CN102234281A - Pyrimidine-fused cyclic derivative - Google Patents
Pyrimidine-fused cyclic derivative Download PDFInfo
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- CN102234281A CN102234281A CN2010101589161A CN201010158916A CN102234281A CN 102234281 A CN102234281 A CN 102234281A CN 2010101589161 A CN2010101589161 A CN 2010101589161A CN 201010158916 A CN201010158916 A CN 201010158916A CN 102234281 A CN102234281 A CN 102234281A
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- 0 Cc(nc1N)nc(N2*)c1N(*)C2=O Chemical compound Cc(nc1N)nc(N2*)c1N(*)C2=O 0.000 description 4
- BTFQKIATRPGRBS-UHFFFAOYSA-N Cc1c(C=O)cccc1 Chemical compound Cc1c(C=O)cccc1 BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 description 1
- BWLOHIMQWHFSQF-UHFFFAOYSA-N Nc(ncnc1Cl)c1[N+]([O-])=O Chemical compound Nc(ncnc1Cl)c1[N+]([O-])=O BWLOHIMQWHFSQF-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to the technical field of medicines, and specifically relates to pyrimidine-fused cyclic derivatives represented by a general formula (I), pharmaceutically acceptable salts of the derivatives, stereo isomers of the derivatives, or solvates of the derivatives. R1, R2, R3 and Q are defined as in the specification. The invention also relates to preparation methods of the compounds, and pharmaceutical compositions containing the compounds. The invention further relates to applications of the compounds in the preparation of medicines used for treating and/or preventing non-insulin-dependent diabetes mellitus, hyperglycemia, hyperlipemia, and insulin resistance.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to Mi Dingbing ring derivatives, its pharmacy acceptable salt, its steric isomer or its solvated compounds, 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 non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia, hyperlipidemia, insulin resistance in preparation.
2, background technology
Diabetes are a kind of whole body chronic metabolic disease that normal level causes that exceed owing to blood sugar is out of control.Substantially be divided into four classes, comprise: I type (insulin-dependent), II type (non-insulin-depending type), other type and gestational diabetes.I type and type ii diabetes belong to primary diabetes mellitus, are modal two kinds of forms, are caused by the h and E factor interaction.The cause of disease of diabetes is very complicated, but is because Regular Insulin is absolute or relative the shortage after all, or insulin resistant.Its characteristics are because the absolute or relative deficiency of Regular Insulin and target cell to the susceptibility reduction of Regular Insulin, cause the metabolism disorder of carbohydrate, protein, fat, ionogen and water.
In recent years, because the rhythm of life that the change of growth in the living standard, dietary structure, day are becoming tight and few moving mode of life of sitting etc. all multifactor more, whole world onset diabetes rate increases rapidly, and diabetes have become the chronic disease of the third-largest serious threat human health after tumour, cardiovascular pathological changes.Present global diabetic subject has surpassed 1.2 hundred million people, China patient people the second in the world of living in groups.According to statistics, the diabetic subject that made a definite diagnosis of China reaches more than 4,000 ten thousand, and with annual 1000000 speed increase.Wherein, the type i diabetes patient accounts for 10%, and the type ii diabetes patient accounts for 90%.Diabetes have become the public health problem of people's growing interests.
The type i diabetes medicine mainly is insulin preparation and surrogate thereof at present; For the treatment of type ii diabetes, main medicine is an oral antidiabetic drug, roughly is divided into sulfourea, biguanides, Chinese medicine preparation, other antidiabetic drugs and adjuvant drug.Though it has good curative effect, medicine can not kept long-term efficacy aspect the hyperglycemia reducing, can not be at the cause of disease and effective mitigate the disease.Many antidiabetic medicines at first can fine controlling blood sugar, but along with the continuity of medication treatment then can not keep curative effect, Here it is, and people adopt conjoint therapy or use one of principal element of other different classes of medicines instead, and existing antidiabetic medicine to lack permanently effective major cause is because their mechanism of action is to increase target tissue to the susceptibility of insulin action or improve the activity that pancreas produces Regular Insulin, but the decay basic cause of disease of these diabetes of pancreatic beta cell function is lacked targeting.
