CN101781274A - Acylated piperazine dipeptidyl peptidase IV inhibitor - Google Patents
Acylated piperazine dipeptidyl peptidase IV inhibitor Download PDFInfo
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Abstract
The invention belongs to the technical field of medicament, and in particular relates to an acylated piperazine dipeptidyl peptidase IV inhibitor shown in a general formula (I), pharmaceutically acceptable salts thereof or isomers thereof, wherein Ar, R1, R1', R3, R3' and R2 are defined in specifications. The invention also relates to methods for preparing the compounds, medicinal compositions containing the compounds and the application of the compounds in the preparation of medicaments for treating and/or preventing diabetes, insulin-independent diabetes, hyperglycemia and insulin resistance.
Description
1, technical field
The invention belongs to medical technical field; be specifically related to acylated piperazine dipeptidyl peptidase IV inhibitor, its pharmacy acceptable salt or its isomer; the preparation method of these compounds; the pharmaceutical composition that contains these compounds, and these compounds treat and/or prevent application in the medicine of diabetes, non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia, insulin resistance in preparation.
2, background technology
Diabetes are a kind of whole body chronic metabolic disease that normal level causes that exceed owing to blood sugar is out of control.Substantially be divided into four classes, comprise: I type (insulin-dependent), II type (non-insulin-depending type), other type and gestational diabetes.I type and type II diabetes belong to primary diabetes mellitus, are modal two kinds of forms, are caused by the h and E factor interaction.The cause of disease of diabetes is very complicated, but is because Regular Insulin is absolute or relative the shortage after all, or insulin resistant.Its characteristics are because the absolute or relative deficiency of Regular Insulin and target cell to the susceptibility reduction of Regular Insulin, cause the metabolism disorder of carbohydrate, protein, fat, ionogen and water.
In recent years, because the rhythm of life that the change of growth in the living standard, dietary structure, day are becoming tight and few moving mode of life of sitting etc. all multifactor more, whole world onset diabetes rate increases rapidly, and diabetes have become the chronic disease of the third-largest serious threat human health after tumour, cardiovascular pathological changes.Present global diabetic subject has surpassed 1.2 hundred million people, China patient people the second in the world of living in groups.According to statistics, the diabetic subject that made a definite diagnosis of China reaches more than 4,000 ten thousand, and with annual 1000000 speed increase.Wherein, 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.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.
Dipeptide amido peptidase TV (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 diabetes B (being non insulin dependent diabetes).The DPP-IV inhibitor is the medicine of a new generation's treatment diabetes.It has protected the activity of GLP-1 and GIP etc. by suppressing the DPP-IV activity, promotes insulin secretion, has the effect of protection β cell function in the time of lowering blood glucose, and can not cause side effects such as hypoglycemia and weight increase.
The DPP-IV inhibitor is the medicine of a new generation's treatment diabetes.The DPP-IV inhibitor sitagliptinphosphate (sitagliptin phosphate) of present listing, structural formula is as follows, DPP-IV had selectivity, the activity that does not suppress DPP-7, 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 sitagliptin phosphate is desirable not enough.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:
The invention provides 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-, 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
2Represent hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, amino-sulfonyl, formamido-, 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
Work as R
2Represent hydrogen atom, C
1-6Alkyl, aryl, heterocyclic radical, aryl C
1-6Alkyl or heterocyclic radical C
1-6During alkyl, R
1, R
3All be not H,
R
4Represent hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, halogen atom, C
1-6Alkoxyl group, C
1-6Alkylthio, C
2-6Thiazolinyl, C
2-6Alkynyl, 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, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, halogen atom, C respectively
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyl-carbonyl, C
1-6Alkyl amine group, 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
10,-SO
2R
10Or-SOR
10, R wherein
10Be C
1-6Alkyl, aryl, aryl C
1-6Alkyl, cycloalkyl, cycloalkyl C
1-6Alkyl, heterocyclic radical or heterocyclic radical C
1-6Alkyl, or R
5With R
6Be interconnected to form the saturated or undersaturated 1-4 of containing heteroatomic cyclic group of 3-8 unit;
R
1With R
2Or R
1' and R
2Be interconnected to form 3-8 unit saturated contain 1-4 heteroatomic cyclic group and piperazine ring carry out thick with, described heteroatoms is selected from N, O or S;
R
1With R
3Or 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;
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, 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.
Another embodiment of the present invention comprises the described compound of formula II, 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 be selected from hydrogen atom or C
1-4Alkyl;
R
2Representation carboxy, amino, hydroxyl, amino-sulfonyl, formamido-, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl, cycloalkyl, heterocyclic radical, aryl C
1-4Alkyl, cycloalkyl C
1-4Alkyl, heterocyclic radical C
1-4Alkyl or
Work as R
2Represent C
1-4Alkyl, heterocyclic radical, aryl C
1-4Alkyl, heterocyclic radical C
1-4During alkyl, R
1, R
3All be not H, R
4Represent amino, cyano group, hydroxyl, formamido-, halogen atom, C
1-4Alkoxyl group, C
2-4Thiazolinyl, aryl C
1-4Alkyl, cycloalkyl C
1-4Alkyl, heterocyclic radical C
1-4Alkyl or
Z representative-S-,-O-,
-SO
2-or-SO-, Y represention oxygen atom wherein, sulphur atom or-NR
9',
R wherein
5, R
6With R
9' independently represent hydrogen atom, amino, hydroxyl, formamyl, halogen atom, C respectively
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl, C
1-4Alkyl amine group, aryl, cycloalkyl, heterocyclic radical, aryl C
1-4Alkyl, cycloalkyl C
1-4Alkyl, heterocyclic radical C
1-4Alkyl, C
1-4Alkylamidoalkyl ,-COR
10,-SO
2R
10Or-SOR
10, R wherein
10Be C
1-4Alkyl, aryl, aryl C
1-4Alkyl, cycloalkyl, cycloalkyl C
1-4Alkyl, heterocyclic radical or heterocyclic radical C
1-4Alkyl, or R
5With R
6Be interconnected to form the saturated or undersaturated 1-4 of containing heteroatomic cyclic group of 3-8 unit;
R
1With R
2Or R
1' with R2 be interconnected to form 3-8 unit saturated contain 1-4 heteroatomic cyclic group and piperazine ring carry out thick with, described heteroatoms is selected from N, O or S;
R
1With R
3Or 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;
Wherein said C
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl further is substituted, and substituting group is selected from hydrogen atom, carboxyl, amino, cyano group, hydroxyl, 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, cyano group, halogen atom, formamido-, formamyl, amino-sulfonyl, 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 or C
1-4The alkyl amine group sulfinyl.
