CN104447763B - Biphenyl tetrazole compound - Google Patents

Biphenyl tetrazole compound Download PDF

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Publication number
CN104447763B
CN104447763B CN201410786984.0A CN201410786984A CN104447763B CN 104447763 B CN104447763 B CN 104447763B CN 201410786984 A CN201410786984 A CN 201410786984A CN 104447763 B CN104447763 B CN 104447763B
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compound
acid
group
angiotensin
alkyl
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CN104447763A (en
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张孝清
包金远
宋志春
蒋玉伟
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Nanjing Huawe Medicine Technology Group Co Ltd
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Nanjing Huawe Medicine Technology Development Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

The invention relates to a biphenyl tetrazole compound which is shown in a formula (I) or pharmaceutical salt, a preparation method and an application thereof, wherein definition of an X group is as the same as that in the specification. The biphenyl tetrazole compound has antagonistic activity of an angiotensin II receptor and can be used for preventing or treating circulation system diseases such as hypertension. The formula is shown in the specification.

Description

Biphenyltetrazoles compounds
Technical field
This area belongs to medical science and organic synthesis field, and in particular to one kind has angiotensin-ii receptor antagonism Biphenyltetrazoles compounds or its pharmaceutical salts of activity and its production and use.
Background technology
Cardiovascular disease incidence rate is high, and complication is weighed more, seriously threatens human health.Hypertension is considered as cardiovascular One of main risk factor of disease (CVD).Non- peptides angiotensin AT1-receptor antagonist (ARB) is to act on feritin-blood One class novel antihypertensive medicine of angiotensin system (RAS), compared with angiotensin-convertion enzyme inhibitor (ACEI), blood pressure lowering Effect significantly, more selectively blocks RAS, and Small side effects, and one of six big class antihypertensive drug have been listed in.
Renin-angiotensin system is to adjusting human blood-pressure, body fluid balance and dielectric balance aspect with important Effect, it activates proangiotensin in blood plasma and generates the angiotensin I (Ang I, decapeptide) without pressor activity.Ang I exist Under angiotensin converting enzyme (ACE) effect, it is changed into Angiotensin II (AngII, octapeptide).Ang II have vasoconstrictive, Promote the effect of Aldosterone Secretion, it is one of main inducing of hypertension, is played in the physiological and pathological of hypertension important Effect.Angiotensin-ii receptor has four kinds of hypotypes, i.e. AT1, AT2, AT3, AT4, based on AT1 and AT2.AT1 receptors are almost All Pathophysiology functions of mediate vascular Angiotensin Converting Enzyme II receptors.AT2 receptor subtypes are known at present very few, it is believed that may be with embryo Cell is bred and breaks up relevant during fetal hair (Crinis Carbonisatus) is educated.Angiotensin ii receptor antagonist is used as RAS system resisting hypertension New drug, shown that affinity is strong, selectivity is high, it is oral effectively, long half time, better tolerance the advantages of, effect is direct, and pair is made With little.From first angiotensin II receptor antagonist losartan of DuPount/Merck companies research and development in 1994 Up to the present potassium had 8 folk prescriptions such as Valsartan, Candesartan, telmisartan and Azilsartan in succession since Sweden's listing Preparation and 3 compound preparation approval listings.Having been enter into the medicine of clinic and preclinical phase has more than 50, and they are mostly with chlorine Sha Tan is lead compound, the AT1 receptor antagonists for carrying out structural modification and transformation and obtaining.Angiotensin-ii receptor antagonism Agent effect clinically includes：Resisting hypertension, heart failure resistance, antithrombus formation, the protection heart, brain, kidney and blood vessel, in addition also With the effect for reversing left ventricular hypertrophy.Due to ARB antihypertensive effects significantly, especially to unique curative effect of cardiovascular disease, ARB has become one of depressor that World Health Organization (WHO) WHO is specified.
WO 1995/26724 describes the side that insulin resistance is improved using Angiotensin II receptor antagonist Method and the method treated to improve insulin sensitivity with hypertension.WO 2007/053406、WO 2007/051007、WO 2007/013078、WO2006/000564、WO2005/288272、WO 2005/020984、WO 2004/053903、WO1996/ 40256、WO 1996/40255、WO2009/137465、WO 2009/118292、WO 2009/039069、US2009/ 0012052 and WO2008/060899 describes the compound of following formula and the compound has Angiotensin II antagonistic activity And hypotensive activity, and as the therapeutic agent of blood circulation diseasess such as hypertension, heart disease, apoplexy etc..
