CN101781273A - dipeptidylpeptidase iv inhibitor containing guanidyl - Google Patents
dipeptidylpeptidase iv inhibitor containing guanidyl Download PDFInfo
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Abstract
The invention belongs to the technical field of medicine, particularly relates to a dipeptidylpeptidase IV inhibitor containing guanidyl, pharmaceutically acceptable salts or an isomer thereof as shown in a general formula (I), wherein meanings of Ar, R1, R1', R3, R3' and R2 are defined as the specification. In addition, the invention also provides preparation methods of the compounds, medical compositions containing the compounds, and application of the compounds in preparing medicaments for treating and/or preventing diabetes mellitus, noninsulin dependent diabetes, hyperglycemia and insulin resistance.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to contain dipeptidyl peptidase IV inhibitor, its pharmacy acceptable salt or its isomer of guanidine radicals, 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, insulin-dependent diabetes mellitus (IDDM) 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 insulin-dependent diabetes mellitus (IDDM) 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.
The sulfonylureas drugs for diabetes thing is topmost Remedies for diabetes, secrete more Regular Insulin by stimulating beta cell, when it is invalid, increase the insulin level of blood plasma by insulin injection, insulin concentration raises and can cause stimulating hyperinsulinism resistance tissue.Biguanides can improve the susceptibility of Regular Insulin, and hyperglycemia is relaxed to some extent, but two kinds of biguanides, and phenformin and N1,N1-Dimethylbiguanide can bring out lactic acidosis and nauseating/diarrhoea.Alpha-glucosidase inhibitor class ofhypoglycemic medicine, by suppressing the activity of mucous membrane of small intestine brush border alpha-glucosidase, reduce and be absorbed again after oligose is decomposed into monose, can delay the absorption of sugar after the meal, suppress blood sugar peak after meal, as acarbose, miglitol, but enteron aisle flatulence, diarrhoea and other side effect are arranged.Other class ofhypoglycemic medicines are as euglycemic agent, insulin resistance hormone inhibitors, glyconeogenesis inhibitor, rhIGF-1, ISU secernent etc.In addition, China has carried out many researchs at the hypoglycemic Chinese medicine of screening, and compositions such as the terpene in the natural medicinal plant, flavonoid, polyose, polypeptide amino acid, unsaturated fatty acids, alkaloid, steroidal and sulfide linkage compound all have certain hypoglycemic activity.Glitazones is the compound that a nearest disclosed class is effectively improved the multiple symptom of type II diabetes, is the agonist of peroxidase multiplication agent activated receptor.This compounds of listing has shown severe side effect at present.The sick medicine of above most of glycosuria is controlling blood sugar to a certain extent, can not fundamentally drive away the cause of disease and prevent complication.
It is a kind of cell surface protein that relates to the various biological function that dipeptide amido peptidase TV is Dipeptidase-IV (DPP-IV).It has tissue distribution (intestines, kidney, liver, pancreas, placenta, thymus gland, spleen, epithelial cell, blood vessel endothelium, lymph and medullary cell, 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.Show the latent effect of this peptase in the various diseases process of human body or other animal.
The DPP-IV inhibitor is the medicine of a new generation's treatment diabetes.The inhibitor of the DPP-IV of listing is sitagliptinphosphate (sitagliptin phosphate) at present, structural formula is as follows, DPP-IV had selectivity, the activity that does not suppress DPP-8 and DPP-9, security preferably and admissibility are arranged, and can not cause weight increase, cause oedema and risk of hypoglycemia.
Yet the pharmaceutical activity of the inhibitor of DPP-IV is not ideal enough, and other albumen selectivity deficiencies to DPP family, in order to solve diabetics's misery, the Regular Insulin of himself is able to " resurrection " and play one's part to the full, blood sugar can be absorbed by the body tissue cell and utilize again, blood sugar is descended, reach steady in a long-term and the purpose of controlling blood sugar all sidedly, the inventor has invented The compounds of this invention through studying for a long period of time.
3, summary of the invention
In order to address the above problem, further improve and optimize the inhibitor of DPP-IV, the inventor provides the inhibitor of the new DPP-IV of a class through great deal of experimental.
Technical scheme of the present invention is as follows:
1, the compound shown in the general formula (I), its pharmacy acceptable salt or its isomer:
Wherein: the Ar representative is replaced or unsubstituted phenyl by 1～5 substituting group;
R
1, R
1', R
3, R
3' independently represent hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, sulfonic acid amido, halogen atom, C respectively
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyl-carbonyl, aryl, cycloalkyl, heterocyclic radical, aryl C
1-6Alkyl, cycloalkyl C
1-6Alkyl, heterocyclic radical C
1-6Alkyl, C
1-6The alkyl amine group formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6The alkyl amine group alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6The alkyl sulfenyl amido, C
1-6Alkyl sulphinyl, C
1-6The alkyl amine group sulfinyl, two (C
1-6Alkyl) amido, two (C
1-6Alkyl) amido formyl radical, two (C
1-6Alkyl) amido alkylsulfonyl, two (C
1-6Alkyl) amido sulfinyl, C
1-6Alkyl oxygen carbonyl or C
1-6Alkyl carbonyl oxy;
R
1With R
3Perhaps R
1' and R
3' be interconnected to form the saturated or undersaturated 0-4 of containing the heteroatoms ring-type group of 3-8 unit and piperazine ring carry out thick with, the first saturated or undersaturated 0-4 of containing the heteroatoms ring-type group of described 3-8 do not comprise phenyl ring, described heteroatoms is selected from N, O or S;
R
2Represent hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, sulfonic acid amido, halogen atom, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyl-carbonyl, aryl, cycloalkyl, 5-member heterocyclic ring containing nitrogen base, aryl C
1-6Alkyl, cycloalkyl C
1-6Alkyl or
Work as R
2Represent hydrogen atom, C
1-6Alkyl, aryl or aryl C
1-6Alkyl, R
1, R
3All be not H;
R
4Represent hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, sulfonic acid amido, halogen atom, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyl-carbonyl, aryl, cycloalkyl, heterocyclic radical, aryl C
1-6Alkyl, cycloalkyl C
1-6Alkyl, heterocyclic radical C
1-6Alkyl or
Z representative-S-,-O-,
-SO
2-,-SO-or-NR
9-, Y represention oxygen atom wherein, sulphur atom or-NR
9',
R wherein
5, R