Further preferred compound is:
Wherein: the Ar representative is replaced or unsubstituted phenyl by 1～5 M, and wherein, M is independently selected from:
(1) fluorine atom,
(2) chlorine atom,
(3) bromine atoms,
(4) CF
3, or
(5)CN；
R
1, R
1', R
3, R
3' independently be selected from hydrogen atom, methyl or ethyl;
R
2Representation carboxy, amino, hydroxyl, amino-sulfonyl, formamido-or
R
4Represent amino, hydroxyl, formamido-, halogen atom or
Z representative-S-,-O-,-SO
2-or-SO-,
R wherein
5With R
6Independently represent hydrogen atom, amino, hydroxyl, methyl, ethyl respectively, propyl group, sec.-propyl, butyl, methoxyl group, oxyethyl group, the methyl amido, ethyl amido, propyl group amido, sec.-propyl amido, phenyl, the 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-chloro-phenyl-, the 4-chloro-phenyl-, 3,4-dichlorophenyl, 4-aminomethyl phenyl, thiazole, thiadiazoles, piperazine, pyrroles, piperidines, pyridine or imidazoles.
Again one the step preferred compound be:
Wherein: Ar is selected from:
(1) phenyl,
(2) 2,4 difluorobenzene base,
(3) 2,5-difluorophenyls,
(4) 2,4, the 5-trifluorophenyl,
(5) 2-fluoro-4-(trifluoromethyl) phenyl,
(6) 2,4 dichloro benzene base, or
(7) 2-cyano group-4, the 5-difluorophenyl;
R
1, R
1', R
3, R
3' independently be selected from hydrogen atom or methyl;
R
2Representation hydroxy, amino-sulfonyl or
R
4Represent amino, hydroxyl, halogen atom or
Z representative-O-or-SO
2-,
R wherein
5, R
6Independently represent hydrogen atom, hydroxyl, methyl, ethyl respectively, sec.-propyl, amino, methyl amido, ethyl amido, the sec.-propyl amido, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-chloro-phenyl-, 4-chloro-phenyl-, 3,4-dichlorophenyl, 4-aminomethyl phenyl, thiazole, thiadiazoles, piperazine, pyridine or imidazoles.
" halogen atom " of the present invention is fluorine atom, chlorine atom, bromine atoms or iodine atom.
" C of the present invention
1-6Alkyl " be the straight chain of 1-6 carbon atom or the alkyl of side chain; comprise methyl; ethyl; n-propyl; sec.-propyl; normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, the 2-methyl butyl, neo-pentyl, the 3-amyl group, n-hexyl, isohexyl, the 3-methyl amyl, the 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, the 2-ethyl-butyl, 1-methyl-2-methyl-propyl, cyclopropyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl etc.
" C of the present invention
1-6Alkoxyl group " be the straight chain of 1-6 carbon atom or the alkoxyl group of side chain; comprise methoxyl group; oxyethyl group; positive propoxy; isopropoxy; n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, 2-methyl butoxy, neopentyl oxygen, the 3-pentyloxy, positive hexyloxy, different hexyloxy, 3-methyl pentyloxy, 2-methyl pentyloxy, 1-methyl pentyloxy, 3,3-dimethyl butoxy, 2,2-dimethyl butoxy, 1,1-dimethyl butoxy, 1,2-dimethyl butoxy, 1,3-dimethyl butoxy, 2,3-dimethyl butoxy, 2-ethyl butoxy, 1-methyl-2-methyl propoxy-, the ring propoxy-, cyclobutoxy group, 1-methyl cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
" C of the present invention
2-6Thiazolinyl " be meant that the carbonatoms that contains two keys is the straight chain of 2-6; and side chain or cyclic thiazolinyl for example can be vinyl; the 1-propenyl; 1-propyl group-2-alkene; 2-propenyl; 1-butylene base, 1-butyl-2-alkene, 1-butyl-3-alkene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1-methyl isophthalic acid-propyl group-2-alkene, 2-methyl isophthalic acid-propyl group-2-alkene, the 1-pentenyl, 1-amyl group-2-alkene, 1-amyl group-3-alkene, 1-amyl group-4-alkene, 1-methyl isophthalic acid-butenyl, the 2-methyl-1-butene thiazolinyl, the 3-methyl-1-butene base, 1-methyl isophthalic acid-butyl-2-alkene, 2-methyl-1-butene base-2-alkene, 3-methyl isophthalic acid-butyl-2-alkene, 1-methyl isophthalic acid-butyl-3-alkene, 2-methyl-1-butene base-3-alkene, 3-methyl isophthalic acid-butyl-3-alkene, the 1-hexenyl, 1-hexyl-2-alkene, 1-hexyl-3-alkene, 1-hexyl-4-alkene, 1-hexyl-5-alkene, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, the 4-methyl-1-pentene base, 1-methyl-1-pentene base-2-alkene, 2-methyl-1-pentene base-2-alkene, 3-methyl-1-pentene base-2-alkene, 4-methyl-1-pentene base-2-alkene, 1-methyl-1-pentene base 3-alkene, 2-methyl-1-pentene base-3-alkene, 3-methyl-1-pentene base-3-alkene, 4-methyl-1-pentene base-3-alkene, 1-methyl-1-pentene base-4-alkene, 2-methyl-1-pentene base-4-alkene, 3-methyl-1-pentene base-4-alkene, 4-methyl-1-pentene base-4-alkene, the cyclobutene base, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl etc.
" C of the present invention
2-6Alkynyl " be meant and contain the straight chain that the triple-linked carbonatoms is 2-6; side chain or cyclic alkynyl for example can be ethynyl; the 1-proyl; 1-propyl group-2-alkynes; ethyl acetylene base; 1-butyl-2-alkynes, 1-butyl-3-alkynes, the 1-pentynyl, 1-amyl group-2-alkynes, 1-amyl group-3-alkynes, 1-amyl group-4-alkynes, 3-methyl isophthalic acid-butynyl, 1-methyl isophthalic acid-butyl-2-alkynes, 1-methyl isophthalic acid-butyl-3-alkynes, 2-methyl-1-butene base-3-alkynes, 1-hexin base, 1-hexyl-2-alkynes, 1-hexyl-3-alkynes, 1-hexyl-4-alkynes, 1-hexyl-5-alkynes, 3-methyl-1-pentene alkynyl, 4-methyl-1-pentene alkynyl, 1-methyl-1-pentene base-2-alkynes, 4-methyl-1-pentene base-2-alkynes, 1-methyl-1-pentene base-3-alkynes, 2-methyl-1-pentene base-3-alkynes etc.
