CN102250006B - 3-pyrazole carboxylic acid amide compounds, preparation method thereof and application thereof in preparation of medicament serving as CB1 receptor inhibitor - Google Patents

3-pyrazole carboxylic acid amide compounds, preparation method thereof and application thereof in preparation of medicament serving as CB1 receptor inhibitor Download PDF

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CN102250006B
CN102250006B CN201110122819.1A CN201110122819A CN102250006B CN 102250006 B CN102250006 B CN 102250006B CN 201110122819 A CN201110122819 A CN 201110122819A CN 102250006 B CN102250006 B CN 102250006B
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范如霖
冯建科
王�华
姚虎
乔林
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Abstract

The invention relates to 3-pyrazole carboxylic acid amide compounds, a preparation method thereof and application thereof in preparation of a medicament serving as a CB1 receptor inhibitor, and belongs to the technical field of pharmaceutical chemistry. The chemical structural general formula of the compounds is shown as (I), wherein R1 is 1,5-disubstituted phenyl-4-R9-pyrazole-3-group, the chemical structural general formula of which is shown as (II). The compounds are characterized in that: R3 in the general formula (I) corresponds to substituted groups except amino and carboxyl in various alpha-amino acid molecules; and R6 and R7 are simultaneously H or O. The compounds have in vitro activity equivalent to that of rimonabant; and compared with the rimonabant, the toxicity of the compounds is obviously reduced.

Description

3-pyrazole carboxylic acid amides compounds, its preparation method and in preparation as the application in CB1 acceptor inhibitor medicine
Technical field
The present invention relates to a kind of 3-arsenic triazole carboxylic acid amides, its preparation method is usingd and preparation as the application in CB1 acceptor inhibitor medicine, be specifically related to its application in preparing anti-additive medicament, slimming medicine and treatment diabetes medicament as CB1 acceptor inhibitor, belong to pharmaceutical chemistry technical field.
Background technology
Since the product profit of French Sanofi-Aventis company is not just like that because the toxic side effect for central nervous system is withdrawn from the market, the many enterprises such as U.S., Fa, Yin,Han, Hungary find the CB1 acceptor inhibitor that they study, although structure is very not identical to each other, all shows same toxicity.Within one not long period, much pharmacy man was once suspected, this toxic side effect may be that CB1 acceptor inhibitor is difficult to avoid.But in the near future, pharmacy men are devoted to research and make its toxicity strategy separated with drug effect.Even someone thinks " the now real beginning of CB1 acceptor inhibitor research just " [1].
Summary of the invention
The object of the invention is, with respect to the toxicity of prior art compared with for strong CB1 acceptor inhibitor, a kind of new hypotoxic CB1 acceptor inhibitor is provided, and the application of this hypotoxic CB1 acceptor inhibitor in preparing anti-additive medicament, the application in preparing slimming medicine, and the application in preparation treatment diabetes medicament.CB1 acceptor inhibitor of the present invention can be used for preparing anti-additive medicament, slimming medicine and treatment diabetes medicament, have and profit suitable external activity just like that not, and the toxicity toxicity of central nervous system (especially for) Billy does not obviously reduce just like that, be expected to overcome the Side effect that the CB1 acceptor inhibitor of prior art shows.
In order to realize technical purpose of the present invention, technical scheme of the present invention is as follows.
One, a 3-arsenic triazole carboxylic acid amides, its chemical structure of general formula is as shown in (I):
Figure BDA0000060859440000011
Structural formula (I)
Wherein, R 1be 1,5-disubstituted phenyl-4-R 9-pyrazole-3-yl, as shown in structural formula (II):
Figure BDA0000060859440000012
Structural formula (II)
In structural formula (II):
A 2, A 3, A 4, A 5, A 6; B 2, B 3, B 4, B 5, B 6being same to each other or different to each other, is H, F, Cl, Br, or I atom, C1-C3 alkyl, C1-C3 alkoxyl group, trifluoromethyl or nitro; B 4or phenyl;
In structural formula (II), A 2, A 3, A 4, A 5, A 6; B 2, B 3, B 4, B 5, B 6in these substituting groups, have at least one to be chlorine atom or methyl; B 4especially chlorine or bromine; A 2and A 4especially chlorine;
Substituent R in structural formula (II) on 4 of pyrazole rings 9for hydrogen or C1-C5 alkyl, especially methyl or ethyl; Alkyl can be straight or branched;
In structural formula (II), the substituting group that pyrazole ring is 3 is corresponding to the acid amides in structural formula (I), and this part is amino acid, or the recessive carboxyl of the multi-form ester of amino acid carboxyl, acid amides or heterocycle form; Or amino acid whose carboxyl is reduced produced alcohol; And the derivative of this alcohol, such as ether or various forms of ester;
In structural formula (I), R 2being the alkyl of H, C1-C5 straight or branched, can be also acyl group;
In structural formula (I), R 4and R 5it is the alkyl of H or C1 to C10 straight or branched; Hydrogen on any one carbon in alkyl can be substituted, and the group of replacement can be halogen, hydroxyl, sulfydryl or sulfonic group; R 4with R 5can be same to each other or different to each other;
In structural formula (I), n can equal 0 (zero), 1,2,3,4 or 5;
In structural formula (I), R 6and R 7be H simultaneously, or be O jointly;
Wherein the first situation is, works as R 6and R 7while being H simultaneously, R 3can be, but be not limited only to H, CH 3, CH 2cH 3, CH 2cH 2cH 3, CH (CH 3) 2, CH 2sH, CH (OH) CH 3, CH 2cOOH, CH 2cH 2cOOH, CH 2c 6h 5, CH 2c 6h 4(2-Cl), CH 2c 6h 4(3-Cl), CH 2c 6h 4(4-Cl), CH 2c 6h 3(2,4-, bis-Cl), CH 2c 6h 3(3,4-, bis-Cl), CH 2c 6h 4(4-OH), CH 2c 6h 4(2-OCH 3), CH 2c 6h 4(4-OCH 3), CH 2c 6h 3(2,4-, bis-OCH 3), CH (CH 3) CH 2cH 3, CH 2cH 2cH 2cH 2nHCOR 1, CH 2cH (CH 3) 2, CH 2cONH 2, CH 2cH 2cONH 2,
Figure BDA0000060859440000021
Figure BDA0000060859440000022
cH 2c 6h 4(4-OCF 3), CH 2cH 2sCH 3, or or CH 2c 6h 4(4-OR 10), R 10be defined as follows and state.
And, work as R 3while being not equal to H, the amino acid whose absolute configuration of amide moieties can be R, can be S, can be also this two racemic mixture;
Work as R 6and R 7while being H simultaneously, R 8oR 10;
Wherein, R 10can be the alkyl of H, (C1-C16) straight chain, side chain or ring-type, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl; R 10it can also be the acyl group of the saturated or undersaturated lipid acid of various C1-C16, these acyl groups can be with the substituting group of halogen, amino, alkoxyl group and so on, such as ethanoyl, chloro ethanoyl, vinylformic acid acyl group, beta-methoxy-carbonyl propionyl, β-carboxypropanoyl, γ-maloyl group etc.; R 10can also be various aromatic acyl groups, such as the benzoyl of benzoyl, replacement etc.; And even various aliphatics or aromatic amino acid whose acyl group, such as the acyl group of L-Ala is, acyl group of phenylalanine, pantonine-(2-thiazolyl)-L-Ala acyl group etc.; Amino acid whose configuration can be R, can be also S, can also be their racemic mixture;
The second situation, in structural formula (I), works as R 6and R 7while being jointly O, R 3cH 2cH 2sCH 3,
Figure BDA0000060859440000024
or CH 2c 6h 4(4-OCF 3);
Now, R 8oR 10or NR 11r 12;
Wherein, R 10can be the alkyl of H, (C1-C16) straight chain, side chain or ring-type, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
At NR 11r 12in, R 11with R 12it can be the alkyl of H, C1-C6 straight chain, side chain or ring-type; In same a part, R 11with R 12can be identical or different;
Work as R 10while equaling H, the present invention includes may be as medicinal, by this acid, reacted with positive ion and the salt that produces, and such as sodium, potassium, magnesium, calcium, or the formed salt of various quaternary ammonium cations;
In structural formula (I), also can be itrile group CN, can be the heterocycle being gone out by carboxylic acid derivatives, comprises
Figure BDA0000060859440000032
Figure BDA0000060859440000033
r in formula 13for hydrogen or C 1-C 6the alkyl of straight chain, side chain or ring-type.
Compound described in the application (I) also comprises other various possible salts, other described possible salts comprise, but be not limited to 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, or 3,5-dimethyl-benzyl sulfonate and and alkyl halide, particularly C 1-C 10the quaternary ammonium salt that the muriate of alkyl, bromide or iodide form.
The CB1 acceptor inhibitor of structural formula (I) representative also comprises: the mixture that the salt of its corresponding free acid of certain ester wherein or acid is formed; Or the mixture forming to other compound that meets structural formula (I) is used for the treatment of the illness relevant with CB1 acceptor.The ratio of each composition in mixture, can give adjustment according to the emphasis for the treatment of.
In a word, the various CB1 acceptor inhibitors of now having delivered with countries in the world are compared, and as a part for molecule, have that introduce, natural or synthetic amino acid primitive by esterification, amidation or alternate manner in structure of the present invention.
Hypotoxic CB1 acceptor inhibitor of the present invention, except the represented compound of claimed structure formula (I) itself and, also require their solvate.
The prioritization scheme that the application recommends, should be top-priority: A 2, A 4, and B 4these three compounds that substituting group is chlorine atom or bromine atoms.
