CN102212058A - Single composite medicament (chiral nitrogenous heterocyclic ester) and synthesis method thereof as well as application of chiral nitrogenous heterocyclic ester in preparing low-toxicity CB1 receptor inhibitor - Google Patents

Single composite medicament (chiral nitrogenous heterocyclic ester) and synthesis method thereof as well as application of chiral nitrogenous heterocyclic ester in preparing low-toxicity CB1 receptor inhibitor Download PDF

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CN102212058A
CN102212058A CN2011100929989A CN201110092998A CN102212058A CN 102212058 A CN102212058 A CN 102212058A CN 2011100929989 A CN2011100929989 A CN 2011100929989A CN 201110092998 A CN201110092998 A CN 201110092998A CN 102212058 A CN102212058 A CN 102212058A
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范如霖
姚虎
冯建科
乔林
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Abstract

The invention provides a single composite medicament (chiral nitrogenous heterocyclic ester) and a synthesis method thereof as well as an application of the chiral nitrogenous heterocyclic ester in preparing a low-toxicity CB1 receptor inhibitor. The chemical general formula of the chiral nitrogenous heterocyclic ester is shown in a formula (I). The invention also relates to physiologically acceptable salts or solvates of the chiral nitrogenous heterocyclic ester and preparation methods thereof as well as application of the salts or solvates in the aspects of rehabilitation, weight losing, diabetes mellitus treatment or cardiovascular diseases prevention and even in every medicine aspect related to CB1 receptor preparations. R1 in the general (I) is shown in a formula (II), R2 is alkyl or oxyl, a structural formula shown in the specification represents an aliphatic nitrogenous heterocyclic ring, X is CH2, NH, N-R5, O or S, R5 is alkyl or acyl, and a -OR3 substituted ester group resulting in chirality is contained on the nitrogenous heterocyclic ring. The single composite medicament is a single compound in vitro, and is converted into two and even three compounds with different medicament effect strength, different function ways and different pharmacological effects so as to synergistically exert the comprehensive effect.

Description

" unitary composite medicine ": chirality Nitrogen-containing Heterocyclic Esters, synthesis method and the application in preparation hypotoxicity CB1 acceptor inhibitor thereof
Technical field
The present invention proposes " unitary composite medicine " theory, specifically relate to a kind of unitary composite medicine: chirality Nitrogen-containing Heterocyclic Esters (the CB1 acceptor inhibitor with chirality), its preparation method reach the application (medical usage) at preparation hypotoxicity CB1 acceptor inhibitor, particularly relate to a class chirality, hypotoxic CB1 acceptor inhibitor, they have diaryl pyrazoles structural motif that replaces and the nitrogenous heterocyclic ester class formation with chirality simultaneously, and physiologically acceptable salt or solvate; The present invention relates to their preparation method and the application in the medicine of preparation drug rehabilitation, fat-reducing, treating diabetes or prevention cardiovascular system diseases thereof, so the purposes of all medical science aspects relevant with the CB1 acceptor inhibitor.
Background technology
The product Rimonabant (Rimonabant) of France Sanofi-Aventis company is a CB1 acceptor inhibitor of going on market that beats the world, its medical functions relates to the unify gastrointestinal system of periphery of central nervous system, can not only resist pharmacological dependence (drug addiction), can suppress drinking habit or craving for tobacco, can also improve the susceptibility of human body for Regular Insulin, promote carbohydrate metabolism, help treatment of diabetes, can also depress appetite, the intravital high ester density cholesterol levels of patient is improved and low lipid density cholesterol levels reduces.So colourful pharmacological action has evoked pharmacy man intensive interest.But in European Union listing soon, it causes depressed toxic side effect promptly to come into one's own in the U.S., and shows gradually in the application of European Union, and in October, 2008 city under the European Union, that class (Surinabant) of the bromine second similar to it also stops research finally.
Figure BDA0000055249820000011
Research quiet after one period short period of time, people turn to how to reduce toxicity with the research emphasis of CB1 acceptor inhibitor.The inventor of this patent develops amino acid (application number 201010187654.1) [2]With 3-hydroxy piperidine (application number 201110027174.3) [3]Two new series, test shows that their toxicity can be very low.This patent proposes and requires patent application (application number 201110027174.3) [3]In do not mentioned, for the achievement in research of 3-hydroxy piperidine ester series.
Reference:
[1] Pyrazole derivatives, method of preparing them and pharmaceutical compositions in which theyare present; Francis Barth; Pierre Casellas, et al; Sanofi, Paris, France; USP 5,624,941. listed here IC 50Numerical value is the measured value in this research.
[2] Fan Rulin; Chinese patent application 201010187654.1.
[3] Fan Rulin; Chinese patent application 201110027174.3.
Summary of the invention
The purpose of this invention is to provide a kind of unitary composite medicine: chirality Nitrogen-containing Heterocyclic Esters and physiologically acceptable salt thereof or solvate, its preparation method and the application on preparation hypotoxicity CB1 acceptor inhibitor thereof.
One of technical problem to be solved by this invention, be to provide " unitary composite medicine " a kind of chirality, that toxicity is extremely low CB1 acceptor inhibitor, specifically provide the CB1 acceptor inhibitor that a class has the nitrogen heterocyclic ring and the pyrazoles structure that diaryl replaces of the replacement of chirality ester group concurrently.
Two of technical problem to be solved by this invention, be to provide the preparation method of " unitary composite medicine " a kind of chirality, that toxicity is extremely low CB1 acceptor inhibitor, the preparation method of the CB1 acceptor inhibitor of a kind of toxicity nitrogen heterocyclic ring extremely low, that have the replacement of chirality ester group and diaryl substituted pyrazole structure promptly is provided.
Three of technical problem to be solved by this invention, be to provide hypotoxic, having the nitrogen heterocyclic ring of chirality ester group replacement and " unitary composite medicine " CB1 acceptor inhibitor of diaryl substituted pyrazole structure quits drug abuse in preparation, fat-reducing, diabetes, application in treatment or the prevention cardiovascular system diseases medicine, and even the purposes of the medical science aspect that all are relevant with the CB1 acceptor inhibitor, promptly provide a kind of hypotoxic, the CB1 acceptor inhibitor that has the pyrazoles of diaryl replacement and these 2 kinds of structural motifs of nitrogen heterocyclic ring that the ester group chirality replaces concurrently is in the preparation drug rehabilitation, fat-reducing, diabetes, application in treatment or the prevention cardiovascular system diseases medicine, and even the purposes of all medical science aspects relevant with the CB1 acceptor inhibitor.
CB1 acceptor inhibitor provided by the invention can be used for drug rehabilitation, fat-reducing and treating diabetes, have the external activity suitable with Rimonabant, its toxicity can overcome toxicity and side effect that other existing C B1 acceptor inhibitor is shown than the obvious reduction of Rimonabant.
The technical scheme of finishing first invention task of the application is: a kind of unitary composite medicine, chirality Nitrogen-containing Heterocyclic Esters and physiologically acceptable salt or solvate, the Nitrogen-containing Heterocyclic Esters of this chirality is a kind of nitrogenous heterocyclic CB1 acceptor inhibitor that the chirality ester group replaces that has, they external be " single " compound, in case enter in the body then be converted into 2 kinds, even 3 kinds of pharmacological action intensity differences, effect emphasis difference, even interaction property " compound medicine " also inequality, they are a kind of hypotoxic, the Nitrogen-containing Heterocyclic Esters of chirality and physiologically acceptable salt or solvate, its structure is shown in general formula (I):
Figure BDA0000055249820000021
(I)
R in this general formula (I) 1Be 1,5-disubstituted phenyl-4-R 4-pyrazole-3-yl, its structure is expressed with general formula (II):
Figure BDA0000055249820000031
In general formula (II), A 2, A 3, A 4, A 5, A 6B 2, B 3, B 4, B 5, B 6Be respectively H, F, C1, Br or I atom, C1-C3 alkyl, C1-C3 alkoxyl group, trifluoromethyl or nitro; Wherein at least one is chlorine atom or methyl; B 4It also can be phenyl; The substituent R that the pyrazoles ring is 4 4For hydrogen, side chain or have ring, saturated or undersaturated C1-C5 alkyl or-oxyl;
R in the general formula (I) 2Be C 1-C 8Straight chain, side chain or have ring filling or unsaturated alkyl or-oxyl;
In the general formula (I)
Figure BDA0000055249820000032
Be aliphatic nitrogenous heterocycle, n, m are the integer of 0-4 in the formula; And n+m equals the integer of 2-5; X is CH 2, NH, N-R 5, O, perhaps S; R 5For the C1-C16 alkyl or as R 3Defined acyl group;
Nitrogen-atoms on the aliphatic nitrogenous heterocycle in the general formula (I) passes through-N-R in turn 2Group and carbonyl C=O and R 1Be connected; Must have on this aliphatic nitrogenous heterocycle cause chirality-OR 3Ester appended; Wave line in the general formula is represented asymmetric connection, just the connection of chirality; R wherein 3Acyl group, aliphatics or aromatic sulphonic acid or phosphonic acyl group for acyl group, aliphatics or the die aromatischen Aminosaeuren of aliphatics or aromatic carboxylic acid; These acyl groups itself can have various possible substituting groups again, for example two keys, triple bond, carboxyl, hydroxyl, cyano group, nitro, saturated or undersaturated-oxyl, halogen, amide group, sulfonamido, sulfonate group, phosphate-based and various aromatic substituting groups or the like.Itself can comprise these substituting groups again, also can not comprise the optics asymmetric center;
Described aliphatic nitrogenous heterocycle is selected from: arsenic is coughed up alkane, imidazolidine, tetrahydrochysene arsenic azoles, thiazolidine, tetrahydrochysene oxazole, tetrahydrochysene isothiazole, tetrahydrochysene isoxzzole, piperidines, six hydrogen arsenic piperazines, hexahydropyrimidine, hexahydro-pyridazine or six hydrogen azatropylidenes; Preferred arsenic is coughed up alkane, piperidines, or six hydrogen azatropylidenes.
Except above-mentioned general molecular formula
Figure BDA0000055249820000033
Nitrogen heterocyclic ring and outer, the desired aliphatic nitrogenous heterocycle of the application also comprises following heterocycle: octahydro indoles, octahydro isoindole, decahydroquinoline, Decahydroisoquinolinpreparation, decahydro naphthyridines, decahydro quinoxaline, ten dihydro carbazoles.
Nitrogen heterocyclic ring is preferably arsenic and coughs up alkane, piperidines, or six hydrogen azatropylidenes; Especially the piperidines that has the three-dimensional ester group that replaces of R or S on the 3-position.
The acyl group that piperidine ring is 3 is preferably: ethanoyl, chloro ethanoyl, fluoro ethanoyl, allyl acyl group; Carboxylic formyl radical, β-carboxypropanoyl, γ-maloyl group; The acyl group of benzoyl, 2-Thenoyl, Phenylsulfonic acid, phosphenylic acid or benzene phosphonous acid that benzoyl, a chlorine or many chlorine replace; α-Bing Ansuan acyl group, α-phenylalanine acyl group, pantonine-2-thienyl propionyl.These acyl groups can have, and also can not have chirality, and when having chirality, two kinds of enantiomorphs of R and S include within inventor's requirement.