6, R
9With R
9' independently represent hydrogen atom, carboxyl, amino, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, sulfonic acid amido, halogen atom, C respectively
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyl-carbonyl, aryl, cycloalkyl, heterocyclic radical, aryl C
1-6Alkyl, cycloalkyl C
1-6Alkyl, heterocyclic radical C
1-6Alkyl, C
1-6Alkylamidoalkyl, C
1-6The alkyl amine group alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6The alkyl sulfenyl amido, C
1-6The alkyl amine group sulfinyl, two (C
1-6Alkyl) amido formyl radical, two (C
1-6Alkyl) amido alkylsulfonyl, two (C
1-6Alkyl) amido sulfinyl, C
1-6Alkyl oxygen carbonyl, C
1-6Alkyl carbonyl oxy or R
5With R
6Be interconnected to form the 5-6 member heterocyclic ring containing nitrogen;
R
6Perhaps represent NR
11R
11', R wherein
11With R
11' independently represent C respectively
1-6Alkyl, C
1-6The alkyl-carbonyl alkyl, cycloalkyl, heterocyclic radical, perhaps R
11With R
11' be interconnected to form saturated or the unsaturated and cyclic group of saturated or unsaturated monocyclic groups of 3-8 unit or 6-10 unit;
R
5, Z and R
11Be interconnected to form the saturated or undersaturated 0-4 of containing the heteroatoms ring-type group of 3-8 unit, R
11' and R
9' be interconnected to form the saturated or undersaturated 0-4 of containing the heteroatoms ring-type group of 3-8 unit;
R
1' and R
5Be interconnected to form the saturated or undersaturated 1-4 of containing of a 5-8 unit heteroatomic cyclic group and piperazine ring carry out thick with, described heteroatoms is selected from N, O or S;
Wherein said C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl, C
2-6Alkynyl further is substituted, and substituting group is selected from hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, sulfonic group, carbamyl, amino-sulfonyl or halogen atom;
Described phenyl, aryl, heterocyclic radical or 3-8 unit cyclic group are further replaced by W, and wherein W is hydrogen atom, carboxyl, amino, hydroxyl, nitro, cyano group, halogen atom, formamido-, formamyl, amino-sulfonyl, sulfonic group, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, carbamyl C
1-6Alkyl, amino-sulfonyl C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyl-carbonyl, C
1-6Alkyl amine group formyl radical, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, C
1-6Alkyl sulphinyl, two (C
1-6Alkyl) amido, C
1-6Alkyl amine group sulfinyl, two (C
1-6Alkyl) amido formyl radical, two (C
1-6Alkyl) amido alkylsulfonyl, two (C
1-6Alkyl) amido sulfinyl, C
1-6Alkyl oxygen carbonyl or C
1-6Alkyl carbonyl oxy.
Preferred compound is:
Wherein: the Ar representative is replaced or unsubstituted phenyl by 1～5 substituting group;
R
1, R
1', R
3, R
3' represent hydrogen atom;
R
2Representation carboxy, amino, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, halogen atom, C
1-4Alkoxyl group, C
2-4Thiazolinyl, C
2-4Alkynyl, C
1-4Alkyl-carbonyl, cycloalkyl, 5-member heterocyclic ring containing nitrogen base, cycloalkyl C
1-4Alkyl or
R
4Represent hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl, C
2-4Alkynyl, C
1-4Alkyl-carbonyl, aryl, cycloalkyl, heterocyclic radical, aryl C
1-4Alkyl, cycloalkyl C
1-4Alkyl, heterocyclic radical C
1-4Alkyl or
During the Y represention oxygen atom, R
5With R
6Be interconnected to form the 5-6 member heterocyclic ring containing nitrogen,
Y representative-NR
9' time, R
6Represent hydrogen atom, carboxyl, amino, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl, C
2-4Alkynyl, C
1-4Alkyl-carbonyl, aryl, cycloalkyl, heterocyclic radical, aryl C
1-4Alkyl, cycloalkyl C
1-4Alkyl, heterocyclic radical C
1-4Alkyl, C
1-6Alkylamidoalkyl, C
1-6The alkyl amine group alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6The alkyl sulfenyl amido, C
1-6The alkyl amine group sulfinyl, two (C
1-4Alkyl) amido formyl radical, two (C
1-4Alkyl) amido alkylsulfonyl, two (C
1-4Alkyl) amido sulfinyl, C
1-4Alkyl oxygen carbonyl, C
1-4Alkyl carbonyl oxy or NR
11R
11', R wherein
11With R
11' independently represent hydrogen atom, C respectively
1-4Alkyl, C
1-4The alkyl-carbonyl alkyl, cycloalkyl, heterocyclic radical or R
11With R
11' be interconnected to form saturated or the unsaturated and cyclic group of saturated or unsaturated monocyclic groups of 5-6 unit or 6-10 unit;
R
5, Z and R
11Be interconnected to form the saturated or undersaturated 0-4 of containing the heteroatoms ring-type group of 5-6 unit, R
11' and R
9' be interconnected to form the saturated or undersaturated 0-4 of containing the heteroatoms ring-type group of 5-6 unit;
R
1' and R
5Be interconnected to form the 5-6 unit heteroatomic cyclic group of the saturated or undersaturated 1-4 of containing and piperazine ring carry out thick with, described heteroatoms is selected from N, O or S;
Wherein said C
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl, C
2-4Alkynyl further is substituted, and substituting group is selected from hydrogen atom, carboxyl, amino, cyano group, hydroxyl or halogen atom;
Described phenyl, aryl, heterocyclic radical or 5-6 unit cyclic group are further replaced by W, and wherein W is hydrogen atom, carboxyl, amino, hydroxyl, cyano group, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, halo C
1-4Alkyl, halo C
1-4Alkoxyl group, carbamyl C
1-4Alkyl, amino-sulfonyl C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, C
1-4Alkyl-carbonyl, C
1-4Alkyl amine group formyl radical, C
1-4Alkyl sulphonyl, C
1-4Alkyl amine group alkylsulfonyl, C
1-4Alkyl sulphinyl, C
1-4Alkyl amine group sulfinyl, two (C
1-4Alkyl) amido.
Another technical scheme of the present invention such as the described compound of general formula (II), its pharmacy acceptable salt or its isomer:
Wherein: the Ar representative is replaced or unsubstituted phenyl by 1～5 substituting group, and described substituting group is selected from hydrogen atom, fluorine atom, chlorine atom, bromine atoms, hydroxyl, cyano group or trifluoromethyl;
R
1, R
1', R
3, R
3' represent hydrogen atom;
R
2Representative
Perhaps
Middle Q representative
Perhaps
R
4Representative
The Z representative
Perhaps
The Z representative
The time, R
6Represent NR
11R
11', R wherein
11With R
11' independently represent hydrogen atom, C respectively
1-4Alkyl, methyl carbonyl methylene radical, cyclopropyl or R
11With R
11' be interconnected to form the saturated or unsaturated monocyclic groups of 5-6 unit or 6 yuan of saturated and cyclic groups,
R
9' represent hydrogen atom, perhaps R
9' and R
11' be interconnected to form the unsaturated nitrogen heterocyclic ring of 5-6 unit,
R
5, Z and R
11Be interconnected to form the saturated or unsaturated nitrogen heterocyclic ring of 5-6 unit,
The Z representative
The time, R
5With R
6Be interconnected to form
R
1' and R
5Be interconnected to form the saturated or undersaturated nitrogen heterocyclic ring of 5-6 unit and piperazine ring carry out thick with.