WO2010/087515 provides a kind of annelation with Angiotensin II antagonistic activity and hypotensive activity Compound and its purposes, it is as follows：
The invention aims to solve the problems, such as that traditional angiotensin receptor antagonist curative effect is not high, there is provided A kind of new biphenyl tetrazole compound and its preparation method and use.
The content of the invention
It is an object of the invention to provide a kind of such as formula（I）A shown class has angiotensin-ii receptor antagonistic activity Biphenyltetrazoles compounds.
Another of the present invention is to provide application of the above-claimed cpd in anti-high blood medicine preparation.
The purpose of the present invention can be reached by following measures：
One class formula（I）Shown compound, or its pharmaceutically acceptable salt, hydrate, solvate or isomer；
WhereinRepresentation carboxy, ester group, amide groups or substituted amido.
Further, X representatives-OX1、-NHX2、Or amino acid residue；
Further, described amino acid residue is：Glycine residue, tyrosine residue, phenylalanine residue, leucine Any one in residue or glutaminic acid residue.
X1Selected from hydrogen atom, alkyl, cycloalkyl, benzyl;
X2Selected from aryl, heteroaryl, alkyl, amino, alkyl amino, wherein aryl, heteroaryl, alkyl are further by one Or it is multiple selected from halogen, trifluoromethyl, amino, alkyl amino, hydroxyl, hydroxyalkyl, alkoxyl, cyano group, nitro, aryl and heteroaryl The group of base is replaced；
R1、R2Separately it is selected from alkyl.
In a kind of scheme, X1Selected from hydrogen atom, C1-4Alkyl, C5-8Cycloalkyl.
In a kind of scheme, X2Selected from phenyl, pyridine radicals, C1-4Alkyl ,-NH2, wherein phenyl, pyridine radicals, C1-4Alkyl enters One step is selected from fluorine, chlorine, trifluoromethyl or-NH by one or more2Group replaced.
The R in a kind of preferred scheme1、R2Separately it is selected from C1-4Alkyl.
Shown below is illustrative, the nonrestrictive instantiation of the compound of the present invention：
Further, the present invention also provides formula（I）The preparation method of compound, is not limited only to methods as described below. All of raw material be all according to meet formula rule target molecule group feature, and by the scheme in these routes, have It is prepared by chemical machine field method well-known to the ordinarily skilled artisan or directly buy.Formula（I）Compound or its pharmaceutically Acceptable salt, hydrate, the preparation of solvate are comprised the following steps：
Formula（I）Compound or its pharmaceutically acceptable salt, hydrate, the preparation of solvate comprise the following steps：
Step one,
Raw material 1 is dissolved in organic solvent, hydrogenation reduction obtains compound in the presence of palladium catalyst（II）.
The palladium catalyst of described hydrogenation reduction selected from four triphenyl phosphorus palladiums, palladium carbon, the miscellaneous carbene palladium complexs of N-, One or more in Palladous chloride. or its part, palladium or its part, preferred palladium carbon.Hydrogenation reaction can be in normal pressure or pressurization Under conditions of carry out.
Step 2,
By compound（II）, compound（III）It is dissolved in organic solvent with tetrabutyl ammonium bromide, in strong alkali aqueous solution The lower reaction of effect obtains compound（IV）.
Step 3,
Compound（IV）In being dissolved in ethanol, methanol or isopropanol equal solvent ,-CPh is taken off in the presence of strong acid3Protection Base reacts, and obtains compound (V), and described strong acid can be hydrochloric acid, hydrobromic acid or trifluoroacetic acid.
