CN105237527A - Benzimidazole derivative, and preparation method and pharmaceutical applications thereof - Google Patents
Benzimidazole derivative, and preparation method and pharmaceutical applications thereof Download PDFInfo
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- CN105237527A CN105237527A CN201510617905.8A CN201510617905A CN105237527A CN 105237527 A CN105237527 A CN 105237527A CN 201510617905 A CN201510617905 A CN 201510617905A CN 105237527 A CN105237527 A CN 105237527A
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- 0 CCCCCC(C)=*c1cccc(C(C(CC)=C)=C)c1C Chemical compound CCCCCC(C)=*c1cccc(C(C(CC)=C)=C)c1C 0.000 description 10
- JKYCXYIUONHFBW-UHFFFAOYSA-N CCOC1N2c(cccc3C(O)=C4CC4)c3N(CC(C=C3)=CCC3c(cccc3)c3C(N3)=NCC3=O)C12 Chemical compound CCOC1N2c(cccc3C(O)=C4CC4)c3N(CC(C=C3)=CCC3c(cccc3)c3C(N3)=NCC3=O)C12 JKYCXYIUONHFBW-UHFFFAOYSA-N 0.000 description 1
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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
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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
- C07D413/14—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
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- 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
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- 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
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- 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 the technical field of pharmaceutical chemistry, and more specifically discloses a benzimidazole derivative, and a preparation method and pharmaceutical applications thereof. The benzimidazole derivative comprises ligustrazine and a NO donor derivative. In vivo, ligustrazine or NO can be released from the benzimidazole derivative quickly, so that effective synergistic effect with Azilsartan is achieved, anti-hypertension curative effect is improved, adverse reaction is reduced, ideal protection effect on livers and kidneys of patients is achieved, and the blank of the prior art is filled.
Description
The application is on February 4th, 2013 for the applying date, application number: 201310042669.2, denomination of invention: the divisional application of benzimidizole derivatives and preparation method thereof and medicinal use.
Technical field
The invention belongs to field of pharmaceutical chemistry technology, be specifically related to class benzimidizole derivatives and preparation method thereof and medicinal use.
Background technology
Hypertension (Hypertension) is modal cardiovascular disorder, is also to cause congestive heart failure, cerebral apoplexy, coronary heart disease, renal failure, the sickness rate of aortic aneurysm and the Major Risk Factors of case fatality rate rising.Antihypertensive drug plays keying action in the treatment and control of high blood pressure disease.Along with deepening continuously to hypertension incidence mechanism understanding, many antihypertensive drug with better curative effect, such as diuretic(s), beta-blocker, calcium-channel antagonists, angiotensin-convertion enzyme inhibitor (ACEI, pril), Angiotensin II AT1 receptor blocking agent (ABR, husky smooth class), constantly find and be successfully applied to clinical.Through clinical practice for many years; confirmation AT1 receptor blocking agent sartans is because it is hypotensive steadily, curative effect is good, long action time, patient tolerability are good; especially prevention palsy, delay diabetes and Non-diabetic nephropathy renal insufficiency, improve left ventricular hypertrophy, in the provide protection of target organ etc., there is more advantage; and do not affect bradykinin degraded and prostaglandin(PG) synthesis; thus do not cause dry cough and vasodilation, now become the main flow kind in global antihypertensive drug market.Although husky smooth class antihypertensive drug has many advantages, it is hypotensive is efficiently approximately about 50-60%, and has untoward reaction to a certain degree.Therefore, exploitation antihypertensive effect is stronger, less adverse effect, simultaneously to other diseases as diabetes have Preferred effects, and have the long-acting depressor of the low dose of better provide protection to become a popular research direction to target organ.
Nitrogen protoxide has extremely important physiological function as messenger substances and effector molecule in mammalian body; comprise and control antiotasis, nerve conduction, hormone secretion, inflammation and immune response etc., in addition adjustment arterial dilation, cell adhesion are also played an important role to blood vessel endothelium and platelet aggregation, vascular smooth muscle cell proliferation and protection ischemical reperfusion injury etc.ACE inhibitor has good step-down and target organ protection function.By suppressing ACE active, inhibit the generation of Angiotensin II and working on the one hand; Inhibit on the other hand the hydrolysis of the endogeneous activity peptides such as bradykinin, cause increasing of bradykinin concentration in body, thus by activating β
2acceptor and strengthen eNOS activity.Promote endothelium hyperpolarizing fac and NO release, and then the effect such as the vasodilator of performance NO mediation and anticoagulant.
Husky smooth class AT1 receptor antagonist be a class optionally with AT1 receptors bind, block AngII effect, thus cause the novel antihypertensive medicament of blood pressure drops.But, compared with ACE inhibitor, AT1 receptor blocking agent lacks the regulatory function of NO mediation, therefore NO donator type AT1 receptor blocking agent is developed, realize the double effects that in AT1 receptor blocking and body, NO function strengthens, more effective result for the treatment of can be had to hypertension, to the treatment of other cardiovascular disordeies, there is potential value simultaneously.
Ligustrazine (Ligustrazine, Lig) is one of main chemical compositions in samphire Ligusticum wallichii and zingiberaceous plant Curcuma wenyujin rhizome and euphorbia plant ventilation manioca stem.Pharmacological research proves, Ligustrazine has effects such as improving microcirculation, vasodilation, increase artery blood flow, anticoagulant and reduction biologically active pdgf, has significant curative effect to cardiovascular disorder.Be widely used in the disease treatments such as cerebral apoplexy, asthma, pulmonary emphysema, pulmonary heart disease, chronic respiratory failure, adult respiratory distress syndrome clinically.Its mechanism of action mainly contains scavenging free radicals, anti peroxidation of lipid, protection Coronary endothelium, promotes the expression of myocardial cell energy metabolism, anti-fibrosis, modulating apoptosis genes involved c-fos and bc1-2, Green Tea Extract damage, affect cytokine, calcium antagonism, anti-myocardial anoxia-reoxygenation injury, antiangiotensin II cause myocardial hypertrophy (blocking-up AT1 acceptor), vasodilation, platelet aggregation-against and thrombosis etc.Exploitation Ligustrazine class AT1 receptor blocking agent; both AT1 receptor blocking agent hypertension curative effect can effectively have been strengthened; also can reach the available protecting effect to liver kidney, to other cardiovascular disordeies, also there is potential therapeutic potential simultaneously, in prior art, there is not yet relevant report.