Further preferred compound is:
Wherein: the Ar representative is replaced or unsubstituted phenyl by 1～5 substituting group, and described substituting group is selected from hydrogen atom, fluorine atom, chlorine atom, bromine atoms, hydroxyl, cyano group or trifluoromethyl;
R
1, R
1', R
3, R
3' represent hydrogen atom;
R
2Representative
Perhaps
Middle R
5Represent hydrogen atom or methyl,
The Z representative
Perhaps
The Z representative
The time, R
6Represent NR
11R
11', R wherein
11With R
11' independently represent hydrogen atom respectively, methyl, propyl group, methyl carbonyl methylene radical, cyclopropyl or R
11With R
11' be interconnected to form
R
9' represent hydrogen atom, perhaps R
9' and R
11' be interconnected to form
R
5, Z and R
11Be interconnected to form
The Z representative
The time, R
5With R
6Be interconnected to form
R
1' and R
5Interconnect the thick and following structure of formation of back and piperazine ring
" halogen atom " of the present invention is meant fluorine atom, chlorine atom, bromine atoms, iodine atom etc.
" 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, 1-ethyl propyl, 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 etc.
" C of the present invention
1-6Alkoxyl group " be methoxyl group, oxyethyl group, propoxy-, butoxy pentyloxy, isopentyl, 2-methyl butyl, neo-pentyl, hexyloxy etc.
" cycloalkyl " of the present invention is 1-methyl-2-methyl-propyl, cyclopropyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl etc.
" C of the present invention
2-6Thiazolinyl " be meant that the carbonatoms that contains two keys is straight or branched or the cyclic thiazolinyl of 2-6, for example can be vinyl, 1-propenyl, 2-propenyl, 1-butylene base, crotyl, pentenyl, hexenyl, cyclopropenyl radical, cyclopentenyl, cyclohexenyl, cyclohexadiene etc.
" C of the present invention
2-6Alkynyl " be meant and contain straight or branched or the cyclic alkynyl that the triple-linked carbonatoms is 2-6, for example can be ethynyl, 1-proyl, ethyl acetylene base, 2-butyne base, pentynyl, hexin base, cyclopropyne base, cyclobutyne base, ring pentynyl, hexamethylene alkynyl etc.
" aryl " of the present invention be meant aromatic ring for example the phenyl of phenyl, replacement (for example benzyl, styroyl) and thick and aromatic nucleus naphthyl etc. for example.
" containing 0-4 the first cyclic group of heteroatomic 3-8 " of the present invention comprises (1) and do not contain the first cyclic group of heteroatomic 3-8, is selected from cyclopropane, tetramethylene, hexanaphthene, suberane, cyclooctane, cyclobutene, cyclopentenes, tetrahydrobenzene, cyclopentadiene, cyclohexadiene or phenyl etc.; (2) contain 1-4 the first cyclic group of heteroatomic 3-8, be selected from ethylenimine, the 2H-ethylenimine, diazacyclo propane, 3H-diazacyclo propylene, azetidine, 1, the 2-diazetidine, azete, 1, the 2-diazetine, the pyrroles, pyrrolin, tetramethyleneimine, imidazoles, 4, the 5-glyoxalidine, imidazolidine, pyrazoles, 4, the 5-pyrazoline, pyrazolidine, 1,2, the 3-triazole, 1,2, the 4-triazole, tetrazolium, pyridine, the 2-pyridone, the 4-pyridone, piperidines, pyridazine, pyrimidine, pyrazine, piperazine, 1,2, the 3-triazine, 1,2, the 4-triazine, 1,3, the 5-triazine, 1,2,4, the 5-tetrazine, the nitrogen heterocyclic heptantriene, 1,2-diazacyclo heptantriene, 1,3-diazacyclo heptantriene, 1,4-diazacyclo heptantriene, the nitrogen heterocyclic octatetraene, 1,4-dihydro-1,4-diazacyclo sarohornene etc., preferred pyrroles, pyridine, oxyethane, dioxirane, thiirane, trimethylene oxide, 1, the 2-dioxetane, Thietane, 1,2-dithia cyclobutene, furans, dihydrofuran, tetrahydrofuran (THF), thiophene, 2, the 5-dihydro-thiophene, tetramethylene sulfide, 1, the 3-dioxolane, 1,2-dithia cyclopentenes, 1, the 3-dithiolane, the 2H-pyrans, the 2H-pyran-2-one, 3,4-dihydro 2H-pyrans, 5,6-dihydro 2H-pyrans, the 4H-pyrans, tetrahydropyrans, 4H-pyrans-4-ketone, 1, the 4-Dioxin, 1,4-dithia cyclohexadiene, 1, the 4-oxathiin, 1, the 4-dioxane, 1, the 3-dioxane, 1, the 3-oxathiane, oxepin, thia cycloheptatriene or 1,4-dioxane sarohornene etc.
" heterocyclic radical " of the present invention for containing 1-4 the first cyclic group of heteroatomic 3-8, wherein 3-8 unit cyclic group as hereinbefore defined.
Particularly preferred compound chemistry title of the present invention and structural formula are as follows:
Chemical name: N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(N, N-dimethyl guanidine radicals) formimino] piperazine, be called for short compound 1, structural formula is as follows:
Chemical name: N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-(guanidine radicals formimino) piperazine, be called for short compound 2, structural formula is as follows:
N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(1-propyl group-1-cyclopropyl guanidine radicals) formimino] piperazine, be called for short compound 3, structural formula is as follows:
N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[[1-(piperidines-1-yl) amidino] formimino] piperazine, be called for short compound 4, 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 raw material 3 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 compound shown in step 7 formula (I)
Add 10% HCl-ethanol in reaction flask, raw material 4 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.Reaction solution is decompressed to dried back with after the methylene dichloride dissolving, be warming up to backflow, 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 pH with sig water under ice bath be 9, separate out solid filtering, water, ethyl acetate washing promptly get compound shown in the formula (I) successively.
Ar in the above reaction equation, R
1, R
1', R
3, R
3' and R
2The 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, copper, ferrous, manganese, bivalent manganese etc., the basic cpd of preferred especially ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium.
Compound contains one or more asymmetric centers shown in the formula (I), thereby can be used as racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.Compound has asymmetric center shown in the formula (I), 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 the while of compound shown in these other medicines and the formula (I) or in succession by a kind of approach and with its usual amounts administration.During administration simultaneously, be preferably the medicinal compositions that contains the unit dosage form of compound shown in described other medicines and the formula (I).Can with compound drug combination shown in the formula (I) 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;
(l) anti-obesity compound, for example Phenfluoramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y 5 inhibitor and beta 3 adrenoreceptor agonists;
(m) ileal bile acid transfer protein inhibitor; With
(n) be used for the medicine of inflammation, for example acetylsalicylic acid, non-steroidal anti-inflammatory drug, glucocorticosteroid, sulphur nitrogen sulphur pyridine and epoxidase 2 are selected inhibitor.
