CN106831473B - 3- amide groups -4- (2 '-alkoxy -4- xenyl) butanoic acid derivative and preparation method thereof, pharmaceutical composition - Google Patents

3- amide groups -4- (2 '-alkoxy -4- xenyl) butanoic acid derivative and preparation method thereof, pharmaceutical composition Download PDF

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CN106831473B
CN106831473B CN201710095167.4A CN201710095167A CN106831473B CN 106831473 B CN106831473 B CN 106831473B CN 201710095167 A CN201710095167 A CN 201710095167A CN 106831473 B CN106831473 B CN 106831473B
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xenyl
base
difluoro
methoxy
carbonyl
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CN106831473A (en
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郁彩红
孙斌
仝朝龙
邹贵祥
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Jiangxi Ruiya Pharmaceutical Co Ltd
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    • 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
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring

Abstract

The invention discloses a kind of 3- amide groups -4- (2 '-alkoxy -4- xenyl) butanoic acid derivative and preparation method thereof, pharmaceutical composition and purposes, 3- amide groups -4- (2'- alkoxy -4- xenyl) butanoic acid derivative and its racemic modification, corresponding isomers, non-corresponding isomers, chiral optically pure isomer are with the following general formula (I) structure: having NEP inhibitory activity, it can be used as nep inhibitor, the drug for the treatment of related disease can be used to prepare, such as hypertension, heart failure, pulmonary hypertension and kidney trouble.