Above-mentioned " unitary composite medicine " CB1 acceptor inhibitor and physiologically acceptable salt thereof with chirality can be: hydrochloride, hydrogen bromide salt, vitriol, sulfur hydrogen salt, dihydrogen orthophosphate, mesylate, methyl sulfate salt, maleate, fumarate, oxalate, naphthalene-2-sulfonic acid salt, gluconate, Citrate trianion, isethionate, tosilate, 3,5-dimethyl-benzyl sulfonate or the quaternary ammonium salt that forms with alkyl halide, described alkyl halide is fluoro, chloro, bromo, or alkane iodide.
Need to prove that alkyl of the present invention,-oxyl can be saturated hydrocarbyl,-oxyl, as alkyl, alkoxyl group; Can be undersaturated alkyl,-oxyl also, as contain two keys or triple-linked alkyl or-oxyl; Perhaps also can be the alkyl that contains one or more aromatic rings, as mononuclear aromatics base (phenyl), or the condensed-nuclei aromatics base, as naphthyl.
The present invention except that requiring general formula (I) described " unitary composite medicine ", also comprise wherein any two or more compounds mixed resulting mixture according to different ratio (perhaps arbitrary proportion); And comprise any compound and the applicant's Chinese patent application 201010187654.1 wherein; Desired amino acid derivative or oxy-compound are according to different ratios blended medicaments compound in addition in the Chinese patent application 201110027174.3.
Compare with the various CB1 acceptor inhibitors that has now delivered countries in the world, main characteristics of the present invention is:
(1) The compounds of this invention is a kind of hypotoxic, single compound when external; In case enter human body, will be converted into 2 kinds, even 3 kinds of efficacy strength differences, even the also different compound of pharmacological action, so be a kind of novel " unitary composite medicine ".
(2) The compounds of this invention is the ester of a class chirality, and by changing ester group, this " unitary composite medicine " enters the ratio of the different compound of 2 kinds of changing into behind the human body even 3 kinds of drug effects and can be regulated.
(3) all compounds of the present invention all have at least one chiral centre, so their selectivity is better, toxic side effect is lower.
(4) water-soluble better polarity is stronger for the secondary species that is transformed in human body of The compounds of this invention and/or they, and is difficult by hemato encephalic barrier (BBB), so toxicity greatly reduces as a rule, lower to the toxicity of central nervous system.
The technical scheme of finishing the 2nd invention task of the application is that the preparation method of the Nitrogen-containing Heterocyclic Esters of above-mentioned chirality and physiologically acceptable salt or solvate is characterized in that step is as follows:
Acyl chlorides with 2 equivalent Rimonabant parent nucleus carboxylic acids is handled 1-amino-3-hydroxy piperidine, just obtains the 3-hydroxy piperidine ester of arsenic triazole carboxylic acid acid amides, ZH-103-1, ZH-203-1; The ZH-703-1 of pentacyclic ZH-503-1, ZH-603-1 and seven-membered ring, ZH-803-1 can cough up alkane by same program from the amino 3-hydroxyl of 1-arsenic, perhaps 1-amino-4-hydroxy azatropylidene preparation:
Figure BDA0000055249820000051
Reaction formula 1, the preparation of the 3-hydroxy piperidine ester of arsenic triazole carboxylic acid acid amides
Acyl chlorides R with aliphatics or aromatic carboxylic acid 3Cl (the R in this up-to-date style 3Be acyl group) handle arsenic triazole carboxylic acid's 3-hydroxy piperidine acid amides, as compound ZH-101-R/S, ZH-101-R, perhaps ZH-201-R/S, promptly obtain various arsenic triazole carboxylic acids' 3-ester group piperidine amide compound ZH-103 and ZH-104 series, perhaps ZH-203 and ZH-204 series are as compound ZH-103-3-R/S, ZH-103-3-R; ZH-203-3-R/S, and ZH-103-4-R or the like, its synthetic route is shown in reaction formula 2.Certainly, this type of product also can be by corresponding carboxylic acid directly and the condensation and getting under the effect of catalyzer of arsenic triazole carboxylic acid's 3-hydroxy piperidine acid amides:
Figure BDA0000055249820000052
The preparation of reaction formula 2 3-ester group piperidine amide compounds
If the mono-methyl acyl chlorides condensation of 3-hydroxy piperidine acid amides and Succinic Acid is just obtained ZH-104-4-SM, make the ZH-104-4-SM hydrolysis, obtain ZH-104-4-SA; With the ZH-104-4-SM reduction, just obtain ZH-104-5-S, shown in reaction formula 3:
Figure BDA0000055249820000061
The preparation route of reaction formula 3 ZH-104-4 and ZH-104-5
Be the 3-ester group piperidine amide compound of preparation corresponding to various aminoacid replacement, should use amino acid or corresponding acyl chlorides through overprotection, its synthetic route is shown in reaction formula 4:
Reaction formula 4 various amino acid whose-preparation of 3-ester group piperidine amide compound
Wherein: Be equivalent to the OR in the general formula (I) 3, be the ester group of aliphatics or die aromatischen Aminosaeuren, such as R 6Can be phenyl, benzyl, the benzyl, 2-thiophene-methylene radical etc. that replacement arranged on the phenyl ring and various natural or synthetic amino acid, especially alpha amino acid corresponding base groups also comprise simple alkyl, as methyl or ethyl; PG is a protecting group, such as tertbutyloxycarbonyl Boc, benzyl etc., below identical.
Described hypotoxic chirality CB1 acceptor inhibitor of general formula of the present invention (I) and physiologically acceptable salt thereof or solvate can be applicable to prepare anti-additive medicament, slimming medicine, diabetes medicament, treatment or preventing cardiovascular disease medicine, and even all medical science aspects relevant with the CB1 acceptor inhibitor.
The technical scheme of finishing the 3rd invention task of the application is the application on preparation hypotoxicity CB1 acceptor inhibitor of the Nitrogen-containing Heterocyclic Esters of above-mentioned chirality and physiologically acceptable salt thereof or solvate.
In sum, the present invention relates to and provide CB1 acceptor inhibitor that novel hypotoxic of a class have the asymmetric ester group of optics and physiologically acceptable salt thereof or solvated compounds, Preparation Method And The Use.Novel hypotoxic amide derivatives and their salt and the solvate with pyrazoles-3-carboxylic acid of optics asymmetry of one class specifically disclosed; Their synthetic route, preparation procedure and technology; And it is independent, perhaps as one of composition of mixture and be used for all medical uses relevant, at first be drug rehabilitation, smoking cessation, fat-reducing and treating diabetes with the CB1 acceptor.
Principle of the present invention
Once reported the hydroxy nitrogen-containing heterocycle CB1 acceptor inhibitor of chirality before the inventor [3], ZH-101-R wherein and ZH-101-S show very strong activity for the CB1 acceptor, reach 1/5th and 1/6th of Rimonabant:
Figure BDA0000055249820000071
Their corresponding methyl ethers, ZH-102-R and ZH-102-S activity are higher, but toxicity significantly strengthens:
Methyl ether itself just shows stronger toxicity, if consider the close ester that it is stronger again, more easily sees through hemato encephalic barrier, and it must be higher than Rimonabant for the toxicity of cental system.
But in further research after this, the inventor uses the arsenic triazole carboxylic acid acyl chlorides and the 1-amino-3-hydroxy piperidine reaction of 2 multiple doses, has obtained last patent [3]Do not mentioned, the carboxylic acid amide esters of above-mentioned oxy-compound ZH-101-R and ZH-101-S, ZH-103-R and ZH-103-S find that they are also very good for the inhibition activity of CB1 acceptor, even also slightly are better than corresponding methyl ether:
Figure BDA0000055249820000081
Especially valuable is to find that in acute toxicity test in mice these two esters are almost completely nontoxic for mouse: though dosage up to 4800mg/Kg, all none death of male and female mouse.So believing the ester class, the inventor is worth further research.
The molecular weight of considering compound ZH-103-R or ZH-103-S is up to 843, substantial deviation Lipinsky rule, absorption in vivo and distribute can be very not desirable.So the inventor is from ZH-101-R and ZH-101-S, perhaps bromine second counterpart ZH-201-R and ZH-201-S just like that sets out, and synthesized the less ester of a series of molecular weight.Therefrom obtained active high derivative, such as ZH-103-3-R/S (IC 50, 16.9nM), ZH-203-3-R/S (IC 50, activity 12.7nM) has reached the same level of Rimonabant:
Figure BDA0000055249820000082
Further simplify the molecular structure of ZH-103-3-R/S, remove the benzene chlorine in ring; Even using aliphatic chloracetyl, the allyl acyl group replaces the 2,4 dichloro benzene formyl radical; from later Fig. 2 as can be seen; the compound activity that obtains like this is all very high: under the concentration of 100nM, all reached 100% for the inhibiting rate of CB1 acceptor, and equally matched with Rimonabant.
The applicant of this patent is described as follows in this proposition " unitary composite medicine " theory:
(1) ZH-103-3-S more easily passes through hemato encephalic barrier (BBB) as an ester, more entering, and effect what central nervous system; But it can be by rapidly hydrolysis in gi tract, produces to have powerful drug effect, and is comparatively hydrophilic, the just difficult ZH-101 that sees through hemato encephalic barrier, and it is with the more peripheral-system that acts on; Hydrolysising by-product 2,4 dichloro benzene formic acid is harmless:
Figure BDA0000055249820000083
Figure BDA0000055249820000091
In view of this, the ester class of the The compounds of this invention 3-hydroxy piperidine (ester of common aromatic acid: corresponding to the ZH-103 series of Rimonabant with corresponding to bromine second ZH-203 series just like that; The ester of common fats acid: corresponding to the ZH-104 series of Rimonabant with corresponding to bromine second ZH-204 series just like that; Amino acid whose ester: corresponding to the ZH-107 series of Rimonabant with corresponding to bromine second ZH-207 series just like that) can be looked at as a kind of " unitary composite agent ", it is made of the hydrolysate hydroxy piperidine compound (such as ZH-101-S) of this ester itself and ester; The former is for the latter's ratio, then enters the ratio that is absorbed behind the human body with the mol that is hydrolyzed corresponding to the prototype ester.
The prototype ester of The compounds of this invention all is " single " compound; But in case enter human body, hydrolysis takes place partly in vivo promptly, become the mixture of prototype compound ester and these two compounds of hydrolysate hydroxy piperidine.Be absorbed in prototype with ester, when mainly acting on cental system, produce comparatively hydrophilic, than the oxy-compound ZH-101-S of multiaction what peripheral nervous system.So The compounds of this invention is a class " a unitary composite medicine ".
And the ratio of this prototype medicine and hydrolysate can be regulated.The method of regulating changes the ester group on the hydroxyl exactly, thereby regulates the prototype ester at the intravital hydrolysis rate of people.The compound ZH-103-3-S and the compound ZH-103-6-S that are outlined in the form 1 for example, because the acyl group difference, hydrolysis rate just has significant difference.
The wetting ability or the close ester of prototype medicine itself also can be regulated.The method of regulating still is the ester group that changes on the hydroxyl.
The result of these two kinds of adjustings, the ratio of having regulated drug effect what cental system and peripheral-system just.This just means, we can develop the different a series of medicines of effect emphasis: have based on central action, be used for drug rehabilitation, smoking cessation and abstinence from alcohol; What have act as the master with periphery, is used for fat-reducing and treating diabetes.
