CN101410400B - Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes - Google Patents

Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes Download PDF

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CN101410400B
CN101410400B CN2007800108743A CN200780010874A CN101410400B CN 101410400 B CN101410400 B CN 101410400B CN 2007800108743 A CN2007800108743 A CN 2007800108743A CN 200780010874 A CN200780010874 A CN 200780010874A CN 101410400 B CN101410400 B CN 101410400B
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compound
dpp
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diabetes
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CN101410400A (en
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T·比夫图
A·E·韦伯
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Merck Sharp and Dohme LLC
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Schering Corp
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Abstract

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula (I) which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Description

Amino tetrahydro pyran as the dipeptidyl peptidase-IV inhibitors that is used for treating diabetes or prevention
Invention field
It is novel for dipeptidyl peptidase-IV enzyme inhibitors (" DPP-4 suppressor factor ") and can be used for wherein relating to the treatment of diseases of dipeptidyl peptidase-IV enzyme or the substituted-amino tetrahydropyrans of prevention to the present invention relates to; Said disease is such as mellitus, and diabetes B particularly.The invention still further relates to the pharmaceutical composition and these compounds and the application of compsn in the prevention of the disease that relates to the dipeptidyl peptidase-IV enzyme is perhaps treated that contain these compounds.
Background of invention
Mellitus are meant the lysis that is caused by the Different types of etiopathogenises factor, and it is characterized in that, after the administration glucose, plasma glucose levels raises or hyperglycemia under fasting state or during oral glucose tolerance test.The hyperglycemia that continues or do not have a control and rising and too early morbidity and deadly relevant.Usually, unusual glucose homeostasis and the metabolic variation of lipid, lipoprotein and apolipoprotein and other metabolism and hematodinamics disease have directly or indirect getting in touch.Therefore, suffer from the diabetes B patient and have extra high aorta and microvascular complication risk, comprise coronary heart disease, apoplexy, peripheral vascular disease, hypertension, ephrosis, neuropathy and retinopathy.Therefore, glucose homeostasis, lipid metabolism and hypertensive therapeutics be controlled at mellitus Clinical Management and the treatment in be vital.
The mellitus that two kinds of generally acknowledged forms are arranged usually.In type i diabetes or Regular Insulin-dependent diabetes (IDDM), the patient produces and seldom or not produces Regular Insulin, and Regular Insulin is the hormone that is used to regulate glucose.In diabetes B or non insulin dependent diabetes (NIDDM), the patient have identical usually with the non-diabetic object or even higher plasma insulin level; Yet; These patients have the resistance of development to the Regular Insulin of glucose in the main insulin sensitivity tissue and lipid metabolism generation hormesis; Said insulin sensitivity is organized as muscle, liver and fatty tissue; Though and insulin level raises, and is not enough to overcome this significant insulin resistance.
The insulin receptor reduced number is not the major cause that causes insulin resistant, and major cause is the binding deficient of acceptor behind the Regular Insulin, is understood fully as yet about this point.This opposing to insulin response causes the Regular Insulin activation of glucose absorption in the muscle, oxidation and storage not enough, and causes the formation and the unsuitable Regular Insulin inhibition of excretory of glucose in the lipolysis and liver in the fatty tissue.
Approve that there is limitation in the therapy that can be used for diabetes B that does not change basically for many years.Though caloric reduction will significantly improve diabetic conditions in sports and the diet, the conformability of this treatment is very poor, and this is because of long-term mode of life of setting up and excessive energy expenditure, particularly contains the food of high saturated fatty amount.Sulfonylurea (for example tolbutamide and glipizide) through the more Regular Insulin of administration stimulating pancreas β emiocytosis or meglitinide and/or; When sulfonylurea or meglitinide become invalid, can cause the insulin concentration height to being enough to stimulate said insulin resistant tissue through insulin injection rising plasma insulin level.Yet the insulin resistant level of the rising that dangerous low plasma glucose levels can be caused and caused by higher plasma insulin level by administration Regular Insulin or insulin secretagogue agent (sulfonylurea or meglitinide) possibly exist.Biguanides rising insulin sensitivity, thus hyperglycemia there are some improvement.Yet, two kinds of biguanides, phenformin and N1,N1-Dimethylbiguanide can bring out lactic acidosis and feel sick/diarrhoea.With respect to phenformin, N1,N1-Dimethylbiguanide has lower spinoff, therefore usually by extensive prescribed treatment diabetes B.
Lattice row ketone (being 5-benzyl thiazolidine-2, the 4-diketone) is one type of potentiality compound with the multiple diabetes B symptom of improvement describing recently.These reagent significantly strengthen the insulin sensitivity in muscle, liver and the fatty tissue in several diabetes B animal models, thereby partly or completely make the plasma glucose levels that raises recover normal, hypoglycemia can not take place.Current commercially available lattice row ketone is the agonist of peroxisome proliferation activated receptor (PPAR), mainly is PPAR-γ hypotype.It has been generally acknowledged that PPAR-γ agonism mainly is responsible for improving observed insulin sensitivity when treating with lattice row ketone.Testing the new PPAR agonist that is used to treat diabetes B is the agonist of the combination of α, γ or δ hypotype or these hypotypes, and chemically is being different from lattice row ketone (that is, they are not U 25560s) in many cases.Use some lattice row ketone, during such as troglitazone, produced severe side effect (for example liver toxicity).
Other method of treating these diseases is still among research.Proposed recently or still comprise with alpha-glucosidase inhibitor (for example acarbose) and Protein Tyrosine Phosphatases-IB (PTP-IB) suppressor factor and treating at the novel biochemical method of exploitation.
For the compound of dipeptidyl peptidase-IV (" DPP-4 ") enzyme inhibitors is also carrying out being used to treat mellitus, and the particularly research of the medicine of diabetes B.Referring to WO 97/40832; WO 98/19998; United States Patent(USP) No. 5,939,560; United States Patent(USP) No. 6,303,661; United States Patent(USP) No. 6,699,871; United States Patent(USP) No. 6,166,063; Bioorg.Med.Chem.Lett., 6:1163-1166 (1996); Bioorg.Med.Chem.Lett., 6:2745-2748 (1996); Ann E.Weber, J.Med.Chem., 47:4135-4141 (2004); People such as D.Kim, J.Med.Chem., 48:141-151 (2005); And K.Augustyns, Exp.Opin.Ther.Patents, 15:1387-1407 (2005).The DPP-4 suppressor factor that is used for the diabetes B treatment can make the fact such as the hyperglycemic-glycogenolytic factor inactivation of peptide-1 (GLP-1) and gastrin inhibitory polypeptide (GIP) in vivo easily based on DPP-4.GLP-1 and GIP are incretin, when consumed foods, produce.Incretin stimulates the formation of Regular Insulin.The restraining effect of DPP-4 causes the reduction of incretin inactivation, and this causes incretin in forming through pancreas stimulation Regular Insulin, to produce the validity that raises conversely.Therefore, the DPP-4 restraining effect causes the serum insulin level that raises.Advantageously because only when food is consumed health produce incretin, so expection DPP-4 restraining effect can not be at unsuitable time rising insulin level, such as between two meal, it can cause low blood sugar (hypoglycemia).Therefore, there is not the risk of rising hypoglycemia simultaneously in the restraining effect Regular Insulin that can raise of expection DPP-4, and this risk is the dangerous side-effects relevant with the use of insulin secretagogue agent.
The DPP-4 suppressor factor also has other therapeutic applications described in this paper.Up to now, the DPP-4 suppressor factor is not carried out broad research, particularly the application except that mellitus.Thus, need new compound, treat mellitus and other disease of potential and situation to be used for treatment with the DPP-4 suppressor factor of finding improvement.Particularly; Need selectivity to surpass to comprise other member of serine stretch protein enzyme family of rest cell proline dipeptidase (QPP), DPP8 and DPP9 the DPP-4 suppressor factor (referring to; People such as G.Lankas; " Dipeptidyl Peptidase-IV Inhibition for the Treatment of Type 2 Diabetes ", Diabetes, 54:2988-2994 (2005)).The therapeutics possibility that the DPP-4 suppressor factor is used to treat diabetes B by D.J.Drucker at Exp.Opin.Invest.Drugs, 12:87-100 (2003); By people such as K.Augustyns at Exp.Opin.Ther.Patents, 13:499-510 (2003); By J.J.Holst, Exp.Opin.Emerg.Drugs, 9:155-166 (2004); By H.-U.Demuth at Biochim.Biophys.Acta, 1751:33-44 (2005); By R.Mentlein, Exp.Opin.Invest.Drugs, 14:57-64 discusses in (2005).
Summary of the invention
The present invention relates to dipeptidyl peptidase-IV enzyme inhibitors (" DPP-4 suppressor factor ") and can be used for wherein relating to the dipeptidyl peptidase-IV enzyme treatment of diseases or the prevention novel substituted 3-amino tetrahydro pyran, such as mellitus and particularly diabetes B.The invention still further relates to the pharmaceutical composition and these compounds and the application of compsn in the prevention of the disease that relates to the dipeptidyl peptidase-IV enzyme is perhaps treated that contain these compounds.
Detailed Description Of The Invention
The present invention relates to can be as the novel substituted 3-amino tetrahydro pyran of dipeptidyl peptidase-iv inhibitor.The compounds of this invention is represented by structural formula I:
Figure BYZ000004403006800041
And pharmacy acceptable salt; Wherein
N is 0,1,2 or 3 independently of one another;
M is 0,1 or 2 independently of one another;
P is 0 or 1 independently of one another;
V is selected from:
Figure BYZ000004403006800042
Figure BYZ000004403006800051
Ar is for choosing wantonly by 1～5 R 1The substituted phenyl of substituting group; With
R 1Be selected from independently of one another
Halogen,
Cyanic acid,
Hydroxyl,
C 1-6Base, optional by 1～5 fluorine replacement,
C 1-6Alkoxyl group, optional by 1～5 fluorine replacement;
R 2Be selected from independently of one another
Hydrogen,
Hydroxyl,
Halogen,
Cyanic acid,
C 1-10Alkoxyl group, wherein alkoxyl group is optional is replaced by 1～5 substituting group that is independently selected from fluorine and hydroxyl,
C 1-10Alkyl, wherein alkyl is optional is replaced by 1～5 substituting group that is independently selected from fluorine and hydroxyl,
C 2-10Thiazolinyl, wherein thiazolinyl is optional is replaced by 1～5 substituting group that is independently selected from fluorine and hydroxyl,
(CH 2) n-aryl, wherein aryl is optional is independently selected from hydroxyl, halogen, cyanic acid, nitro, CO by 1～5 2H, C 1-6Alkoxy carbonyl, C 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are optional is replaced by 1～5 fluorine,
(CH 2) n-heteroaryl, wherein heteroaryl is optional is independently selected from hydroxyl, halogen, cyanic acid, nitro, CO by 1～3 2H, C 1-6Alkoxy carbonyl, C 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are optional is replaced by 1～5 fluorine,
(CH 2) n-heterocyclic radical, wherein heterocyclic radical is optional is independently selected from oxo, hydroxyl, halogen, cyanic acid, nitro, CO by 1～3 2H, C 1-6Alkoxy carbonyl, C 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are optional is replaced by 1～5 fluorine,
(CH 2) n-C 3-6Naphthenic base, wherein naphthenic base is optional is independently selected from halogen, hydroxyl, cyanic acid, nitro, CO by 1～3 2H, C 1-6Alkoxy carbonyl, C 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are optional is replaced by 1～5 fluorine,
(CH 2) n-COOH，
(CH 2) n-COOC 1-6Alkyl,
(CH 2) n-NR 4R 5，
(CH 2) n-CONR 4R 5，
(CH 2) n-OCONR 4R 5，
(CH 2) n-S?O 2NR 4R 5，
(CH 2) n-SO 2R 6，
(CH 2) n-NR 7SO 2R 6，
(CH 2) n-NR 7CONR 4R 5，
(CH 2) n-NR 7COR 7And
(CH 2) n-NR 7CO 2R 6；
(CH wherein 2) nIn any single methylene radical (CH 2) carbon atom is optional is independently selected from fluorine, hydroxyl, C by 1～2 1-4Alkyl and C 1-4The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are optional is replaced by 1～5 fluorine;
R 3aAnd R 3bBe hydrogen or optional independently of one another by 1～5 substituted C of fluorine 1-4Alkyl;
R 4And R 5Be selected from independently of one another
Hydrogen,
(CH 2) m-phenyl,
(CH 2) m-C 3-6Naphthenic base and
C 1-6Alkyl, wherein alkyl is optional is replaced and wherein phenyl and naphthenic base are chosen wantonly and be independently selected from halogen, hydroxyl, C by 1～5 by 1～5 substituting group that is independently selected from fluorine and hydroxyl 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are optional is replaced by 1～5 fluorine;
Perhaps R 4And R 5The nitrogen-atoms that is connected with them forms the heterocycle that is selected from azetidine, tetramethyleneimine, piperidines, piperazine and morpholine altogether, and wherein said heterocycle is optional to be independently selected from halogen, hydroxyl, C by 1～3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are optional is replaced by 1～5 fluorine;
Each R 6Be C independently 1-6Alkyl, wherein alkyl is optional is replaced by 1～5 substituting group that is independently selected from fluorine and hydroxyl;
R 7Be hydrogen or R 6With
R 8Be selected from
Hydrogen,
(CH 2) p-phenyl,
(CH 2) p-C 3-6Naphthenic base and
C 1-6Alkyl, wherein alkyl is optional is replaced and wherein phenyl and naphthenic base are chosen wantonly and be independently selected from halogen, hydroxyl, C by 1～5 by 1～5 substituting group that is independently selected from fluorine and hydroxyl 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are optional is replaced by 1～5 fluorine.