Description

3- amide groups -4- (2 '-alkoxy -4- xenyl) butanoic acid derivative and its preparation side Method, pharmaceutical composition
Technical field
The present invention relates to a kind of 3- amide groups -4- (2 '-alkoxy -4- xenyl) butanoic acid derivative and preparation method thereof, Pharmaceutical composition and purposes.The compound has NEP inhibitory activity, can be used as nep inhibitor.
Background technique
NEP (neutral endopeptidase, also known as Neprilysin) is the Metalloproteinase familv that M13 zinc relies on A kind of II type transmembrane glycoprotein, also referred to as enkephalinase, the zinc atom having thereon be in the active site of enzyme.NEP molecular weight About 97kDa is made of 750 amino acid, includes a signal peptide and two hydrophilic domains, and segment intracellular has 26 amino Acid, extracellular segment have 700 amino acid.NEP may act on the aminoterminal of polypeptide, hydrolyze polypeptide chain.For the first time since 1974 Since being defined, a kind of degrading enzyme of the NEP as neuropeptide has been found to be distributed widely in endothelial cell, vascular smooth muscle thin Born of the same parents, cardiac muscle cell, kidney epithelia cell, fibroblast are also present in lung, intestines, adrenal gland, brain etc., and have numerous groups Knit specific function.Natriurtic peptide is mainly degraded by NEP, and NEP can also be catalyzed adrenal medella and bradykinin.NEP selection Property inhibitor inhibit NEP activity, the concentration of natriurtic peptide and bradykinin can be improved, distend the blood vessels, heart discharge increase, Aldosterone level declines and inhibits RAAS (renin-angiotensin-aldosterone system), reduces the forward and backward load of heart, delays the heart Flesh reconstruct, improves the heart function of heart failure patient.
The research of the double inhibitor of last decade NEP is very more, including (blood vessel is tight by NEP/ACE double inhibitors, NEP/ARB Peptide receptor) double inhibitors, NEP/ECE (endothelin converting enzyme) double inhibitors and NEP/APN (Aminopeptidase N) double inhibition Agent.Nep inhibitor is used alone or drug combination is expected to as treatment hypertension/heart failure modern weapon, but there is presently no A kind of drug based on NEP inhibiting mechanism emerges.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of 3- amide groups -4- (2 '-alkoxy -4- xenyl) butyric acid Derivative, these compounds have NEP inhibitory activity, can be used as nep inhibitor, can be used to treat related disease, such as Hypertension, heart failure, pulmonary hypertension and kidney trouble.
The present invention the technical solution adopted is that provides 3- shown in a kind of the following general formula (I) to solve above-mentioned technical problem Amide groups -4- (2'- alkoxy -4- xenyl) butanoic acid derivative and its racemic modification, corresponding isomers, non-corresponding isomers, Chiral optically pure isomer:
Wherein R1For hydrogen, C1-C8Alkyl, C3-C6Naphthenic base, alkali metal, alkaline-earth metal, R5For hydrogen, C1-C3Alkyl or C3-C6Naphthenic base；R6For C1-C6Alkyl, C3-C6Naphthenic base；R2For hydrogen atom, Halogen atom, C3-C6Naphthenic base, C1-C6Alkyl；R3For hydrogen or fluorine；R4For
Further, the derivative is 4- (2'- difluoro-methoxy-xenyl -4- base) -3- [(5- carbonyl -4,5- bis- Hydrogen-[1,3,4] oxadiazoles -2- carbonyl)-amino] ethyl butyrate；(R) -4- (the chloro- 2'- difluoro-methoxy-xenyl -4- of 5'- Base) -3- [(5- carbonyl -4,5- dihydro-[1,3,4] oxadiazoles -2- carbonyl)-amino] butyric acid；4- (2'- difluoro-methoxy -5'- Fluoro- xenyl -4- base) -3- [(5- carbonyl -4,5- dihydro-[1,3,4] oxadiazoles -2- carbonyl)-amino] ethyl butyrate；4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- [(5- carbonyl -4,5- dihydro-[1,3,4] oxadiazoles -2- carbonyl) - Amino] butyric acid；4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- [(dislikes two in dihydro-[1,3,4] 5- carbonyl -4,5- Azoles -2- carbonyl)-amino]-butyric acid -1- cyclohexyloxy carbon oxygroup ethyl ester；(R, R) -4- (fluoro- biphenyl of 2'- difluoro-methoxy -5'- Base -4- base) -3- [(5- carbonyl -4,5- dihydro-[1,3,4] oxadiazoles -2- carbonyl)-amino]-butyric acid -1- cyclohexyloxy carbon oxygen Base ethyl ester；[(dihydro-[1,3,4] 5- carbonyl -4,5- (R, S) -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- Oxadiazoles -2- carbonyl)-amino]-butyric acid -1- cyclohexyloxy carbon oxygroup ethyl ester；4- (the fluoro- xenyl-of 2'- difluoro-methoxy -5'- 4- yl) -3- [(5- carbonyl -4,5- dihydro-[1,3,4] oxadiazoles -2- carbonyl)-amino]-butyric acid -1- isopropoxy carbon oxygroup second Ester；4- (the chloro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- [(5- carbonyl -4,5- dihydro-[1,3,4] oxadiazoles -2- carbonyl Base)-amino]-butyric acid -1- cyclohexyloxy carbon oxygroup ethyl ester；4- (the chloro- 2'- difluoro-methoxy of 5'--xenyl -4- base) -3- [(5- carbonyl -4,5- dihydro-[1,3,4] oxadiazoles -2- carbonyl)-amino]-butyric acid -1- isopropoxy carbon oxygroup ethyl ester；(R)- Amino) -4- (the chloro- xenyl -4- base of 