Dipeptidase-IV (DPP-IV) extensively exists in vivo, it is a kind of cell surface protein that relates to the various biological function, the interior various active enzyme of the body of can degrading, as glucagon-like-peptide-1 (glucagons-like peptide 1, GLP-1), glucose pancreotropic hormone polypeptide (glucose-dependent insulinotropic polypeptide, GIP), neuropeptide, P material and chemokine etc.And the shortage of GLP-1, GIP all is the major cause of type ii diabetes (being non insulin dependent diabetes).The DPP-IV inhibitor is the medicine of a new generation's treatment diabetes.It has protected the activity of GLP-1 and GIP etc. by suppressing the DPP-IV activity, promotes insulin secretion, lowering blood glucose, and can not cause side effects such as hypoglycemia, weight increase, oedema.Its blood sugar reducing function no longer continues the performance blood sugar reducing function after reaching normal glucose level, the hypoglycemia situation can not occur, and life-time service, the function that can repair beta cell.
Sitagliptin (sitagliptin) is the DPP-IV inhibitor of first listing, becomes a cookle of Merck after the listing in 2006 rapidly.On July 31st, 2009, FDA ratifies Sha Gelieting (saxagliptin) listing of AstraZeneca and Bristol Myers Squibb exploitation again.Active and the selectivity of the SYR-322 of military field (Taketa) company all is better than sitagliptin and Sha Gelieting, be in registration at present before.In addition, also have 3 medicines to be in vast BI-1356 (linagliptin), the PF-734200 (gosogliptin) of Pfizer, the PHX1149 (dutogliptin) of phenomix company of phase III stage: Bo Mingge Yin Dynasty's lattice.The medicine that is in phase II has 9, is in have 7 of phase I.
Yet types of drugs is limited, can not meet clinical needs, and the medicine of being badly in need of the more DPP-IV inhibitor of exploitation satisfies clinical application.
3, summary of the invention
In order to address the above problem, further improve and optimize the DPP-IV inhibitor, the inventor provides a class new DPP-IV inhibitor through great deal of experimental.
Technical scheme of the present invention is as follows:
The invention provides the compound shown in the general formula (I), its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein: R
1Be the phenyl C that is not substituted or is replaced by 1-5 substituting group V
1-6Alkyl, described substituting group V independently selected from halogen atoms, cyano group, cyano group C
1-6Alkyl, C
2-6Alkynyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, carboxyl, carboxyl C
1-6Alkyl, hydroxyl, hydroxyl C
1-6Alkyl, amino, amino C
1-6Alkyl, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, formamyl, C
1-6Alkyl amine group carbonyl or C
1-6The alkyl amine group alkylsulfonyl;
R
2Be hydrogen atom, halogen atom, cyano group, amino, hydroxyl, C
3-6Cycloalkyl, or the C that is not substituted or is replaced by halogen atom, hydroxyl, amino, carboxyl, cyano group, formamyl or amino-sulfonyl
1-6Alkyl or C
1-6Alkoxyl group;
R
3Be selected from C
1-6Alkyl;
The 4-7 first saturated or undersaturated heterocyclic radical that contain a nitrogen-atoms of Q for not being substituted or being replaced by 1-5 substituting group W,
Described substituting group W independently selected from halogen atoms, amino, C
1-6Alkyl or C
1-6Alkyl amine group.
Be preferably:
Wherein: R
1Be the phenyl C that is not substituted or is replaced by 1-3 substituting group V
1-4Alkyl, described substituting group V independently selected from halogen atoms, cyano group, cyano group C
1-4Alkyl, C
2-4Alkynyl, C
1-4Alkyl, halo C
1-4Alkyl, C
1-4Alkoxyl group, halo C
1-4Alkoxyl group, carboxyl, carboxyl C
1-4Alkyl, hydroxyl, hydroxyl C
1-4Alkyl, amino, amino C
1-4Alkyl, C
1-4Alkyl amine group, formamyl, C
1-4Alkyl amine group carbonyl or C
1-4The alkyl amine group alkylsulfonyl;
R
2Be hydrogen atom, cyano group, hydroxyl, or the C that is not substituted or is replaced by halogen atom
1-4Alkyl or C
1-4Alkoxyl group;
R
3Be selected from C
1-4Alkyl;
Q is not for being substituted or by pyrrolidyl, pyrryl or the piperidyl of 1-3 substituting group W replacement,
Described substituting group W independently selected from halogen atoms, amino, C
1-4Alkyl or C
1-4Alkyl amine group.
Be preferably:
Wherein: R
1Be the benzyl that is not substituted or is replaced by 1-3 substituting group V, described substituting group V is independently selected from fluorine atom, cyano group, ethynyl, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy, amino, amino methyl, methylamino, formamyl, methylamine formyl radical or methylamine alkylsulfonyl;
R
2Be hydrogen atom, cyano group, hydroxyl, methyl, trifluoromethyl, methoxyl group or trifluoromethoxy;
R
3Be selected from methyl or ethyl;
Q is not for being substituted or by the pyrrolidyl or the piperidyl of 1-2 substituting group W replacement,
Described substituting group W is independently selected from fluorine atom, amino or methyl.