" aryl " of the present invention be meant the aromatic series cyclic group for example the phenyl of phenyl, replacement (for example benzyl, styroyl) and thick and fragrant cyclic group 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, pentamethylene, 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, 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, the thia cycloheptatriene, 1,4-dioxane sarohornene oxazole, 4,5-dihydro-oxazole isoxazole, 4, the 5-dihydro-isoxazole, 1,2, the 3-oxadiazole, thiazole, 4, the 5-thiazoline, isothiazole, 1,2, the 3-thiadiazoles, 2H-1, the 2-oxazine, 4H-1, the 2-oxazine, 6H-1, the 2-oxazine, 2H-1, the 3-oxazine, 4H-1, the 3-oxazine, 5,6-dihydro-4H-1, the 3-oxazine, 6H-1, the 3-oxazine, 2H-1, the 4-oxazine, 4H-1, the 4-oxazine, 2H-1, the 3-thiazine, 4H-1, the 3-thiazine, 5,6-dihydro-4H-1, the 3-thiazine, 6H-1, the 3-thiazine, 2H-1, the 4-thiazine, 4H-1,4-thiazine or tetrazolium 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 is as follows:
Chemical name: N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(to the Methyl benzenesulfonyl amido) formyl radical] 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 '-[(p-chloro benzenesulfonamide base) formyl radical] piperazine, be called for short compound 2, structural formula is as follows:
Chemical name: N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(benzene sulfonamido) formyl radical] piperazine, be called for short compound 3, structural formula is as follows:
Chemical name: N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(N-piperazine sulfoamido) formyl radical] piperazine, be called for short compound 4, structural formula is as follows:
Chemical name: N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[[(thiazole-5-yl) sulfoamido] formyl radical] piperazine, be called for short compound 5, structural formula is as follows:
Chemical name: N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(isopropylamine base sulfoamido) formyl radical] piperazine, be called for short compound 6, structural formula is as follows:
Chemical name: N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(to the fluorobenzene sulfoamido) formyl radical] piperazine, be called for short compound 7, 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 drips Boc
2O, 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
Throw compd E under room temperature, HOBT adds DCC then, the stirring at room reaction.Cross to filter out and react the solid that generates, filtrate continuation adds in the reaction flask, adds raw material 3, the 60 ℃ of stirrings that heat up, and reaction finishes, and adds entry, separates out solid, with methyl alcohol and ethyl acetate mixed solution recrystallization, gets compound F 17-hydroxy-corticosterone.
The preparation of step 7 Compound I
Add 10% HCl-ethanol in reaction flask, raw material 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.With after the methylene dichloride dissolving, be warming up to backflow after reaction solution is decompressed to and does, be added dropwise to 5N hydrochloric acid under the vigorous stirring, behind the reaction 1h, reduce to room temperature, tell organic layer, water layer is transferred pH 9 with sig water under ice bath, separate out solid filtering, water, ethyl acetate washing promptly get Compound I successively.
Ar in the above reaction equation, R
1, R
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 or inorganic base salts.Organic acid comprises acetate, Phenylsulfonic acid, phenylformic acid, tosic acid, butene dioic acid, (2R, 3R)-2,3-dyhydrobutanedioic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, pamoic acid, pantothenic acid, succsinic acid, tartrate etc., preferred especially Phenylsulfonic acid, tosic acid, butene dioic acid, citric acid, toxilic acid, fumaric acid, tartrate.Mineral acid comprises Hydrogen bromide, spirit of salt, nitric acid, sulfuric acid, phosphoric acid etc., preferred especially Hydrogen bromide, spirit of salt, sulfuric acid, phosphoric acid.Organic bases comprises primary, the second month in a season and tertiary amine, be substituted amine and comprise naturally occurring replacement amine, cyclammonium and basic ion exchange resin, be selected from arginine, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, meglumine, glucosamine, Histidine, Hai Baming, isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, polyamides resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.Mineral alkali comprises the basic cpd of ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminium, iron, copper, ferrous, manganese, bivalent manganese etc., the basic cpd of preferred especially ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium.
The compounds of this invention contains one or more asymmetric centers, thereby can be used as racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.The compounds of this invention has asymmetric center, and each will independently produce two optical isomers this class asymmetric center, and scope of the present invention comprises all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.The present invention includes all isomeric forms of these compounds.Part of compounds of the present invention can exist with tautomeric forms, and it has the tie point of different hydrogen by one or more double-bond shifts.For example, ketone and its enol form are the keto-enol tautomerism bodies.Each tautomer and composition thereof all is included in the compound of the present invention.
Compound of the present invention can be united with one or more other medicines, and is more safer or more effective than single medicine.Can be with these other medicines and formula (I) compound simultaneously or in succession by a kind of approach and with its usual amounts administration.During administration simultaneously, be preferably the medicinal compositions of the unit dosage form that contains described other medicines and formula (I) compound.Can with formula (I) compound drug combination, respectively administration or in same medicinal compositions other activeconstituents of administration include, but are not limited to:
(a) other pepx IV inhibitor;
(b) insulin sensitisers comprises: (i) PPAR gamma agonist, as glitazones (for example troglitazone, pioglitazone, englitazone, MCC-555, Rosiglitazone etc.) and other PPAR part, comprise PPAR α/γ economic benefits and social benefits agonist, as KRP-297, with PPAR alfa agonists such as Fenofibric Acid derivative (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (ii) biguanides, for example N1,N1-Dimethylbiguanide and phenformin and (iii) albumen network propylhomoserin phosphoesterase-1B (PTP-1B) inhibitor;
(c) Regular Insulin or insulin-mimickers;
(d) sulfonylurea and other Regular Insulin succagoga, for example tolbutamide and Glipizide, meglitinide and related drugs;
(e) alpha-glucosidase inhibitor (for example acarbose)
(f) glucagon receptor antagonist;
(g) GLP-1, GLP-1 stand-in and GLP-1 receptor stimulant;
(h) GLP and GLP stand-in and GLP receptor stimulant;
(i) PACAP, PACAP stand-in and PACAP acceptor 3 agonists;
(j) cholesterol reducing agent, (i) HMG-CoA reductase inhibitor (lovastatin for example, Simvastatin, Pravastatin, fluvastatin, Ah appropriate cuts down his spit of fland, Rivastatin, itavastatin, superstatin and other statins), (ii) inner complex (Colestyramine, the dialkyl aminoalkyl derivative of colestipol and crosslinked dextran), (iii) nicotinic alcohol, nicotinic acid or other salt, (iv) PPAR alfa agonists, Fenofibric Acid derivative (gemfibrozil for example, clofibrate, fenofibrate and bezafibrate), (v) PPAR α/γ economic benefits and social benefits agonist, for example KRP-297; (vi) cholesterol absorption inhibitor, for example β-Gu Zaichun and ezetimibe, (vii) ethanoyl CoA, chole-sterol acyltransferase inhibitor, for example avasimibe and (viii) antioxidant, for example probucol;
(k) PPAR delta agonists;
(l) anti-obesity compound, for example Phenfluoramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y 5 inhibitor and beta 3 adrenoreceptor agonists;
(m) ileal bile acid transfer protein inhibitor; With
(n) be used for the medicine of inflammation, for example acetylsalicylic acid, non-steroidal anti-inflammatory drug, glucocorticosteroid, sulphur nitrogen sulphur pyridine and epoxidase 2 are selected inhibitor.