Summary of the invention
For the deficiencies in the prior art; a series of benzoglyoxaline has been the object of the present invention is to provide to spread out class biology; comprise Ligustrazine and NO donor analog derivative; this compounds discharges rapidly Ligustrazine or NO in vivo; thus occur effectively to act synergistically with Azilsartan; strengthen hypertension curative effect, reduce untoward reaction, to patient liver kidney, there is comparatively ideal provide protection.
In order to realize object of the present invention, the technical scheme that the present invention takes is as follows:
Benzimidizole derivatives shown in general formula I and pharmacy acceptable salt, solvate or polymorphic form.
It is characterized in that, R representative in general formula I
or
wherein, a=0,1,2,3,4,5 or 6;
Further, R
1represent C
2-C
8alkyl, C
2-C
8alkylene, C
2-C
8alkynes base,
(CH
2)
no (CH
2)
m,
phenyl, substituted-phenyl, fragrant heterocycle or replacement virtue heterocycle, wherein, b, c=0,1,2,3,4,5 or 6; N, m=1,2,3,4,5 or 6;
Further, R
2represent hydrogen, halogen, trifluoromethyl, C
1-C
8alkoxyl group, C
1-C
8alkyl, nitro, sulfoamido, amino or itrile group;
Further, R
3represent C
1-C
8alkoxyl group, C
2-C
8olefin oxy, C
2-C
8alkynes-oxyl, (C
1-C
6) O (C
1-C
6),
phenyl, substituted-phenyl, fragrant heterocycle or replacement virtue heterocycle, wherein, b, c=0,1,2,3,4,5 or 6;
Further, R
4represent phenyl, substituted-phenyl, benzenesulfonyl, the fragrant heterocycle of 5-6 unit, 5-6 unit replacement fragrant heterocycle, itrile group, trifluoromethyl, C
1-C
8alkoxyl group, C
1-C
8nitric ether or C
1-C
8alkyl;
Further, R
5represent phenyl, substituted-phenyl, the fragrant heterocycle of 5-6 unit, the 5-6 unit's fragrant heterocycle of replacement (preferred Ligustrazine replacement), itrile group, trifluoromethyl, C
1-C
8alkoxyl group, C
1-C
8nitric ether, C
1-C
8alkyl, C
1-C
8alkylene, C
1-C
8alkynes base,
or (CH
2)
no (CH
2)
m, wherein, R
3, R
4, a, n, m definition with described in above;
Further, R
6and R
7represent hydrogen, C
1-C
8alkoxyl group or C
1-C
8alkyl;
Further, R
8and R
9represent hydrogen, C
1-C
8alkoxyl group, C
1-C
8nitric ether or C
1-C
8alkyl;
Described substituted-phenyl refers to and is one or morely selected from hydroxyl, C
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, nitro, amino, itrile group, trifluoromethyl ,-CH=CHCO
2r
11the phenyl replaced, each substituting group may be the same or different, R wherein
11represent hydrogen or C
1-C
6alkyl;
Described fragrant heterocycle refers to that described heteroatoms is selected from O, S or N independently of one another containing 1-4 heteroatomic 5-7 unit aromatic nucleus;
Described replacement virtue heterocycle is for be optionally selected from C by one or more
1-C
6alkyl, C
1-C
6the group of alkoxyl group, halogen replaces, and each substituting group may be the same or different.
Compound representative in general formula I of the present invention is as follows:
QR01002:(sec.-propyl oxo phosphinylidyne oxygen) and methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01003:1-(sec.-propyl oxo phosphinylidyne oxygen) ethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01004: Acetoxvethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01005: pivaloyloxymethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01006:(3,5,6-trimethylpyrazine-2-base) and methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01007:6-(nitroxide ester) six hydrogen base furans [3,2-b] furans-3-base-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01008:4-nitroxide butyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01009:(4-phenyl-1,2,5,-oxadiazole-2-oxide compound-3-) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01010:(4-phenyl-1,2,5,-oxadiazole-2-oxide compound-3-) methoxyphenoxy-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01011:4-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide compound-3-) oxygen-butyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01012:2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzoglyoxaline-7-carboxylic acid-(N-phenyl-N'-hydroxyl guanidine) ester;
QR01013:5-methyl-2-sulfo--1,3 ,-dioxole-4-bases) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01014:(3-methyl-5,6-dioxy-5,6-dihydro-1,4-dioxa-2-) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01015:3-[hydroxyl-oxalic acid ethyl ester]-2-oxo-butyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01016:2-nitroxide ethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01017:(3,5,6-trimethylpyrazine-2-methoxyl group-oxo phosphinylidyne oxygen) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01019:1-(3,5,6-trimethylpyrazine-2-methoxyl group-oxo phosphinylidyne oxygen) ethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01020:(3-methyl isophthalic acid, 2,5-oxadiazole-2-oxide compound-3-methoxyl group-oxo phosphinylidyne oxygen) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01021:1-(3-methyl isophthalic acid, 2,5-oxadiazole-2-oxide compound-3-methoxyl group-oxo phosphinylidyne oxygen) ethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01023:4-(3-methyl isophthalic acid, 2,5-oxadiazole-2-oxide compound) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01025:3-(4-methyl isophthalic acid, 2,5-oxadiazole-2-oxide compound) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01026:4-(the 3-tertiary butyl-1,2,5-oxadiazole-2-oxide compound) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01027:1-(3,5,6-trimethylpyrazine-2-methoxyl group-oxo phosphinylidyne oxygen) isobutyl--2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01028:1-(3,5,6-trimethylpyrazine-2-methoxyl group-oxo phosphinylidyne oxygen) neo-pentyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01029:1-(6-methyl pyridazine-2-methoxyl group-oxo phosphinylidyne oxygen) ethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01030:(isoxzzole-5-methoxyl group-oxo phosphinylidyne oxygen) and methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01031:(1-Methylimidazole-4-methoxyl group-oxo phosphinylidyne oxygen) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01032:(1-methylpyrrole-3-methoxyl group-oxo phosphinylidyne oxygen) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01033:1-(1-methylpyrrole-3-methoxyl group-oxo phosphinylidyne oxygen) ethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01034:4-(3-nitrate-1,2,5-oxadiazole-2-oxide compound) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
QR01035:4-{-2 oxyethyl group-1-[(2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzoglyoxaline-7-carboxylic acid-5,6-dihydro-4H-cyclopentyl [c] [1,2,5] oxadiazole-2 oxide compounds }-1 methyl esters
QR01036:4-(3-itrile group-1,2,5-oxadiazole-2-oxide compound) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
The chemical structural formula that above-claimed cpd QR01002-QR01036 is corresponding is as follows:
Present invention also offers the multiple preparation method of the compound shown in formula I:
(1) Azilsartan and acylation reaction generate mixed acid anhydride in the presence of a base, and this mixed acid anhydride is obtained by reacting Azilsartan with corresponding alcohol in the presence of a base, wherein R
10there is no particular requirement;
(2) Azilsartan and thionyl chloride react generation acyl chlorides in the presence of a catalyst, and this acyl chlorides and corresponding alcohol are obtained by reacting Azilsartan in the presence of a base;
(3) Azilsartan and required alkylating reagent are obtained by reacting Azilsartan in the presence of a base;
(4) Azilsartan and corresponding alcohol carry out esterification and obtain Azilsartan under condensing agent exists;
(5) when R representative
during substituting group, the haloalkyl alcohol that preparation method comprises Azilsartan and different chain length is obtained by reacting ester, then reacts with Silver Nitrate, obtained compound of Formula I; Or under the catalysis of DCC/DMAP, Azilsartan and glycol compound are obtained by reacting ester, then react with nitrosonitric acid, obtained compound of Formula I;
In above-mentioned reaction formula X represent Cl, Br or;
(6) when R representative
during substituting group, preparation method: under the catalysis of DCC/DMAP, Azilsartan and the condensation of N-aryl-N'-hydroxyl guanidine obtain compound of Formula I;
Concrete reactions steps is as follows:
(7) when R representative
time, preparation method: at DCC/DMAP or Et
3n/N-methyl pyrrole under alkane ketone condition, Azilsartan and the condensation of furoxan-based NO donors class (Furoxan) NO donor obtain the compound of general formula I;
Concrete reactions steps is as follows:
(8) R representative in general formula I
its preparation method is as follows:
Compared with prior art, the advantage of technical solution of the present invention and beneficial effect are:
1, the present invention discloses a series of benzimidazoles derivative, mainly comprise and Ligustrazine, nitric oxide donors, (5-methyl-2-sulfo--1,3 ,-dioxole-) methyl alcohol becomes ester and (3-methyl-5,6-dioxy-5,6-dihydro-Isosorbide-5-Nitrae-dioxa-2-) methyl alcohol becomes the derivative of ester.
2, new compound of the present invention enters rapid metabolization after in body is Azilsartan and Ligustrazine or the NO discharging certain level, thus greatly strengthen Azilsartan antihypertensive active.
3, Ligustrazine class AT1 receptor blocking agent, both effectively can strengthen AT1 receptor blocking agent hypertension curative effect, also can reach the available protecting effect of liver kidney.
Accompanying drawing explanation
Fig. 1 is the LCMS spectrogram of the product QR01023 that embodiment 23 prepares, MS+:569.2;
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of the product QR01023 that embodiment 23 prepares.
Embodiment
Applicant will the present invention is described in further detail in conjunction with specific embodiments below; object is to make those skilled in the art more clearly understand the present invention, but following content should not be understood to the restriction of the scope to claims request protection of the present invention by any way.
If do not specialize, the conventional means that technique means used in embodiment is well known to the skilled person.
Embodiment 1
(sec.-propyl oxo phosphinylidyne oxygen) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01002-IN-01 (3.3mmol, 1.5 equivalents) is dissolved in 20mLN-methyl-2-pyrrolidone, add triethylamine (4.4mmol, 2.0 equivalents), be heated to 65 DEG C, TLC monitors reaction, reacts complete.In reaction solution, add water and ethyl acetate, extraction separatory, organic layer is washed, saturated common salt water washing.Organic layer drying is concentrated, and column chromatography purification obtains target compound QR01002, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 2
1-(sec.-propyl oxo phosphinylidyne oxygen) ethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01003-IN-01 (3.3mmol, 1.5 equivalents) is dissolved in 20mLN-methyl-2-pyrrolidone, add triethylamine (4.4mmol, 2.0 equivalents), be heated to 65 DEG C, TLC monitors reaction, reacts complete.In reaction solution, add water and ethyl acetate, extraction separatory, organic layer is washed, saturated common salt water washing.Organic layer drying is concentrated, and column chromatography purification obtains target compound QR01003, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 3
Acetoxvethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01004-IN-03 (3.3mmol, 1.5 equivalents) is dissolved in 20mLN-methyl-2-pyrrolidone, add triethylamine (4.4mmol, 2.0 equivalents), be heated to 65 DEG C, TLC monitors reaction, reacts complete.In reaction solution, add water and ethyl acetate, extraction separatory, organic layer is washed, saturated common salt water washing.Organic layer drying is concentrated, and column chromatography purification obtains target compound QR01004, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 4
Pivaloyloxymethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01005-IN-01 (3.3mmol, 1.5 equivalents) is dissolved in 20mLN-methyl-2-pyrrolidone, add triethylamine (4.4mmol, 2.0 equivalents), be heated to 65 DEG C, TLC monitors reaction, reacts complete.In reaction solution, add water and ethyl acetate, extraction separatory, organic layer is washed, saturated common salt water washing.Organic layer drying is concentrated, and column chromatography purification obtains target compound QR01005, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 5
(3,5,6-trimethylpyrazine-2-base) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
By QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01006-IN-01 (2.6mmol, 1.2 equivalents) be dissolved in 20ml dimethyl formamide, be cooled to 10 DEG C, add salt of wormwood (2.6mmol, 1.2 equivalents), Tosyl chloride (2.6mmol, 1.2 equivalents), catalyzer Dimethylamino pyridine, stirs 3h.React complete, in reaction solution, add water, extraction into ethyl acetate.Organic layer is washed, saturated common salt water washing.Dry concentrated crude product obtains target compound QR01006 through column chromatography purification, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 6
6-(nitroxide ester) six hydrogen base furans [3,2-b] furans-3-base-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
By QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01007-IN-01 (2.6mmol, 1.2 equivalents) be dissolved in 20mL dimethyl formamide, be cooled to 10 DEG C, add salt of wormwood (2.6mmol, 1.2 equivalents), Tosyl chloride (2.6mmol, 1.2 equivalents), catalyzer Dimethylamino pyridine, stirs 3h.React complete, in reaction solution, add water, extraction into ethyl acetate.Organic layer is washed, saturated common salt water washing.Dry concentrated crude product obtains target compound QR01007 through column chromatography purification, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 7