More preferably:
Wherein: R
1Be the benzyl that is not substituted or is replaced by 1-3 substituting group V, described substituting group V is independently selected from fluorine atom, cyano group, ethynyl, methyl, trifluoromethyl, methoxyl group or trifluoromethoxy;
R
2Be hydrogen atom, cyano group, methyl or methoxy;
R
3Be selected from methyl or ethyl;
Q is not for being substituted or by the pyrrolidyl or the piperidyl of 1-2 substituting group W replacement,
Described substituting group W is independently selected from fluorine atom, amino or methyl.
More preferably:
Wherein: R
1Be the benzyl that is not substituted or is replaced by 1-2 substituting group V, described substituting group V is independently selected from fluorine atom, cyano group, ethynyl, methyl, trifluoromethyl, methoxyl group or trifluoromethoxy;
R
2Be hydrogen atom, methyl or methoxy;
R
3Be selected from methyl or ethyl;
Q is not for being substituted or by the piperidyl of 1-2 substituting group W replacement,
Described substituting group W is independently selected from fluorine atom, amino or methyl.
Further be preferably:
Wherein: R
1Be the benzyl that is not substituted or is replaced by 1-2 substituting group V, described substituting group V is independently selected from fluorine atom or cyano group;
R
2Be hydrogen atom, methyl or methoxy;
R
3Be selected from methyl or ethyl;
Q is not for being substituted or by the piperidyl of 1-2 substituting group W replacement,
Described substituting group W is independently selected from fluorine atom, amino or methyl.
Further be preferably:
Wherein: R
1Be the benzyl that is not substituted or is replaced by 1-2 substituting group V, described substituting group V is independently selected from fluorine atom or cyano group;
R
2Be hydrogen atom, methyl or methoxy;
R
3Be selected from methyl or ethyl;
Q is not for being substituted or by the piperidyl of 1-2 amino replacement.
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" C of the present invention
1-6Alkyl " hydrocarbon that refers to contain 1～6 carbon atom partly removes the alkyl of a hydrogen atom deutero-straight or branched; as methyl; ethyl; n-propyl; sec.-propyl; normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, the 2-methyl butyl, neo-pentyl, the 1-ethyl propyl, 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 etc.Term " C
1-4Alkyl " refer to the specific examples that contains 1～4 carbon atom in the above-mentioned example.
" C of the present invention
1-6Alkoxyl group " refer to term " C
1-6Alkyl " group that is connected with other structures by Sauerstoffatom, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc.Term " C
1-4Alkoxyl group " refer to term " C
1-4Alkyl " group that is connected with other structures by Sauerstoffatom.
" halo C of the present invention
1-6Alkyl, halo C
1-4Alkyl, halo C
1-6Alkoxyl group, halo C
1-4Alkoxyl group " in " halo " be meant C
1-6Alkyl, C
1-4Alkyl, C
1-6Alkoxyl group, C
1-4One or more hydrogen atom on the carbon atom in the alkoxyl group is replaced by halogen atom.
" C of the present invention
2-6Alkynyl " be meant that containing the triple-linked carbonatoms is 2～6 straight or branched or cyclic alkynyl, as ethynyl, proyl, 2-butyne base, valerylene base, 3-pentynyl, 2-hexin base, 3-hexin base, cyclopropyne base, cyclobutyne base, ring pentynyl, hexamethylene alkynyl etc." C of the present invention
2-4Alkynyl " be meant that the carbonatoms that contains two keys is 2～4 the straight or branched or the example of cyclic alkynyl.
" C of the present invention
3-6Cycloalkyl " finger ring propyl group, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl etc.
The specific examples of " the saturated or undersaturated heterocyclic radical that contains a nitrogen-atoms of 5-6 unit " of the present invention such as pyrroles, pyrrolin, tetramethyleneimine, pyridine, dihydropyridine, piperidines etc.
Preferred compound:
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:
Raw material 1 formula A compound formula B compound
Formula C compound formula D compound formula E compound
The preparation of step 1 formula A compound
In the exsiccant reaction flask, add ethanol, raw material 1, raw material 2, triethylamine, stirring at room, the reaction solution drying under reduced pressure is separated out solid, gets formula A compound.
The preparation of step 2 formula B compound
In the exsiccant reaction flask, add formula A compound, raw material 3 is dissolved in the butanols, adds methylethylolamine solution, high-temperature stirring, and the reaction solution drying under reduced pressure is separated out solid, gets formula B compound.
