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CN106032378B - New A RB compound and application thereof - Google Patents

New A RB compound and application thereof Download PDF

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Publication number
CN106032378B
CN106032378B CN201510124540.5A CN201510124540A CN106032378B CN 106032378 B CN106032378 B CN 106032378B CN 201510124540 A CN201510124540 A CN 201510124540A CN 106032378 B CN106032378 B CN 106032378B
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base
methyl
carboxylic acid
oxo
oxadiazoles
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CN106032378A (en
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马建义
葛建
徐传瑞
王朝东
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Wuhan QR Pharmaceuticals Co Ltd
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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
    • C07D413/14—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
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D413/12—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 chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention belongs to field of pharmaceutical chemistry technology, specifically disclose a kind of novel hypertension II acceptor inhibitor and its medical usage with good pharmaceutical activity.This kind of compound includes ligustrazine and NO donor analog derivative; ligustrazine or NO can be discharged rapidly out into the human body; both blood pressure lowering curative effect can be played; there is a degree of protective effect to liver kidney again, this kind of drug is suitable for prevention or treatment circulation systemic disease such as hypertension or heart disease such as cardiac hypertrophy, heart failure, cardiac infarction etc..

Description

New A RB compound and application thereof
Technical field
The present invention relates to medical compounds research and development technology fields, and in particular to a kind of new A RB compound and application thereof, it should New A RB compound is the novel hypertension II acceptor inhibitor with good pharmaceutical activity。
Background technique
AngiotensinⅡ (Ang II) is the important regulating and controlling factor that body fluid dynamic equilibrium is adjusted in body, be related to blood pressure, Electrolyte balance etc., lot of documents confirm, Ang II high blood pressure, arterial disease, cardiomegaly, heart failure and diabetes, Main effect is all played in the pathogenesis of nephrosis etc..Since the horizontal aberrant continuation of Ang II increases and hypertension, heart fertilizer The occurrence and development of thickness, heart failure etc. are directly related, therefore,It blocks Ang II in conjunction with the receptor of its specificity, heart and brain can be played The protective effect of blood vessel, Angiotensin Ⅱ receptor antagonist (Angiotensin Receptor Blockers, ARB) are dropping It is confirmed in many randomized clinical trials in terms of low cardiovascular death rate and the benefit of disability rate, ARB drug In the external wide prevention and treatment for high blood pressure and other cardiorenal diseases, the ARB of clinical use can divide according to structure at present For 2 classes: (1) Biphenyltetrazoles, including Losartan (losartan), Valsartan (valsartan), Irbesartan (irbesartan), candesartan Cilexetil (candesartan cilexetil) and Losartan (tasosartan) etc..(2) non- Benzene tetrazole, including Eprosartan (eprosartan) and Telmisartan (telmisartan).
Nitric oxide has extremely important physiological function, packet as messenger substances and effector molecule in the mammalian body Control antiotasis, nerve conduction, hormone secretion, inflammation and immune response etc. are included, furthermore to adjusting 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.
Ligustrazine (Ligustrazine, Lig) is umbelliferae Rhizoma Chuanxiong 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 increases artery blood flow, inhibits the effects of platelet aggregation and reduction biologically active pdgf, has significant curative effect to cardiovascular disease. 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.
Ligustrazine or NO donor chemical structure are coupled on ARB compound by the applicant, form a kind of new A RB chemical combination Object, such compound not only has II receptor active of antagonizing angiotensin compared with compound known in the art, but also has to liver kidney There is a degree of protective effect.
Summary of the invention
For the deficiencies in the prior art, the present invention carries out structural modification to the ARB compound clinically used, repairs Compound after decorations can discharge rapidly out ligustrazine or NO in vivo, to occur effectively rush to be cooperateed with to inhale with former ARB compound Adduction not only increases anti-hypertension curative effect, also has certain preventive and therapeutic effect to dyslipidemia and diabetic complication.
A kind of ARB compound provided by the invention, general formula are as follows: Ar-CH2-X
Wherein, X is represented
Wherein, L is singly-bound or-O-；R0It is C1-6Alkyl replaces alkyl or 3 to 6 yuan of naphthenic base；
R1aRepresentative-CH2OC (=O) OR1aa、-CH(C1-4Alkyl) OC (=O) OR1aa、
Wherein, R1aaIt represents
Wherein, R6Represent phenyl, substituted-phenyl, heteroaromatic, replace heteroaromatic, benzenesulfonyl, itrile group, trifluoromethyl ,- C1-4Alkylene nitrate or-C1-4Alkyl；
Wherein, R2And R3It is identical or different, and respectively represent hydrogen, C1-6Alkyl or phenyl；
Wherein, Y1It is C2-7 alkylidenes or Y1For by alkyl, hydroxyl, carboxyl, amido, guanidine radicals ,-C3-6Naphthenic base or phenyl Substituted alkylidene, or be-(CH2)p-(CY3R4)q-(CH2) r-, wherein when p is 0 or 1, r is 0 or 1, q 1；When p is When 2-8, q and r are respectively 0；
Wherein, R4Represent hydrogen or C1-6Alkyl；
Y2For C=O, O=S=O or-O-C (=O)-, wherein the carbon atom for being connected with carbonyl in-O-C (=O)-is connected toIn nitrogen-atoms；
Y3It is C1-4 alkyl, phenyl, or by hydroxyl, C1-4Alkyl, C3-6The C that naphthenic base, phenyl, imidazole radicals replace1-4Alkane Base, or the phenyl replaced by hydroxyl, 3 to 6 yuan of naphthenic base, phenyl, imidazole radicals；
Ar is selected from following aryl:
Wherein, R1For-COORa、-SO2NHR1c、-SO2OH、-O-CH(R2)-COOH, tetrazole radical -5- base,
Wherein, RaRepresent hydrogen, morpholine ,-C1-6Alkyl ,-C1-3Alkylene aryl ,-C1-3Alkylene heteroaryl ,-C3-6Cycloalkanes Base ,-CH (C1-4Alkyl) OC (=O) R1b、-C1-6Alkylene morpholine ,-CH2OC (=O) OR1b、-CH(C1-6 alkyl) OC (=O) OR1b、-CH(C1-6 alkoxies) OC (=O) OR1b or
Wherein, R1bIt is C1-4 alkyl replace alkyl, phenyl, substituted-phenyl, heteroaromatic, virtue substituted on carbon atom Heterocycle, itrile group, trifluoromethyl, C1-6Alkoxy ,-C1-6Alkylene nitrate, C1-6Alkyl, C2-6Alkylene, C2-6Alkynes base ,-O- C1-6Alkyl, C3-6Naphthenic base, NR1abR1acOr-CH (NH2)CH2COOCH3；
Wherein R1abAnd R1acRespectively represent hydrogen, C1-6Alkyl or benzyl or R1abR1acFor C3-6Naphthenic base；
R1cRepresent hydrogen, aryl ,-C1-6Alkyl, C2-6Alkylene-OH, C0-6Alkylene-O-C1-6Alkyl, C0-6Alkylene-O- C1-6Alkyl ,-C1-5Alkylene-NR1cdR1cc、-C1-4Alkylene aryl ,-CHO ,-C (=O) C1-6Alkyl ,-C (=O) NH2Or-C (=O) NH-C1-6Alkyl, wherein R1cdAnd R1ccRespectively represent hydrogen and-C1-6Alkyl, or it is combined into-(CH together2)2-O-(CH2)2- Or-(CH2)2- N [C (=O) CH3]-(CH2)2-；
The substitution alkyl refers to one or more selected from hydroxyl, C1-6Alkyl, C1-6Alkoxy, halogen, nitro, ammonia The alkyl that base, itrile group, trifluoromethyl replace, each substituent group may be the same or different；
The substituted-phenyl refers to one or more selected from hydroxyl, C1-6Alkyl, C1-6Alkoxy, halogen, nitro, ammonia The phenyl that base, itrile group, trifluoromethyl replace, each substituent group may be the same or different；
The heteroaromatic refers to containing 1-4 heteroatomic 5-7 member aromatic rings, the hetero atom be each independently selected from O, S or N；
The heteroaromatic substituted on carbon atom is optionally to be selected from C by one or more1-6Alkyl, C1-6Alcoxyl The heteroaromatic of the group substitution of base, halogen, each substituent group may be the same or different.
