CN110156761A - Containing cumarin-biphenyl backbone compound, preparation method and applications - Google Patents

Containing cumarin-biphenyl backbone compound, preparation method and applications Download PDF

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CN110156761A
CN110156761A CN201910525585.1A CN201910525585A CN110156761A CN 110156761 A CN110156761 A CN 110156761A CN 201910525585 A CN201910525585 A CN 201910525585A CN 110156761 A CN110156761 A CN 110156761A
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methyl
sodium
amido
nmr
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施秀芳
张振中
由丹
李鹏
付东阳
安义平
冉艳格
李秀君
王真
王楠
丁一凡
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Zhengzhou University
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Abstract

The invention belongs to field of medicinal chemistry, disclose a kind of with cumarin-biphenyl backbone compound, preparation method and applications.It has the following structure general formula:

Description

Containing cumarin-biphenyl backbone compound, preparation method and applications
Technical field
The present invention relates to field of medicinal chemistry, and in particular to it is a kind of containing cumarin-biphenyl backbone compound, they Preparation method and its application as a new class of drug for hypertension.
Background technique
In the therapeutic agent of hypertension, angiotensinⅡ (Ang II) receptor antagonist with its higher safety and Favor of the less adverse reaction by the world of medicine and numerous hypertensive patients.Currently, in the drug for hypertension market in China On, II receptor antagonist of Ang with calcium-ion channel antagonists (CCB) and angiotensinⅠ (Ang I) converting enzyme inhibitor (ACE I) forms situation of standing like the legs of a tripod.Since the English name of II receptor antagonist of Ang is all with " Sartan " ending, Ang II receptor antagonist is commonly referred to as sartans again.
II receptor antagonist of Ang is a kind of important drugs for acting on renin-angiotensin system, and mechanism of action is not Be same as I converting enzyme inhibitor of Ang (ACE I), their property of can choose and AT1Receptor combines, and the effect of antagonism Ang II causes Blood pressure decline.Drug currently used for clinical treatment is selective AT1Receptor antagonist, it can be effectively reduced blood It presses and shows tolerance more better than other types hypertension therapeutic drug and protection renal function, antihypertensive effect duration It is longer, and be not in that (Zhang Zhi is superfine, and Chinese pharmaceutical chemistry is miscellaneous for the adverse reactions such as dry cough and mortality angioneurotic edema Will .2012,22 (5): 442-451).
From first II receptor antagonist losartan of Ang of Du Pond Merck company in 1994 since Sweden's listing, So far have more than ten of a sartans listing, and be in clinical there are also a drug candidate about more than 40 or preclinical grind Study carefully.Make a general survey of at present listed and the chemical structure of the sartans in clinical research (Chen Qingqi is based on initiating creativity Small-molecule drug invent Science Press (Beijing), p216-238. 2012.5), they be mostly using Losartan as prototype, it is right Its each position carries out structural modification or chemical improvement, mostly contains Biphenylmethyl imidazole structure, tetrazole or carboxylic in molecule The groups such as base.In addition, containing heterocycle structure in the structure of sartans, such as (1) imidazoles more: Losartan, eprosartan, Olmesartan, Erie's sand are smooth；(2) benzimidazole: Telmisartan, Candesartan, Azilsartan；(3) pyridine or benzo pyridine Class: A81988, Bms 183920, Ici D8731.(4) pyridinone: Embusartan, Emd66684；(5) pyrrolopyridine Class: L158338；(6) biphenyl furodiazole: Azilsartan；(7) pyrimidine or Pyrimdinone: Tasosartan, milfasartan (Mifasartan),Fimasartan,Cgp48369；(8) benzofurans: Zolasartan, Saprisartan；(9) triazole Quinoline ketone: Ripisartan；(10) non-heterocycle: Valsartan, Abitesartan etc..
Cumarin is a kind of native compound with benzopyrone ring, and it is wide that research finds that coumarin kind compound has The bioactivity of spectrum, such as protease inhibitors, antibacterial, antitumor, anti-hypertension, Antiarthritic etc..Therefore, it is based on cumarin Skeleton introduces the biphenyl active group of husky smooth class compound, studies its antihypertensive active, for novel antihypertensive The exploitation of drug is of great significance.
Summary of the invention
For above situation, the purpose of the present invention is to provide a kind of novel tonka-beans with preferable antihypertensive active Element-biphenyl backbone compound, and its new synthetic method and its application in terms of preparing drug for hypertension are provided.
Purpose to realize the present invention using the natural benzopyrone ring structure of cumarin, while considering vasotonia Plain II receptor antagonist is needed containing there are two structure divisions: negative electricity region and hydrophobic region, the present invention have using triazole ring Biggish dipole moment and H-bonding capability introduce triazole group to be conducive to itself and the intracorporal a variety of enzymes of biology and receptor It combines.
Technical solution is as follows:
Described there is cumarin-biphenyl backbone compound to have the following structure general formula:
Wherein,
Y can be bonded on 5 or 6 or 7 or 8 of coumarin ring, and preferably Y is bonded in 7 of coumarin ring On, wherein Y is O or NH or S, preferably O or NH.
N is 0~2；
Contain the substituent group of triazole structure in general formula IWith the substituent group in general formula IIWith and Substituent R2It can be bonded on 3 or 4 of coumarin ring, preferablyIt is bonded on 4, R2Key It is connected in 3 of coumarin ring.
R1Or R2For hydrogen atom, halogen (F, Cl, Br) or selected from I or II or III or iv or v:
It i) is the aliphatic group containing 1-10 carbon atom, the cycloalkyl group containing 3-10 carbon atom；It is miscellaneous by aromatic ring, virtue It is cyclosubstituted to contain 1~6 fat of carbon atom alkyl；The alkane or cycloalkane being optionally substituted by halogen；
It ii) is aromatic ring yl, aromatic heterocyclic or substituted aromatic ring yl, substituted aromatic heterocyclic；Substituent group can be for containing 1~6 The linear or branched alkyl group of carbon atom, alkoxy, halogen (F, Cl, Br)；Hetero atom can be nitrogen, oxygen, sulphur；
It iii) is the fatty linear chain or branched chain amino containing 1-10 carbon atom, the cycloalkanes amido containing 3-10 carbon atom Or the substituted cycloalkanes amido containing 3-10 carbon atom, substituent group are containing 1~6 carbon atom hydroxyalkyl；Or containing nitrogen, 6 member ring alkylamino radicals of oxygen, sulfur heteroatom；Or by the cyclosubstituted amido of fragrance, aromatic rings is by hydroxyl, cyano or nitro or halogen (F, Cl, Br) replaces.
Iv) phenylol, substituted phenylol.Substituent group can be aromatic ring yl, by C1-3 alkyl, halogen (F, Cl, Br), first The aromatic ring yl that oxygroup, hydroxyl, formoxyl, acetyl group, amide groups, cyano or nitro replace.
V) sulfenyl replaced.Substituent group can for benzyl, aromatic ring yl, by C1-3 alkyl, halogen (F, Cl, Br), methoxyl group, The aromatic ring yl that hydroxyl, formoxyl, acetyl group, amide groups, cyano or nitro replace.
R3For carboxyl (- COOH) or tetrazole baseIt is preferred that carboxyl (- COOH).
Two serial compounds with the preferably following general structure of cumarin-biphenyl backbone compound:
Wherein,
Y is O or NH；N is 0~2；
R1Or R2It can be hydrogen atom (H), halogen (F, Cl, Br), methylTrifluoromethyl (CF3), ethyl PropylIsopropylNormal-butylIsobutyl groupTert-butylN-pentylIsopentylTertiary pentylN-hexylCyclopropylCyclobutylCyclopentaCyclohexylAzido (N3), N- piperidyl2- methyl-N- piperidyl3,5- dimethyl-N-piperidylN- piperazinylN '-methyl-N- piperazinylN- morpholinyl4- methylol-N- piperidylN, N- dimethyl amidoN, N- diethyl amidoN, N- diη-propyl amidoN, N- di-n-butyl amidoN- methyl-N- ethoxy amidoTri- nitrogen of 1,2,4- AzolesChlorobenzene amidoPhenylMethoxyphenylChlorophenylAminomethyl phenylEthylphenylN-propyl phenylN-butylphenylBenzylPyridine -2- basePyridin-3-ylPyridin-4-yl2- picoline -4- basePyridine -4- methyl2- picoline -4- methylPhenoxy groupMethylphenoxyMethoxyphenoxyHalogeno-benzene Oxygroup (X=F, Cl, Br), nitro-phenoxyCyano-benzene oxygenFormoxyl benzene OxygroupAcetylbenzene oxygroup4- formoxyl -2- methoxyphenoxy4- Acetylamino phenoxy group3-N- urethanes phenoxyl4- allyl -2- Difluoro-phenoxyβ-naphthoxyBenzylthio3- methoxybenzene sulphur Base
R3For carboxyl (- COOH) or tetrazole base
It is more preferable: R1For one of above-mentioned group, R2For hydrogen atom, halogen, phenyl or benzyl；N is 0 or 1.
On the basis of above-mentioned preferred general formula I or general formula II, cumarin-biphenyl backbone compound preferably has following substitution The compound of base:
1 generalformulaⅰcompound structure of table
2 general formula of table, II compound structure
It is of the present invention that there is cumarin-biphenyl backbone compound to be realized by following several synthetic routes: general formula I Synthetic route can be carried out by a-b-c-d synthesis step, can also be carried out according to a-e-f-d synthesis step, or according to g-h-f-d Synthesis step carries out.The synthetic route of general formula II can synthesize step according to g-i-j and carry out or carry out according to k-l-j synthesis step.
II compound synthesis route of general formula I and general formula
Key intermediate in several above-mentioned synthetic routes is respectively compound 3,4,5 and 8.