In a kind of embodiment of The compounds of this invention, R 1Be selected from fluorine, chlorine, bromine, methyl, trifluoromethyl and trifluoromethoxy independently of one another.
In second embodiment of The compounds of this invention, R 3aAnd R 3bAll be hydrogen.
In the 3rd embodiment of The compounds of this invention, the Ar and the NH that on two that the are labeled as * three-dimensional tetrahydropyrans carbon atoms that form, have trans direction are provided 2The structural formula Ia of three-dimensional chemical configuration shown in substituent and Ib compound:
Figure BYZ000004403006800071
Wherein Ar and V are as stated.
In a type of the 3rd embodiment, the Ar and the NH that on two that the are labeled as * three-dimensional tetrahydropyrans carbon atoms that form, have trans direction are provided 2The structural formula Ia compound of the chemical structure of absolute stereo shown in substituent:
Figure BYZ000004403006800081
In second type of this embodiment, the structural formula Ic of three-dimensional chemical configuration shown in providing and Id compound, it has trans direction on three that the are labeled as * three-dimensional tetrahydropyrans carbon atoms that form Ar and NH 2The NH of the Ar of substituting group, trans direction and V substituting group and cis direction 2With the V substituting group:
Figure BYZ000004403006800082
In such subclass, the structural formula Ic compound of absolute stereo chemical structure shown in providing, it has trans direction on three that the are labeled as * three-dimensional tetrahydropyrans carbon atoms that form Ar and NH 2The NH of the Ar of substituting group, trans direction and V substituting group and cis direction 2With the V substituting group:
Figure BYZ000004403006800083
In the subclass of this subclass, V is selected from:
R wherein 2And R 8As above define.
In the 3rd type of the 3rd embodiment, the structural formula Ie of three-dimensional chemical configuration shown in providing and If compound, it has trans direction on three that the are labeled as * three-dimensional tetrahydropyrans carbon atoms that form Ar and NH 2The NH of the Ar of substituting group, cis direction and V substituting group and trans direction 2With the V substituting group:
Figure BYZ000004403006800092
In such subclass, the structural formula Ie compound of absolute stereo chemical structure shown in providing, it has trans direction on three that the are labeled as * three-dimensional tetrahydropyrans carbon atoms that form Ar and NH 2The NH of the Ar of substituting group, cis direction and V substituting group and trans direction 2With the V substituting group:
Figure BYZ000004403006800093
In the subclass of this subclass, V is selected from:
R wherein 2And R 8As above define.
In the 4th embodiment of The compounds of this invention, R 2And R 8Be selected from hydrogen independently of one another,
C 1-6Alkyl, wherein alkyl optional by 1～5 fluorine replace and
C 3-6Naphthenic base, wherein naphthenic base is optional is independently selected from halogen, hydroxyl, C by 1～3 1-4Alkyl and C 1-4The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are optional is replaced by 1～5 fluorine.
In a type of the 4th embodiment of The compounds of this invention, R 2And R 8Be selected from hydrogen, C independently of one another 1-3Alkyl, trifluoromethyl, 2,2,2-trifluoroethyl and cyclopropyl.
Can be as the limiting examples of the The compounds of this invention of dipeptidyl peptidase-iv inhibitor following on three three-dimensional tetrahydropyrans carbon atoms that form, have shown in the structure of absolute stereo chemical structure:
Figure BYZ000004403006800111
And pharmacy acceptable salt.
Be suitable for to give a definition in this article.
" alkyl " and other have the group of prefix " alkane ", such as alkoxyl group and alkyloyl or the like, only if carbochain has definition in addition, are meant to be the carbochain of straight chain, side chain or its combination.Examples of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, sec.-butyl and the tertiary butyl, amyl group, hexyl, heptyl, octyl group and nonyl or the like.When the concrete number of carbon atom allows, for example, C 3-10The time, term alkyl also comprises group of naphthene base and the straight chain that combines with the naphthenic base structure or the combination of branched alkyl chain.When carbon atom number does not offer some clarification on, mean C 1-6
" naphthenic base " is the subclass of alkyl, and is meant the saturated carbon ring with given number carbon atom.The instance of naphthenic base comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group or the like.Except as otherwise noted, group of naphthene base monocyclic cycloalkyl normally.Except as otherwise noted, group of naphthene base is saturated.
Term " alkoxyl group " is meant specifies carbon atom number (for example, C 1-C 10The straight chain or the branched alkane oxide compound of any number [that is, methoxyl group (MeO-), oxyethyl group, isopropoxy or the like] alkoxyl group) or in this scope.
Term " alkylthio " is meant specifies carbon atom number (for example, C 1-C 10The straight chain or the branched alkane sulfide of any number [that is, methylthio group (MeS-), ethylmercapto group, iprotiazem base or the like] alkylthio) or in this scope.
Term " alkylamino " is meant specifies carbon atom number (for example, C 1-6The straight chain or the branched-chain alkyl amine of any number alkylamino) or in this scope [that is, methylamino, ethylamino, isopropylamino, uncle's fourth amino or the like].
Term " alkyl sulphonyl " is meant specifies carbon atom number (for example, C 1-6Alkyl sulphonyl) any number [that is methylsulfonyl (MeSO, or in this scope 2-), ethylsulfonyl, sec.-propyl alkylsulfonyl or the like] straight chain or branched-chain alkyl alkylsulfonyl.
Term " alkoxy carbonyl " is meant specifies carbon atom number (for example, C 1-6The straight chain or the branched ester of the carboxylic acid derivative of the present invention of any number [that is, methoxycarbonyl (MeOCO-), ethoxy carbonyl or butoxy carbonyl] alkoxy carbonyl) or in this scope.
" aryl " is meant monocycle or the many cyclophanes ring that contains carboatomic ring atom.Preferred aryl groups is monocycle or two ring 6-10 unit aromatic ring systems.Phenyl and naphthyl are preferred aryl groups.Most preferred aryl is a phenyl.
Term " heterocyclic radical " is meant and contains the heteroatoms that at least one is selected from O, S and N, comprises that further the oxidised form of sulphur (is SO and SO 2) saturated or unsaturated non-aromatic ring or ring system.The heterocyclic instance comprises THF (THF), dihydrofuran-, 1; 4-dioxane, morpholine, 1; 4-dithiane, piperazine, piperidines, 1; 3-dioxolane, imidazolidine, tetrahydroglyoxaline, pyrroline, tetramethyleneimine, tetrahydropyrans, dihydropyrane, oxathiolane, dithiolane, 1; 3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, pyrrolidone,
Figure BYZ000004403006800121
azoles alkane-2-ketone, imidazolidin-2-one, pyridone or the like.
" heteroaryl " is meant fragrance or the part aromatic heterocycle that contains at least one ring hetero atom that is selected from O, S and N.Heteroaryl also comprises the heteroaryl on the ring that is fused to other kind, the chain rate of said other kind such as aryl, naphthenic base and nonaromatic heterocycles.The instance of heteroaryl comprises pyrryl, different
Figure BYZ000004403006800122
azoles base, isothiazolyl, pyrazolyl, pyridyl, 2-oxo-(1H)-pyridyl (2-hydroxyl-pyridyl),
Figure BYZ000004403006800123
azoles base, 1; 2; 4-
Figure BYZ000004403006800124
di azoly, 1; 3; 4-
Figure BYZ000004403006800125
di azoly, thiadiazolyl group, thiazolyl, imidazolyl, triazolyl, tetrazyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, benzisoxa
Figure BYZ000004403006800126
azoles base, benzo
Figure BYZ000004403006800127
azoles base, benzothiazolyl, diazosulfide base, dihydro benzo furyl, indolinyl, pyridazinyl, indazolyl, pseudoindolyl, dihydrobenzo thienyl, pyrrocoline base, cinnolines base, phthalazinyl, quinazolyl, naphthyridinyl, carbazyl, benzo dioxolyl, quinoxalinyl, purine radicals, furazan base, different benzyl furyl, benzimidazolyl-, benzofuryl, benzothienyl, quinolyl, indyl, isoquinolyl, dibenzofuran group, imidazo [1; 2-a] pyridyl, [1; 2; The 4-triazolo] [4; 3-a] pyridyl, pyrazolo [1; 5-a] pyridyl, [1; 2; The 4-triazolo] [1; 5-a] pyridyl, 2-oxo-1,3-benzo
Figure BYZ000004403006800131
azoles base, 4-oxo-3H-quinazolyl, 3-oxo-[1,2; 4]-triazolo [4; 3-a]-2H-pyridyl, 5-oxo-[1,2,4]-4H-
Figure BYZ000004403006800132
di azoly, 2-oxo-[1; 3; 4]-and 3H-
Figure BYZ000004403006800133
di azoly, 2-oxo-1,3-dihydro-2H-imidazolyl, 3-oxo-2,4-dihydro-3H-1; 2,4-triazolyl or the like.For heterocyclic radical and heteroaryl, comprise the ring system that contains 3～15 atoms, it forms 1～3 ring.
" halogen " is meant fluorine, chlorine, bromine and iodine.Usually preferred chlorine and fluorine.When halogen replaces on alkyl or alkoxyl group, fluorine (CF for example most preferably 3O and CF 3CH 2O).
The compounds of this invention can contain one or more asymmetric centers, and can exist with racemoid, racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer thus.Particularly, in formula Ia, Ib, Ic, Id, Ie and If, The compounds of this invention has the carbon atom asymmetric center of the solid formation that is labeled as *.Depend on multiple substituent person's character on the molecule, can have other asymmetric center.Each said asymmetric center will form two kinds of optical isomers independently, and perhaps possible optical isomer and diastereomer pure or partial purification compound form comprise within the scope of the present invention intention with the promising mixture of institute.The invention is intended to comprise all above-mentioned isomeric form of these compounds.
Some said compounds contain alkene double bond, unless expressly stated otherwise,, are meant to comprise E and Z geometrical isomer.
Some said compounds can be used as tautomer and exist, and are accompanied by the transfer of one or more pair key, and it has different hydrogen tie points.For example, ketone and its enol form are the keto-enol tautomerism body.Single tautomer and composition thereof all is included in the scope of The compounds of this invention.It is following that intention is included in the instance diagram of the tautomer in the The compounds of this invention scope:
Figure BYZ000004403006800134
Formula I has shown do not have preferred other structure of stereochemical compounds.Formula Ia has shown with Ib and on amylene oxide ring, has been connected NH 2Form the preferred stereochemistry on the carbon atom with the solid of Ar group.Formula Ic has shown with Id and on amylene oxide ring, has been connected NH 2, Ar and V group solid form the preferred stereochemistry on the carbon atom.
Know like those skilled in the art, through appropriate variations method disclosed herein, the independence of these diastereomers is synthesized or their chromatographic separation can be accomplished.Their absolute stereo compound can be confirmed through the X-ray crystalline diffraction method of crystal product or derivatize crystal midbody, if necessary, uses the reagent of the asymmetric center that contains known absolute configuration that it is carried out derivatize.
If expectation can separate the racemic mixture of compound, thereby make that single enantiomer obtains separating.Said separation can be carried out through method well known in the art; Such as, make the racemic mixture and the coupling of optical siomerism pure compound of compound, thereby form non-enantiomer mixture; Separate single diastereomer through standard method subsequently, such as fractional crystallization or chromatography.Said linked reaction uses pure acid of optical siomerism or alkali to form salt usually.Then, the chirality residue through cracking adds can change into pure enantiomer with non-mapping verivate.The racemic mixture of compound can also directly separate through the chromatography of utilizing chiral stationary phase, and this method is a method well known in the art.