The inventor has designed and synthesized numerous esters, exactly in order to carry out this adjusting.
This " unitary composite medicine " also may have the advantage of superior especially absorption and distribution aspect in vivo, also may be comparatively long-acting.
(2) ZH-104-4-SA is a kind of extreme case, and itself just has very strong polarity, enter in the body after, be difficult to by hemato encephalic barrier, even more difficult than its hydrolysate ZH-101-S, expect that this compound will act on peripheral nervous system more:
Figure BDA0000055249820000092
The compound ZH-104-4-SA of this " single " in a single day enters human body, just becomes " compound medicine " that 2 components (ZH-104-4-SA and ZH-101-S) are constituted.
(3) as seen from following Fig. 2, the activity of compound ZH-104-4-SM is identical with Rimonabant, it is as " single " compound, in case enter in the body, then become be 3 " the compound medicine " that active principle constituted: prototype ZH-104-4-SM as a kind of ester, more easily enter central nervous system; ZH-104-4-SA then because polarity is very strong, mainly acts on the what peripheral-system; Secondary hydrolysate ZH-101-S then is situated between between the two:
Figure BDA0000055249820000101
So this is a kind of single triple compound medicines.
(4) patent application person thinks, chirality can improve the selectivity of compound under many circumstances or reduce the toxicity of compound, in order to introduce second asymmetric center, utilizes optically active amino acid to prepare the compound of ZH-107-1-S-S and so on:
They are " unitary composite medicine " equally, in case enter in the body, just become the mixture of prototype medicine ZH-107-1-S-S and ZH-101-S, and amino acid is complete harmless by product:
Figure BDA0000055249820000111
Owing to there is hydrophilic, alkaline amino, the salt of this compounds not only solubleness is good, and the form of getting positive ion; It is compared with the ZH-104-4-S that gets the negative ion form, may show different absorptions, distribution and excretory feature.
(5) ZH-104-5-S is a more special example, and it enters the human body posthydrolysis and becomes ZH-101-S and 4 hydroxybutyric acid:
Figure BDA0000055249820000112
Two kinds of compounds of prototype medicine ZH-104-5-S and ZH-101-S all are the CB1 acceptor inhibitors, but it is different with by product phenylformic acid, succsinic acid, methyl alcohol or L-Ala in aforementioned 4 examples, the by product 4 hydroxybutyric acid here but is not an inert, it is a kind of stimulant, makes the pill taker produce floaty euphoria.
We know, the reason of the CB1 acceptor inhibitor Rimonabant of listing failure once is to be that it causes depressed side effect, the adjustment by 4 hydroxybutyric acid so, best just solution.
So ZH-104-5-S is a kind of " single triple compound medicines ".
In sum, the present invention has chirality " unitary composite medicine " CB1 acceptor inhibitor and has than once in the higher wetting ability of the Rimonabant (Rimonabant) of European Union listing and suitable fat-soluble, they are with the less central nervous system that acts on, so its maincenter toxicity is low than Rimonabant; On the other hand, because higher in the concentration of peripheral-system, more peripheral nerve and the gastrointestinal system of acting on, its fat-reducing effect may be strong than Rimonabant then.
" unitary composite medicine " CB1 acceptor inhibitor with chirality of the present invention can be regulated by different ester groups, and its effect emphasis can be a cental system, also can be peripheral-system.
The major objective that the present invention pursued is the toxicity that reduces for central nervous system, would rather the sacrificial section drug effect.But test shows, some compounds that derive by esterification active identical with Rimonabant substantially, such as ZH-103-3-R/S, and ZH-203-3-R/S or the like has exceeded author's expection.
The applicant of this patent is pursuing the highest one-tenth property of medicine, but not the highest activity is a strategic objective, and based on the not possible meta-bolites and the consideration of hydroxyl hydrophilic in human body just like that of profit, a series of novel " unitary composite medicine " synthesized in design.Their solubleness and bioavailability also may be better than the Rimonabant of France.
Pharmacological evaluation:
One, external activity experiment
In the external activity screening, most compounds all show active, the relevant IC of very high or sufficiently high inhibition to the CB1 acceptor 50Data or inhibiting rate are listed following table 1 respectively in to table 4 according to the classification of compound, Fig. 1 and Fig. 2.Rimonabant with France is a reference, and activity data system measures by two kinds of methods:
First method, measure by U.S.'s associated mechanisms:
Experimental procedure: at first radioactivity [3H]-Li Mo is dissolved in just like that the binding buffer liquid based on HEPES that contains 0.25%BSA (pH 7.4), concentration is 2-5nM; Put into the Chinese hamster ovary celI membranin that 3 μ g have expressed the CB1 acceptor in 96 apertures on test panel; Sample is dissolved in DMSO with the ratio of 1: 100 (weight ratio) and is incorporated in these apertures.Allow test panel at room temperature hatch 1.5 hours; Changing reaction mixture over to the GF/B filter plate with a Packard cell harvestor stops association reaction.The washing filter plate, the material on the plate calculates with Packard scintillometer (Packard Top Count Scintillation Counter); Add excessive 1000 times inactive profit and do not measure non-special connection just like that; Deduct non-special connection from sum and be special connection.With non-special the connection CPM is scaled the inhibition percentage based on sum; With suppressing data and curve calculation IC 50Value.
Second method, measure by Zhejiang University's school of life and health sciences bio-technology department:
1. cell cultures and stable expression cell strain make up: the cell strain that is used for this project is mainly the HEK293 cell.This cell adopts the DMEM substratum to add 10%FBS.Cell transfecting or cotransfection expression of receptor carrier and reporter gene expression carrier Lipofectamine-2000.After the transfection 24 hours, add G418, the HEK293 cell is 800 μ g/ml, changes in three-four days once to contain the G418 fresh culture.After two weeks, as seen tangible population of cells, after choosing 20-30 population of cells's amplification, effect with functional experiment or flow cytometry recipient cell surface expression and reporter gene, frozen high expressing cell strain or the strain of function test good cell amplification back, be used for drug screening, functionally active test and in conjunction with experiments such as active testings.
2. the detection of cAMP concentration in the cell: in cannabinoid CB 1 receptor and CRE-Luciferase stable expression cell strain cell, add the serum-free DMEM that contains the different concns compound, preincubate 15min, adding CB1 agonist win55212-2 again, to make final concentration be 1 μ M, detects the cAMP activity after stimulating 4-5h.
3. the mensuration of luciferase activity: the cell levels high flux screening model adopts cAMP response element (CRE) control luciferase expression carrier sense cAMP down, and the final detection luciferase activity that adopts is determined the cAMP activity.Uciferase activity detection method: at first inhale the substratum that removes to contain part, every hole adds 100 μ L lysates, after shaking table is hatched 15min, drawing 20 μ L lysate sample mixes with the 20 μ L detection liquid for preparing, put into the F12 detector rapidly, read the average canbdle power in 5 seconds, with what of the expression amount of luminous intensity reflection luciferase.Convert thus for the inhibiting rate of CB1 acceptor.
For the result of related the first and second two kinds of different measuring methods, used 3 compounds measuring with first method as interior mark.The mark compound is in used three:
1) Rimonabant: the result of first method, IC 50Be 11.2nM; The result of second method: under the concentration of 100nM, be 100% for the inhibiting rate of CB1 acceptor.
2) (R/S)-piperidines-3-base-5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-arsenic azoles-3-carboxylicesters (ZH-105-1-R/S) [2]: the result of first method: IC 50Be 120.5nM; The result of second method: under the concentration of 100nM, be 47% for the inhibiting rate of CB1 acceptor.
3) (S)-5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-N-(3-hydroxyl arsenic is coughed up alkane-1-yl)-4-methyl isophthalic acid H-arsenic azoles-3-methane amide (ZH-501-S) [2]: the result of first method: IC 50Be 216.9nM; The result of second method: under the concentration of 100nM, be 42% for the inhibiting rate of CB1 acceptor.
Express what table 1 to table 4 according to the determination data of first method; Measurement result according to second method is expressed what Fig. 1 and Fig. 2.
Table 1, the inhibition activity data of six-membered heterocycle aromatic series acid esters CB1 acceptor
Figure BDA0000055249820000131
Figure BDA0000055249820000141
Annotate: 1) Kd is dissociation equilibrium constant (De-association), in order to characterize the action intensity of reagent and acceptor or enzyme, as reference.
Table 2, the inhibition activity data of six-membered heterocycle aliphatic acid ester CB1 acceptor
Figure BDA0000055249820000151
Figure BDA0000055249820000161
Table 3, the inhibition activity data of six-membered heterocycle amino acid ester CB1 acceptor
Figure BDA0000055249820000162
Figure BDA0000055249820000171
Table 4, the inhibition activity data of five yuan and seven member heterocyclic ring containing nitrogen ester CB1 acceptors
Referring to Fig. 1: above-mentioned table 1 to the table 4 part of compounds under the concentration of 1 μ M for the inhibiting rate of CB1 acceptor.
Referring to Fig. 2: above-mentioned table 1 to the table 4 part of compounds under the concentration of 0.1 μ M for the inhibiting rate of CB1 acceptor.
Two, the acute toxicity tentative experiment of mouse
1, test objective: the toxicity of oxy-compound, ether or the ester that makes for the present invention obtains preliminary notion, knows that they cause the roughly dosage of mouse 0% until 100% mortality ratio.
2, sample is prepared
According to the synthetic testing compound of the described preparation procedure of preamble, HPLC detects its purity and surpasses 99%.According to 9: 3: 1 part by weight, each compound all was made into the sample of three kinds of different concns.Testing compound (1200mg) is added the 1%CMC aqueous solution (4.2mL), become the mashed prod of homogeneous with the ultrasonic wave homogenize after milling, concentration is 240mg/mL.Get this solution of part, be diluted to the solution that concentration is 80mg/mL with the 1%CMC of 2 times of volumes; Therefrom take out small portion again, further be diluted to the solution of 27mg/mL.The sample for preparing Rimonabant according to the same manner is as controlled trial.
3, test method
Test is buied from Jiangsu University's Animal House with mouse, 22 days ages of mouse, body weight 18～22g, male and female half and half.Mouse is divided into 3 groups, and every group 4 female 4 heros divide and support in 2 cages.Allow its ad lib and drinking-water, after breeding observing 3 days is normal, 3 groups of mouse are poured into the sample of above-mentioned 3 kinds of different concns respectively, every about 0.4mL of animal, accurate dose is adjusted according to the body weight of each animal.About the same in high dosage, 4800mg/Kg, median dose 1600mg/Kg, low dosage 530mg/Kg.In contrast, the sample of Rimonabant also is used to three groups of mouse according to the same manner distribution.Other gets a treated animal, and 4 female 4 heros are fed with the 1%CMC aqueous solution as blank it.Began to observe 7 days the record mortality of mice from medication.
4, result and discussion
The blank group of feeding with the 1%CMC aqueous solution does not have dead mouse.
Rimonabant group in contrast is under high dosage, and whole 8 mouse are dead in 5 days; Following 5 survivals of median dose, 3 female 2 heros; Low dosage is all survivals down.