Wherein, Y is O or NH；N is 0~2；R is hydroxyl (- OH) or amino (- NH2)；R3For carboxyl (- COOH) or tetrazole BaseR4For CN, COOCH3, COOEt, COOi-Bu, orR1Or R2Can for hydrogen atom (H), halogen (F, Cl, Br), methylTrifluoromethyl (CF3), ethylPropylIsopropylNormal-butylIsobutyl groupTert-butylN-pentylIsopentylUncle penta BaseN-hexylCyclopropylCyclobutylCyclopentaRing HexylAzido (N3), N- piperidyl2- methyl-N- piperidyl3,5- dimethyl- N- piperidylN- piperazinylN '-methyl-N- piperazinylN- morpholinyl4- methylol-N- piperidylN, N- dimethyl amidoN, N- diethyl amidoN, N- diη-propyl amidoN, N- di-n-butyl amidoN- methyl-N- ethoxy amido1,2,4- triazoleChlorobenzene amidoPhenylMethoxyphenylChlorophenylAminomethyl phenylEthylphenylN-propyl phenylN-butylphenylBenzylPyridine -2- basePyridin-3-ylPyridin-4-yl2- picoline -4- basePyridine -4- methyl2- methyl pyrrole Pyridine -4- methylPhenoxy groupMethylphenoxyMethoxyphenoxyHalogenated phenoxy (X=F, Cl, Br), nitro-phenoxyCyano-benzene oxygenFormvlphenoxvAcetylbenzene oxygroup4- formoxyl -2- first Oxygroup phenoxy group4- acetylamino phenoxy group3-N- urethanes phenoxyl4- allyl -2- Difluoro-phenoxyβ-naphthoxyBenzyl sulphur Base3- Methoxv-phenylsulfanvl
(1) general formula I or II compound of general formula are hydrolyzed by compound 4 or compound 8 under alkaline condition respectively is prepared；
Alkali used can be selected in potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide It is a kind of；Solvent for use is one or both of methanol, ethyl alcohol, acetonitrile, tetrahydrofuran, dioxane；
(2) compound 4 or compound 5 or compound 6 or compound 8 are respectively by compound 3 or compound 1 or compound 2 Or compound 7 and halogenated sartanbiphenyl in the presence of organic solvent and acid binding agent nucleo philic substitution reaction and be prepared；
Wherein, starting halo sartanbiphenyl used is bromomethyl sartanbiphenyl or chloromethyl sartanbiphenyl；Bromomethyl is husky Smooth biphenyl is 2- cyano -4'- bromomethylbiphenyl, 4'- bromomethylbiphenyl -2- carboxylate methyl ester, 4'- bromomethylbiphenyl -2- carboxylic acid second One of ester, 4'- bromomethylbiphenyl -2- carboxylic acid tert-butyl ester or 2- triphenyltetrazolium chloride -4'- bromomethylbiphenyl；Used has Solvent is methanol, ethyl alcohol, acetonitrile, acetone, tetrahydrofuran, methylene chloride, ethyl acetate, N,N-dimethylformamide or N, N- One or both of dimethyl acetamide；Acid binding agent used is potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, hydroxide One of sodium, potassium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide or Sodamide；
(3) compound 3 or compound 4 respectively by compound 2 or compound 6 and alkynes through 1,3- cycloaddition reaction (i.e. Click reaction) it introduces triazole and is prepared；
Wherein, in 1, the 3- cycloaddition reaction (Click reaction) step, catalyst choice monovalence copper, copper powder+sulfuric acid Copper, copper sulphate+sodium ascorbate, cuprous iodide, stannous chloride, cuprous bromide, cyano is cuprous or other organic ligands and monovalence Cu (I) complex compound that copper is formed；Organic solvent used be tetrahydrofuran, acetonitrile, ethyl alcohol, isopropanol, methylene chloride, toluene, N, Dinethylformamide, water or mixed solvent of more than two kinds；Acid binding agent used is preferably sodium carbonate, potassium carbonate or carbonic acid Caesium；
(4) compound 2 or compound 6 can be obtained by compound 1 or compound 5 with reaction of sodium azide respectively；
In the azido reaction step, solvent is selected as n,N-Dimethylformamide, dimethyl sulfoxide, acetonitrile, dichloromethane One of alkane, tetrahydrofuran or acetone；
(5) compound 8 can be made by compound 5 and different phenols, aminated compounds nucleo philic substitution reaction；
Organic solvent used is tetrahydrofuran, acetonitrile, methanol, ethyl alcohol, isopropanol, methylene chloride, acetone, toluene, N, N- 1 kind in dimethylformamide or water or mixed solvent of more than two kinds；Acid binding agent used is sodium carbonate, potassium carbonate, hydrogen Sodium oxide molybdena, potassium hydroxide or cesium carbonate；Catalyst selects potassium iodide or sodium iodide.
Advantage of the present invention and innovative point: structural modification is carried out based on coumarin skeleton, has been synthesized a series of containing cumarin- The compound of biphenyl backbone, preparation method is simple, and yield is higher, 40% or more total recovery.And its antihypertensive active is carried out Primary Study, external activity evaluation test show provided by the invention there is cumarin-biphenyl backbone compound to have obviously Expansion blood vessel function, can be used as that further exploitation is candidate or lead compound, applied to preparing drug for hypertension, for The exploitation of novel antihypertensive medicament is of great significance.
Specific embodiment
To better illustrate the invention, as follows for embodiment: the content of compound as described below is quality Percentage composition.
The preparation of embodiment 1, chemical compounds I -1
(1) into 50ml flask be added 4- chloromethyl-umbelliferone 1.05g, be added 20ml acetonitrile dissolution, then plus Enter sodium azide 0.975g, is heated to reflux 10 hours.After fully reacting, into system plus water quenching is gone out, reaction system acetic acid Ethyl ester extraction.Ethyl acetate layer uses water, saturated common salt water washing respectively, and anhydrous sodium sulfate is dry.Filtering, filter vacuum concentration, Obtain 4- azido-methyl -0.915 g of umbelliferone yellow solid, yield 84.3%.
(2) 4- azido-methyl-umbelliferone 0.868g is added into 50ml flask, uses THF-H2The dissolution of O mixed liquor, Then 1- hexin 0.328g, cupric sulfate pentahydrate 0.05g, sodium ascorbate 0.0792g is added, reacts at room temperature 2 hours, tracking prison Survey reaction.After reaction, 10ml water is added into system, reaction system is extracted with ethyl acetate.Ethyl acetate layer is used respectively Water, saturated common salt water washing, anhydrous sodium sulfate are dry.Filtering, filter vacuum concentration, column chromatograph the product that triazole is made, White solid 0.988g, yield 82.6%.
(3) above-mentioned triazole product 0.598g is added in 20ml DMF, 4'- bromomethyl -2- formic acid first is then added Ester biphenyl 0.732g, potassium carbonate 0.336g, 4 hours of stirring at normal temperature, tracking and monitoring reacts.After reaction, system is poured into In ice water, it is extracted with ethyl acetate.Ethyl acetate layer uses water, saturated common salt water washing respectively, and anhydrous sodium sulfate is dry.Filtering, Biphenyl condensation product, white solid 0.891g, yield 85.2% is made in filter vacuum concentration, column chromatography for separation.
(5) above-mentioned biphenyl condensation product 0.523g is added in 5ml methanol, the sodium hydroxide water of 5ml 5% is then added Solution is heated to reflux 2 hours.After reaction, most of solvent is evaporated off, the dilution of 5ml water is added, with the hydrochloric acid tune of 2mol/L PH until no longer generating precipitating, is filtered, is washed, drying obtains chemical compounds I -1, white solid 0.422g, yield is to acidity 82.9%.1HNMR (400MHz, DMSO) δ: 0.90 (t, J=7.3Hz, 3H), 1.25~1.39 (m, 2H), 1.51~1.65 (m, 2H), 2.65 (t, J=7.6Hz, 2H), 5.29 (s, 2H), 5.65 (s, 1H), 5.89 (s, 2H), 7.13 (dd, J=8.9, 2.2Hz, 1H), 7.19 (d, J=2.2Hz, 1H), 7.39 (t, J=8.0Hz, 3H), 7.47 (t, J=7.6Hz, 1H), 7.52 (d, J=8.0Hz, 2H), 7.59 (t, J=7.5Hz, 1H), 7.77 (dd, J=17.4,8.3,2H), 8.01 (s, 1H), 12.79 (s, 1H)；13CNMR (400MHz, CDCl3) δ: 14.13,22.09,25.07,31.47,49.55,70.26,102.46,110.85, 111.22,113.46,123.39,126.42,127.85,128.28,128.96,129.62,130.96,131.39, 132.70,135.46,141.03,141.21,148.01,151.02,155.45,160.31,162.26,170.01.
The synthesis of embodiment 2, chemical compounds I -21
(1) preparation of 2- chlorphenyl propargyl ether: o-chlorphenol (1.0eqv) is dissolved in suitable acetone, then successively It is added Anhydrous potassium carbonate (1.2eqv), 3- propargyl bromide (1.0eqv) is finished, is refluxed overnight；Reaction solution is cooled to room temperature, filtering, Concentration, obtains 2- chlorphenyl propargyl ether (colorless oil, yield 98%).
(2) tetrahydrofuran and 5ml water of 5ml are added into 50ml round-bottomed flask, it is folded that the 4- prepared in example 1 is then added N-methyl-umbelliferone 1.0g, 2- chlorphenyl propargyl ether 0.765g, 0.037 g of anhydrous cupric sulfate, sodium ascorbate Then 0.456g is stirred at room temperature 4 hours under nitrogen protection, TLC monitoring reaction terminates；It removes tetrahydrofuran under reduced pressure, adds water 60ml, then extracted with 90ml ethyl acetate, organic layer is dried, filtered with anhydrous sodium sulfate, it is concentrated to get the product of triazole, White solid 1.176g, yield 80%.
(3) above-mentioned triazole product 1.0g is taken, is dissolved in 8ml DMF, then addition 0.518 g of Anhydrous potassium carbonate, 4 '- Bromomethyl -2- diphenic acid ethyl ester 1.452g, is then stirred overnight at room temperature, suitable quantity of water is added to stir, be extracted with ethyl acetate, anhydrous Magnesium sulfate dries, filters, concentration, and column chromatography obtains biphenyl condensation product, white solid 0.511g, yield 30%.