General formula Ar-CH of the invention2Representative compound is as follows in-X:
QR1009:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic Sour (phenyl -1,2,5 4-,-oxadiazoles -2- oxo -3- base) methyl esters
QR1017:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic Sour (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen) methyl esters
QR1019:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic Sour [1- (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester
QR1020:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic Sour (3- methyl-1,2,5- oxadiazoles -2- oxo -4- methoxyl group-oxo phosphinylidyne oxygen) methyl esters
QR1021:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic Sour [1- (3- methyl-1,2,5- oxadiazoles -2- oxide -4- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester
QR1023:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic Sour (3- methyl-1,2,5- oxadiazoles -2- oxide -4- base) methyl esters
QR1034:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic Sour (3- nitrate -1,2,5- oxadiazoles -2- oxo -4- base) methyl esters
QR1036:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic Sour (3- itrile group -1,2,5- oxadiazoles -2- oxo -4- base) methyl esters
QR2009:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] imidazoles - 5- carboxylic acid (phenyl -1,2,5 4-,-oxadiazoles -2- oxo -3-) methyl esters
QR2017:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] imidazoles - 5- carboxylic acid (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen) methyl esters
QR2019:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] imidazoles - 5- carboxylic acid [1- (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester
QR2020:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] imidazoles - 5- carboxylic acid (3- methyl-1,2,5- oxadiazoles -2- oxo -4- methoxyl group-oxo phosphinylidyne oxygen) methyl esters
QR2021:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] imidazoles - 5- carboxylic acid [1- (3- methyl-1,2,5- oxadiazoles -2- oxide -4- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester
QR2034:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] imidazoles - 5- carboxylic acid (3- nitrate -1,2,5- oxadiazoles -2- oxo -4- base) methyl esters
{ [(5- oxo -4,5- dihydro -1,2,4- is disliked 2- 4- QR2109:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- Diazole -3)-phenyl] benzyl } imidazole-5-carboxylic acid (phenyl -1,2,5 4-,-oxadiazoles -2- oxo -3-) methyl esters
{ [(5- oxo -4,5- dihydro -1,2,4- is disliked 2- 4- QR2117:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- Diazole -3)-phenyl] benzyl } imidazole-5-carboxylic acid (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen) methyl esters
{ [(5- oxo -4,5- dihydro -1,2,4- is disliked 2- 4- QR2119:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- Diazole -3)-phenyl] benzyl } imidazole-5-carboxylic acid (phenyl -1,2,5 4-,-oxadiazoles -2- oxo -3-) methyl esters
{ [(5- oxo -4,5- dihydro -1,2,4- is disliked 2- 4- QR2120:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- Diazole -3)-phenyl] benzyl } imidazole-5-carboxylic acid (3- methyl-1,2,5- oxadiazoles -2- oxo -4- methoxyl group-oxo phosphinylidyne oxygen) Methyl esters
{ [(5- oxo -4,5- dihydro -1,2,4- is disliked 2- 4- QR2121:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- Diazole -3)-phenyl] benzyl } imidazole-5-carboxylic acid [1- (3- methyl-1,2,5- oxadiazoles -2- oxide -4- methoxyl group-oxo carbon Acyl-oxygen)] ethyl ester
{ [(5- oxo -4,5- dihydro -1,2,4- is disliked 2- 4- QR2123:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- Diazole -3)-phenyl] benzyl } imidazole-5-carboxylic acid (3- methyl-1,2,5- oxadiazoles -2- oxo -4- base) methyl esters
{ [(5- oxo -4,5- dihydro -1,2,4- is disliked 2- 4- QR2136:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- Diazole -3)-phenyl] benzyl } imidazole-5-carboxylic acid (3- itrile group -1,2,5- oxadiazoles -2- oxo -4- base) methyl esters
QR3009:N- [1- carboxylic acid (phenyl -1,2,5 4-,-oxadiazoles -2- oxo -3- base) methyl esters -2- methyl-propyl -1- Base]-N- valeryl-N- [2'- (1H-TETRAZOLE -5- base)-biphenyl -4- base-methyl]-amine
QR3017:N- [1- carboxylic acid (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen) methyl esters -2- methyl-prop Base -1- base]-N- valeryl-N- [2'- (1H-TETRAZOLE -5- base)-biphenyl -4- base-methyl]-amine
QR3019:N- { 1- carboxylic acid [1- (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester -2- methyl Propyl -1- base }-N- valeryl-N- [2'- (1H-TETRAZOLE -5- base)-biphenyl -4- base-methyl]-amine
QR3020:N- [1- carboxylic acid (3- methyl-1,2,5- oxadiazoles -2- oxo -4- methoxyl group-oxo phosphinylidyne oxygen) methyl esters - 2- methyl-propyl -1- base]-N- valeryl-N- [2'- (1H-TETRAZOLE -5- base)-biphenyl -4- base-methyl]-amine
QR3021:N- { 1- carboxylic acid [1- (3- methyl-1,2,5- oxadiazoles -2- oxide -4- methoxyl group-oxo phosphinylidyne Oxygen)] ethyl ester -2- methyl-propyl -1- base }-N- valeryl-N- [2'- (1H-TETRAZOLE -5- base)-biphenyl -4- base-methyl]-amine
QR3034:N- [1- carboxylic acid (3- nitrate -1,2,5- oxadiazoles -2- oxo -4- base) methyl esters -2- methyl-propyl - 1- yl]-N- valeryl-N- [2'- (1H-TETRAZOLE -5- base)-biphenyl -4- base-methyl]-amine
QR3109:N- [1- carboxylic acid (phenyl -1,2,5 4-,-oxadiazoles -2- oxo -3- base) methyl esters -2- methyl-propyl -1- Base]-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-methyl]-amine
QR3117:N- [1- carboxylic acid (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen) methyl esters -2- methyl-prop Base -1- base]-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-methyl] - Amine
QR3119:N- { 1- carboxylic acid [1- (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester -2- methyl Propyl -1- base }-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-first Base]-amine
QR3120:N- [1- carboxylic acid (3- methyl-1,2,5- oxadiazoles -2- oxo -4- methoxyl group-oxo phosphinylidyne oxygen) methyl esters - 2- methyl-propyl -1- base]-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- Base-methyl]-amine
QR3121:N- { 1- carboxylic acid [1- (3- methyl-1,2,5- oxadiazoles -2- oxide -4- methoxyl group-oxo phosphinylidyne Oxygen)] ethyl ester -2- methyl-propyl -1- base }-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base) - Biphenyl -4- base-methyl]-amine
QR3123:N- [1- carboxylic acid (3- methyl-1,2,5- oxadiazoles -2- oxo -4- base) methyl esters -2- methyl-propyl -1- Base]-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-methyl]-amine
QR3134:N- [1- carboxylic acid (3- nitrate -1,2,5- oxadiazoles -2- oxo -4- base) methyl esters -2- methyl-propyl - 1- yl]-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-methyl]-amine
The corresponding chemical structural formula of above compound is as follows:
Compound or pharmaceutically acceptable salt thereof provided by the present invention can be used for treating needs selectivity excitement AT2The disease of receptor Disease.
Pharmaceutical preparation made of the compounds of this invention and its salt can be used for treating hypertension, heart failure, chronic stable Angina pectoris, vasospastic, apoplexy, myocardial infarction, transient ischemic attack, cardiovascular disease, atherosclerosis, Diabetes, the disease of insulin resistance, glucose tolerance reduction, pre-diabetes, diabetes B, diabetic nephropathy, metabolism Syndrome (syndrome X), obesity, dyslipidemia, hypertriglyceridemia, Serum Apoprotein concentration is higher, serum is low Density lipoprotein-cholesterol concentration is higher, serum lipoprotein associated phospholipase concentration is higher, serum High Density Lipoprotein Cholesterol Concentration is relatively low, serum hdl (2b) cholesterol concentration is relatively low, serum adiponectin concentration is relatively low.
Another aspect of the present invention provides the pharmaceutical preparation containing the compounds of this invention or its officinal salt, and the preparation can To be dispersible tablet, Liposomal formulation or sustained release preparation, wherein dispersible tablet includes lactose, microcrystalline cellulose, low substituted hydroxy-propyl fibre Tie up element, crospovidone, PVP K30, superfine silica gel powder, magnesium stearate and/or aspartame；Liposomal formulation includes phosphatidyl Choline, cholesterol, NaGC and/or sojasterol；Sustained release preparation includes carbomer and/or Compritol 888 ATO.
Compared with prior art, it is the advantages of technical solution of the present invention with beneficial effect:
New A RB compound provided by the present invention not only has as angiotensin receptor antagonist structure novel Good hypotensive activity, and bioavilability is high, is suitable for prevention or treatment circulation systemic disease such as hypertension, heart Sick (cardiac hypertrophy, heart failure, cardiac infarction etc.) and metabolic disease such as diabetic complication and dyslipidemia etc..
Specific 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 Field technical staff more clearly understands the present invention, but the following contents should not be construed in any way to want the application right Ask the limitation of the claimed range of book.
Unless otherwise specified, the conventional hand that technological means used in embodiment is well known to the skilled person Section.