Additionally, any enantiomer of compound can be through using the optical purity raw material or the reagent of isomery configuration, carries out through method well known in the art that stereoselectivity is synthetic to be obtained.
Should be appreciated that in this article that the relevant structural formula I compound that uses also means comprises pharmacy acceptable salt and the non-pharmacy acceptable salt that when as the precursor of free cpds or their pharmacy acceptable salts, perhaps in other synthetic operation, uses.
The compounds of this invention can also carry out administration with the form of pharmacy acceptable salt.Term " pharmacy acceptable salt " is meant the salt that is prepared by pharmaceutically acceptable nontoxic alkali or acid (comprising inorganic or organic bases and inorganic or organic acid).The salt that is included in the basic cpd in the scope of term " pharmacy acceptable salt " is meant usually through making the non-toxic salt of free alkali and the suitable organic or The compounds of this invention that inorganic acid reaction prepares.The exemplary salt of basic cpd of the present invention includes but not limited to following: acetate; Benzene sulfonate; Benzoate; Supercarbonate; Hydrosulfate; The Tartaric acid hydrogen salt; Borate; Bromide; D-camphorsulfonic acid salt; Carbonate; Muriate; CLAV; Citrate trianion; Dihydrochloride; Edetate; Edetate; Rely on salt; Esilate; Fumarate; Gluceptate; Glyconate; Glutaminate; The glycoloyl arsanilate; Hexylresorcin salt; Breathe out amine; Hydrobromate; Hydrochloride; Hydroxynaphthoate; Iodide; Different thiosulphate; Lactic acid salt; Lactobionate (lactobionate); Lauroleate; Malate; PHENRAMINE MALEATE; Mandelate; Mesylate; MB; Methyl nitrate salt; Methyl-sulfate; Mucate; Naphthalenesulfonate; Nitrate salt; N-methyl glucoside amine ammonium salt; Oleate; Oxalate; Embonate (embonate); Palmitate; Pantothenate; Phosphate/phosphor acid hydrogen salt; Polygalacturonate; Salicylate; Stearate; Vitriol; Subacetate; SUMATRIPTAN SUCCINATE; Tannate; Tartrate; Teoclate; Tosylate; Triethyl iodate thing and valerate.In addition; When The compounds of this invention has acidic moiety; Its suitable pharmacy acceptable salt includes but not limited to that the salt of being derived and being obtained by mineral alkali, said mineral alkali comprise aluminium, ammonium, calcium, copper, ferric iron, ferrous, lithium, magnesium, manganic, manganese, potassium, sodium, zinc or the like.Preferred especially ammonium, calcium, magnesium, potassium and sodium salt.Comprise primary amine salt, secondary amine salt, tertiary ammonium salt, cyclammonium salt and cation ion exchange resin salt by the pharmaceutically acceptable organic nontoxic alkali salt that obtains of deriving; Such as l-arginine, trimethyl-glycine, theine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, thanomin, quadrol, N-ethyl-morpholine, N-ethylpiperidine, glycosamine, glycosamine, Histidine, Kazakhstan amine, Isopropylamine, Methionin, methyl glucoside amine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine and tromethane or the like.
And; Carboxylic acid (COOH) or alcohol groups be present in the situation in the The compounds of this invention; Can use the ester of pharmaceutically acceptable carboxylic acid derivative; Such as methyl esters, ethyl ester or new pentane acyloxy methyl esters, perhaps pure acyl derivative is such as O-ethanoyl, O-valeryl, O-benzoyl-and O-aminoacyl.Wherein also comprise the known ester and the carboxyl groups that are used for modification dissolving or hydrolysis properties in those this areas as slowly-releasing or prodrug formulation.
Solvolyte, and particularly the hydrate of structural formula I compound is also included within the scope of the invention.
Be utilized in embodiment and compound disclosed herein comes illustrations the present invention.
The compounds of this invention is used in the method that suppresses the dipeptidyl peptidase-IV enzyme among the patient (such as Mammals) who needs said inhibition, comprises the compound of effective dosage.The present invention relates to the purposes of compound disclosed herein as the dipeptidyl peptidase-IV activity inhibitor.
Except primate, outside the mankind, multiple other Mammals can be treated according to the inventive method.For example, Mammals be can treat, ox, sheep, goat, horse, dog, cat, cavy, rat or other ox, sheep, horse, dog, cat, rodent or marine animal species included but not limited to.Yet this method also can be put into practice in other species, for example bird (for example, chicken).
The invention still further relates to the method that is manufactured on the medicine that is used to suppress the dipeptidyl peptidase-IV enzymic activity in human or the animal, comprise associating The compounds of this invention and pharmaceutically acceptable carrier or thinner.More special; The present invention relates to compound in structural formula I and be used for treating the purposes of the medicine of the situation that is selected from Mammals hyperglycemia, diabetes B, obesity and lipid disease in manufacturing, wherein said lipid disease is selected from blood fat illness, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL.
The object of treatment normally expects to suppress the Mammals of dipeptidyl peptidase-IV enzymic activity in the methods of the invention, and is preferred human, the male sex or women.Term " treatment significant quantity " is meant the amount with the target compound that causes tissue, system, animal or human biological respinse or drug reaction, and this amount is explored by researchist, animal doctor, medical doctor or other clinicians.
Term " compsn " in this use means the product that comprises the special component that contains specified quantitative, and any product that the branch combination directly perhaps obtains indirectly that is designated as by specified amount.This term that relates to pharmaceutical composition means and comprises the product that contains activeconstituents and the inert fraction of forming carrier, and any by combination, cooperate or assemble any two kinds or more kinds of composition, decompose one or more compositions, or by other type reaction of one or more compositions or interact directly or the product that obtains indirectly.In view of the above, pharmaceutical composition of the present invention comprises any through mixing the compsn that The compounds of this invention and pharmaceutically acceptable carrier prepare." pharmaceutically acceptable " means carrier, thinner or vehicle must be compatible with other preparation composition and harmless to its receptor.
Term " administration " compound is to be understood that the individuality that offers the needs treatment for the prodrug with The compounds of this invention or The compounds of this invention.
Compound according to the present invention can be confirmed through methods known in the art as the application of dipeptidyl peptidase-IV activity inhibitor.It is definite according to being described below to suppress constant.Utilize a kind of successive fluorometric investigation method, adopt substrate Gly-Pro-AMC to carry out, this substrate discharges fluorescence AMC leavings group through the DPP-4 cracking.The kinetic parameter of describing this reaction is following: K m=50 μ M; k Cat=75s -1k Cat/ K m=1.5 * 10 6M -1s -1General reaction contains about 50pM enzyme, 50 μ MGly-Pro-AMC and damping fluid (100mM HEPES, pH 7.5,0.1mg/ml BSA), and the total reaction amount is 100 μ l.In 96 orifice plates, use 360nm excitation wavelength and 460nm emission wavelength that monitoring continuously is carried out in the release of AMC.Under these conditions, under 25 ℃, after 30 minutes, produce about 0.8 μ MAMC.The enzyme that in these researchs, uses is the solubility that in baculovirus expression system (Bac-To-Bac, Gibco BRL), forms (membrane spaning domain and endochylema spread an except) human protein.The kinetic constant of finding Gly-Pro-AMC and GLP-1 hydrolysis is consistent with the literature value of natural enzyme.In order to measure the dissociation constant of compound, the DMSO solution of suppressor factor is joined (final DMSO concentration is 1%) in the reaction that contains enzyme and matrix.All tests all at room temperature use aforesaid standard reaction to carry out.In order to confirm dissociation constant (Ki), speed of reaction is fitted to the Michaelis-Menton equation that is used for competitive inhibition through non-linear regression.The error of reproducing dissociation constant is generally less than 2 times.
Particularly, in said determination, the compound of following examples has the activity that suppresses the dipeptidyl peptidase-IV enzyme, its IC 50Usually less than about 1 μ M.Said result has shown that these compounds have the intrinsic activity as the dipeptidyl peptidase-IV activity inhibitor.
Dipeptidyl peptidase-IV enzyme (DPP-4) is to have the cell surface protein of getting in touch with the various biological function.It has tissue distribution (intestines, kidney, liver, pancreas, placenta, thymus gland, spleen, epithelial cell, blood vessel endothelium, lymph appearance and medullary cell, serum) and significantly tissue and cell type expression level widely.DPP-4 is equal to T cell activation affinity tag CD26, and it can, endocrine and neurologic peptide that regulate in external cracking panimmunity.This has shown the effect in the multiple lysis in the mankind or other species of this peptase.
In view of the above, target compound can be used for preventing or treating the method for following disease, illness and situation.
Type ii diabetes and associated conditions: confirm fully that incretin GLP-1 and GIP are in vivo by the rapid deactivation of DPP-IV.Use DPP-4 (-/-)The research that the shortage mouse carries out shows that with preliminary clinical trial the DPP-4 restraining effect increases the Css of GLP-1 and GIP, causes the glucose tolerance of improveing.Analogize according to GLP-1 and GIP, other relates to the glycoregulatory hyperglycemic-glycogenolytic factor family peptides of grape and possibly be inactivated through DPP-4 (for example PACAP) equally.These peptides also possibly play a role in glucose homeostasis through the inactivation that DPP-4 produces.Therefore; DPP-4 suppressor factor of the present invention has purposes in treatment and the prevention of situation of type ii diabetes followed in the treatment of type ii diabetes and multiple usually, these situations comprise syndrome X (also claiming metabolic syndrome), reactive hypoglycemia and diabetic hyperlipemia.The obesity of below discussing is the situation that the another kind of type ii diabetes of handling with the response The compounds of this invention is usually found.
Following disease, illness and situation are relevant with diabetes B, therefore can obtain medical treatment, control or in some situations, obtain prevention through handling with The compounds of this invention: (1) hyperglycemia, (2) low dextrose tolerance, (3) insulin resistant; (4) obesity, (5) lipid disease, (6) hyperlipemia, (7) hyperlipidaemia; (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL level; (12) atherosclerosis and sequela thereof, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel; Comprise Crohn disease and ulcerative colitis, (16) other inflammatory situation, (17) pancreatitis, (18) abdominal obesity is sick; (19) neurodegenerative disease, (20) retinopathy, (21) ephrosis; (22) neuropathy, (23) syndrome X, (24) ovarian hyperandrogenism (polycystic ovary syndrome) and other insulin resistant are the diseases of component wherein.At syndrome X, also claim in the metabolic syndrome, think that obesity promotes the risk of insulin resistant, mellitus, hyperlipemia, hypertension and increase neovascular disorders.Therefore, the DPP-4 suppressor factor can also be used to treat the hypertension relevant with this symptom.
Obesity: the DPP-4 suppressor factor can be used to treat obesity.This is based on GLP-1 and the GLP-2 inhibiting discovery to food intake and stomach emptying.Exogenous administration human body GLP-1 can significantly reduce ingestion of food and the stomach emptying that slows down (Am.J.Physiol., 277:R910-R916 (1999)).ICV administration GLP-1 also has far-reaching influence (Nature Med1c1ne, 2:1254-1258 (1996)) to ingestion of food in rat and mouse.At GLP-1R (-/-)Do not find the restraining effect of this feeding in the mouse, show that these influences are receptor-mediated through brain GLP-1.Similar with GLP-1, GLP-2 is regulated by DPP-4 also probably.The ICV administration of GLP-2 suppresses ingestion of food equally, and this is similar to the observed effect of GLP-1 (Nature Med1c1ne, 6:802-807 (2000)) of using.In addition, use the research of DPP-4 disappearance mouse to show that these animals have resistance to the obesity that food brings out with relevant disease (for example, hyperinsulinemia).
Cardiovascular disorder: show, when administration patient after Acute Myocardial Infarction, shown that GLP-1 is useful, the lethality rate (Circulation, 109:962-965 (2004)) that left ventricular function that it causes improving and initial stage postangioplasty reduce.The GLP-1 administration can also be used to treat the left ventricle cardiac systolic function obstacle of suffering from DCM and the dog with left ventricular dysfunction that ischemic brings out, can confirm that thus it can be used to treat and suffers from patient (US2004/0097411) in heart failure.The capability list that expectation DPP-4 stablizes endogenous GLP-1 through them reveals similar effect.