(4) 10ml anhydrous methanol, above-mentioned biphenyl condensation product 0.5g are added in 25ml round-bottomed flask；Then it is added 10% Sodium hydroxide solution 1ml, reflux, TLC, which is monitored to reaction, to be terminated；It removes anhydrous methanol under reduced pressure, dissolves concentrate with 15ml water, stir It mixes down, with 3mol/L HCl solution tune pH to 3 or so, stirs 5 minutes, there are a large amount of white solids to be precipitated, filtering, drying at room temperature, Obtain I -21, white solid 0.438g, yield 88.5%.1H NMR(400MHz,DMSO)δ12.62(s,1H,-COOH),8.41 (d, J=3.3Hz, 1H, Ar-H), 7.77 (dd, J=26.3,8.3Hz, 1H, Ar-H), 7.67-7.10 (m, 8H, Ar-H), 7.06-6.80 (m, 1H, Ar-H), 6.64-6.36 (m, 1H, Ar-H), 6.11 (s, 1H, Ar-H), 6.01 (d, J=20.0Hz, 1H, C=C-H), 5.68 (s, 2H ,-Ar-CH2-),5.45–4.95(m,4H,-CH2-O-).13C NMR(101 MHz,DMSO)δ 169.42,162.08,161.68,155.85,150.82,150.09,142.55,141.53, 140.81,140.13, 132.42,130.45,130.14,129.87,129.18,128.76,128.25,127.85, 127.46,124.72, 123.81,123.57,122.66,116.33,115.15,114.70,111.70,105.32,70.96, 58.50,51.60.
The preparation of embodiment 3, chemical compounds I -32
(1) eugenol the synthesis of 4- allyl -2- methoxyl group -1- propynyloxy base benzene: is added in 25ml round-bottomed flask 0.150g, potassium carbonate 0.160g, 10ml acetonitrile, is heated to reflux 30min, and 0.109 g of 3- propargyl bromide is then added dropwise, and flows back in 70 DEG C Stirring 2 to 3 hours, TLC are monitored after reaction, are filtered after reaction solution is cooled to room temperature, reduction vaporization solvent, and rear pillar layer Analysis purifying, obtains yellow oil product 0.241g, yield about 80%.
(2) 0.005g anhydrous cupric sulfate, sodium ascorbate 0.018mg, tetrahydrofuran-water are added into 25ml round-bottomed flask Solution, stirring at normal temperature 30min, solution are yellow cloudy state；Then 4- allyl -2- methoxyl group -1- propynyloxy base benzene is added 0.100g, 4- azido-methyl-umbelliferone 0.107g continue stirring at normal temperature about 3 hours.TLC is monitored after reaction, 5ml water is added, is extracted with ethyl acetate three times.Merge organic phase, use 10ml water respectively, 10ml saturated common salt water washing is organic It is dry that appropriate anhydrous sodium sulfate is added in phase.Filtering evaporation solvent, column chromatographic purifying obtain the triazole product of cumarin, rice White solid 0.130g, yield about 65%.
(3) triazole product 0.100g, the 4'- bromomethyl -2- first of above-mentioned cumarin is added into 25ml round-bottomed flask Tert-butyl acrylate biphenyl 0.073g, potassium carbonate 0.033g, n,N-Dimethylformamide 3ml, stirring at normal temperature 3 hours, TLC monitoring was anti- Answer, after reaction, ice bath be added dropwise about 10ml water, after be extracted with ethyl acetate 3 times.Organic phase is washed with 10ml saturated common salt Organic phase is washed, adds appropriate anhydrous sodium sulfate dry.Drying terminates, and filtering evaporation solvent, column chromatographic purifying obtains biphenyl condensation and produces Object, white solid 0.110g, yield about 65%.
(4) clean 25ml flask is taken, the biphenyl condensation product of 0.090g, 10% sodium hydroxide solution 2ml, 4ml is added Acetonitrile；It is heated to reflux stir about 2 hours, T=60 DEG C, reactant gradually dissolves, in colorless and transparent, TLC monitoring reaction, reaction After, the dilution of 3ml water is added, acetonitrile is evaporated under reduced pressure；Ice bath and be 5 to 6 with 10% hydrochloric acid water transfer pH value of solution, gradually has a large amount of White solid is precipitated, and filtration drying obtains I -32, white solid about 0.079g, yield about 88%.276-279 DEG C of fusing point.1H NMR(400MHz,CDCl3) δ 7.85 (dd, J=7.7,1.0Hz, 1H), 7.68 (s, 1H), 7.58-7.49 (m, 2H), 7.43 (dt, J=7.6,4.8Hz, 3H), 7.36 (dd, J=10.0,4.5Hz, 3H), 6.98-6.89 (m, 3H), 6.75-6.65 (m, 2H), 5.91 (d, J=3.5Hz, 1H), 5.65 (s, 2H), 5.27 (s, 2H), 5.18 (s, 2H), 5.12-5.02 (m, 2H), 4.12 (q, J=7.2Hz, 1H), 3.66 (s, 3H), 3.32 (d, J=6.7Hz, 2H), 2.17 (s, 3H), 2.04 (s, 2H), 1.62 (s,2H),1.31–1.19(m,3H)。13C NMR(101MHz,CDCl3)δ168.79,162.37,160.17, 155.67,149.61,147.78,145.71,145.67,142.00,141.61,137.46,134.40,134.19, 131.42,130.78,130.60,129.95,128.79,127.41,127.21,124.74,123.31,120.54, 115.79,114.74,113.64,112.36,112.28,110.71,102.46,70.43,63.42,55.81,52.01, 50.34,39.81。
The preparation of embodiment 4, chemical compounds I -39
(1) methylene chloride of 35ml is added into 100ml round-bottomed flask, 7- amino -4- chloromethyl-tonka-bean is then added Plain 1.584g, Sodium azide 2.451g are stirred at reflux 6 hours；Then reaction solution is cooled to room temperature, removes extra dichloro under reduced pressure The water of 90ml is added in methane thereto, stirs 5 minutes, is then extracted with 120ml ethyl acetate, anhydrous sodium sulfate is dry, mistake Filter, is concentrated to get 7- amino -4- azido-methyl cumarin, faint yellow solid 1.451g, yield 89.1%.
(2) acetone of 35ml is added into 100ml round-bottomed flask, 7- amino -4- azido-methyl-cumarin is then added 1.239g, 4 '-bromomethyls -2 '-cyanobiphenyl 2.623g, natrium carbonicum calcinatum 0.730g flow back 6 hours, TLC monitoring reaction knot Beam；It removes extra acetone under reduced pressure, 90ml water is added, then extracted with 90ml ethyl acetate, filtered, concentration, column chromatographs to obtain Cyanobiphenyl condensation product 2.287g, yield 90.5%.
(3) tetrahydrofuran of 2.5ml and the water of 2.5ml are added into 25ml round-bottomed flask, above-mentioned preparation is then added Cyanobiphenyl condensation product 0.5g, phenylacetylene 0.116g, anhydrous cupric sulfate 0.009g, sodium ascorbate 0.113g, nitrogen protection Under be stirred at room temperature 4 hours, TLC monitor after reaction, remove extra tetrahydrofuran under reduced pressure, add appropriate amount of water, use ethyl acetate Extraction, anhydrous magnesium sulfate is dry, chromatographs to obtain Clickization triazole product, faint yellow solid 0.371g, yield 60% through column.
(4) triazole the product 0.371g, dehydrated alcohol 10ml of above-mentioned preparation are added into 25ml round-bottomed flask；Stirring Then dissolution is added 15% sodium hydroxide ethanol solution 5ml, is refluxed overnight, obtains red brown solid 0.192g, yield 53.1%,1H NMR (400MHz, DMSO) δ 7.92 (d, J=7.3Hz, 1H, Ar-H), 7.71 (d, J=7.6Hz, 2H, Ar- ), H 7.67-7.10 (m, 17H, Ar-H), 6.30 (s, 1H, C=C-H), 5.07-4.63 (m, 4H, Ar-CH2).13C NMR (101MHz,DMSO)δ169.71,145.80,140.52, 139.28,132.35,131.44,130.79,130.44, 129.25,128.88,128.45,127.15,126.42, 125.27,122.11,120.68,51.85,17.51.
The preparation of embodiment 5, chemical compounds I -40
(1) mixed liquor of suitable tetrahydrofuran and water is added into 50ml round-bottomed flask, is then added in example 4 and makes Standby cyanobiphenyl condensation product 1.80g, N- propargyl morpholine 0.56g, anhydrous cupric sulfate 0.325g, sodium ascorbate 0.40g, It under nitrogen protection, is stirred at room temperature 4 hours, TLC is monitored after reaction, is removed extra tetrahydrofuran under reduced pressure, is added appropriate amount of water, is used Ethyl acetate extraction, anhydrous magnesium sulfate dry, filter, and are concentrated, and column chromatography obtains triazole product, red brown solid 0.693g, yield 30.5%.
(2) triazole product 0.693g, the acetonitrile 10ml of above-mentioned preparation are added into 25ml round-bottomed flask, stirs molten Solution；Then 20% sodium hydroxide acetonitrile solution 5ml is added, is refluxed overnight, obtains I -40 compound 0.142g, yield 21%.1H NMR(400MHz,CDCl3) δ 7.83 (d, J=7.4Hz, 1H, Ar-H), 7.65 (s, 1H, Ar-H), 7.60-7.48 (m, 1H, ), Ar-H 7.46-7.21 (m, 7H, Ar-H), 6.79-6.68 (m, 1H, Ar-H), 6.60 (dd, J=27.8,5.3Hz, 1H, C= ), C-H 5.69 (d, J=12.6Hz, 1H, Ar-CH2), 5.61(s,1H,Ar-CH2),4.82(s,1H,Ar-NH-),2.74– 2.38 (m, 2H ,=C-CH2),2.29–2.13 (m,8H,-O-CH2-CH2-N-).13C NMR(101MHz,CDCl3)δ214.27, 210.93,168.90, 161.09,156.02,152.44,152.10,148.28,141.99,141.94,140.58, 135.53,131.42, 130.77,130.54,129.87,128.97,128.77,127.31,126.96,126.05, 124.72,124.54, 109.96,109.06,107.22,99.29,69.79,69.56,66.55,55.03,54.42, 53.87,53.23,52.02, 31.77,29.38,29.24.
The preparation of embodiment 6, compound ii -2
(1) 4- chloromethyl-umbelliferone 0.500g, 4'- bromomethyl -2- formic acid first is added into 50ml round-bottomed flask Ester biphenyl 0.724g, acetonitrile 10ml, stirring.Then potassium carbonate 0.328g is added, is heated to reflux stirring 3~4 hours, solution is in Yellow is muddy, and TLC is monitored after reaction, is filtered after reaction solution is cooled to room temperature, and obtains weak yellow liquid, is evaporated under reduced pressure molten Agent, column chromatographic purifying obtain 4- chloromethyl biphenyl cumarin condensation product, white solid 1.05g, yield about 85%.
