CN105237527B - Benzimidizole derivatives and preparation method thereof and medical usage - Google Patents

Benzimidizole derivatives and preparation method thereof and medical usage Download PDF

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CN105237527B
CN105237527B CN201510617905.8A CN201510617905A CN105237527B CN 105237527 B CN105237527 B CN 105237527B CN 201510617905 A CN201510617905 A CN 201510617905A CN 105237527 B CN105237527 B CN 105237527B
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bases
compound
methyl
azilsartan
preparation
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CN105237527A (en
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葛建
马建义
项光亚
王玮
王朝东
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Wuhan LL Science and Technology Development Co Ltd
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Wuhan Lang Lai Development In Science And Technology Co Ltd
Wuhan QR Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Abstract

The invention belongs to field of pharmaceutical chemistry technology, specifically discloses a kind of benzimidizole derivatives and preparation method thereof and medical usage.Benzimidazole spreads out, and class is biological to include ligustrazine and NO donor analog derivatives; such compound discharges rapidly ligustrazine or NO in vivo; so as to which effective synergy occur with Azilsartan; strengthen anti-hypertension curative effect; reduce adverse reaction; there is comparatively ideal protective effect to patient's liver kidney, filled up blank of the prior art.

Description

Benzimidizole derivatives and preparation method thereof and medical usage
The application be for the applying date be on 2 4th, 2013, application number：201310042669.2 denomination of invention：Benzo The divisional application of imdazole derivatives and preparation method thereof and medical usage.
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of benzimidizole derivatives and preparation method thereof and doctor Medicinal way.
Background technology
Hypertension (Hypertension) is most common angiocardiopathy, and causes congestive heart failure, brain soldier In, the incidence of disease of coronary heart disease, renal failure, aortic aneurysm and the elevated Major Risk Factors of case fatality rate.Drug for hypertension Key effect is played in the treatment and preventing and treating of high blood pressure disease.With being deepened continuously to hypertension incidence mechanism understanding, permitted There is the drug for hypertension of preferable curative effect, such as diuretics, beta-blocker, calcium-channel antagonists, angiotensins more Converting enzyme inhibitor (ACEI, pril), Angiotensin II AT1 receptor blocking pharmacons (ABR, husky smooth class), constantly find and into Work(is applied to clinic.By clinical practice for many years, confirmation AT1 receptor blocking pharmacons sartans due to its hypotensive is steady, Curative effect is good, long action time, patient tolerability are good, especially in prevention palsy, delays diabetes and the kidney function of Non-diabetic nephropathy Can not entirely, improve left ventricular hypertrophy, protective effect to target organ etc. there is more advantage, and do not influence bradykinin and degrade Synthesized with prostaglandin, so as to not cause dry cough and angioneurotic edema, as global drug for hypertension market Main flow kind.Although husky smooth class drug for hypertension has many advantages, its efficient hypotensive is about 50-60% or so, And there is a certain degree of adverse reaction.Therefore, develop that antihypertensive effect is stronger, less adverse effect, while to other diseases such as Diabetes have Preferred effects, and have to target organ the low dose of long-acting depressor of preferable protective effect turned into one it is popular Research direction.
Nitric oxide has extremely important physiological function as messenger substances and effector molecule in mammal body, bag Control antiotasis, nerve conduction, hormone secretion, inflammation and immune response etc. are included, in addition to regulation arterial dilation, cell Be adhered to blood vessel endothelium and platelet aggregation, vascular smooth muscle cell proliferation and protection ischemical reperfusion injury etc. also have it is important Effect.Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe has good decompression and target organ protection function.By suppressing ACE activity, on the one hand inhibit blood vessel tight Open plain II generation and work；On the other hand the hydrolysis of the endogeneous activity peptide such as bradykinin is inhibited, causes internal bradykinin Concentration increases, so as to by activating β2Acceptor and strengthen eNOS activity.Promote endothelium hyperpolarizing fac and NO releases, Jin Erfa Wave the vasodilator of NO mediations and suppress the effect such as platelet aggregation.
Husky smooth class AT1 receptor antagonists are that one kind is optionally combined with AT1 acceptors, Ang II effects are blocked, so as to lead Cause the novel antihypertensive medicament of drop in blood pressure.However, compared with Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, AT1 receptor blocking pharmacons lack the tune of NO mediations Function is saved, therefore develops NO donator type AT1 receptor blocking pharmacons, realizes AT1 receptor blockings and the dual work(of internal NO functions enhancing Effect, can have significantly more efficient therapeutic effect, while the treatment to other angiocardiopathies has potential value to hypertension.
Ligustrazine (Ligustrazine, Lig) is samphire Ligusticum wallichii and zingiberaceous plant Curcuma wenyujin rhizome and Euphorbiaceae One of main chemical compositions in plant ventilation manioca stem.Pharmacological research proves that ligustrazine has improvement microcirculation, expansion blood Pipe, increase artery blood flow, suppress platelet aggregation and reduce the effect such as biologically active pdgf, have significant curative effect to angiocardiopathy. Clinically it is widely used in the diseases such as cerebral apoplexy, asthma, pulmonary emphysema, pulmonary heart disease, chronic respiratory failure, adult respiratory distress syndrome (ARDS) Treatment.Its mechanism of action, which mainly has, removes free radical, anti peroxidation of lipid, protection Coronary endothelium, promotion cardiac muscle cell's energy generation Thank, anti-fibrosis, modulating apoptosis related gene c-fos and bc1-2 expression, Green Tea Extract damage, to influence cell factor, calcium short of money Anti- effect, anti-myocardial anoxia-reoxygenation, antiangiotensin II cause myocardial hypertrophy (blocking AT1 acceptors), expansion blood vessel, resisted Platelet aggregation and thrombosis etc..Ligustrazine class AT1 receptor blocking pharmacons are developed, both can effectively strengthen AT1 receptor blocking pharmacons and resist Hypertension curative effect, effective protective effect to liver kidney is also can reach, while also there is potential treatment to other angiocardiopathies Meaning, in the prior art there is not yet relevant report.
The content of the invention
For the deficiencies in the prior art, spread out class life object of the present invention is to provide a series of benzimidazoles Thing, including ligustrazine and NO donor analog derivatives, such compound discharge rapidly ligustrazine or NO in vivo, so that and A Qi Effective synergy occurs for Sha Tan, strengthens anti-hypertension curative effect, reduces adverse reaction, has comparatively ideal guarantor to patient's liver kidney Shield acts on.
In order to realize the purpose of the present invention, the technical scheme that the present invention takes is as follows：
Benzimidizole derivatives and its pharmaceutically acceptable salt, solvate or polymorph shown in formula I.