Two, the preparation method of 3-arsenic triazole carboxylic acid amides of the present invention:
First by amino acid by sulfur oxychloride and methyl alcohol esterification, obtain the hydrochloride of amino acid methyl ester, with 5-(4-halogenophenyl)-1-(2,4 dichloro benzene base)-4-alkyl-1H-pyrazoles-3-carboxylic acid chloride (II) condensation, obtain product methyl esters (III) again; Ester obtains corresponding free acid (IV) through basic hydrolysis.Under the catalysis of EDC.HCl, HOBT, this acid is reacted with alcohol and is obtained ester (V); Or react with amine and obtain acid amides (VI).As shown in reaction formula 1:
Figure BDA0000060859440000034
Figure BDA0000060859440000041
Reaction formula 1: the preparation of product methyl esters, free acid, other forms of ester class and acid amides
In order to prepare the ester (V) of other form, also can first amino acid be reacted and be converted into expected amino acid ester (VII) with corresponding alcohol, then with above-mentioned acyl chlorides (II) condensation, as shown in reaction formula 2.The preparation method of intermediate (VII) can be identical with methyl esters; Can under acid (as tosic acid hydrate) catalysis, amino acid and corresponding alcohol be utilized to water trap reflux, dehydration esterification.Also can, from N-Boc amino acid, under the catalysis of EDC hydrochloride, HOBT, DMAP with after alcohol condensation, slough again protecting group Boc.
Figure BDA0000060859440000042
Reaction formula 2: other method of preparing ester class
As by aforesaid amino acid methyl ester (I) ammonia solution in addition, the amino acid amide producing (VIII) and acyl chlorides (II) condensation, obtain the acid amides (IX) of unsubstituted on nitrogen, as reaction formula 3:
Reaction formula 3: the acid amides of preparing unsubstituted on nitrogen.
The acid amides obtaining is processed and just to be produced nitrile with phosphorus oxychloride, as reaction formula 4:
Figure BDA0000060859440000052
Reaction formula 4: prepare nitrile from acid amides
Condenses methyl esters, with the hydrogen reduction of lithium boron, is just obtained to corresponding alcohol; Make amino acid condensation under the effect of catalyzer of this alcohol and various aliphatics or aromatic carboxylic acid, protection, or with the acyl chlorides direct polycondensation of above-mentioned various acid, just obtain corresponding various ester, as reaction formula 5:
Figure BDA0000060859440000053
Reaction formula 5: methyl esters is reduced to alcohol, and be further converted to various esters
R in formula 10for various aliphatics or aromatic carboxylic acid or amino acid whose acyl group.
Contriver is in patent application before [2]in once mentioned condenses (compounds X III, the IC of tyrosine 50227.4nM); Find afterwards, once by the HM on its phenyl ring, just improve a lot (compound ZH-313-SM, IC for the inhibition activity of CB1 acceptor 5026.3nM).In this application, for pursuing stronger activity, inventor obtains (XIV) by this hydroxyl trifluoromethylation; Reply as after methyl esters (XV), restore into alcohol (XVI), with various acyl chlorides or acid, react with it and form ester (XVII), as reaction formula 6:
Figure BDA0000060859440000061
Reaction formula 6, the ester of fluorine, the preparation of compound (XVII)
Or; if first protect the hydroxyl on tyrosine condenses (XIII) to provide intermediate (XVIII); reduction produces alcohol (XIX); trifluoromethylation obtains (XX); slough again protecting group and just obtain compound (XXI); finally with various acyl chlorides or acid, react with it and just form another class ester (XXII), as reaction formula 7:
Reaction formula 7, another kind of fluorine-containing ester, the preparation of compound (XXI).
Three, 3-arsenic triazole carboxylic acid amides of the present invention is being prepared as the application in CB1 acceptor inhibitor medicine.
Wherein, described application refers to its application in preparing anti-additive medicament, stop smoking medicine or Temperance medicine.
Described application refers to its application in preparing slimming medicine.
Described application refers to that it is in the application in preparation treatment diabetes medicament.
Action principle of the present invention and beneficial effect are:
In view of the reality that existing CB1 acceptor inhibitor Rimonabant is eliminated because toxicity is too high, what strategy of the present invention was the drug effect of seeking this type of medicine with its toxicity is separated; With the highest one-tenth property of medicine, but not the highest activity is for pursuing a goal.The IC of a lot of marketed drug 50numerical value be with μ M (1,000nM) represent, and according to contriver's experimental value, the IC of Rimonabant 50for 11.2nm, its activity is very high as seen.In order to pursue the reduction of toxicity, so high activity, can tolerate sacrifice to a certain degree completely.First part of related application applicant [2]in, the IC of compound ZH-303-SA 50numerical value is up to 3,500nM, under the concentration of 10 μ M, but just corresponding to the inhibiting rate of CB1 receptor 9 5%.Based on this fact, contriver thinks, with regard to CB1 acceptor inhibitor, and every IC 50numerical value, lower than the compound of 5,000nM (5 μ M), needs only toxicity very low, the clinical medicine that just may become.For this reason, contriver introduces molecule by each seed amino acid with the form of ester, be hydrolyzed into after free carboxy acid, from carboxylic acid derivatives, go out again the recessive carboxyl of multi-form ester, acid amides or heterocycle form, or be reduced into alcohol, and be further converted to various ester, and improve thus the wetting ability of compound, increase donor and/or the acceptor number of hydrogen bond simultaneously.Last patent application applicant [2]in, contriver has proposed phenylalanine etc. and arsenic triazole carboxylic acid's condenses, a lot of show strong activity all, and also toxicity is very low.Contriver is once discovery in the research of polypeptide drug, and when with pantonine-(2-thienyl)-propionic acid substituted benzene L-Ala, the activity of product is often more powerful.In view of this, contriver synthesized last stage research and on once application [2]in pantonine-(2-thienyl)-propionic acid of not related to and arsenic triazole carboxylic acid's condenses; Consider the specific action of fluorine atom, contriver has studied the condenses of pantonine-(4-trifluoromethyl-phenyl)-propionic acid; And for mentioning in last patent application, but the methionine(Met) condenses of further investigation has not been done further exploitation.
In general, hydrophilic radical itself just may make drug toxicity decline; It must fall again the penetrating rate of low molecular hemato encephalic barrier, makes the less central nervous system that enters of medicine.These factors should weaken and cause depressed side effect.Moreover, because inhibitor is also incomplete same for the pharmacological action of CB1 acceptor in peripheral nerve and central nervous system, compound of the present invention may act on periphery and gi tract neural system more, will show certain characteristic, may show better fat-reducing effect first exactly.
By the higher ester of the penetrating rate of the hemato encephalic barrier free acid lower from the penetrating rate of hemato encephalic barrier in different ratio compound uses, particularly by this compounds and formerly patent application of applicant [2,3,4]middle applied for compound merges use, and likely optionally emphasis acts on cental system or peripheral nervous system, thereby produces different pharmacological effects.
As a rule, introduce the amino acid whose while and also just introduced asymmetric center.Contriver thinks, since life itself is exactly chirality, the molecule with chirality will may have single-minded drug effect more, also may make toxicity reduce.
Make a general survey of the high reactivity CB1 acceptor inhibitor found so far, can finding out any one position in this quasi-molecule,---they can replaced or modify---all do not have very strong specificity, molecule itself be likely one of common trait of this quasi-molecule closely.By introducing different amino acid, contriver is regulated " tightness " or the profile of molecule, and contriver expects that this also will contribute to facilitate the separated of drug effect and toxic side effect.
Amino acid whose introducing also may improve the bioavailability of compound.
In fact, the toxicity of CB1 acceptor inhibitor can be separated with its drug effect, and contriver's preliminary study goes out amino-acid compound and two classifications of 3-hydroxy piperidine compound [2,3,4], they all show enough powerful, the external activity identical with Rimonabant even, and toxicity is very low; A lot of compounds that this patent is applied for are also like this.
This patent research discovery again, the alcohol that the methyl esters of amino condensation compound produces through reduction still shows very strong activity, and representational compound is listed in table 4 below; From this alcohol, can further derive again hypotoxicity, highly active ester class, as above-mentioned reaction formula 5,6, shown in 7; Part of compounds is listed in table 5 hereinafter and table 6.
Applicant also proposes a kind of new theory at this point: " single composite medicine ".The ZH-303-SAL-13 of hereby take in table 5 is explained as example, as reaction formula 8:
Figure BDA0000060859440000081
Reaction formula 8, compound ZH-303-SAL-13 enters the variation after human body
Compound ZH-303-SAL-13 is the compound of a kind of " single ", once enter human body, in the absorbed while of part, certainly will in gi tract, partly be hydrolyzed into ZH-303-SAL-00 and 2,4 dichloro benzene formic acid.The latter is the by product of non-activity, safety; The former is but activated (IC 50198.1nM), it is also absorbed by health.So " single " once compound ZH-303-SAL-13 enters human body, just become the two " dual composite medicine " of this prototype and its hydrolysate, thereby produces comprehensive effect.Prototype compound ZH-303-SAL-13, as a kind of ester, more easily sees through hemato encephalic barrier; And hydrolysate ZH-303-SAL-00 is because wetting ability is stronger, by the less cental system that enters.The ratio of these two active compounds, is just equaling the ratio that prototype compound is absorbed and is hydrolyzed substantially; And this ratio can regulate; The method regulating is to change ester group.In fact the penetrating rate of the hemato encephalic barrier of prototype ester itself also can regulate, and the mode of adjusting is still that the penetrating rate of hemato encephalic barrier that changes ester group: ZH-303-SAL-01 is obviously different from ZH-303-SAL-13.
Reference:
[1]F.J.Bermudez-Silva，d，□M.P.Viverosb，J.M.McPartland?c，F.Rodriguez?de?Fonseca?a；“The?endocannabinoid?system，eating?behavior?and?energy?homeostasis：The?end?or?a?new?beginning？”；Pharmacology，Biochemistry?and?Behavior；95(2010)375-382.