(2) into 25ml round-bottomed flask, above-mentioned 4- chloromethyl biphenyl cumarin condensation product 1.00g, 20% hydroxide is added Potassium solution 5ml, 10ml methanol；It is heated to reflux stir about 2 hours, it is in colorless and transparent, TLC monitoring reaction that reactant, which gradually dissolves, After reaction, suitable quantity of water dilution is added, methanol is evaporated under reduced pressure；Ice bath and with 10% hydrochloric acid water transfer pH value of solution be 3 or so, gradually There are a large amount of white solids to be precipitated, filtration drying obtains compound ii -2, white solid 0.62g, yield 55.6%,1HNMR (400MHz,CDCl3) δ 7.83 (d, J=7.7Hz, 1H), 7.61-7.29 (m, 8H), 7.09 (d, J=1.9Hz, 2H), 6.99 (d, J=8.5Hz, 1H), 5.14 (s, 2H), 3.79-3.57 (m, 2H)13C NMR(101MHz,CDCl3)δ175.36, 169.07, 157.32,156.12,142.26,142.13,141.07,135.81,131.35,130.75,129.87, 128.59, 127.28,127.21,121.14,119.85,112.66,112.41,97.50,70.43,51.99,29.39.
The preparation of embodiment 7, compound ii -3
(1) synthesis of 3- oxo-(3- pyridyl group) ethyl propionate: 10ml ethyl acetate being added into 25ml round-bottomed flask, Ethyl nicotinate 1.0g, tert-butyl alcohol lithium 0.794g, back flow reaction 4 hours, TLC monitoring reaction terminated；Reaction solution is cooled to room temperature, to 60ml 3M HCl solution is wherein added, stirs 5 minutes；Then, organic layer is separated, water layer is extracted with 90ml ethyl acetate, is merged Organic layer is dried, filtered with anhydrous sodium sulfate, and concentration obtains compound 3- oxo-(3- pyridyl group) ethyl propionate, colorless oil Shape object 0.474g, yield 37.1%.
(2) the 6ml concentrated sulfuric acid, resorcinol 1.0g, 3- oxo-(3- pyridyl group) propionic acid are added into 25ml round-bottomed flask Ethyl ester 1.18g is stirred 4 hours under ice bath, and TLC is monitored after reaction.Then reaction solution 60ml ice water is added dropwise to mix It closes and is stirred 30 minutes in object, that is, there are a large amount of white solids to be precipitated, filter, 4- (3- pyridyl group) tonka-bean can be obtained in drying at room temperature Element, white solid 1.382g, yield 86.4%.
(3) N, N '-dimethyl formamide 8ml, 4- (3- pyridyl group) cumarin 0.5g are added into 25ml round-bottomed flask, 4 '-bromomethyl -2- diphenic acid methyl esters 0.866g, Anhydrous potassium carbonate 0.470g are stirred overnight at room temperature, TLC monitoring reaction knot Beam；Reaction solution is poured into 60ml water and is stirred 5 minutes, then is extracted with 90ml ethyl acetate, organic layer is dry with anhydrous magnesium sulfate, Filtering, is concentrated to get crude product, then column chromatographs to obtain biphenyl product, white solid 0.738g, yield 65%.
(4) 10ml anhydrous methanol, above-mentioned biphenyl compound 0.5g are added into 25ml round-bottomed flask；Then 20% hydrogen is added Sodium oxide molybdena 2ml, is refluxed overnight, and TLC monitoring reaction terminates；It removes anhydrous methanol under reduced pressure, dissolves concentrate, stirring with 15ml water Under, with 3M HCl solution tune pH to 3 or so, stirs 5 minutes, obtain target product II -3, white solid 0.393g, yield 53.3%,1H NMR (400MHz, DMSO) δ 12.49 (s, 1H), 8.87-8.68 (m, 1H), 8.47 (ddd, J=6.2,4.7, 2.4Hz, 1H, Ar-H), 8.10-7.93 (m, 1H, Ar-H), 7.73 (d, J=7.6Hz, 1H, Ar-H), 7.67-7.17 (m, 12H, Ar-H), 7.14-7.03 (m, 1H, Ar-H), 6.64-6.47 (m, 1H, Ar-H), 6.38 (d, J=2.1Hz, 1H, C=C- ), H 5.32 (d, J=18.7Hz, 1H, Ar-CH2), 5.10 (d, J=4.3Hz, 1H, Ar-CH2-).13C NMR(101MHz, DMSO)δ161.71,159.72,155.39,151.95,150.61,148.58,140.55,138.11,136.29, 134.97, 133.50,130.82,130.45,129.10,128.47,128.38,127.75,127.63,127.50, 127.30, 123.66,113.17,112.34,105.42,102.18,69.78,68.93.
The preparation of embodiment 8, compound ii -9
(1) eugenol 0.198g is added into 50ml round-bottomed flask, potassium carbonate 0.167g is dissolved in 15ml acetonitrile, It is heated to reflux stirring 30min, reaction solution is in 4- chloromethyl biphenyl perfume faint yellow, that then in addition embodiment 6 prepared by (1) Legumin condensation product 0.522g, potassium iodide 0.199g, return stirring about 4 hours, TLC was monitored after reaction, cooling to reaction solution It is filtered after to room temperature, obtains yellow liquid, solvent is evaporated under reduced pressure, column chromatographic purifying obtains the compound of eugenol substitution, white Solid about 0.443g, yield about 63%.
(2) into 25ml round-bottomed flask, the compound 0.40g that above-mentioned eugenol replaces, 10% sodium hydroxide solution is added 5ml, 10ml ethyl alcohol；It is heated to reflux stir about 2 hours, reactant gradually dissolves, in colorless and transparent, TLC monitoring reaction, reaction After, suitable quantity of water dilution is added, ethyl alcohol is evaporated under reduced pressure；Ice bath and be 5 or so with 10% hydrochloric acid water transfer pH value of solution, gradually has big It measures white solid to be precipitated, filtration drying obtains II -9, white solid 0.29g, yield about 75%.1H NMR(400MHz,DMSO- D6) δ 8.20 (s, 1H), 8.05 (dd, J=8.2,1.6Hz, 1H), 7.68-7.53 (m, 3H), 7.51-7.21 (m, 5H), 7.00 (d, J=2.3Hz, 1H), 6.93-6.76 (m, 3H), 6.67 (dt, J=1.9,1.1Hz, 1H), 6.31 (s, 1H), 5.95 (p, J =9.9 Hz, 1H), 5.55-5.23 (m, 2H), 5.08 (d, J=9.6Hz, 2H), 4.97 (t, J=1.0Hz, 2H), 3.36 (dt, J=10.0,0.9Hz, 2H).13C NMR(101MHz,DMSO-d6)δ168.55,161.81,160.67, 154.33, 147.17,146.20,145.68,138.28,137.54,136.95,136.73,135.31,131.14, 130.37, 129.32,129.25,128.98,127.52,127.31,126.23,123.08,119.79,115.98, 115.91, 115.89,114.90,113.27,112.83,112.62,101.72,70.63,69.35,39.53。
The preparation of embodiment 9, compound ii -13
(1) 4- chloromethyl-umbelliferone 0.500g, potassium carbonate 0.33g, potassium iodide are added into 50ml round-bottomed flask 0.40g, DMF 15ml, heating stirring are added 4- methylphenol 0.305g to 60 DEG C, continue stir about 4 hours, and TLC monitoring is anti- It after answering, is filtered after reaction solution is cooled to room temperature, obtains yellow liquid, be evaporated under reduced pressure solvent, and rear pillar chromatographic purifying, it washes De- agent ratio ethyl acetate: petroleum ether=1:6 obtains white solid about 0.42g, yield 58%.
(2) above-mentioned white solid 0.42g, 4'- bromomethyl -2- methyl formate biphenyl are added into 50ml round-bottomed flask 0.44g, ethyl alcohol 10ml, stirring.Then potassium carbonate 0.19g is added, is heated to reflux stirring 3~4 hours, solution is muddy in yellow, TLC is monitored after reaction, is filtered after reaction solution is cooled to room temperature, and obtains weak yellow liquid, is evaporated under reduced pressure solvent, and rear pillar Chromatographic purifying, eluant, eluent ratio ethyl acetate: petroleum ether=1:10 is evaporated under reduced pressure solvent and obtains biphenyl condensation product, white solid 0.49g, yield 65%.
(3) into 25ml round-bottomed flask, above-mentioned biphenyl condensation product 0.40g, 10% sodium hydroxide solution 5ml, 10ml is added Ethyl alcohol；It is heated to reflux stir about 2 hours, reactant gradually dissolves, and in colorless and transparent, TLC monitoring reaction after reaction, adds Enter suitable quantity of water dilution, ethyl alcohol is evaporated under reduced pressure；Ice bath and be 5 or so with 10% hydrochloric acid water transfer pH value of solution, gradually has a large amount of whites solid Body is precipitated, and filtration drying obtains II -13,0.21 g of white solid, yield 55%.1H NMR(400MHz,CDCl3)δ7.85 (dd, J=7.7,1.4Hz, 1H), 7.59-7.30 (m, 8H), 7.15-6.86 (m, 6H), 6.51 (d, J=1.4Hz, 1H), 5.32-4.98 (m, 4H), 3.66 (s, 3H), 2.29 (d, J=14.7Hz, 3H).13C NMR(101MHz,DMSO-d6)δ 167.85,161.84, 160.65,157.26,154.30,146.47,140.88,137.59,136.95,130.87, 130.17,129.89, 129.62,129.27,129.20,128.98,127.09,127.01,114.57,113.27, 112.87,112.37, 101.87,69.50,68.59,51.92,20.62。
The preparation of embodiment 10, compound ii -26
(1) 4- chloromethyl -7- aminocoumarin 0.500g, 4'- bromomethyl -2- cyano connection are added into 50ml round-bottomed flask Benzene 0.724g, tetrahydrofuran 10ml, agitating and heating dissolution.Then potassium carbonate 0.328g is added, is heated to reflux stirring 3~4 hours, Solution is muddy in yellow, and TLC is monitored after reaction, filters after reaction solution is cooled to room temperature, obtains weak yellow liquid, depressurizes Solvent is evaporated, column chromatographic purifying obtains biphenyl cumarin condensation product, white solid 0.653g, yield about 53%.