4-nitroxide fourth-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
By QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01008-IN-02 (3.3mmol, 1.5 equivalents) be dissolved in 20mL dimethyl formamide, be cooled to 10 DEG C, add salt of wormwood (2.6mmol, 1.2 equivalents), Tosyl chloride (2.6mmol, 1.2 equivalents), catalyzer Dimethylamino pyridine, stirs 3h.React complete, in reaction solution, add water, extraction into ethyl acetate.Organic layer is washed, saturated common salt water washing.Dry concentrated crude product obtains target compound QR01008 through column chromatography purification, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 8
3-(4-phenyl-1,2,5,-oxadiazole-2-oxide compound-3-) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
By QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01009-IN-02 (2.6mmol, 1.2 equivalents) be dissolved in 20mL dimethyl formamide, be cooled to 10 DEG C, add salt of wormwood (2.6mmol, 1.2 equivalents), Tosyl chloride (2.6mmol, 1.2 equivalents), catalyzer Dimethylamino pyridine, stirs 3h.React complete, in reaction solution, add water, extraction into ethyl acetate.Organic layer is washed, saturated common salt water washing.Dry concentrated crude product obtains target compound QR01009 through column chromatography purification, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 9
3-(4-phenyl-1,2,5,-oxadiazole-2-oxide compound-3-) methoxyphenoxy-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
By QR01000-IN-01 (2.2mmol, 1.0 equivalents) be dissolved in 20mL methylene dichloride with QR01010-IN-02 (2.6mmol, 1.2 equivalents), add dicyclohexylcarbodiimide (4.4mmol, 2.0 equivalents), stirred overnight at room temperature.React complete, in reaction solution, add water, dichloromethane extraction.Organic layer is washed, saturated common salt water washing.Dry concentrated crude product obtains target compound QR01010 through column chromatography purification, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 10
4-(3-benzenesulfonyl-1; 2,5-oxadiazole-2-oxide compound-3-) oxygen-butyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1; 2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
QR01000-IN-01 (2.2mmol, 1.0 equivalents) be dissolved in 20mL methylene dichloride with QR01011-IN-05 (2.6mmol, 1.2 equivalents), add dicyclohexylcarbodiimide (4.4mmol, 2.0 equivalent), catalyzer Dimethylamino pyridine.Stirred overnight at room temperature.React complete, in reaction solution, add water, dichloromethane extraction.Organic layer is washed, saturated common salt water washing.Dry concentrated crude product obtains target compound QR01011 through column chromatography purification, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 11
2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzoglyoxaline-7-carboxylic acid-(N-phenyl-N'-hydroxyl guanidine) ester
QR01000-IN-01 (2.2mmol, 1.0 equivalents) be dissolved in 20mL methylene dichloride with QR01012-IN-03 (2.6mmol, 1.2 equivalents), add dicyclohexylcarbodiimide (4.4mmol, 2.0 equivalent), catalyzer Dimethylamino pyridine.Stirred overnight at room temperature.React complete, in reaction solution, add water, dichloromethane extraction.Organic layer is washed, saturated common salt water washing.Dry concentrated crude product obtains target compound QR01012 through column chromatography purification, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 12
(5-methyl-2-sulfo--1,3 ,-dioxole-4-bases) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
By QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01013-IN-04 (2.6mmol, 1.2 equivalents), be dissolved in 20mL dimethyl formamide, be cooled to 10 DEG C, add salt of wormwood (2.6mmol1.2 equivalent), Tosyl chloride (2.6mmol, 1.2 equivalents), catalyzer Dimethylamino pyridine, stirs 3h.React complete, in reaction solution, add water, extraction into ethyl acetate.Organic layer is washed, saturated common salt water washing.Dry concentrated crude product obtains target compound QR01013 through column chromatography purification, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 13
(3-methyl-5,6-dioxy-5,6-dihydro-1,4-dioxa-2-) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
By QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01014-IN-04 (2.6mmol, 1.2 equivalents), be dissolved in 20mL dimethyl formamide, be cooled to 10 DEG C, add salt of wormwood (2.6mmol, 1.2 equivalents), Tosyl chloride (2.6mmol, 1.2 equivalents), catalyzer Dimethylamino pyridine, stirs 3h.React complete, in reaction solution, add water, extraction into ethyl acetate.Organic layer is washed, saturated common salt water washing.Dry concentrated crude product obtains target compound QR01014 through column chromatography purification, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 14
3-[hydroxyl-oxalic acid ethyl ester]-2-oxo-butyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01015-IN-01 (3.3mmol, 1.5 equivalents) is dissolved in 20mLN-methyl-2-pyrrolidone, add triethylamine (4.4mmol, 2.0 equivalents), be heated to 65 DEG C, TLC monitors reaction, reacts complete.In reaction solution, add water and ethyl acetate, extraction separatory, organic layer is washed, saturated common salt water washing.Organic layer drying is concentrated, and column chromatography purification obtains target compound QR01015, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 15
2-nitroxide ethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
By QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01016-IN-01 (3.3mmol, 1.5 equivalents) be dissolved in 20mL dimethyl formamide, be cooled to 10 DEG C, add salt of wormwood (2.6mmol, 1.2 equivalents), Tosyl chloride (2.6mmol, 1.2 equivalents), catalyzer Dimethylamino pyridine, stirs 3h.React complete, in reaction solution, add water, extraction into ethyl acetate.Organic layer is washed, saturated common salt water washing.Dry concentrated crude product obtains target compound QR01016 through column chromatography purification, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
Embodiment 16
(3,5,6-trimethylpyrazine-2-methoxyl group-oxo phosphinylidyne oxygen) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate:
Step (1): add QR01006-IN-01 (500mg in 50ml there-necked flask, 3.29mmol), methylene dichloride (10mL), chloromethylchloroformate (460mg, 3.6mmol), mixed solution temperature control is at-2 degree, drip pyridine (0.32mL) control temperature and be no more than 3 DEG C, dropwise reaction solution and be warmed up to room temperature for overnight, it is complete that TLC (petrol ether/ethyl acetate=1:3) monitors raw material reaction, reacting liquid filtering, filtrate is spin-dried for, obtain 1.1g yellow oil, prepare plate purifying and obtain 620mg yellow liquid, yield: 77.3%.LCMS and HNMR spectrogram confirms the structure of target compound.