Characterized in that, R is represented in formula I OrWherein, a=0,1,2,3,4,5 or 6；
Further, R1Represent C2-C8Alkyl, C2-C8Alkylene, C2-C8Alkynes base,(CH2)nO (CH2)m、Phenyl, substituted-phenyl, heteroaromatic or substitution heteroaromatic, wherein, b, c=0,1,2,3,4,5 or 6；n、m =1,2,3,4,5 or 6；
Further, R2Represent hydrogen, halogen, trifluoromethyl, C1-C8Alkoxy, C1-C8Alkyl, nitro, sulfoamido, amino Or itrile group；
Further, R3Represent C1-C8Alkoxy, C2-C8Olefin oxy, C2-C8Alkynes epoxide, (C1-C6)O(C1-C6)、Phenyl, substituted-phenyl, heteroaromatic or substitution heteroaromatic, wherein, b, c=0,1,2,3,4,5 or 6；
Further, R4Represent phenyl, substituted-phenyl, benzenesulfonyl, 5-6 members heteroaromatic, 5-6 member substitution heteroaromatic, itrile group, Trifluoromethyl, C1-C8Alkoxy, C1-C8Nitrate or C1-C8Alkyl；
Further, R5Representing the first substitution heteroaromatic of phenyl, substituted-phenyl, 5-6 members heteroaromatic, 5-6, (preferably ligustrazine takes Generation), itrile group, trifluoromethyl, C1-C8Alkoxy, C1-C8Nitrate, C1-C8Alkyl, C1-C8Alkylene, C1-C8Alkynes base, Or (CH2)nO(CH2)m, its In, R3、R4, a, n, m it is as defined above text described in；
Further, R6And R7Represent hydrogen, C1-C8Alkoxy or C1-C8Alkyl；
Further, R8And R9Represent hydrogen, C1-C8Alkoxy, C1-C8Nitrate or C1-C8Alkyl；
Described substituted-phenyl refers to one or more selected from hydroxyl, C1-C6Alkyl, C1-C6Alkoxy, halogen, nitro, Amino, itrile group, trifluoromethyl ,-CH=CHCO2R11Substituted phenyl, each substituent may be the same or different, R therein11Represent hydrogen Or C1-C6Alkyl；
Described heteroaromatic refers to containing 1-4 heteroatomic 5-7 members aromatic rings, the hetero atom be each independently selected from O, S or N；
Described substitution heteroaromatic is optionally to be selected from C by one or more1-C6Alkyl, C1-C6The group of alkoxy, halogen Substitution, each substituent may be the same or different.
Representative compound is as follows in the formula I of the present invention：
QR01002:(isopropyl oxo phosphinylidyne oxygen) methyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2, 4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01003:1- (isopropyl oxo phosphinylidyne oxygen) ethyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1, 2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01004:Acetoxvethyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) - 3- yls) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01005：Pivaloyloxymethyl -2- ethyoxyls -1- { [2'- (5- oxo -4,5- dihydro -1,2,4- Evil bis- Azoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01006：(3,5,6- trimethylpyrazine -2- bases) methyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydros - 1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01007：6- (nitroxide ester) hexahydro base furans [3,2-b] furans -3- base -2- ethyoxyls -1- { [2'- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01008：4- nitro oxygen-butyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) - 3- yls) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01009：(4- phenyl -1,2,5,-oxadiazole -2- oxides -3-) methyl -2- ethyoxyls -1- { [2'- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01010:(4- phenyl -1,2,5,-oxadiazole -2- oxides -3-) methoxyphenoxy -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole -7- carboxylic acids Ester；
QR01011：4- (3- benzenesulfonyl -1,2,5- oxadiazole -2- oxides -3-) oxygen-butyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole -7- carboxylic acids Ester；
QR01012：2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- Base] methyl } -1H- benzimidazole -7- carboxylic acids-(N- phenyl-N'- hydroxyls guanidine) ester；
QR01013：5- methyl -2- thio -1,3,-dioxole -4- bases) methyl -2- ethyoxyl -1- { [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01014：(3- methyl -5,6- dioxy -5,6- dihydro -1,4- dioxas -2-) methyl -2- ethyoxyl -1- { [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01015:3- [hydroxyl-ethanedioic acid ethyl ester] -2- oxo-butyl -2- ethyoxyls -1- { [2'- (5- oxos -4,5- Dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01016:2- nitroxide ethyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) - 3- yls) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01017:(3,5,6- trimethylpyrazines -2- methoxyl groups-oxo phosphinylidyne oxygen) methyl -2- ethyoxyl -1- { [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01019:1- (3,5,6- trimethylpyrazines -2- methoxyl groups-oxo phosphinylidyne oxygen) ethyl -2- ethyoxyl -1- { [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01020:(3- methyl isophthalic acids, 2,5- oxadiazole -2- oxides -3- methoxyl groups-oxo phosphinylidyne oxygen) methyl -2- ethoxies Base -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazoles -7- Carboxylate；
QR01021:1- (3- methyl isophthalic acids, 2,5- oxadiazole -2- oxides -3- methoxyl groups-oxo phosphinylidyne oxygen) ethyl -2- second Oxy-1-[2'- (5- oxo-4,5- dihydro-1,2,4- oxadiazoles)-3- bases) biphenyl-4- bases] methyl }-1H- benzimidazoles- 7- carboxylates；
QR01023：4- (3- methyl isophthalic acids, 2,5- oxadiazole -2- oxides) methyl -2- ethyoxyls -1- [2'- (5- oxos - 4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01025：3- (4- methyl isophthalic acids, 2,5- oxadiazole -2- oxides) methyl -2- ethyoxyls -1- [2'- (5- oxos - 4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01026：4- (the 3- tert-butyl group -1,2,5- oxadiazole -2- oxides) methyl -2- ethyoxyls -1- { [2'- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01027:1- (3,5,6- trimethylpyrazines -2- methoxyl groups-oxo phosphinylidyne oxygen) isobutyl group -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole -7- carboxylic acids Ester；
QR01028:1- (3,5,6- trimethylpyrazines -2- methoxyl groups-oxo phosphinylidyne oxygen) neopentyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole -7- carboxylic acids Ester；
QR01029：1- (6- methyl pyridazine -2- methoxyl groups-oxo phosphinylidyne oxygen) ethyl -2- ethyoxyls -1- { [2'- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01030：(isoxazole -5- methoxyl groups-oxo phosphinylidyne oxygen) methyl -2- ethyoxyls -1- { [2'- (5- oxos -4,5- Dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01031：(1- methylimidazoles -4- methoxyl groups-oxo phosphinylidyne oxygen) methyl -2- ethyoxyls -1- [2'- (5- oxos - 4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01032：(1- methylpyrroles -3- methoxyl groups-oxo phosphinylidyne oxygen) methyl -2- ethyoxyls -1- [2'- (5- oxos - 4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01033：1- (1- methylpyrroles -3- methoxyl groups-oxo phosphinylidyne oxygen) ethyl -2- ethyoxyls -1- { [2'- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01034:4- (3- nitrate -1,2,5- oxadiazole -2- oxides) methyl -2- ethyoxyls -1- { [2'- (5- Oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