[2] Fan Rulin; Chinese patent application 201010187654.1.
[3] Fan Rulin, Chen Zhiyuan; Chinese patent application 201110027174..
[4] Fan Rulin; Chinese patent application 201110092998.9.
Accompanying drawing explanation
Fig. 1 determines the detected result (first group) of product external activity by measuring the inhibiting rate of CB1 acceptor;
Fig. 2 determines the detected result (second group) of product external activity by measuring the inhibiting rate of CB1 acceptor.
The external activity of product
The 5-of synthesized of the present invention (4-halogenophenyl)-1-(2, the carboxylic acid derivative of 4-dichlorophenyl)-4-alkyl-1H-pyrazoles-3-carboxylic acid or its acyl chlorides and amino acid whose condenses and these condensess, comprise ester, acid amides, the free acid of methyl esters, other form, the recessive carboxylic compound of heterocycle form and reduzate alcohol or the ester class that further derived by this alcohol, in vitro in screening active ingredients, majority all shows very high or high inhibition activity, relevant IC to CB1 acceptor 50data are listed respectively table 2 below in to table 5 according to the classification of compound.IC 50data system measures by two kinds of methods:
First method ，You U.S. associated mechanisms is measured, experimental procedure:
First radioactivity [3H]-Li Mo is dissolved in just like that contain 0.25%BSA (pH 7.4) take HEPES as basic binding buffer liquid, concentration is 2～5nM; In 96 The Small Wells on test panel, put into the Chinese hamster ovary celI membranin that 3 μ g have expressed CB1 acceptor; Ratio by sample with 1: 100 is dissolved in DMSO and is incorporated in these The Small Wells.Allow test panel at room temperature hatch 1.5 hours; With a Packard cell harvestor, reaction mixture being proceeded to GF/B filter plate stops association reaction.Washing filter plate, the material on plate calculates with Packard scintillometer (Packard TopCount Scintillation Counter); Add the inactive profit of excessive 1000 times not measure just like that non-specific connection; From sum, deduct non-specific connection and be special connection.Based on sum and non-specific connection, CPM is scaled to inhibition percentage; With suppressing data and curve calculation IC50 value.
Second method ，You Zhejiang University school of life and health sciences bio-technology department is measured.With 3 compounds once measuring according to first method as interior mark, (ginseng table 1), experimental procedure:
1. cell cultures and stable expression cell strain build: the cell strain for this project is mainly HEK293 cell.This cell adopts DMEM substratum to add 10%FBS.Cell transfecting or cotransfection expression of receptor carrier and reporter gene expression carrier Lipofectamine-2000.After transfection 24 hours, add G418, HEK293 cell is 800 μ g/mL, within three-tetra-days, changes once containing G418 fresh culture.After two weeks, visible obvious population of cells, choose after 20-30 population of cells's amplification, effect with functional experiment or flow cytometry recipient cell surface expression and reporter gene, frozen after overexpression cell line or the amplification of the good cell strain of function test, for drug screening, functionally active test with in conjunction with experiments such as active testings.
2. the detection of cAMP concentration in cell: add the serum-free DMEM containing different concns compound in cannabinoid CB 1 receptor and CRE-Luciferase stable expression cell strain cell, preincubate 15min, adding CB1 agonist win55212-2 to make final concentration is 1 μ M again, after stimulation 4-5h, detects cAMP activity.
3. the mensuration of luciferase activity: cell levels high flux screening model adopts cAMP response element (CRE) to control lower luciferase expression carrier sense cAMP, final employing detected luciferase activity and determined cAMP activity.Luciferase assays method: first suck the substratum that contains part, every hole adds 100 μ L lysates, shaking table is hatched after 15min, drawing 20 μ L lysate sample mixes with the 20 μ L detection liquid that prepare, put into rapidly F12 detector, read the average canbdle power in 5 seconds, with the expression amount of luminous intensity reflection luciferase number.Convert thus for the inhibiting rate of CB1 acceptor.
The result of the mensuration of this patent compound is respectively in table 2 to table 6; The measurement result of second method referring to accompanying drawing 1 and accompanying drawing 2.
Table 1, the result of two kinds of analytical procedures: for the IC of CB1 acceptor 50the reference of numerical value and inhibition percentage
Figure BDA0000060859440000091
Figure BDA0000060859440000101
Table 2, the ester of amino acid condensation and sour external activity, for the IC of CB1 acceptor 50numerical value or inhibiting rate
Figure BDA0000060859440000102
Figure BDA0000060859440000111
Table 3, the acid amides of amino acid condensation and the external activity of nitrile, for the IC of CB1 acceptor 50numerical value or inhibiting rate
Figure BDA0000060859440000121
Figure BDA0000060859440000131
Table 4, the external activity of the alcohol of amino acid condensation, for the IC of CB1 acceptor 50numerical value or inhibiting rate
Figure BDA0000060859440000132
Figure BDA0000060859440000141
Table 5, the ester of amino acid condensation alcohol or the external activity of ether, for the IC of CB1 acceptor 50numerical value
Figure BDA0000060859440000142
Figure BDA0000060859440000151
Figure BDA0000060859440000161
Table 6, the external activity of the amino acid ester of amino acid condensation alcohol, for the IC of CB1 acceptor 50numerical value
Figure BDA0000060859440000162
Figure BDA0000060859440000171
The compounds of this invention is for the acute toxicity of mouse
In the compounds of this invention, the toxicity of some compound is very low, and for example the ZH-303-SAL-13 in above-mentioned tabular compound is almost completely nontoxic for mouse.
Compound ZH-303-SAL-13 acute toxicity test:
Animal: body weight 18～22g mouse, male and female half and half.Explore the dosage range of 0 and 100% mortality ratio.
Method: get each 9 of male and female mouse, be respectively divided into 3 groups, ZH-303-SAL-13 and 1%CMC are configured to 5,000mg/Kg, 1,670mg/Kg, 557mg/Kg Three doses (9: 3: 1), give respectively three groups of mouse stomach administrations.
Rimonabant is made into same solution, 3 groups of mouse are made to parallel controlled trial.Separately get each 3 of male and female mouse, by 1%CMC gavage (blank group).Breeding observing 7 days.ZH-303-SAL-13 group is without dead mouse.And profit in contrast group just like that not, 5, under the dosage of 000mg/Kg, mouse is all dead in 5 days, 1, and Mortality under 670mg/Kg dosage.
Compound is synthetic
Embodiment 1:2-(S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide group]-4-first sulfydryl methyl-butyrate (ZH-301-SM) and corresponding acid (ZH-301-SA) thereof.
Figure BDA0000060859440000172
A) L-Methionine methyl ester hydrochloride
Under ice-salt bath is cooling, by the SOCl newly distilling 27.2mL (98.7mmol) is slowly added drop-wise to 100mL CH 3in OH, temperature is controlled at below-10 ℃, dropwises rear continuation and stirs 1 hour; Add wherein L-Methionine 8.19g (54.9mmol), temperature rising reflux 1 hour; Remove solvent under reduced pressure to dry; The CH that adds again 50mL 2M HCl 3oH solution, refluxed after 1 hour, and concentrating under reduced pressure, vacuum-drying, obtain 8.5g white solid.Yield 77.6%, mp, 147.9～148.2 ℃. 1H-NMR(400MHz，D 2O)δ：2.05(s，3H)；2.2(m，2H)；2.62(m，2H)；3.80(s，3H)；4.25(dd，1H)。
B) 2-(S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide group]-4-first sulfydryl methyl-butyrate (ZH-301SM).
Under nitrogen protection, 5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid chloride (2.0g, 5mmol, leq.) is dissolved in to 20mLCH 2cl 2, be cooled to 0 ℃; Slowly drip wherein L-Methionine methyl ester hydrochloride (1.20g, 6mmol) and Et 3n (1.52g, 15mmol) is at 20mLCH 2cl 2in solution, control temperature of reaction 0 ℃ of left and right.Dropwise and finish reaction; Water and saturated NaCl solution washing successively; With anhydrous Na 2sO 4dry, be evaporated to oily, vacuum-drying.Through column chromatography purification (eluent: EA: Hex=1: 4) obtain 2.11g solid, yield 80.2%, mp, 79.1～81.0 ℃; 1h-NMR (400MHz, CDCl 3) δ: 2.10 (m, 1H); 2.13 (s, 3H); 2.28 (m, 1H); 2.38 (s, 3H); 2.62 (m, 2H); 3.80 (s, 3H); 4.95 (m, 1H); 7.07-7.46 (m, 7H).
C) 2-(S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide group]-4-first sulfydryl butyric acid (ZH-301SA)
By 2-(S)-[5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-amide group]-4-first sulfydryl methyl-butyrate (ZH-301SM) (1.35g, 2.6mmol) join 50mLCH with the KOH methanol solution (3.9mL, 7.8mmol) of 2M 3in OH, under room temperature, stir after 2 hours, remove solvent under reduced pressure.In residuum, add 40mLH 2o, with 2 * 40mLEtOAc washing, water is acidified to pH2 with 6M HCl; Under room temperature, stir 2 hours, then use 5 * 10mLEA to extract, extracting solution is through anhydrous Na 2sO 4be dried, be evaporated to oily; Vacuum-drying obtains solid 1.13g, yield 86.26%, mp, 103.1～104.6 ℃; 1h-NMR (400MHz, CDCl 3) δ: 2.15 (s, 3H); 2.16 (m, 1H); 2.32 (m, 1H); 2.35 (s, 3H); 2.66 (m, 2H); 4.91 (m, 1H); 7.07-7.51 (m, 8H).