The preparation of step 3 formula C compound
In the exsiccant reaction flask, add formula B compound, be dissolved in the methyl alcohol, add Pd-C under the room temperature, feed hydrogen, stir, reacting liquid filtering, vacuum-drying by column chromatography purification, gets formula C compound.
The preparation of step 4 formula D compound
In the exsiccant reaction flask, add triphosgene (triphosgene or claim two (trichloromethyl) carbonic ether), triethylamine is dissolved in the tetrahydrofuran (THF), low temperature adds formula C compound, be dissolved in the tetrahydrofuran (THF), stir the reaction solution ethyl acetate extraction, with saturated sodium carbonate solution and strong brine washing, the organic layer anhydrous sodium sulfate drying, column chromatography purification gets formula D compound.
The preparation of step 5 formula E compound
In the exsiccant reaction flask, add formula D compound, be dissolved in DMF (N, dinethylformamide), low temperature splashes into raw material 4, salt of wormwood, stirring reaction under the room temperature, reaction solution ethyl acetate extraction, the saturated nacl aqueous solution washing, the organic layer anhydrous sodium sulfate drying, column chromatography purification gets formula E compound.
R in the above reaction equation
1, R
2, R
3, Q 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 formic acid, acetate, Phenylsulfonic acid, phenylformic acid, tosic acid, (2R, 3R)-2,3-dyhydrobutanedioic acid, camphorsulfonic acid, citric acid, methylsulfonic acid, ethyl sulfonic acid, propanesulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, glactaric acid, pamoic acid, pantothenic acid, succsinic acid, tartrate etc., preferred especially phenylformic acid, Phenylsulfonic acid, tosic acid, citric acid, toxilic acid, fumaric acid, tartrate.Mineral acid comprises Hydrogen bromide, spirit of salt, nitric acid, sulfuric acid, phosphoric acid etc., preferred especially Hydrogen bromide, spirit of salt, sulfuric acid, phosphoric acid.Organic bases comprises primary, the second month in a season and tertiary amine, be substituted amine and comprise naturally occurring replacement amine, cyclammonium and basic ion exchange resin, be selected from arginine, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylin ethanol, the 2-dimethylamino-ethanol, 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.The salt that is solid form can exist with more than one crystalline structure, also can be with the form of hydrate.
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 shown in the general formula (I), its pharmacy acceptable salt, its steric isomer can be the solvated compounds forms.Solvated compounds is under the situation of hydrate, and hydration can be finished in preparation process or can be utilized the water absorbability of original anhydrous product to carry out gradually.
Compound of the present invention can be united with one or more other medicines, and is more safer or more effective than single medicine.Can be with these other medicines and formula (I) compound simultaneously or in succession by a kind of approach and with its usual amounts administration.During administration simultaneously, be preferably the medicinal compositions of the unit dosage form that contains described other medicines and formula (I) compound.Can with formula (I) compound drug combination or respectively administration or in same medicinal compositions other activeconstituents of administration include, but are not limited to:
(a) other pepx IV inhibitor;
(b) insulin sensitisers comprises: (i) PPAR gamma agonist, as glitazones (as troglitazone, pioglitazone, englitazone, MCC-555, Rosiglitazone etc.) and other PPAR part, comprise PPAR α/γ economic benefits and social benefits agonist, as KRP-297 and PPAR alfa agonists such as Fenofibric Acid derivative (gemfibrozil, clofibrate, fenofibrate and bezafibrate); (ii) biguanides is as N1,N1-Dimethylbiguanide and phenformin; (iii) albumen network propylhomoserin phosphoesterase-1B (PTP-1B) inhibitor;
(c) Regular Insulin or insulin-mimickers;
(d) sulfonylurea and other Regular Insulin succagoga are as tolbutamide and Glipizide, meglitinide and related drugs;
(e) alpha-glucosidase inhibitor (as acarbose)
(f) glucagon receptor antagonist;
(g) GLP-1, GLP-1 stand-in and GLP-1 receptor stimulant;
(h) GLP and GLP stand-in and GLP receptor stimulant;
(i) PACAP, PACAP stand-in and PACAP acceptor 3 agonists;
(j) cholesterol reducing agent, as (i) HMG-CoA reductase inhibitor (lovastatin, Simvastatin, Pravastatin, fluvastatin, Ah appropriate cuts down his spit of fland, rivastatin, itavastatin, superstatin and other statins), (ii) inner complex (Colestyramine, the dialkyl aminoalkyl derivative of colestipol and crosslinked dextran), (iii) nicotinic alcohol, nicotinic acid or other salt, (iv) PPAR alfa agonists, as Fenofibric Acid derivative (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPAR α/γ economic benefits and social benefits agonist is as KRP-297; (vi) cholesterol absorption inhibitor, as β-Gu Zaichun and ezetimibe, (vii) ethanoyl CoA, chole-sterol acyltransferase inhibitor is as avasimibe with (viii) antioxidant is as probucol;
(k) PPAR delta agonists;
(l) anti-obesity compound, for example Phenfluoramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y 5 inhibitor and beta 3 adrenoreceptor agonists;
(m) ileal bile acid transfer protein inhibitor; With
(n) be used for the medicine of inflammation, for example acetylsalicylic acid, non-steroidal anti-inflammatory drug, glucocorticosteroid, sulphur nitrogen sulphur pyridine and epoxidase II select inhibitor.