Above-mentioned unite comprise compound of the present invention not only with a kind of other active compound and also with the associating of two or more other active compounds.Non-limiting example comprises that the have formula compound of (I) and two or more are selected from the associating of the active compound of biguanides, sulfonylurea, HMG-CoA reductase inhibitor, PPAR agonist, PTP-1B inhibitor, other DPP-IV inhibitor and anti-obesity compound.
The weight ratio of compound and second kind of activeconstituents can change shown in the formula (I), 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 and other medicines shown in the formula (I) generally between 200: 1 to about 1: 200, is preferably between about 20: 1 to about 1: 20.The drug combination of compound and other activeconstituents shown in the formula (I) 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 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 studies show that of the defective mouse of DPP-IV: 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) metabolic syndrome X, 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 the dipeptidyl peptidase IV inhibitor that contains guanidine radicals 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).
The dipeptidyl peptidase IV inhibitor that contains guanidine radicals 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) the present invention's dipeptidyl peptidase IV inhibitor of containing guanidine radicals has good security and tolerance in vivo, and incidence rate of adverse reaction reduces;
(3) 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: The compounds of this invention 1-4, self-control, its chemical name and structural formula are as mentioned before;
Reference substance: sitagliptin phosphate, Vildagliptin, 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, Vildagliptin, add the DMSO dissolving, fully mixing is made into 100mM.Then with DMSO with above-mentioned mother liquor stepwise dilution to 10mM, 1mM, 100 μ M, 10 μ M.Get above-mentioned solution 4 μ L, add the damping fluid of 396 μ L, fully mixing is made into 100 μ M, 10 μ M, 1 μ M, 100nM.
1, fluorescent method detects the restraining effect to DPP-IV:
Get 5 μ L normal mouse serum, add the testing compound and the 24 μ L MgCl of 1 μ L different concns
2Damping fluid, preincubate 5 minutes in the room temperature behind the mixing, add 10 μ L, 100 μ M reaction substrates and 20 μ L damping fluids then, carry out fluorometric assay (excitation wave 380nm/ transmitted wave 460nm) behind the lucifuge mixing, measured 1 time every 3 minutes, add 25% acetate, 40 μ L termination reactions in the time of the 20th minute, the room temperature lucifuge was placed after 5 minutes, carried out fluorometric assay once more.
2, the fluorescent method detection compound is to the restraining effect of DPP-7:
Damping fluid (pH 5.5) with the cacodylate of the BSA of 0.1mg/mL and 100mM is a reaction solution, and the Nle-Pro-AMC of 5 μ M is that substrate and 1 μ L compound are 15 minutes (exciting light and wavelength of transmitted light are respectively 360nm and 460nm) of 37 ℃ of reactions.
3, the fluorescent method detection compound is to the restraining effect of DPP-8:
With the BSA of 0.1mg/mL and the sodium phosphate buffer of 50mM (pH 8.0) is reaction solution, and the Ala-Pro-7-amino-4-trifluormethylcoumarin of 100 μ M is that substrate and 1 μ L compound react 15 minutes (exciting light and wavelength of transmitted light are respectively 400nm and 505nm) at 37 ℃.
4, the fluorescent method detection compound is to the restraining effect of DPP-9:
With the BSA of 0.1mg/mL and the Tris/HCl damping fluid of 100mM (pH 7.4) is reaction solution, and the Gly-Pro-AMC of 100 μ M is that substrate and 1 μ L compound react 30 minutes (exciting light and wavelength of transmitted light are respectively 360nm and 460nm) at 37 ℃.
Experimental result and conclusion:
Table 1 The compounds of this invention is to activity and the selectivity of DPP-IV
By table 1 as seen, compare with blank, The compounds of this invention, sitagliptin phosphate, Vildagliptin all have active preferably to DPP-IV; Compare with sitagliptin phosphate, The compounds of this invention 1-3 is better active to DPP-IV's; Compare with Vildagliptin, 1,2 and 4 couples of DPP-7 of The compounds of this invention have selectivity preferably; And differing multiple, the selectivity of the The compounds of this invention 3 and the 4 couples of DPP-IV and DPP-7 is respectively 60 times and 40 times, Vildagliptin differs 100 times to the selectivity of DPP-IV and DPP-7, as seen The compounds of this invention 3 and 4 selectivity are poor slightly than Vildagliptin, and the selectivity of the compound 1 and the 2 couples of DPP-IV and DPP-7 is better.In general, The compounds of this invention 1 and 2 activity data are better, and the activity data of The compounds of this invention 3 and 4 is a little bit poorer slightly.
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 1N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(N, N-dimethyl
Guanidine radicals) formimino]
The preparation of piperazine
Step 1, (5S)-3,6-dimethoxy-5-sec.-propyl-2-(2,4, the 5-trifluoro) benzyl-2, the preparation of 5-dihydro pyrazine
Under the nitrogen protection, in the reaction flask of 250mL, add (2S)-(+)-3; 6-dimethoxy-2-sec.-propyl-2,5-dihydro pyrazine 18.4g (100mmol), tetrahydrofuran (THF) 300mL are added dropwise to n-Butyl Lithium 48mL (120mmol then in-78 ℃, 30min; 2.5N), stir 30min.Be added dropwise to 2,4 then, the tetrahydrofuran (THF) cold soln 100mL of 5-three fluorine-based benzyl chloride 19.8g (110mmol) ,-78 ℃ of stirring reaction 5h.Add entry 200mL cancellation reaction under-78 ℃, reaction solution concentrates, and residuum adds ethyl acetate and 1N hydrochloric acid, divide water-yielding stratum, use ethyl acetate extraction three times, merge organic layer, salt is washed, anhydrous sodium sulfate drying, concentrating under reduced pressure, silicagel column purifying (eluent is the mixed solution of ethyl acetate and hexanaphthene) gets i.e. (5S)-3 of thick compound, 6-dimethoxy-5-sec.-propyl-2-(2,4, the 5-trifluoro) benzyl-2,5-dihydro-pyrazine 24g, yield: 73.4%.