QR01035:4- -2 ethyoxyl -1- [(2 '-(5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl - 4- yls] methyl } -1H- benzimidazole -7- carboxylic acid -5,6- dihydro -4H- cyclopenta [c] [oxide of 1,2,5] oxadiazoles -2 } -1 Methyl esters
QR01036:4- (3- itrile group -1,2,5- oxadiazole -2- oxides) methyl -2- ethyoxyls -1- [2'- (5- oxos - 4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
Chemical structural formula corresponding to above-claimed cpd QR01002-QR01036 is as follows：
Present invention also offers a variety of preparation methods of the compound shown in formula I：
(1) Azilsartan and acylation reaction generation mixed acid anhydride in the presence of a base, the mixed acid anhydride in the presence of a base with Corresponding alcohol reacts to obtain Azilsartan, wherein R10There is no particular/special requirement；
(2) Azilsartan reacts generation acyl chlorides in the presence of a catalyst with thionyl chloride, and the acyl chlorides is with corresponding alcohol in alkali In the presence of reaction obtain Azilsartan；
(3) Azilsartan reacts to obtain Azilsartan in the presence of a base with required alkylating reagent；
(4) Azilsartan carries out esterification in the presence of condensing agent with corresponding alcohol and obtains Azilsartan；
(5) when R is representedDuring substituent, preparation method includes Azilsartan and the haloalkyl of different chain length Alcohol reacts to obtain ester, then with nitric acid silver reaction, compound of Formula I is made；Or under DCC/DMAP catalysis, Azilsartan with Glycol compound reacts to obtain ester, then is reacted with fuming nitric aicd, and compound of Formula I is made；
In above-mentioned reaction equation X represent Cl, Br or；
(6) when R is representedDuring substituent, preparation method：Under DCC/DMAP catalysis, Azilsartan and N- virtues Compound of Formula I is made in the condensation of base-N'- hydroxyls guanidine；
Specific reactions steps are as follows：
(7) when R is representedWhen, preparation method： DCC/DMAP or Et3N/N- methyl pyrroles under the conditions of alkanone, Azilsartan and furoxan-based NO donors class (Furoxan) NO donors It is condensed to yield compounds of formula I；
Specific reactions steps are as follows：
(8) R is represented in formula IIts preparation method is as follows：
Compared with prior art, it is the advantages of technical solution of the present invention with beneficial effect：
1st, the invention discloses a series of benzimidazoles derivatives, mainly include and ligustrazine, nitric oxide donors, (5- methyl -2- thio -1,3,-dioxole -) methanol is into ester and (3- methyl -5,6- dioxy -5,6- dihydros -1,4- Dioxa -2-) methanol into ester derivative.
2nd, rapid metabolization is Azilsartan and ligustrazine or discharged certain after novel compound of present invention enters in vivo Horizontal NO, so as to greatly strengthen Azilsartan antihypertensive active.
3rd, ligustrazine class AT1 receptor blocking pharmacons, AT1 receptor blocking pharmacon anti-hypertension curative effects both can effectively have been strengthened, it is also reachable To effective protective effect of liver kidney.
Brief description of the drawings
The LCMS spectrograms for the product QR01023 that Fig. 1 is prepared for embodiment 23, MS+：569.2；
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram for the product QR01023 that embodiment 23 is prepared.
Embodiment
Applicant will the present invention is described in further detail in conjunction with specific embodiments below, it is therefore intended that so that this Art personnel more clearly understand the present invention, but herein below should not be construed in any way to the right to the present invention The limitation of the claimed scope of claim.
Unless otherwise specified, the conventional hand that technological means used in embodiment is well known to the skilled person Section.
Embodiment 1
(isopropyl oxo phosphinylidyne oxygen) methyl -2- ethyoxyls -1- { [2'- (5- oxo -4,5- dihydro -1,2,4- Evil bis- Azoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01002-IN-01 (3.3mmol, 1.5 equivalents) is dissolved In 20mLN- methyl pyrrolidones, triethylamine (4.4mmol, 2.0 equivalents) is added, is heated to 65 DEG C, TLC monitorings are reacted, instead It should finish.Water and ethyl acetate are added into reaction solution, extracts liquid separation, organic layer washing, saturated common salt water washing.Organic layer is done Dry concentration, column chromatography purify to obtain target compound QR01002, and its structure obtains double through LCMS spectrograms and hydrogen nuclear magnetic resonance spectrogram Confirm again.
Embodiment 2
1- (isopropyl oxo phosphinylidyne oxygen) ethyl -2- ethyoxyls -1- { [2'- (5- oxo -4,5- dihydro -1,2,4- Evil bis- Azoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01003-IN-01 (3.3mmol, 1.5 equivalents) is dissolved In 20mLN- methyl pyrrolidones, triethylamine (4.4mmol, 2.0 equivalents) is added, is heated to 65 DEG C, TLC monitorings are reacted, instead It should finish.Water and ethyl acetate are added into reaction solution, extracts liquid separation, organic layer washing, saturated common salt water washing.Organic layer is done Dry concentration, column chromatography purify to obtain target compound QR01003, and its structure obtains double through LCMS spectrograms and hydrogen nuclear magnetic resonance spectrogram Confirm again.
Embodiment 3
Acetoxvethyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) connection Benzene -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01004-IN-03 (3.3mmol, 1.5 equivalents) is dissolved In 20mLN- methyl pyrrolidones, triethylamine (4.4mmol, 2.0 equivalents) is added, is heated to 65 DEG C, TLC monitorings are reacted, instead It should finish.Water and ethyl acetate are added into reaction solution, extracts liquid separation, organic layer washing, saturated common salt water washing.Organic layer is done Dry concentration, column chromatography purify to obtain target compound QR01004, and its structure obtains double through LCMS spectrograms and hydrogen nuclear magnetic resonance spectrogram Confirm again.
Embodiment 4
Pivaloyloxymethyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) connection Benzene -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01005-IN-01 (3.3mmol, 1.5 equivalents) is dissolved In 20mLN- methyl pyrrolidones, triethylamine (4.4mmol, 2.0 equivalents) is added, is heated to 65 DEG C, TLC monitorings are reacted, instead It should finish.Water and ethyl acetate are added into reaction solution, extracts liquid separation, organic layer washing, saturated common salt water washing.Organic layer is done Dry concentration, column chromatography purify to obtain target compound QR01005, and its structure obtains double through LCMS spectrograms and hydrogen nuclear magnetic resonance spectrogram Confirm again.