Above-mentioned unite comprise compound of the present invention not only with a kind of other active compound and also with the associating of two or more other active compounds.Non-limiting example comprises that the have formula compound of (I) and two or more are selected from the associating of the active compound of biguanides, sulfonylurea, HMG-CoA reductase inhibitor, PPAR agonist, PTP-1B inhibitor, other DPP-IV inhibitor and anti-obesity compound.
The weight ratio of The compounds of this invention and second kind of activeconstituents can change, and it depends on the effective dose of various compositions.In general, with the effective dose that adopts separately.Therefore for example when compound of the present invention and other medicines drug combination, the weight ratio of The compounds of this invention and other medicines generally between about 1000: 1 to about 1: 1000, is preferably between about 200: 1 to about 1: 200.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, its steric isomer or its solvated compounds 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 1mg～100mg shown in the general formula (I) of physiology significant quantity, can be described activeconstituentss such as 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 50mg, 75mg, 100mg.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, its steric isomer or its solvated compounds can be applied to the patient who needs this treatment in oral mode.
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 Mi Dingbing ring derivatives to be used for the treatment of and/or to prevent purposes in the medicine of following disease in preparation.
Type ii diabetes and relative disease, now full confirmation GLP-1 and GIP can be by DPP-IV quick inactivatings in vivo, therefore DPP-IV inhibitor of the present invention can be used for treating a large amount of illnesss that type ii diabetes and treatment and prevention are followed type ii diabetes, comprises metabolic syndrome X, reactive hypoglycemia and glycosuria sexual abnormality lipidemia.Following disease, illness is relevant with type ii diabetes with symptom, therefore can treat by the methods of treatment that adopts The compounds of this invention, control or prevention in some cases: (1) hyperglycemia, (2) low dextrose tolerance, (3) insulin resistance, (4) obesity, (5) matter fat disease, (6) unusual lipidemia, (7) hyperlipidaemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high HDL level, (12) atherosclerosis and sequela thereof, (13) vascular restenosis, (14) irritable bowel syndrome, (15) enteritis comprises crohnShi disease and ulcerative colitis, (16) retinopathy, (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.
DPP-IV inhibitor of the present invention compared with prior art has the following advantages:
(1) The compounds of this invention can suppress the activity of DPP-IV preferably, makes the interior GLP-1 level of body more stable;
(2) DPP-IV inhibitor of the present invention is effective, and clinical consumption is few, saves cost;
(3) DPP-IV inhibitor of the present invention has good security and tolerance in vivo, and incidence rate of adverse reaction reduces more;
(4) DPP-IV inhibitor preparation technology 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 The compounds of this invention
Trial-product: The compounds of this invention, self-control, its chemical name and structural formula are as mentioned before.
Experimental technique:
The preparation DPPIV-Glo of reaction solution
TMDamping fluid needs to melt in advance, and the freeze-drying fluorescein needs to put to room temperature from taking out in the refrigerator in advance.With DPPIV-Glo
TMSubstrate is dissolved into the water mesoscale eddies mixing of 110 μ l as mother liquor (concentration is 10mmol), fluorescein is put into filled 50mL DPPIV-Glo
TMIn the damping fluid ampoule.Then 100 μ l are contained DPPIV-Glo
TMThe solution of substrate and 50mL contain the DPPIV-Glo of fluorescein
TMThe damping fluid mixing obtains reaction solution.Reaction solution need be preserved at-20 ℃ of refrigerators.
1, fluorescent method detects the restraining effect to DPP-IV:
The total volume in every hole is 25 μ l in the mensuration of DPP-IV enzyme, comprise 12 μ l solution (66pM DPP-4 is dissolved in the 10mmol tris buffer, pH=7.5), the compound of 0.5 μ l (dissolving), the reaction solution of 12.5 μ l with DMSO.Compound needs ten times of dilutions with DMSO before experiment, need 8 concentration of dilution.The solution and the compound that at first contain the DPP-IV enzyme before the test are hatched 10min in RT, and then the adding reaction solution is hatched 30min.Not enzyme-added in the negative control group.Measure fluorescent signal behind the 30min, need to measure twice.