Embodiment 1: the preparation of each compound, such as following (1)-(34) Xiang Suoshu
(1) QR1009:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole - The synthesis of 7- carboxylic acid (phenyl -1,2,5 4-,-oxadiazoles -2- oxo -3- base) methyl esters
10.0g cinnamyl alcohol and 10ml glacial acetic acid are added into 50ml there-necked flask, is cooled to 0 DEG C after stirring and dissolving,It will 15.50g (3eq) sodium nitrite is dissolved in wiring solution-forming in 20g water, and the water-soluble of sodium nitrite is added dropwise between 0 DEG C to 5 DEG C in temperature control Liquid is added dropwise, and after 0 DEG C of stirring 5min, is warming up to room temperature reaction 12h.Stop reaction, 50ml water, ethyl acetate extraction is added (40ml*2), merges organic phase, and saturated common salt washing is primary,Anhydrous sodium sulfate is dry, is spin-dried for, obtains 20.0g crude product；Crude product is used 10.0g acidic alumina is added in the dissolution of 40ml acetonitrile, and 60 DEG C are stirred at reflux reaction 3h, and solvent is spin-dried for, solid 100ml acetic acid Ethyl ester dissolution, filters, and solid is washed (50ml*2) with ethyl acetate, and it is 8- that filtrate, which is washed till pH value with dilute sodium hydroxide (5%-10%), 9, primary (50ml) is extracted with ethyl acetate in liquid separation, water phase again, merges organic phase, saturated common salt washing,Anhydrous sodium sulfate is dry, It is spin-dried for.Silica gel post separation (petroleum ether: ethyl acetate=7:1-3:1) obtains 2- oxo -3- hydroxymethyl -4- phenyl -1,2, 5 ,-oxadiazoles sterling 5.0g, yield 35.0%.
By 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic acid (2.2mmol, 1.0 equivalents) and phenyl -1,2,5 2- oxo -3- hydroxymethyl -4-,-oxadiazoles (2.6mmol, 1.2 equivalents) are molten Solution is cooled to 10 DEG C in 20mL dimethylformamide, is added potassium carbonate (2.6mmol, 1.2 equivalents), paratoluensulfonyl chloride (2.6mmol, 1.2 equivalents), catalyst dimethylamino naphthyridine,Stir 3h.Water and acetic acid second are added into reaction solution for end of reaction Ester extraction.Organic layer is successively washed, saturated common salt water washing.Dry concentration crude product obtains target compound through column chromatographic purifying, Its structure is confirmed through hydrogen nuclear magnetic resonance spectrogram.H-NMR(CDCl3, 400MHz) and δ: 7.88-7.90 (1H, m), 7.76-7.79 (2H, M), 7.46-7.59 (4H, m), 7.30 (2H, m), 7.08-7.17 (4H, m), 5.63 (2H, s), 5.14 (2H, d), 4.25 (2H, Q), 1.48 (3H, t).
Compound 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic Acid can refer to the preparation of method described in CN1055927 patent document.
(2) QR1017:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole - The synthesis of 7- carboxylic acid (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen) methyl esters
Step (1): addition 2- methylol -3,5 in 50ml there-necked flask, 6- trimethylpyrazine (500mg, 3.29mmol), Methylene chloride (10mL), chloro-methyl-chloroformate (460mg, 3.6mmol), mixed liquor temperature control are added dropwise pyridine (0.32mL) at -2 DEG C It controls temperature and 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) raw material fully reacting, reaction solution filtering are monitored, filtrate is spin-dried for, obtains 1.1g yellow oil, prepare plate and purify to obtain 620mg 3,5,6- trimethylpyrazine -2- methoxyl group carbonic acid chloromethyl ester.
Step (2): 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- is sequentially added in 50mL there-necked flask Base] methyl } -1H- benzimidazole -7- carboxylic acid (0.77g, 1.69mmol), 3,5,6- trimethylpyrazine -2- methoxyl group carbonic acid chloromethanes Ester (0.62g, 2.54mmol), N-Methyl pyrrolidone (15mL), triethylamine (0.34g, 3.39mmol).Mixed liquor is at 65 DEG C Stirring 2 hours, TLC contact plate (methylene chloride:Methanol=10:1), fully reacting.
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 Na2SO4It is dry, it is spin-dried for, obtains 1.2g yellow Liquid, silicagel column obtain 586mg white object compound after purification, and structure is confirmed through hydrogen nuclear magnetic resonance spectrogram.H-NMR (CDCl3, 400MHz) and δ: 7.87-7.90 (1H, m), 7.76-7.80 (2H, m), 7.51-7.62 (4H, m), 7.30 (2H, m), 7.07-7.15 (3H, m), 5.63 (2H, s), 5.12 (2H, d), 4.23 (2H, q), 2.35 (3H, s), 2.25 (6H, s), 1.49 (3H, t).
(3) QR1019:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole - The synthesis of 7- carboxylic acid [1- (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester
Step 1): addition 2- methylol -3,5 in 50ml there-necked flask, 6- trimethylpyrazine (500mg, 3.29mmol), two Chloromethanes (10mL), chloro-carbonic acid 1- chloroethene ester (460mg, 3.6mmol), mixed liquor temperature control are added dropwise pyridine (0.32mL) at -2 DEG C It controls temperature and 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) raw material fully reacting, reaction solution filtering are monitored, filtrate is spin-dried for, obtains 1.1g yellow oil, prepare plate and purify to obtain 650mg 3,5,6- trimethylpyrazine -2- methoxyl group carbonic acid 1- chloroethene ester.
Step 2): 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] is sequentially added in 50mL there-necked flask Methyl } -1H- benzimidazole -7- carboxylic acid (0.77g, 1.69mmol), 3,5,6- trimethylpyrazine -2- methoxyl group carbonic acid 1- chloroethenes Ester (0.62g, 2.4mmol), N-Methyl pyrrolidone (15mL), triethylamine (0.34g, 3.39mmol).Mixed liquor is at 65 DEG C Stirring 2 hours, TLC contact plate (methylene chloride: methanol=10:1), fully reacting.
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 Na2SO4 is dry, is spin-dried for, and obtains 1.2g Huang Color liquid, silicagel column obtain 550mg target compound after purification, and structure is confirmed through hydrogen nuclear magnetic resonance spectrogram.H-NMR (CDCl3, 400MHz) and δ: 7.88-7.90 (1H, m), 7.75-7.78 (2H, m), 7.53-7.61 (4H, m), 7.26 (2H, m), 7.05-7.18 (2H, m), 6.88-6.92 (1H, q), 5.64 (2H, s), 5.14 (2H, d), 4.27 (2H, q), 2.31 (3H, s), 2.23 (6H, s), 1.57-1.60 (3H, d), 1.48 (3H, t).
(4) QR1020:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole - The synthesis of 7- carboxylic acid (3- methyl-1,2,5- oxadiazoles -2- oxo -4- methoxyl group-oxo phosphinylidyne oxygen) methyl esters
For synthetic method with (2) item in embodiment 1, but by raw material 2- methylol -3,5,6- trimethylpyrazine changes 3- into Methyl -2- oxo -4- methylol -1,2,5- oxadiazoles, chloro-carbonic acid 1- chloroethene ester are changed to chloro-methyl-chloroformate, 3- methyl -2- oxygen Generation -4- methylol -1,2, described in (1) the item first segment of 5- oxadiazoles during the preparation method is the same as that of Example 1, but starting material is by meat Cinnamic alcohol changes 2- butenol into；
3- methyl -2- oxo -4- methylol -1,2,5- oxadiazoles and chloro-methyl-chloroformate generate 3- methyl-1, and 2,5- is disliked Diazole -2- oxo -4- methoxyl group carbonic acid chloromethyl ester, product again with 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- Base] methyl } -1H- benzimidazole -7- carboxylic acid reaction obtains target compound, and structure is confirmed through hydrogen nuclear magnetic resonance spectrogram.H-NMR (CDCl3, 400MHz) and δ: 7.90-7.92 (1H, m), 7.74-7.79 (2H, m), 7.55-7.63 (4H, m), 7.23 (2H, m), 7.04-7.20 (3H, m), 5.61 (2H, s), 5.20 (2H, d), 4.23 (2H, q), 2.35 (3H, s), 1.52 (3H, t).
(5) QR1021:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole - The synthesis of 7- carboxylic acid [1- (3- methyl-1,2,5- oxadiazoles -2- oxide -4- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester
For synthetic method with (3) item in embodiment 1, but by raw material 2- methylol -3,5,6- trimethylpyrazine changes 3- into Methyl -2- oxo -4- methylol -1,2,5- oxadiazoles, target compound structure are confirmed through hydrogen nuclear magnetic resonance spectrogram.H-NMR (CDCl3, 400MHz) and δ: 7.89-7.92 (1H, m), 7.73-7.76 (2H, m), 7.57-7.68 (4H, m), 7.24 (2H, m), 7.08-7.14 (2H, m), 6.84-6.89 (1H, q), 5.59 (2H, s), 5.02 (2H, d), 4.27 (2H, q), 2.33 (3H, s), 1.58-1.63 (3H, d), 1.46 (3H, t).