Embodiment 2:(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide group]-4-first sulfydryl butyric acid ring pentyl ester-(ZH-301-SAE-3)
A) L-Methionine ring pentyl ester trifluoroacetate
N-Boc-L-methionine(Met) 0.8g (3.2mmol) is dissolved in to 10mL methylene dichloride, ice bath is cooled to 0 ℃, add wherein cyclopentanol 0.34mL (3.74mmol), EDC.HCl 1.19g (6.2mmol) and DMAP38mg (0.31mmol), then add triethylamine 1.2mL (9mmol).Allowing reaction solution slowly rise to room temperature and to continue stirs 12 hours; Add after completion of the reaction the dilution of 30mL methylene dichloride, use in turn appropriate 1N HCl, 1N NaHCO 3with saturated common salt water washing.Organic layer is through anhydrous magnesium sulfate drying; Concentrate the quick column purification of crossing of gained crude product, obtain the N-Boc-L-methionine(Met) ring pentyl ester of 0.7g oily, yield 69%. 1H-NMR(CDCl 3)：δ：1.45(s，9H)；1.61-1.93(m，10H)；2.11(s，3H)；2.52-2.54(m，2H)；4.34-4.35(m，1H)；5.14-5.22(m，1H)
This ring pentyl ester 0.7g (2.20mmol) is dissolved in TFA/DCM (v/v=1/1) 30mL, and stirring at room 3 hours, obtains the trifluoroacetate of amino acid ring pentyl ester after concentrating under reduced pressure.
B)(ZH-301-SAE-3)
By 5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid chloride 202mg (0.5mmol) is dissolved in 5mLDCM, slowly adds and be dissolved with the trifluoroacetate (0.6mmol) of the above-mentioned amino acid ring of 200mg pentyl ester and the DCM solution 3mL of 0.21mL triethylamine under ice-water bath; Under room temperature, stir 10 minutes, TLC shows that reaction is complete; After concentrating under reduced pressure, through column chromatography purification, obtain 190mg, yield 55%; Mp, 52-52.8 ℃; 1h-NMR (CDCl 3): δ: 1.62-1.89 (m, 8H); 2.05-2.09 (m, 1H); 2.13 (s, 3H); 2.23-2.26 (m, 1H); 2.37 (s, 3H); 2.54-2.62 (m, 2H); 4.85-4.87 (m, 1H); 5.24-5.26 (m, 1H); 7.07-7.49 (7H).
Embodiment 3:2-(S)-[5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-amide group]-4-first sulfydryl methyl-butyrate (ZH-401-SM) and corresponding acid (ZH-401-SA) thereof
Under nitrogen protection, 5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-carboxylic acid chloride 2.0g (4.36mmol) is dissolved in to 20mLCH 2cl 2, be cooled to 0 ℃; Slowly drip wherein L-Methionine methyl ester hydrochloride (1.20g, 6mmol) and Et 3n (1.52g, 15mmol) is at 20mLCH 2cl 2in solution, control temperature of reaction 0 ℃ of left and right.Dropwise and finish reaction; Water and saturated NaCl solution washing successively; With anhydrous Na 2sO 4dry, be evaporated to oily, vacuum-drying.Through column chromatography purification (eluent: EA: Hex=1: 4) obtain 2.5g solid, yield 84%, mp, 47.0-47.6 ℃; 1h-NMR (400MHz, CDCl 3) δ: 1.18-1.22 (m, 3H); 2.07-2.08 (m, 1H); 2.13 (s, 3H); 2.26-2.31 (m, 1H); 2.60-2.64 (m, 2H); 2.77-2.83 (m, 2H); 3.80 (s, 3H); 4.92-4.94 (m, 1H); 7.02-7.48 (m, 8H).
According to the preparation procedure of ZH-301-SA, ZH-401-SM hydrolysis is just obtained to corresponding sour ZH-401-SA.
Embodiment 4:(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-amide group]-4-first sulfydryl butyric acid ring pentyl ester (ZH-401-SAE-3)
Operation is with the preparation procedure of (ZH-301-SAE-3), yield, 82%; Mp, 72.5-83.1 ℃; 1h-NMR (CDCl 3): δ: 1.18-1.24 (t, 3H); 1.62-1.88 (m, 8H); 2.07-2.09 (m, 1H); 2.13 (s, 3H); 2.23-2.27 (m, 1H); 2.60-2.64 (m, 2H); 2.77-2.78 (m, 2H); 4.85-4.87 (m, 1H); 5.24-5.26 (m, 1H); 7.02-7.48 (m, 8H).
Embodiment 5:(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-(4-benzyl oxy phenyl) methyl propionate (ZH-302B-SM)
By (S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-(4-hydroxy phenyl) methyl propionate (ZH-302-SM) [2]5g (9.0mmol) is dissolved in DMF50ml, adds Anhydrous potassium carbonate 4.2g (30mmol), benzyl bromine 1.85g (10.8mmol); Heating reflux reaction 4 hours; After cooling, pour into and in frozen water, obtain white suspension; With ethyl acetate 50mL extraction three times, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, the concentrated rear column purification of crossing obtains expected benzyl derivative 2.63g; Yield 45.1%. 1H-NMR(400MHz，CDCl 3)：δ：2.38(s，3H)；3.16(m，2H)；3.75(s，3H)；5.03(m，1H)；5.23(s，2H)；6.72(d，2H)；7.05-7.45(m，14H)。
Embodiment 6:(S)-2-[5-(4-chloro-phenyl-)-1-(2 ,-dichlorophenyl)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-(thiophene-2-yl) methyl propionate (ZH-314-SM) and corresponding acid (ZH-314-SA) thereof
Operate identical with (ZH-301-SM) and preparation procedure (ZH-301-SA).(ZH-301-SM) yield 69%; Mp, 57.5-58.0 ℃; 1h-NMR (400MHz, CDCl 3) δ: 2.39 (s, 3H); 3.49-3.50 (m, 2H); 3.77 (s, 3H); 5.08-5.09 (m, 1H); 6.88-7.54 (m, 10H).
(ZH-314-SA) yield 80%; Mp, 74.5-75.0 ℃; 1h-NMR (400MHz, CDCl 3) δ: 2.36 (s, 3H); 3.45-3.56 (m, 2H); 5.07-5.08 (m, 1H); 6.90-7.64 (m, 10H).
Embodiment 7:(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-(thiophene-2-yl) propionic acid ring pentyl ester ZH-314-SAE-3
A) N-Boc-(S)-2-amino-3-(thiophene-2-yl) propionic acid
In 25mL round-bottomed flask, thienyl amino acid 0.5g (2.92mmol) is dissolved in 5mL methylene dichloride, adds Boc acid anhydrides 0.67g (3.07mmol) and 0.95mL triethylamine under normal temperature, reaction is spent the night.After removing solvent under reduced pressure, obtain 642mg; Yield 81%, directly carries out next step reaction.
By the amino acid 257mg (0.95mmol) of above-mentioned Boc protection; EDC.HCl384mg (2.00mmol) is dissolved in 6mL methylene dichloride in 25mL round-bottomed flask; add again cyclopentanol 0.11mL (1.21mmol), triethylamine 0.42mL's (3.24mmol) and 12mg DMAP; normal-temperature reaction 16h, TLC demonstration reacts completely.Add 1mL saturated ammonium chloride cancellation reaction, ethyl acetate 30mL extraction three times, then with saturated ammonium chloride, salt solution, wash successively anhydrous sodium sulfate drying.Concentrating under reduced pressure, column chromatography obtain encircling pentyl ester 154mg, yield 47% after purifying.
B) (S)-2-amino-3-(thiophene-2-yl) propionic acid ring pentyl ester trifluoroacetate
N-Boc-(S)-2-amino-3-(thiophene-2-yl) propionic acid 157mg (0.58mmol) is dissolved in to 5mL methylene dichloride, ice bath is cooled to 0 ℃, add wherein cyclopentanol 0.111mL (1.22mmol), EDC.HCl0.384g (2.0mmol) and DMAP12mg (0.01mmol), then add triethylamine 0.417mL (3.14mmol).Allowing reaction solution slowly rise to room temperature and to continue stirs 12 hours; Add after completion of the reaction the dilution of 30mL methylene dichloride, use in turn appropriate 1N HCl, 1NNaHCO 3with saturated common salt water washing.Organic layer is through anhydrous magnesium sulfate drying; Concentrated gained crude product, the quick column purification of crossing, obtains the BOC-amino acid ring pentyl ester of 150mg oily, yield 48%. 1H-NMR(CDCl 3)：δ： 1H-NMR(CDCl 3)：δ：1.46(s，9H)；1.60-1.87(m，8H)；2.34-2.35(m，2H)；4.32-4.35(m，1H)；5.15-5.21(m，1H)；6.82(s，1H)；6.94(d，1H)；7.18(s，1H)。
This ring pentyl ester 0.15g (0.44mmol) is dissolved in TFA/DCM (v/v=1/1) 30mL, and stirring at room 3 hours, obtains the trifluoroacetate of amino acid ring pentyl ester after concentrating under reduced pressure, directly drop into next step reaction.
C) (S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-(thiophene-2-yl) propionic acid ring pentyl ester (ZH-314-SAE-3)
By 5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid chloride 200mg (0.50mmol) is dissolved in 5mLDCM, and ice-water bath is dissolved with by the made trifluoroacetate (0.44mmol) of 150mgN-Boc-amino acid ring pentyl ester and the solution of 0.21mL triethylamine in methylene dichloride 3mL cooling lower slowly adding; Under room temperature, stir 10 minutes, TLC shows that reaction is complete; After concentrating under reduced pressure, through column chromatography purification, obtain 0.25g; Yield 94%; Mp, 61.2-61.7 ℃; 1h-NMR (CDCl 3): δ: 1.58-1.84 (m, 8H); 2.39 (s, 3H); 3.47-3.48 (m, 2H); 5.01-5.03 (m, 1H); 5.21-5.23 (m, 1H); 6.88-7.59 (m, 10H).