Above-mentioned unite comprise compound of the present invention not only with a kind of other active compound and also with the associating of two or more other active compounds.Non-limiting example comprises that the have formula compound of (I) and two or more are selected from the associating of the active compound of biguanides, sulfonylurea, HMG-CoA reductase inhibitor, PPAR agonist, PTP-1B inhibitor, other DPP-IV inhibitor and anti-obesity compound.
The weight ratio of The compounds of this invention and second kind of activeconstituents can change, and it depends on the effective dose of various compositions.In general, with the effective dose that adopts separately.Therefore for example when compound of the present invention and other medicines drug combination, the weight ratio of The compounds of this invention and other medicines generally between about 200: 1 to about 1: 200, is preferably between about 20: 1 to about 1: 20.The drug combination of The compounds of this invention and other activeconstituents generally also can be in above-mentioned scope, but under each situation, should use the effective dose of each activeconstituents.
The present invention is claimed arbitrary compound recited above, its pharmacy acceptable salt or its isomer of comprising further; pharmaceutical composition with one or more pharmaceutical carriers and/or thinner; for clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral preparations or injection.Wherein contain the compound 0.01g～10g shown in the general formula (I) of physiology significant quantity, preferred 0.02g～5g can be described activeconstituentss such as 0.025g, 0.05g, 0.075g, 0.125g, 0.25g, 0.5g, 0.6g, 0.75g, 0.8g, 0.9g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g.Can be by 1～4 time arrangement every day, give described compound 1～2 time preferred every day.
The arbitrary compound of the present invention, its pharmacy acceptable salt or its isomer, can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1mL, 2mL, 5mL, 10mL, 20mL, 50mL, 100mL, 200mL, 250mL, 500mL etc., and wherein large volume (generally the being not less than 100mL) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
Dipeptidase-IV (DPP-IV) is a kind of cell surface protein that relates to the various biological function.It has tissue distribution (intestines, kidney, liver, pancreas, placenta, thymus gland, spleen, epithelial cell, blood vessel endothelium, lymph and myelocyte, serum) and tissue and cell type expression level widely clearly.DPP-IV is confirmed as T type cell-stimulating mark CD26, and it can be at immunoregulatory in a large number, the endocrine and neurologic peptide of external cracking.This shows that there is the effect of diving in this peptase in the various diseases process of human body or other animal.
Pharmacological evaluation proves that the DPP-IV inhibitor can significantly suppress the DPP-IV activity, and protection GLP-1 activity promotes insulin secretion, reduces hyperglycemic-glycogenolytic factor after the meal, and lowering blood glucose improves anti-sugar amount; And have the active effect of protection GIP, can improve the concentration of GIP, strengthen the effect of its insulin secretion accelerating; The DPP-IV inhibitor can also improve glycolipid metabolism, prevents weight increase.
The present invention also provides new acylated piperazine dipeptidyl peptidase IV inhibitor to be used for the treatment of, to control in preparation or has prevented purposes in the medicine of following disease.
Type II diabetes and relative disease, now full confirmation GLP-1 and GIP can be by DPP-IV quick inactivatings in vivo, therefore DPP-IV inhibitor of the present invention can be used for treating a large amount of illnesss that type II diabetes and treatment or prevention are followed type II diabetes, comprises metabolic syndrome X, reactive hypoglycemia and glycosuria sexual abnormality lipidemia.Following disease, illness is relevant with type II diabetes with symptom, therefore can treat by the methods of treatment that adopts The compounds of this invention, control or prevention in some cases: (1) hyperglycemia, (2) low dextrose tolerance, (3) insulin resistance, (4) obesity, (5) matter fat disease, (6) unusual lipidemia, (7) hyperlipidaemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high HDL level, (12) atherosclerosis and sequela thereof, (13) vascular restenosis, (14) irritable bowel syndrome, (15) enteritis comprises cRohnShi disease and ulcerative colitis, (16) retinopathy, (17) ephrosis, (18) neuropathy, (19) X syndromes, the hyperandrogenism (polycystic ovary syndrome) of (20) ovary and the disease of other tool insulin resistance; And the growth hormone deficiency disease, damage of intestines, immunosuppressive action, HIV infects, hemopoietic, neuronal disease, brain tumor is invaded and is shifted benign prostatauxe, seminal fluid motility, oulitis, osteoporosis etc.
Acylated piperazine dipeptidyl peptidase IV inhibitor of the present invention is compared with immediate prior art, has the following advantages:
(1) acylated piperazine dipeptidyl peptidase IV inhibitor of the present invention can suppress the activity of DPP-IV (being responsible for the enzyme of degraded GLP-1) preferably, makes the interior GLP-1 level of body more stable;
(2) acylated piperazine dipeptidyl peptidase IV inhibitor of the present invention has good security and tolerance in vivo, and incidence rate of adverse reaction obviously reduces;
(3) acylated piperazine dipeptidyl peptidase IV inhibitor of the present invention has the advantage of DPP-IV inhibitor and sulfonylurea, has double effects.
(4) acylated piperazine dipeptidyl peptidase 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 1 The compounds of this invention
Trial-product: compound 1～7, self-control, its chemical name and structural formula are as mentioned before.