(6) QR1023:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole - The synthesis of 7- carboxylic acid (3- methyl-1,2,5- oxadiazoles -2- oxide -4- base) methyl esters
By 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzene in 100ml single port bottle And imidazoles -7- carboxylic acid (1.46g, 3.2mmol) is dissolved in 25mL n,N-Dimethylformamide, sequentially adds 2- oxo -3- first Base -4- methylol -1,2,5,-oxadiazoles (0.5g, 3.85mmol), paratoluensulfonyl chloride (0.73g, 3.85mmol), potassium carbonate Reaction 3 hours, contact plate (petroleum ether: second is stirred at room temperature in (0.06g) lutidines amine of (0.88g, 6.4mmol) and catalytic amount Acetoacetic ester=1:3) detection.
Post-processing: being added 50 milliliters of water in reaction solution, ethyl acetate extracts (60ml*3), and organic phase successively uses 100 milliliters Saturated sodium bicarbonate is washed, 100 milliliters of saturated common salt water washings.Anhydrous sodium sulfate dries, filters,It is spin-dried for, obtains 1.9g yellow oil Shape liquid, column chromatography for separation (petroleum ether: ethyl acetate=1.5:1-1:2), obtains 800mg white object compound, structure It is confirmed through hydrogen nuclear magnetic resonance spectrogram.H-NMR(CDCl3, 400MHz) and δ: 7.91-7.93 (1H, m), 7.76-7.82 (2H, m), 7.54-7.61 (4H, m), 7.21 (2H, m), 7.06-7.17 (2H, m), 5.64 (2H, d), 5.13 (2H, d), 4.20 (2H, q), 2.39 (3H, s), 1.50 (3H, t).
(7) QR1034:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole - The synthesis of 7- carboxylic acid (3- nitrate -1,2,5- oxadiazoles -2- oxo -4- base) methyl esters
Step 1): by 3- methyl -2- oxo -4- methylol -1,2,5- oxadiazoles (0.05mol) in 100mL single port bottle It is dissolved in methylene chloride (50mL), N- bromo-succinimide (0.06mol) and benzoyl peroxide (2.5mM) is added, adds Heat 5 hours of reflux, TLC detection, raw material disappear；
Post-processing: 50mL saturated sodium bicarbonate solution is added and is quenched；Methylene chloride extracts (60mL*3), 100 milliliters of saturations Brine It.Anhydrous sodium sulfate dries, filters, and is spin-dried for, and obtains 6.5g yellow oily liquid, and column chromatography for separation obtains 2.0g 2- oxo -3- bromomethyl -4- methylol -1,2,5- oxadiazoles.
Step 2): by 2- oxo -3- bromomethyl -4- methylol -1,2,5- oxadiazoles in 100mL single port bottle (0.0048mol) is dissolved in acetonitrile (50mL), is added silver nitrate (0.0055mol), and 0.5 hour, TLC inspection are heated to reflux It surveys, raw material disappears；
Post-processing: 50mL water quenching is added and goes out；Methylene chloride extracts (60mL*3), 100 milliliters of saturated common salt water washings.It is anhydrous Sodium sulphate dries, filters, and is spin-dried for, and obtains 0.9g yellow oily liquid, column chromatography for separation,Obtain 630mg 2- oxo -3- nitric acid Methyl -4- methylol -1,2,5- oxadiazoles.
Step 3): 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic Sour (2.2mmol, 1.0 equivalents) and 2- oxo -3- nitrate -4- methylol -1,2,5- oxadiazoles (2.6mmol, 1.2 equivalents) It is dissolved in 20mL methylene chloride, N, N'- Dicyclohexylcarbodiimide (4.4mmol, 2.0 equivalents), catalyst diformazan ammonia is added Yl pyridines.It is stirred overnight at room temperature.Water, methylene chloride extraction are added into reaction solution for end of reaction.Organic layer is successively washed with water, Saturated common salt water washing.Dry concentration crude product obtains target compound through column chromatographic purifying, and structure is through hydrogen nuclear magnetic resonance spectrogram Confirmation.H-NMR(CDCl3, 400MHz) and δ: 7.87-7.90 (1H, m), 7.78-7.84 (2H, m), 7.52-7.60 (4H, m), 7.22 (2H, m), 7.04-7.18 (2H, m), 5.66 (2H, d), 5.12 (2H, d), 4.93 (2H, d), 4.22 (2H, q), 1.47 (3H, t).
(8) QR1036:2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole - The synthesis of 7- carboxylic acid (3- itrile group -1,2,5- oxadiazoles -2- oxo -4- base) methyl esters
By 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic acid (2.2mmol, 1.0 equivalents) and 2- oxo -3- itrile group -4- bromomethyl -1,2,5- oxadiazoles (3.3mmol, 1.5 equivalents) are dissolved in It in 20mL N-Methyl pyrrolidone, is added triethylamine (4.4mmol, 2.0 equivalents), is heated to 65 DEG C, TLC monitoring reaction is reacted It finishes.Water and ethyl acetate are added into reaction solution, extracts liquid separation, organic layer is successively washed with water, saturated common salt water washing.It is organic The dry concentration of layer, column chromatographic purifying obtain target compound, and structure is confirmed through hydrogen nuclear magnetic resonance spectrogram.H-NMR(CDCl3, 400MHz) δ: 7.89-7.93 (1H, m), 7.79-7.83 (2H, m), 7.54-7.62 (4H, m), 7.23 (2H, m), 7.03-7.13 (2H, m), 5.59 (2H, d), 5.16 (2H, d), 4.19 (2H, q), 1.46 (3H, t).
The preparation method of 2- oxo -3- itrile group -4- bromomethyl -1,2,5- oxadiazoles refers to Medicinal Chemistry Research,11(6),322-332；2002.
(9) QR2009:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] miaow The synthesis of azoles -5- carboxylic acid (phenyl -1,2,5 4-,-oxadiazoles -2- oxo -3-) methyl esters
Synthetic method is with (1) item in embodiment 1, and preparing raw material, { [2'- (1H-TETRAZOLE -5- base) joins by 2- ethyoxyl -1- Benzene -4- base] methyl } -1H- benzimidazole -7- carboxylic acid is changed to 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- Tetrazolium -5- phenyl) benzyl] imidazole-5-carboxylic acid, structure confirms through hydrogen nuclear magnetic resonance spectrogram.H-NMR(CDCl3, 400MHz) and δ: 7.87-7.90 (1H, m), 7.61-7.68 (4H, m), 7.34-7.43 (7H, m), 7.08-7.17 (2H, m), 5.48 (2H, d), 5.04 (2H, d), 2.68 (H, t), 2.2 (1H, s), 1.73 (2H, m), 1.62 (6H, d), 1.02 (3H, t).
4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] imidazole-5-carboxylic acid Synthetic method with reference to method described in CN1045770 patent.
(10) QR2017:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] The synthesis of imidazole-5-carboxylic acid (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen) methyl esters
Synthetic method is with (2) item in embodiment 1, and preparing raw material, { [2'- (1H-TETRAZOLE -5- base) joins by 2- ethyoxyl -1- Benzene -4- base] methyl } -1H- benzimidazole -7- carboxylic acid is changed to 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- Tetrazolium -5- phenyl) benzyl] imidazole-5-carboxylic acid, structure confirms through hydrogen nuclear magnetic resonance spectrogram.H-NMR(CDCl3, 400MHz) and δ: 7.85-7.89 (2H, m), 7.63-7.69 (2H, d), 7.44 (2H, m), 7.10-7.15 (3H, m), 5.53 (2H, d), 5.12 (2H, d), 2.66 (H, t), 2.35 (3H, s), 2.25 (6H, s), 2.0 (1H, s), 1.75 (2H, m), 1.64 (6H, d), 1.04 (3H, t).
(11) QR2019:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] The synthesis of imidazole-5-carboxylic acid [1- (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester
Synthetic method is with (3) item in embodiment 1, and preparing raw material, { [2'- (1H-TETRAZOLE -5- base) joins by 2- ethyoxyl -1- Benzene -4- base] methyl } -1H- benzimidazole -7- carboxylic acid is changed to 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- Tetrazolium -5- phenyl) benzyl] imidazole-5-carboxylic acid, structure confirms through hydrogen nuclear magnetic resonance spectrogram.H-NMR(CDCl3, 400MHz) and δ: 7.83-7.87 (2H, m), 7.66-7.71 (2H, d), 7.46 (2H, m), 7.08-7.14 (3H, m), 6.91-6.95 (1H, q), 5.50 (2H, d), 5.18 (2H, d), 2.62 (H, t), 2.31 (3H, s), 2.22 (6H, s), 2.3 (1H, s), 1.88 (3H, d), 1.77 (2H, m), 1.60 (6H, d), 0.98 (3H, t).