Step 4,
Compound (V) is added in into hydrolysis in the presence of sodium hydrate aqueous solution and obtains compound (VI), as compound (I- 2)。
Step 5, according to formula（Ⅰ）The architectural feature of the target molecule required for compound, compound (VI) is entered respectively Row esterification or amidation process, specifically, work as formula（Ⅰ）InWhen representing ester group, formula（Ⅰ）The preparation side of compound Method is as follows：
By compound (VI) and alcohol compound X1-OH（X1Definition it is identical with the above-mentioned part definition of description）Organic Esterification is carried out in solvent, target compound is obtained, described esterification is the conventional esterification in this area, Ke Yi Carry out under the catalytic action of the condensation catalysts such as diethyl azodiformate/triphenyl phosphorus, using alcohol/thionyl chloride into ester side Method one-step synthesis ester or by compound (VI) be prepared into acyl chlorides again with alcohol react.
Work as formula（Ⅰ）InWhen representing amide groups or substituted amido, formula（Ⅰ）The preparation method of compound is as follows：
By compound (VI) and the ammoniac compounds containing amino or imino group be, for example, amino-acid compound in a solvent Jing amidation process obtains target compound, and described amidation process is the conventional amidation process in this area, can urged Carry out in the presence of agent, wherein catalyst is selected from 1,3- dicyclohexylcarbodiimides（DCC）, N, N'- diisopropyls carbon two is sub- Amine (DIC), 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides（EDC）And its hydrochlorate, 1- (3- dimethyl aminopropyls)- 3- ethylcarbonyl group diamidogen methiodides, DIPEA (DIEA), I-hydroxybenzotriazole（HoBt）, 2- (7- azo benzos Triazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester（HATU）, BTA-N, N, N', N'- tetramethylurea hexafluoro Phosphate ester (HBTU), 6- Chloro-Benzotriazole -1,1,3,3- tetramethylurea hexafluorophosphoric acid ester（HCTU）, 2- (1H- benzo trisazo-s L-1- yls) -1,1,3,3- tetramethylurea Tetrafluoroboric acid ester（TBTU）, 2- succinimido -1,1,3,3- tetramethylurea tetrafluoro Borate（TSTU）, 5- norborene -2,3- dicarbapentaborane-N, N, N', N'- tetramethylurea Tetrafluoroboric acid ester（TNTU）In one Plant or several combinations.The ratio of condensing agent is about at 1 ~ 3 times.In addition can also the contracting such as diethyl azodiformate/triphenyl phosphorus Amidatioon is carried out under the catalytic action for closing catalyst, ingredient proportion is compound (VI)：Diethyl azodiformate：Triphenyl Phosphorus：Aminated compoundss=1:1~4:1~4:1~2.
Invention further provides the medicine of formula (I) compound with angiotensin-ii receptor antagonistic activity Compositionss, wherein the compound or pharmaceutically acceptable salt thereof containing therapeutically effective amount, and pharmaceutically acceptable one or more Carrier, can be by the mixture of compound itself or its pharmaceutical salts and pharmaceutically acceptable excipient, diluent etc. with tablet, capsule, granule The form oral administration of agent, powder or syrup or in the form of injection non-oral administration.The pharmaceutical composition is preferably comprised Weight ratio is 0. 1% -99. 5% compound or pharmaceutically acceptable salt thereof with angiotensin-ii receptor antagonistic activity of the invention Used as active component, further preferably weight ratio is 0. 5% -99. 5% active component.Above-mentioned preparation can pass through conventional manner It is prepared by method.
Unless otherwise stated, the following term in claims and description has following implication.
" amino acid residue " is represented and refers to incomplete aminoacid.One complete aminoacid includes a carboxyl（— COOH), an amino (- NH2), a H, a R base.It is all amino acid residue to lack a part.Such as glycine residue For: - NH-CH2-CO-.
" alkyl " represents the aliphatic group of the saturation of 1-20 carbon atom, including straight chain and branched group（Carry in this specification The digital scope for arriving, such as " 1-20 ", refer to the group, are now alkyl, can contain 1 carbon atom, 2 carbon atoms, 3 carbon Atom etc., until including 20 carbon atoms）.Alkyl in the present invention includes " alkylidene ".Alkyl containing 1-4 carbon atom claims For low alkyl group.When low alkyl group does not have substituent group, unsubstituted low alkyl group is called.It is further preferred that alkyl is that have The medium sized alkyl of 1-10 carbon atom, such as methyl, ethyl, ethylidene, propyl group, propylidene, 2- propyl group, normal-butyl, Isobutyl group, butylidene, the tert-butyl group, amyl group etc..Preferably, alkyl is the low alkyl group for having 1-4 carbon atom, for example methyl, second Base, propyl group, 2- propyl group, normal-butyl, butylidene, isobutyl group or tert-butyl group etc..Alkyl can be substituted or unsubstituted.