Growth hormone deficiency: the DPP-4 restraining effect can be used to treat GHD, and this is based on somatotropin releasing factor (GRF), and the peptide that a kind of stimulating growth hormone discharges from prepituitary gland is through DPP-4 enzyme cracked hypothesis (WO 00/56297) in vivo.It is the evidence of endogenous matrix that following data provide GRF: (1) GRF is in the effective cracking of external quilt, thereby produces nonactive product G RF [3-44] (BBA 1122:147-153 (1992)); (2) GRF is degraded into GRF [3-44] rapidly in blood plasma; This can obtain prevention through DPP-4 suppressor factor diproton A; (3) GRF [3-44] is found in the blood plasma of the genetically modified pig of human GRF (J.Clin.Invest., 83:1533-1540 (1989)).Thus, the DPP-4 suppressor factor can be used for having considered in the same range as of the short indication of secreting agent of tethelin.
Damage of intestines: use the DPP-4 suppressor factor to handle the possibility of damage of intestines; By showing that glucagon-like-peptide-2 (GLP-2) (the possible endogenous matrix of DPP-4) can demonstrate the Study on Nutrition Function result to enteric epithelium and propose (Regulatory Peptides, 90:27-32 (2000)).The administration of GLP-2 causes producing in the rodent small intestine quality that raises and in suffering from the rodents model of colitis and enteritis, produces the damage of intestines that weakens.
Immunosuppressive action: the DPP-4 restraining effect can be used to regulate immunoreation, and this is based on relating to the DPP-4 enzyme in T cell activation and the research in the chemokine process, and the DPP-4 suppressor factor is in vivo on the basis of the effectiveness in the disease model.Show that DPP-4 is equal to the cell surface marker thing CD26 of activating immune cell.The expression of CD26 is regulated through the differentiation and the active state of immunocyte.It is generally acknowledged that CD26 plays costimulatory molecules in the external model of T cell activation.Multiple chemokine contains proline(Pro) in penultimate, infers through non-specific aminopeptidase to prevent degraded.In several situations (RANTES, LD78-β, MDC, eotaxin, SDF-1 α), cracking causes mutagenic activity in chemotaxi and signal measuring.In some situations, receptor-selective also shows change (RANTES) has taken place.In the cell in vitro culture systems, identify the form of many n terminal truncations of multiple chemokine, comprised the DPP-4 hydrolysis prods of expection.
In transplanting and arthritic animal model, the DPP-4 suppressor factor has been proved to be effective immunosuppressor.Prodipine (Pro-Pro-phenylbenzene-phosphoric acid salt), a kind of irreversible DPP-4 suppressor factor shows that rat is had double heart transplantation survival rate (from 7 days to 14 days) (Transplantation, 63:1495-1500 (1997)).The DPP-4 suppressor factor is tested in the mouse sacroiliitis that collagen protein and alkyl diamine bring out; The result is illustrated in this model; There is statistical abated effect [Int.J.Immunopharmacology in back foot swelling; 19:15-24 (1997) and Immunopharmacology, 40:21-26 (1998)].DPP-4 just regulates in the various autoimmune disease, and said disease comprises rheumatic arthritis, multiple cerebral sclerosis, Graves' disease and struma lymphomatosa (Immunology Today, 20:367-375 (1999)).
HIV infects: the DPP-4 restraining effect can be used for treatment or prevention of HIV infects or AIDS, because the chemokine that multiple inhibition HIV cell gets into all is potential DPP-4 matrix (Immunology Today 20:367-375 (1999)).In the situation of SDF-1 α, cracking reduces antiviral activity (PNAS, 95:6331-6 (1998)).Thus, the SDF-1 α stabilization expection that produces through inhibition DPP-IV can reduce the HIV infectivity.
Hemoposieis: the DPP-4 restraining effect can be used for treatment or prevent hemoposieis, because DPP-4 maybe be relevant with hemopoietic.The DPP-4 suppressor factor, Val-Boro-Pro, the mouse model moderate stimulation hemoposieis (WO 99/56753) that the neutrophilic leukocyte that brings out at endoxan reduces.Neuronal disease: the DPP-4 restraining effect can be used for treatment or prevent multiple neurone or Psychiatric disorders, carries out cracking because many peptides that relates to multiple neurone process are all external through DPP-4.Thus, the DPP-4 suppressor factor possibly have the therapeutics benefit in the treatment of neuronal disease.Interior morphine peptide-2, beta-caseins morphine peptide and P material all are proved to be the external matrix of DPP-4.In all scenario, external cracking is all highly effective, k Cat/ K mBe about 10 6M -1s -1Perhaps higher.In rat lenitive electric shock skip test model, the DPP-4 suppressor factor shows the remarkable effect (Brain Research, 815:278-286 (1999)) that exogenous interior morphine peptide-2 exists that is independent of.The neuroprotective of DPP-4 suppressor factor and the effect of neurotization property equally through suppressor factor protection motor neuron avoid the ability of motor neuron in the irritability necrocytosis, the neural ability that distributes of striatum of protection dopaminergic neuron and the ability that promotes the neural distribution density of striatum to demobilize when after the MPTP treatment, giving with the therapeutics mode are confirmed [referring to Yong-Q.Wu when with MPTP administration simultaneously; Deng the people; " Neuroprotective Effects ofInhibitors of Dipeptidyl Peptidase-IV In Vitro and In Vivo; " Int.Conf.On Dipeptidyl Aminopeptidases:Basic Science and Clinical Applications; September26-29; 2002 (Berlin, Germany)].
Anxiety: the rat of natural shortage DPP-4 has the anxiety phenotype, and (WO 02/34243; People such as Karl, Physiol.Behav.2003).Use porsolt and bright/dark model, DPP-4 lacks mouse and has the anxiety phenotype equally.Thus, can confirm that the DPP-4 suppressor factor can be used to treat anxiety and associated conditions.
Memory and cognition: people such as During (Nature Med.9:1173-1179 (2003)) confirm; The GLP-1 agonist has activity in study (passive escape, Morris water maze) and neuronal damage (the neuronal cell program that kainate brings out is dead) model.This result has shown the physiological role of GLP-1 in study and neuro-protective.The GLP-1 stabilization that expection DPP-4 suppressor factor causes shows similar effect.
Myocardial infarction: show that when administration patient after Acute Myocardial Infarction, GLP-1 is useful (Circulation, 109:962-965 (2004)).The capability list that expectation DPP-4 stablizes endogenous GLP-1 through them reveals similar effect.
Tumour is invaded and shifted: the DPP-4 restraining effect can be used for treating perhaps prophylaxis of tumours intrusion and shift, because in malignant phenotype's conversion process, observed the perhaps reduction (J.Exp.Med..190:301-305 (1999)) of rising that several kinds of exopeptidases (comprising DPP-4) are expressed at normal cell.These proteinic rises or downward modulation all show the specificity of tissue and cell type.For example, the CD26/DPP-4 of rising expresses and in T cell lymphoma, T cell acute lymphoblastic leukemia, the thyroid carcinoma that comes from cell, rodent cancer and mammary cancer, observes.Thus, the DPP-4 suppressor factor possibly have purposes in said treatment for cancer.
Benign prostatauxe: the DPP-4 restraining effect can be used to treat benign prostatauxe; Because the DPP-4 activity that raises is noted (Eur.J.Clin.Chem.Clin.Biochem., 30:333-338 (1992)) in suffering from patient's prostata tissue of BPH.
Motility of sperm/male contraceptive: the DPP-4 restraining effect can be used to change motility of sperm and male contraceptive; Because in seminal fluid; Prostaglandin(PG); The very important prostate gland derived cell of motility of sperm utensil there is very high-caliber DPP-4 active (Eur.J.Clin.Chem.Clin.Biochem., 30:333-338 (1992)).
Gingivitis: the DPP-4 restraining effect can be used to treat gingivitis, because in the gingival sulcus liquid neutralization research relevant with the periodontopathy severity, found DPP-4 active (Arch.Oral Biol., 37:167-173 (1992)).
Osteoporosis: the DPP-4 restraining effect can be used for treatment or preventing osteoporosis disease, because gip receptor is present in the scleroblast.
Stem cell transplantation: DPP-4 has demonstrated the marrow that can cause them the reset enhancing of efficient and immigration and the rising of mouse survival rate people such as (, Science, 305:1000-1003 (2004)) Christopherson to giving the effect of soma cell inhibiting.Thus, the DPP-4 suppressor factor is used for bone marrow transplantation.
The compounds of this invention has purposes in one or more following situations or treatment of diseases or prevention: (1) hyperglycemia, (2) low dextrose tolerance, (3) insulin resistant, (4) obesity, (5) lipid disease; (6) hyperlipemia, (7) hyperlipidaemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels; (11) high LDL level, (12) atherosclerosis and sequela thereof, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel; Comprise Crohn disease and ulcerative colitis, (16) other inflammatory situation, (17) pancreatitis, (18) abdominal obesity is sick, (19) neurodegenerative disease; (20) retinopathy, (21) ephrosis, (22) neuropathy, (23) syndrome X; (24) ovarian hyperandrogenism (polycystic ovary syndrome), (25) diabetes B, (26) GHD, (27) neutrophilic leukocyte reduces; (28) neuronal disease, (29) metastases, (30) benign prostatauxe, (32) gingivitis; (33) hypertension, (34) osteoporosis, (35) anxiety, (36) memory impairment; (37) cognitive defect, (38) apoplexy, (39) alzheimer disease and other can be through suppressing the situation that DPP-4 treats or prevents.
Target compound further can be worked in coordination with the method that other reagent is used for preventing or treating above-mentioned disease, illness and situation.
The compounds of this invention can be worked in coordination with other medicines and is used for treatment, prevention, compacting or improve formula I compound or adaptable disease of other medicines or symptom, and wherein these drug combinations are more safer or more effective than the independent use of any medicine.Said other medicines can be with to this normally used approach and dosage and formula I compound simultaneously or the order administration.When formula I compound and one or more other medicines use simultaneously, preferably in unit dosage, contain the pharmaceutical composition of said other medicines and formula I compound.Yet said conjoint therapy can also be included in the therapy of Medicine-feeding type I compound and one or more other medicines in the negative lap schedule not.It is also contemplated that when using The compounds of this invention and other activeconstituents can use with the dosage that is lower than the dosage when using separately separately with one or more other activeconstituentss are collaborative.In view of the above, pharmaceutical composition of the present invention also contains one or more other activeconstituentss except formula I compound.
Can cooperating type I compound administration and or instance individually dosed or other activeconstituents of administration in the same medicine compsn include but not limited to:
(a) other DPP IV (DPP-4) suppressor factor;
(b) insulin sensitizer; Comprise (i) PPAR gamma agonist; Such as lattice row ketone (for example; Troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, Ba Gelie ketone or the like) and other PPAR part; Comprise PPAR α/γ binary agonist, such as KRP-297, Mo Geta azoles, naveglitazar, for Sai Gelieta, TAK-559, PPAR alfa agonists; Such as Procetofenic acid verivate (Ji Feibei acid, Serotinex, fenofibrate and bezafibrate) and selective PPAR gamma modulators (SPPAR γ M ' s), such as being disclosed among WO02/060388, WO02/08188, WO2004/019869, WO2004/020409, WO2004/020408 and the WO2004/066963 those; (ii) biguanides is such as N1,N1-Dimethylbiguanide and phenformin and (iii) Protein Tyrosine Phosphatases-1B (PTP-1B) suppressor factor;
(c) Regular Insulin or insulin mimetic;
(d) sulfonylurea and other insulin secretagogue agent are such as tolbutamide, Glyburide, glipizide, glimepiride and meglitinide, such as Starsis and repaglinide;
(e) alpha-glucosidase inhibitor (such as acarbose and miglitol);
(f) glucagon receptor antagonist is such as those antagonists that are disclosed among WO 97/16442, WO98/04528, WO98/21957, WO98/22108, WO98/22109, WO99/01423, WO 00/39088 and WO 00/69810, WO 2004/050039 and the WO 2004/069158;
(g) GLP-1, GLP-1 analogue or stand-in and GLP-1 receptor stimulant are such as exendin-4 (exendin), Li Lalu peptide (NN-2211), CJC-1131, LY-307161 be disclosed among WO 00/42026 and the WO 00/59887 those;
(h) GIP and GIP stand-in are such as those and the gip receptor agonist that are disclosed among the WO 00/58360;
(i) PACAP, PACAP stand-in and PACAP receptor stimulant are such as being disclosed among the WO 01/23420 those;
(j) decreasing cholesterol reagent, such as (i) HMG-CoA reductase inhibitor (lovastatin, SV, pravastatin, Cerivastatin, fluvastatin, Zarator, itavastatin and superstatin and other statin), (ii) sequestering agent (the dialkyl aminoalkyl verivate of Cholestyramine, colestipol and crosslinked Expex); (iii) nicotinic alcohol, nicotinic acid or its salt, (iv) PPAR alfa agonists is such as Procetofenic acid verivate (gemfibrozil, Serotinex, fenofibrate and bezafibrate); (v) PPAR α/γ binary agonist; Such as naveglitazar and Mo Geta azoles, (vi) cholesterol absorption inhibitor is such as β-Gu Zaichun and ezetimibe; (vii) acyl CoA: chole-sterol acyltransferase inhibitor; Such as avasimibe with (viii) inhibitor is such as probucol;
(k) PPAR delta agonists is such as being disclosed among the WO 97/28149 those;
(l) obesity compound is such as fenfluramine, dextrorotation fenfluramine, PHENTERMINE, sibutramin, orlistat, neuropeptide Y 1 or Y5 antagonist, CBl receptor inverse agonists and antagonist, beta 3 adrenoreceptor agonists, melanocortin-4 receptor agonists (particularly melanocortin-4 receptor agonist), ghrelin antagonist, the plain receptor stimulant of bell toad (such as the plain receptor subtype-3 agonist of bell toad), cholecystokinin 1 (CCK-1) receptor stimulant and melanochrome-concentrated hormone (MCH) receptor antagonist;
(m) ileal bile acid transfer protein inhibitor;
(n) be used for the reagent of inflammatory situation, such as Asprin, non-steroidal anti-inflammatory drugs (NSAIDs), suprarenal gland glucocorticosteroid, sulfasalazine and selective cyclooxygenase 2 (COX-2) suppressor factor;
(o) antihypertensive drug is such as ACE inhibitor (enalapril, lisinopril, captopril, quinapril, tandolapril), A-II receptor blocking agent (losartan, TCV-116, Irb, valsartan, telmisartan and Yi Puluoshatan), Beta receptor blockers and calcium channel blocker;
(p) activators of glucokinase (GKAs) is such as being disclosed among WO 03/015774, WO04/076420 and the WO 04/081001 those;
(q) 11 beta-hydroxy steroid dehydrogenase type 1 suppressor factor, such as being disclosed in United States Patent(USP) No. 6,730,690, among WO 03/104207 and the WO 04/058741 those;
(r) cholesteryl ester transfer protein (CETP) suppressor factor is such as Tuo Chepu; With
(s) fructose 1,6-diphosphatase suppressor factor, and such as being disclosed in United States Patent(USP) Nos. 6,054, those in 587,6,110,9036,284,748,6,399,782 and 6,489,476.