Step (2): add QR01000-IN-01 (0.77g successively in 50mL there-necked flask, 1.69mmol), QR01017-IN-01 (0.62g, 2.54mmol), N-Methyl pyrrolidone (15mL), triethylamine (0.34g, 3.39mmol).Mixed solution stirs 2 hours at 65 DEG C, and TLC point plate (methylene dichloride: methyl alcohol=10:1), reacts completely.
Aftertreatment: poured into by reaction solution in 75mL water, adds 1NHCl adjust ph to 6-7, and solution is white " milky " liquid, and methylate tertbutyl ether extraction (50mL), saturated NaCl washes twice (50mL*2), anhydrous Na
2sO
4drying, is spin-dried for, and obtains 1.2g yellow liquid, and obtain 586mg white gum thing after silica column purification, LCMS and HNMR spectrogram confirms the structure of target compound QR01017.
Embodiment 17
1-(3,5,6-trimethylpyrazine-2-methoxyl group-oxo phosphinylidyne oxygen) ethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
Step (1): add QR01006-IN-01 (500mg in 50ml there-necked flask, 3.29mmol), methylene dichloride (10mL), chloroformic acid 1-chloroethene ester (460mg, 3.6mmol), mixed solution temperature control is at-2 DEG C, drip pyridine (0.32mL) control temperature and be no more than 3 DEG C, dropwise reaction solution and be warmed up to room temperature for overnight, it is complete that TLC (petrol ether/ethyl acetate=1:3) monitors raw material reaction, reacting liquid filtering, and filtrate is spin-dried for, obtain 1.1g yellow oil, prepare plate purifying and obtain 650mg yellow liquid.LCMS and HNMR spectrogram confirms the structure of target compound.
Step (2): add QR01000-IN-01 (0.77g successively in 50mL there-necked flask, 1.69mmol), QR01019-IN-01 (0.62g, 2.4mmol), N-Methyl pyrrolidone (15mL), triethylamine (0.34g, 3.39mmol).Mixed solution stirs 2 hours at 65 DEG C, and TLC point plate (methylene dichloride: methyl alcohol=10:1), reacts completely.
Aftertreatment: poured into by reaction solution in 75mL water, adds 1NHCl adjust ph to 6-7, and solution is white " milky " liquid, and methylate tertbutyl ether extraction (50mL), saturated NaCl washes twice (50mL*2), anhydrous Na
2sO
4drying, is spin-dried for, and obtains 1.2g yellow liquid, and obtain 550mg white gum thing after silica column purification, LCMS and HNMR spectrogram confirms the structure of target compound QR01019.
Embodiment 18
(3-methyl isophthalic acid, 2,5-oxadiazole-2-oxide compound-3-methoxyl group-oxo phosphinylidyne oxygen) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
Concrete operations are with embodiment 16, and by QR01006-IN-01, change to QR01020-IN-01, other are constant;
Concrete operations are with embodiment 16, and by QR01017-IN-01, change to QR01020-IN-02, other are constant;
LCMS and HNMR spectrogram confirms the structure of target compound QR01020.
Embodiment 19
1-(3-methyl isophthalic acid, 2,5-oxadiazole-2-oxide compound-3-methoxyl group-oxo phosphinylidyne oxygen) ethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
Concrete operations are with embodiment 17, and by QR01006-IN-01, change to QR01020-IN-01, other are constant;
Concrete operations are with embodiment 17, and by QR01019-IN-01, change to QR01021-IN-01, other are constant;
LCMS and HNMR spectrogram confirms the structure of target compound QR01021.
Embodiment 20
4-(3-methyl isophthalic acid, 2,5-oxadiazole-2-oxide compound) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
QR01000-IN-01 (1.46g in 100ml single port bottle, 3.2mmol) be dissolved in 25mLN, in dinethylformamide, add (0.5g successively, 3.85mmol) QR01020-IN-003, Tosyl chloride (0.73g, 3.85mmol), salt of wormwood (0.88g, 6.4mmol) and (0.06g) N, N-lutidine amine of catalytic amount, stirring at room temperature reacts 3 hours, point plate (sherwood oil: ethyl acetate=1:3) detects a new point, also has a small amount of raw material QR01020-IN-01 to remain.
