23.64%
Theoretical value: C, 52.29%; H, 6.34%; F, 13.79; N, 23.71%
Mass spectrum (m/z): 414 (M+1)
Hydrogen spectrum (CDCl
3, 400MHz): δ (ppm): 2.10～2.15 (br, 3H), 2.31 (q, 1H), 2.55 (q, 1H), 2.71 (q, 1H), 2.86 (s, 6H), 2.94 (q, 1H), 3.01 (t, 4H), 3.25 (m, 1H), 3.52 (t, 4H), 5.19 (br, 2H), 6.72 (m, 1H), 7.89 (m, 1H).
The preparation of embodiment 8 compounds 1 tablet
1, prescription:
Prescription 1
Prescription 2
Prescription 3
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) or its pharmacy acceptable salt:
Wherein: Ar represents by 1～5 R
4Replace or unsubstituted phenyl, wherein, R
4Be independently selected from:
(1) halogen,
(2) straight or branched is replaced or unsubstituted C by 1～5 halogen atom
1-6Alkyl,
(3) straight or branched is replaced or unsubstituted C by 1～5 halogen atom
1-6Alkoxyl group,
(4) CN, or
(5) hydroxyl;
R
1, R
2And R
3Independently be selected from hydrogen atom or C
1-6Alkyl.
2. the described compound of claim 1 or its pharmacy acceptable salt shown in the formula (II):
Wherein, Ar, R
1, R
2And R
3Such as claim 1 definition.
3. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein: Ar represents by 1～5 R
4Replace or unsubstituted phenyl, wherein, R
4Be independently selected from:
(1) fluorine atom,
(2) chlorine atom,
(3) bromine atoms,
(4) CF
3, or
(5)CN；
R
1, R
2And R
3Independently be selected from hydrogen atom or C
1-4Alkyl.
4. compound as claimed in claim 3 or its pharmacy acceptable salt:
Wherein, Ar is selected from:
(1) phenyl,
(2) 2,4 difluorobenzene base,
(3) 2,5-difluorophenyls,
(4) 2,4, the 5-trifluorophenyl,
(5) 2-fluoro-4-(trifluoromethyl) phenyl,
(6) 2,4 dichloro benzene base, or
(7) 2-cyano group-4, the 5-difluorophenyl;
R
1, R
2And R
3Independently be selected from hydrogen atom or methyl.
5. compound as claimed in claim 4 or its pharmacy acceptable salt are N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl]-N '-(N, N-dimethyl guanidine radicals) formimino piperazine or its pharmacy acceptable salt.
6. as the described compound of the arbitrary claim of claim 1～5 or its pharmacy acceptable salt, its pharmacy acceptable salt refers to be selected from organic acid salt or inorganic acid salt by the salt of pharmaceutically acceptable non-toxicity acid preparation.
7. the pharmaceutical composition that comprises the described compound of the arbitrary claim of claim 1～5 or its pharmacy acceptable salt and other active pharmaceutical ingredients.
8. the pharmaceutical composition of forming as the described compound of the arbitrary claim of claim 1～5 or its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner is pharmaceutically acceptable arbitrary formulation.
9. pharmaceutical composition as claimed in claim 8 is characterized in that containing the described compound of the arbitrary claim of claim 1～5 or its pharmacy acceptable salt 10mg～10g as essential activeconstituents.
As the described compound of the arbitrary claim of claim 1～5 or its pharmacy acceptable salt by suppressing the application that the dipeptide amido peptidase TV activity is used for preparing the medicine of treatment, control or prevent diabetes, hyperglycemia, insulin resistance.
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|---|---|---|---|
| CN2008101660874A CN101417988B (en) | 2007-10-24 | 2008-10-18 | Biguanide piperazines dipeptidyl peptidase IV inhibitor |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1245494A (en) * | 1996-12-18 | 2000-02-23 | 默克专利股份公司 | New 4-(1-piperazinyl) benzoic acid derivatives, process for preparing them and their therapeutic applications |
| CN1496347A (en) * | 2001-03-21 | 2004-05-12 | Ĭ��ר������˾ | Biguanide Derivatives |
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2008
- 2008-10-18 CN CN2008101660874A patent/CN101417988B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1245494A (en) * | 1996-12-18 | 2000-02-23 | 默克专利股份公司 | New 4-(1-piperazinyl) benzoic acid derivatives, process for preparing them and their therapeutic applications |
| CN1496347A (en) * | 2001-03-21 | 2004-05-12 | Ĭ��ר������˾ | Biguanide Derivatives |
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