Embodiment 5
(3,5,6- trimethylpyrazine -2- bases) methyl -2- ethyoxyls -1- { [2'- (5- oxo -4,5- dihydro -1,2,4- Evil Diazole) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01006-IN-01 (2.6mmol, 1.2 equivalents) is dissolved In 20ml dimethylformamides, 10 DEG C are cooled to, adds potassium carbonate (2.6mmol, 1.2 equivalents), paratoluensulfonyl chloride (2.6mmol, 1.2 equivalents), catalyst dimethylamino naphthyridine, stir 3h.Reaction is finished, and water, acetic acid second are added into reaction solution Ester extracts.Organic layer is washed, saturated common salt water washing.Concentration crude product is dried to purify to obtain target compound through column chromatography QR01006, its structure obtain dual confirmation through LCMS spectrograms and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 6
6- (nitroxide ester) hexahydro base furans [3,2-b] furans -3- base -2- ethyoxyls -1- { [2'- (5- oxos -4,5- two Hydrogen -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01007-IN-01 (2.6mmol, 1.2 equivalents) is dissolved In 20mL dimethylformamides, 10 DEG C are cooled to, adds potassium carbonate (2.6mmol, 1.2 equivalents), paratoluensulfonyl chloride (2.6mmol, 1.2 equivalents), catalyst dimethylamino naphthyridine, stir 3h.Reaction is finished, and water, acetic acid second are added into reaction solution Ester extracts.Organic layer is washed, saturated common salt water washing.Concentration crude product is dried to purify to obtain target compound through column chromatography QR01007, its structure obtain dual confirmation through LCMS spectrograms and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 7
4- nitroxide butyl- 2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl - 4- yls] methyl -1H- benzimidazole-7-carboxylates synthesis
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01008-IN-02 (3.3mmol, 1.5 equivalents) is dissolved In 20mL dimethylformamides, 10 DEG C are cooled to, adds potassium carbonate (2.6mmol, 1.2 equivalents), paratoluensulfonyl chloride (2.6mmol, 1.2 equivalents), catalyst dimethylamino naphthyridine, stir 3h.Reaction is finished, and water, acetic acid second are added into reaction solution Ester extracts.Organic layer is washed, saturated common salt water washing.Concentration crude product is dried to purify to obtain target compound through column chromatography QR01008, its structure obtain dual confirmation through LCMS spectrograms and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 8
3- (4- phenyl -1,2,5,-oxadiazole -2- oxides -3-) methyl -2- ethyoxyls -1- { [2'- (5- oxos -4,5- Dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01009-IN-02 (2.6mmol, 1.2 equivalents) is dissolved In 20mL dimethylformamides, 10 DEG C are cooled to, adds potassium carbonate (2.6mmol, 1.2 equivalents), paratoluensulfonyl chloride (2.6mmol, 1.2 equivalents), catalyst dimethylamino naphthyridine, stir 3h.Reaction is finished, and water, acetic acid second are added into reaction solution Ester extracts.Organic layer is washed, saturated common salt water washing.Concentration crude product is dried to purify to obtain target compound through column chromatography QR01009, its structure obtain dual confirmation through LCMS spectrograms and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 9
3- (4- phenyl -1,2,5,-oxadiazole -2- oxides -3-) methoxyphenoxy -2- ethyoxyls -1- { [2'- (5- Oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01010-IN-02 (2.6mmol, 1.2 equivalents) is dissolved In 20mL dichloromethane, dicyclohexylcarbodiimide (4.4mmol, 2.0 equivalents) is added, is stirred overnight at room temperature.React Finish, water, dichloromethane extraction are added into reaction solution.Organic layer is washed, saturated common salt water washing.Concentration crude product is dried through post layer Analysis purifying obtains target compound QR01010, and its structure obtains dual confirmation through LCMS spectrograms and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 10
4- (3- benzenesulfonyl -1,2,5- oxadiazole -2- oxides -3-) oxygen-butyl -2- ethyoxyls -1- { [2'- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01011-IN-05 (2.6mmol, 1.2 equivalents) is dissolved in In 20mL dichloromethane, dicyclohexylcarbodiimide (4.4mmol, 2.0 equivalents), catalyst dimethylamino naphthyridine are added.Room Temperature is stirred overnight.Reaction is finished, and water, dichloromethane extraction are added into reaction solution.Organic layer is washed, saturated common salt water washing. Dry concentration crude product to purify to obtain target compound QR01011 through column chromatography, its structure is through LCMS spectrograms and proton nmr spectra Figure obtains dual confirmation.
Embodiment 11
2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } - The synthesis of 1H- benzimidazole -7- carboxylic acids-(N- phenyl-N'- hydroxyls guanidine) ester
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01012-IN-03 (2.6mmol, 1.2 equivalents) is dissolved in In 20mL dichloromethane, dicyclohexylcarbodiimide (4.4mmol, 2.0 equivalents), catalyst dimethylamino naphthyridine are added.Room Temperature is stirred overnight.Reaction is finished, and water, dichloromethane extraction are added into reaction solution.Organic layer is washed, saturated common salt water washing. Dry concentration crude product to purify to obtain target compound QR01012 through column chromatography, its structure is through LCMS spectrograms and proton nmr spectra Figure obtains dual confirmation.
Embodiment 12
(5- methyl -2- thio -1,3,-dioxole -4- bases) methyl -2- ethyoxyls -1- [2'- (5- oxos - 4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
By QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01013-IN-04 (2.6mmol, 1.2 equivalents), dissolving In 20mL dimethylformamides, 10 DEG C are cooled to, adds potassium carbonate (equivalents of 2.6mmol 1.2), paratoluensulfonyl chloride (2.6mmol, 1.2 equivalents), catalyst dimethylamino naphthyridine, stir 3h.Reaction is finished, and water, acetic acid second are added into reaction solution Ester extracts.Organic layer is washed, saturated common salt water washing.Concentration crude product is dried to purify to obtain target compound through column chromatography QR01013, its structure obtain dual confirmation through LCMS spectrograms and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 13
(3- methyl -5,6- dioxy -5,6- dihydro -1,4- dioxas -2-) methyl -2- ethyoxyls -1- [2'- (5- oxos - 4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
By QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01014-IN-04 (2.6mmol, 1.2 equivalents), dissolving In 20mL dimethylformamides, 10 DEG C are cooled to, adds potassium carbonate (2.6mmol, 1.2 equivalents), paratoluensulfonyl chloride (2.6mmol, 1.2 equivalents), catalyst dimethylamino naphthyridine, stir 3h.Reaction is finished, and water, acetic acid second are added into reaction solution Ester extracts.Organic layer is washed, saturated common salt water washing.Concentration crude product is dried to purify to obtain target compound through column chromatography QR01014, its structure obtain dual confirmation through LCMS spectrograms and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 14
3- [hydroxyl-ethanedioic acid ethyl ester] -2- oxo-butyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2, 4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01015-IN-01 (3.3mmol, 1.5 equivalents) is dissolved In 20mLN- methyl pyrrolidones, triethylamine (4.4mmol, 2.0 equivalents) is added, is heated to 65 DEG C, TLC monitorings are reacted, instead It should finish.Water and ethyl acetate are added into reaction solution, extracts liquid separation, organic layer washing, saturated common salt water washing.Organic layer is done Dry concentration, column chromatography purify to obtain target compound QR01015, and its structure obtains double through LCMS spectrograms and hydrogen nuclear magnetic resonance spectrogram Confirm again.