The preparation of step 2, (R)-N-2-(tertbutyloxycarbonyl)-3-(2,4, the 5-trifluorophenyl) alanine methyl ester
With (5S)-3,6-dimethoxy-5-sec.-propyl-2-(2,4, the 5-trifluoro) benzyl-2,5-dihydro pyrazine 23.0g (70mmol) is dissolved in the 100mL acetonitrile, drips the hydrochloric acid 100mL of 1N then, stirring at room 24h.Add methyl alcohol, be concentrated into driedly, this operates triplicate.And then repeat once with toluene, white solid.This solid slowly adds triethylamine 100g with methylene dichloride 400mL dissolving back, and then slowly is added dropwise to (Boc)
2O 24g (110mmol).Stirring at room 8h, the solid that the filtering reaction generates, filtrate is diluted with ethyl acetate, and HCl solution and the saturated brine with 1N washs respectively, anhydrous magnesium sulfate drying, the silicagel column purifying, eluent is the mixed solution of acetonitrile and sherwood oil, obtains white solid, both got (R)-N-2-(tertbutyloxycarbonyl)-3-(2,4, the 5-trifluorophenyl)-alanine methyl ester 10.1g, yield: 43.3%.
The preparation of step 3, (R)-N-2-(tertbutyloxycarbonyl)-3-(2,4, the 5-trifluorophenyl) L-Ala
Add tetrahydrofuran (THF) 200mL and water 100mL in (R)-N-2-(tertbutyloxycarbonyl)-3-(2,4, the 5-trifluorophenyl)-alanine methyl ester 10.0g (30mmol), the ice bath cooling is added dropwise to 2.2g (90mmol) lithium hydroxide, reaction solution stirring at room 15h then.Concentrating under reduced pressure, the residuum acetic acid ethyl dissolution is transferred pH to 6.0 with the hydrochloric acid of 1N, sodium bicarbonate and saturated common salt washing, anhydrous magnesium sulfate drying.Concentrating under reduced pressure gets (R)-N-2-(tertbutyloxycarbonyl)-3-(2,4, the 5-trifluorophenyl)-L-Ala 7.7g, yield: 80.3%.
Step 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 6.4g (20mmol), ether 150mL adds triethylamine 2.5g (25mmol) and isobutyl chlorocarbonate 4mL then under-30 ℃, finish,-30 ℃ of stirring reaction 30min, add the ethyl acetate solution that contains diazomethane 4.2g (100mL), 0 ℃ of following stirring reaction 1h of reaction solution, the acetate quencher of excessive diazomethane then.Mixed solution dilutes with ethyl acetate, saturated sodium bicarbonate and salt water washing, anhydrous magnesium sulfate drying, be evaporated to dried white solid (R)-3-[(tertbutyloxycarbonyl) amino]-1-diazonium-4-(2,4, the 5-trifluorophenyl) butyl-2-ketone 6.0g, yield is 88.2%.
Step 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 5.1g (15mmol) is dissolved among the methyl alcohol 300mL, is cooled to-30 ℃, adds diisopropyl ethyl amine 7.1g (45mmol) 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 0.6g (25mmol) lithium hydroxide reaction solution stirring at room 16h.With the ethyl acetate dilution, anhydrous magnesium sulfate drying is used in saturated sodium bicarbonate and salt washing behind the concentration of reaction solution, concentrates to such an extent that white solid is (R)-3-[(tertbutyloxycarbonyl) amino]-4-(2,4, the 5-trifluorophenyl) butyric acid 2.7g, yield: 54.2%.
Step 6, (R)-1-[3-(tertbutyloxycarbonyl) amino-4-(2,4, the 5-trifluorophenyl)] preparation of butyryl piperazine
Under room temperature, throw (R)-3-[(tertbutyloxycarbonyl) amino]-4-(2,4, the 5-trifluorophenyl) butyric acid 2.7g (8mmol), HOBT (1-hydroxy benzo triazole) 1.34g (10mmol), DMF100mL, add DCC (dicyclohexylcarbodiimide) 6.7g (25mmol) then, stirring at room reaction 1h.Cross and filter out the solid that reaction generates, filtrate continuation adds in the reaction flask, adds piperazine 6.9g (80mmol), heats up 60 ℃ and stirs 3h, reaction is finished, add 300mL water, separate out solid, with methyl alcohol and ethyl acetate mixed solution recrystallization, get (R)-1-[3-(tertbutyloxycarbonyl) amino-4-(2,4, the 5-trifluorophenyl)] butyryl piperazine 2.3g, yield is 72.1%.
Step 7, N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-preparation of N '-[(N, N-dimethyl guanidine radicals) formimino] piperazine
HCl-ethanol 50mL, the cyano group dimethylguanidine 0.7g (6mmol) of adding 10% in reaction flask, in stirring at room 2h, add ethanol 100mL dissolving again after removing solvent under reduced pressure, slowly add (R)-1-[3-(tertbutyloxycarbonyl) amino-4-(2 then in batches, 4, the 5-trifluorophenyl)] butyryl piperazine 2.0g (5mmol) refluxes to stir and spends 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 pH to 9 with sodium hydrogen carbonate solution under ice bath, separate out solid filtering, successively water, ethyl acetate washing; get crude product; get white solid N-[(R with ethyl alcohol recrystallization)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(N; N-dimethyl guanidine radicals) formimino] piperazine 0.7g, yield is 34.6%.
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)
1H?NMR(300MHz，CD
3OD)：δ8.49(s，2H)，7.39～7.51(m，1H)，7.21～35(m，1H)，3.82～3.96(m，1H)，3.73～3.54(m，8H)，3.54～3.71(m，2H)，3.01～3.14(m，6H)，2.75～3.92(m，2H).
Embodiment 2N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-preparation of N '-(guanidine radicals formimino) piperazine
Step 7 in preparation method's reference example 1; throw dicyanodiamide 0.5g (6mmol); (R)-1-[3-(tertbutyloxycarbonyl) amino-4-(2; 4; the 5-trifluorophenyl)] butyryl piperazine 2.0g (5mmol) gets N-[(R)-3-amino-4-(2,4; the 5-trifluorophenyl)-the 1-butyryl radicals]-N '-(guanidine radicals formimino) piperazine 1.5g, yield is 76.1%.
Molecular formula: C
16H
22F
3N
7O
Molecular weight: 385.39
Ultimate analysis: measured value: C:49.72%; H:5.87%; F:14.48; N:25.25%
Theoretical value: C:49.86%; H:5.75%; F:14.79; N:25.44%
Mass spectrum (m/z): 386 (M+1)
1H?NMR(300MHz，CD
3OD)：δ7.21～7.42(m，2H)，3.76～3.96(m，1H)，3.55～3.79(m，8H)，3.01～3.17(m，2H)，2.65～2.86(m，2H).
Embodiment 3N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(1-propyl group-1-cyclopropyl guanidine radicals) imines first
Base] preparation of piperazine
Step 7 in preparation method's reference example 1; throw 1-propyl group-1-cyclopropyl 3-dicyanodiamide 1.0g (6mmol); (R)-1-[3-(tertbutyloxycarbonyl) amino-4-(2; 4; the 5-trifluorophenyl)] butyryl piperazine 2.0g (5mmol) gets N-[(R)-3-amino-4-(2,4; the 5-trifluorophenyl)-and the 1-butyryl radicals] N '-(guanidine radicals formimino) piperazine 0.6g, yield is 26.7%.