2, the fluorescent method detection compound is to the restraining effect of DPP-8:
The total volume in every hole is 25 μ l in the mensuration of DPP-8 enzyme, comprise 12 μ l solution (111.9pM DPP-8 is dissolved in the 10mmol tris buffer, pH=7.5), the compound of 0.5 μ l (dissolving), the reaction solution of 12.5 μ l with DMSO.Compound needs ten times of dilutions with DMSO before experiment, need 8 concentration of dilution.The solution and the compound that at first contain the DPP-8 enzyme before the test are hatched 10min in RT, and then the adding reaction solution is hatched 30min.Not enzyme-added in the negative control group.Measure fluorescent signal behind the 30min, need to measure twice.
3, the fluorescent method detection compound is to the restraining effect of DPP-9:
The total volume in every hole is 25 μ l in the mensuration of DPP-9 enzyme, comprise 12 μ l solution (26pM DPP-9 is dissolved in the 10mmol tris buffer, pH=7.5), the compound of 0.5 μ l (dissolving), the reaction solution of 12.5 μ l with DMSO.Compound needs ten times of dilutions with DMSO before experiment, need 8 concentration of dilution.The solution and the compound that at first contain the DPP-9 enzyme before the test are hatched 10min in RT, and then the adding reaction solution is hatched 30min.Not enzyme-added in the negative control group.Measure fluorescent signal behind the 30min, need to measure twice.
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, The compounds of this invention has better inhibited activity to DPP-IV, to DPP-8, DPP-9 unrestraint activity, DPP-IV is had higher selectivity.The compounds of this invention is safe and effective.
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.
Embodiment 1 (R)-2-[[6-(3-amino piperidine-1-yl)-9-methyl-8-oxo-8,9-dihydro-7H-purine-7-yl] methyl] the benzene first
The preparation of nitrile (compound 1)
(1) preparation of 6-chloro-N-methyl-5-nitro pyrimidine-4-amine
In the exsiccant reaction flask, with 4,6-two chloro-5-nitro-pyrimidine 3.0g (15.15mmol) are dissolved in the 150mL tetrahydrofuran (THF),-78 ℃ drip methylamine (2N, 10mL), triethylamine 1.5g (15mmol), stir 30min, room temperature adds the shrend reaction of going out, and removes tetrahydrofuran (THF), the residue dichloromethane extraction, organic layer merges, and dried over sodium sulfate concentrates, get product 2.8g, yield 98.0%.
(2) (R)-and 1-[6-(methylamino)-5-nitro-pyrimidine-4-yl] preparation of piperidines-3-base amido formic acid tertiary butyl ester
In the exsiccant reaction flask, with (R)-piperidines-3-amine 2.8g (15.0mmol), triethylamine 6g (60mmol) is dissolved in tetrahydrofuran (THF),-78 ℃, the 50mL tetrahydrofuran solution of adding 6-chloro-N-methyl-5-nitro pyrimidine-4-amine 2.8g (15.0mmol) stirred 3 hours, room temperature reaction spends the night, and adds Boc
2O 3.4g (15.0mmol) and trifluoroacetic acid 1.8g (18mmol) stirred 4 hours, column chromatography purification (ethyl acetate: sherwood oil=1: 3), get product 2.4g, yield 45.0%.
(3) (R)-and 1-[5-amino-6-(methylamino) pyrimidine-4-yl] preparation of piperidines-3-base amido formic acid tertiary butyl ester
In the exsiccant reaction flask, add (R)-1-[6-(methylamino)-5-nitro-pyrimidine-4-yl] piperidines-3-base amido formic acid tertiary butyl ester 2.4g (6.8mmol), iron powder 3.4g (61mmol), ammonium chloride 4.1g (78mmol), 150mL methyl alcohol and 50mL water, heating reflux reaction 2 hours, suction filtration, filtrate concentrates, residue adds water, ethyl acetate extraction, organic layer anhydrous sodium sulfate drying, get product 1.4g, yield 63.9%.
(4) (R)-and 1-[5-(2-cyano group benzylamine)-6-(methylamino) pyrimidine-4-yl] preparation of piperidines-3-base amido formic acid tertiary butyl ester
In the exsiccant reaction flask, with (R)-1-[5-amino-6-(methylamino) pyrimidine-4-yl] piperidines-3-base amido formic acid tertiary butyl ester 1.4g (4.3mmol), 2-formyl cyanobenzene 569mg (4.3mmol) is dissolved in the 200mL methylene dichloride, adds 2mL acetic acid and NaBH (OAc)
3, stirring is spent the night, washing, and the organic layer anhydrous sodium sulfate drying concentrates, and gets product 2.4g.