Aftertreatment: add 50 ml waters in reaction solution, extraction into ethyl acetate (60ml*3), organic phase 100 milliliters of saturated sodium bicarbonates are washed, 100 milliliters of saturated common salt water washings.Anhydrous sodium sulfate drying, filter, be spin-dried for, obtain 1.9g yellow oily liquid, column chromatography for separation (sherwood oil: ethyl acetate=1.5:1-1:2), obtains 800mg white solid, yield: 44.4%.
LCMS and the HNMR spectrogram of accompanying drawing 1 confirms the structure of target compound QR01023, in LCMS spectrogram, and MS+:569.2.
Embodiment 21
3-(4-methyl isophthalic acid, 2,5-oxadiazole-2-oxide compound) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
Concrete operations are with embodiment 20, and by QR01020-IN-01, change to QR01025-IN-01, other are constant;
LCMS spectrogram and HNMR confirm the structure of target compound QR01025.
Embodiment 22
4-(the 3-tertiary butyl-1,2,5-oxadiazole-2-oxide compound) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
Concrete operations are with embodiment 20, and by QR01020-IN-01, change to QR01026-IN-01, other are constant;
LCMS spectrogram and HNMR confirm the structure of target compound QR01026.
Embodiment 23
1-(3,5,6-trimethylpyrazine-2-methoxyl group-oxo phosphinylidyne oxygen) isobutyl--2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
Concrete operations are with embodiment 16, and by chloromethylchloroformate, change to chloroformic acid 1-chlorine isobutyl ester, other are constant;
Concrete operations are with embodiment 16, and by QR01018-IN-01, change to QR01027-IN-01, other are constant;
LCMS and HNMR spectrogram confirms the structure of target compound QR01027.
Embodiment 24
1-(3,5,6-trimethylpyrazine-2-methoxyl group-oxo phosphinylidyne oxygen) neo-pentyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate;
Concrete operations are with embodiment 16, and by chloromethylchloroformate, change to chloroformic acid 1-chlorine peopentyl ester, other are constant;
Concrete operations are with embodiment 16, and by QR01018-IN-01, change to QR01028-IN-01, other are constant;
LCMS and HNMR spectrogram confirms the structure of target compound QR01028.
Embodiment 25
1-(6-methyl pyridazine-2-methoxyl group-oxo phosphinylidyne oxygen) ethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
Concrete operations are with embodiment 17, and by QR01006-IN-01, change to QR01024-IN-01, other are constant;
Concrete operations are with embodiment 17, and by QR01019-IN-01, change to QR01029-IN-01, other are constant;
LCMS and HNMR spectrogram confirms the structure of target compound QR01029.
Embodiment 26
(isoxzzole-5-methoxyl group-oxo phosphinylidyne oxygen) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
Concrete operations are with embodiment 16, and by QR01006-IN-01, change to QR01030-IN-01, other are constant;
Concrete operations are with embodiment 16, and by QR01017-IN-01, change to QR01030-IN-02, other are constant;
LCMS and HNMR spectrogram confirms the structure of target compound QR01030.
Embodiment 27
(1-Methylimidazole-4-methoxyl group-oxo phosphinylidyne oxygen) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
Concrete operations are with embodiment 16, and by QR01006-IN-01, change to QR01030-IN-01, other are constant;
Concrete operations are with embodiment 16, and by QR01017-IN-01, change to QR01031-IN-01, other are constant;
LCMS and HNMR spectrogram confirms the structure of target compound QR01031.
Embodiment 28
(1-methylpyrrole-3-methoxyl group-oxo phosphinylidyne oxygen) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
Concrete operations are with embodiment 16, and by QR01006-IN-01, change to QR01032-IN-01, other are constant;
Concrete operations are with embodiment 16, and by QR01017-IN-01, change to QR01032-IN-02, other are constant;
LCMS and HNMR spectrogram confirms the structure of target compound QR01032.
Embodiment 29
1-(1-methylpyrrole-3-methoxyl group-oxo phosphinylidyne oxygen) ethyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate
Concrete operations are with embodiment 17, and by QR01006-IN-01, change to QR01032-IN-01, other are constant;
Concrete operations are with embodiment 17, and by QR01019-IN-01, change to QR01033-IN-01, other are constant;
LCMS and HNMR spectrogram confirms the structure of target compound QR01033.
Embodiment 30
(4-nitrate-1,2,5 ,-oxadiazole-2-oxide compounds) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate:
In 100mL single port bottle, QR01019-IN-01 (0.05mol) is dissolved in methylene dichloride (50mL), add the benzoyl peroxide of N-bromo-succinimide (0.06mol) and 5% mol ratio, reflux 5 hours, TLC detects, and raw material disappears;
Aftertreatment: add the cancellation of 50mL saturated sodium bicarbonate solution; Dichloromethane extraction (60mL*3), 100 milliliters of saturated common salt water washings.Anhydrous sodium sulfate drying, filter, be spin-dried for, obtain 6.5g yellow oily liquid, column chromatography for separation, obtains 2.0gQR01034-IN-01.
In 100mL single port bottle, QR01034-IN-01 (0.0048mol) is dissolved in acetonitrile (50mL), adds Silver Nitrate (0.0055mol), reflux 0.5 hour, and TLC detects, and raw material disappears;
Aftertreatment: add 50mL shrend and go out; Dichloromethane extraction (60mL*3), 100 milliliters of saturated common salt water washings.Anhydrous sodium sulfate drying, filter, be spin-dried for, obtain 0.9g yellow oily liquid, column chromatography for separation, obtains 630mgQR01034-IN-02.
QR01000-IN-01 (2.2mmol, 1.0 equivalents) be dissolved in 20mL methylene dichloride with QR01034-IN-02 (2.6mmol, 1.2 equivalents), add dicyclohexylcarbodiimide (4.4mmol, 2.0 equivalent), catalyzer Dimethylamino pyridine.Stirred overnight at room temperature.React complete, in reaction solution, add water, dichloromethane extraction.Organic layer is washed, saturated common salt water washing.Dry concentrated crude product obtains target compound QR01034 through column chromatography purification, and its structure is confirmed through LCMS and HNMR spectrogram.