Can comprise with compound in structural formula I bonded dipeptidyl peptidase-iv inhibitor and be disclosed in the following document those: United States Patent(USP) No. 6,699,871; WO 02/076450 (on October 3rd, 2002); WO 03/004498 (on January 16th, 2003); WO 03/004496 (on January 16th, 2003); EP 1 258 476 (on November 20th, 2002); WO 02/083128 (on October 24th, 2002); WO 02/062764 (on August 15th, 2002); WO 03/000250 (on January 3rd, 2003); WO 03/002530 (on January 9th, 2003); WO 03/002531 (on January 9th, 2003); WO 03/002553 (on January 9th, 2003); WO 03/002593 (on January 9th, 2003); WO 03/000180 (on January 3rd, 2003); WO 03/082817 (on October 9th, 2003); WO 03/000181 (on January 3rd, 2003); WO 04/007468 (on January 22nd, 2004); WO 04/032836 (on April 24th, 2004); WO 04/037169 (on May 6th, 2004); With WO 04/043940 (on May 27th, 2004).Concrete DPP-4 inhibitor compound comprises Isoleucine thiazolidine (P32/98), NVP-DPP-728, Vildagliptin (LAF 237), P93/01 and saxagliptin (BMS 477118).
Can comprise fenfluramine, preferred fenfluramine, PHENTERMINE, sibutramin, orlistat, neuropeptide Y 1 or Y5 antagonist, type cannabinol CB 1 receptor antagonist or inverse agonist, melanocortin-4 receptor agonists (particularly melanocortin-4 receptor agonist), ghrelin antagonist, the plain receptor stimulant of bell toad and melanin concentration hormone (MCH) receptor antagonist with the obesity compound that compound in structural formula I is united use.For the summary that can unite the obesity compound of use with compound in structural formula I; Referring to people such as S.Chaki; " Recent advances in feeding suppressing agents:potential therapeutic strategy for the treatment of obesity ", Expert Opin.Ther.Patents.11:1677-1692 (2001); D.Spanswick and K.Lee, " Emerging antiobesity drugs ", Expert Opin.Emerging Drugs, 8:217-237 (2003); With people such as J.A.Fernandez-Lopez, " Pharmacological Approaches for the Treatment of Obesity ", Drugs, 62:915-944 (2002).
Can comprise with the neuropeptide Y 5 antagonist that compound in structural formula I is united use and be disclosed in United States Patent(USP) No. 6,335, those antagonists among 345 (on January 1st, 2002) and the WO 01/14376 (March 1 calendar year 2001); With the particular compound of confirming as GW 59884A, GW 569180A, LY366377 and CGP-71683A.
Can comprise that those are disclosed in the open WO 03/007887 of the antagonist in the following document: PCT with the class cannabinol CB1 receptor antagonist that formula I compound is united use; United States Patent(USP) No. 5,624,941 is such as SR141716A; The open WO 02/076949 of PCT is such as SLV-319; United States Patent(USP) No. 6,028,084; The open WO 98/41519 of PCT; The open WO 00/10968 of PCT; The open WO 99/02499 of PCT; United States Patent(USP) No. 5,532,237; United States Patent(USP) No. 5,292,736; The open WO 05/000809 of PCT; The open WO 03/086288 of PCT; The open WO 03/087037 of PCT; The open WO 04/048317 of PCT; The open WO 03/007887 of PCT; The open WO 03/063781 of PCT; The open WO 03/075660 of PCT; The open WO03/077847 of PCT; The open WO 03/082190 of PCT; The open WO 03/082191 of PCT; The open WO 03/087037 of PCT; The open WO 03/086288 of PCT; The open WO 04/012671 of PCT; The open WO 04/029204 of PCT; The open WO 04/040040 of PCT; The open WO01/64632 of PCT; The open WO 01/64633 of PCT; With the open WO 01/64634 of PCT.
Melanocortin-4 receptor (MC4R) agonist that can be used for the present invention includes but not limited to that those are disclosed in the agonist in the following document: US 6,294,534, US 6,350; 760,6,376,509,6,410; 548,6,458,790, US 6; 472,398, US 5837521, US 6699873, their full content is hereby incorporated by; With the agonist that is disclosed in the following document: the open Nos.US 2002/0004512 of US patented claim, US2002/0019523, US2002/0137664, US2003/0236262, US2003/0225060, US2003/0092732, US2003/109556, US 2002/0177151, US 2002/187932, US 2003/0113263, their full content is hereby incorporated by; With at WO 99/64002; WO 00/74679; WO 02/15909; WO 01/70708; WO 01/70337; WO 01/91752; WO02/068387; WO 02/068388; WO 02/067869; WO 03/007949; WO2004/024720; WO 2004/089307; WO 2004/078716; WO 2004/078717; WO 2004/037797; WO 01/58891; WO 02/070511; WO 02/079146; WO03/009847; WO 03/057671; WO 03/068738; WO 03/092690; WO02/059095; WO 02/059107; WO 02/059108; WO 02/059117; WO02/085925; WO 03/004480; WO 03/009850; WO 03/013571; WO03/031410; WO 03/053927; WO 03/061660; WO 03/066597; WO03/094918; WO 03/099818; WO 04/037797; WO 04/048345; WO02/018327; WO 02/080896; WO 02/081443; WO 03/066587; WO03/066597; WO 03/099818; WO 02/062766; WO 03/000663; WO03/000666; WO 03/003977; WO 03/040107; WO 03/040117; WO03/040118; WO 03/013509; WO 03/057671; WO 02/079753; WO02//092566; WO 03/-093234; Among WO 03/095474 and the WO 03/104761 those.
The safety that is used to treat the glucokinase (GKAs) of mellitus is discussed in people such as J.Grimsby with the effective potential application of acvator; " Allosteric Activators of Glucokinase:Potential Role in Diabetes Therapy ", among the Science.301:370-373 (2003).
When The compounds of this invention and one or more other medicines use simultaneously, preferably except The compounds of this invention, also contain the compsn of said other medicines.In view of the above, pharmaceutical composition of the present invention comprises except The compounds of this invention, also contains those pharmaceutical compositions of one or more other activeconstituentss.
The weight ratio of the The compounds of this invention and second activeconstituents can change, and this will depend on the effective dose of various compositions.Usually will use the effective dose of various preparations.Thus, for example, unite when using when The compounds of this invention and other reagent, the weight ratio of The compounds of this invention and other reagent will be about 1000: 1～about 1: 1000 usually, preferably about 200: 1～about 1: 200.The associating of compound of the present invention and other activeconstituents usually also in above-mentioned scope, but in each situation, should use the effective dose of each activeconstituents.
In said compsn, The compounds of this invention can individually dosed or administation of combination with other promoting agent.In addition, a kind of administration of component can be before other reagent administration, simultaneously or after carry out.
But The compounds of this invention administered through oral, parenteral (for example intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or inculcate, subcutaneous injection or implantation); Through sucking spraying, nose, vagina, rectum, hypogloeeis or topical administration, and can be separately or be formulated in together in the appropriate dose unit formulation that contains the pharmaceutically acceptable carrier of conventional non-toxicity, auxiliary agent and the vehicle that are suitable for various route of administration.Except the treatment warm-blooded animal, outside mouse, rat, horse, ox, sheep, domesticated dog, cat, monkey or the like, The compounds of this invention can be effective to the human treatment.
Any method preparation that the medicinal compsns that is used for administration compound of the present invention desirably is present in dosage unit form and can knows through pharmaceutical field.All methods all comprise above-mentioned activeconstituents are incorporated into and the step that comprises in the carrier of one or more auxiliary agents.Usually, pharmaceutical composition prepares in the following manner: combine with liquid vehicle or solid carrier in small, broken bits or the two nearly activeconstituents is all even, subsequently, and if necessary, with the preparation of said formed product for expectation.In pharmaceutical composition, active target compound is included in wherein with the amount that is enough to lysis or symptom are produced desired result.Term " compsn " intention of using in this article comprises the product of the appointment composition that contains specified amount, and the compsn of any appointment composition by specified amount directly or the product that obtains indirectly.
The pharmaceutical composition that contains said activeconstituents can for example, be tablet, tablet, lozenge, water or oil suspension, dispersible powder or granula, emulsion, hard or soft capsule or syrup or elixir for being applicable to the form of oral application.The pharmaceutical composition that is designed for oral application can prepare according to any currently known methods that pharmaceutical composition is made in this area; And for pharmaceutically exquisite and good to eat preparation are provided, said compsn can contain one or more reagent that is selected from sweeting agent, sweetener, tinting material and sanitas.Tablet contains the activeconstituents with the nontoxic pharmaceutically acceptable mixed with excipients that is fit to the manufacturing tablet.These vehicle can for, inert diluent for example is such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example W-Gum or alginic acid; Tackiness agent, for example starch, gel or gum arabic; And lubricant, for example Magnesium Stearate, Triple Pressed Stearic Acid or talcum.Said tablet can not have dressing or they can carry out dressing with disintegration and the absorption of delay in gi tract through known technology, thereby the continuous action of long period is provided.For example, can use time-delay material (such as glyceryl monostearate or distearin).They also can be through the technology coatings of describing in the USP 4256108,4166452 and 4265874, to be formed for the osmotic therapeutic tablets of sustained release.
The preparation that is used for oral application can also exist as hard capsule; Wherein activeconstituents is mixed with inert solid diluent (for example lime carbonate, calcium phosphate or kaolin); Perhaps exist, wherein activeconstituents is mixed with water or oils medium (for example peanut oil, whiteruss or sweet oil) as soft capsule.
Aqueous suspensions contains the active substance with the mixed with excipients that is fit to the manufacturing aqueous suspensions.Said vehicle is a suspending agent, for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodium-alginate, Vinylpyrrolidone polymer, Tragacanth and Sudan Gum-arabic; Disperse or wetting agent can be naturally occurring phosphatide, for example condensation product of the condensation product of Yelkin TTS or oxyalkylene and lipid acid (for example polyoxyethylene 8 stearate salt) or ethylene oxide and long chain aliphatic (for example 17 alkene oxygen base Tego Alkanol 16s) or ethylene oxide and be derived from the partial ester of lipid acid and condensation product of hexitol (such as octadecanoic acid ester of polyethylene glycol) or ethylene oxide and be derived from the partial ester of lipid acid and the condensation product of hexitol acid anhydrides (for example Vilaterm sorbitan monooleate).Said water suspension can also contain one or more sanitass, such as ethylparaben or PHB n-propyl; One or more tinting materials; One or more sweetener; With one or more sweeting agents, such as sucrose or asccharin.