(5) (R)-and 1-[7-(2-cyano group benzyl)-9-methyl-8-oxo-8,9-dihydro-7H-purine-6-yl] preparation of piperidines-3-base amido formic acid tertiary butyl ester
In the exsiccant reaction flask, with triphosgene 1.4g (4.3mmol), triethylamine 2.0g (20mmol) is dissolved in the 150mL tetrahydrofuran (THF),-10 ℃ of adding (R)-1-[5-(2-cyano group benzylamine)-6-(methylamino) pyrimidine-4-yl] piperidines-3-base amido formic acid tertiary butyl ester 2.4g (5.0mmol), heating reflux reaction spends the night, and reaction solution concentrates, column chromatography purification, get product 1.2g, yield 60.2%.
(6) (R)-and 2-[[6-(3-amino piperidine-1-yl)-9-methyl-8-oxo-8,9-dihydro-7H-purine-7-yl] methyl] preparation of cyanobenzene
In the exsiccant reaction flask, with (R)-1-[7-(2-cyano group benzyl)-9-methyl-8-oxo-8,9-dihydro-7H-purine-6-yl] piperidines-3-base amido formic acid tertiary butyl ester 1.2g (2.6mmol), be dissolved in trifluoroacetic acid (20mL), methylene dichloride (100mL) stirred 2 hours, reaction solution concentrates, preparation liquid phase purifying gets product 600mg, yield 53.1%.
Molecular formula: C
19H
21N
7O molecular weight: 363.42 mass spectrums (M+1): 364
1H-NMR(400MHz，CD
3OD)：δ8.48(1H，s)，7.77(1H，dd)，7.64(1H，m)，7.47(1H，m)，7.31(1H，d)，5.37-5.48(2H，dd)，3.73(1H，dd)，3.50(3H，s)，3.32(2H，m)，3.17(1H，m)，3.05(1H，m)，2.13(1H，m)，1.72(1H，m)，1.57(2H，m)
With reference to above-mentioned preparation method, can also prepare following compound:
Claims (10)
1. the compound shown in the general formula (I), its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein: R
1Be the phenyl C that is not substituted or is replaced by 1-5 substituting group V
1-6Alkyl, described substituting group V independently selected from halogen atoms, cyano group, cyano group C
1-6Alkyl, C
2-6Alkynyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, carboxyl, carboxyl C
1-6Alkyl, hydroxyl, hydroxyl C
1-6Alkyl, amino, amino C
1-6Alkyl, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, formamyl, C
1-6Alkyl amine group carbonyl or C
1-6The alkyl amine group alkylsulfonyl;
R
2Be hydrogen atom, halogen atom, cyano group, amino, hydroxyl, C
3-6Cycloalkyl, or the C that is not substituted or is replaced by halogen atom, hydroxyl, amino, carboxyl, cyano group, formamyl or amino-sulfonyl
1-6Alkyl or C
1-6Alkoxyl group;
R
3Be selected from C
1-6Alkyl;
The 4-7 first saturated or undersaturated heterocyclic radical that contain a nitrogen-atoms of Q for not being substituted or being replaced by 1-5 substituting group W,
Described substituting group W independently selected from halogen atoms, amino, C
1-6Alkyl or C
1-6Alkyl amine group.
2. compound as claimed in claim 1, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein: R
1Be the phenyl C that is not substituted or is replaced by 1-3 substituting group V
1-4Alkyl, described substituting group V independently selected from halogen atoms, cyano group, cyano group C
1-4Alkyl, C
2-4Alkynyl, C
1-4Alkyl, halo C
1-4Alkyl, C
1-4Alkoxyl group, halo C
1-4Alkoxyl group, carboxyl, carboxyl C
1-4Alkyl, hydroxyl, hydroxyl C
1-4Alkyl, amino, amino C
1-4Alkyl, C
1-4Alkyl amine group, formamyl, C
1-4Alkyl amine group carbonyl or C
1-4The alkyl amine group alkylsulfonyl;
R
2Be hydrogen atom, cyano group, hydroxyl, or the C that is not substituted or is replaced by halogen atom
1-4Alkyl or C
1-4Alkoxyl group;
R
3Be selected from C
1-4Alkyl;
Q is not for being substituted or by pyrrolidyl, pyrryl or the piperidyl of 1-3 substituting group W replacement,
Described substituting group W independently selected from halogen atoms, amino, C
1-4Alkyl or C
1-4Alkyl amine group.