Reference substance: sitagliptin phosphate: self-control, its chemical name and structural formula are as mentioned before.
Vildagliptin: self-control.
Experimental technique:
Accurately take by weighing trial-product and reference substance sitagliptin phosphate and 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 (pH5.5) with the cacodylate of the BSA of 0.1mg/mL and 100mM is a reaction solution, and the Nle-PRo-AMC of 5 μ M is that substrate and 1 μ L compound are 15 minutes (exciting light and wavelength of transmitted light are respectively 360nm and 460nm) of 37 ℃ of reactions.
3, the fluorescent method detection compound is to the restraining effect of DPP-8:
With the BSA of 0.1mg/mL and the sodium phosphate buffer of 50mM (pH8.0) is reaction solution, and the Ala-PRo-7-amino-4-tRifluoRmethylcoumaRin of 100 μ M is that substrate and 1 μ L compound react 15 minutes (exciting light and wavelength of transmitted light are respectively 400nm and 505nm) at 37 ℃.
4, the fluorescent method detection compound is to the restraining effect of DPP-9:
With the BSA of 0.1mg/mL and the TRis/HCl damping fluid (pH7.4) of 100mM is reaction solution, and the Gly-PRo-AMC of 100 μ M is that substrate and 1 μ L compound react 30 minutes (exciting light and wavelength of transmitted light are respectively 360nm and 460nm) at 37 ℃.
Experimental result and conclusion:
Table 1 The compounds of this invention is to activity and the selectivity of DPP-IV
By table 1 as seen, compare with blank, The compounds of this invention, sitagliptin phosphate, Vildagliptin all have active preferably to DPP-IV.
The specific activity Vildagliptin of 1 couple of DPP-IV of compound of the present invention omits; The too late Vildagliptin of the activity of compound 2 and 7 couples of DPP-IV of compound, but slightly better than sitagliptin phosphate; The selectivity of compound 1, compound 2 and compound 7 couples of DPP-7, DPP-8, DPP-9 is all suitable with sitagliptin phosphate, has good selectivity.
6 couples of DPP-IV of compound have active preferably, and are suitable with Vildagliptin; The activity of DPP-IV and DPP-7 and DPP-IV and DPP-8 is differed multiple be about 28 times and 36 times respectively, and Vildagliptin differs 43 times and more than 71 times to the activity of DPP-IV and DPP-7 and DPP-IV and DPP-8, and the selectivity of visible The compounds of this invention 6 is poor slightly than Vildagliptin.
Specific activity sitagliptin phosphate and the Vildagliptin of compound 3 and 5 couples of DPP-IV of compound are all poor; The activity of DPP-IV and DPP-7 is differed multiple be about 19 times and 31 times respectively, promptly the selectivity of compound 3 and compound 5 is not as good as Vildagliptin.
The activity of 4 couples of DPP-IV of compound is not as good as sitagliptin phosphate and Vildagliptin, and is all suitable with sitagliptin phosphate to the selectivity of DPP-7, DPP-8, DPP-9, promptly has good selectivity.
Therefore, from experimental result, compound 1, compound 2 and compound 7 are not only safe but also 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.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
Embodiment 1 N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(to the Methyl benzenesulfonyl amido) formyl radical]
The preparation of piperazine
Step 1, (2R, 5S)-2,5-dihydro-3,6-dimethoxy-2-[(2,4,5-trifluorophenyl) methyl]-preparation of 5-isopropylpyrazine
9.2g (50mmol) (2S)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine is dissolved in the 300mL tetrahydrofuran (THF), drips 24mL (60mmol, the hexane solution of n-Butyl Lithium 2.5N), insulated and stirred 30min then in-78 ℃, 30min.Drip 2,4 of 9.9g (55mmol) then, the 50mL tetrahydrofuran (THF) cold soln of 5-three fluorine-based benzyl chlorides ,-78 ℃ of stirring reaction 5h.-78 ℃ add down the 100mL shrend reaction of going out, reaction solution concentrates, and residuum adds ethyl acetate and 1N hydrochloric acid, divides water-yielding stratum, with ethyl acetate extraction three times, merge organic layer, salt is washed, anhydrous magnesium sulfate drying, concentrating under reduced pressure, silicagel column purifying (eluent is the mixed solution of ethyl acetate and hexanaphthene) gets 12g colloidal solid target compound, yield: 73.4%.
The preparation of step 2, (R)-N-2-(tertbutyloxycarbonyl)-3-(2,4, the 5-trifluorophenyl) alanine methyl ester
16.4g (50mmol) (2R, 5S)-2,5-dihydro-3,6-dimethoxy-2-[(2,4,5-trifluorophenyl) methyl]-the 5-isopropylpyrazine is dissolved in the 100mL acetonitrile, drips the hydrochloric acid of 100mL 1N then, add methyl alcohol behind the reaction solution stirring at room 24h, be concentrated into driedly, this operates triplicate.And then repeat once with toluene, solid.This solid slowly adds the triethylamine of 50g with 400mL methylene dichloride dissolving back, and then slowly is added dropwise to 24g (110mmol) Boc
2O.Reaction solution stirring at room 8h, the solid that the filtering reaction generates, filtrate is diluted with methylene dichloride, HCl solution and saturated brine with 1N washs respectively, anhydrous magnesium sulfate drying, silicagel column purifying, eluent are the mixed solution of acetonitrile and sherwood oil, obtain 10.5g solid target compound, yield: 63.3%.
The preparation of step 3, (R)-N-2-(tertbutyloxycarbonyl)-3-(2,4, the 5-trifluorophenyl) L-Ala
(R)-N-2-(tertbutyloxycarbonyl)-3-(2 of 10g (30mmol), 4,5-trifluorophenyl) adds the 200mL tetrahydrofuran (THF) in the alanine methyl ester, the ice bath cooling, be added dropwise to the 200mL aqueous solution of 2.15g (90mmol) lithium hydroxide then, reaction solution stirring at room 15h.Concentrating under reduced pressure, residuum acetic acid ethyl dissolution, saturated sodium bicarbonate and salt solution washing, anhydrous magnesium sulfate drying.Steaming desolventize the 7.7g solid, yield: 80.3%.