(12) QR2020:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] The synthesis of imidazole-5-carboxylic acid (3- methyl-1,2,5- oxadiazoles -2- oxo -4- methoxyl group-oxo phosphinylidyne oxygen) methyl esters
Synthetic method is with (4) item in embodiment 1, and preparing raw material, { [2'- (1H-TETRAZOLE -5- base) joins by 2- ethyoxyl -1- Benzene -4- base] methyl } -1H- benzimidazole -7- carboxylic acid is changed to 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- Tetrazolium -5- phenyl) benzyl] imidazole-5-carboxylic acid, structure confirms through hydrogen nuclear magnetic resonance spectrogram.H-NMR(CDCl3, 400MHz) and δ: 7.83-7.88 (2H, m), 7.65-7.74 (2H, d), 7.42 (2H, m), 7.12-7.16 (3H, m), 5.54 (2H, d), 5.10 (2H, d), 2.69 (H, t), 2.33 (3H, s), 2.30 (1H, s), 1.71 (2H, m), 1.60 (6H, d), 1.01 (3H, t).
(13) QR2021:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] The synthesis of imidazole-5-carboxylic acid [1- (3- methyl-1,2,5- oxadiazoles -2- oxide -4- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester
Synthetic method is with (5) item in embodiment 1, and preparing raw material, { [2'- (1H-TETRAZOLE -5- base) joins by 2- ethyoxyl -1- Benzene -4- base] methyl } -1H- benzimidazole -7- carboxylic acid is changed to 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- Tetrazolium -5- phenyl) benzyl] imidazole-5-carboxylic acid, structure confirms through hydrogen nuclear magnetic resonance spectrogram.H-NMR(CDCl3, 400MHz) and δ: 7.79-7.85 (2H, m), 7.62-7.68 (2H, d), 7.48 (2H, m), 7.03-7.10 (3H, m), 6.95-6.99 (1H, q), 5.57 (2H, d), 5.15 (2H, d), 2.65 (H, t), 2.30 (3H, s), 2.15 (1H, s), 1.85 (3H, d) 1.73 (2H, m), 1.68 (6H, d), 0.96 (3H, t).
(14) QR2034:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] The synthesis of imidazole-5-carboxylic acid (3- nitrate -1,2,5- oxadiazoles -2- oxo -4- base) methyl esters
Synthetic method is with (7) item in embodiment 1, and preparing raw material, { [2'- (1H-TETRAZOLE -5- base) joins by 2- ethyoxyl -1- Benzene -4- base] methyl } -1H- benzimidazole -7- carboxylic acid is changed to 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- Tetrazolium -5- phenyl) benzyl] imidazole-5-carboxylic acid, structure confirms through hydrogen nuclear magnetic resonance spectrogram.H-NMR(CDCl3, 400MHz) and δ: 7.83-7.88 (2H, m), 7.65-7.74 (2H, d), 7.42 (2H, m), 7.12-7.16 (3H, m), 5.54 (2H, d), 5.10 (2H, d), 4.91 (2H, s), 2.69 (H, t), 2.30 (1H, s), 1.71 (2H, m), 1.60 (6H, d), 1.01 (3H, t).
(15) QR2109:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- 4- [2- (dihydro -1,2 5- oxo -4,5-, 4- oxadiazoles -3)-phenyl] benzyl imidazole-5-carboxylic acid (phenyl -1,2,5 4-,-oxadiazoles -2- oxo -3-) methyl esters synthesis
Synthetic method is with (1) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- { 4- [2- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles -3)-phenyl] benzyl } imidazole-5-carboxylic acid, structure confirms through hydrogen nuclear magnetic resonance spectrogram. H-NMR(CDCl3, 400MHz) and δ: 7.97 (1H, m), 7.85-7.89 (1H, m), 7.71-7.76 (1H, m), 7.48-7.54 (3H, M), 7.30-7.38 (7H, m), 7.08-7.12 (2H, m), 5.45 (2H, d), 5.11 (2H, d), 2.63 (H, t), 2.32 (1H, S), 1.71 (2H, m), 1.66 (6H, d), 1.04 (3H, t).
4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- { 4- [2- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles - 3)-phenyl] benzyl imidazole-5-carboxylic acid preparation method refer to Journal of medicinal chemistry.1996,39 (26): 5228-5235 and patent CN1045770.
(16) QR2117:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- 4- [2- (dihydro -1,2 5- oxo -4,5-, 4- oxadiazoles -3)-phenyl] benzyl } imidazole-5-carboxylic acid (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen) methyl esters Synthesis
Synthetic method is with (2) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- { 4- [2- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles -3)-phenyl] benzyl } imidazole-5-carboxylic acid, structure confirms through hydrogen nuclear magnetic resonance spectrogram. H-NMR(CDCl3, 400MHz) and δ: 7.95 (1H, m), 7.87-7.89 (1H, m), 7.73-7.78 (1H, m), 7.45-7.52 (3H, M), 7.32-7.36 (1H, m), 7.06-7.10 (3H, m), 5.48 (2H, d), 5.06 (2H, d), 2.67 (H, t), 2.38 (3H, S), 2.29 (6H, s), 2.02 (1H, s), 1.73 (2H, m), 1.63 (6H, d), 0.96 (3H, t).
(17) QR2119:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- 4- [2- (dihydro -1,2 5- oxo -4,5-, 4- oxadiazoles -3)-phenyl] benzyl imidazole-5-carboxylic acid (phenyl -1,2,5 4-,-oxadiazoles -2- oxo -3-) methyl esters synthesis
Synthetic method is with (3) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- { 4- [2- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles -3)-phenyl] benzyl } imidazole-5-carboxylic acid, structure confirms through hydrogen nuclear magnetic resonance spectrogram. H-NMR(CDCl3, 400MHz) and δ: 7.98 (1H, m), 7.84-7.88 (1H, m), 7.71-7.77 (1H, m), 7.42-7.54 (3H, M), 7.30-7.34 (1H, m), 7.09-7.13 (2H, m), 6.73 (H, q), 5.52 (2H, d), 5.12 (2H, d), 2.63 (H, t), 2.34 (3H, s), 2.26 (6H, s), 2.00 (1H, s), 1.87 (3H, d), 1.75 (2H, m), 1.60 (6H, d), 0.99 (3H, t).
(18) QR2120:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- 4- [2- (dihydro -1,2 5- oxo -4,5-, 4- oxadiazoles -3)-phenyl] benzyl } imidazole-5-carboxylic acid (3- methyl-1,2,5- oxadiazoles -2- oxo -4- methoxyl group-oxo carbon Acyl-oxygen) methyl esters synthesis
Synthetic method is with (4) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- { 4- [2- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles -3)-phenyl] benzyl } imidazole-5-carboxylic acid, structure confirms through hydrogen nuclear magnetic resonance spectrogram. H-NMR(CDCl3, 400MHz) and δ: 7.90 (1H, m), 7.85-7.88 (1H, m), 7.74-7.79 (1H, m), 7.43-7.58 (3H, M), 7.37-7.40 (1H, m), 7.08-7.14 (3H, m), 5.42 (2H, d), 5.10 (2H, d), 2.60 (H, t), 2.45 (3H, S), 2.12 (1H, s), 1.68 (2H, m), 1.59 (6H, d), 1.08 (3H, t).
(19) QR2121:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- 4- [2- (dihydro -1,2 5- oxo -4,5-, 4- oxadiazoles -3)-phenyl] benzyl } imidazole-5-carboxylic acid [1- (3- methyl-1,2,5- oxadiazoles -2- oxide -4- methoxyl group-oxygen For phosphinylidyne oxygen)] synthesis of ethyl ester
Synthetic method is with (5) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- { 4- [2- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles -3)-phenyl] benzyl } imidazole-5-carboxylic acid, structure confirms through hydrogen nuclear magnetic resonance spectrogram. H-NMR(CDCl3, 400MHz) and δ: 7.97 (1H, m), 7.82-7.86 (1H, m), 7.76-7.78 (1H, m), 7.45-7.52 (3H, M), 7.32-7.35 (1H, m), 7.08-7.11 (2H, m), 6.75 (H, q), 5.50 (2H, d), 5.03 (2H, d), 2.67 (H, t), 2.39 (3H, s), 2.16 (1H, s), 1.72 (3H, d), 1.68 (2H, m), 1.59 (6H, d), 0.96 (3H, t).
(20) QR2123:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- 4- [2- (dihydro -1,2 5- oxo -4,5-, 4- oxadiazoles -3)-phenyl] benzyl imidazole-5-carboxylic acid (3- methyl-1,2,5- oxadiazoles -2- oxo -4- base) methyl esters synthesis
Synthetic method is with (6) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- { 4- [2- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles -3)-phenyl] benzyl } imidazole-5-carboxylic acid, structure confirms through hydrogen nuclear magnetic resonance spectrogram. H-NMR(CDCl3, 400MHz) and δ: 7.95 (1H, m), 7.84-7.91 (1H, m), 7.77-7.79 (1H, m), 7.48-7.53 (3H, M), 7.35-7.38 (1H, m), 7.10-7.13 (2H, m), 5.63 (2H, d), 5.21 (2H, d), 2.69 (H, t), 2.45 (3H, S), 2.21 (1H, s), 1.64 (2H, m), 1.67 (6H, d), 1.12 (3H, t).