3. compound as claimed in claim 2, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein: R
1Be the benzyl that is not substituted or is replaced by 1-3 substituting group V, described substituting group V is independently selected from fluorine atom, cyano group, ethynyl, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy, amino, amino methyl, methylamino, formamyl, methylamine formyl radical or methylamine alkylsulfonyl;
R
2Be hydrogen atom, cyano group, hydroxyl, methyl, trifluoromethyl, methoxyl group or trifluoromethoxy;
R
3Be selected from methyl or ethyl;
Q is not for being substituted or by the pyrrolidyl or the piperidyl of 1-2 substituting group W replacement,
Described substituting group W is independently selected from fluorine atom, amino or methyl.
4. compound as claimed in claim 3, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein: R
1Be the benzyl that is not substituted or is replaced by 1-3 substituting group V, described substituting group V is independently selected from fluorine atom, cyano group, ethynyl, methyl, trifluoromethyl, methoxyl group or trifluoromethoxy;
R
2Be hydrogen atom, cyano group, methyl or methoxy;
R
3Be selected from methyl or ethyl;
Q is not for being substituted or by the pyrrolidyl or the piperidyl of 1-2 substituting group W replacement,
Described substituting group W is independently selected from fluorine atom, amino or methyl.
5. compound as claimed in claim 4, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein: R
1Be the benzyl that is not substituted or is replaced by 1-2 substituting group V, described substituting group V is independently selected from fluorine atom, cyano group, ethynyl, methyl, trifluoromethyl, methoxyl group or trifluoromethoxy;
R
2Be hydrogen atom, methyl or methoxy;
R
3Be selected from methyl or ethyl;
Q is not for being substituted or by the piperidyl of 1-2 substituting group W replacement,
Described substituting group W is independently selected from fluorine atom, amino or methyl.
6. compound as claimed in claim 5, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein: R
1Be the benzyl that is not substituted or is replaced by 1-2 substituting group V, described substituting group V is independently selected from fluorine atom or cyano group;
R
2Be hydrogen atom, methyl or methoxy;
R
3Be selected from methyl or ethyl;
Q is not for being substituted or by the piperidyl of 1-2 substituting group W replacement,
Described substituting group W is independently selected from fluorine atom, amino or methyl.
7. compound as claimed in claim 6, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein: R
1Be the benzyl that is not substituted or is replaced by 1-2 substituting group V, described substituting group V is independently selected from fluorine atom or cyano group;
R
2Be hydrogen atom, methyl or methoxy;
R
3Be selected from methyl or ethyl;
Q is not for being substituted or by the piperidyl of 1-2 amino replacement.
8. compound as claimed in claim 7, its pharmacy acceptable salt, its steric isomer or its solvated compounds, described compound is selected from:
(R)-and 2-[[6-(3-amino piperidine-1-yl)-9-methyl-8-oxo-8,9-dihydro-7H-purine-7-yl] methyl] cyanobenzene.
9. as the pharmaceutical composition of the described compound of the arbitrary claim of claim 1～8, its pharmacy acceptable salt, its steric isomer or its solvated compounds and one or more pharmaceutical carriers and/or thinner, be pharmaceutically acceptable arbitrary formulation.
As the described compound of the arbitrary claim of claim 1～8, its pharmacy acceptable salt, its steric isomer and solvated compounds thereof in the application that is used for preparing the medicine that treats and/or prevents non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia, hyperlipidemia, insulin resistance.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1150428A (en) * | 1994-06-08 | 1997-05-21 | 辉瑞大药厂 | Corticotropin releasing factor antagonists |
| CN1720246A (en) * | 2003-04-21 | 2006-01-11 | 捷克共和国乌斯塔夫化学与生物化学研究院 | (Purin-6-yl) amino acid and production method thereof |
| CN1745080A (en) * | 2002-12-04 | 2006-03-08 | 卫材株式会社 | 1,3-dihydroimidazole fused-ring compound |
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2010
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1150428A (en) * | 1994-06-08 | 1997-05-21 | 辉瑞大药厂 | Corticotropin releasing factor antagonists |
| CN1745080A (en) * | 2002-12-04 | 2006-03-08 | 卫材株式会社 | 1,3-dihydroimidazole fused-ring compound |
| CN1720246A (en) * | 2003-04-21 | 2006-01-11 | 捷克共和国乌斯塔夫化学与生物化学研究院 | (Purin-6-yl) amino acid and production method thereof |
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