Molecular formula: C
22H
32F
3N
7O
Molecular weight: 467.53
Ultimate analysis: measured value: C:56.38%; H:6.72%; F:14.01; N:20.75%
Theoretical value: C:56.52%; H:6.90%; F:12.19; N:20.97%
Mass spectrum (m/z): 468 (M+1)
1H?NMR(300MHz，CD
3OD)：δ7.37～7.13(m，2H)，3.92～3.71(m，1H)，3.79～3.61(m，8H)，3.59～3.42(m，3H)，3.18～3.01(m，2H)，2.95～3.73(m，2H)，1.67～1.42(m，6H)，1.12(t，3H).
Embodiment 4N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[[1-(piperidines-1-yl) amidino] imines first
Base] preparation of piperazine
Step 7 in preparation method's reference example 1; throw 1-(N-cyano group amidino) piperidines 0.9g (6mmol); (R)-1-[3-(tertbutyloxycarbonyl) amino-4-(2; 4; the 5-trifluorophenyl)] butyryl piperazine 2.0g (5mmol) gets N-[(R)-3-amino-4-(2,4; the 5-trifluorophenyl)-the 1-butyryl radicals]-N '-[[1-(piperidines-1-yl) amidino] formimino] piperazine 0.4g, yield is 19.5%.
Molecular formula: C
21H
30F
3N
7O
Molecular weight: 453.5
Ultimate analysis: measured value: C:55.48%; H:6.81%; F:12.34; N:21.43%
Theoretical value: C:55.62%; H:6.67%; F:12.57; N:21.62%
Mass spectrum (m/z): 454 (M+1)
1H?NMR(300MHz，CD
3OD)δ：7.36～7.12(m，2H)，3.92～3.61(m，1H)，3.78～3.47(m，12H)，3.21～2.97(m，2H)，2.89～2.61(m，2H)，1.62～1.37(m，6H)。
With reference to above-mentioned preparation method, also prepared following compound:
| Chemical name | Molecular formula | Molecular weight | Mass spectrum (m/e) |
| N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(5-N, N-dimethylamino)-[1,3,4]-triazole-2-yl] piperazine | ??C 18H 24F 3N 7O | ??411.4 | ??412 |
| N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[[(2-imido grpup-tetrahydrochysene)-1H-pyrimidine-1-yl] formimino] piperazine | ??C 19H 26F 3N 7O | ??425.5 | ??426 |
| N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[[(N-propyl group-2-ketone) guanidine radicals] formimino] piperazine | ??C 19H 26F 3N 7O 2 | ??441.5 | ??442 |
| N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(N-cyclopropyl guanidine radicals) formimino] piperazine | ??C 19H 26F 3N 7O | ??425.5 | ??426 |
| N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[[1-(pyrroles-1-yl) amidino] formimino] piperazine | ??C 20H 24F 3N 7O | ??435.5 | ??436 |
| N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[N-(imidazoles-2-yl) amidino] piperazine | ??C 18H 22F 3N 7O | ??409.4 | ??410 |
| N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(ring Valerolactim-1-yl) formimino] piperazine | ??C 19H 24F 3N 5O 2 | ??411.4 | ??412 |
| N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[[1-(3-azabicyclic [3.1.0] hexane-3-yl) amidino] formimino] piperazine | ??C 21H 28F 3N 7O | ??451.5 | ??452 |
| N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[[1-(tetramethyleneimine-1-yl) amidino] formimino] piperazine | ??C 20H 28F 3N 7O | ??439.5 | ??440 |
| Chemical name | Molecular formula | Molecular weight | Mass spectrum (m/e) |
| N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-([1,3,4]-triazole-2-yl) piperazine | ??C 16H 19F 3N 6O | ??368.4 | ??369 |
| N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-(imidazoles-2-yl) piperazine | ??C 17H 20F 3N 5O | ??367.4 | ??368 |
| 2-(N, N-dimethyl methyl amidino groups)-3-imido grpup-7-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-1,2,5,6,8,9-six hydrogen imidazos [1,5-α] pyrazine | ??C 19H 26F 3N 7O | ??425.5 | ??426 |
| N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(N, N, N '-trimethylammonium guanidine radicals) formimino] piperazine | ??C 19H 28F 3N 7O | ??427.5 | ??428 |
| 2-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-6-imido grpup-7-(N, N-dimethyl methyl amidino groups)-1,3,4,5,7,8,9,10-octahydro pyrazine is [1,2-f] pyrimidine also | ??C 20H 28F 3N 7O | ??439.5 | ??440 |
| N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-(tetrazolium-5-yl) piperazine | ??C 15H 18F 3N 7O | ??369.3 | ??370 |
| N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(N, N-dimethyl guanidine radicals) sulphomethyl] piperazine | ??C 18H 25F 3N 6OS | ??430.5 | ??431 |
The preparation of embodiment 5 The compounds of this invention tablets
1, prescription:
Prescription 1
Compound 1 125g
Starch 190g
Hydroxypropylcellulose 40g
Microcrystalline Cellulose 45g
The 50% aqueous ethanolic solution 95g of 1%HPMC
Micropowder silica gel 3g
Magnesium Stearate 2g
?????????????????????????????????????
Prepare 1000 altogether
Prescription 2
Compound 2 50g
Starch 200g
Hydroxypropylcellulose 50g
Microcrystalline Cellulose 55g
The 50% aqueous ethanolic solution 140g of 1%HPMC
Micropowder silica gel 3g
Magnesium Stearate 2g
????????????????????????????????????????
Prepare 1000 altogether
Prescription 3
Compound 3 25g
Starch 225g
Hydroxypropylcellulose 50g
Microcrystalline Cellulose 55g
The 50% aqueous ethanolic solution 140g of 1%HPMC
Micropowder silica gel 3g
Magnesium Stearate 2g
??????????????????????????????????????????
Prepare 1000 altogether
Prescription 4
Compound 4 100g
Starch 200g
Hydroxypropylcellulose 50g
Microcrystalline Cellulose 45g
The 50% aqueous ethanolic solution 100g of 1%HPMC
Micropowder silica gel 3g
Magnesium Stearate 2g
??????????????????????????????????????????
Prepare 1000 altogether
2, preparation technology: take by weighing raw material and auxiliary material according to prescription, raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively; Raw material, starch, hydroxypropylcellulose and Microcrystalline Cellulose are mixed, add mixer-granulator, add 50% aqueous ethanolic solution of 1%HPMC, stirred 15 minutes, make particle; Particle is dried being lower than under 60 ℃ the condition; Dry good particle adds micropowder silica gel and Magnesium Stearate, and whole grain mixes; Sampling, the work in-process chemical examination; According to the definite sheet weight sheet of chemical examination; Finished product is examined entirely, the packing warehouse-in.