Step 4, (R)-3-[(tertbutyloxycarbonyl) amino]-preparation of 1-diazonium-4-(2,4, the 5-trifluorophenyl) butyl-2-ketone
(R)-N-2-(the tertbutyloxycarbonyl)-3-(2 that adds 8g (25mmol), 4, the 5-trifluorophenyl) L-Ala, the 150mL ether, then in-30 ℃ of triethylamine and 4mL isopropyl chlorocarbonates that add 3g (30mmol) down, finish,-30 ℃ of stirring reaction 30min, add the ethyl acetate solution that contains the 5.3g diazomethane then, add an amount of 1-methyl-3-nitro-1-nitrosoguanidine down in 0 ℃ and be dissolved in ether and 40% sodium hydroxide mixing solutions, 0 ℃ of following stirring reaction 20min of reaction solution, 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 7.6g solid target compound, yield: 88.2%.
Step 5, (R)-3-[(tertbutyloxycarbonyl) amino]-the butyro-preparation of 4-(2,4, the 5-trifluorophenyl)
With 13.7g (40mmol) (R)-the 3-[(tertbutyloxycarbonyl) amino]-1-diazonium-4-(2,4, the 5-trifluorophenyl) butyl-2-ketone is dissolved in the 300mL methyl alcohol, be cooled to-30 ℃ of silver benzoates that add 18.9g (120mmol) diisopropyl ethyl amine and 2.3g (10mmol), reaction solution rises to stirring at room 3h.Reaction is finished, and removes methyl alcohol under reduced pressure, and residuum dissolves with the 200mL methylene dichloride, filtering insoluble solid thing, and filtrate concentrates, and the silicagel column purifying obtains solid.This solid is dissolved in the 100mL tetrahydrofuran (THF), adds in the water of the 100mL that contains 1.8g (75mmol) lithium hydroxide reaction solution stirring at room 16h then.With ethyl acetate dilution, anhydrous magnesium sulfate drying use in saturated sodium bicarbonate and salt washing behind the concentration of reaction solution, concentrated 7.2g white solid compound, yield: 54.2%.
The preparation of step 6, (R)-3-(tertbutyloxycarbonyl) amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl piperazine
Under room temperature, throw (R)-3-[(tertbutyloxycarbonyl of 16.7g (50mmo1)) amino]-4-(2,4, the 5-trifluorophenyl) butyric acid, 6.8g (50mmol) HOBT (1-hydroxy benzo triazole), DMF 100mL, add 20g (75mmol) DCC (dicyclohexyl charcoal imide) then, stirring at room reaction 1h.Cross and filter out the solid that reaction generates, filtrate continuation adds in the reaction flask, adds 19.2g (100mmol) piperazine, heats up 60 ℃ and stirs 3h, reaction is finished, and adds 300mL water, separates out solid, with methyl alcohol and ethyl acetate mixed solution recrystallization, get product 14.5g, yield: 72.1%.
Step 7, N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl]-preparation of N '-[(to the Methyl benzenesulfonyl amido) formyl radical] piperazine
In reaction flask, add (R)-3-(tertbutyloxycarbonyl) amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl piperazine 18.1g (45mmol), after the dissolving of 100mL methylene dichloride, reduce temperature to 0～5 ℃.Slowly drip tolysulfonyl urea chloride 10.5g (45mmol), elevated temperature to 40 ℃, stirring reaction 6h.Be warming up to backflow again, be added dropwise to 40mL 5N hydrochloric acid under the vigorous stirring, behind the reaction 1h, reduce to room temperature, tell organic layer, water layer is transferred pH9 with sig water under ice bath, separates out solid filtering, successively water, ethyl acetate washing, get crude product, get product 16.9g with ethyl alcohol recrystallization, yield: 75.3%.
Molecular formula: C
22H
25F
3N
4O
4S
Molecular weight: 518.94
Ultimate analysis:
Measured value: C:53.15%; H:5.26%; F:11.22%; N:11.08%; S:6.22%
Theoretical value: C:53.00%; H:5.05%; F:11.43%; N:11.24%; S:6.43%
Mass spectrum (m/z): 499 (M+1)
1H-NMR(CD
3OD，300MHz)：
δ(ppm)：7.78-7.81(2H，d)；7.40-7.44(2H，d)；7.23-7.36(2H，m)；3.77-3.80(1H，s)；3.39-3.50(8H，m)；2.32-2.35(3H，s)；2.79-3.00(2H，d)；2.61-2.77(2H，m)
Embodiment 2 N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(p-chloro benzenesulfonamide base) formyl radical] piperazine
The preparation of piperazine
Step 7 in preparation method's reference example 1 is thrown (R)-3-(tertbutyloxycarbonyl) amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl piperazine 18.1g (45mmol), to chlorobenzene sulfonamido formyl chloride 11.4g (45mmol), gets product 18g, yield: 77.2%.
Molecular formula: C
21H
22ClF
3N
4O
4S
Molecular weight: 518.94
Ultimate analysis:
Measured value: C:49.33%; H:4.51%; Cl:6.92%; F:10.81%; N:10.75%; S:6.24%
Theoretical value: C:48.60%; H:4.27%; Cl:6.83%; F:10.98%; N:10.80%; S:6.18%
Mass spectrum (m/z): 519 (M+1)
1H-NMR(CDCl
3，300MHz)：
δ(ppm)：7.74-7.77(2H，d)；7.31-7.34(2H，d)；7.09-7.28(2H，m)；3.70-3.79(1H，s)；3.20-3.47(8H，m)；2.92-2.95(2H，d)；2.52-2.74(2H，m)
Embodiment 3 N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(benzene sulfonamido) formyl radical] piperazine
Preparation
Step 7 in preparation method's reference example 1 is thrown (R)-3-(tertbutyloxycarbonyl) amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl piperazine 18.7g (45mmol), and benzene sulfonamido formyl chloride 9.9g (45mmol) gets product 17.1g, yield: 78.4%.
Molecular formula: C
21H
23F
3N
4O
4S
Molecular weight: 484.49
Ultimate analysis:
Measured value: C:51.45%; H:4.82%; F:10.81%; N:10.45%; S:6.74%
Theoretical value: C:52.06%; H:4.78%; F:11.76%; N:11.56%; S:6.62%
Mass spectrum (m/z): 485 (M+1)
1H-NMR(CDCl
3，300MHz)：
δ(ppm)：7.89-7.93(2H，d)；7.43-7.49(3H，d)；7.24-7.35(2H，m)；3.82-3.83(1H，s)；3.39-3.54(8H，m)；3.02-3.04(2H，d)；2.64-2.79(2H，m)
Embodiment 4 N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(N-piperazine sulfoamido) formyl radical] piperazine
The preparation of piperazine
Step 7 in preparation method's reference example 1 is thrown (R)-3-(tertbutyloxycarbonyl) amino-5-(2,4, the 5-trifluorophenyl)-1-butyryl piperazine 2.1g (5mmol), (4-tert-butoxycarbonyl-piperazine-1-yl) sulfonamido formyl chloride 1.6g (5mmol) gets product 1.5g, yield: 60.4%.