Embodiment 8:(S)-2-[5-(4-bromophenyl)-1-(2 ,-dichlorophenyl)-4-ethyl-1-H-arsenic azoles-3-amide group]-3-(thiophene-2-yl) methyl propionate ZH-414-SM
Operation is with the preparation of (ZH-314-SM), only with 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1-H-arsenic azoles-3-carboxylic acid chloride replaces 5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl)-4-methyl isophthalic acid-H-arsenic azoles-3-carboxylic acid chloride, yield 81%; Mp, 65.2-66.0 ℃; 1h-NMR (400MHz, CDCl 3) δ: 1.20-1.23 (t, 3H); 2.77-2.80 (m, 2H); 3.49-3.50 (m, 2H); 3.77 (s, 3H); 5.08-5.09 (m, 1H); 6.88-7.55 (m, 10H).
Embodiment 9:(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-(4-(trifluoromethoxy) phenyl) methyl propionate (ZH-315-SM) and corresponding acid (ZH-315-SA) thereof
A) trifluoromethylation, preparation (ZH-315-SA)
The condenses of Rimonabant parent nucleus and TYR methyl esters (ZH-302-SM, referring to document 2) 1.2g (2.15mmol) is dropped into 50mL round-bottomed bottle, with DMF10mL, dissolve, add 60% sodium hydride 172mg (4.3mmol), start and stir; About 3g bromotrifluoromethane in balloon is imported to reaction flask and seals bottleneck.Under high voltage mercury lamp radiation, in room temperature reaction, spend the night; After TLC demonstration is residual without raw material, pour in 30mL frozen water; With 6N salt acid for adjusting pH; Be extracted with ethyl acetate three times, each 20mL, merges organic phase, dry; Column chromatography purification.Due to the hydrolysis of methyl esters in trifluoromethylation, product is (ZH-315-SA), obtains 783mg; Yield 59.5%; 1h-NMR (400MHz, CDCl 3) δ: 2.26 (3H, s); 3.06 (2H, dd); 4.92 (1H, d); 7.45-6.66 (11H, m); 9.8 (1H, bs).
B) methylating (ZH-315-SA), preparation (ZH-315-SM)
(ZH-315-SA) 700mg (1.14mmol) is dissolved in to 10mL ethyl acetate; To the diazomethane diethyl ether solution 4mL that drips new system in this solution, stir half an hour after raw material disappear, column chromatography purification obtains white solid 600mg; Yield 84%; 1h-NMR (400MHz, CDCl 3) δ: 2.33 (3H, s); 3.15 (2H, dd); 3.68 (3H, s); 5.01 (1H, d); 7.49-6.71 (12H, m). 19F-NMR(400MHz，CDCl 3)δ：-62.03(3F，s)
Embodiment 10:2-(S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide group]-4-first sulfydryl butyric acid methane amide (ZH-301-SAA-2)
Under nitrogen protection, by 2-(S)-[5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-amide group]-4-first sulfydryl butyric acid (350mg, 0.68mmol), be dissolved in 5mL DCM and add wherein EDC.HCl 0.20mg (1.04mmol), HOBt 0.14g (1.04mmol) and triethylamine 0.28mL (2.15mmol); Add again methylamine hydrochloride 55mg (0.81mmol), under room temperature, stir and spend the night; Pour in 15mL frozen water, filter the white solid of separating out, after washing, being dried, obtain pure product 220mg, yield: 62%; Mp, 89.0-90.0 ℃; 1h-NMR (400MHz, CDCl 3) δ: 2.06-2.08 (m, 1H); 2.13 (s, 3H); 2.25-2.30 (m, 1H); 2.37 (s, 3H); 2.59-2.64 (m, 2H); 2.84 (s, 3H); 4.77-4.80 (m, 1H); 6.59-7.50 (m, 7H).
Embodiment 11:2-(S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide group]-4-first sulfydryl butyric acid diformamide (ZH-301-SAA-3)
Method is with the preparation procedure of (ZH-301-SAA-2), and difference is to replace methylamine hydrochloride with dimethylamine hydrochloride, yield 60%; Mp, 81.1-81.8 ℃; 1h-NMR (400MHz, CDCl 3) δ: 1.97-2.10 (m, 2H); 2.13 (s, 3H); 2.36 (s, 3H); 2.59-2.65 (m, 2H); 2.99 (s, 3H); 3.20 (s, 3H); 5.33 (m, 1H); 7.05-7.41 (m, 7H); 7.68 (d, 1H).
Embodiment 12:2-(S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide group]-4-first sulfydryl butyric acid cyclopropyl amide (ZH-301-SAA-4)
Method is with the preparation procedure of (ZH-301-SAA-3), and difference is to replace dimethylamine hydrochloride with cyclopropylamine, yield 82%; Mp, 80.6-81.4 ℃; 1h-NMR (400MHz, CDCl 3) δ: 0.54-0.79 (m, 4H); 2.03-2.06 (m, 1H); 2.12 (s, 3H); 2.22-2.25 (m, 1H); 2.37 (s, 3H); 2.57-2.64 (m, 2H); 2.73-2.75 (m, 1H); 4.71-4.73 (m, 1H); 7.06-7.46 (m, 7H).
Embodiment 13:2-(S)-[5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-amide group]-4-first sulfydryl butyric acid cyclopropyl amide (ZH-401-SAA-4)
Operation is with (ZH-301-SAA-2), with cyclopropylamine, replace methylamine hydrochloride, with 2-(S)-[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazoles-3-amide group]-4-first sulfydryl butyric acid replacement 2-(S)-[5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-amide group]-4-first sulfydryl butyric acid, yield 84%; Mp, 98.0-99.0 ℃; 1h-NMR (400MHz, CDCl 3) δ: 0.50-0.79 (m, 4H); 1.18-1.21 (m, 3H); 2.02-2.05 (m, 1H); 2.12 (s, 3H); 2.28 (m, 1H); 2.55-2.65 (m, 2H); 2.74-2.97 (m, 3H); 4.69-4.71 (m, 1H); 7.01-7.48 (m, 7H); 8.03 (s, 1H).
Embodiment 14:(S)-5-(4-chloro-phenyl-)-N-[1-(cyclopropyl-amino)-1-oxygen-3-(thiophene-2-yl) third-2-yl]-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acid amides (ZH-314-SAA-4)
The same ZH-314-SAE-3 of operation of uncle-butoxy carbonyl protected amino acid
Boc protected amino acid 514mg (1.89mmol) is dissolved in 5mL methylene dichloride; EDC.HCl (3.00mmol), the HOBt405mg (3.00mmol) and the triethylamine 0.84mL (6.49mmol) that add 576mg; after fully stirring, add 0.16mL cyclopropylamine (2.30mmol), reaction is spent the night.After 24h, react completely, add 50mL dichloromethane extraction, successively water, ammonium chloride solution, salt solution washing; With anhydrous sodium sulfate drying, filter; Column chromatography after concentrating under reduced pressure, obtains N-Boc-ring propionic acid amide 320mg, yield 55%. 1H-NMR(CDCl 3)：δ：0.41-0.42(m，2H)；0.72-0.74(m，2H)；1.44(s，9H)；2.65-2.66(m，1H)；2.64-2.65(m，1H)；3.24-3.33(m，2H)；4.82-4.83(m，1H)；6.85(s，1H)；6.94(d，1H)；7.18(s，1H)
The amino acid amide of above-mentioned protection is dissolved in TFA/DCM (1: the 3) mixing solutions of 4mL, reacts after half an hour, react completely, concentrated draining, obtains 300mg, is directly used in the next step.
Under nitrogen protection, 5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid chloride 195mg (2.05mmol) is dissolved in to 5mLCH 2cl 2, be cooled to 0 ℃; Slowly drip wherein thienyl acid amides trifluoroacetate 150mg (0.46mmol) and Et 3n0.2mL (1.54mmol) is at 5mLCH 2cl 2in solution, control temperature of reaction 0 ℃ of left and right.Dropwise and finish reaction; Water and saturated NaCl solution washing successively; With anhydrous Na 2sO 4dry, be evaporated to oily, vacuum-drying.Through column chromatography purification product.Yield; Mp, 92.5-93.0 ℃; 1h-NMR (CDCl 3): δ: 0.42-0.45 (m, 2H); 0.71-0.73 (m, 2H); 2.36 (s, 3H); 2.66-2.67 (m, 1H); 3.39-3.43 (m, 2H); 4.78-4.80 (m, 1H); 6.92-7.44 (s, 10H).
Embodiment 15:(S)-5-(4-chloro-phenyl-)-N-[1-cyano group-2-(thiophene-2-yl) ethyl]-1-(2 ,-dichlorophenyl)-4-methyl isophthalic acid-H-arsenic azoles-3-acid amides (ZH-314-SAC-1)
(S)-3-(2-thienyl)-2 alanine 200mg (1.17mmol) are dissolved in to 2mL toluene, add wherein 28% ammoniacal liquor 2mL (33mmol); Under room temperature, vigorous stirring is 16 hours, and concentrating under reduced pressure obtains white solid 3-(2-thienyl)-2 aminopropan acid amides, directly carries out the next step.