Embodiment 15
2- nitroxide ethyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) connection Benzene -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01016-IN-01 (3.3mmol, 1.5 equivalents) is dissolved In 20mL dimethylformamides, 10 DEG C are cooled to, adds potassium carbonate (2.6mmol, 1.2 equivalents), paratoluensulfonyl chloride (2.6mmol, 1.2 equivalents), catalyst dimethylamino naphthyridine, stir 3h.Reaction is finished, and water, acetic acid second are added into reaction solution Ester extracts.Organic layer is washed, saturated common salt water washing.Concentration crude product is dried to purify to obtain target compound through column chromatography QR01016, its structure obtain dual confirmation through LCMS spectrograms and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 16
(3,5,6- trimethylpyrazines -2- methoxyl groups-oxo phosphinylidyne oxygen) methyl -2- ethyoxyls -1- [2'- (5- oxo -4, 5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis：
Step (1)：QR01006-IN-01 (500mg, 3.29mmol), dichloromethane are added in 50ml there-necked flasks (10mL), chloro-methyl-chloroformate (460mg, 3.6mmol), mixed liquor temperature control is in -2 degree, dropwise addition pyridine (0.32mL) control temperature No more than 3 DEG C, reaction solution is added dropwise it is warming up to and be stirred overnight at room temperature, TLC (petrol ether/ethyl acetate=1:3) monitoring is former Material reaction is complete, and reacting liquid filtering, filtrate is spin-dried for, and obtains 1.1g yellow oils, prepares plate and purifies to obtain 620mg yellow liquid Body, yield:77.3%.LCMS and HNMR spectrograms confirm the structure of target compound.
Step (2)：QR01000-IN-01 (0.77g, 1.69mmol), QR01017- are sequentially added in 50mL there-necked flasks IN-01 (0.62g, 2.54mmol), 1-METHYLPYRROLIDONE (15mL), triethylamine (0.34g, 3.39mmol).Mixed liquor is 65 Stirred 2 hours at DEG C, TLC point plate (dichloromethane：Methanol=10:1), reaction is complete.
Post processing：Reaction solution is poured into 75mL water, adds 1N HCl to adjust pH value to 6-7, the white emulsion of solution, adds Methyl tertiary butyl ether(MTBE) extracts (50mL), and saturation NaCl washes (50mL*2) twice, anhydrous Na2SO4Dry, be spin-dried for, obtain 1.2g yellow Liquid, silicagel column obtain 586mg white gum things after purification, LCMS and HNMR spectrograms confirm target compound QR01017's Structure.
Embodiment 17
1- (3,5,6- trimethylpyrazines -2- methoxyl groups-oxo phosphinylidyne oxygen) ethyl -2- ethyoxyls -1- [2'- (5- oxos - 4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
Step (1)：QR01006-IN-01 (500mg, 3.29mmol), dichloromethane are added in 50ml there-necked flasks Pyridine (0.32mL) control temperature is added dropwise at -2 DEG C in (10mL), chloro-carbonic acid 1- chloroethenes ester (460mg, 3.6mmol), mixed liquor temperature control Degree is no more than 3 DEG C, reaction solution is added dropwise is warming up to and be stirred overnight at room temperature, TLC (petrol ether/ethyl acetate=1:3) monitor Raw material reaction is complete, and reacting liquid filtering, filtrate is spin-dried for, and obtains 1.1g yellow oils, prepares plate and purifies to obtain 650mg yellow liquid Body.LCMS and HNMR spectrograms confirm the structure of target compound.
Step (2)：QR01000-IN-01 (0.77g, 1.69mmol), QR01019- are sequentially added in 50mL there-necked flasks IN-01 (0.62g, 2.4mmol), 1-METHYLPYRROLIDONE (15mL), triethylamine (0.34g, 3.39mmol).Mixed liquor is at 65 DEG C Lower stirring 2 hours, TLC point plate (dichloromethane：Methanol=10:1), reaction is complete.
Post processing：Reaction solution is poured into 75mL water, adds 1N HCl to adjust pH value to 6-7, the white emulsion of solution, adds Methyl tertiary butyl ether(MTBE) extracts (50mL), and saturation NaCl washes (50mL*2) twice, anhydrous Na2SO4Dry, be spin-dried for, obtain 1.2g yellow Liquid, silicagel column obtain 550mg white gum things after purification, LCMS and HNMR spectrograms confirm target compound QR01019's Structure.
Embodiment 18
(3- methyl isophthalic acids, 2,5- oxadiazole -2- oxides -3- methoxyl groups-oxo phosphinylidyne oxygen) methyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates Synthesis
Concrete operations by QR01006-IN-01, are changed to QR01020-IN-01, other are constant with embodiment 16；
Concrete operations by QR01017-IN-01, are changed to QR01020-IN-02, other are constant with embodiment 16；
LCMS and HNMR spectrograms confirm target compound QR01020 structure.
Embodiment 19
1- (3- methyl isophthalic acids, 2,5- oxadiazole -2- oxides -3- methoxyl groups-oxo phosphinylidyne oxygen) ethyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates Synthesis
Concrete operations by QR01006-IN-01, are changed to QR01020-IN-01, other are constant with embodiment 17；
Concrete operations by QR01019-IN-01, are changed to QR01021-IN-01, other are constant with embodiment 17；
LCMS and HNMR spectrograms confirm target compound QR01021 structure.