" halogen " represents fluorine, chlorine, preferably bromine or iodine, fluorine, chlorine or bromine.
" nitro " expression-NO2Group.
" haloalkyl " represents alkyl, low alkyl group preferably as defined above, and it is identical or different by one or more Halogen atom replace, such as-CH2Cl、-CF3、-CCl3、-CH2CF3、-CH2CCl3Deng.
" alkoxyl " expression-O-（Unsubstituted alkyl）With-O-（Unsubstituted cycloalkyl）.Representative example include but not It is limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..
" aryl " represent 6 to 12 carbon atoms full carbon is monocyclic or fused polycycle group, the pi-electron with total conjugated System.The non-limiting examples of aryl have phenyl, naphthyl and anthryl.The aryl rings can condense in heteroaryl, heterocyclic radical or On cycloalkyl ring, wherein being aryl rings with the ring that precursor structure links together.Aryl can be substituted or unsubstituted. When substituted, substituent group is preferably one or more, more preferably one, two or three, so more preferably one or Two, independently selected from by low alkyl group, three alkylhalide groups, halogen, hydroxyl, lower alkoxy, sulfydryl,（Low alkyl group）Sulfenyl, Cyano group, acyl group, Thioacyl, O- carbamoyls, N- carbamoyls, O- thiocarbamoyls, N- thiocarbamoyls Base, C- acylamino-s, N- acylamino-s, nitro, N- sulfonamidos, S- sulfonamidos.
" heteroaryl " represents the monocyclic or fused ring group of 5 to 12 annular atoms, containing one, two, three or four Selected from the ring hetero atom of N, O or S, remaining annular atom is C, in addition the pi-electron system with total conjugated.The heteroaryl ring can To condense on aryl, heterocyclic radical or cycloalkyl ring, wherein being heteroaryl ring with the ring that precursor structure links together.Heteroaryl Base can be substituted or unsubstituted.When substituted, substituent group is preferably one or more, more preferably one, two It is individual or three, and then it is more highly preferred to one or two.Unsubstituted heteroaryl base non-limiting examples have pyrroles, furan, thiophene, Imidazoles, oxazoles, thiazole, pyrazoles, pyrimidine, quinoline, isoquinolin, purine, tetrazolium, triazine and carbazole.
" pharmaceutically acceptable salt " represents those salt for retaining the biological effectiveness and property of parent compound.This kind of salt Including：
（1）With acid into salt, obtained, mineral acid example by the free alkali and mineral acid of parent compound or the reaction of organic acid Such as（But it is not limited to）Hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, Metaphosphoric acid, sulphuric acid, sulfurous acid and perchloric acid etc., organic acids are such as（But It is not limited to）Acetic acid, propanoic acid, acrylic acid, oxalic acid,（D）Or（L）Malic acid, fumaric acid, maleic acid, hydroxy benzoic acid, γ-hydroxyl Butanoic acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethyl sulfonic acid, naphthalene -1- sulfonic acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, water Poplar acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or malonic acid etc..
" Pharmaceutical composition " refers to one or more compound described here or theirs is pharmaceutically acceptable Salt and prodrug and other chemical compositions, the mixture of such as pharmaceutically acceptable carrier and excipient.Pharmaceutical composition Purpose is to promote the administration of compound on organism body.
" pharmaceutically acceptable carrier " refers to not cause organism obvious zest and does not disturb giving The biological activity of compound and the carrier of property or diluent.
" excipient " refers to be added in Pharmaceutical composition with the further convenient inert substance for giving compound.Assign The example of shape agent includes（It is not limited to）Calcium Carbonate, calcium phosphate, various saccharides and polytype starch, cellulose derivative, Gelatin, vegetable oil and Polyethylene Glycol.
Present invention also offers application of the compound or pharmaceutically acceptable salt thereof in terms of high blood is treated, studies and shows that it has Significant angiotensin-ii receptor antagonistic activity.Chu Walk study on mechanism results show：Such compound has preferable Resisting hypertension effect, has potential application prospect in the drug world for the treatment of hypertension.