Get above-mentioned propionic acid amide 85mg (0.50mmol), be dissolved in 3mL methylene dichloride, add 0.2mL triethylamine, slowly add 1-(2,4 dichloro benzene base)-4-methyl-5-(4-chloro-phenyl-)-1H-3-pyrazol formyl chloride 200mg (0.50mmol) in batches; Continue to stir 10 minutes, concentrate and obtain crude product, after column chromatography purification, obtain 491mg, yield 92%. 1H-NMR(CDCl 3)：δ2.33(s，3H)；3.43(m，2H)；4.91-4.95(m，1H)；5.90(s，1H)；6.41(s，1H)；6.94-7.55(m，10H)。
Get above-mentioned condenses acid amides 0.230mg (0.43mmol), add in the solution being formed by pyridine 1.25mL and methylene dichloride 0.25mL, be cooled to-10 ℃, slowly add phosphorus oxychloride 0.06mL (0.64mmol), at this temperature, continue to stir one hour; Reaction solution is poured in frozen water, be extracted with ethyl acetate; Organic layer is concentrated after anhydrous sodium sulfate drying, crosses column purification and obtains the product that 160mg expects, yield 72%, mp:49.3-50.0 ℃; 1H-NMR (CDCl3): δ 2.39 (s, 3H); 3.44 (m, 2H); 5.32 (m.1H); 7.02-7.47 (m, 10H).
Embodiment 16:(S)-5-(4-bromophenyl)-N-[1-(cyclopropyl-amino)-1-oxygen-3-(thiophene-2-yl) third-2-yl]-1-(2,4 dichloro benzene base)-4-ethyl-1-H-arsenic azoles-3-acid amides (ZH-414-SAA-4)
Operation is with the preparation of (ZH-314-SAA-4), make (S)-amino N-cyclopropyl-3-(thiophene-2-yl)-propionic acid amide under the existence of triethylamine with 5-(4-bromophenyl)-1-(2, the acyl chlorides condensation of 4-dichlorophenyl)-4-ethyl-1-H-arsenic azoles-3-carboxylic acid, yield 75%; Mp, 87.8-88.4 ℃; 1h-NMR (CDCl 3): δ: 0.41-0.44 (m, 2H); 0.71-0.73 (m, 2H); 1.18-1.19 (t, 3H); 2.66-2.67 (m, 2H); 2.75-2.77 (m, 1H); 3.39-3.42 (m, 2H); 4.76-4.78 (m, 1H); 6.92-7.48 (s, 10H).
Embodiment 17:2-(S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide group]-4-first Mercaptobutanol (ZH-301-SAL-00)
Under nitrogen protection, in 10mL round-bottomed flask, make 2-(S)-[5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazoles-3-amide group]-4-first sulfydryl methyl-butyrate (ZH-301SM) (280mg, 0.53mmol) is dissolved in 3mLTHF; Under ice-water bath is cooling, add 50mg LiBH 4solution 2.4mL (0.55mmol) in 10mLTHF, reaction adds saturated ammonium chloride 1mL cancellation reaction after half an hour, with 3 * 10mLEA, extract, and extracting solution is water and saturated NaCl solution washing successively; With anhydrous Na 2sO 4dry, concentrating under reduced pressure, column chromatography purification (elutriant EA: Hex=1: 3) obtain 190mg solid, yield 71%, mp, 64.8-65.5 ℃; 1h-NMR (400MHz, CDCl 3) δ: 1.90-1.98 (m, 2H); 2.13 (s, 3H); 2.38 (s, 3H); 2.61-2.66 (m, 2H); 3.76-3.87 (m, 2H); 4.23-4.26 (bs, 1H); 7.07-7.45 (m, 7H).
Embodiment 18:2-(S)-[5-(4-chloro-phenyl-)-1-(2,4-chloro-phenyl-)-4-ethyl-1H-pyrazoles-3-amide group]-4-first Mercaptobutanol (ZH-401-SAL-00)
2-(S)-[5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-amide group]-4-first sulfydryl methyl-butyrate (ZH-401SM) of take is raw material, and preparation procedure is with (ZH-301-SAL-00, yield: 83%; Mp, 61.0-61.5 ℃; 1h-NMR (400MHz, CDCl 3) δ: 1.19-1.23 (t, 3H); 1.94-1.99 (m, 2H); 2.14 (s, 3H); 2.61-2.64 (m, 2H); 2.76-2.80 (m, 2H); 3.76-3.85 (m, 2H); 4.23-4.25 (bs, 1H); 7.02-7.49 (m, 7H).
Embodiment 19:(S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-N-[1-hydroxyl-3-(4-benzyl oxy phenyl)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-acid amides (ZH-302B-SAL-00)
By benzyl compounds (S)-2-[5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-(4-benzyl oxy phenyl) methyl propionate (ZH-302B-SM) 2.5g (3.9mmol) is dissolved in THF50mL, repeatedly adds lithium borohydride 0.175g (8mmol) under room temperature in batches; Add rear continuation stirring reaction 2 hours, add water 1mL stopped reaction; The solid that filtering is separated out, concentrated post after solution is dry, obtained reduzate (ZH-302B-SAL-00) 2.16g, yield 89%; 1h-NMR (400MHz, CDCl 3) δ: 2.37 (s, 3H); 2.95 (bs, 1H); 2.97 (m, 2H); 3.70 (m, 1H); 3.80 (m, 1H); 4.36 (bs, 1H); 7.06-7.54 (m, 16H).
Embodiment 20:(S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-N-[1-hydroxyl-3-phenyl-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-acid amides (ZH-303-SAL-00)
The same ZH-301-SAL-1 of preparation procedure, with LiBH4 to (S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-phenyl) methyl propionate reduces, yield 81%; Mp, 70.0-71.5 ℃; 1h-NMR (400MHz, CDCl 3) δ: 2.37 (s, 3H); 2.95 (bs, 1H); 2.99 (m, 2H); 3.69 (m, 1H); 3.79 (m, 1H); 4.36 (bs, 1H); 7.06-7.45 (m, 12H).
Embodiment 21:(S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-N-[1-hydroxyl-3-(thiophene-2-yl) third-2-yl]-4-methyl isophthalic acid-H-arsenic azoles-3-acid amides (ZH-314-SAL-00)
With lithium boron hydrogen, ZH-314-SM is reduced, operation is with the preparation of ZH-301-SAL-00; Yield 85%; Mp, 79.0-80.0 ℃; 1h-NMR (400MHz, CDCl 3) δ: 2.38 (s, 3H); 3.22-3.24 (m, 2H); 3.76-3.83 (m, 2H); 4.35 (bs, 1H); 6.93-7.45 (m, 10H).
Embodiment 22:(S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-N-[1-hydroxyl-3-(4-trifluoromethyl-phenyl)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-acid amides (ZH-315-SAL-00)
By (S)-2-[5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-(4-trifluoromethyl-phenyl)-methyl propionate (ZH-315-SM) 0.5g (0.8mMol) is dissolved in THF5mL, add lithium borohydride 52mg (2.4mMol), stirring at room 48 hours.Add 0.5mL that water reaction is stopped; After the solid that filtering is separated out, reaction solution is concentrated, cross column purification, reclaim unreacted raw material 231mg, obtain reduzate 187mg, yield 72.6%; 1h-NMR (400MHz, CDCl 3) δ: 2.37 (s, 3H); 2.91 (m, 2H); 3.67-3.81 (m, 2H); 4.30 (bs, 1H); 6.76-7.46 (m, 11H).
Embodiment 23:(S)-[5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl) N-[1-trifluoromethoxy-3-(4-benzyl oxy phenyl)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-acid amides (ZH-316-SAL-31) and (S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-N-1-(4-hydroxyl-phenyl)-3-(trifluoromethoxy)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-acid amides (ZH-316-SAL-00)
A) by (S)-[5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl)-N-[1-hydroxyl-3-(4-benzyl oxy phenyl)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-acid amides (ZH-302B-SAL-00) 1.28g (2.06mmol) and DMF10mL devote 50mL stainless steel voltage-resistant reactor, add solid potassium hydroxide 100mg (2.5mmL), crown ether 18-C-610mg, bathes cooling lower importing CF3I 900mg (4.6mmL) at cryosel; Airtight after input stirring bar magnet; Under agitation in 80 ℃ of reactions 4 hours.Cooling with cryosel bath, carefully open reactor, rise to gradually room temperature.By reactant impouring 30mL frozen water; Be extracted with ethyl acetate three times, each 20mL, merges organic phase; Dry, concentrated, obtain the crude product 1.01g of intermediate (S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base) N-[1-trifluoromethoxy-3-(4-benzyl oxy phenyl)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-acid amides (ZH-316-SAL-00).Do not refine, be directly used in next step hydrogenation debenzylation reaction.
B) resulting crude product 1.01g is dissolved in to ethyl acetate 50mL, adds 5%Pd/C300mg, under the pressure of balloon hydrogen, in 50 ℃ of stirring reactions, spend the night.Raw material reaction is complete; Filter; Concentrated; Column chromatography purification, obtains expected product 523mg; For benzyl oxy phenyl raw material yield 42.4%; 1h-NMR (400MHz, CDCl 3) δ: 2.38 (s, 3H); 2.95 (m, 1H); 3.00 (m, 1H); 3.89 (m, 1H); 3.99 (m, 1H); 4.61 (bs, 1H); 6.71-7.51 (m, 11H).
Embodiment 24:(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acid amides]-3-phenyl propyl acetic ester (ZH-303-SAL-01)
By (S)-5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl) N-(1-hydroxyl-3-phenyl-propyl-2-yl)-4-methyl isophthalic acid-H-arsenic azoles-3-acid amides (ZH-313-SAL-00) 515mg (1mmol) is dissolved in the DCM that 15mL is dry, adds 1.5mL Et 3n (10mmol), adds CH under cooling 3cOCl 0.26mL (3.6mmol), reacts 0.5h under room temperature, and TLC shows to react completely.Steaming desolventizes, and adds the vinyl acetic monomer of 80mL; With 2 * 20mL water washing twice, then with saturated aqueous common salt 20mL washing once.Anhydrous Na 2sO 4after dry, steam to 1mL; Directly, through silicagel column purifying, use sherwood oil: vinyl acetic monomer (2: 1) wash-out, obtains 320mg compound, yield 57.5%.