(2) N methyl piperazine 0.138g, potassium carbonate 0.15g are added into 50ml round-bottomed flask, is dissolved in 10 ml DMF In, it is heated to reflux stirring 30min, then above-mentioned biphenyl cumarin condensation product 0.500g, iodate is added in faint yellow in reaction solution Potassium 0.19g, return stirring about 4 hours, TLC was monitored after reaction, is filtered after reaction solution is cooled to room temperature, is obtained yellow liquid Body, is evaporated under reduced pressure solvent, and column chromatographic purifying obtains methyl piperazine substituted compound, white solid about 0.373g, yield about 65%.
(3) into 25ml round-bottomed flask, the compound 0.373g that above-mentioned methyl piperazine replaces is added, 10% potassium hydroxide is molten Liquid 5ml, 10ml ethyl alcohol；It is heated to reflux stir about 2 hours, reactant gradually dissolves, in colorless and transparent, TLC monitoring reaction, reaction After, suitable quantity of water dilution is added, ethyl alcohol is evaporated under reduced pressure；Ice bath and be 5 or so with 10% hydrochloric acid water transfer pH value of solution, gradually has big It measures white solid to be precipitated, filtration drying obtains II -26, white solid 0.25g, yield about 70%.1H NMR(400MHz, DMSO-d6) δ 8.07 (dd, J=8.2,1.5Hz, 1H), 7.69-7.52 (m, 3H), 7.44-7.22 (m, 5H), 7.01 (d, J= 2.3Hz, 1H), 6.82 (dd, J=8.5,2.4Hz, 1H), 6.14 (s, 1H), 4.97 (t, J=1.0Hz, 2H), 3.98-3.52 (m, 2H),2.94–2.43(m,8H),2.25(s,3H)。13C NMR(101MHz,DMSO-d6)δ168.65, 161.75, 160.53,154.42,150.10,137.77,136.93,131.04,130.54,129.31,129.01, 128.10, 127.68,125.59,123.12,115.15,112.73,112.49,101.72,69.58,57.43,53.38, 52.49, 45.00。
Embodiment 11, the present invention relates to chemical compounds I -1~I -40 and II -1~II -27, but are not limited only to these Compound, the method that the synthetic method of other compounds can refer to Examples 1 to 10 carry out.Wherein, representative other The nuclear magnetic data of compound is as follows:
Compound I-9, white solid,1HNMR (400MHz, DMSO) δ: 11.0 (s, 1H), 8.58 (s, 1H), 7.84~ 7.71 (m, 2H), 7.58 (t, J=7.6Hz, 1H), 7.52 (d, J=8.1Hz, 2H), 7.49~7.44 (m, 1H), 7.39 (t, J =7.7Hz, 3H), 7.20 (d, J=2.4Hz, 1H), 7.13 (dd, J=8.9,2.4Hz, 1H), 6.06 (s, 2H), 5.71 (s, 1H), 5.29 (s, 2H), 4.43 (s, 2H), 3.05~2.87 (m, 4H), 1.73 (t, J=7.9Hz, 4H), 1.28 (q, J= 7.3Hz, 4H), 0.88 (t, J=7.3Hz, 6H)；13CNMR (101MHz, DMSO) δ: 169.9,162.3,160.2,155.4, 150.7,141.2,141.0,137.4,135.4,132.7,131.3,130.9,129.6,128.9,128.7,128.2, 127.8,126.4,113.5,111.0,110.8,102.4,70.2,52.2,49.8,46.0,25.5,19.9,13.9.
Compound I-10, white solid,1HNMR (400MHz, DMSO) δ: 8.31 (s, 1H), 7.77 (dd, J=29.0, 7.8Hz, 2H), 7.63~7.33 (m, 7H), 7.19 (s, 1H), 7.13 (d, J=8.2Hz, 1H), 5.98 (s, 2H), 5.68 (s, 1H), 5.29 (s, 2H), 3.87 (s, 3H), 2.63 (s, 3H), 1.58 (s, 4H), 1.41 (s, 2H),；13CNMR (101MHz, DMSO) δ: 170.1,162.2,160.28,155.4,150.8,141.9,141.2,140.8,135.4,133.1,131.2, 130.9,129.5,128.9,128.2,127.8,126.6,126.4,113.4,111.1,110.8,102.4,70.2, 53.1,52.3,49.6,24.6,23.3.
Compound I-14, beige solid,1H NMR (400MHz, DMSO-d6) δ 8.14 (s, 1H), 8.02 (dd, J= 8.2,1.8Hz, 1H), 7.65-7.51 (m, 3H), 7.48-7.32 (m, 3H), 7.32-7.21 (m, 2H), 7.01 (d, J= 2.1Hz, 1H), 6.82 (dd, J=8.6,2.1Hz, 1H), 6.26 (s, 1H), 5.36 (s, 2H), 4.97 (t, J=1.0Hz, 2H),3.90–3.73(m,2H),2.61–2.30(m,8H),2.13(s,3H)。13C NMR(101MHz,DMSO-d6)δ168.52, 161.84,161.82,153.90,148.14,143.02, 138.27,137.52,136.96,131.00,130.30, 129.31,129.25,128.82,128.13,127.43, 125.59,123.79,123.12,112.58,112.40, 112.36,101.73,69.36,53.81,52.50,48.04, 44.89。
Compound I-15, beige solid,1H NMR (400MHz, DMSO-d6) δ 8.32 (s, 1H), 8.02 (dd, J= 8.2,1.7Hz,1H),7.67–7.53(m,3H),7.45–7.38(m,2H),7.38–7.31(m, 1H),7.31–7.23(m, 3H), 7.13 (ddd, J=8.2,2.1,1.3Hz, 1H), 7.01 (d, J=2.2Hz, 1H), 6.95-6.87 (m, 2H), 6.82 (dd, J=8.5,2.1Hz, 1H), 6.51 (t, J=8.5Hz, 1H), 6.26 (s, 1H), 5.36 (s, 2H), 4.97 (t, J= 0.9Hz, 2H), 4.83 (d, J=8.5Hz, 2H).13C NMR(100 MHz,DMSO-d6)δ168.60,161.72,160.49, 153.90,148.24,146.68,144.87,138.27, 136.98,133.02,131.04,130.03,129.33, 128.80,128.13,127.46,125.59,124.50, 123.49,122.36,116.04,113.18,112.63, 112.56,112.41,101.73,69.40,52.45,39.01。
Compound I-16, white solid,1H NMR(400MHz,CDCl3)δ8.07–7.78(m,1H,Ar-H), 7.68– 7.32 (m, 3H, Ar-H), 6.93 (t, J=17.9Hz, 1H, Ar-H), 6.00 (d, J=13.3Hz, 1H, C=C-H), 5.70 (d, J=11.5Hz, 2H, Ar-CH2), 5.15 (d, J=10.9Hz, 2H, Ar-CH2-). 13C NMR(101MHz,CDCl3)δ 158.62,155.72,131.44,130.78,129.97,128.95, 128.81,128.63,127.43,127.21, 125.83,124.80,119.89,113.72,110.72,102.54, 70.46,52.02,50.53.
Compound I-17, white solid,1H NMR(400MHz,CDCl3) δ 7.86 (d, J=6.7Hz, 1H), 7.67 (s, 1H), 7.61-7.20 (m, 14H), 7.05-6.86 (m, 5H), 5.92 (s, 1H), 5.66 (d, J=8.8 Hz, 2H), 5.20 (d, J =20.9Hz, 4H), 3.64 (d, J=14.0Hz, 3H)13C NMR(101MHz, CDCl3)δ168.79,162.43,160.20, 158.02,155.70,147.74,145.58,141.65,134.38, 131.44,130.79,130.60,129.97, 129.60,128.81,127.43,127.21,124.69,123.09, 121.46,114.78,113.71,112.30, 110.67,102.52,70.46,61.93,52.02,50.41.
Compound I-18, white solid,1H NMR(400MHz,CDCl3) δ 7.97 (d, J=7.8Hz, 1H), 7.86 (d, J =6.8Hz, 2H), 7.73 (s, 1H), 7.65 (s, 2H), 7.59-7.29 (m, 22H), 7.14-7.03 (m, 5H), 7.00-6.83 (m, 9H), 5.92 (s, 1H), 5.65 (d, J=8.7Hz, 3H), 5.32-5.11 (m, 4H), 2.29 (d, J=5.4Hz, 3H)13C NMR(101MHz,CDCl3)δ168.55,162.08,161.68, 156.63,150.82,150.09,141.53,140.81, 140.52,140.13,132.94,131.52,131.34, 129.70,129.48,129.44,128.76,128.07, 127.85,123.57,122.66,116.14,115.15, 114.70,111.70,105.32,70.96,57.51,52.13, 51.60,21.15.
Compound I-19, white solid,1H NMR(400MHz,CDCl3)δ7.90–7.81(m,1H),7.65 (s,1H), 7.59-7.50 (m, 2H), 7.50-7.31 (m, 6H), 7.17 (t, J=8.0Hz, 1H), 7.00-6.91 (m, 2H), 6.78 (t, J =8.2Hz, 3H), 5.92 (s, 1H), 5.67 (s, 2H), 5.20 (d, J=13.6Hz, 4H), 3.66 (s, 3H), 2.32 (s, 3H).13C NMR(101MHz,CDCl3)δ162.43,160.17,158.07, 155.71,147.74,145.74,142.02, 139.72,134.39,131.43,130.78,130.62,129.97, 129.32,128.82,127.43,127.21, 124.69,122.99,122.29,115.66,113.70,112.33, 111.59,110.69,102.53,70.47,61.94, 52.00,50.40,21.52.
Compound I-20, white solid,1H NMR(400MHz,CDCl3) δ 7.96 (d, J=6.8Hz, 1H), 7.89- 7.83(m,2H),7.69(s,3H),7.61–7.29(m,12H),7.05–6.82(m,1H),4.01– 3.74(m,4H),3.72– 3.61(m,3H).13C NMR(101MHz,CDCl3)δ147.71,131.43, 130.79,129.96,128.98,128.82, 127.20,124.73,122.25,120.93,114.74,113.68, 112.37,111.96,102.51,70.46,63.27, 55.84,52.01,50.40.
Compound I-23, white solid,1H NMR(400MHz,CDCl3) δ 7.86 (dd, J=7.7,1.1Hz, 1H), 7.65(s,1H),7.60–7.31(m,10H),6.99–6.92(m,2H),6.90–6.79(m,2H), 5.92(s,1H),5.68 (s, 2H), 5.19 (d, J=4.3Hz, 4H)13C NMR(101MHz,CDCl3)δ 162.47,155.73,147.64, 142.80,132.43,131.43,130.78,129.98,129.54,128.82, 128.34,127.21,125.09, 123.12,116.64,113.72,112.35,102.55,70.48,62.14,52.00.