Specific embodiment
Following examples further describe the present invention, but, these embodiments are only for the explanation present invention, rather than right The restriction of the scope of the invention.
The preparation of the compounds I -1 of embodiment 1
15 g raw materials 1 are added in the single-necked flask of 1000 ml, 450 ml methanol and 0.5 g Pd/C, room temperature bar is added The h of hydrogenating reduction 24 under part.Kieselguhr aided filter, filter vacuum is spin-dried for, and obtains the g of faint yellow solid 15, and yield is 99%.
The toluene of 500 ml is added in the single-necked flask of 1000 ml, sequentially add 15 g II, 42.6 g III, The sodium hydrate aqueous solution of 4.2 g tetrabutyl ammonium bromide and 180 ml 4%, is warming up to 50 DEG C of 18 h of reaction.Reactant liquor saturation Brine It（3×200 ml）, anhydrous sodium sulfate drying, filter, filtrate revolving remove, obtain yellow oil, silica gel crosses post The g of isolated white solid 20.3, the % of yield 48.
10 g IV are added in the flask of 250 ml and are dissolved with 200 ml ethanol, 10 ml concentrated hydrochloric acid are added, in room temperature The lower h of stirring reaction 6.After screwing out most of ethanol, plus the dissolving of 100 ml ethyl acetate, with 3 × 200 ml water washings, anhydrous sulfur Sour sodium is dried, and mixes sample and crosses post and obtains the g of white solid 5.7, yield 85%.1H NMR (DMSO-d6)δ1.28 (3H, t), 2.90 (2H, m), 3.68~ 3.70 (4H, m), 4.26~4.33(4H, m), 7.07 (2H, d, J=7.9 Hz), 7.25 (2H, d, J=7.9 Hz), 7.43~7.61(4H, m). m/z =498 (M+H+).
The preparation of the compounds I -2 of embodiment 2
5 g V are added in the flask of 500 ml, 200 ml water are added, 2.5 g sodium hydroxide are added, 12 are stirred at room temperature h.Reactant liquor is poured in 500 ml water, adjusts pH to 2 ~ 3, the ml of ethyl acetate 3 × 200 extractions, anhydrous sodium sulfate drying to be spin-dried for Obtain compound（VI）The g of white solid 2.7<As compound（I-2）>, yield 55%.1H NMR (DMSO-d6)δ3.12 (2H, s), 3.86~3.93 (4H, m), 4.33(2H, s), 7.07 (2H, d, J=7.9 Hz), 7.25 (2H, d, J= 7.9 Hz), 7.43~7.61(4H, m). m/z =470 (M+H+).
The preparation of the compounds I -3 of embodiment 3
10 mlDMF are added in the single-necked flask of 100 ml, then by 0.2 g VI, 0.33 g HBTU, the second of 0.17 g tri- Amine is added, the h of stirring reaction 0.5 under room temperature.0.08 g methyl-P-tyrosines are added in reaction, 12 h are stirred at room temperature.By reactant liquor In pouring 200 ml water into, ethyl acetate extraction, anhydrous sodium sulfate drying, column chromatography for separation obtains 0.14 g, and yield is 51 %.1H NMR (DMSO-d6)δ2.87(2H, m), 3.28 ~ 4.05 (13H, m), 4.22(1H, br), 4.62(1H, br), 6.65 (2H, d, J=5.8 Hz), 7.02 (2H, d, J=7.1 Hz) , 7.09 (2H, d, J=7.6 Hz), 7.29 (2H, d, J=6.0 Hz) , 7.58~7.66(4H, m), 9.27(1H, s),. m/z =647 (M+H+).
The preparation of the compounds I -4 of embodiment 4
The DMF of 10 ml is added in the single-necked flask of 100 ml, add 0.2 g intermediate V, 0.36 g HBTU and 0.15 g triethylamines, the min of room temperature reaction 10；It is subsequently adding 0.06 g valine methyl esters, the h of room temperature reaction 15.Reactant liquor is fallen In entering 300 ml water, the ml of ethyl acetate 3 × 60 extractions, organic faciess anhydrous sodium sulfate drying, isolated 0.16 g of chromatographic column consolidates Body.1H NMR (DMSO-d6)δ1.02 (6H, m), 1.12 (1H, m), 3.15 (2H,s), 3.62 (3H, s), 3.83~3.99 (4H, m), 4.19 (1H, m), 4.37(2H, s), 7.01~7.15 (4H, m), 7.24~7.35 (4H, m), 7.45~7.69(5H, m), 9.17(1H, s). m/z =583(M+H+).