Binuclear compound ZH-103-1-R/S is very interesting: do not had any death (under this dosage, the very fast whole death of Rimonabant mice in control group) unexpectedly even the dosage height, tries mouse to the threshold dose of 4800mg/Kg.And its IC 50Numerical value even be lower than corresponding oxy-compound, this has caused the very big interest of inventor.So inventor's preparation has also been studied the less ester class of more molecular weight.
The present invention has proposed the notion of " unitary composite medicine " first, this " unitary composite medicine ": external be single compound; Be converted into 2 kinds in vivo, in addition the compound that 3 kinds of efficacy strength differences, action pathway difference, pharmacological action also may be different, the net effect that performance is collaborative.Test shows that their toxicity can be very low.
Description of drawings
Fig. 1 part of compounds that is table 1 to the table 4 under the concentration of 1 μ M for the inhibiting rate histogram of CB1 acceptor;
Fig. 2 part of compounds that is table 1 to the table 4 under the concentration of 0.1 μ M for the inhibiting rate histogram of CB1 acceptor.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1:(R/S)-1-(5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide group) piperidines-3-base 5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylicesters (ZH-103-1-R/S)
(7.8mmol 2.1eq) is dissolved in 25ml CH with acyl chlorides 3.111g 2Cl 2, (11.8mmol 3.2eq), is cooled to 0 ℃ to add pyridine 0.935g; Amino-(3.7mmol is 1eq) at 10mlCH for 3-hydroxy piperidine 0.430g to drip racemize 1-in this solution 2Cl 2In solution.After dropwising, stirred 3 hours in 0 ℃; Check reaction with TLC: product Rf, 0.4 (silica gel, EtOAc/ sherwood oil=1/2).Reaction solution washes with water (uses saturated sodium-chloride water solution (2 * 40ml) washings again after 2 * 40ml); The organic phase anhydrous Na 2SO 4Dry; Steaming desolventizes, and obtains crude product 2.76g, yield 88.3%.
This crude product is made column chromatography by silica gel 45 grams; With EtOAc/ sherwood oil 1/4 is eluent; 30 milliliters of each flow points.Product Rf:0.12 (silica gel, EtOAc/pet.ether=1/3); (0.4 silica gel, EtOAc/ sherwood oil=1/2); 0.75 (silica gel, EtOAc/ sherwood oil=1/1) obtains product 2.22g; Yield 71.0%.mp:162.9-163.3 ℃. 1H-NMR (CDCl 3) identical with (ZH-101-1-R).
The acyl chlorides that utilizes 5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-carboxylic acid is that raw material must be corresponding to bromine second derivative (ZH-203-1-R/S) just like that according to same programmed value.
Embodiment 2:(R)-1-(5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide group) piperidines-3-base 5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylicesters (ZH-103-1-R)
(12.6mmol 2.1eq) is dissolved in 50ml CH with the acyl chlorides 5.04g of 5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid 2Cl 2, (18.65mmol 3.1eq), is cooled to 0 ℃ to add triethylamine 2.6ml; In 65 minutes, (6.0mmol is 1eq) at 30mlCH to drip utilization fractionation resulting (R)-1-amino-3-hydroxy piperidine 0.697g in this solution 2Cl 2In solution.After dropwising, stirred 3 hours in 0 ℃; Check reaction with TLC: product Rf, [(there is a speckle 0.57 (silica gel, EtOAc/ sherwood oil=1/2): 0 in addition; 0.05; 0.10; 0.29; 0.70; (0.86 residual raw materials acyl chlorides)).Reaction solution washes with water (after 2 * 50ml), uses saturated sodium-chloride water solution (2 * 50ml) washings again; The organic phase anhydrous Na 2SO 4Dry; Steaming desolventizes, and obtains crude product 4.524g, yield 89.4%.
This crude product is made column chromatography by 7 gram silica gel; With EtOAc/ sherwood oil=1/4 and 1/3.5 is eluent; Rf 0.44 (silica gel, EtOAc sherwood oil=1/2); Obtain product 3.6546g; Yield 72.3%.mp：150.4-150.8℃；[α] D：-39.3°(C，0.749，EtOAc，25℃) 1H-NMR(CDCl 3)：.1.66(1H，m)；1.86(1H，br.s)；1.94(1H，br.s)；2.10(1H，br.s)；2.35(3H，s)；2.38(3H，s)；2.92(1H，dd)；3.13(1H，dd)；3.23(1H，br.s)；3.55(1H，d)；5.4(1H，br.s)；7.06-7.45(14H，m)；7.95(1H，s)。
The acyl chlorides that utilizes 5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-carboxylic acid be raw material according to same program, promptly get corresponding to bromine second derivative ZH-203-1-R just like that.
Embodiment 3:(S)-1-(5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide group) piperidines-3-base 5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylicesters (ZH-103-1-S)
(13.75mmol 2.1eq.) is dissolved in 50ml CH with acyl chlorides 5.5008g 2Cl 2, (20.84mmol 3.2eq), is cooled to 0 ℃ to add triethylamine 2.9ml; In 55 minutes, (6.55mmol is 1eq.) at 30mlCH by splitting resulting (S)-1-amino-3-hydroxy piperidine 0.761g in dropping in this solution 2Cl 2In solution.After dropwising, stirred 3 hours in 0 ℃; Check reaction with TLC: product Rf, 0.4 (silica gel, EtOAc/ sherwood oil=1/2).Reaction solution washes with water (uses saturated sodium-chloride water solution (2 * 10ml) washings again after 2 * 20ml); The organic phase anhydrous Na 2SO 4Dry; Steaming desolventizes, and obtains crude product 4.55g, yield 82.4%.
This crude product is done column chromatography by silica gel 70 grams; With EtOAc/ sherwood oil=1/4 is eluent; 0.42 (silica gel, EtOAc/ sherwood oil=1/2) obtains product 3.802g; Yield 69.3%.
Mp:152.3-152.7 ℃; [α] D:+38.3 ° (C, 0.757, EtOAc, 25 ℃). 1H-NMR (CDCl 3) identical with (ZH-103-1-R).
The acyl chlorides that utilizes 5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-carboxylic acid is that raw material makes corresponding to bromine second derivative ZH-203-1-S just like that according to same program.
Embodiment 4:(R/S)-and 1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-4-methyl isophthalic acid H-arsenic azoles-3-amide group] piperidines-3-base-2,4 dichloro benzene manthanoate (ZH-103-3-R/S)
(A) 2,4 dichloro benzene formic acid 0.573g (3mmol) is dissolved in the 20ml toluene solution, the ice-water bath cooling drips 0.7138g (6mmol) SOCl 2Solution in 10ml toluene, temperature rising reflux reacts to TLC and shows that raw material reaction finishes; Concentrating under reduced pressure, solvent evaporated and remaining sulfur oxychloride get yellow oily liquid 0.597g, thick product yield 95%.
(B) (R/S)-5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-R/S) 0.479g (1mmol) is dissolved in 15mlCH 2Cl 2In, ice-water bath is cooled to 5 ℃, drips 2,4 dichlorobenzyl chloride 0.209g (1mmol) at 10ml CH 2Cl 2In solution, add 0.306g (3.02mmol) triethylamine, after stirring reaction, TLC detect raw material reaction and finish, with twice of 15ml water washing; The organic phase saturated NaCl solution washing of 15ml; Through anhydrous Na SO 4After the drying, filtering and concentrating; Column chromatography gets white solid 341.4mg (0.523mmol), mp:69.7～72.0; Yield 52.3%. 1H-NMR(CDCl 3)：δ，1.82(m，2H)；2.05(m，2H)；2.37(s，3H)；3.21(bs，1H)；3.33(bs，1H)；3.45(d，1H)；3.75(bs，1H)；5.35(bs，1H)；7.05-7.46(m，10H)；8.01(bs，1H)。
Embodiment 5:(S)-1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-and 4-methyl isophthalic acid H-arsenic azoles-3-amide group] piperidines-3-base-2,4-dichlorobenzoic acid ester (ZH-103-3-S) and (R)-1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-and 4-methyl isophthalic acid H-arsenic azoles-3-amide group] piperidines-3-base-2,4 dichloro benzene manthanoate (ZH-103-3-R)
With (S)-5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-S) 300mg (0.625mmol), 2,4-dichlorobenzoic acid 119mg (0.625mmol), HOBT0.269g (2mmol), EDC.HCl0.768g (4mmol) place reaction flask, vacuum-drying 2 hours.Add DMF 15ml and triethylamine 0.4ml; Room temperature reaction spends the night under nitrogen protection.Reaction solution is poured in the frozen water, and the white solid that the filter collection is separated out is behind column chromatography purification, obtain product (S)-1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-and 4-methyl isophthalic acid H-arsenic azoles-3-amide group] piperidines-3-base-2,4 dichloro benzene manthanoate 186.3mg, yield 65.6%.Mp:69.0～72.4 ℃; 1H-NMR is identical with ZH-103-3-R/S.
From (R)-5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-R) sets out, according to same program preparation (R)-1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-and 4-methyl isophthalic acid H-arsenic azoles-3-amide group] piperidines-3-base-2,4-dichlorobenzoic acid ester (ZH-103-3-R) 1H-NMR is identical with ZH-103-3-R/S.
Embodiment 6:(R/S)-and 1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-4-methyl isophthalic acid H-arsenic azoles-3-amide group] piperidines-3-base-2-chloro-benzoic acid ester (ZH-103-4-R/S)
With (R/S)-5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-R/S) 300mg (0.625mmol), 2-chloro-benzoic acid 97.8mg (0.625mmol), HOBT0.269g (2mmol), EDC.HCl 0.768g (4mmol) place reaction flask, vacuum-drying 2 hours.Add DMF 15ml and triethylamine 0.4ml; Room temperature reaction spends the night under nitrogen protection.Reaction solution is poured in the frozen water, and the white solid that the filter collection is separated out behind column chromatography purification, obtains product 221.8mg, yield 57.4%.Product mp:114.9～116.9C. 1H-NMR(CDCl 3)：δ，1.82(m，2H)；2.03(m，2H)；2.38(s，3H)；2.98～3.02(t，1H)；3.14(t，1H)；3.24(bs，1H)；3.55(d，1H)；5.30(s，1H)；7.06(d，2H)；7.26～7.44(m，8H)；7.85(d，1H)；8.07(s，1H)。
Embodiment 7:(S)-1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-and 4-methyl isophthalic acid H-arsenic azoles-3-amide group] piperidines-3-base-2-chloro-benzoic acid ester (ZH-103-4-S) and R-1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-4-methyl isophthalic acid H-arsenic azoles-3-amide group] piperidines-3-base-2-chloro-benzoic acid ester (ZH-103-4-R)
From (S)-5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-S) sets out, obtain product S-1-[5-(4-chloro-phenyl)-1-(2 according to same program, 4-two chloro-phenyl)-and 4-methyl isophthalic acid H-arsenic azoles-3-amide group] piperidines-3-base-2-chloro-benzoic acid ester 205.6mg, yield 53.2%.mp：125.1～127.4C。Same preparation procedure provides the R enantiomorph, (ZH-103-4-R); 1H-NMR is identical with (ZH-103-4-R/S).