Compound I-24, beige solid,1H NMR(400MHz,CDCl3) δ 7.96 (dd, J=7.5,1.0 Hz, 1H), 7.56 (s, 1H), 7.54 (td, J=7.6,1.2Hz, 2H), 7.43 (d, J=7.7Hz, 2H), 7.46-7.18 (m, 3H), 7.05-6.90 (m, 2H), 6.91 (dt, J=6.7,3.9Hz, 2H), 5.92 (s, 1H), 5.63 (s, 2H), 5.12 (s, 3H), 3.68 (d, J=10.4Hz, 3H).13C NMR(101MHz,CDCl3)δ167.35, 160.21,159.47,154.65, 153.11,146.04,144.25,140.98,140.62,133.34,130.41, 129.75,129.56,128.94, 127.78,125.41,126.19,123.64,123.15,115.07,114.95, 114.87,114.84,112.68, 111.21,109.60,101.47,69.43,61.54,50.99,49.37。
Compound I-27, white solid,1H NMR(400MHz,DMSO)δ12.55(s,1H),10.12– 9.43(m, 1H), 8.44 (s, 2H), 8.04-6.98 (m, 17H), 6.57 (d, J=2.6Hz, 1H), 5.98 (s, 1H), 5.71 (s, 1H), 5.45–4.92(m,4H).13C NMR(101MHz,DMSO)δ191.30, 168.39,162.84,154.97,150.14, 142.65,140.81,131.74,131.50,130.76,130.51, 129.90,129.31,128.31,128.22, 127.80,127.49,125.91,115.24,110.68,102.07, 61.38,51.89,49.24.
Compound I-28, beige solid,1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),8.16 (s,1H), 8.02 (dd, J=8.2,1.7Hz, 1H), 7.64-7.50 (m, 3H), 7.47-7.31 (m, 5H), 7.30-7.19 (m, 2H), 7.08 (d, J=8.0Hz, 1H), 7.01 (d, J=2.2Hz, 1H), 6.82 (dd, J=8.5,2.1Hz, 1H), 6.26 (s, 1H), 5.37 (s, 2H), 5.26 (s, 2H), 4.97 (t, J=0.9Hz, 2H), 3.87 (s, 3H).13C NMR(100MHz,DMSO-d6)δ 191.07,168.60,161.74,160.49,153.95, 150.20,148.25,142.03,138.27,136.92, 135.85,130.75,130.41,130.02,129.33, 128.82,128.55,127.50,125.59,124.90, 123.56,122.41,115.00,112.84,112.76, 112.14,111.78,101.73,69.51,61.22,56.03, 52.45。
Compound I-30, white solid,1H NMR(400MHz,DMSO)δ9.79(s,1H),8.37(s,1H), 5.96 (s,2H),5.71(s,1H),5.30(s,2H),5.13(s,2H),2.00(s,3H).13C NMR(101MHz, DMSO)δ 168.39,167.72,161.74,154.97,143.40,140.81,132.93,131.50,130.77, 130.51, 129.31,128.31,127.81,125.95,125.54,120.41,114.77,113.02,110.70, 102.08,69.71, 61.20,51.90,23.78.
Compound I-31, white solid,1H NMR (400MHz, DMSO) δ 12.42 (s, 1H, COOH), 9.61 (d, J= 4.8Hz,2H,Ar-NH2), 8.38 (d, J=6.3Hz, 1H, Ar-H), 7.94-6.97 (m, 16H, Ar-H), 6.62 (dd, J= 52.9,5.4Hz, 4H, Ar-H), 5.96 (s, 1H, C=C-H), 5.72 (s, 1H, C=C-CH2-),5.44–4.87(m,4H,- CH2- O-), 4.12 (dd, J=7.1,3.5Hz, 2H ,-O-CH2- C), 1.24 (td, J=7.1,2.4Hz, 3H ,-O-C-CH3) .13C NMR(101MHz,DMSO) δ168.45,158.31,153.42,140.44,131.48,130.51,129.53, 129.31,128.31,128.22, 127.80,127.49,127.00,110.96,108.16,105.03,60.94,60.11, 51.89,14.47.
Compound I-33, beige solid,1H NMR(400MHz,CDCl3) δ 8.20 (d, J=7.9Hz, 1H), 7.88- 7.83 (m, 1H), 7.78 (d, J=7.5Hz, 1H), 7.72 (s, 1H), 7.53 (ddd, J=11.5,6.4,2.6Hz, 2H), 7.50-7.45 (m, 3H), 7.43 (d, J=6.9Hz, 3H), 7.39 (dd, J=7.6,2.0 Hz, 1H), 7.36 (t, J= 3.5Hz, 3H), 7.34 (d, J=1.7Hz, 1H), 7.26 (s, 1H), 6.98-6.89 (m, 3H), 5.91 (s, 1H), 5.66 (s, 2H), 5.41 (d, J=6.9Hz, 2H), 5.16 (s, 2H), 3.64 (d, J=14.4Hz, 3H).13C NMR(101MHz,CDCl3) δ168.79,162.40,160.22,155.66,153.73, 147.79,145.57,142.00,141.63,134.53, 134.38,131.43,130.78,130.59,129.96, 128.80,127.53,127.42,127.22,126.54, 125.76,125.55,125.39,124.66,123.13, 121.87,121.07,113.67,112.22,110.66, 105.45,102.49,70.44,62.34,52.01,50.39。
Compound I-34, white solid,1H NMR(400MHz,DMSO)δ12.79(s,1H),8.15(s, 1H),7.80 (d, J=8.9Hz, 1H), 7.74 (dd, J=7.6,1.0Hz, 1H), 7.58 (td, J=7.6,1.3Hz, 1H), 7.51 (d, J= 8.2Hz, 2H), 7.47 (td, J=7.6,1.2Hz, 1H), 7.40 (s, 1H), 7.37 (d, J=8.3Hz, 3H), 7.34-7.29 (m, 4H), 7.24 (td, J=8.6,4.0Hz, 1H), 7.13 (dd, J=8.9,2.5 Hz, 1H), 5.93 (s, 2H), 5.68 (s, 1H), 5.28 (s, 2H), 3.72 (d, J=8.0Hz, 4H), 3.34 (s, 3H), 2.56-2.46 (m, 3H).13C NMR(101MHz, DMSO)δ169.50,161.78,159.78,154.98, 150.29,145.04,140.71,140.54,138.13,134.95, 132.19,130.89,130.46,129.13, 128.91,128.46,128.35,127.79,127.35,126.84, 125.93,124.04,112.97,110.70, 110.50,101.98,69.76,49.21,34.97,24.84,22.48。
Compound I-35, beige solid,1H NMR (400MHz, DMSO) δ 8.10 (s, 1H), 7.75 (d, J= 8.7Hz, 2H), 7.63 (td, J=7.6,1.3Hz, 1H), 7.59-7.47 (m, 3H), 7.45 (d, J=7.6Hz, 1H), 7.33 (d, J=8.1Hz, 2H), 7.26-7.14 (m, 2H), 6.95-6.84 (m, 2H), 6.74 (dd, J=8.1,2.2Hz, 1H), 5.90 (s,2H),5.57(s,1H),5.29(s,2H),4.33(s,2H),3.59(s,3H), 3.33(s,4H)。13C NMR(101MHz, DMSO)δ168.39,161.71,159.69,159.51,154.91, 150.37,144.24,140.80,140.27,136.83, 135.15,131.49,130.75,130.51,129.77, 129.31,128.30,127.80,127.52,125.87, 124.34,120.29,113.35,112.97,111.83, 110.63,110.24,102.01,69.69,55.05,51.89, 49.14,26.96。
Compound I-36, red brown solid,1H NMR (400MHz, DMSO) δ 12.76 (s, 1H), 7.96 (d, J= 5.0Hz, 1H), 7.72 (d, J=7.4Hz, 3H), 7.65-7.24 (m, 9H), 6.85 (d, J=9.1Hz, 1H), 6.66 (s, 1H), 5.78 (s, 1H), 5.42 (s, 1H), 4.95 (s, 1H), 4.83-4.65 (m, 2H), 2.63 (t, J=7.4Hz, 2H), 1.65-1.47 (m, 2H), 1.40-1.16 (m, 2H), 0.88 (t, J=7.4Hz, 3H)13C NMR(101MHz,DMSO)δ 169.66,160.29,155.35,151.54,150.64,140.49,139.55, 136.73,132.29,130.81, 130.45,129.00,128.64,127.21,126.30,122.85,109.71, 106.67,53.89,48.92,30.97, 24.56,21.60,13.63.
Compound I-37, red brown solid,1H NMR(400MHz,CDCl3)δ8.01–7.77(m,1H), 7.64–7.11 (m, 8H), 6.82 (dd, J=9.1,2.5Hz, 1H), 6.74-6.56 (m, 1H), 5.80 (d, J=13.4Hz, 1H), 5.54 (d, J=17.3Hz, 1H), 4.78 (t, J=10.8Hz, 2H ,=C-CH2),2.76– 2.55(m,2H),1.64(s,2H),1.29 (ddd, J=23.7,21.9,17.6Hz, 2H), 0.85 (t, J=20.4 Hz, 3H)13C NMR(101MHz,CDCl3)δ 169.42,162.08,156.65,150.09,149.84, 148.83,142.55,140.38,138.85,132.42, 130.45,130.14,129.48,129.18,128.17, 127.46,123.59,120.79,114.79,114.70, 113.74,97.74,51.60,47.11,30.91,27.90, 26.71,23.16,14.00.
Compound I-38, rufous grease,1H NMR(400MHz,CDCl3) δ 7.84 (d, J=6.9Hz, 1H), 7.54 (td, J=7.7,1.1Hz, 1H), 7.48-7.19 (m, 7H), 6.72 (dd, J=8.9,2.1Hz, 1H), 6.64 (d, J= 2.3Hz,1H),5.74(s,1H),5.56(s,1H),4.82(s,2H),3.67(s,3H),2.80– 2.55(m,3H),2.23– 2.06 (m, 2H), 1.76-1.57 (m, 2H), 0.91 (dt, J=13.4,7.1Hz, 3H)13C NMR(101MHz,CDCl3)δ 210.96,168.89,161.12,156.09,152.43,148.35, 142.03,140.66,135.55,131.44, 130.83,130.58,129.92,129.02,127.34,126.06, 124.77,109.96,109.27,107.35,99.36, 69.55,54.47,53.80,52.06,50.22,31.78,31.52, 29.27,29.22,28.92,25.67,22.54, 14.07.