Embodiment 5 ~ 18 is prepared with reference to description process route above, the preparation process of compound and embodiment 3 and The method of embodiment 4 is similar to.Following table gives the test data of the object of experiment product of each embodiment.
The preparation of the compounds I -19 of embodiment 19
30 ml methanol and 0.2 g intermediate VI are added in the single-necked flask of 100 ml, 0 DEG C is cooled to, then by 1 ml's Thionyl chloride is instilled, and moves to the h of room temperature reaction 0.5, then temperature rising reflux reacts 3 h.Reactant liquor is poured in 300 ml water, acetic acid The ml of ethyl ester 3 × 60 is extracted, organic faciess anhydrous sodium sulfate drying, the isolated 0.16 g solids of chromatographic column.1H NMR (DMSO- d6)δ, 3.02 (2H,m), 3.86~3.93 (5H, m) 4.22~4.34(4H, m), 7.09 (2H, d, J=7.1 Hz), 7.27 (2H, d, J=7.1 Hz), 7.43~7.59(4H, m). m/z =484(M+H+).
The preparation of the compounds I -20 of embodiment 20
Add 30 ml acetonitriles in the single-necked flask of 100 ml, then by 0.2 g intermediate VI, 0.15 g bromobenzyls, 0.15 g Potassium carbonate and 0.1 g tetrabutyl ammonium bromide, temperature rising reflux reacts 4 h.Reactant liquor is poured in 300 ml water, ethyl acetate 3 × 60 ml are extracted, organic faciess anhydrous sodium sulfate drying, the isolated 0.16 g solids of chromatographic column.1H NMR (DMSO-d6)δ, 3.02 (2H,m), 3.86~3.93 (4H, m) 4.22~4.34(2H, s),5.16 (2H, s), 7.09~7.49 (9H, d, J=7.1 Hz), 7.43~7.59(4H, m). m/z =560(M+H+).
The preparation of the compounds I -21 of embodiment 21
2 ml thionyl chlorides are added in the single-necked flask of 100 ml, then 0.2 g intermediate VI is added, back flow reaction 1h.Thionyl chloride is steamed, 10 ml tetrahydrofurans are added, then 0.1 g p-fluorophenols and 0.1 g triethylamines are added, room temperature is anti- Answer 3 h.Reactant liquor is poured in 300 ml water, the ml of ethyl acetate 3 × 60 extractions, organic faciess anhydrous sodium sulfate drying, chromatographic column point From obtaining 0.16 g solids.1H NMR (DMSO-d6) δ,3.17 (2H,s), 3.84~4.12 (4H, m), 4.38(2H, s), 7.07 ~7.19(4H, m), 7.26~7.36 (4H, m), 7.44~7.64(4H, m). m/z =564(M+H+).
Pharmacologically active is tested：
Pharmacological testing proves that the compound of the present invention is respectively provided with angiotensin-ii receptor antagonistic activity.Therefore it is of the invention Compound can be used to prepare the medicine for the treatment of hypertension.The pharmacodynamics test and result of part of compounds of the present invention is presented herein below.Change The structural formula of compound is shown in embodiment 1-21.
Pharmacologically active test case
Embodiment 22 evaluates AT1 receptor antagonist activities
The each compound sample prepared in description embodiment is selected to carry out the test of AT1 receptor antagonist activities, and It is compared in the AT1 receptor antagonist activities of Azilsartan, pharmacological testing is proved, the compound of the present invention is respectively provided with vasotonia Plain II receptor antagonist activities.Therefore the compounds of this invention can be used to prepare the medicine for the treatment of hypertension.The structural formula of compound is shown in Embodiment 1-21.