Embodiment 31
4-{-2 oxyethyl group-1-[(2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl }-1H-benzoglyoxaline-7-carboxylic acid-5, the synthesis of 6-dihydro-4H-cyclopentyl [c] { [1,2,5] oxadiazole-2 oxide compounds }-1 methyl esters:
In 100ml there-necked flask, add QR01035-IN-01 (0.071mol), 10ml acetic acid, slowly drips NaNO
2saturated solution (0.25mol is dissolved in 21mL water), control temperature is no more than 20 DEG C, TLC point plate, and have two new dot generation (PE:EA=1:1), raw material reaction is complete.Aftertreatment: add 50mL water in reaction solution, adds dichloromethane extraction (100mL*3), and organic phase merges washing (100mL), anhydrous Na
2sO
4drying, is spin-dried for, and obtains 7.2g yellow oil, yield: 78.8%.
In 100ml there-necked flask, QR01035-IN-02 (0.023mol) is dissolved in 10mLMeOH, and temperature control, to-10 DEG C, slowly adds NaBH
4(0.047mol) solid, control temperature is no more than 10 DEG C, adds NaBH
4solid, reaction solution is warming up to 10 DEG C of reactions 2 hours, TLC point plate, and raw material reaction completely (sherwood oil: ethyl acetate=1:1).Aftertreatment: reaction solution temperature control slowly drips 40mL water at 0 DEG C, control temperature is no more than 10 DEG C, adds, extraction into ethyl acetate (100mL*2), and organic phase merges anhydrous sodium sulfate drying, is spin-dried for, obtains 2.2g yellow liquid, yield: 72.2%.
By QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01035-IN-03 (2.6mmol, 1.2 equivalents) be dissolved in 20ml dimethyl formamide, be cooled to 10 DEG C, add salt of wormwood (2.6mmol, 1.2 equivalents), Tosyl chloride (2.6mmol, 1.2 equivalents), catalyzer Dimethylamino pyridine, stirs 3h.React complete, in reaction solution, add water, extraction into ethyl acetate.Organic layer is washed, saturated common salt water washing.Dry concentrated crude product obtains target compound QR01035 through column chromatography purification, and its structure is confirmed through LCMS and HNMR spectrogram.
Embodiment 32
(4-itrile group-1,2,5-oxadiazole-2-oxide compound) methyl-2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole)-3-base) biphenyl-4-base] methyl } synthesis of-1H-benzimidazole-7-carboxylate:
QR01000-IN-01 (2.2mmol, 1.0 equivalents) and QR01036-IN-01 (3.3mmol, 1.5 equivalents) is dissolved in 20mLN-methyl-2-pyrrolidone, add triethylamine (4.4mmol, 2.0 equivalents), be heated to 65 DEG C, TLC monitors reaction, reacts complete.In reaction solution, add water and ethyl acetate, extraction separatory, organic layer is washed, saturated common salt water washing.Organic layer drying is concentrated, and column chromatography purification obtains target compound QR01036, and its structure obtains dual confirmation through LCMS spectrogram and hydrogen nuclear magnetic resonance spectrogram.
(the preparation reference MedicinalChemistryResearch of remarks: QR01036-IN-01,11 (6), 322-332; 2002)
The pharmacological effect research of general formula compound of the present invention (embodiment 1-32 obtains product QR01002-QR01036)
1. oral benzimidazole derivative single-dose is to the hypotensive effect of renal hypertensive rat
Wistar rat (is provided by Disease Prevention Control Center, Hubei Prov, Wuhan, Hubei), male, body weight, 180-200g, be divided into 5 groups at random, negative control group (0.5%CMC-Na), positive controls (take Azilsartan as positive drug, open pharmaceutical chemistry portion of auspicious medicine company optical valley biological city research and development centre synthesize by Wuhan) and test-compound QR01002-QR01036 are low, in, high three dosage group (0.5,1.0,2.0mg/kg, all medicines are all formulated in 0.5%CMC-Na), often organize 6-8 animal.The ligation side Renal artery, form Two-kidney One-clip type renal hypertensive rat (RHR) model, Post operation measures weekly a blood pressure, continuous surrounding, and the rat that blood pressure stabilization raises 4kPa is the successful rat of modeling.Before measuring blood pressure, the rat circulator bath tail cover of 39 DEG C is heated to mouse tail, after tail veins is expanded, overlap method (BP2010A non-invasive blood pressure instrument, Ji'an, Beijing get Er Science and Technology Ltd. with tail, No. one, ShangDi, Haidian District, BeiJing City ten street) measure rat administration before, after gastric infusion 1,3,5,7,10 and the blood pressure of 10h and heart rate, each time point is surveyed three times and is averaged.Pressure value X100% before maximum hypotensive value/administration after maximum hypotensive activity (%)=administration.
Table 1. oral benzimidazole derivative QR01002-QR01036 and positive drug are to the hypotensive effect of renal hypertensive rat
Conclusion: in ligation Renal artery Hypertension Rats animal model, the hypotensive activity of the equal showed different of all test compounds prepared by the present invention, wherein QR-01005, QR-01009, QR-01017, QR01019, QR01020, the hypotensive activity intensity of QR01023, QR01034 and QR01036 is obviously better than positive drug Azilsartan, the hypotensive activity time length and Azilsartan fat close.After administration 24 hours, the hypotensive effect of positive drug Azilsartan fat is 20%, QR-01005 is 21%, QR01009 be 25%, QR01017 is 20%, QR01019 is 26%, QR01020 is 15%, QR01023 be 18%, QR01034 is 25%, QR01036 is 24%, and hypotensive effect and Azilsartan fat are close.Other compounds, the maximum blood pressure lowering effect as QR01003, QR01008, QR01011, QR01021, QR01032 and QR01035 is close with Azilsartan fat.All test compounds prepared by the present invention all have certain reducing effect to ligation Renal artery rat heart rate, show except significant hypotensive activity, this compounds still have to a certain degree heart rate function is fallen.