1H-NMR(CDCl 3，300MHZ)：δ，2.10(s，3H)；2.38(s，3H)；2.95(m，1H)；3.05(m，1H)；4.15(m，2H)；4.64(bs，1H)；7.07-7.12(m，3H)；7.26-7.31(m，8H)；7.46(1H，s)。
Embodiment 25:(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acid amides]-3-phenyl propyl propylene propionic ester (ZH-303-SAL-02)
Preparation procedure is with (ZH-303-SAL-01), with the acyl chlorides replacement Acetyl Chloride 98Min. of allyl acid, yield 52.7%.
1H-NMR(CDCl 3，300MHZ)：δ，2.38(s，3H)；2.93-3.09(m，2H)；4.24(m，2H)；4.69(m，1H)；5.87(d，1H)；6.20(dd，1H)；6.47(dd，1H)；7.07-7.08(m，3H)；7.46(s，1H)；7.28-7.32(m，8H)。
Embodiment 26:(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acid amides]-3-phenyl propyl chloracetic acid ester (ZH-303-SAL-03)
Preparation procedure, with (ZH-303-SAL-01), replaces Acetyl Chloride 98Min., yield 49.0% with chloroacetyl chloride. 1H-NMR(CDCl 3，300MHZ)：δ，2.38(s，3H)；2.95(m，1H)；3.06(m，1H)；4.10(bs，2H)；4.23(d，1H)；4.32(d，1H)；4.69(m，1H)；7.07-7.09(m，3H)；7.28-7.32(m，8H)；7.47(s，1H)。
Embodiment 27:(S)-2-[5-(4-chloro-phenyl-)-1-(2; 4-dichlorophenyl)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-phenyl propyl succsinic acid methyl ester (ZH-303-SAL-04M) and (S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-N-(4-methoxyl group-4-oxygen-butyryl radicals)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-phenyl propyl succsinic acid methyl ester (ZH-303-SAL-04MM)
Preparation procedure is with (ZH-303-SAL-01), and the acyl chlorides replacement Acetyl Chloride 98Min. with beta-methoxycarbonyl propionic acid, obtains faint yellow product, yield 31.8%; 1h-NMR (400MHz, CDCl 3): δ, 2.38 (s, 3H); 2.66-2.69 (m, 4H), 2.90-3.06 (m, 2H); 3.68 (s, 3H); 4.18 (m, 2H); 4.64 (bs, 1H); 7.07-7.12 (m, 3H); 7.24-7.31 (m, 8H); 7.46 (s, 1H).
When obtaining expected product ZH-303-SAL-04M, also obtained the acylate ZH-303-SAL-04MM on amide nitrogen, yield 18.2%; 1h-NMR (400MHz, CDCl 3): δ, 2.37 (s, 3H); 2.52-2.68 (m, 3H); 2.80-3.20 (m, 7H); 3.66 (s, 3H); 3.68 (s, 3H); 4.23 (d, 1H); 4.32 (d, 1H); 4.66 (bs, 1H); 7.07-7.08 (d, 2H); 7.45 (s, 1H); 7.26-7.31 (m, 9H).
Embodiment 28:(S)-4{2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-phenyl-propoxy-}-4-oxygen-butyric acid (ZH-303-SAL-04A)
By (S)-5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl)-N-(1-hydroxyl-3-phenyl-propyl-2-yl)-4-methyl isophthalic acid-H-arsenic azoles-3-acid amides (ZH-313-SAL-00) 515mg (1mmol) is dissolved in L acetone 50m, add Succinic anhydried 400mg (4mmol) and DMAP25mg, stir lower backflow 12 hours.Steaming desolventizes, and adds methylene dichloride 50mL and 10mL water; After layering, water layer extracts once with methylene dichloride 50mL again; Merge organic layer, by saturated aqueous common salt 30mL washed twice.Organic layer is evaporate to dryness after anhydrous sodium sulfate drying.Resistates, through silicagel column purifying, obtains faint yellow product 415mg; Yield 67.9%. 1H-NMR(400MHz，CDCl 3)：δ，2.35(s，3H)，2.67(m，4H)，2.90-3.04(m，2H)，4.18(dd，2H)，4.64(bs，1H)，7.06-7.8(m，3H)，7.22-7.30(m，8H)，7.44(s，1H)。
Embodiment 29:(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acid amides]-3- phenyl propyl 2,4 dichloro benzene manthanoate (ZH-303-SAL-13)
A) preparation of 2,4 dichlorobenzyl chloride
2,4 dichloro benzene formic acid 286mg (1.5mmol) is dissolved in dry DCM, drips (COCl) 20.22mL and 1 DMF, react 0.5-1 hour under normal temperature; Solvent evaporated, adds 2mLDCM; Evaporate to dryness, obtains faint yellow 2,4 dichlorobenzyl chloride crude product again, is directly used in next step reaction.
B) preparation procedure, with (ZH-303-SAL-01), replaces Acetyl Chloride 98Min. with 2,4 dichlorobenzyl chloride.Yield 42.2%; 1h-NMR (400MHz, CDCl 3): δ, 2.39 (s, 3H); 2.99-3.04 (m, 1H); 3.11-3.15 (m, 1H); 4.41 (m, 2H); 4.78 (bs, 1H); 7.07-7.08 (m, 2H); 7.28-7.30 (m, 10H); 7.47 (m, 2H); 7.84 (d, 1H).
Embodiment 30:(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acid amides]-3-phenyl propyl benzoic ether (ZH-303-SAL-16)
Preparation procedure, with (ZH-303-SAL-01), replaces Acetyl Chloride 98Min., yield 54.9% with Benzoyl chloride.
1H-NMR(400MHz，CDCl 3)：δ，2.39(s，3H)；3.01-3.18(m，2H)；4.40(m，2H)；4.79(m，1H)；7.06-7.09(m，3H)；7.21-7.33(m，8H，)；7.43-7.47(m，3H)；7.58(dd，1H)，8.07(d，2H)。
Embodiment 31:(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acid amides]-3-(2-thienyl)-propyl group acetic ester (ZH-314-SAL-01)
Under nitrogen protection, by amino acid whose condenses alcohol (ZH-314-SAL-00) 185mg (0.36mmol), be dissolved in 5mL methylene dichloride, add triethylamine 0.10mL (0.8mmol), be cooled to 0 ℃; Slowly drip wherein Acetyl Chloride 98Min. 0.032mL (about 0.4mmol), control temperature of reaction 0 ℃ of left and right.Dropwise and finish reaction; Water and saturated NaCl solution washing successively; With anhydrous Na 2sO 4dry, be evaporated to oily, through column chromatography purification, obtain product 200mg, yield 99%, mp:42.5-43.5 ℃. 1H-NMR(CDCl 3)：δ2.11(s，3H)；2.39(s，3H)；3.32(m，2H)；4.19(m，2H)；4.65(m.1H)；6.91-7.46(m，10H)
Embodiment 32:(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acid amides]-3-(4-trifluoromethoxy-phenyl)-propyl group acetic ester (ZH-315-SAL-01)
By (S)-5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl) N-[1-hydroxyl-3-(4-trifluoromethyl-phenyl)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-acid amides (ZH-315-SAL-00) 45mg (0.075mMol) is dissolved in methylene dichloride 8mL, add triethylamine 15mg (0.15mMol), Acetyl Chloride 98Min. 69mg (0.08mmol), stirring at room concentrated column purification after half an hour, obtain acetylate 38mg, yield 79.1%; 1h-NMR (CDCl 3): δ 2.10 (s, 3H); 2.38 (s, 3H); 2.91-3.01 (dm, 2H); 4.17 (bs, 2H); 4.63 (bs, 1H); 7.03-7.05 (m, 3H); 7.29-7.31 (m, 7H); 7.46 (bs, 1H).
Embodiment 33:(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acid amides]-3-(4-trifluoromethoxy-phenyl)-propyl group acid allyl ester (ZH-315-SAL-02)
By (S)-5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl)-N-[1-hydroxyl-3-(4-trifluoromethyl-phenyl)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-acid amides (ZH-315-SAL-00) is dissolved in methylene dichloride 8mL by reduzate 47mg (0.075mMol), add again triethylamine 18mg (0.15mMol), acrylate chloride 7mg (0.08mmol), stirring at room concentrated column purification after half an hour, obtain allyl acylate 43mg, yield 87.9%; 1h-NMR (CDCl 3): δ, 2.38 (s, 3H); 2.95-3.08 (m, 2H); 4.27 (bs, 2H); 4.68 (bs, 1H); 5.95 (d, 1H); 6.20 (m, 1H); 6.45 (d, 1H); 7.09-7.46 (m, 11H).
Embodiment 34:(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acid amides]-3-(4-trifluoromethoxy-phenyl)-propyl group-(the chloro-benzoic ether of 2-) is (ZH-315-SAL-14)
By (S)-5-(4-chloro-phenyl-)-1-(2,4-dichlorophenyl) N-[1-hydroxyl-3-(4-trifluoromethyl-phenyl)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-acid amides (ZH-315-SAL-00) 44mg (0.075mMol) is dissolved in methylene dichloride 8mL, add again triethylamine 16mg (0.15mMol), o-chlorobenzoyl chloride 14mg (0.08mmol), stirring at room is concentrated after half an hour, cross column purification, obtain expected product 48mg, yield 86.8%; 1h-NMR (CDCl 3): δ, 2.39 (s, 3H); 3.09-3.14 (m, 2H); 4.47 (bs, 2H); 4.79 (bs, 1H); 7.09-7.54 (m, 15H); 8.05 (bs, 1H).