Compound ii -1, white solid,1H NMR (400MHz, DMSO) δ 7.73 (t, J=9.7Hz, 2H), 7.63- 7.29(m,8H),7.20–7.02(m,1H),6.57–6.39(m,2H),5.06(s,2H),1.48(s, 3H).13C NMR (101MHz,DMSO)δ169.64,158.13,155.99,1 40.49, 130.72,130.4,129.02,128.34, 127.35,126.26,104.96,102.73,72.64,68.78,30.11, 18.12.
Compound ii -4, white solid,1H NMR(400MHz,CDCl3) δ 7.86 (d, J=7.7Hz, 1H), 7.64 (d, J =9.0Hz, 1H), 7.58-7.32 (m, 7H), 7.07 (dd, J=8.9,2.5Hz, 1H), 6.96 (d, J=2.5Hz, 1H), 5.19 (d, J=5.6Hz, 2H), 4.83 (s, 2H), 3.66 (s, 3H)13C NMR(101 MHz,CDCl3)δ168.55, 163.25,159.12,158.02,141.87,140.81,140.52,140.13, 132.94,131.52,129.48, 129.44,128.76,128.07,127.85,126.03,124.64,109.82, 109.76,104.83,70.96,52.13, 44.28.
Compound ii -5, white solid,1H NMR(400MHz,CDCl3)δ8.06–7.91(m,1H),7.62 –7.28(m, 11H), 7.04 (d, J=8.3Hz, 1H), 6.98 (d, J=2.5Hz, 1H, Ar-H), 6.64-6.55 (m, 1H), 5.79 (d, J= 1.1Hz, 1H), 5.37 (d, J=1.0Hz, 1H), 5.13 (d, J=31.1Hz, 2H)13C NMR(101MHz,CDCl3)δ 172.18,159.99,154.25,145.16,142.98,140.81, 139.87,135.98,132.14,131.22, 131.17,130.76,129.17,128.76,128.66,128.57, 128.39,127.31,127.23,120.44, 116.10,107.62,102.15,69.94.
Compound ii -6, white solid,1H NMR(400MHz,CDCl3) δ 7.96 (d, J=7.6Hz, 1H), 7.63- 7.13(m,14H),7.00–6.87(m,2H),5.15(s,2H),4.03(s,2H),2.40(s,3H). 13C NMR(101MHz, CDCl3)δ172.05,162.33,161.00,153.88,147.75,142.83, 141.17,139.15,135.01, 132.18,131.20,130.78,129.16,128.89,128.53,128.28, 127.42,127.23,126.26, 125.67,122.21,114.38,112.90,101.71,70.26,32.82,15.39.
Compound ii -7, white solid,1H NMR(400MHz,DMSO-d6) δ 8.76 (d, J=7.8Hz, 1H), 8.15 (d, J=16.9Hz, 1H), 7.91-7.05 (m, 18H), 6.54 (d, J=10.9Hz, 1H), 5.75 (t, J=21.0Hz, 2H), 5.29 (d, J=5.6Hz, 2H), 5.11 (d, J=5.4Hz, 1H)13C NMR(101 MHz,DMSO-d6)δ161.69, 151.98,150.58,145.35,131.50,130.51,129.30,128.46, 128.30,127.81,125.93, 102.04,78.00,51.90,48.50.
Compound ii -8, white solid,1H NMR(400MHz,CDCl3) δ 7.86 (d, J=7.5Hz, 1H), 7.71 (d, J =8.8Hz, 1H), 7.62-7.31 (m, 7H), 7.07 (dd, J=8.8,2.2Hz, 1H), 6.95 (d, J=2.2Hz, 1H), 6.67(s,1H),5.21(s,2H),3.67(s,2H).13C NMR(101MHz,CDCl3)δ 168.74,163.49,158.30, 155.59,141.99,141.79,134.06,131.47,130.79,130.56, 130.01,128.87,127.48, 127.25,127.18,126.95,119.70,114.39,113.25,109.29, 102.47,70.70,52.04.
Compound ii -10, white solid,1H NMR (400MHz, DMSO-d6) δ 8.07 (dd, J=8.2,1.5Hz, 1H),8.00–7.83(m,2H),7.64–7.51(m,3H),7.49–7.41(m,2H),7.40– 7.27(m,3H),7.06– 6.92 (m, 3H), 6.82 (dd, J=8.5,2.4Hz, 1H), 6.37 (s, 1H), 5.35 (s, 2H), 4.96 (t, J=1.0Hz, 2H),2.58(s,3H)。13C NMR(101MHz,DMSO-d6)δ196.67, 168.52,163.12,161.84,160.65, 154.25,146.47,138.09,137.51,136.93,131.03, 130.38,130.29,130.22,129.31, 128.98,127.84,127.14,126.23,123.08,115.01, 113.25,112.87,112.51,101.94,69.47, 68.59,26.42。
Compound ii -11, rice white,1H NMR (400MHz, DMSO-d6) δ 8.06 (dd, J=8.2,1.5 Hz, 1H), 7.63-7.55 (m, 3H), 7.48-7.41 (m, 2H), 7.39-7.33 (m, 1H), 7.33-7.28 (m, 2H), 7.00 (d, J= 2.3Hz, 1H), 6.98-6.87 (m, 4H), 6.82 (dd, J=8.5,2.4Hz, 1H), 6.27 (s, 1H), 5.35 (s, 2H), 4.97 (t, J=1.0Hz, 2H).13C NMR(101MHz,DMSO-d6)δ 168.55,161.84,160.65,157.85, 156.13,154.11,146.42,138.09,137.56,136.95, 131.13,130.44,129.31,129.24, 128.98,127.68,127.18,125.59,123.10,116.62, 116.33,113.33,112.83,112.39, 101.89,69.58。
Compound ii -12, rice white,1H NMR (400MHz, DMSO-d6) δ 8.07 (dd, J=8.2,1.5 Hz, 1H), 7.64–7.53(m,5H),7.48–7.42(m,2H),7.39–7.32(m,1H),7.32–7.27 (m,2H),7.10–7.04(m, 2H), 7.00 (d, J=2.3Hz, 1H), 6.82 (dd, J=8.5,2.4Hz, 1H), 6.37 (s, 1H), 5.35 (s, 2H), 4.96 (t, J=1.0Hz, 2H).13C NMR(101MHz,DMSO-d6)δ 168.55,161.84,161.61,160.60,154.30, 146.47,138.33,137.58,136.93,133.86, 131.31,130.43,129.31,128.98,127.68, 127.14,125.59,123.08,118.44,115.34, 113.27,112.78,112.37,104.01,101.87,69.54, 68.59。
Compound ii -14, rice white,1H NMR (400MHz, DMSO-d6) δ 8.07 (dd, J=8.2,1.5Hz, 1H), 7.69-7.52 (m, 3H), 7.44-7.22 (m, 5H), 7.01 (d, J=2.3Hz, 1H), 6.82 (dd, J=8.5,2.4Hz, 1H), 6.14 (s, 1H), 4.97 (t, J=1.0Hz, 2H), 3.98-3.52 (m, 2H), 2.94-2.43 (m, 8H), 2.25 (s, 3H).13C NMR(101MHz,DMSO-d6)δ168.65, 161.75,160.53,154.42,150.10,137.77,136.93, 131.04,130.54,129.31,129.01, 128.10,127.68,125.59,123.12,115.15,112.73, 112.49,101.72,69.58,57.43,53.38, 52.49,45.00。
Compound ii -15, rice white,1H NMR (400MHz, DMSO-d6) δ 8.07 (dd, J=8.2,1.5 Hz, 1H), 7.61-7.54 (m, 3H), 7.45-7.27 (m, 5H), 7.26-7.16 (m, 2H), 7.01 (d, J=2.3Hz, 1H), 6.87- 6.78 (m, 2H), 6.66 (dd, J=7.9,1.5Hz, 1H), 6.56 (t, J=6.6Hz, 1H), 6.36 (s, 1H), 4.96 (t, J =0.9Hz, 2H), 4.79 (d, J=6.5Hz, 2H).13C NMR (101MHz,DMSO-d6)δ168.52,161.84,160.61, 154.50,149.02,143.75,138.33, 137.57,136.93,131.22,130.44,129.63,129.31, 128.98,128.38,127.68,127.61, 125.59,123.12,121.78,117.84,116.24,113.49, 112.74,101.81,69.58,48.93。
Compound ii -16, white solid,1H NMR (400MHz, DMSO-d6) δ 8.07 (dd, J=8.2,1.5Hz, 1H), 7.71-7.55 (m, 3H), 7.50-7.39 (m, 2H), 7.38-7.22 (m, 3H), 7.01 (d, J=2.3Hz, 1H), 6.83 (dd, J=8.5,2.3Hz, 1H), 6.13 (s, 1H), 4.97 (t, J=1.0Hz, 2H), 4.31 (t, J=6.9Hz, 1H), 3.98 (s, 2H), 3.69 (q, J=6.9Hz, 2H), 2.74 (t, J=6.9Hz, 2H), 2.38 (s, 3H).13C NMR(101MHz, DMSO-d6)δ168.79,161.96,160.51,154.84, 150.24,137.58,136.93,131.04,130.44, 129.22,128.99,128.10,127.68,126.13, 123.26,114.87,113.03,112.49,101.70,69.54, 58.73,43.19。
Compound ii -17, red brown solid,1H NMR(400MHz,DMSO-d6) δ 7.70 (dd, J=4.9,2.6Hz, 1H), 7.64-7.20 (m, 6H), 6.70 (dd, J=8.8,2.1Hz, 1H), 6.45 (d, J=2.1Hz, 1H), 5.92 (s, 1H), 4.93(s,1H),4.72(s,1H),2.30(s,3H).13C NMR(101MHz, DMSO-d6)δ169.64,160.64, 155.52,153.70,152.30,140.57,139.42,138.11,132.29, 130.77,130.42,128.99, 128.62,128.37,127.15,126.96,126.29,126.00,108.99, 107.63,96.77,45.60,17.99.