Embodiment 8:(S)-and 1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-4-methyl isophthalic acid H-arsenic azoles-3-amide group] piperidines-3-base-4-chloro-benzoic acid ester (ZH-103-5-S)
With (S)-5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-S) 300mg (0.625mmol), 4-chloro-benzoic acid 97.8mg (0.625mmol), HOBT0.269g (2mmol), EDC.HCl0.768g (4mmol) place reaction flask, vacuum-drying 2 hours.Add DMF 15ml and triethylamine 0.4ml; Room temperature reaction spends the night under nitrogen protection.Reaction solution is poured in the frozen water, the white solid that the filter collection is separated out behind column chromatography purification, obtains S-1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-and 4-methyl isophthalic acid H-arsenic azoles-3-amide group] piperidines-3-base-4-chloro-benzoic acid ester 207.1mg, yield 53.6%.mp：133.6～139.9℃。 1H-NMR(CDCl 3)：δ，1.73～1.80(m，2H)；2.00～2.02(m，2H)；2.38(s，3H)；3.10(bs，1H)；3.22(bs，1H)；3.32(bs，1H)；3.60(bs，1H)；5.30(s，1H)；7.05-7.07(d，2H)；7.27～7.45(m，8H)；8.03～8.05(d，2H)。
Embodiment 9:(S)-and 1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-4-methyl isophthalic acid H-arsenic azoles-3-amide group] piperidines-3-base-chloro-benzoic acid ester (ZH-103-6-S)
(A) with (S)-5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-S) 300mg (0.625mmol), phenylformic acid 76.3mg (0.625mmol), HOBT0.269g (2mmol), EDC.HCl 0.768g (4mmol) place reaction flask, vacuum-drying 2 hours.Add DMF15ml, triethylamine 0.4ml; Room temperature reaction spends the night under nitrogen protection.Reaction solution is poured in the frozen water, and the white solid that the filter collection is separated out behind column chromatography purification, obtains S-1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-4-methyl isophthalic acid H-arsenic azoles-3-amide group] piperidines-3-base-benzoic ether 181.8mg, yield 49.6%.Product mp:59.8～60.8 ℃. 1H-NMR(CDCl 3)：δ，1.65～1.68(m，1H)；1.80～1.83(m，1H)；1.97～2.04(m，2H)；2.38(s，3H)；3.00～3.05(t，1H)；3.13～3.18(t，1H)；3.24～3.26(bs，1H)；3.54～3.56(d，1H)；5.28(s，1H)；7.05-7.07(d，2H)；7.26～7.66(m，8H)；8.06(d，2H)；8.32(d，1H)。
(B) phenylformic acid 0.366g (3mmol) is dissolved in the 20ml toluene solution, the ice-water bath cooling drips 0.7138g (6mmol) SOCl 2Solution in 10ml toluene, temperature rising reflux reacts to TLC and shows that raw material reaction finishes; Concentrating under reduced pressure, solvent evaporated and remaining sulfur oxychloride get yellow oily liquid 0.361g, thick product yield 86%.
(S)-5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-S) 0.479g (1mmol) is dissolved in 15mlCH 2Cl 2In, ice-water bath is cooled to 5 ℃, drips Benzoyl chloride 0.140g (1mmol) at 10ml CH 2Cl 2In solution, add 0.101g (1mmol) triethylamine, stirring reaction; After TLC detection raw material reaction finishes, with twice of 15ml water washing; The organic phase saturated NaCl solution washing of 15ml; Through anhydrous Na SO 4After the drying, filtering and concentrating; Column chromatography gets white solid 253mg (0.433mmol), mp: yield 43.3%.
Embodiment 10:(S)-and 1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-amide group] piperidines-3 bases-thiophene-2-carboxylic acid ester (ZH-103-7-S)
With (S)-5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-S) 337mg (0.625mmol), thiophene-2-carboxylic acid 80.1mg (0.625mmol), HOBT0.269g (2mmol), EDC.HCl 0.768g (4mmol) place reaction flask, vacuum-drying 2 hours.Add DMF15ml, triethylamine 0.4ml; Room temperature reaction spends the night under nitrogen protection.Reaction solution is poured in the frozen water, and white solid is separated out; Filter collects this solid and behind column chromatography purification, obtains product (S)-1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-amide group] piperidines-3-base-thiophene-2-carboxylic acid ester 117.9mg, yield 30%. 1H-NMR(CDCl 3)：δ，1.65～1.67(m，1H)；1.79～1.81(m，1H)；2.01(m，2H)；2.38(s，3H)；3.03(m，1H)；3.15(m，1H)；3.28(m，1H)；3.57～3.59(m，1H)；5.24(s，1H)；7.06-7.08(m，3H)；7.31～7.86(m，6H)；8.18(s，1H)。
Embodiment 11:(S)-and 1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-amide group] piperidines-3-base-benzene sulfonate (ZH-103-8-S)
With S-5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-103-S) 300mg (0.625mmol), benzene sulfonyl chloride 110.4mg (0.625mmol) place reaction flask, vacuum-drying 2 hours.Add DMF 15ml, triethylamine 0.4ml; Room temperature reaction spends the night under nitrogen protection.Reaction solution is poured in the frozen water, white solid is separated out, and filter collects this solid and behind column chromatography purification, obtains product S-1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-and 4-methyl isophthalic acid H-pyrazoles-3-amide group] piperidines-3-base-benzene sulfonate 204.6mg, yield 52.8%.Product mp:125.1～128.7 ℃. 1H-NMR(CDCl 3)：δ，1.71(m，2H)；1.84(m，2H)；2.36(s，3H)；2.81(bs，1H)；2.93(bs，1H)；3.21(bs，1H)；3.45～4.47(d，1H)；4.69(bs，1H)；7.05-7.66(m，10H)；8.01(m，2H)。
Embodiment 12:(R/S)-and 1-[5-(4-bromo-phenyl)-1-(2,4-two chloro-phenyl)-4-ethyl-1H-arsenic azoles-3-amide group] piperidines-3-base-2,4 dichloro benzene manthanoate (ZH-203-3-R/S)
(R/S)-5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-201-R/S) 0.5382g (1.0mmol) is dissolved in 15mlCH 2Cl 2In, ice-water bath is cooled to 5 ℃, to wherein dripping 2,4 dichlorobenzyl chloride 0.2095g (1.0mmol) at 10ml CH 2Cl 2In solution; Add 0.306g (1.5mmol) triethylamine, it is residual that stirring reaction detects no raw material to TLC; With twice of 15ml water washing; The organic phase saturated NaCl solution washing of 15ml; Through anhydrous Na SO 4Dry after-filtration concentrates; Column chromatography gets white solid 386.9g (0.544mmol), mp, 113.8～119.3; Yield 54.4%. 1H-NMR(CDCl 3)：δ，1.30(bs，3H)；1.81～1.82(m，2H)；2.02～2.04(m，2H)；2.77～2.79(m，2H)；3.03～3.05(m，1H)；3.14～3.16(m，2H)；3.55～3.57(m，1H)；5.30(s，1H)；7.01～8.12(m，10H)。
Embodiment 13:(S)-and 1-[5-(4-bromo-phenyl)-1-(2,4-two chloro-phenyl)-4-ethyl-1H-arsenic azoles-3-amide group] piperidines-3-base-2,4 dichloro benzene manthanoate (ZH-203-3-S) and (R) enantiomorph (ZH-203-3-R) thereof
With 5-(4-bromophenyl)-1-(2, the 4-dichlorophenyl)-4-ethyl-1H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-103-S) 337mg (0.625mmol), 2,4-dichlorobenzoic acid 119mg (0.625mmol), HOBT0.269g (2mmol), EDC.HCl0.768g (4mmol) place reaction flask, vacuum-drying 2 hours.Add DMF 15ml, triethylamine 0.4ml; Room temperature reaction spends the night under nitrogen protection.Reaction solution is poured in the frozen water, and white solid is separated out, this solid of filter collection and behind column chromatography purification, obtain product S-1-[5-(4-bromo-phenyl)-1-(2,4-two chloro-phenyl)-and 4-ethyl-1H-pyrazoles-3-amide group] piperidines-3-base-2,4 dichloro benzene manthanoate 167mg, yield 37.6%.Product mp:77.8～79.2 ℃. 1H-NMR(CDCl 3)：δ，1.28(bs，3H)；1.81～1.83(m，2H)；2.02～2.06(m，2H)；2.77～2.78(m，2H)；3.04(m，1H)；3.15～3.27(m，2H)；3.56～3.59(m，1H)；5.30(s，1H)；7.01～8.14(m，10H)。According to same program preparation (ZH-203-3-R).
Embodiment 14:(S)-and 1-[5-(4-bromo-phenyl)-1-(2,4-two chloro-phenyl)-4-ethyl-1H-arsenic azoles-3-amide group] piperidines-3-base-benzoic ether (ZH-203-6-S)
With (S)-5-(4-bromophenyl)-1-(2, the 4-dichlorophenyl)-4-ethyl-1H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-201-S) 337mg (0.625mmol), phenylformic acid 79.4mg (0.625mmol), HOBT 0.269g (2mmol), EDC.HCl0.768g (4mmol) place reaction flask, vacuum-drying 2 hours.Add DMF 15ml, triethylamine 0.4ml; Room temperature reaction spends the night under nitrogen protection.Reaction solution is poured in the frozen water, and white solid is separated out; Filter collects this solid and behind column chromatography purification, obtains product (S)-1-[5-(4-bromo-phenyl)-1-(2,4-two chloro-phenyl)-4-ethyl-1H-pyrazoles-3-amide group] piperidines-3-base-benzoic ether 83mg, yield 20.6%. 1H-NMR(CDCl 3)：δ，1.28(bs，3H)；1.82～1.84(m，2H)；1.99～2.03(m，2H)；2.77～2.78(m，2H)；3.04(m，1H)；3.16(m，1H)；3.29(m，1H)；3.58～3.60(m，1H)；5.29(s，1H)；7.01～7.03(d，2H)；7.44～7.55(m，7H)；8.07～8.09(d，2H)；8.16(s，1H)。
Embodiment 15:(R/S)-and 1-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-arsenic azoles-3-amide group] piperidines-3-base acetic ester (ZH-104-1-R/S)
(R/S)-5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-R/S) 0.479g (1mmol) is dissolved in 15mlCH 2Cl 2In, frozen water is cooled to 5 ℃, and dripping acetyl chloride 0.0942g (1.2mmol) is at 10ml CH 2Cl 2In solution; Add 0.306g (3.0mmol) triethylamine, stirring reaction detects raw material to TLC and exhausts; With 15ml water washing twice, the organic phase saturated NaCl solution washing of 15ml; Through anhydrous Na SO 4Dry after-filtration concentrates; Column chromatography, white solid 0.385g (0.737mmol), yield 73.7%, mp:75.9～82.3 ℃.
1H-NMR(CDCl 3)：δ，1.48～1.53(t，1H)；1.73～1.75(d，2H)；1.90～1.92(d，1H)；2.05(s，3H)；2.32(s，3H)；2.77～2.84(q，2H)；2.97(s，1H)；3.17～3.20(d，1H)；4.98(s，1H)；7.21-7.59(7H，m)。
Use (R)-5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-R) to be raw material, then to obtain ZH-104-1-R.
Use (S)-5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-S) to be raw material, then to obtain ZH-104-1-S.