Molecular formula: C
19H
27F
3N
6O
4S
Molecular weight: 492.52
Ultimate analysis:
Measured value: C:46.18%; H:5.74%; F:11.38%; N:16.86%; S:6.62%
Theoretical value: C:46.33%; H:5.53%; F:11.76%; N:11.56%; S:6.62%
Mass spectrum (m/z): 493 (M+1)
1H-NMR(CDCl
3，300MHz)：
δ(ppm)：7.09-7.28(2H，d)；3.71-3.79(1H，s)；3.20-3.47(8H，m)；2.92-2.95(2H，d)；2.52-2.74(2H，m)；2.45-2.69(2H，q)；1.91-1.94(1H，s)
Embodiment 5 N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[[(thiazole-5-yl) sulfoamido] formyl radical]
The preparation of piperazine
Step 7 in preparation method's reference example 1 is thrown (R)-3-(tertbutyloxycarbonyl) amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl piperazine 2.1g (5mmol), (thiazole-5-yl) sulfonamido formyl chloride 1.1g (5mmol) gets product 1.8g, yield: 71.3%.
Molecular formula: C
18H
20F
3N
5O
4S
2
Molecular weight: 491.51
Ultimate analysis:
Measured value: C:43.78%; H:4.26%; F:11.49%; N:14.06%; S:13.14%
Theoretical value: C:43.99%; H:4.10%; F:11.60%; N:14.25%; S:13.05%
Mass spectrum (m/z): 492 (M+1)
1H-NMR(CDCl
3，300MHz)：
δ(ppm)：9.13-9.15(1H，s)；7.75-7.78(1H，s)；7.28-7.09(2H，m)；3.72-3.81(1H，s)；3.20-3.47(8H，m)；2.92-2.95(2H，d)；2.52-2.74(2H，m)
Embodiment 6 N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(isopropylamine base sulfoamido) formyl radical]
The preparation of piperazine
Step 7 in preparation method's reference example 1 is thrown (R)-3-(tertbutyloxycarbonyl) amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl piperazine 2.1g (5mmol), and isopropylamine base sulfonamido formyl chloride 1.0g (5mmol) gets product 1.7g, yield: 73.5%.
Molecular formula: C
18H
26F
3N
5O
4S
Molecular weight: 465.49
Ultimate analysis:
Measured value: C:46.25%; H:5.82%; F:12.11%; N:14.91%; S:6.97%
Theoretical value: C:46.44%; H:5.63%; F:12.24%; N:15.05%; S:6.89%
Mass spectrum (m/z): 466 (M+1)
1H-NMR(CDCl
3，300MHz)：
δ(ppm)：7.09-7.28(2H，m)；3.70-3.79(1H，s)；3.20-3.49(9H，m)；2.90-2.93(2H，d)；2.52-2.74(2H，m)；1.91-1.94(6H，d)
Embodiment 7 N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(to the fluorobenzene sulfoamido) formyl radical] piperazine
The preparation of piperazine
Step 7 in preparation method's reference example 1 is thrown (R)-3-(tertbutyloxycarbonyl) amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl piperazine 18.1g (45mmol), to fluorobenzene sulfonamido formyl chloride 10.7g (45mmol), gets product 14g, yield: 61.7%.
Molecular formula: C
21H
22F
4N
4O
4S
Molecular weight: 502.48
Ultimate analysis:
Measured value: C:51.13%; H:4.49%; F:14.86%; N:10.92%; S:6.42%
Theoretical value: C:50.20%; H:4.41%; F:15.12%; N:11.15%; S:6.38%
Mass spectrum (m/z): 502 (M+1)
1H-NMR(CDCl
3，300MHz)：
δ(ppm)：7.81-7.85(2H，d)；7.25-7.29(2H，d)；7.11-7.30(2H，m)；3.72-3.81(1H，s)；3.22-3.49(8H，m)；2.93-2.96(2H，d)；2.54-2.77(2H，m)
With reference to above preparation method, can also prepare following compound
The preparation of example of formulations 1 The compounds of this invention tablet
1, prescription:
Prescription 1:
Compound 1 125g
Starch 200g
Hydroxypropylcellulose 40g
Microcrystalline Cellulose 45g
The 50% aqueous ethanolic solution 120g of 1%HPMC
Micropowder silica gel 3g
Magnesium Stearate 2g
Prepare 1000 altogether
Prescription 2:
Compound 2 50g
Starch 200g
Hydroxypropylcellulose 50g
Microcrystalline Cellulose 55g
The 50% aqueous ethanolic solution 100g of 1%HPMC
Micropowder silica gel 3g
Magnesium Stearate 2g
Prepare 1000 altogether
Prescription 3:
Compound 3 25g
Starch 225g
Hydroxypropylcellulose 50g
Microcrystalline Cellulose 55g
The 50% aqueous ethanolic solution 100g of 1%HPMC
Micropowder silica gel 3g
Magnesium Stearate 2g
Prepare 1000 altogether
2, preparation technology: take by weighing raw material and auxiliary material according to prescription, raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively; Raw material, starch, hydroxypropylcellulose and Microcrystalline Cellulose are mixed, add mixer-granulator, add 50% aqueous ethanolic solution of 1%HPMC, stirred 15 minutes, make particle; Particle is dried being lower than under 60 ℃ the condition; Dry good particle adds micropowder silica gel and Magnesium Stearate, and whole grain mixes; Sampling, the work in-process chemical examination; According to the definite sheet weight sheet of chemical examination; Finished product is examined entirely, the packing warehouse-in.