Oil suspension can obtain preparation through activeconstituents being suspended in vegetables oil (for example peanut oil, sweet oil, til or Oleum Cocois) or being suspended in the MO (such as whiteruss).Said oil suspension can contain thickening material, for example beeswax, paraffinum durum or Tego Alkanol 16.Can sweeting agent and the sweetener such as act as listed above be added wherein, thereby good to eat oral prepns is provided.These compsns can be preserved through adding inhibitor (such as xitix).
Being applicable to through adding dispersible powder and the granula that entry preparation contains aqueous suspension provides and dispersion agent or wetting agent, suspending agent and one or more sanitas blended activeconstituentss.The suitable dispersion agent or the illustration of wetting agent and suspending agent are as stated.Can also there be other vehicle, such as sweeting agent, seasonings and tinting material.
Pharmaceutical composition of the present invention can also be the form of oil-water emulsifiers.Said oil phase can be vegetables oil (such as sweet oil or peanut oil), MO (such as whiteruss) or their mixture.Examples of suitable emulsifiers can be naturally occurring natural gum, for example Sudan Gum-arabic or Tragacanth; Naturally occurring phosphatide, for example soybean phospholipid, Yelkin TTS; With the ester or the partial ester of deriving and obtaining, for example sorbitan monooleate by lipid acid and hexitol acid anhydrides; With the condensation product of said partial ester and ethylene oxide, T 46155 sorbitan monooleate for example.。Said emulsion can also contain sweeting agent and sweetener.
Syrup and elixir can use sweeting agent (such as glycerine, Ucar 35, sorbyl alcohol or sucrose) to prepare.Said preparation can also contain negative catalyst, sanitas, seasonings and tinting material.
The pharmaceutical composition of The compounds of this invention can be sterile injectable aqueous suspensions or sterile injectable oil suspensoid.Said suspensoid can utilize above-mentioned suitable dispersion agent or wetting agent and suspending agent to prepare according to methods known in the art.Said injectable sterile preparation can also for example be a 1,3 butylene glycol solution at nontoxic parenteral acceptable diluent or injectable sterile solution or the suspension-s in the solvent.In acceptable vehicle and solvent, operable is water, Ringer's solution and isotonic sodium chlorrde solution.In addition, usually aseptic, fixed oil are used as solvent or suspension medium.Based on above-mentioned purpose, any tasteless fixed oil can be used, and comprises synthetic single or triglyceride.In addition, in injectable formulation, can use such as oleic lipid acid.
The compounds of this invention can also be for being used for the suppository form of rectal administration medicine.Thereby these compsns can through with medicine with at normal temperatures for solid but under rectal temperature for liquid and will in rectum, melt the suitable nonirritant excipient that discharges medicine thus and mix and obtain preparing.Said material is theobroma oil and polyoxyethylene glycol.
For topical application, can use ointment, paste, jelly, liquor or suspensoid of containing The compounds of this invention or the like.(based on application aims, topical application should comprise mouth wash shua and gargle.)
Medicine of the present invention and method can further contain other therapeutical active compound that is generally used for treating above-mentioned pathology symptom of pointing out in this article.
Suppress in the treatment or prevention of situation of dipeptidyl peptidase-IV enzymic activity at needs, suitable dosage level will be about 0.01～500 milligram/kg weight in patients/sky usually, can single dose perhaps a plurality of dosed administrations.Preferred said dosage level is about 0.1～about 250mg/kg/ days; More preferably from about about 0.5～about 100mg/kg/ days.The appropriate dosage level can be about 0.01～250mg/kg/ days, about 0.05～100mg/kg/ days or about 0.1～50mg/kg/ days.Dosage in this scope can be 0.05～0.5,0.5～5 or 5～50mg/kg/ days.For oral administration; Said compsn preferably provides with the tablet form that contains 1.0～1000mg activeconstituents; Particularly 1.0,5.0,10.0,15.0,20.0,25.0,50.0,75.0,100.0,150.0,200.0,250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0 and the 1000.0mg activeconstituents, regulate the patient who treats is carried out symptom.Said compound can be according to the scheme administration of administration every day 1～4 time, and be administered once or twice preferred every day.
When treatment or prevent diabetes and/or hyperglycemia or hypertriglyceridemia or other need the disease of formula I compound; When The compounds of this invention with about 0.1mg～about 100mg/ kilogram the weight of animals every day, dosage carried out administration the time; Preferably with single dose or every day dosage be divided into 2～6 administrations; During perhaps with the slowly-releasing form administration, can obtain gratifying result usually.For most of Mammalss, total per daily dose is about 1.0mg～about 1000mg, preferably about 1mg～about 50mg.For the adult situation of 70kg, said total per daily dose will be generally about 7mg～about 350mg.Can regulate this dosage, thereby best therapeutics response is provided.
Yet; Be to be understood that; Concrete dosage level for any concrete patient can be different with the dosed administration frequency; And this will depend on multiple factor, comprise: the activity of the particular compound of use, the metabolic stability of said compound and action time, age, body weight, general health, sex, diet, mode of administration and time, discharge rate, drug combination, the severity of concrete symptom and the object that stands to treat.
The compound method of preparation The compounds of this invention is illustrated among following scheme and the embodiment.Raw material can market buys or can prepare or graphic extension prepares like this paper according to methods known in the art.
The compounds of this invention can be utilized standard reductive amination condition to carry out deprotection subsequently and prepared by those midbodys such as formula II and III,
Figure BYZ000004403006800301
Wherein Ar and V as above define and the nitrogen-protecting group of P for suiting, such as tertbutyloxycarbonyl (BOC), carbobenzoxy-(Cbz) (Cbz) or 9-fluorenylmethyloxycarbonyl (Fmoc).The preparation of these midbodys is described in the following scheme.
Scheme 1
Figure BYZ000004403006800302
Formula II midbody method known or that can desirably know through multiple those skilled in the art in document prepares.A kind of general routes outlined is illustrated in the scheme 1.Substituted benzoyl-halogenide 1 exists down at alkali (such as N, the N-diisopropylethylamine) to be handled with phenol, thereby forms ester 2.Use the anionic treatments 2 of using sodium hydride to produce by Nitromethane 99Min., provide nitroketone 3.Additionally, nitroketone 3 can be through the preparation of following method, aldehyde 1a and Nitromethane 99Min. is reacted and with oxygenant (such as Jones reagent) oxidation gained nitroalcohol 1b in the presence of alkali.Heating nitroketone 3 and 3-iodo-2-(iodomethyl) third-1-alkene provide pyrans 4, when with sodium borohydride reduction with use such as 1, when the alkali of 8-diazabicylo [5.4.0] 11-7-alkene (DBU) carries out isomerizing, trans pyrans 5 are provided.In this step, 5 enantiomer can be separated through the known several different methods of those skilled in the art.Eligibly, racemoid can utilize chiral column to split through HPLC.Then,, for example use zinc and acid (such as spirit of salt) to reduce and the amine 6 of gained is protected, be its BOC verivate for example, thereby provide 7 through using tert-Butyl dicarbonate to handle with its protection with substituted pyrans 5 reduction of nitro.With perosmic anhydride and N-methylmorpholine N-oxide process 7, form glycol 8, through handling, provide midbody pyrone IIa with sodium periodate.
Scheme 2
Formula III midbody method known or that can desirably know through multiple those skilled in the art in document prepares.A kind of general routes outlined for preparing Pyrrolidine and pyrazoles IIIa is illustrated in the scheme 2.The several different methods that the pyrrolidinol 9 of trityl or Boc protection can be known is by one of skill in the art usually carried out oxidation; Such as the Swern method, thereby provide ketone 10, through using N; Dinethylformamide dimethylacetal (DMF-DMA) is handled and is heated, and provides 11.Then, through the solution of heating 11 in The suitable solvent (such as ethanol) with hydrazine 12, choose wantonly in the presence of alkali (such as sodium ethylate), remove the protection base with acid subsequently, the intermediate III a of expectation can obtain easily.
Scheme 3
Figure BYZ000004403006800321
Like institute's diagram in the scheme 3; Structural formula of the present invention (I) compound can prepare through following method; In the presence of intermediate III; In such as methylene dichloride, THF or methanol solvate, use reagent that intermediate II is carried out reductive amination, thereby intermediate compound IV is provided such as sodium cyanoborohydride, Decaboron tetradecahydride or sodium triacetoxy borohydride.This reaction is chosen wantonly in the presence of Lewis acid (such as titanium tetrachloride or titanium tetraisopropylate) and is carried out.This reaction can also obtain promoting through the acid that adds such as acetate.In some situations, intermediate III can be salt, such as hydrochloride or trifluoroacetate with in these situations, and can desirably (be generally N, N-diisopropylethylamine () joins in the reaction mixture with alkali.Then, will protect base to remove, for example in the situation of Boc, use trifluoroacetic acid or methanolizing hydrogenchloride, and perhaps in the situation of Cbz, use palladium/carbon and hydrogen, thereby provide the amine I of expectation.If necessary, this product can be through recrystallization, grinding, preparative thin layer chromatography, on silica gel, carry out flash chromatography (such as the device that uses
Figure BYZ000004403006800322
) or HPLC carries out purifying.Compound through the HPLC purifying can be separated into its corresponding salt.
In some situations, above scheme diagrammatic product I or synthetic intermediate can further change, for example, and through the substituting group on Ar or the V is handled.Said processing includes but not limited to, the reduction that those skilled in the art know usually, oxidation, alkylation, acylations and hydrolysis reaction.
In some situations, can the order that carry out above-mentioned reaction scheme be changed, thereby promote reaction or avoid unnecessary reactor product.Following examples are provided, so that can understand more fully to the present invention.These embodiment only are illustrative ground, should by any way it be regarded as limitation of the present invention.
Midbody 1
Figure BYZ000004403006800331
[(2R, 3S)-5-oxo-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] the t-butyl carbamate steps A: 2,4,5-trifluoromethyl benzonitrile acid phenenyl ester
Pyrogentisinic Acid in ice bath (13.3g, anhydrous methylene chloride 141mmol) (370mL) solution cools off, and uses N, N-diisopropylethylamine (34mL; 193mmol) handle, under 15 fens clock times, add 2 subsequently to wherein dripping; 4, and the 5-trifluorobenzoyl chloride (25g, 129mmol).Ice bath is removed; At room temperature continue to stir two hours, then with solution change in the separating funnel with the gained organic layer with the hydrochloric acid solution (2N, 150mL), saturated sodium bicarbonate aqueous solution (150mL) washs with salt solution (150mL) in proper order; Use anhydrous sodium sulfate drying; Filter, evaporation and gained solid phase prod portioning on silicon-dioxide carry out purifying, with hexane with use the suitable gradient sequentially eluting of the hexane solution of 0-5% ether then, thereby obtains being 2 of white solid; 4,5-trifluoromethyl benzonitrile acid phenenyl ester.
Step B:2-nitro-1-(2,4, the 5-trifluorophenyl) ethyl ketone
(12g is 60% in oil to sodium hydride, 297mmol) with hexane (4x100mL) flushing, purges with dry nitrogen, is suspended in N, and dinethylformamide (350mL) neutralizes then and Nitromethane 99Min. (44mL, 81mmol) reaction.At room temperature the gained mixture was stirred 2.5 hours, is cooled to 0 ℃, then in two hours time with 2,4,5-trifluoromethyl benzonitrile acid phenenyl ester (22.8g, N 90.0mmol), dinethylformamide (180mL) solution-treated.Reaction mixture remained on to spend the night under the temperature same as described above stirred one hour in addition with at room temperature continuing.Mixture is poured in ice (400g) and the dense spirit of salt (48mL).Aqueous mixture extracts with ETHYLE ACETATE (3x250mL).The organic layer that merges is used anhydrous sodium sulfate drying with salt solution (40mL) washing, filters and under reduced pressure evaporates.With the thick product of gained be dissolved in ether-hexane (1: 1,240mL) and in the water (200mL).With the organic layer separation, will carry out drying through the crystal recovery of placement and cooling formation in water cooler and to it through filtering, thereby obtain 2-nitro-1-(2,4, the 5-trifluorophenyl) ethyl ketone into pale solid.