2. oral benzimidazole derivative multiple dosing is to the hypotensive effect of spontaneous hypertensive rat (SHR)
Male SHR (Beijing Vital River Experimental Animals Technology Co., Ltd., Beijing), 40 week age, body weight 250-300 gram, be divided into 5 groups at random, negative control group (0.5%CMC-Na), positive controls (Azilsartan, open the pharmaceutical chemistry portion synthesis of auspicious medicine company optical valley biological city research and development centre by Wuhan to provide, be formulated in 0.5%CMC-Na), test-compound is low, in, high three dosage groups (all compounds are all formulated in 0.5%CMC-Na), often organize 4-5 animal, every day is administered once, successive administration 14 days, each administration measured blood pressure and heart rate after 1 hour.Before measuring blood pressure, the rat circulator bath tail cover of 39 DEG C is heated to mouse tail, after tail veins is expanded, method (BP2010A non-invasive blood pressure instrument is overlapped with tail, Ji'an, Beijing get Er Science and Technology Ltd., No. one, ShangDi, Haidian District, BeiJing City ten street) measure rat administration before, blood pressure after gastric infusion and heart rate, each time point is surveyed three times and is averaged.Pressure value X100% before maximum hypotensive value/administration after maximum hypotensive activity (%)=administration.
Table 2. oral benzimidazole derivative is to the hypotensive effect of spontaneous hypertensive rat (SHR)
Conclusion: in spontaneous hypertensive rat (SHR) animal model, all test compounds prepared by the present invention all show stronger hypotensive activity, wherein QR01005, QR01009, QR01017, QR01019, QR01021, the action intensity of QR01023, QR01034, QR01036 is obviously better than Azilsartan.After long term administration, the hypotensive activity of compound is stablized, and animal state is all better than Azilsartan administration group.The hypotensive activity intensity of other compound is suitable with Azilsartan fat.In whole administration process, compound Q R01005 prepared by the present invention, QR01009, QR01017, QR01019, QR01020, QR01021, QR01023, QR01034, QR01036 all shows reducing effect to a certain degree to SHR rat heart rate, shows that this compounds is except significant hypotensive effect, still has better effect of falling heart rate.
3. oral benzimidazole derivative single-dose is on the impact of normal rat blood pressure
Wistar rat (is provided by Disease Prevention Control Center, Hubei Prov, Wuhan, Hubei), male, body weight, 200-250g, is divided into 5 groups at random, and negative control group (0.5%CMC-Na), positive controls (take Azilsartan as positive drug, open pharmaceutical chemistry portion of auspicious medicine company optical valley biological city research and development centre by Wuhan to synthesize) and test-compound QR01002-QR01036 low, in, high three dosage groups (0.5,1.0,2.0mg/kg, p.o., all medicines are all formulated in 0.5%CMC-Na), often organize 8-10 animal.Before measuring blood pressure, the rat circulator bath tail cover of 39 DEG C is heated to mouse tail, after tail veins is expanded, overlap method (BP2010A non-invasive blood pressure instrument, Ji'an, Beijing get Er Science and Technology Ltd. with tail, No. one, ShangDi, Haidian District, BeiJing City ten street) measure rat administration before, after gastric infusion 0.5,1,2,4, the blood pressure of 8h and heart rate, each time point is surveyed three times and is averaged.
Result and conclusion: three dosage (0.5 of all test-compounds prepared by the present invention, 1.0 and 2.0mg/kg, p.o., be formulated in 0.5%CMC-Na) to normal rat blood pressure and heart rate all without remarkable effect, show that this compounds aligns normal blood pressure and heart rate does not make significant difference.
Claims (6)
1. the compound shown in general formula I:
It is characterized in that, described structural formula of compound is:
2. the compound shown in general formula I of claim 1 pharmaceutically acceptable salt, solvate or polymorphic form.
3. the preparation method of the compound shown in a general formula I according to claim 1: described R representative
under the existence of organic bases or mineral alkali, elder generation and R
5oH is obtained by reacting an intermediate, then with Azilsartan condensation and get final product.
4., the purposes of falling in the medicine of heart rate, treatment and prevention other cardiovascular diseases hypotensive in preparation of the compound shown in general formula I according to claim 1.
5. pharmaceutically acceptable salt, solvate or polymorphic form, the purposes of falling in the medicine of heart rate, treatment and prevention other cardiovascular diseases hypotensive in preparation of the compound shown in general formula I according to claim 2.
6. the compound shown in general formula I that obtains of preparation method according to claim 3, the purposes of falling in the medicine of heart rate, treatment and prevention other cardiovascular diseases hypotensive in preparation.
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| CN107400122A (en) * | 2016-05-20 | 2017-11-28 | 武汉朗来科技发展有限公司 | Compound and preparation method thereof, composition and application |
| WO2018010622A1 (en) * | 2016-07-11 | 2018-01-18 | 武汉朗来科技发展有限公司 | Crystalline form of chemical compound, and preparation method, composition, and application thereof |
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| CN103709154B (en) * | 2012-09-28 | 2016-06-15 | 武汉朗来科技发展有限公司 | Benzimidizole derivatives and preparation method thereof and medical usage |
| CN105622595A (en) * | 2014-11-21 | 2016-06-01 | 重庆朗天制药有限公司 | Novel preparation method of azilsartan medoxomil sylvite and its intermediate |
| US9708306B2 (en) | 2015-03-18 | 2017-07-18 | Wuhan Ll Science And Technology Development Co., Ltd | Benzimidazole derivatives and preparation process and pharmaceutical uses thereof |
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| CN110237071B (en) | 2018-03-09 | 2022-03-22 | 武汉朗来科技发展有限公司 | Pharmaceutical preparation and use thereof |
| CN110237072B (en) * | 2018-03-09 | 2022-03-25 | 武汉朗来科技发展有限公司 | Process for preparing pharmaceutical composition |
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