Embodiment 16:(S)-and 1-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group] piperidines-3-base allyl acid acid esters (ZH-104-2-S)
(S)-5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-S) 305mg (0.63mmol) is dissolved in the 5ml methylene dichloride; Add the 0.3ml triethylamine, the ice bath cooling slowly add down acrylate chloride 85mg ((0.93mmol), add afterreaction liquid from colourless become brown.Continue to stir half an hour, the TLC demonstration reacts completely.Pressure reducing and steaming solvent, resistates are crossed column purification and are got the 227mg white solid product, yield 67.7%; Fusing point 80.1-80.4 ℃; 1H-NMR (CDCl 3): δ, 1.62 (bs, 1H); 1.74 (m, 1H); 1.93 (m, 2H); 2.38 (s, 3H); 3.04 (m, 2H); 3.19 (bs, 1H); 3.42 (d, 1H); 5.12 (bs, 1H); 5.78 (d, 1H); 6.17 (m, 1H); 6.43 (d, 1H); 7.29-7.45 (m, 7H); 8.18 (s, 1H).
Embodiment 17:(S)-and 1-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group] piperidines-3-base chloracetate (ZH-104-3-S)
With (S)-5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid-3-(S)-hydroxy piperidine-1-yl) acid amides 300mg (0.63mmol) is dissolved in the 5ml methylene dichloride; Add the 0.3ml triethylamine, the ice bath cooling slowly add down chloroacetyl chloride 105mg ((0.93mmol), reaction solution from colourless become brown.Continue to stir half an hour, the TLC demonstration reacts completely.Vacuum rotary steam removes and desolvates, and resistates is crossed column purification and got the 317mg white solid product, yield 90.5%; Fusing point, 79.0-79.5 ℃; 1H-NMR (CDCl 3): δ, 1.71 (m, 2H); 1.92 (m, 2H); 2.37 (s, 3H); 3.02-3.16 (m, 3H); 3.37 (d, 1H); (4.10 s 2H); 5.13 (bs, 1H); 7.06-7.45 (m, 7H); (8.15 s 1H).
Embodiment 18:(S)-and 1-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group] piperidines-3-base-monomethyl succinate (ZH-104-4-SM)
1) monomethyl succinate:
Succinyl oxide 8g (80mmol) and anhydrous methanol 3.9ml (96mmol) are dropped into 50ml single port flask, connect the reflux condensing tube of band drying tube after, heated and stirred refluxes in 100 ℃ of oil baths.The solid succinyl oxide all disappears after about 25 minutes, and reactant becomes solution; Continue stir about half an hour, stopped reaction.Remove unreacted methanol under reduced pressure, wait not have distillate after, pour colourless liquid into beaker while hot, stir cooling down, become solid.
2) monomethyl succinate acyl chlorides:
Will be behind the gained white solid monomethyl succinate grinding powder add 50ml single port flask, add sulfur oxychloride 11.6ml (160mmol), low-grade fever is to 30-40 ℃, stirring reaction 1 hour; Be cooled to room temperature, standing over night; Second day again low-grade fever to 30-40 ℃ of stirring reaction two hours; Remove unreacted sulfur oxychloride and low boilers under reduced pressure, 62-63 ℃ of colourless cut collected in underpressure distillation under the what oil pump vacuum, gets 10.5g; Two step total recoverys 87.2%. 1H-NMR(CDCl 3)：δ，2.59(bs，2H)；3.13(bs，2H)；3.60(s，3H)。
3) (S)-and 1-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group] piperidines-3-base-monomethyl succinate (ZH-104-4-SM)
(S)-5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides 905mg (1.89mmol) is dissolved in the 15ml methylene dichloride; Add the 0.5ml triethylamine, the ice bath cooling slowly adds monomethyl succinate acyl chlorides 400mg ((2.66mmol) down.Reaction solution darkens, and continues to stir half an hour, and the TLC demonstration reacts completely.Remove solvent under reduced pressure; Resistates is crossed column purification and is got the 1.05g white solid product, yield 93.6%;
Fusing point, 50.5-51.3 ℃; 1H-NMR (CDCl 3): δ, 1.56 (m, 1H); 1.71 (m, 1H); 1.89 (bs, 2H); 2.36 (s,, 3H); 2.62 (bs, 4H); 2.95 (m, 2H); 3.15 (m, 1H); 3.36 (m, 1H); 3.69 (s, 3H); 5.04 (flat, 1H); 7.05-7.43 (m, 7H); 8.14 (s, 1H).
Embodiment 19:(S)-and 4-{1-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group] piperidines-3-oxygen)-4-oxy butyrate (ZH-104-4-SA)
With (S)-1-[5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-and 4-methyl isophthalic acid-H-arsenic azoles-3-amide group] piperidines-3-base-monomethyl succinate (ZH-104-4-SM) 200mg (0.34mmol) devotes among the DMF 5ml, adds 5% aqueous solution 1.0ml (0.9mmol) and the about 10mg of 18-C-6 of KOH; Spend the night with stirring under room temperature, vacuum-evaporation is to doing; Behind several 5% hcl acidifyings, be dissolved in DCM, column chromatography purification obtains the product that 31mg expects, yield 15.9%. 1H-NMR(CDCl 3)：δ，1.56(m，1H)；1.71(m，1H)；1.91(bs，2H)；2.36(s，，3H)；2.64(bs，4H)；2.96(m，2H)；3.15(m，1H)；3.41(m，1H)；5.07(bs，1H)；7.07-7.45(m，7H)。
Embodiment 20:(S)-and 1-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group] piperidines-3-base-4 hydroxybutyric acid ester (ZH-104-5-S)
Above-mentioned S-monomethyl succinate (ZH-104-4-SM) 200mg (0.42mmol) is dissolved in 5ml THF, room temperature adds lithium borohydride 15mg (0.56mmol) next time, stir sampling after 10 minutes, two products occur, one of them is the S-butyric ester of being expected.Most of raw material unreacted still after half an hour, but the S-4-oxy-compound obviously increases.Stopped reaction is crossed column purification, reclaims raw material 108mg; Get S-4-butyric ester 19mg; Yield 16.8%; NMR (CDCl 3):, and 1.70-1.89 (m, 4H); 2.06 (m, 2H); 2.34 (s, 3H); 2.36 (t, 2H); 2.90 (m, 2H); 3.06 (m, 1H); 3.23, (m, 1H); 3.66 (t, 2H); 5.09 (m, 1H); 7.05-7.44 (m, 7H); 8.01 (s, 1H).
Embodiment 21:S-1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-amide group] piperidines-3-base-triflate (ZH-104-7-S)
(S)-5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-S) 330mg (0.6mmol) is dissolved in 15ml CH 2Cl 2In, ice-water bath is cooled to 5 ℃, drips trifluoromethanesulfchloride chloride 101.1mg (0.6mmol) 10ml CH 2Cl 2Solution adds 306mg (1.67mmol) triethylamine, and reaction can not be complete, and TLC detects has product to generate, with twice of 15ml water washing; The organic phase saturated NaCl solution washing of 15ml, anhydrous Na SO 4Drying, filtering and concentrating, column chromatography gets white solid 11mg (0.364mmol), yield 2.9%. 1H-NMR(CDCl 3)：δ，1.96～1.98(m，2H)；2.38(s，3H)；2.77-2.83(m，2H)；2.97(m，1H)；3.12(m，1H)；3.22(m，1H)；3.43～3.46(m，1H)；4.55(s，1H)；7.06-7.44(m，7H)；8.25(s，1H)。
Embodiment 22:(R/S)-and 1-[5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1-H-arsenic azoles-3-amide group] piperidines-3-base acetic ester (ZH-204-1-R/S) and (R)-enantiomorph (ZH-204-1-R) and (S) enantiomorph (ZH-204-1-S)
(R/S)-5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-201-R/S) 0.538g (1.0mmol) is dissolved in 15ml CH 2Cl 2In, ice-water bath is cooled to 5 ℃, and dripping acetyl chloride 0.0942g (1.2mmol) is at 10ml CH 2Cl 2In solution, add 0.306g (3.0mmol) triethylamine, stirring reaction detects raw material to TLC and exhausts; With twice of 15ml water washing; The organic phase saturated NaCl solution washing of 15ml, anhydrous Na SO 4Drying, filtering and concentrating, column chromatography gets white solid 0.411g (0.767mmol), yield 76.7%.mp：87.1～91.1℃； 1H-NMR(CDCl 3)：δ，1.20～1.23(m，3H)；1.67(bs，1H)；1.82(bs，2H)；1.87～1.90(bs，1H)；2.11(s，3H)；2.76～2.78(m，2H)；3.17(bs，1H)；3.40～3.41(m，2H)；3.60(bs，1H)；5.09(s，1H)；7.01～7.49(7H，m)。
From (R)-5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-201-R), then obtain ZH-204-1-R.
From (S)-5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-201-S), then obtain ZH-204-1-S, mp:152.8～156.0 ℃.
Embodiment 23:(S)-(R/S)-1-[(5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group)]-piperidines-3-base-2-alanine ester (ZH-107-1-S-R/S)
(A) with (R/S)-5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-R/S) 0.479g (1mmol), N-Boc-L-L-Ala 0.1894g (1mmol), HOBT0.269g (2mmol), EDC.HCl0.768g (4mmol) place reaction flask, vacuum-drying 30 minutes.Add DMF15ml, triethylamine 0.4ml; Room temperature reaction spends the night under nitrogen protection.Reaction solution is poured in the frozen water, white solid is separated out, this solid of filter collection and behind column chromatography purification, obtain product (S)-(R/S)-1-[(5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group)]-piperidines-3-base-2-tertbutyloxycarbonyl-alanine ester 124mg, yield 19.4%.Reclaim raw material acid amides 0.244g, the rate of recovery 51%.Product mp; 83.6～87.4 ℃. 1H-NMR(CDCl 3)：δ，1.36(d，3H)；1.47(s，9H)；1.69(m，4H)；2.31(s，3H)；3.02～3.49(m，4H)；4.30(s，1H)；5.09(s，1H)；7.06-7.45(m，7H)；8.20(bs，1H)；8.40(bs，1H)
(B) above-mentioned intermediate 124mg is dropped in the solution 5ml of trifluoroacetic acid 25% concentration in methylene dichloride, stirring at room 2 hours shows that until TLC raw material reaction finishes.Steaming desolventizes, and column chromatography purification obtains product (ZH-107-1-S-R/S) 73mg that expected, yield 70%. 1H-NMR(CDCl 3)：δ，1.20-1.38(m，3H)；1.71(bs，3H)；2.06(s，1H)；2.31(s，3H)；2.85(bs，1H)；3.01-3.20(m，2H)；3.48～3.52(m，1H)；4.18(bs，1H)；5.18(bs，1H)；7.04-7.42(m，7H)；8.02(d，1H)。
Embodiment 24:(S)-(S)-1-[(5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group)]-piperidines-3-base-2-alanine ester (ZH-107-1-S-S) and (S)-(R)-1-[(5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group)]-piperidines-3-base-2-alanine ester (ZH-107-1-S-R)
(A) with (S)-5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-S) 700mg (1.45mmol), N-Boc-L-L-Ala 400mg (2.11mmol), HOBT538mg (4mmol), EDC.HCl 1.5g (7.8mmol) place reaction flask, vacuum-drying 2 hours.Add DMF30ml, triethylamine 0.8ml; Room temperature reaction spends the night under nitrogen protection.Reaction solution is poured in the frozen water, the white solid that the filter collection is separated out, behind column chromatography purification, obtain product (S)-(S)-1-[(5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group)]-piperidines-3-base-2-tertbutyloxycarbonyl-alanine ester 420mg, yield 45.3%.