The main experimental step that AT1 receptor antagonist activities are evaluated is as follows:
(1) preparation of the CHO-K1 cellular membrane fractions of people's AT1 receptors is expressed
The CHO-K1 cells for being possible to stable expression people's AT1 receptors are cultivated, are reclaimed, are suspended in homogenization buffer (10mM NaHCO3,<pH7.4>, 5mM EDTA, 1x is entirely without EDTA) in, and homogenizing.Homogenate is centrifuged under the low speed (800x G, 10 minutes, 4 DEG C), reclaim supernatant, and ultracentrifugation (80,000x g, 1 hour, 4 DEG C).Supernatant is removed, and will Precipitate is resuspended in buffer suspension liquid (50mM Tris<pH7.4>, 1mMEDTA, 1x is entirely without EDTA) in.
Evaluate AT1 receptor antagonist activities
In the presence of AT1 films and test compound, 100 μ L (total overall reaction volume) reaction buffer (50mM's Tris<pH7.4>, 10mM MgCl2<Supplement or do not supplement the bovine serum albumin of 0.3mg/mL not fatty acids>) in, make Test is combined with 22.5pM [125I]-Angiotensin II (9 μ g).At room temperature, will be anti-in 96 hole polypropylene boards Answer mixture culture 1 hour, and lavation buffer solution (is used by GF/C filters<50mM Tris,pH7.4>) process, carry out Fast filtering (96 hole cell harvestor), by reaction quenching.Subsequently, with the lavation buffer solution of the ice cooling of 0.3mL by filter Washing 5 times.Filter is air-dried, with Top Count scintillation counters [125I]-Angiotensin II is checked With reference to radioactivity.Total binding is determined in the presence of 1%DMSO, in the presence of 1 μM of Azilsartan non-specific binding is determined.
Analysis combines data B/B0 (%), and calculates the IC50 values (maximum of display suppression percentage of test compound 50% when compound concentration).[125I]-Angiotensin II is calculated by following formula (below, to be abbreviated as in formula [125I]-AII) AT1 receptor bindings ratio (B/B0 (%)).
B/B0 (%)=[([125I] AII in the presence of test compound combines level-non-specific binding water It is flat)]/[([125I] the AII total binding levels-non-specific binding level in the case of without test compound)] × 100
Non-specific binding level is [the 125I]-blood vessel obtained in the presence of 1 μM of cold Angiotensin II Angiotensin Converting Enzyme II combines level.
Test result is as shown in table 2 below:
By upper table 2 as can be seen that the compound of the present invention shows superior AT1 receptor antagonist activities.
Embodiment 23
Male rat is anaesthetized with pentobarbital sodium (50mg/kg, i.p.).(heparin (200U/ is included with filled with saline ML polyethylene catheter insertion left femoral artery)).In the external conduit in the rear portion of neck, and each rat is individually placed in cage, Place two or four days, to recover.(used and multipotency logging recorder system (Nihon Kohden by systemic blood pressure Corporation) the pressure transducer of connection, is monitored by femoral artery) obtain mean blood pressure (MBP).It is spaced by blood pressure pulse Determine heart rate.Will be above the rat of the MBP of 150mmHg is used to test.When blood pressure stabilization, solvent (0.5w/v% is orally given Methylcellulose) or compound.All Compound Compound samples to be measured are suspended in 0.5w/v% methylcellulose, and Orally give the volume of 2mL/kg.After administration, during 24 hours MBP was determined.As a result show as shown in table 3 below：
By upper table 3 as can be seen that the compound of the present invention shows superior resisting hypertension effect.

Claims (4)

1. the compound and its pharmaceutically acceptable salt shown in formula I structure：
It is characterized in that X representative-OX in formula (I)1、-NHX2；
Wherein X1Selected from hydrogen atom or C1-4Alkyl；
X2Selected from phenyl, pyridine radicals, C1-4Alkyl, wherein phenyl, pyridine radicals are further selected from fluorine, chlorine, alcoxyl by one or more The group of base is replaced, and described alkoxyl is selected from methoxyl group, ethyoxyl, propoxyl group, butoxy.
2. a kind of compound and its pharmaceutically acceptable salt, it is characterised in that compound is selected from：
3. a kind of pharmaceutical composition, free form of the pharmaceutical composition comprising therapeutically effective amount or pharmaceutical acceptable salt
Claim 1 or 2 defined in compound as active component；One or more medicinal carrier substance and/
Or diluent.
4. application of the pharmaceutical composition of claim 3 in hypertension drug is prepared.
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