Claims (10)
1. the compound shown in the general formula (I), its pharmacy acceptable salt or its isomer:
Wherein: the Ar representative is replaced or unsubstituted phenyl by 1～5 substituting group;
R
1, R
1', R
3, R
3' independently represent hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, sulfonic acid amido, halogen atom, C respectively
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyl-carbonyl, aryl, cycloalkyl, heterocyclic radical, aryl C
1-6Alkyl, cycloalkyl C
1-6Alkyl, heterocyclic radical C
1-6Alkyl, C
1-6The alkyl amine group formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6The alkyl amine group alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6The alkyl sulfenyl amido, C
1-6Alkyl sulphinyl, C
1-6The alkyl amine group sulfinyl, two (C
1-6Alkyl) amido, two (C
1-6Alkyl) amido formyl radical, two (C
1-6Alkyl) amido alkylsulfonyl, two (C
1-6Alkyl) amido sulfinyl, C
1-6Alkyl oxygen carbonyl or C
1-6Alkyl carbonyl oxy;
R
1With R
3Perhaps R
1' and R
3' be interconnected to form the saturated or undersaturated 0-4 of containing the heteroatoms ring-type group of 3-8 unit and piperazine ring carry out thick with, the first saturated or undersaturated 0-4 of containing the heteroatoms ring-type group of described 3-8 do not comprise phenyl ring, described heteroatoms is selected from N, O or S;
R
2Represent hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, sulfonic acid amido, halogen atom, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyl-carbonyl, aryl, cycloalkyl, 5-member heterocyclic ring containing nitrogen base, aryl C
1-6Alkyl, cycloalkyl C
1-6Alkyl or
Work as R
2Represent hydrogen atom, C
1-6Alkyl, aryl or aryl C
1-6Alkyl, R
1, R
3All be not H;
Middle Q representative-S-,-O-,
-SO-or-NR
7-, wherein X represent sulphur atom or-NR
7', R
7With R
7' independently represent hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, sulfonic acid amido, halogen atom, C respectively
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyl-carbonyl, aryl, cycloalkyl, heterocyclic radical, aryl C
1-6Alkyl, cycloalkyl C
1-6Alkyl, heterocyclic radical C
1-6Alkyl, C
1-6Alkylamidoalkyl, C
1-6The alkyl amine group alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6The alkyl sulfenyl amido, C
1-6The alkyl amine group sulfinyl, two (C
1-6Alkyl) amido, two (C
1-6Alkyl) amido formyl radical, two (C
1-6Alkyl) amido alkylsulfonyl, two (C
1-6Alkyl) amido sulfinyl, C
1-6Alkyl oxygen carbonyl, C
1-6Alkyl carbonyl oxy ,-COR
8,-SO
2R
8Perhaps-SOR
8, R wherein
8Be C
1-6Alkyl, aryl, aryl C
1-6Alkyl, cycloalkyl, cycloalkyl C
1-6Alkyl, heterocyclic radical or heterocyclic radical C
1-6Alkyl,
R
4Represent hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, sulfonic acid amido, halogen atom, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyl-carbonyl, aryl, cycloalkyl, heterocyclic radical, aryl C
1-6Alkyl, cycloalkyl C
1-6Alkyl, heterocyclic radical C
1-6Alkyl or
Z representative-S-,-O-,
-SO
2-,-SO-or-NR
9-, Y represention oxygen atom wherein, sulphur atom or-NR
9',
R wherein
5, R
6, R
9With R
9' independently represent hydrogen atom, carboxyl, amino, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, sulfonic acid amido, halogen atom, C respectively
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyl-carbonyl, aryl, cycloalkyl, heterocyclic radical, aryl C
1-6Alkyl, cycloalkyl C
1-6Alkyl, heterocyclic radical C
1-6Alkyl, C
1-6Alkylamidoalkyl, C
1-6The alkyl amine group alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6The alkyl sulfenyl amido, C
1-6The alkyl amine group sulfinyl, two (C
1-6Alkyl) amido formyl radical, two (C
1-6Alkyl) amido alkylsulfonyl, two (C
1-6Alkyl) amido sulfinyl, C
1-6Alkyl oxygen carbonyl, C
1-6Alkyl carbonyl oxy or R
5With R
6Be interconnected to form the 5-6 member heterocyclic ring containing nitrogen;
R
6Perhaps represent NR
11R
11', R wherein
11With R
11' independently represent C respectively
1-6Alkyl, C
1-6The alkyl-carbonyl alkyl, cycloalkyl, heterocyclic radical, perhaps R
11With R
11' be interconnected to form saturated or the unsaturated and cyclic group of saturated or unsaturated monocyclic groups of 3-8 unit or 6-10 unit;
R
5, Z and R
11Be interconnected to form the saturated or undersaturated 0-4 of containing the heteroatoms ring-type group of 3-8 unit, R
11' and R
9' be interconnected to form the saturated or undersaturated 0-4 of containing the heteroatoms ring-type group of 3-8 unit;
R
1' and R
5Be interconnected to form the saturated or undersaturated 1-4 of containing of a 5-8 unit heteroatomic cyclic group and piperazine ring carry out thick with, described heteroatoms is selected from N, O or S;
Wherein said C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl, C
2-6Alkynyl further is substituted, and substituting group is selected from hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, sulfonic group, carbamyl, amino-sulfonyl or halogen atom;
Described phenyl, aryl, heterocyclic radical or 3-8 unit cyclic group are further replaced by W, and wherein W is hydrogen atom, carboxyl, amino, hydroxyl, nitro, cyano group, halogen atom, formamido-, formamyl, amino-sulfonyl, sulfonic group, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, carbamyl C
1-6Alkyl, amino-sulfonyl C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyl-carbonyl, C
1-6Alkyl amine group formyl radical, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, C
1-6Alkyl sulphinyl, two (C
1-6Alkyl) amido, C
1-6Alkyl amine group sulfinyl, two (C
1-6Alkyl) amido formyl radical, two (C
1-6Alkyl) amido alkylsulfonyl, two (C
1-6Alkyl) amido sulfinyl, C
1-6Alkyl oxygen carbonyl or C
1-6Alkyl carbonyl oxy.