Embodiment 20
4- (3- methyl isophthalic acids, 2,5- oxadiazole -2- oxides) methyl -2- ethyoxyls -1- { [2'- (5- oxos -4,5- two Hydrogen -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
QR01000-IN-01 (1.46g, 3.2mmol) is dissolved in 25mLN, dinethylformamide in 100ml single port bottles In, sequentially add (0.5g, 3.85mmol) QR01020-IN-003, paratoluensulfonyl chloride (0.73g, 3.85mmol), potassium carbonate (0.06g) N, N- lutidines amine of (0.88g, 6.4mmol) and catalytic amount, reaction 3 hours is stirred at room temperature, puts plate (oil Ether：Ethyl acetate=1：3) detection has a new point, and also a small amount of raw material Q R 01020-I N-01 are remaining.
Post processing：50 milliliters of water, ethyl acetate extraction (60ml*3), 100 milliliters of saturations of organic phase are added in reaction solution Sodium acid carbonate is washed, 100 milliliters of saturated common salt water washings.Anhydrous sodium sulfate drying, filtering, is spin-dried for, obtains 1.9g yellow oily liquid Body, column chromatography for separation (petroleum ether：Ethyl acetate=1.5:1-1:2) 800mg white solids, yield, are obtained：44.4%.
LCMS the and HNMR spectrograms of accompanying drawing 1 confirm target compound QR01023 structure, in LCMS spectrograms, MS+： 569.2。
Embodiment 21
3- (4- methyl isophthalic acids, 2,5- oxadiazole -2- oxides) methyl -2- ethyoxyls -1- { [2'- (5- oxos -4,5- two Hydrogen -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
Concrete operations by QR01020-IN-01, are changed to QR01025-IN-01, other are constant with embodiment 20；
LCMS spectrograms and HNMR confirm target compound QR01025 structure.
Embodiment 22
4- (the 3- tert-butyl group -1,2,5- oxadiazole -2- oxides) methyl -2- ethyoxyls -1- { [2'- (5- oxos -4,5- two Hydrogen -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
Concrete operations by QR01020-IN-01, are changed to QR01026-IN-01, other are constant with embodiment 20；
LCMS spectrograms and HNMR confirm target compound QR01026 structure.
Embodiment 23
1- (3,5,6- trimethylpyrazines -2- methoxyl groups-oxo phosphinylidyne oxygen) isobutyl group -2- ethyoxyls -1- { [2'- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
Concrete operations, by chloro-methyl-chloroformate, are changed to chloro-carbonic acid 1- chlorine isobutyl esters, other are constant with embodiment 16；
Concrete operations by QR01018-IN-01, are changed to QR01027-IN-01, other are constant with embodiment 16；
LCMS and HNMR spectrograms confirm target compound QR01027 structure.
Embodiment 24
1- (3,5,6- trimethylpyrazines -2- methoxyl groups-oxo phosphinylidyne oxygen) neopentyl -2- ethyoxyls -1- { [2'- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl } -1H- benzimidazole-7-carboxylates；
Concrete operations, by chloro-methyl-chloroformate, are changed to chloro-carbonic acid 1- chlorine peopentyl esters, other are constant with embodiment 16；
Concrete operations by QR01018-IN-01, are changed to QR01028-IN-01, other are constant with embodiment 16；
LCMS and HNMR spectrograms confirm target compound QR01028 structure.
Embodiment 25
1- (6- methyl pyridazine -2- methoxyl groups-oxo phosphinylidyne oxygen) ethyl -2- ethyoxyls -1- { [2'- (5- oxos -4,5- two Hydrogen -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
Concrete operations by QR01006-IN-01, are changed to QR01024-IN-01, other are constant with embodiment 17；
Concrete operations by QR01019-IN-01, are changed to QR01029-IN-01, other are constant with embodiment 17；
LCMS and HNMR spectrograms confirm target compound QR01029 structure.
Embodiment 26
(isoxazole -5- methoxyl groups-oxo phosphinylidyne oxygen) methyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydro -1, 2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
Concrete operations by QR01006-IN-01, are changed to QR01030-IN-01, other are constant with embodiment 16；
Concrete operations by QR01017-IN-01, are changed to QR01030-IN-02, other are constant with embodiment 16；
LCMS and HNMR spectrograms confirm target compound QR01030 structure.
Embodiment 27
(1- methylimidazoles -4- methoxyl groups-oxo phosphinylidyne oxygen) methyl -2- ethyoxyls -1- { [2'- (5- oxos -4,5- two Hydrogen -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
Concrete operations by QR01006-IN-01, are changed to QR01030-IN-01, other are constant with embodiment 16；
Concrete operations by QR01017-IN-01, are changed to QR01031-IN-01, other are constant with embodiment 16；
LCMS and HNMR spectrograms confirm target compound QR01031 structure.
Embodiment 28
(1- methylpyrroles -3- methoxyl groups-oxo phosphinylidyne oxygen) methyl -2- ethyoxyls -1- { [2'- (5- oxos -4,5- two Hydrogen -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
Concrete operations by QR01006-IN-01, are changed to QR01032-IN-01, other are constant with embodiment 16；
Concrete operations by QR01017-IN-01, are changed to QR01032-IN-02, other are constant with embodiment 16；
LCMS and HNMR spectrograms confirm target compound QR01032 structure.
Embodiment 29
1- (1- methylpyrroles -3- methoxyl groups-oxo phosphinylidyne oxygen) ethyl -2- ethyoxyls -1- { [2'- (5- oxos -4,5- two Hydrogen -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis
Concrete operations by QR01006-IN-01, are changed to QR01032-IN-01, other are constant with embodiment 17；
Concrete operations by QR01019-IN-01, are changed to QR01033-IN-01, other are constant with embodiment 17；
LCMS and HNMR spectrograms confirm target compound QR01033 structure.
Embodiment 30
(4- nitrate -1,2,5,-oxadiazole -2- oxides) methyl -2- ethyoxyls -1- { [2'- (5- oxos -4,5- Dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis：
QR01019-IN-01 (0.05mol) is dissolved in dichloromethane (50mL) in 100mL single port bottles, adds N- bromines For succimide (0.06mol) and the benzoyl peroxide of 5% mol ratio, 5 hours, TLC detections are heated to reflux, raw material disappears Lose；
Post processing:50mL saturated sodium bicarbonate solutions are added to be quenched；Dichloromethane extracts (60mL*3), 100 milliliters of saturations Brine It.Anhydrous sodium sulfate drying, filtering, is spin-dried for, obtains 6.5g yellow oily liquids, column chromatography for separation, obtain 2.0g QR01034-IN-01。
QR01034-IN-01 (0.0048mol) is dissolved in acetonitrile (50mL) in 100mL single port bottles, adds silver nitrate (0.0055mol), is heated to reflux 0.5 hour, TLC detections, and raw material disappears；
Post processing:50mL water quenchings are added to go out；Dichloromethane extracts (60mL*3), 100 milliliters of saturated common salt water washings.It is anhydrous Sodium sulphate is dried, and filtering, is spin-dried for, is obtained 0.9g yellow oily liquids, column chromatography for separation, obtain 630mg QR01034-IN-02.