(21) QR2136:4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- 4- [2- (dihydro -1,2 5- oxo -4,5-, 4- oxadiazoles -3)-phenyl] benzyl imidazole-5-carboxylic acid (3- itrile group -1,2,5- oxadiazoles -2- oxo -4- base) methyl esters synthesis
Synthetic method is with (7) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- { 4- [2- (5- oxygen Generation -4,5- dihydro -1,2,4- oxadiazoles -3)-phenyl] benzyl } imidazole-5-carboxylic acid, structure confirms through hydrogen nuclear magnetic resonance spectrogram. H-NMR(CDCl3, 400MHz) and δ: 7.99 (1H, m), 7.81-7.85 (1H, m), 7.73-7.75 (1H, m), 7.43-7.50 (3H, M), 7.31-7.34 (1H, m), 7.07-7.10 (2H, m), 5.59 (2H, d), 5.16 (2H, d), 2.62 (H, t), 2.13 (1H, S), 1.58 (2H, m), 1.63 (6H, d), 1.01 (3H, t).
(22) QR3009:N- [1- carboxylic acid (phenyl -1,2,5 4-,-oxadiazoles -2- oxo -3- base) methyl esters -2- methyl-prop Base -1- base]-N- valeryl-N- [2'- (1H-TETRAZOLE -5- base)-biphenyl -4- base-methyl]-amine synthesis
Synthetic method is with (1) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to N- (1- carboxylic acid -2- methyl-propyl -1- base)-N- valeryl-N- [2 ' - (1H-TETRAZOLE -5- base)-biphenyl -4- base-methyl]-amine, structure confirms through hydrogen nuclear magnetic resonance spectrogram.H-NMR (CDCl3, 400MHz) δ: 7.79-7.82 (1H, m), 7.69-7.76 (4H, m), 7.36-7.49 (7H, m), 7.18 (2H, m), 5.54 (2H, S), 4.86 (3H, m), 3.25 (H, m), 2.28 (1H, t), 1.68 (2H, m), 1.39 (2H, m), 0.94-1.13 (9H, m).
N- (1- carboxylic acid -2- methyl-propyl -1- base)-N- valeryl-N- [2 '-(1H-TETRAZOLE -5- base)-biphenyl -4- bases-first Base]-amine synthetic method referenced patent US5399578.
(23) QR3017:N- [1- carboxylic acid (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen) methyl esters -2- methyl Propyl -1- base]-N- valeryl-N- [2'- (1H-TETRAZOLE -5- base)-biphenyl -4- base-methyl]-amine synthesis
Synthetic method is with (2) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to N- (1- carboxylic acid -2- methyl-propyl -1- base)-N- valeryl-N- [2 ' - (1H-TETRAZOLE -5- base)-biphenyl -4- base-methyl]-amine, structure confirms through hydrogen nuclear magnetic resonance spectrogram.H-NMR(CDCl3, 400MHz) δ: 7.80-7.83 (1H, m), 7.72-7.75 (2H, m), 7.37-7.45 (4H, m), 7.15 (2H, m), 6.98 (2H, S), 5.59 (2H, s), 4.88 (3H, m), 3.15 (H, m), 2.34 (3H, s), 2.31 (1H, t), 2.25 (6H, s), 1.65 (2H, M), 1.43 (2H, m), 0.97-1.15 (9H, t).
(24) QR3019:N- { 1- carboxylic acid [1- (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen)] acetyl -2- Methyl-propyl -1- base }-N- valeryl-N- [2 '-(1H-TETRAZOLE -5- base)-biphenyl -4- bases-methyl]-amine synthesis
Synthetic method is with (3) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to N- (1- carboxylic acid -2- methyl-propyl -1- base)-N- valeryl-N- [2 ' - (1H-TETRAZOLE -5- base)-biphenyl -4- base-methyl]-amine, structure confirms through hydrogen nuclear magnetic resonance spectrogram.H-NMR(CDCl3, 400MHz) δ: 7.80-7.83 (1H, m), 7.72-7.75 (2H, m), 7.37-7.45 (4H, m), 7.15 (2H, m), 6.98 (2H, S), 6.72 (H, q), 5.59 (2H, s), 4.88 (3H, m), 3.15 (H, m), 2.34 (3H, s), 2.31 (1H, t), 2.25 (6H, S), 1.86 (3H, d), 1.65 (2H, m), 1.43 (2H, m), 0.96-1.13 (9H, t).
(25) QR3020:N- [1- carboxylic acid (3- methyl-1,2,5- oxadiazoles -2- oxo -4- methoxyl group-oxo phosphinylidyne oxygen) Formyl -2- methyl-propyl -1- base]-N- valeryl-N- [2 '-(1H-TETRAZOLE -5- base)-biphenyl -4- bases-methyl]-amine synthesis
Synthetic method is with (4) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to N- (1- carboxylic acid -2- methyl-propyl -1- base)-N- valeryl-N- [2 ' - (1H-TETRAZOLE -5- base)-biphenyl -4- base-methyl]-amine, structure confirms through hydrogen nuclear magnetic resonance spectrogram.H-NMR(CDCl3, 400MHz) δ: 7.86-7.89 (1H, m), 7.75-7.79 (2H, m), 7.39-7.47 (4H, m), 7.18 (2H, m), 6.95 (2H, S), 5.53 (2H, s), 4.94 (3H, m), 3.21 (H, m), 2.38 (3H, s), 2.28 (1H, t), 1.67 (2H, m), 1.48 (2H, M), 0.95-1.14 (9H, t).
(26) QR3021:N- { 1- carboxylic acid [1- (3- methyl-1,2,5- oxadiazoles -2- oxide -4- methoxyl group-oxo carbon Acyl-oxygen)] ethyl ester -2- methyl-propyl -1- base }-N- valeryl-N- [2'- (1H-TETRAZOLE -5- base)-biphenyl -4- base-methyl]-amine Synthesis
Synthetic method is with (5) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to N- (1- carboxylic acid -2- methyl-propyl -1- base)-N- valeryl-N- [2 ' - (1H-TETRAZOLE -5- base)-biphenyl -4- base-methyl]-amine, structure confirms through hydrogen nuclear magnetic resonance spectrogram.H-NMR(CDCl3, 400MHz) δ: 7.82-7.85 (1H, m), 7.70-7.73 (2H, m), 7.39-7.45 (4H, m), 7.13 (2H, m), 6.94 (2H, S), 6.79 (H, q), 5.65 (2H, s), 4.84 (3H, m), 3.22 (H, m), 2.38 (3H, s), 2.30 (1H, t), 1.89 (3H, D), 1.60 (2H, m), 1.47 (2H, m), 0.94-1.09 (9H, t).
(27) QR3034:N- [1- carboxylic acid (3- nitrate -1,2,5- oxadiazoles -2- oxo -4- base) methyl esters -2- methyl Propyl -1- base]-N- valeryl-N- [2 '-(1H-TETRAZOLE -5- base)-biphenyl -4- bases-methyl]-amine synthesis
Synthetic method is with (7) item in embodiment 1, and preparing raw material, { [2'- (1H-TETRAZOLE -5- base) joins by 2- ethyoxyl -1- Benzene -4- base] methyl } -1H- benzimidazole -7- carboxylic acid is changed to N- (1- carboxylic acid -2- methyl-propyl -1- base)-N- valeryl-N- [2 '-(1H-TETRAZOLE -5- base)-biphenyl -4- bases-methyl]-amine, structure are confirmed through hydrogen nuclear magnetic resonance spectrogram.H-NMR(CDCl3, 400MHz) δ: 7.88-7.93 (1H, m), 7.76-7.79 (2H, m), 7.42-7.48 (4H, m), 7.15 (2H, m), 6.93 (2H, S), 5.58 (2H, s), 5.18 (2H, s), 4.80 (3H, m), 3.28 (H, m), 2.33 (3H, s), 2.22 (1H, t), 1.62 (2H, M), 1.45 (2H, m), 0.98-1.19 (9H, t).
(28) QR3109:N- [1- carboxylic acid (phenyl -1,2,5 4-,-oxadiazoles -2- oxo -3- base) methyl esters -2- methyl-prop Base -1- base]-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-methyl] - The synthesis of amine
Synthetic method is with (1) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to N- (1- carboxylic acid -2- methyl-propyl -1- base)-N- valeryl-N- [2 ' - (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-methyl]-amine, structure is through hydrogen nuclear magnetic resonance spectrogram Confirmation.H-NMR(CDCl3, 400MHz) and δ: 7.82-7.86 (1H, m), 7.76-7.80 (1H, m), 7.57-7.63 (3H, m), 7.42-7.46 (7H, m), 7.24 (2H, m), 5.64 (2H, s), 4.93 (3H, m), 3.32 (1H, m), 2.57 (1H, t), 1.74 (2H, m), 1.45 (2H, m), 0.99-1.18 (9H, m).