2. the compound shown in claim 1, its pharmacy acceptable salt or its isomer:
Wherein: the Ar representative is replaced or unsubstituted phenyl by 1～5 substituting group;
R
1, R
1', R
3, R
3' represent hydrogen atom;
R
2Representation carboxy, amino, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, halogen atom, C
1-4Alkoxyl group, C
2-4Thiazolinyl, C
2-4Alkynyl, C
1-4Alkyl-carbonyl, cycloalkyl, 5-member heterocyclic ring containing nitrogen base, cycloalkyl C
1-4Alkyl or
R
4Represent hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl, C
2-4Alkynyl, C
1-4Alkyl-carbonyl, aryl, cycloalkyl, heterocyclic radical, aryl C
1-4Alkyl, cycloalkyl C
1-4Alkyl, heterocyclic radical C
1-4Alkyl or
During the Y represention oxygen atom, R
5With R
6Be interconnected to form the 5-6 member heterocyclic ring containing nitrogen,
Y representative-NR
9' time, R
6Represent hydrogen atom, carboxyl, amino, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl, C
2-4Alkynyl, C
1-4Alkyl-carbonyl, aryl, cycloalkyl, heterocyclic radical, aryl C
1-4Alkyl, cycloalkyl C
1-4Alkyl, heterocyclic radical C
1-4Alkyl, C
1-6Alkylamidoalkyl, C
1-6The alkyl amine group alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6The alkyl sulfenyl amido, C
1-6The alkyl amine group sulfinyl, two (C
1-4Alkyl) amido formyl radical, two (C
1-4Alkyl) amido alkylsulfonyl, two (C
1-4Alkyl) amido sulfinyl, C
1-4Alkyl oxygen carbonyl, C
1-4Alkyl carbonyl oxy or NR
11R
11', R wherein
11With R
11' independently represent hydrogen atom, C respectively
1-4Alkyl, C
1-4The alkyl-carbonyl alkyl, cycloalkyl, heterocyclic radical or R
11With R
11' be interconnected to form saturated or the unsaturated and cyclic group of saturated or unsaturated monocyclic groups of 5-6 unit or 6-10 unit;
R
5, Z and R
11Be interconnected to form the saturated or undersaturated 0-4 of containing the heteroatoms ring-type group of 5-6 unit, R
11' and R
9' be interconnected to form the saturated or undersaturated 0-4 of containing the heteroatoms ring-type group of 5-6 unit;
R
1' and R
5Be interconnected to form the 5-6 unit heteroatomic cyclic group of the saturated or undersaturated 1-4 of containing and piperazine ring carry out thick with, described heteroatoms is selected from N, O or S;
Wherein said C
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl, C
2-4Alkynyl further is substituted, and substituting group is selected from hydrogen atom, carboxyl, amino, cyano group, hydroxyl or halogen atom;
Described phenyl, aryl, heterocyclic radical or 5-6 unit cyclic group are further replaced by W, and wherein W is hydrogen atom, carboxyl, amino, hydroxyl, cyano group, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, halo C
1-4Alkyl, halo C
1-4Alkoxyl group, carbamyl C
1-4Alkyl, amino-sulfonyl C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, C
1-4Alkyl-carbonyl, C
1-4Alkyl amine group formyl radical, C
1-4Alkyl sulphonyl, C
1-4Alkyl amine group alkylsulfonyl, C
1-4Alkyl sulphinyl, C
1-4Alkyl amine group sulfinyl, two (C
1-4Alkyl) amido.
3. the described compound of claim 2, its pharmacy acceptable salt or its isomer shown in the formula (II):
Wherein: the Ar representative is replaced or unsubstituted phenyl by 1～5 substituting group, and described substituting group is selected from hydrogen atom, fluorine atom, chlorine atom, bromine atoms, hydroxyl, cyano group or trifluoromethyl;
R
1, R
1', R
3, R
3' represent hydrogen atom;
R
2Representative
Perhaps
Middle R
5Represent hydrogen atom or C
1-4Alkyl,
The Z representative
Perhaps
The Z representative
The time, R
6Represent NR
11R
11', R wherein
11With R
11' independently represent hydrogen atom, C respectively
1-4Alkyl, methyl carbonyl methylene radical, cyclopropyl or R
11With R
11' be interconnected to form the saturated or unsaturated monocyclic groups of 5-6 unit or 6 yuan of saturated and cyclic groups,
R
9' represent hydrogen atom, perhaps R
9' and R
11' be interconnected to form the unsaturated nitrogen heterocyclic ring of 5-6 unit,
R
5, Z and R
11Be interconnected to form the saturated or unsaturated nitrogen heterocyclic ring of 5-6 unit,
The Z representative
The time, R
5With R
6Be interconnected to form
R
1' and R
5Be interconnected to form the saturated or undersaturated nitrogen heterocyclic ring of 5-6 unit and piperazine ring carry out thick with.
4. compound as claimed in claim 3, its pharmacy acceptable salt or its isomer:
Wherein: the Ar representative is replaced or unsubstituted phenyl by 1～5 substituting group, and described substituting group is selected from hydrogen atom, fluorine atom, chlorine atom, bromine atoms, hydroxyl, cyano group or trifluoromethyl;
R
1, R
1', R
3, R
3' represent hydrogen atom;
R
2Representative
Perhaps
The Z representative
Perhaps
The Z representative
The time, R
6Represent NR
11R
11', R wherein
11With R
11' independently represent hydrogen atom respectively, methyl, propyl group, methyl carbonyl methylene radical, cyclopropyl or R
11With R
11' be interconnected to form
R
9' represent hydrogen atom, perhaps R
9' and R
11' be interconnected to form
R
5, Z and R
11Be interconnected to form
The Z representative
The time, R
5With R
6Be interconnected to form
R
1' and R
5Interconnect the thick and following structure of formation of back and piperazine ring
5. compound as claimed in claim 4; its pharmacy acceptable salt or its isomer; wherein compound is selected from; N-[(R)-3-amino-4-(2; 4; the 5-trifluorophenyl)-the 1-butyryl radicals]-N '-[(N; N-dimethyl guanidine radicals) formimino] piperazine; N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-(guanidine radicals formimino) piperazine; N-[(R)-3-amino-4-(2; 4, the 5-trifluorophenyl)-the 1-butyryl radicals]-N '-[(1-propyl group-1-cyclopropyl guanidine radicals) formimino] piperazine, and N-[(R)-3-amino-4-(2; 4, the 5-trifluorophenyl)-the 1-butyryl radicals]-N '-[[1-(piperidines-1-yl) amidino] formimino] piperazine.
6. as the described compound pharmacy acceptable salt of the arbitrary claim of claim 1～5, it is characterized in that comprising organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts by the salt of pharmaceutically acceptable, non-toxic bases or acid preparation.
7. comprise the pharmaceutical composition that the described compound of the arbitrary claim of claim 1～5, its pharmacy acceptable salt or its isomer and other active pharmaceutical ingredients are formed.
8. make pharmaceutically acceptable arbitrary formulation as the described compound of the arbitrary claim of claim 1～5, its pharmacy acceptable salt or its isomer and one or more pharmaceutical carriers and/or thinner.
9. pharmaceutical composition as claimed in claim 8 is characterized in that containing the described compound of the arbitrary claim of claim 1～5, its pharmacy acceptable salt or its isomer 10mg～10g as essential activeconstituents.
10. as the described compound of the arbitrary claim of claim 1～5, its pharmacy acceptable salt or its isomer, it is characterized in that being used for preparing the application of the medicine of treatment, control or prevent diabetes, non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia, insulin resistance.
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