Step C:3-methylene radical-5-nitro-6-(2,4, the 5-trifluorophenyl)-3,4-dihydro-2H-pyrans
With 3-chloro-2-(chloromethyl) third-1-alkene (1.0g, 8mmol) and Soiodin (6.6g, acetone 44mmol) (60mL) mixture at room temperature stirred 20 hours, vapourisation under reduced pressure be dissolved in methylene dichloride (150mL) and the water (50mL).The gained organic layer is used dried over sodium sulfate, filter and evaporate, thereby to obtain is 3-iodo-2-(iodomethyl) third-1-alkene (2.45g) of incarnadine oil.With N, N-diisopropylethylamine (0.20mL) joins 2-nitro-1-(2,4; The 5-trifluorophenyl) ethyl ketone (110mg, N 0.5mmol), dinethylformamide (3mL) and 3-iodo-2-(iodomethyl) third-1-alkene (170mg; 0.55mmol) solution in; Under 60 ℃ with mixture heating up 2.5 hours, evaporation and go up in Biotage
Figure BYZ000004403006800341
system (silicon-dioxide, the hexane solution of gradient 0-30% methylene dichloride) and to carry out purifying through chromatography; Thereby obtain 3-methylene radical-5-nitro-6-(2; 4, the 5-trifluorophenyl)-3,4-dihydro-2H-pyrans.
Step D: (2R, 3S)-5-methylene radical-3-nitro-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans
To 3-methylene radical-5-nitro-6-(2,4, the 5-trifluorophenyl)-3; 4-dihydro-2H-pyrans (798mg; 2.94mmol) chloroform (42mL) and Virahol (7.8mL) solution in add silica gel (5.1g) and Peng Qinghuana (420mg 11.1mmol), and at room temperature stir reaction mixture 30 minutes.Then, (6mL 2N) with the reaction mixture quencher, filters through dripping the adding spirit of salt.The gained solid residue washs with ETHYLE ACETATE (100mL).The filtrating that merges with saturated sodium bicarbonate aqueous solution and salt solution order wash, with anhydrous sodium sulfate drying with evaporate.The succinol (802mg) of gained is dissolved in the THF (15mL), and with 1,8-diazabicylo [5.4.0] 11-7-alkene (DBU, 40 μ L) adds wherein.With solution stirring 105 minutes, then it is changed in the separating funnel that contains ETHYLE ACETATE (100mL) and 1N spirit of salt (50mL).Organic layer is used ethyl acetate extraction with brine wash and water layer.The organic layer that merges with anhydrous sodium sulfate drying, filter and evaporate, thereby obtain thick product, it passes through flash chromatography (silicon-dioxide; The hexane solution of 8-10% ether) carries out purifying; Thereby obtain trans-5-methylene radical-3-nitro-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans.This product of part (388mg) splits through HPLC (ChiralCel OD, the n-heptane solution of 1.5% Virahol), thereby obtains the slower enantiomer that flows, (2R, 3S)-5-methylene radical-3-nitro-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans.
Step e: (2R, 3S)-5-methylene radical-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-amine
To vigorous stirring (2R, 3S)-5-methylene radical-3-nitro-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans (200mg, 0.73mmol) and zinc powder (561mg, add in ethanol 8.59mmol) (7mL) suspension-s 6N spirit of salt (2.3mL, 14mmol).After one hour, mixture is with ether (100mL) and aqueous sodium hydroxide solution (2.5N, 40mL) processing.Organic layer washs with saturated brine, with anhydrous sodium sulfate drying with evaporate, thereby obtain that (2R, 3S)-5-methylene radical-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-amine, it need not to be further purified promptly and can be used in the next step.
Step F: [(2R, 3S)-5-methylene radical-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] t-butyl carbamate
To (2R, 3S)-(177mg, (239mg 1.1mmol), and at room temperature stirs mixture 2.5 hours 5-methylene radical-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-amine to add tert-Butyl dicarbonate in methylene dichloride 0.73mmole) (5mL) solution.Under reduced pressure solution is evaporated, thus be given white solid [(2R, 3S)-5-methylene radical-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] t-butyl carbamate.It need not be further purified promptly and can be used in the next step.
Step G: [(2R, 3S)-5-hydroxyl-5-(methylol)-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] t-butyl carbamate
To [(2R; 3S)-5-methylene radical-2-(2; 4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] (203mg adds perosmic anhydride (0.113mL in trimethyl carbinol 0.59mmol) (6mL), acetone (3mL) and water (1.5mL) solution to t-butyl carbamate; 2.5% solution in the trimethyl carbinol, 0.009mmol).At room temperature the gained mixture was stirred 10 minutes, (92mg 0.79mmol) handles and stirs two days to use N-methylmorpholine N-oxide compound then.After two days, (5mL 2.0N) handles reaction mixture, handles 10 minutes with ETHYLE ACETATE subsequently with aqueous solution of sodium bisulfite.Organic layer is with 2N spirit of salt and the washing of saturated sodium bicarbonate aqueous solution order; Use anhydrous sodium sulfate drying, filter and evaporate, thereby obtain [(2R; 3S)-5-hydroxyl-5-(methylol)-2-(2; 4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] t-butyl carbamate, it need not be further purified promptly and can be used in the next step.
Step H: [(2R, 3S)-5-oxo-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] t-butyl carbamate
To [(2R; 3S)-5-hydroxyl-5-(methylol)-2-(2; 4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] (223mg adds sodium periodate (143mg in THF 0.59mmol) (4mL) solution to t-butyl carbamate; 0.67mmol) water (1.3mL) solution, and mixture stirred 3 hours.Mixture concentrates and passes through flash chromatography (silicon-dioxide; The chloroformic solution of gradient 5-20% ETHYLE ACETATE) carry out purifying, thus obtain into white solid [(2R, 3S)-5-oxo-2-(2; 4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] t-butyl carbamate.
Midbody 2
[(2R, 3S)-5-oxo-2-(2, the 5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] t-butyl carbamate steps A: 1-(2, the 5-difluorophenyl)-2-nitroethyl alcohol
In 1 hour time, to 5 ℃ sodium hydroxide (1N 3L) and in the methyl alcohol (1500mL) drip to add 2, the 5-difluorobenzaldehyde (350g, 2.46mol) and Nitromethane 99Min. (157mL, methyl alcohol 2.9mol) (350mL) solution.Then, reaction mixture neutralizes with Glacial acetic acid min. 99.5 (165mL).Carry out aqueous treatment, provide the nitroalcohol of expectation.
Step B:2-nitro-1-(2, the 5-difluorophenyl) ethyl ketone
In 30 fens clock times, methylene dichloride (600mL) solution of the high iodine alkane of Dess-Martin (125g) joined in 10 ℃ the nitroalcohol solution (46.3g) of steps A preparation.Continue to stir 2 hours, then reaction mixture is poured in water (3L) mixture of sodium hydrogencarbonate (300g) and Sulfothiorine (333g).The product of expectation (2L) extracts with MTBE (MTBE).The gained water layer is with HCl (2N, 1.5L) neutralization and extract with MTBE (3L).The organic layer that merges carries out purifying with anhydrous magnesium sulfate drying, filtration, evaporation and resistates through chromatography (silica gel is used the methylene dichloride wash-out), thus the nitroketone that obtains expecting.
Step C:3-iodo-2-(iodomethyl) third-1-alkene
With 3-chloro-2-(chloromethyl) third-1-alkene (1.0g, 8mmol) and Soiodin (6.6g, acetone 44mmol) (60mL) mixture at room temperature stirred 20 hours, vapourisation under reduced pressure and it is distributed in methylene dichloride (150mL) and the water (50mL).The gained organic layer is used dried over sodium sulfate, filter and evaporate, thereby to obtain is 3-iodo-2-(iodomethyl) third-1-alkene of incarnadine oil.Step D:3-methylene radical-5-nitro-6-(2, the 5-difluorophenyl)-3,4-dihydro-2H-pyrans
With N, N-diisopropylethylamine (184mL) joins 2-nitro-1-(2, the 5-difluorophenyl) ethyl ketone, and ((156g is in solution 507mmol) for dinethylformamide (1000mL) and 3-iodo-2-(iodomethyl) third-1-alkene for 92.7g, N 461mmol).Under 60 ℃ with mixture heating up 2 hours, evaporation and carry out purifying through chromatography (silica gel, the hexane solution of gradient 0-30% methylene dichloride), thus obtain 3-methylene radical-5-nitro-6-(2, the 5-difluorophenyl)-3,4-dihydro-2H-pyrans.Step e: (2R, 3S)-5-methylene radical-3-nitro-2-(2, the 5-difluorophenyl) tetrahydrochysene-2H-pyrans
This compound is through preparing with the said identical method of midbody 1 step D.
Step F: (2R, 3S)-5-methylene radical-2-(2, the 5-difluorophenyl) tetrahydrochysene-2H-pyrans-this compound of 3-amine is through preparing with the said identical method of midbody 1 step e.
Step G: [(2R, 3S)-5-methylene radical-2-(2, the 5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] t-butyl carbamate
This compound is through preparing with the said identical method of midbody 1 step F.
Step H: [(2R, 3S)-5-hydroxyl-5-(methylol)-2-(2, the 5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] t-butyl carbamate
This compound is through preparing with the said identical method of midbody 1 step G.
Step I: [(2R, 3S)-5-oxo-2-(2, the 5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] t-butyl carbamate
To 0 ℃ [(2R, 3S)-5-hydroxyl-5-(methylol)-2-(2, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] add pyridine (7.8mL) and lead tetraacetate (21.7g) in methyl alcohol (100mL) solution of t-butyl carbamate (10.5g).Reaction mixture was stirred 20 minutes.With ETHYLE ACETATE hydrous matter is carried out aftertreatment, provide thick product, through chromatography (silicon-dioxide; The 0-50% ethyl acetate/heptane) carries out purifying; Thereby obtain into white solid [(2R, 3S)-5-oxo-2-(2, the 5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-yl] t-butyl carbamate.
Midbody 3
Figure BYZ000004403006800381
Steps A: (3Z)-3-[(dimethylamino) methylene radical]-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester
(40g, (267g 2241mmol) handles, and under 105 ℃, is heated 40 minutes solution 216mmol) 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester with DMF-DMA.With solution cooling and vapourisation under reduced pressure and gained orange solids with hexane (200mL) processing and in water cooler, cooled off weekend.Through filtering the tawny solid of collecting gained, carry out drying and need not be further purified promptly can be used in the next step.
Step B:1,4,5, the 6-Pyrrolidine is [3,4-c] pyrazoles also
In ST, with hydrazine (3mL) and (3Z)-ethanol (40mL) solution of 3-[(dimethylamino) methylene radical]-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (19.22g) is 85 ℃ of heating 4 hours down.Under reduced pressure solvent is removed and the gained resistates grinds with methylene dichloride (160mL) and ETHYLE ACETATE (15mL).The gained solid is filtered.Filtrating is concentrated and the gained solid grinds once more and filters.The solid that merges was handled and is stirred 6 hours with 4N spirit of salt (250mL) in methyl alcohol.Reaction mixture is concentrated and dry.In methyl alcohol, use 4N spirit of salt (250mL) with gained solids treatment 6 hours once more.Concentrate with drying after, the gained hydrochloride be used in ammonia in the methyl alcohol (2N, 300mL) with ammonium hydroxide aqueous solution (28%, 30mL) processing, and it is concentrated into drying.The solid that obtains is with methyl alcohol (70mL) and water (5mL) processing with at Biotage system's (silicon-dioxide; Gradient contains the ethyl acetate solution of 10% dense volatile caustic of 5-17% methyl alcohol) go up and divide three batches of purifying; Thereby obtain 1; 4; 5, the 6-Pyrrolidine is [3,4-c] pyrazoles also.
1H NMR (500MHz, CD 3OD): δ 4.04 (d, 4H), 7.39 (s, 1H). midbody 4
The 1-methyl isophthalic acid, 4,5, the 6-Pyrrolidine is [3,4-c] pyrazoles also
Steps A: 1-methyl-5-trityl-1,4,5,6-Pyrrolidine be [3,4-c] pyrazoles also
In ST, with methyl hydrazine (0.11mL) and (4Z)-ethanol (5mL) solution of 4-[(dimethylamino) methylene radical]-1-trityl tetramethyleneimine-3-ketone (678mg) is 84 ℃ of heating 3 hours down.Under reduced pressure with solvent remove with the gained resistates at Biotage
Figure BYZ000004403006800392
system's (silicon-dioxide; 5% methyl alcohol/0.5% strong aqua/94.5% methylene dichloride) carry out purifying on; Thereby obtain 1-methyl-5-trityl-1; 4; 5, the 6-Pyrrolidine is [3,4-c] pyrazoles also.