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01034-IN-02 (2.6mmol, 1.2 equivalents) is dissolved in In 20mL dichloromethane, dicyclohexylcarbodiimide (4.4mmol, 2.0 equivalents), catalyst dimethylamino naphthyridine are added.Room Temperature is stirred overnight.Reaction is finished, and water, dichloromethane extraction are added into reaction solution.Organic layer is washed, saturated common salt water washing. Dry concentration crude product to purify to obtain target compound QR01034 through column chromatography, its structure is confirmed through LCMS and HNMR spectrograms.
Embodiment 31
4- { -2 ethyoxyl -1- [(2 '-(5- oxo -4,5- dihydro -1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] first Base } -1H- benzimidazole -7- carboxylic acid -5,6- dihydro -4H- cyclopenta [c] { [oxide of 1,2,5] oxadiazoles -2 } -1 methyl esters conjunction Into：
QR01035-IN-01 (0.071mol) is added in 100ml there-necked flasks, 10ml acetic acid, NaNO is slowly added dropwise2It is full With solution (0.25mol is dissolved in 21mL water), control temperature is no more than 20 DEG C, TLC point plates, there is two new point generation (PE：EA=1: 1), raw material reaction is complete.Post processing：50mL water is added in reaction solution, adds dichloromethane extraction (100mL*3), it is organic to be harmonious And wash (100mL), anhydrous Na2SO4Dry, be spin-dried for, obtain 7.2g yellow oils, yield：78.8%.
In 100ml there-necked flasks, QR01035-IN-02 (0.023mol) is dissolved in 10mL MeOH, and temperature control is to -10 DEG C, slowly Add NaBH4(0.047mol) solid, control temperature are no more than 10 DEG C, add NaBH4Solid, reaction solution are warming up to 10 DEG C of reactions 2 Hour, TLC point plates, raw material reaction (petroleum ether completely：Ethyl acetate=1:1).Post processing：Reaction solution temperature control at 0 DEG C slowly 40mL water is added dropwise, control temperature is no more than 10 DEG C, added, and ethyl acetate extraction (100mL*2), organic phase merges anhydrous sodium sulfate Dry, be spin-dried for, obtain 2.2g yellow liquids, yield：72.2%.
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01035-IN-03 (2.6mmol, 1.2 equivalents) is dissolved In 20ml dimethylformamides, 10 DEG C are cooled to, adds potassium carbonate (2.6mmol, 1.2 equivalents), paratoluensulfonyl chloride (2.6mmol, 1.2 equivalents), catalyst dimethylamino naphthyridine, stir 3h.Reaction is finished, and water, acetic acid second are added into reaction solution Ester extracts.Organic layer is washed, saturated common salt water washing.Concentration crude product is dried to purify to obtain target compound through column chromatography QR01035, its structure are confirmed through LCMS and HNMR spectrograms.
Embodiment 32
(4- itrile group -1,2,5- oxadiazole -2- oxides) methyl -2- ethyoxyls -1- [2'- (5- oxo -4,5- dihydros - 1,2,4- oxadiazoles) -3- bases) biphenyl -4- bases] methyl -1H- benzimidazole-7-carboxylates synthesis：
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01036-IN-01 (3.3mmol, 1.5 equivalents) is dissolved In 20mLN- methyl pyrrolidones, triethylamine (4.4mmol, 2.0 equivalents) is added, is heated to 65 DEG C, TLC monitorings are reacted, instead It should finish.Water and ethyl acetate are added into reaction solution, extracts liquid separation, organic layer washing, saturated common salt water washing.Organic layer is done Dry concentration, column chromatography purify to obtain target compound QR01036, and its structure obtains double through LCMS spectrograms and hydrogen nuclear magnetic resonance spectrogram Confirm again.
(remarks：QR01036-IN-01 preparation refers to Medicinal Chemistry Research, 11 (6), 322- 332；2002)
The pharmacological effect research of the general formula compound (product QR01002-QR01036 is made in embodiment 1-32) of the present invention
1. oral benzimidazole derivative single-dose is to the antihypertensive effect of renal hypertensive rat
Wistar rats (are provided, Wuhan, Hubei) by Disease Prevention Control Center, Hubei Prov, male, body weight, 180- 200g, is randomly divided into 5 groups, negative control group (0.5%CMC-Na), positive controls (using Azilsartan as positive drug, by Open the synthesis of auspicious medicine company optical valley biology city pharmaceutical chemistry portion of research and development centre in Wuhan) and test-compound QR01002-QR01036 it is low, In, high three dosage groups (0.5,1.0,2.0mg/kg, all medicines are prepared in 0.5%CMC-Na), every group of 6-8 is only moved Thing.The side arteria renalis is ligatured, forms Two-kidney One-clip type renal hypertensive rat (RHR) model, Post operation determines weekly a blood Pressure, continuous surrounding, blood pressure stabilization rise 4kPa rat is the successful rat of modeling.Before measuring blood pressure, 39 DEG C of circulation of rat Water-bath tail sleeve heats to rat-tail, after expanding tail veins, with tail sleeve method (BP2010A non-invasive blood pressure instruments, Beijing Ji'an get Er Ke Skill Co., Ltd, the street No.1 of ShangDi, Haidian District, BeiJing City ten) measure rat administration before, 1,3,5,7,10 and 10h after gastric infusion Blood pressure and heart rate, each time point surveys and averages three times.Maximum hypotensive value after maximum hypotensive activity (%)=administration/ Pressure value X100% before administration.
The decompression of the oral benzimidazole derivative QR01002-QR01036 of table 1. and positive drug to renal hypertensive rat Effect
Conclusion：In arteria renalis Hypertension Rats animal model is ligatured, all test compounds prepared by the present invention are aobvious Show different degrees of hypotensive activity, wherein QR-01005, QR-01009, QR-01017, QR01019, QR01020, QR01023, QR01034 and QR01036 hypotensive activity intensity are substantially better than positive drug Azilsartan, hypotensive activity Duration approaches with Azilsartan fat.24 hours after administration, the antihypertensive effect of positive drug Azilsartan fat is 20%, QR- 01005 is 21%, QR01009 25%, and QR01017 20%, QR01019 26%, QR01020 15%, QR01023 are 18%, QR01034 25%, QR01036 24%, antihypertensive effect approach with Azilsartan lipid phase.Other compounds, such as QR01003, QR01008, QR01011, QR01021, QR01032 and QR01035 maximum blood pressure lowering effect and Azilsartan fat It is close.All test compounds prepared by the present invention have certain reduction to act on ligation arteria renalis rat heart rate, show to remove Outside significant hypotensive activity, such compound still has a certain degree of drop heart rate function.