Embodiment 35:(S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-N-1-(4-acetoxyl group-phenyl)-3-(trifluoromethoxy)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-acid amides (ZH-316-SAL-01)
Preparation procedure, with the preparation of (ZH-315-SAL-01), be take ZH-316-SAL-00 as raw material.Yield 69.5%.
1H-NMR(400MHz，CDCl 3)δ：2.18(s，3H)；2.38(s，3H)；2.96(m，1H)；3.00(m，1H)；3.90(m，1H)；4.00(m，1H)；4.60(bs，1H)；7.24-7.55(m，11H)。
Embodiment 36:(S)-(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-phenyl propyl] 2-amino-propionic ester (ZH-303-SAL-21)
By raw alcohol (ZH-303-SAL-00) 515mg (1mmol), EDC.HCl 288mg (1.5mmol), DAMP 50mg, (S)-N-Boc-L-L-Ala 327mg (1.73mmol) drops into the single port bottle of 50mL, vacuumize 0.5 hour, vacuumize again 0.5 hour after being filled with nitrogen; Dry methylene dichloride 10mL is injected to bottle, under room temperature, react 24 hours; TLC shows to show that reaction is substantially complete.Steaming desolventizes; The solid obtaining is not purified directly carries out next step reaction, sloughs Boc protecting group.
Resulting solid is dissolved in methylene dichloride 6mL, adds TFA 3mL, react 2 hours, raw material disappears substantially.At 30 ℃, steam except most of solvent.In residuum, add ethyl acetate 50mL; Use saturated NaHCO 3solution washing is to neutral; Again through anhydrous Na 2sO 4after dry, steam to 1mL, directly through silicagel column purifying, use sherwood oil: ethyl acetate (2: 1) wash-out, obtains the compound that 205mg expects, yield 35.0%.
1H-NMR(CDCl 3，300MHz)：δ1.35(d，3H)；2.37(bs，3H)，2.91(d，1H)，3.05(d，1H)；3.57(d，1H)；4.15(d，1H)；4.22(d，1H)；4.68(bs，1H)；7.06-7.10(m，3H)；7.25-7.31(m，8H)；7.46(s，1H)。
Embodiment 37:(S)-(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-phenyl propyl] 2-amino-3-phenylpropionic acid ester (ZH-303-SAL-22)
Use N-Boc-L-phenylalanine to replace N-Boc-L-L-Ala, according to the same program preparation of ZH-303-SAL-21.Obtain light yellow solid, yield 39.3%. 1H-NMR(CDCl 3)：δ，2.38(bs，3H)；2.82-2.89(m，2H)；2.98(m，1H)；3.10(m，1H)；3.77(bs，1H)；4.15(d，1H)；4.25(d，1H)；4.66(bs，1H)；7.05-7.09(m，3H)；7.24-7.31(m，13H)；7.44(s，1H)。
Embodiment 38:(S)-(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-(2-thienyl)-propyl group] 2-amino-propionic ester (ZH-314-SAL-21)
Under nitrogen protection, the alcohol of amino condensation compound (ZH-314-SAL-00) 155mg (0.30mmol) is dissolved in DMF5mL, add triethylamine 0.10mL (0.8mmol), EDC hydrochloride 192mg (1.0mmol), and DMAP16mg (0.13mmol), and N-Boc-L-Ala 91mg (0.48mmol), normal-temperature reaction is spent the night, successively water and saturated NaCl solution washing; With anhydrous Na 2sO 4dry, be evaporated to oily, through column chromatography purification product 160mg, yield 77%. 1H-NMR(CDCl 3)：δ1.11(m，3H)；1.49(s，9H)；2.38(s，3H)；3.22(m，2H)；4.25-4.37(m，2H)；4.67(m，1H)；5.06(m.1H)；6.92-7.33(m，10H)
Above-mentioned condenses is dissolved in TFA/DCM (volume ratio 1/2) mixed solution 3mL, stirs half an hour, react completely, be concentrated into oily.Methylene dichloride dissolves this product, passes into after a small amount of ammonia, and column chromatography obtains product 130mg, productive rate 95%; Mp:51.0-52.0 ℃. 1H-NMR(CDCl 3)：δ1.38-1.39(m，3H)；2.38(s，3H)；3.16-3.22(m，2H)；3.65-3.67(m，1H)；4.23-4.29(m，2H)；4.67(m.1H)；6.91-7.33(m，10H)
Embodiment 39:(S)-(S)-2-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide group]-3-(4-trifluoromethoxy-phenyl) propyl group] 2-amino-propionic ester (ZH-315-SAL-21)
Preparation procedure is with the preparation of (ZH-303-SAL-21), with (S)-[5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base) N-[1-hydroxyl-3-(4-trifluoromethyl-phenyl)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-acid amides (ZH-315-SAL-00), replace (ZH-303-SAL-00) and (S)-N-Boc-L-L-Ala condensation; Intermediate product is not refining, with TFA, processes, and sloughs protecting group; Through column chromatography purification, obtain expected product.Yield 33%; 1h-NMR (CDCl 3, 300MHz): δ, 1.35 (d, 3H); 2.37 (bs, 3H); 2.84 (d, 1H), 2.99 (d, 1H); 3.57 (d, 1H); 4.13 (d, 1H); 4.22 (d, 1H); 4.68 (bs, 1H); 6.99-7.03 (m, 2H); 7.09-7.47 (m, 9H).

Claims (3)

1. a 3-pyrazole carboxylic acid amides compounds, it comprises the compound of following chemical structural formula:
Figure FDA0000424999730000011
Figure FDA0000424999730000021
2. 3-pyrazole carboxylic acid amides compounds claimed in claim 1 is being prepared as the application in CB1 acceptor inhibitor medicine.
3. 3-pyrazole carboxylic acid amides compounds according to claim 2, in preparation as the application in CB1 acceptor inhibitor medicine, is characterized in that the application in preparing anti-additive medicament, stop smoking medicine, Temperance medicine, slimming medicine or treatment diabetes medicament.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003088968A1 (en) * 2002-04-15 2003-10-30 Research Triangle Institute Compounds having unique cb1 receptor binding selectivity and methods for their production and use
WO2007106721A2 (en) * 2006-03-10 2007-09-20 Jenrin Discovery Cannabinoid receptor antagonists/inverse agonists useful for treating obesity
CN101795569A (en) * 2007-09-07 2010-08-04 詹里恩探索公司 Cannabinoid receptor antagonists/inverse agonists useful for treating obesity
CN102260246A (en) * 2010-05-28 2011-11-30 范如霖 Low-toxicity CB1 receptor inhibitor, preparation method thereof and application thereof in preparation of medicaments for drug abstention, weight reduction or diabetes treatment

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2665898B1 (en) * 1990-08-20 1994-03-11 Sanofi DERIVATIVES OF AMIDO-3 PYRAZOLE, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
FR2692575B1 (en) * 1992-06-23 1995-06-30 Sanofi Elf NOVEL PYRAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
JP2003513064A (en) * 1999-11-05 2003-04-08 ユニバーシティ カレッジ ロンドン Activator of soluble guanylate cyclase
US20080200527A1 (en) * 2005-06-17 2008-08-21 Carex Sa Cannabinoid Receptor Modulators
CN101062919B (en) * 2006-04-26 2012-08-15 中国人民解放军军事医学科学院毒物药物研究所 4-methyl-1H-diaryl pyrromonazole derivative and medicament usage thereof
CN101062916B (en) * 2006-04-29 2012-12-26 中国人民解放军军事医学科学院毒物药物研究所 Three-substituted 1H-pyrromonazole compound, preparation method, medicament composition and pharmacy use thereof
DE102009036604A1 (en) * 2009-07-30 2011-02-03 Aicuris Gmbh & Co. Kg Substituted bis-arylpyrazolamides with terminal primary amide functionality and their use
CN102250006B (en) * 2011-05-12 2014-03-05 范如霖 3-pyrazole carboxylic acid amide compounds, preparation method thereof and application thereof in preparation of medicament serving as CB1 receptor inhibitor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003088968A1 (en) * 2002-04-15 2003-10-30 Research Triangle Institute Compounds having unique cb1 receptor binding selectivity and methods for their production and use
WO2007106721A2 (en) * 2006-03-10 2007-09-20 Jenrin Discovery Cannabinoid receptor antagonists/inverse agonists useful for treating obesity
CN101795569A (en) * 2007-09-07 2010-08-04 詹里恩探索公司 Cannabinoid receptor antagonists/inverse agonists useful for treating obesity
CN102260246A (en) * 2010-05-28 2011-11-30 范如霖 Low-toxicity CB1 receptor inhibitor, preparation method thereof and application thereof in preparation of medicaments for drug abstention, weight reduction or diabetes treatment

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
3D-QSAR Studies of Arylpyrazole Antagonists of Cannabinoid Receptor Subtypes CB1 and CB2. A Combined NMR and CoMFA Approach;Jian-Zhong Chen et al.;《J. Med. Chem.》;20051224;第49卷(第2期);625-636 *
Jian-Zhong Chen et al..3D-QSAR Studies of Arylpyrazole Antagonists of Cannabinoid Receptor Subtypes CB1 and CB2. A Combined NMR and CoMFA Approach.《J. Med. Chem.》.2005,第49卷(第2期),625-636.
Ruoxi Lan et al..Structure-Activity Relationships of Pyrazole Derivatives as Cannabinoid Receptor Antagonists.《J. Med. Chem.》.1999,第42卷(第4期),769-776.
Structure-Activity Relationships of Pyrazole Derivatives as Cannabinoid Receptor Antagonists;Ruoxi Lan et al.;《J. Med. Chem.》;19990206;第42卷(第4期);769-776 *

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