(B) above-mentioned intermediate 420mg is dropped in the solution 15ml (25% concentration) of trifluoroacetic acid in methylene dichloride, stirring at room 2 hours shows that until TLC raw material reaction finishes.Steaming desolventizes, and column chromatography purification obtains product (ZH-104-4-S-S) 148.3mg that expected, yield 41.3%; Fusing point: 114.8～116.3 ℃.
1H-NMR(CD 3OD)：δ，1.30(m，3H)；1.74-1.83(m，3H)；2.07～2.18(m，1H)；2.33(s，3H)；2.84(m，1H)；2.98(bs，1H)；3.06(bs，1H)；3.30(bs，1H)；4.09(bs，1H)；5.16(s，1H)；7.21-7.59(m，7H)。
From (R)-5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-R) sets out, according to same program preparation (S)-(R)-1-[(5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group)]-piperidines-3-base-2-alanine ester (ZH-107-1-S-R)
Embodiment 25:S-1-[5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-amide group] piperidines-3-base-phenylalanine ester (ZH-107-2-S-S)
(A) with (S)-5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-101-S) 600mg (1.25mmol), N-Boc-L-phenylalanine-3,4-quinone 32mg (1.25mmol), HOBT538mg (4mmol), EDC.HCl1.538g (8mmol) place reaction flask, vacuum-drying 2 hours.Add DMF30ml, triethylamine 0.8ml; Room temperature reaction spends the night under nitrogen protection.Reaction solution is poured in the frozen water, white solid is separated out, this solid of filter collection and behind column chromatography purification, obtain product (S)-(S)-1-[(5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-4-methyl isophthalic acid-H-pyrazoles-3-amide group)]-piperidines-3-base-2-tertbutyloxycarbonyl-amino-benzene ethylformic acid ester 378mg, yield 41.6%.
(B) above-mentioned intermediate 378mg is dropped in the solution 15ml of trifluoroacetic acid 25% concentration in methylene dichloride, stirring at room 2 hours shows that until TLC raw material reaction finishes.Steaming desolventizes, and column chromatography purification obtains product S-1-5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-amide group of being expected] piperidines-3-base-phenylalanine ester 212mg, yield 65%.Fusing point: 107.3～111.3 ℃. 1H-NMR(CDCl 3)：δ，1.59～1.62(m，2H)；1.81(s，1H)；2.04(m，1H)；2.31(s，3H)；2.86～2.92(m，2H)；2.99～3.03(m，1H)；3.29～3.45(m，3H)；4.42(s，1H)；5.20(s，1H)；7.06-7.44(m，14H).
Embodiment 26:(S)-(S)-1-[(5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1-H-pyrazoles-3-amide group)]-piperidines-3-base-alanine ester (ZH-207-1-S-S)
(A) with 5-(4-bromophenyl)-1-(2, the 4-dichlorophenyl)-4-ethyl-1H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-201-S) 336mg (0.625mmol), N-Boc-L-L-Ala 400mg (2.11mmol), HOBT538mg (4mmol), EDC.HCl1.5g (7.8mmol) place reaction flask, vacuum-drying 2 hours.Add DMF 30ml, triethylamine 0.8ml; Room temperature reaction spends the night under nitrogen protection.Reaction solution is poured in the frozen water, white solid is separated out, this solid of filter collection and behind column chromatography purification, obtain product (S)-(S)-1-[(5-(4-bromophenyl)-1-(2, the 4-dichlorophenyl)-4-ethyl-1-H-pyrazoles-3-amide group)]-piperidines-3-base-2-tertbutyloxycarbonyl-alanine ester 248mg, yield 58%.
(B) above-mentioned intermediate 248mg is dropped in the solution 15ml of trifluoroacetic acid 25% concentration in methylene dichloride, stirring at room 2 hours shows that until TLC raw material reaction finishes.Steaming desolventizes, column chromatography purification, obtain product (S)-(S)-1-[(5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1-H-pyrazoles-3-amide group of being expected)]-piperidines-3-base-alanine ester (ZH-207-1-S-S) 136.8mg, yield 64.1%.141.5～145.7 ℃ of fusing points. 1H-NMR(CDCl 3)：δ，1.18(bs，3H)；1.69(m，3H)；1.76(m，3H)；2.29(m，1H)；2.76(m，3H)；2.90(s，1H)；3.14(s，1H)；3.42(m，1H)；4.16(bs，1H)；5.26(s，1H)；7.01-7.48(m，7H)；7.82(s，1H)。
Embodiment 27:(S)-(S)-1-[(5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1-H-pyrazoles-3-amide group)]-piperidines-3-base-amino-benzene ethylformic acid ester (ZH-207-2-S-S)
(A) with 5-(4-bromophenyl)-1-(2, the 4-dichlorophenyl)-4-ethyl-1H-pyrazoles-3-carboxylic acid (3-hydroxy piperidine-1-yl) acid amides (ZH-201-S) 336mg (0.625mmol), N-Boc-L-phenylalanine-3,4-quinone 31mg (1.25mmol), HOBT400mg (3mmol), EDC.HCl1.1g (6mmol) place reaction flask, vacuum-drying 2 hours.Add DMF 30ml, triethylamine 0.8ml; Room temperature reaction spends the night under nitrogen protection.Reaction solution is poured in the frozen water, white solid is separated out, this solid of filter collection and behind column chromatography purification, obtain product (S)-(S)-1-[(5-(4-bromophenyl)-1-(2, the 4-dichlorophenyl)-4-ethyl-1-H-pyrazoles-3-amide group)]-piperidines-3-base-2-tertbutyloxycarbonyl-amino-benzene ethylformic acid ester 373mg, yield 59.7%.
(B) above-mentioned intermediate 373mg is dropped in the solution 15ml of trifluoroacetic acid 25% concentration in methylene dichloride, stirring at room 2 hours shows that until TLC raw material reaction finishes.Steaming desolventizes, column chromatography purification, obtain product (S)-(S)-1-[(5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1-H-pyrazoles-3-amide group of being expected)]-piperidines-3-base-amino-benzene ethylformic acid ester 161mg, fusing point: 123.1～126.7 ℃.Yield 63%. 1H-NMR(CDCl 3)：δ，1.18(s，3H)；1.62(m，3H)；2.01(m，1H)；2.72(m，3H)；2.88(d，1H)；2.99(m，1H)；3.19(s，1H)；3.39～3.50(m，2H)；4.40(s，1H)；5.18(s，1H)；7.01-7.48(m，12H)。
Embodiment 28:(S)-and 1-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-arsenic azoles-3-formamido-] arsenic coughs up alkane-3-base-5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-arsenic azoles-3-manthanoate (ZH-503-1-S)
A) (S) 1-nitroso-group-3-hydroxyl-arsenic is coughed up alkane
With (S)-3-hydroxy-pyrrolidine hydrochloride 1.855g (15.0mmol), NaNO 2, 2.07g (30.0mmol) is dissolved in respectively in 5ml and the 10ml water, mixes, and is cooled to 0 ℃.Under in 0 to 5 ℃,, in 15 minutes, add to wherein slowly dripping HOAc 1.36g (22.7mmol); It is complete to stir 4 hours afterreactions in 0 ℃ again.TLC:0.80 (product nitroso-group thing); (0.28 raw material) (ethanol: ammoniacal liquor=10: 1).With Na 2CO 3Among the 2g and remaining acetic acid; Use CH 2Cl 2Extract each 15ml 6 times; Merge organic phase; Use anhydrous Na 2SO 4Dry; Filter; Concentrate, get yellow liquid 1.418g; Yield 81.4%.Be directly used in next step reduction reaction.
B) (S) 1-amino-3-hydroxyl-arsenic is coughed up alkane
(24.3mmol 2eq) adds 15ml through the dry also distilled anhydrous THF of sodium Metal 99.5, stirs 15 minutes in about 40 ℃ with lithium aluminium hydride 0.924g; In this suspension, drip nitroso compound crude product 1.418g (12.21m mol, 1eq) solution in the anhydrous THF of 100ml.Controlled temperature is 40-45 ℃ during dropping, drips to last 20 minutes.Reflux 8 hours; Be cooled to room temperature, to the mixed solution of THF that wherein adds the 10ml undried and 10ml water (1: 1); 30 ℃ of stirring at room of what 0.5 hour.Filter; Filter cake washs (3 * 10ml) with THF; Again filter cake was dropped among the 15ml THF reflux 10 minutes, and refiltered; This operation repeats twice.Merge all filtrates; Use anhydrous Na 2SO 4Dry, concentrate crude product 0.97g, column chromatography concentrates, obtain the faint yellow dope of 0.48g (4.69mmol) after the vacuum-drying; Yield 38.4%.
C)ZH-503-1-S
(2.95mmol 2.1eq) is dissolved in 50ml CH with the acyl chlorides 1.18g of 5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid 2Cl 2, (4.5mmol 3.2eq), is cooled to 0 ℃ to add triethylamine 0.6ml; In 25 minutes, in this solution, be added dropwise to (S)-1-amino-3-hydroxyl arsenic and cough up alkane 0.143g (1.40mmol 1eq) stirred 3 hours in 0 ℃; Check with TLC and to react completely; Filter the solid of separating out, make column chromatography after the drying, (developping agent: ethyl acetate: sherwood oil=1: 1); Collection Rf is 0.7 flow point.Promptly obtain double-core product ZH-503-1-S, get 1.057g, yield 91.0%; Mp:153.4～158.1 ℃; 1H-NMR (CDCl 3): δ, 2.07 (m, 1H); 2.34 (s, 3H); 2.39 (s, 3H); 2.52 (m, 1H); 3.33 (m, 3H); 3.75 (m, 1H); 5.57 (s, 1H); 7.06～7.43 (m, 14H), 7.91 (s, 1H).
Embodiment 29:(S)-and 1-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-arsenic azoles-3-formamido-] arsenic coughs up alkane-3-base-acetic ester (ZH-503-2-S)
(S)-5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-N (3-hydroxyl arsenic is coughed up alkane-1-yl)-4-methyl isophthalic acid H-arsenic azoles-3-methane amide 40mg (0.086mmol) is dissolved among the 10ml DCM, adds Ac 2O 0.120ml and arsenic pyridine 0.5ml stir under the room temperature and spend the night, and TLC shows that primitive reaction finishes.Conventional processing obtains crude product, and (sherwood oil: wash-out vinyl acetic monomer 3: 1) obtains white product 24mg, yield 55.0% through the silicagel column purifying.
1H-NMR(400MHz，CDCl 3)：δ，1.55-1.70(m，2H)；2.14(s，3H)；2.18(s，3H)；3.88-3.93(m，2H)；4.23-4.26(m，2H)；5.19(m，1H)；7.10-7.12(m，2H)；7.29-7.32(m，4H)；7.42(s，1H)。
Embodiment 30:(S)-and 1-[5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-arsenic azoles-3-formamido-] arsenic coughs up alkane-3-base-5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-arsenic azoles-3-manthanoate (ZH-603-1-S).