N- (1- carboxylic acid -2- methyl-propyl -1- base)-N- valeryl-N- [2 '-(5- oxo -4,5- dihydro -1,2,4- evils two Azoles -3- base)-biphenyl -4- base-methyl]-amine synthetic method referenced patent US5399578.
(29) QR3117:N- [1- carboxylic acid (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen) methyl esters -2- methyl Propyl -1- base]-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-first Base]-amine synthesis
Synthetic method is with (2) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to N- [1- carboxylic acid -2- methyl-propyl -1- base]-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-methyl]-amine, structure is through hydrogen nuclear magnetic resonance spectrogram Confirmation.H-NMR(CDCl3, 400MHz) and δ: 7.88-7.90 (1H, m), 7.78-7.82 (1H, m), 7.59-7.61 (1H, m), 7.40-7.45 (3H, m), 7.32 (1H, m), 7.24 (2H, m), 7.03 (2H, d), 5.57 (2H, s), 4.89 (3H, m), 3.12 (H, m), 2.36 (3H, s), 2.32 (1H, t), 2.27 (6H, s), 1.68 (2H, m), 1.40 (2H, m), 0.99-1.18 (9H, t).
(30) QR3119:N- { 1- carboxylic acid [1- (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester -2- Methyl-propyl -1- base }-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4-Diazole -3- base)-biphenyl -4- base - Methyl]-amine synthesis
Synthetic method is with (3) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to N- (1- carboxylic acid -2- methyl-propyl -1- base)-N- valeryl-N- [2 ' - (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-methyl]-amine, structure is through hydrogen nuclear magnetic resonance spectrogram Confirmation.δ: 7.89-7.93 (1H, m), 7.77-7.80 (1H, m), 7.56-7.59 (1H, m), 7.41-7.44 (3H, m), 7.36 (1H, m), 7.26 (2H, m), 6.70 (H, q), 5.56 (2H, s), 4.87 (3H, m), 3.20 (H, m), 2.38 (3H, s), 2.37 (1H, t), 2.27 (6H, s), 1.89 (3H, d), 1.67 (2H, m), 1.48 (2H, m), 0.99-1.16 (9H, t).
(31) QR3120:N- [1- carboxylic acid (3- methyl-1,2,5- oxadiazoles -2- oxo -4- methoxyl group-oxo phosphinylidyne oxygen) Methyl esters -2- methyl-propyl -1- base]-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-connection Benzene -4- base-methyl]-amine synthesis
Synthetic method is with (4) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to N- (1- carboxylic acid -2- methyl-propyl -1- base)-N- valeryl-N- [2 ' - (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-methyl]-amine, structure is through hydrogen nuclear magnetic resonance spectrogram Confirmation.δ: 7.87-7.91 (1H, m), 7.74-7.78 (1H, m), 7.58-7.64 (1H, m), 7.44-7.48 (3H, m), 7.38 (1H, m), 7.29 (2H, m), 6.87 (2H, s), 5.57 (2H, s), 4.93 (3H, m), 3.24 (H, m), 2.37 (3H, s), 2.32 (1H, t), 1.72 (2H, m), 1.43 (2H, m), 0.93-1.11 (9H, t).
(32) QR3121:N- { 1- carboxylic acid [1- (3- methyl-1,2,5- oxadiazoles -2- oxide -4- methoxyl group-oxo carbon Acyl-oxygen)] acetyl -2- methyl-propyl -1- base }-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- Base)-biphenyl -4- base-methyl]-amine synthesis
Synthetic method is with (5) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to N- (1- carboxylic acid -2- methyl-propyl -1- base)-N- valeryl-N- [2 ' - (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-methyl]-amine, structure is through hydrogen nuclear magnetic resonance spectrogram Confirmation.δ: 7.85-7.90 (1H, m), 7.72-7.76 (1H, m), 7.58-7.63 (1H, m), 7.46-7.50 (3H, m), 7.36 (1H, m), 7.24 (2H, m), 6.83 (H, q), 5.69 (2H, s), 4.97 (3H, m), 3.29 (H, m), 2.38 (3H, s), 2.28 (1H, t), 1.85 (3H, d), 1.67 (2H, m), 1.54 (2H, m), 0.93-1.12 (9H, t).
(33) QR3123:N- [1- carboxylic acid (3- methyl-1,2,5- oxadiazoles -2- oxo -4- base) methyl esters -2- methyl-propyl - 1- yl]-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-methyl]-amine Synthesis
Synthetic method is with (6) item in embodiment 1, by raw material 2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl - 4- yl] methyl } -1H- benzimidazole -7- carboxylic acid is changed to N- [1- carboxylic acid -2- methyl-propyl -1- base]-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-methyl]-amine, structure is through hydrogen nuclear magnetic resonance spectrogram Confirmation.δ: 7.82-7.88 (1H, m), 7.72-7.76 (1H, m), 7.53-7.57 (1H, m), 7.42-7.49 (3H, m), 7.32 (1H, m), 7.18 (2H, m), 5.69 (2H, s), 5.31 (2H, s), 4.81 (3H, m), 3.39 (H, m), 2.25 (1H, t), 1.58 (2H, m), 1.48 (2H, m), 0.94-1.13 (9H, t).
(34) QR3134:N- [1- carboxylic acid (3- nitrate -1,2,5- oxadiazoles -2- oxo -4- base) methyl esters -2- methyl Propyl -1- base]-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-first Base]-amine synthesis
Synthetic method is with (7) item in embodiment 1, and preparing raw material, { [2'- (1H-TETRAZOLE -5- base) joins by 2- ethyoxyl -1- Benzene -4- base] methyl } -1H- benzimidazole -7- carboxylic acid is changed to N- [1- carboxylic acid -2- methyl-propyl -1- base]-N- valeryl-N- [2'- (5- oxo -4,5- dihydro -1,2,4- oxadiazoles -3- base)-biphenyl -4- base-methyl]-amine, structure is through hydrogen nuclear magnetic resonance Spectrogram confirmation.δ: 7.88-7.92 (1H, m), 7.76-7.78 (1H, m), 7.55-7.60 (1H, m), 7.48-7.53 (3H, m), 7.39 (1H, m), 7.25 (2H, m), 5.62 (2H, s), 5.25 (2H, s), 4.87 (3H, m), 3.32 (H, m), 2.38 (3H, s), 2.26 (1H, t), 1.57 (2H, m), 1.41 (2H, m), 0.95-1.21 (9H, t).
Embodiment 2
Test-compound (34 kinds of noval chemical compounds prepared by embodiment 1) single-dose is tested to the drop of renal hypertensive rat Pressure effect
Method: Wistar rat (is provided, Wuhan, Hubei) by Disease Prevention Control Center, Hubei Prov, male, weight, 180-200g is randomly divided into 3 groups, and negative control group (0.5%CMC-Na), positive controls are (with the Olmesartan of 1.0ml/kg Ester is positive drug) and test-compound group (dosage 1.0mg/kg, in addition to number be QR3009, QR3017, QR3019, The dosage of QR3020, QR3021, QR3034, QR3109, QR3117, QR3119, QR3120, QR3123 and QR3134 is Other than 10mg/kg, all drugs are prepared in 0.5%CMC-Na), every group of 6-8 animal.The side arteria renalis is ligatured, is formed Two-kidney One-clip type renal hypertensive rat (RHR) model, measures weekly a blood pressure, continuous surrounding, blood pressure stabilization liter after operation The rat of high 4kPa is the successful rat of modeling.Before measuring blood pressure, rat is heated with 39 DEG C of circulator bath tail sleeve to rat-tail, makes tail After portion's blood vessel dilatation, with tail sleeve method (BP2010A non-invasive blood pressure instrument, Beijing Ji'an get Er Science and Technology Ltd., Haidian District, Beijing City Ten street No.1 of Shangdi) measurement rat administration before, after gastric infusion 1,3,5,7,10 and 10h blood pressure, each time point survey three times It is averaged.Pressure value × 100% before maximum blood pressure lowering value/administration after maximum hypotensive activity (%)=administration.
Experimental result: it is shown in Table 1
Influence of 1 test drug of table to the antihypertensive effect of renal hypertensive rat
Conclusion: in ligation arteria renalis Hypertension Rats animal model, 34 kinds of compounds prepared by the present invention are shown not With the hypotensive activity of degree.
Embodiment 3
Detect influence of the test-compound (34 kinds of noval chemical compounds prepared by embodiment 1) to rat lipid metaboli
Method: Wistar rat (is provided, Wuhan, Hubei) by Disease Prevention Control Center, Hubei Prov, male,Weight, 180-200g is randomly divided into 5 groups, and negative control group (0.5%CMC-Na), positive controls are (with the Olmesartan of 1.0ml/kg Ester is positive drug) and test-compound group (1.0mg/kg, in addition to number be QR3009, QR3017, QR3019, QR3020, The dosage of QR3021, QR3034, QR3109, QR3117, QR3119, QR3120, QR3123 and QR3134 are 10mg/kg, are owned Drug is prepared in 0.5%CMC-Na), every group of 5-6 animal.High lipid food is fed groups of animals 8 weeks, at the 5th week, yin Property control group uses the physiological saline stomach-filling of 0.5%CMC-Na daily, and positive controls and tested group use positive drug or tested daily Medicine (1.0mg/kg) carries out stomach-filling.After feeding 8 weeks, that anesthetized rat of amobarbital, abdominal aortic blood divides after collecting blood From serum, freeze to be measured.Internal organs and perirenal fat are separated after rat extracting blood.It is solid with the total gallbladder of full automatic biochemical apparatus enzymatic assays serum Alcohol (TC).