Compound ii -18, red brown solid,1H NMR(400MHz,DMSO-d6) δ 7.70 (d, J=7.5 Hz, 1H), 7.56 (ddd, J=10.0,7.5,5.8Hz, 1H), 7.51-7.21 (m, 5H), 6.96-6.74 (m, 1H), 4.77 (d, J= 56.5Hz,2H),3.70–3.42(m,2H).13C NMR(101MHz,DMSO-d6) δ171.94,169.68,168.56, 140.54,139.30,132.37,131.40,130.73,130.41,129.21, 128.92,128.47,128.26, 127.12,126.34,113.70.
Embodiment 12, general formula I, the anti-blood pressure determination of activity of Compound ira vitro shown in general formula II
(1) bibliography method carries out isolated rat thoracic aortic ring using isolated rat aorta ring test method Preparation and fixation, carry out endothelium integrity test.(concentration in bath is made to reach 10 when sodium nitroprussiate or acetylcholine is added- 5Mol/L), continue balance after ten minutes, if it is possible to reach the pre-shrunk vasodilation value of NE (norepinephrine) 80%, i.e., it is believed that endothelium integrality is good, it can be used for testing measurement.
(2) compound diastolic rate measures: 37 DEG C of water bath with thermostatic control temperature of setting replaces the Krebs liquid in each sink, goes forward side by side Row oxygenation (95%O2, 5%CO2), after vascular circle is stable again, NE, which is added, makes NE final concentration in bath reach 10-5Mol/L, After balancing 20 minutes vascular circle stabilizations, its tension value is recorded.No. 1 slot is solvent (blank) control group, and 2,3, No. 4 slots are drug survey Examination group, it is blank group that DMSO is first added in No. 1 bath, and it is molten that the DMSO containing untested compound is added in 2,3, No. 4 slots Liquid, poor drug concentration are 10-5Mol/L records its tension value after vascular circle is stablized；Then vascular circle is rinsed with Krebs liquid It 3 times, after vascular circle stablizes recovery basal tension about 1.5g, then is tested next time.
(3) data processing method: we are by NE (10-5Mol/L the maximum shrinkage amplitude for) inducing blood vessel is set to 100%, with Antiotasis amplitude and NE after drug is added induce the change of the ratio reflection antiotasis between the maximum shrinkage amplitude of blood vessel Change, i.e. diastole percentage (the sample diastolic rate of test is shown in Table 3).All data are with mean+SDIt indicates.
Wherein, y indicates diastole percentage；Max indicates that NE (10 is added-6Mol/L average when) vessel retraction is stablized afterwards Power；Mean tension when vessel retraction is stablized after min expression addition drug；1.5 indicate the basal tension of blood vessel before addition NE.
The diastolic rate test result of 3 compound of table
The results showed that compound I-1, I-9, I-16, I-20, I-21, I-23, I-28, I-32, II -3, II -7, II -8, II -17 antihypertensive active is slightly above positive control drug Telmisartan, can be used as candidate or the guide's chemical combination of exploitation Object, applied to preparing drug for hypertension.

Claims (5)

1. containing cumarin-biphenyl backbone compound, which is characterized in that have structure shown in following general formula I or II:
Wherein,
Y is O or NH；N is 0~2；
R1Or R2For hydrogen atom (H), halogen (F, Cl, Br), methylTrifluoromethyl (CF3), ethylPropylIsopropylNormal-butylIsobutyl groupTert-butylN-pentylIsopentylTertiary pentylN-hexylCyclopropylCyclobutylCyclopentaCyclohexylAzido (N3), N- piperidyl2- methyl-N- piperidyl3,5- dimethyl-N-piperidylN- piperazinyl N '-methyl-N- piperazinylN- morpholinyl4- methylol-N- piperidylN,N- Dimethyl amidoN, N- diethyl amidoN, N- diη-propyl amidoN, N- di-n-butyl AmidoN- methyl-N- ethoxy amido1,2,4- triazoleChlorobenzene amidoPhenylMethoxyphenylChlorophenylAminomethyl phenylEthylphenylN-propyl phenylN-butylphenylBenzylPyridine -2- basePyridin-3-ylPyridin-4-yl2- picoline -4- basePyridine -4- methyl2- picoline -4- methylPhenoxy groupMethylbenzene OxygroupMethoxyphenoxyHalogenated phenoxy (X=F, Cl, Br), nitrobenzene oxygen BaseCyano-benzene oxygenFormvlphenoxvAcetylbenzene oxygroup4- formoxyl -2- methoxyphenoxy4- acetylamino phenoxy group3-N- urethanes phenoxyl4- allyl -2- Difluoro-phenoxyβ-naphthoxyBenzylthio3- Methoxv-phenylsulfanvl
R3For carboxyl (- COOH) or tetrazole base
2. as described in claim 1 containing cumarin-biphenyl backbone compound, which is characterized in that R1For claim 1 institute State one of group, R2For hydrogen atom, halogen, phenyl or benzyl；N is 0 or 1.
3. containing cumarin-biphenyl backbone compound as described in claim 1,2, which is characterized in that select following compound:
4. preparing the method containing cumarin-biphenyl backbone compound described in one of claim 1-3, feature exists In realized by following several synthetic routes: the synthetic route of general formula I is carried out by a-b-c-d synthesis step, or according to a-e-f- D synthesis step carries out, or carries out according to g-h-f-d synthesis step；The synthetic route of general formula II is carried out according to g-i-j synthesis step Or it is carried out according to k-l-j synthesis step；
Wherein, Y is O or NH；N is 0~2；R is hydroxyl (- OH) or amino (- NH2)；R3Carboxyl (- COOH) or tetrazole baseR4For CN, COOCH3, COOEt, COOi-Bu, orR1Or R2For hydrogen atom (H), halogen (F, Cl, Br), MethylTrifluoromethyl (CF3), ethylPropylIsopropylNormal-butyl Isobutyl groupTert-butylN-pentylIsopentylTertiary pentyl N-hexylCyclopropylCyclobutylCyclopentaCyclohexylAzido (N3), N- piperidyl2- methyl-N- piperidyl3,5- dimethyl-N-piperidines BaseN- piperazinylN '-methyl-N- piperazinylN- morpholinyl4- hydroxyl first Base-N- piperidylN, N- dimethyl amidoN, N- diethyl amidoN, N- diη-propyl AmidoN, N- di-n-butyl amidoN- methyl-N- ethoxy amido1,2,4- TriazoleChlorobenzene amidoPhenylMethoxyphenylChlorophenylAminomethyl phenylEthylphenylN-propyl phenylN-butylphenylBenzylPyridine -2- basePyridin-3-ylPyridin-4-yl2- picoline -4- basePyridine -4- methyl2- picoline -4- methylPhenoxy groupMethylphenoxyMethoxyphenoxyHalogeno-benzene oxygen Base (X=F, Cl, Br), nitro-phenoxyCyano-benzene oxygenFormoxyl benzene oxygen BaseAcetylbenzene oxygroup4- formoxyl -2- methoxyphenoxy 4- acetylamino phenoxy group3-N- urethanes phenoxyl4- allyl- 2- Difluoro-phenoxyβ-naphthoxyBenzylthio3- methoxybenzene sulphur Base
(1) general formula I or II compound of general formula are hydrolyzed by compound 4 or compound 8 under alkaline condition respectively is prepared；
Alkali used selects one of potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide；It is used Solvent is one or both of methanol, ethyl alcohol, acetonitrile, tetrahydrofuran, dioxane；
(2) compound 4 or compound 5 or compound 6 or compound 8 by compound 3 or compound 1 or compound 2 or are changed respectively Close object 7 and halogenated sartanbiphenyl in the presence of organic solvent and acid binding agent nucleo philic substitution reaction and be prepared；
Wherein, starting halo sartanbiphenyl used is bromomethyl sartanbiphenyl or chloromethyl sartanbiphenyl；Bromomethyl Sha Tanlian Benzene be 2- cyano -4'- bromomethylbiphenyl, 4'- bromomethylbiphenyl -2- carboxylate methyl ester, 4'- bromomethylbiphenyl -2- carboxylic acid, ethyl ester, One of 4'- bromomethylbiphenyl -2- carboxylic acid tert-butyl ester or 2- triphenyltetrazolium chloride -4'- bromomethylbiphenyl；Used is organic molten Agent is methanol, ethyl alcohol, acetonitrile, acetone, tetrahydrofuran, methylene chloride, ethyl acetate, N,N-dimethylformamide or N, N- diformazan One or both of yl acetamide；Acid binding agent used be potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, sodium hydroxide, One of potassium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide or Sodamide；
(3) by compound 2 or compound 6 and alkynes, through 1,3- cycloaddition reaction, (i.e. Click is anti-respectively for compound 3 or compound 4 Answer) it introduces triazole and is prepared；
Wherein, in 1, the 3- cycloaddition reaction (Click reaction) step, catalyst choice monovalence copper, copper powder+copper sulphate, Copper sulphate+sodium ascorbate, cuprous iodide, stannous chloride, cuprous bromide, cyano is cuprous or other organic ligands and monovalence copper shape At Cu (I) complex compound；Organic solvent used is tetrahydrofuran, acetonitrile, ethyl alcohol, isopropanol, methylene chloride, toluene, N, N- bis- Methylformamide, water or mixed solvent of more than two kinds；Acid binding agent used selects sodium carbonate, potassium carbonate or cesium carbonate；
(4) compound 2 or compound 6 can be obtained by compound 1 or compound 5 with reaction of sodium azide respectively；The nitrine Change in reaction step, solvent selects in n,N-Dimethylformamide, dimethyl sulfoxide, acetonitrile, methylene chloride, tetrahydrofuran or acetone One kind；
(5) compound 8 can be made by compound 5 and different phenols, aminated compounds nucleo philic substitution reaction；It is used organic Solvent be tetrahydrofuran, acetonitrile, methanol, ethyl alcohol, isopropanol, methylene chloride, acetone, toluene, N,N-dimethylformamide or 1 kind in water or mixed solvent of more than two kinds；Acid binding agent used is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide Or cesium carbonate；Catalyst selects potassium iodide or sodium iodide.
5. the answering in medicine preparation containing cumarin-biphenyl backbone compound as described in one of claims 1 to 3 With, which is characterized in that it combines as active constituent or with other drugs, is mixed with acceptable auxiliary element in drug Afterwards, routinely pharmaceutical methods and technique, are prepared into drug for hypertension.
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