With 5-(4-bromophenyl)-1-(2, the 4-dichlorophenyl)-the acyl chlorides 1.69g (3.68mmol of 4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid, 2.1eq), (S)-1-amino-3-hydroxyl pyrrolidine 0.18g (1.75mmol, 1eq), triethylamine 0.7ml (5.0mmol, 2.9eq) add in three mouthfuls of round-bottomed flasks of 50ml, what reacted 3 hours down for 0 ℃; After TLC tracking reaction finished, conventional aftertreatment obtained crude product; Column chromatography purification (eluent: ethyl acetate: sherwood oil=1: 1; RF=0.7), promptly obtain double-core product carboxylic acid amide esters ZH-603-1-S, must measure 1.46g, yield 88.0%, mp:132.1～134.0 ℃; 1H-NMR (CDCl 3):, 1.22 (m, 6H); 2.33 (m, 1H); 2.20 (m, 1H); 2.72～2.79 (m, 4H); 3.28 (m, 2H); 3.78 (m, 2H); 5.57 (s, 1H); 7.03～7.48 (m, 14H); 7.89 (s, 1H).

Claims (11)

1. unitary composite medicine: chirality Nitrogen-containing Heterocyclic Esters and physiologically acceptable salt or solvate, this chirality Nitrogen-containing Heterocyclic Esters and physiologically acceptable salt thereof or solvate external for the simplification compound, in case enter in the body then be converted into 2 kinds, even 3 kinds of pharmacological action intensity differences, effect emphasis difference, even interaction property " compound medicine " also inequality, its structure is shown in general formula (I):
Figure FDA0000055249810000011
R in this general formula (I) 1Be 1,5-disubstituted phenyl-4-R 4-pyrazole-3-yl, its structure is expressed with general formula (II):
Figure FDA0000055249810000012
In general formula (II), A 2, A 3, A 4, A 5, A 6B 2, B 3, B 4, B 5, B 6Be respectively H, F, Cl, Br or I atom, C1-C3 alkyl, C1-C3 alkoxyl group, trifluoromethyl or nitro; Wherein at least one is chlorine atom or methyl; B 4It also can be phenyl; The substituent R that the pyrazoles ring is 4 4For hydrogen, have side chain or have ring, saturated or undersaturated C1-C5 alkyl or-oxyl;
R in the general formula (I) 2Be C 1-C 8Straight chain, side chain or have ring filling or unsaturated alkyl or-oxyl;
In the general formula (I)
Figure FDA0000055249810000013
Be aliphatic nitrogenous heterocycle, n, m are the integer of 0-4 in the formula; And n+m equals the integer of 2-5; X is CH 2, NH, N-R 5, O, perhaps S; R 5For the C1-C16 alkyl or as R 3Defined acyl group;
Nitrogen-atoms on the aliphatic nitrogenous heterocycle in the general formula (I) passes through-N-R in turn 2Group and carbonyl C=O and R 1Be connected; Must have on this aliphatic nitrogenous heterocycle cause chirality-OR 3Ester appended; Wave line in the general formula is represented asymmetric connection; R wherein 3Acyl group for acyl group, aliphatics or aromatic sulphonic acid, phosphonic acids or the phosphonous acid of acyl group, aliphatics or the die aromatischen Aminosaeuren of aliphatics or aromatic carboxylic acid.
2. unitary composite medicine according to claim 1: chirality Nitrogen-containing Heterocyclic Esters and physiologically acceptable salt or solvate, it is characterized in that described aliphatic nitrogenous heterocycle is selected from: arsenic is coughed up alkane, imidazolidine, tetrahydrochysene arsenic azoles, thiazolidine, tetrahydrochysene oxazole, tetrahydrochysene isothiazole, tetrahydrochysene isoxzzole, piperidines, six hydrogen arsenic piperazines, hexahydropyrimidine, hexahydro-pyridazine or six hydrogen azatropylidenes;
Described aliphatic nitrogenous heterocycle also is selected from following heterocycle: octahydro indoles, octahydro isoindole, decahydroquinoline, Decahydroisoquinolinpreparation, decahydro naphthyridines, decahydro quinoxaline, ten dihydro carbazoles.
3. unitary composite medicine according to claim 2: chirality Nitrogen-containing Heterocyclic Esters and physiologically acceptable salt or solvate is characterized in that described nitrogen heterocyclic ring is that arsenic is coughed up alkane, piperidines, or six hydrogen azatropylidenes.
4. unitary composite medicine according to claim 3: chirality Nitrogen-containing Heterocyclic Esters and physiologically acceptable salt or solvate; it is characterized in that; described is the Nitrogen-containing Heterocyclic Esters of chirality, and physiologically acceptable salt or solvate, wherein causes the substituted acyl R of chirality on the piperidine ring 3For: ethanoyl, chloro ethanoyl, fluoro ethanoyl, allyl acyl group; Carboxylic formyl radical, 3-carboxypropanoyl, 4-maloyl group; The acyl group of acyl group, phosphenylic acid or the benzene phosphonous acid of the benzoyl that benzoyl, a chlorine or many chlorine replace, 2-Thenoyl, Phenylsulfonic acid; 2-amino-propionyl, 2-amino-3-phenyl propionyl, 2-amino-3-(2-thienyl)-propionyl, perhaps other acyl groups natural or synthesizing amino acid; These acyl groups have, and perhaps do not have chirality; When having chirality, comprise two kinds of enantiomorphs of R and S.
5. unitary composite medicine according to claim 1: chirality Nitrogen-containing Heterocyclic Esters and physiologically acceptable salt or solvate is characterized in that described is Nitrogen-containing Heterocyclic Esters and the physiologically acceptable salt or the solvate of chirality, described acyl group R 3Itself can have or do not have substituting group, substituting group is selected from: two keys, triple bond, carboxyl, hydroxyl, cyano group, nitro, saturated or undersaturated alkyl or-oxyl, halogen, amide group, sulfonamido, sulfonate group, phosphate-based and various aromatic substituting group; These substituting groups itself comprise or do not comprise the optics asymmetric center.
6. unitary composite medicine according to claim 1: chirality Nitrogen-containing Heterocyclic Esters and physiologically acceptable salt or solvate is characterized in that the R in the described structural formula (II) 4Be methyl or ethyl.
7. unitary composite medicine according to claim 1: chirality Nitrogen-containing Heterocyclic Esters and physiologically acceptable salt or solvate is characterized in that described A 2And A 4Be respectively Cl; Described B 4Be Cl or Br; Described A 3, A 5, A 6B 2, B 3, B 5, B 6Be difference H.
8. according to the described unitary composite medicine of one of claim 1～7: chirality Nitrogen-containing Heterocyclic Esters and physiologically acceptable salt or solvate, it is characterized in that, described is Nitrogen-containing Heterocyclic Esters and the physiologically acceptable salt or the solvate of chirality, acceptable salt is a hydrochloride on its physiology, hydrogen bromide salt, vitriol, sulfur hydrogen salt, dihydrogen orthophosphate, mesylate, methyl sulfate salt, maleate, fumarate, oxalate, naphthalene-2-sulfonic acid salt, gluconate, Citrate trianion, isethionate, tosilate, 3,5-dimethyl-benzyl sulfonate, or the quaternary ammonium salt that forms with alkyl halide, described alkyl halide is a fluorine, chlorine, bromine, or alkane iodide.
9. described unitary composite medicine of claim 1: the preparation method of chirality Nitrogen-containing Heterocyclic Esters and physiologically acceptable salt or solvate is characterized in that step is as follows:
Acyl chlorides with 2 equivalent Rimonabant parent nucleus carboxylic acids is handled 1-amino-3-hydroxy piperidine, just obtains the 3-hydroxy piperidine ester of arsenic triazole carboxylic acid acid amides, ZH-103-1, ZH-203-1; The ZH-703-1 of pentacyclic ZH-503-1, ZH-603-1 and seven-membered ring, ZH-803-1 can cough up alkane by same program from the amino 3-hydroxyl of 1-arsenic, perhaps 1-amino-4-hydroxy azatropylidene preparation:
Figure FDA0000055249810000031
Reaction formula 1, the preparation of the 3-hydroxy piperidine ester of arsenic triazole carboxylic acid acid amides
Acyl chlorides R with aliphatics or aromatic carboxylic acid 3Cl handles arsenic triazole carboxylic acid's 3-hydroxy piperidine acid amides, promptly obtains various arsenic triazole carboxylic acids' 3-ester group piperidine amide compound ZH-103 and ZH-104 series, perhaps ZH-203 and ZH-204 series, its synthetic route shown in reaction formula 2, the R in graphic 3Be various acyl groups.The compound ZH-503-2-S of same type also is preparation like this;
Figure FDA0000055249810000032
The preparation of reaction formula 2 3-ester group piperidine amide compounds
Perhaps, this type of product by corresponding carboxylic acid directly and the condensation and getting under the effect of catalyzer of arsenic triazole carboxylic acid's 3-hydroxy piperidine acid amides.
When with the mono-methyl acyl chlorides condensation of 3-hydroxy piperidine acid amides and Succinic Acid, just obtain ZH-104-4-SM, make the ZH-104-4-SM hydrolysis, obtain ZH-104-4-SA; With the ZH-104-4-SM reduction, just obtain ZH-104-5-S, shown in reaction formula 3:
Figure FDA0000055249810000041
The preparation route of reaction formula 3 ZH-104-4 and ZH-104-5
Be the 3-ester group piperidine amide compound of preparation corresponding to various aminoacid replacement, should use amino acid or corresponding acyl chlorides through overprotection, its synthetic route is shown in reaction formula 4:
Figure FDA0000055249810000042
Reaction formula 4 various amino acid whose-preparation of 3-ester group piperidine amide compound
Wherein:
Figure FDA0000055249810000043
Be equivalent to the OR in the general formula (I) 3, be the ester group of aliphatics or die aromatischen Aminosaeuren, PG is a protecting group, below identical.
Described various arsenic triazole carboxylic acids' 3-ester group piperidine amide compound is selected from ZH-103 and ZH-104 series, perhaps ZH-203 and ZH-204 series;
The 3-ester group piperidine amide compound of described various aminoacid replacement is compound ZH-107 and ZH-207 series;
The ester group of described aliphatics or die aromatischen Aminosaeuren, the R in the described reaction formula 4 6Be phenyl, benzyl, or benzyl, the 2-thiophene-methylene radical of replacement are arranged on the phenyl ring; With the various natural or corresponding substituting groups of synthetic amino acid;
Described PG is that protecting group is selected from, tertbutyloxycarbonyl Boc, benzyl.
10. the described unitary composite medicine of claim 1: chirality Nitrogen-containing Heterocyclic Esters and physiologically acceptable salt thereof or the solvate application on preparation hypotoxicity CB1 acceptor inhibitor.
11. unitary composite medicine according to claim 10: chirality Nitrogen-containing Heterocyclic Esters and physiologically acceptable salt thereof or the solvate application on preparation hypotoxicity CB1 acceptor inhibitor, it is characterized in that described hypotoxicity CB1 acceptor inhibitor is drug rehabilitation, smoking cessation, fat-reducing and treatment of diabetes medicine.
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