Claims (10)
1. 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-, 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
2Represent hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, amino-sulfonyl, formamido-, 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
Work as R
2Represent hydrogen atom, C
1-6Alkyl, aryl, heterocyclic radical, aryl C
1-6Alkyl or heterocyclic radical C
1-6During alkyl, R
1, R
3All be not H,
R
4Represent hydrogen atom, carboxyl, amino, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, halogen atom, C
1-6Alkoxyl group, C
1-6Alkylthio, C
2-6Thiazolinyl, C
2-6Alkynyl, 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, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, halogen atom, C respectively
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyl-carbonyl, C
1-6Alkyl amine group, 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
10,-SO
2R
10Or-SOR
10, R wherein
10Be C
1-6Alkyl, aryl, aryl C
1-6Alkyl, cycloalkyl, cycloalkyl C
1-6Alkyl, heterocyclic radical or heterocyclic radical C
1-6Alkyl, or R
5With R
6Be interconnected to form the saturated or undersaturated 1-4 of containing heteroatomic cyclic group of 3-8 unit;
R
1With R
2Or R
1' and R
2Be interconnected to form 3-8 unit saturated contain 1-4 heteroatomic cyclic group and piperazine ring carry out thick with, described heteroatoms is selected from N, O or S;
R
1With R
3Or 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;
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, 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 described compound of claim 1, 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;
R
1, R
1', R
3, R
3' independently be selected from hydrogen atom or C
1-4Alkyl;
R
2Representation carboxy, amino, hydroxyl, amino-sulfonyl, formamido-, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl, cycloalkyl, heterocyclic radical, aryl C
1-4Alkyl, cycloalkyl C
1-4Alkyl, heterocyclic radical C
1-4Alkyl or
Work as R
2Represent C
1-4Alkyl, heterocyclic radical, aryl C
1-4Alkyl, heterocyclic radical C
1-4During alkyl, R
1, R
3All be not H, R
4Represent amino, cyano group, hydroxyl, formamido-, halogen atom, C
1-4Alkoxyl group, C
2-4Thiazolinyl, aryl C
1-4Alkyl, cycloalkyl C
1-4Alkyl, heterocyclic radical C
1-4Alkyl or
Z representative-S-,-O-,
-SO
2-or-SO-, Y represention oxygen atom wherein, sulphur atom or-NR
9',
R wherein
5, R
6With R
9' independently represent hydrogen atom, amino, hydroxyl, formamyl, halogen atom, C respectively
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl, C
1-4Alkyl amine group, aryl, cycloalkyl, heterocyclic radical, aryl C
1-4Alkyl, cycloalkyl C
1-4Alkyl, heterocyclic radical C
1-4Alkyl, C
1-4Alkylamidoalkyl ,-COR
10,-SO
2R
10Or-SOR
10, R wherein
10Be C
1-4Alkyl, aryl, aryl C
1-4Alkyl, cycloalkyl, cycloalkyl C
1-4Alkyl, heterocyclic radical or heterocyclic radical C
1-4Alkyl, or R
5With R
6Be interconnected to form the saturated or undersaturated 1-4 of containing heteroatomic cyclic group of 3-8 unit;
R
1With R
2Or R
1' and R
2Be interconnected to form 3-8 unit saturated contain 1-4 heteroatomic cyclic group and piperazine ring carry out thick with, described heteroatoms is selected from N, O or S;
R
1With R
3Or 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;
Wherein said C
1-4Alkyl, C
1-4Alkoxyl group, C
2-4Thiazolinyl further is substituted, and substituting group is selected from hydrogen atom, carboxyl, amino, cyano group, hydroxyl, 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, cyano group, halogen atom, formamido-, formamyl, amino-sulfonyl, 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 or C
1-4The alkyl amine group sulfinyl.
3. compound as claimed in claim 2, its pharmacy acceptable salt or its isomer:
Wherein: the Ar representative is replaced or unsubstituted phenyl by 1～5 M, and wherein, M is independently selected from:
(1) fluorine atom,
(2) chlorine atom,
(3) bromine atoms,
(4) CF
3, or
(5)CN；
R
1, R
1', R
3, R
3' independently be selected from hydrogen atom, methyl or ethyl;
R
2Representation carboxy, amino, hydroxyl, amino-sulfonyl, formamido-or
R
4Represent amino, hydroxyl, formamido-, halogen atom or
Z representative-S-,-O-,-SO
2-or-SO-,
R wherein
5With R
6Independently represent hydrogen atom, amino, hydroxyl, methyl, ethyl respectively, propyl group, sec.-propyl, butyl, methoxyl group, oxyethyl group, the methyl amido, ethyl amido, propyl group amido, sec.-propyl amido, phenyl, the 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-chloro-phenyl-, the 4-chloro-phenyl-, 3,4-dichlorophenyl, 4-aminomethyl phenyl, thiazole, thiadiazoles, piperazine, pyrroles, piperidines, pyridine or imidazoles.
4. compound as claimed in claim 3, its pharmacy acceptable salt or its isomer:
Wherein: Ar is selected from:
(1) phenyl,
(2) 2,4 difluorobenzene base,
(3) 2,5-difluorophenyls,
(4) 2,4, the 5-trifluorophenyl,
(5) 2-fluoro-4-(trifluoromethyl) phenyl,
(6) 2,4 dichloro benzene base, or
(7) 2-cyano group-4, the 5-difluorophenyl;
R
1, R
1', R
3, R
3' independently be selected from hydrogen atom or methyl;
R
2Representation hydroxy, amino-sulfonyl or
R
4Represent amino, hydroxyl, halogen atom or
Z representative-O-or-SO
2-,
R wherein
5, R
6Independently represent hydrogen atom, hydroxyl, methyl, ethyl respectively, sec.-propyl, amino, methyl amido, ethyl amido, the sec.-propyl amido, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-chloro-phenyl-, 4-chloro-phenyl-, 3,4-dichlorophenyl, 4-aminomethyl phenyl, thiazole, thiadiazoles, piperazine, pyridine or imidazoles.
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)-1-butyryl radicals]-N '-[(to the Methyl benzenesulfonyl amido) formyl radical] piperazine,
N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(p-chloro benzenesulfonamide base) formyl radical] piperazine,
N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(benzene sulfonamido) formyl radical] piperazine,
N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(N-piperazine sulfoamido) formyl radical] piperazine,
N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[[(thiazole-5-yl) sulfoamido] formyl radical] piperazine,
N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(isopropylamine base sulfoamido) formyl radical] piperazine and
N-[(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-butyryl radicals]-N '-[(to the fluorobenzene sulfoamido) formyl radical] piperazine.
6. as the described compound pharmacy acceptable salt of the arbitrary claim of claim 1～5, it is characterized in that it being the salt for preparing by pharmaceutically acceptable, non-toxic bases or acid, comprise organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts.
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 0.01g～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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| CN109721555B (en) * | 2019-01-04 | 2023-10-20 | 广东东阳光药业股份有限公司 | Acylated piperazine compound and application thereof |
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