2. oral benzimidazole derivative multiple dosing is to spontaneous hypertensive rat (SHR) antihypertensive effect
Male SHR (Beijing Vital River Experimental Animals Technology Co., Ltd., Beijing), 40 week old, 250-300 grams of body weight, 5 groups are randomly divided into, negative control group (0.5%CMC-Na), positive controls (Azilsartan, auspicious medicine company optical valley are opened by Wuhan Biological pharmaceutical chemistry portion of city research and development centre synthesis provides, and prepares in 0.5%CMC-Na), test-compound is low, in, it is high three Dosage group (all compounds are prepared in 0.5%CMC-Na), every group of 4-5 animal, is administered once a day, successive administration 14 My god, administration every time determines blood pressure and heart rate after 1 hour.Before measuring blood pressure, rat is heated with 39 DEG C of circulator bath tail sleeve to rat-tail, After expanding tail veins, with tail sleeve method (BP2010A non-invasive blood pressure instruments, Beijing Ji'an get Er Science and Technology Ltd.s, Beijing sea The street No.1 of shallow lake area Shangdi ten) before measure rat administration, blood pressure and heart rate after gastric infusion, each time point surveys and is averaged three times Value.Pressure value X100% before maximum hypotensive value/administration after maximum hypotensive activity (%)=administration.
Antihypertensive effect of the oral benzimidazole derivative of table 2. to spontaneous hypertensive rat (SHR)
Conclusion：In spontaneous hypertensive rat (SHR) animal model, all test compounds prepared by the present invention are aobvious Show stronger hypotensive activity, wherein QR01005, QR01009, QR01017, QR01019, QR01021, QR01023, QR01034, QR01036 action intensity are substantially better than Azilsartan.After long term administration, the hypotensive activity of compound is steady Fixed, animal state is superior to Azilsartan administration group.The hypotensive activity intensity of other compounds is worked as with Azilsartan lipid phase. In whole administration process, compound Q R01005, QR01009, QR01017, QR01019, QR01020 prepared by the present invention, QR01021, QR01023, QR01034, QR01036 show a certain degree of reduction effect to SHR rat heart rates, show such Compound removes significant antihypertensive effect, still has the function that preferably to drop heart rate.
3. influence of the oral benzimidazole derivative single-dose to normal rat blood pressure
Wistar rats (are provided, Wuhan, Hubei) by Disease Prevention Control Center, Hubei Prov, male, body weight, 200- 250g, is randomly divided into 5 groups, negative control group (0.5%CMC-Na), positive controls (using Azilsartan as positive drug, by Open the synthesis of auspicious medicine company optical valley biology city pharmaceutical chemistry portion of research and development centre in Wuhan) and test-compound QR01002-QR01036 it is low, In, high three dosage groups (0.5,1.0,2.0mg/kg, p.o., all medicines are prepared in 0.5%CMC-Na), every group of 8-10 Animal.Before measuring blood pressure, rat is heated with 39 DEG C of circulator bath tail sleeve to rat-tail, after expanding tail veins, with tail sleeve method (BP2010A non-invasive blood pressure instruments, Beijing Ji'an get Er Science and Technology Ltd.s, the street No.1 of ShangDi, Haidian District, BeiJing City ten) determines rat Before administration, after gastric infusion 0.5,1,2,4,8h blood pressure and heart rate, each time point surveys and averages three times.
As a result with conclusion：All test-compounds prepared by the present invention three dosage (0.5,1.0 and 2.0mg/kg, P.o., prepare in 0.5%CMC-Na) to normal rat blood pressure and heart rate without remarkable effect, show that such compound aligns Normal blood pressure and heart rate do not make significant difference.

Claims (14)

1. the compound shown in formula I：
Characterized in that, R is represented in formula I OrA=1 or 2；
The R1Represent C2-C8Alkyl, (CH2)nO(CH2)m、Wherein (CH2)nO(CH2)mIn n, m=1,2,3,4, 5 or 6；
The R2Represent hydrogen, halogen, trifluoromethyl, C1-C8Alkoxy, C1-C8Alkyl, nitro, amino or itrile group；
The R9Represent hydrogen, C1-C8Alkoxy, C1-C8Nitrate or C1-C8Alkyl.
2. following compounds：
3. compound described in claim 1 or 2 pharmaceutically acceptable salt.
4. a kind of preparation method of the compound of claim 1 or 2, in the presence of a base Azilsartan and acylation reaction generation Mixed acid anhydride, the mixed acid anhydride reacts with corresponding alcohol in the presence of a base to be produced.
5. a kind of preparation method of the compound of claim 1 or 2, Azilsartan are anti-in the presence of a catalyst with thionyl chloride Acyl chlorides should be generated, the acyl chlorides reacts in the presence of a base with corresponding alcohol to be produced.
6. a kind of preparation method of the compound of claim 1 or 2, Azilsartan exists with required alkylating reagent in alkali Under react and produce.
7. a kind of preparation method of the compound of claim 1 or 2, Azilsartan enter with corresponding alcohol in the presence of condensing agent Row esterification produces.
8. a kind of preparation method of the compound of claim 1 or 2, the R is representedAzilsartan from it is different The halohydrocarbons reaction of chain length obtains ester, then with nitric acid silver reaction, produce.
9. a kind of preparation method of the compound of claim 1 or 2, the R is representedIn urging for DCC/DMAP Under change, Azilsartan reacts to obtain ester with glycol compound, then is reacted with fuming nitric aicd, produces.
10. a kind of preparation method of the compound of claim 1 or 2, the R is representedIn urging for DCC/DMAP Under change, Azilsartan is condensed with N- aryl-N'- hydroxyl guanidines and produced.
11. a kind of preparation method of the compound of claim 1 or 2, the R is represented DCC/DMAP or Et3Under the conditions of N/N- methyl pyrrolidones, Azilsartan is condensed with furoxan-based NO donors class NO donors and produced.
12. the compound of claim 1 or 2 is preparing hypotensive, drop heart rate, is treating and preventing other cardiovascular diseases Purposes in medicine.
Pharmaceutically 13. acceptable salt is preparing hypotensive, drop heart rate, is treating and preventing it compound described in claim 3 Purposes in the medicine of his cardiovascular disease.
14. compound made from the preparation method according to any one of claim 4-11 prepare hypotensive, drop heart rate, Treat and prevent the purposes in the medicine of other cardiovascular diseases.
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