Step B:1-methyl isophthalic acid, 4,5, the 6-Pyrrolidine is [3,4-c] pyrazoles also
1-methyl-5-the trityl-1,4,5 that in above steps A, obtains, 6-Pyrrolidine also [3,4-c] pyrazoles (670mg) are handled with 4N spirit of salt (4mL).1.5 after hour, reaction mixture is concentrated.The gained resistates is at Biotage
Figure BYZ000004403006800393
system's (silicon-dioxide; Gradient contains the dichloromethane solution of 10% strong aqua of 10-19% methyl alcohol) on carry out purifying; Thereby obtain the 1-methyl isophthalic acid, 4,5; The 6-Pyrrolidine is [3,4-c] pyrazoles also.LC-MS?124.1(M+1).
Pyrrolidine shown in the table 1 and pyrazoles prepare according to preparation midbody 4 described methods basically.
Table 1
Figure BYZ000004403006800394
Midbody 7
The 3-methyl isophthalic acid, 4,5, the 6-Pyrrolidine is [3,4-c] pyrazoles also
Steps A: 3-ethanoyl-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester
In THF (20mL) solution of-78 ℃ 3-oxo-pyrrolidines-1-carboxylic acid tert-butyl ester (370mg), add two (trimethyl silyl) sodium amide (4.18mL, 1.0M in THF).Reaction mixture was stirred 1.5 hours, use diacetyl oxide (0.21mL) to handle and at room temperature stirred 20 minutes then.Add entry with the reaction mixture quencher through dropping, under vacuum, concentrate.Add ETHYLE ACETATE (50mL) and saturated sodium bicarbonate aqueous solution (30mL) and isopyknic water in the alkalitropism resistates.Water layer is separated, be acidified to pH 3 through adding spirit of salt carefully, and extract with ETHYLE ACETATE (75mL).The gained organic layer is used brine wash, uses anhydrous sodium sulfate drying, and filter and evaporate, thus the product that obtains expecting, it need not be further purified promptly and can be used in the next step.
Step B:3-methyl-4,6-pyrrolin be [3,4-c] pyrazoles-5 (1H)-carboxylic acid tert-butyl ester also
This step basically according to undertaken by the described method of midbody 2 preparation process A products.
Step C:3-methyl isophthalic acid, 4,5, the 6-Pyrrolidine is [3,4-c] pyrazoles also
This step basically according to undertaken by the described method of midbody 2 preparation process B products.LC-MS?124.2(M+1).
Embodiment 1
Figure BYZ000004403006800402
(2R, 3S, 5R)-(1-methyl-4,6-pyrrolin be [3,4-c] pyrazoles-5 (1H)-yl)-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-amine dihydrochloride also for 5-
Steps A: [(2R, 3S, 5R)-(1-methyl-4,6-pyrrolin be [3,4-c] pyrazoles-5 (1H)-yl)-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-aminocarbamic acid tert-butyl ester also for 5-
(50mg, 0.145mmol) (29mg, (6mg 0.048mmol), and stirs mixture 15 hours and under reduced pressure evaporates to add Decaboron tetradecahydride in methyl alcohol 0.235mmol) (1.0mL) solution with midbody 4 to the midbody 1 that stirs.The preparative thin layer chromatography of the dichloromethane solution of product (TLC flow relatively poor diastereomer) through using 5% methyl alcohol carries out purifying; Thereby provide [(2R, 3S, 5S)-5-(1-methyl-4; 6-pyrrolin also [3; 4-c] pyrazoles-5 (1H)-yl)-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-aminocarbamic acid tert-butyl ester.LC-MS?453.17(M+1).
Step B: (2R, 3S, 5R)-(1-methyl-4,6-pyrrolin be [3,4-c] pyrazoles-5 (1H)-yl)-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-amine dihydrochloride also for 5-
Be obtained from steps A [(2R, 3S, 5S)-5-(1-methyl-4,6-pyrrolin also [3; 4-c] pyrazoles-5 (1H)-yl)-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-aminocarbamic acid tert-butyl ester is dissolved in the hydrogen chloride solution (1mL, 3N in ETHYLE ACETATE); After two hours, evaporate, thereby obtain (2R, 3S, 5S)-5-(1-methyl-4; The 6-pyrrolin is [3,4-c] pyrazoles-5 (1H)-yl)-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-amine dihydrochloride also. 1H?NMR(500MHz，CD 3OD)：δ7.57-7.50(m，1H)；7.39(s，1H)；7.34-7.27(m，1H)；4.91-4.80(m，2H)；4.75(d，1H，J＝10Hz)；4.72-4.62(m，1H)；4.52-4.46(m，1H)；4.2-4.12(m，1H)；3.92(t，1H，J＝12Hz)；3.88(s，3H)；3.68(td，1H，J＝12，4Hz)；3.33-3.29(m，1H)；2.89-2.82(m，1H)；2.24(q，1H，J＝12Hz)；LC-MS?353.17(M+1).
Embodiment 2
(2R, 3S, 5R)-(1-methyl-4,6-pyrrolin be [3,4-c] pyrazoles-5 (1H)-yl)-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-amine dihydrochloride also for 5-
This compound is to prepare with mode like the embodiment 1 step category-B; But be to use the TLC flowability that obtains by embodiment 1 steps A preferably diastereomer [(2R, 3S, 5R)-5-(1-methyl-4; 6-pyrrolin also [3; 4-c] pyrazoles-5 (1H)-yl)-2-(2,4, the 5-trifluorophenyl) tetrahydrochysene-2H-pyrans-3-aminocarbamic acid tert-butyl ester. 1H?NMR(500MHz，CD 3OD)：δ8.14-8.05(m，1H)；7.41(s，1H)；7.31-7.24(m，1H)；4.96-4.82(m，4H)；4.52(d，1H，J＝16Hz)；4.20(s，1H)；4.14-4.04(m，2H)；3.90(s，3H)；3.33-3.28(m，1H)；2.83(d，1H，J＝16Hz)；2.41(t，1H，J＝16Hz)；LC-MS?353.17(M+1).
Embodiment 3
Figure BYZ000004403006800421
(2R, 3S, 5R)-2-(2, the 5-difluorophenyl) tetrahydrochysene)-(4, the 6-pyrrolin is [3,4-c] pyrazoles-5 (1H)-yl) tetrahydrochysene-2H-pyrans-3-amine dihydrochloride also for 5-
Steps A: [(2R, 3S, 5R)-2-(2, the 5-difluorophenyl)-5-(4, the 6-pyrrolin also [3,4-c] pyrazoles-5 (1H)-yl)-) tetrahydrochysene-2H-pyrans-3-aminocarbamic acid tert-butyl ester
(6.03g, 18.4mmol) ((674mg 5.53mmol) handles to use Decaboron tetradecahydride then for 2.61g, methyl alcohol 23.94mmol) (135mL) solution stirring 30 minutes with midbody 3 with midbody 2.With mixture stirred overnight and vapourisation under reduced pressure.The gained resistates is at
Figure BYZ000004403006800422
(silicon-dioxide; With ETHYLE ACETATE (6L), contain 5-6% alcoholic acid 10% ammoniacal liquor ethyl acetate solution (2L), contain ethyl acetate solution (3L) sequentially eluting of 8-12% alcoholic acid 10% ammoniacal liquor) on carry out purifying; Thereby obtain being the relatively poor diastereomer of the flowability title compound of (silicon-dioxide, TLC contain the dichloromethane solution of 6% methyl alcohol of 10% ammonia). 1H?NMR(500MHz，CD 3OD)：δ1.18-1.24(m，9H)，1.59-1.65(q，1H)，2.4(m，1H)，3.06(m，1H)，338(m，1H)，3.75(m，1H)，3.86(m，4H)，4.30(m，1H)，4.35(d，1H，J＝10Hz)，7.02(m，2H)，7.20(m，1H)，7.38(s，1H).
Step B: (2R, 3S, 5R)-2-(2, the 5-difluorophenyl) tetrahydrochysene)-(4, the 6-pyrrolin is [3,4-c] pyrazoles-5 (1H)-yl) tetrahydrochysene-2H-pyrans-3-amine dihydrochloride also for 5-
Be obtained from steps A [(2R, 3S, 5R)-2-(2; The 5-difluorophenyl)-5-(4, the 6-pyrrolin also [3,4-c] pyrazoles-5 (1H)-yl)-) tetrahydrochysene-2H-pyrans-3-aminocarbamic acid tert-butyl ester (5g) is dissolved in hydrogen chloride solution (300mL; 3N in ETHYLE ACETATE) in, and with its stirring 3 hours.With solution evaporation, be dissolved in 200mL methyl alcohol neutralization evaporation once more again, thereby remove the remaining hydrogenchloride of trace.The gained resistates is ground with ethanol (50mL) and methyl alcohol (4mL), thereby title compound is provided. 1H?NMR(500MHz，CD 3OD)：δ2.27(dd，1H，J＝11.7，23.6Hz)，2.90-2.92(m，1H)，3.67-3.70(m，1H)，3.94(t，1H，J＝11Hz)，4.15-4.19(m，1H)，4.54(m，1H)，4.72(br，4H)，4.78(d，1H，J＝10.3Hz)，7.24(m，2H)，7.34(m，1H)，7.63(s，1H)；LC-MS?321.3(M+1).
The embodiment of pharmaceutical prepn
As the specific embodiments of combination of oral medication, 100mg usefulness tablet comprise among the 100mg embodiment 1-3 any, 268mg Microcrystalline Cellulose, 20mg croscarmellose (croscarmellose) sodium and 4mg Magnesium Stearate.At first activeconstituents, Microcrystalline Cellulose and croscarmellose are mixed.Then, through Magnesium Stearate the gained mixture is lubricated and it is struck out tablet.
Invention has been described and explanation though with reference to some specific embodiments; But those skilled in the art are to be understood that; Can carry out multiple modification, change, modification, replacement, deletion or interpolation to said method and scheme, this does not deviate from the spirit and scope of the present invention.For example, because variation has taken place in the Mammals response that above-claimed cpd of the present invention is received treatment when treating any symptom, therefore can use and be different from the effective dose of concrete dosage as stated.Equally; Viewed concrete pharmacology response can basis with depend on selected concrete active compound or whether exist pharmaceutical carrier and applied preparation type and mode of administration to change that consequent expection variant or difference are considered to the object of the invention and put into practice consistent.Therefore, the scope that the invention is intended to the claim through subsequently limits, and should these claims be interpreted as wide scope rationally.

Claims (13)

1. compound in structural formula I:
Figure FSB00000683066200011
Perhaps its pharmacy acceptable salt; Wherein
V is selected from:
Figure FSB00000683066200012
Ar is for choosing wantonly by 1～5 R 1The substituted phenyl of substituting group;
R 1Be selected from fluorine, chlorine, bromine, methyl, trifluoromethyl and trifluoromethoxy independently of one another;
R 3aAnd R 3bAll be hydrogen; With
R 2And R 8Be selected from hydrogen, C independently of one another 1-3Alkyl, trifluoromethyl, 2,2,2-trifluoroethyl and cyclopropyl.
2. the compound of the claim 1 of structural formula Ia or Ib, its two solids with the * mark form have on the carbon atoms shown in three-dimensional chemical configuration:
3. the compound of the claim 2 of structural formula Ia, its two solids with the * mark form have on the carbon atoms shown in the absolute stereo chemical structure:
Figure FSB00000683066200021
4. the compound of the claim 2 of structural formula Ic and Id, its three solids with the * mark form have on the carbon atoms shown in three-dimensional chemical configuration:
Figure FSB00000683066200022
5. the compound of the claim 4 of structural formula Ic, its three solids with the * mark form have on the carbon atoms shown in the absolute stereo chemical structure:
6. the compound of claim 5, wherein V is:
Figure FSB00000683066200031
7. the compound of the claim 2 of structural formula Ie and If, its three solids with the * mark form have on the carbon atoms shown in three-dimensional chemical configuration:
Figure FSB00000683066200032
8. the compound of the claim 7 of structural formula Ie, its three solids with the * mark form have on the carbon atoms shown in the absolute stereo chemical structure:
9. the compound of claim 8, wherein V is:
Figure FSB00000683066200034
10. compound is selected from:
Figure FSB00000683066200041
Perhaps its pharmacy acceptable salt.
11. a pharmaceutical composition contains the compound and the pharmaceutically acceptable carrier of claim 1.
12. be used for the purposes in the medicine of situation that Mammals treatment in the said treatment of needs is selected from insulin resistant, hyperglycemia, diabetes B in preparation according to the compound of claim 1.
13. the pharmaceutical composition of claim 11 contains N1,N1-Dimethylbiguanide in addition.
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