As a result: being shown in Table 2
Influence of 2 test drug of table to experimental rat weight, perirenal fat and total cholesterol
Conclusion: the weight and adipose tissue for the reduction high fat diet rat that 34 kinds of test-compounds can be different degrees of, and It is adjustable lipid metaboli.
Embodiment 4
Antihypertensive effect of the oral QR1019 sylvite single-dose to renal hypertensive rat
Wistar rat (is provided, Wuhan, Hubei) by Disease Prevention Control Center, Hubei Prov, male, weight, 180- 200g is randomly divided into 5 groups, and negative control group (0.5%CMC-Na), positive controls are (with the Azilsartan potassium of 1.0mg/kg Salt is positive drug) and test-compound QR1019 sylvite (1.0mg/kg), every group of 6-8 animal.The side arteria renalis is ligatured, Two-kidney One-clip type renal hypertensive rat (RHR) model is formed, measures a blood pressure after operation weekly, continuous surrounding, blood pressure is steady Surely the rat for increasing 4kPa is the successful rat of modeling.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 instrument, Beijing Ji'an get Er Science and Technology Ltd., Beijing sea Ten street No.1 of shallow lake area Shangdi) measurement rat administration before, after gastric infusion 1,3,5,7,10 and 10h blood pressure and heart rate, Mei Geshi Between point survey be averaged three times.Pressure value * 100% before maximum blood pressure lowering value/administration after maximum hypotensive activity (%)=administration.
Table 5. takes orally QR1019 sylvite and positive drug to the antihypertensive effect of renal hypertensive rat
As a result with conclusion: the QR1019 sylvite of test-compound prepared by the present invention is right compared to positive under Isodose There is significant antihypertensive effect according to group, and it is also significantly better than positive controls to the adjusting of heart rate.
Embodiment 5
34 Ar-CH prepared by embodiment 12In-X compound any one, lactose and microcrystalline cellulose premix 5min stirs 3rpm, cuts 30rpm；PVP k30 is dissolved in suitable quantity of water and (is dissolved in the conversion of 2g water by 0.36g PVP k30), is opened Stirring cutting is opened, while binder aqueous solution is added, softwood crosses the granulation of 30 meshes,60 DEG C of dryings of wet granular to moisture 1%-2%, 24 mesh sieves, dry particl weighing, croscarmellose sodium and magnesium stearate are added in dry particl, are uniformly mixed, pressure Tablet is made in piece.
Embodiment 6
34 Ar-CH prepared by the embodiment 1 of micronization of learning from else's experience2Any one in-X compound, lactose, microcrystalline cellulose Element, low-substituted hydroxypropyl cellulose mix 5 minutes in wet granulator, and the adhesive for being gradually added into 5% PVP K30 is molten Then liquid adds suitable purified water, pelletize 3 minutes, crosses 24 mesh screens, wet granular is placed in pallet, in 55 DEG C of baking Dry in case, rewinding, the particle of drying crosses 20 mesh whole grains, mixes 15 with additional crospovidone, superfine silica gel powder, magnesium stearate Minute, tabletting is to get dispersible tablet.
The composition of raw materials of the present embodiment is as follows:
Embodiment 7
34 Ar-CH prepared by embodiment 12In-X compound any one, Dioleoyl Phosphatidylcholine, gallbladder it is solid Alcohol, NaGC and sojasterol are dissolved in the in the mixed solvent of ethyl alcohol and n-hexane, are uniformly mixed, in rotary film evaporator On organic solvent is removed under reduced pressure, obtain immobilized artificial membrane；Citric acid-sodium citrate buffer solution that pH is 6.0 is added, shakes, stirring 30 minutes, make the complete aquation of immobilized artificial membrane, with the homogeneous emulsification of tissue mashing machine's high speed 10 minutes, 0.45 μm of filtering with microporous membrane, system The liposome powder of drug containing is made in liposome turbid liquor, spray drying, then by itself and mannitol, microcrystalline cellulose and crosslinking Sodium carboxymethylcellulose mixing is crossed 60 meshes and is uniformly mixed, and hydroxypropyl cellulose is added, and ethanol solution prepares softwood, crosses 20 mesh Dry particl and magnesium stearate are uniformly mixed by sieve granulation, 50 DEG C of dryings, cross 18 mesh sieves, tabletting, and liposome is made in coating Tablet.
Embodiment 8
34 Ar-CH prepared by Example 12Any one in-X compound and Compritol 888 ATO (Compritol), calcium phosphate dibasic anhydrous, lactose mixing, sufficiently stir evenly, add adhesive PVP K30 solution, mix in high-speed stirred Wet granular is made in granulator, is then dried；Sieving whole grain, is added carbomer (CarbopolR971P), magnesium stearate And talcum powder, it mixes, tabletting.
The composition of raw materials of the present embodiment is as follows:

Claims (8)

1. general formula is Ar-CH2The compound of-X or its pharmaceutically acceptable salt:
Wherein, X is representedOr
R0It is C1-4Alkyl；
R1a representative-CH2OC (=O) OR1aa、-CH(C1-4Alkyl) OC (=O) OR1aa、
R1aaIt represents
R6Represent phenyl, itrile group, trifluoromethyl ,-C1-4Alkylene nitrate or C1-4Alkyl；
R2And R3It is identical or different, and respectively represent hydrogen or C1-4Alkyl；
Ar isWherein R1For tetrazole radical -5- base.
2. the sylvite of compound described in claim 1.
3. compound:
2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic acid (4- phenyl - 1,2,5,-oxadiazoles -2- oxo -3- base) methyl esters,
2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic acid (3,5,6- tri- Methylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen) methyl esters,
2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic acid [1- (3,5, 6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester,
2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic acid (3- methyl - 1,2,5- oxadiazoles -2- oxo -4- methoxyl group-oxo phosphinylidyne oxygen) methyl esters,
2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic acid [1- (3- first Base -1,2,5- oxadiazoles -2- oxide -4- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester,
2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic acid (3- methyl - 1,2,5- oxadiazoles -2- oxide -4- base) methyl esters,
2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic acid (3- nitric acid first Base -1,2,5- oxadiazoles -2- oxo -4- base) methyl esters,
2- ethyoxyl -1- { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic acid (3- itrile group - 1,2,5- oxadiazoles -2- oxo -4- base) methyl esters,
4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] imidazole-5-carboxylic acid (4- benzene Base -1,2,5,-oxadiazoles -2- oxo -3-) methyl esters,
4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] imidazole-5-carboxylic acid (3,5, 6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen) methyl esters,
4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] imidazole-5-carboxylic acid [1- (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester,
4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] imidazole-5-carboxylic acid (3- first Base -1,2,5- oxadiazoles -2- oxo -4- methoxyl group-oxo phosphinylidyne oxygen) methyl esters,
4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] imidazole-5-carboxylic acid [1- (3- methyl-1,2,5- oxadiazoles -2- oxide -4- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester,
4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- [4- (2-1H- tetrazolium -5- phenyl) benzyl] imidazole-5-carboxylic acid (3- nitre Acid methyl -1,2,5- oxadiazoles -2- oxo -4- base) methyl esters or its pharmaceutically acceptable salt.
Compound 2- ethyoxyl -1- 4. { [2'- (1H-TETRAZOLE -5- base) biphenyl -4- base] methyl } -1H- benzimidazole -7- carboxylic acid The sylvite of [1- (3,5,6- trimethylpyrazine -2- methoxyl group-oxo phosphinylidyne oxygen)] ethyl ester.
5. any compound is used to prepare the purposes of drug in claim 1-4, the drug is needed for treating or preventing It will selectivity excitement AT2The illness of receptor, treatment AngII endogenous generate insufficient illness, and treatment needs to enhance AngII effect Illness.
6. any compound is used to prepare the purposes of drug in claim 1-4, the drug is for treating hypertension, the heart Force failure, myocardial infarction, atherosclerosis, diabetic complication, dyslipidemia or hypertriglyceridemia.
7. a kind of pharmaceutical composition, it includes the compound or its pharmaceutically acceptable salt any in claim 1-4, And it chooses any one kind of them or a variety of pharmaceutically acceptable carriers and/or diluent.
8. peroral dosage form, wherein any compound in the claim 1-4 containing therapeutically effective amount, wherein the dosage form is Tablet, dispersible tablet, Liposomal formulation or sustained release preparation.
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