2'- difluoro-methoxy -5'-)-butyric acid-cyclohexyloxy carbon oxygroup ethyl ester；(R) -3- (3- carboxylic Base-propionamido) -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-)-butyric acid 1- cyclohexyloxy carbon oxygroup ethyl ester； (R) -3- (3- carboxyl-propionamido) -4- (the chloro- 2'- difluoro-methoxy of 5'--xenyl -4- base)-butyric acid-isopropoxy carbon oxygen Base ethyl ester；(R) -3- (3- carboxyl-propionamido) -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) ethyl butyrate；3- (3- carboxyl-propionamido) -4- (2'- difluoro-methoxy-xenyl -4- base) butyric acid-cyclohexyloxy carbon oxygroup ethyl ester；3-(3- Carboxyl-propionamido) -4- (2'- difluoro-methoxy-xenyl -4- base) butyric acid 1- isopropoxy carbon oxygroup-ethyl ester；3-(3- Carboxyl-propionamido) -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) butyric acid isopropoxy carbon oxygroup methyl esters；3- (3- carboxyl-propionamido) -4- (the chloro- 2'- difluoro-methoxy of 5'--xenyl -4- base)-butyric acid isopropoxy carbon oxygroup methyl esters； (R) -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- (3- phosphorus carboxyl-propionamido) ethyl butyrate；4-(5'- Chloro- 2'- difluoro-methoxy-xenyl -4- base) -3- (3- phosphorus carboxyl-propionamido) ethyl butyrate；4- (2'- difluoro-methoxy- Fluoro- xenyl -4- the base of 5'-) -3- (3- phosphorus carboxyl-propionamido)-butyric acid -5- base -2- carbonyl-[1,3] dioxazole -4- Ji Jia Ester；(R) -4- (the chloro- 2'- difluoro-methoxy of 5'--xenyl -4- base) -3- (3- phosphorus carboxyl-propionamido)-butyric acid -5- methyl - 2- carbonyl-[1,3] dioxazole -4- base methyl esters；Or (R) -4- (the fluoro- 2'- trifluoromethoxy of 5'--xenyl -4- base) -3- [(5- Carbonyl -4,5- dihydro-[1,3,4] oxadiazoles -2- carbonyl)-amino] ethyl butyrate.
Another technical solution that the present invention uses to solve above-mentioned technical problem is to provide a kind of pharmaceutical composition, contains Above-mentioned 3- amide groups -4- (2'- alkoxy -4- xenyl) butanoic acid derivative, pharmaceutically acceptable load of therapeutically effective amount Body and pharmaceutically acceptable salt.
Further, press down in described pharmaceutical composition containing angiotensin receptor blocker or angiotensin converting enzyme Preparation.
Further, the angiotensin receptor blocker is Valsartan, Aomei sandy beach or Losartan；The blood vessel is tight Opening plain converting enzyme inhibitor is enalapril or lisinopril.
The third technical solution that the present invention uses to solve above-mentioned technical problem is to provide a kind of 4- (2'- difluoro first Oxygroup-xenyl -4- base) -3- [(5- carbonyl -4,5- dihydro-[1,3,4] oxadiazoles -2- carbonyl)-amino] ethyl butyrate system Preparation Method includes the following steps: (1) by (R) -4- (the bromo- phenyl of 4-) -3- tertbutyloxycarbonylamino ethyl butyrate and 2- difluoro Methoxyphenylboronic acid is dissolved in toluene, and sodium carbonate, water and PdCl is added2(dppf)2, reaction system is heated to reflux under nitrogen atmosphere, Be cooled to room temperature rear liquid separation, water phase is extracted through ethyl acetate, merge organic phase, with anhydrous sodium sulfate it is dry, filter, steam filter Liquid, purified by chromatography purify to obtain (R) -3- { [5- (tert-butyl-dimethyl-silane oxygroup)-[1,3,4] oxadiazoles -2- carbonyl Base]-amino } -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) butyric acid；(2) by (R) -3- tert-butoxycarbonyl ammonia Base -4- (2'- difluoro-methoxy-xenyl -4- base) ethyl butyrate is dissolved in methylene chloride, and trifluoroacetic acid is added dropwise under ice water is cooling, Solvent is steamed with Rotary Evaporators after stirring, residue is dissolved in methylene chloride, and triethylamine, the cooling lower dropwise addition oxalyl chloride of ice water is added Mono ethyl ester is added dropwise after being stirred at room temperature and saturated sodium bicarbonate aqueous solution is added, and liquid separation, water phase is extracted with dichloromethane, and merges Methylene chloride phase, with anhydrous sodium sulfate it is dry, filter, steam filtrate, purified by chromatography purifies to obtain (R) -4- (2'- difluoro Methoxy-biphenyl -4- base) -3- (ethyoxyl oxalyl<oxalyl>- amino) ethyl butyrate；(3) step (2) is obtained (R) -4- (2'- difluoro-methoxy-xenyl -4- base) -3- (ethyoxyl oxalyl<oxalyl>- amino) ethyl butyrate be dissolved in nothing Water-ethanol is added hydrazine hydrate, cold water is added after stirring, and white solid is precipitated after stirring and filters, and obtains after collecting solid drying (R) -4- (2'- difluoro-methoxy-xenyl -4- base) -3- (diazanyl<hydrazino>oxalyl<oxalyl>- amino) ethyl butyrate； (4) (R) -4- (2'- difluoro-methoxy-xenyl -4- base) -3- (diazanyl<hydrazino>oxalyl<second two obtained step (3) Acyl >-amino) ethyl butyrate is dissolved in methylene chloride at room temperature, carbonyl dimidazoles are added, reaction system is stirred at room temperature, and uses Rotary Evaporators steam solvent, and residue obtains (R) -4- (2'- difluoro-methoxy-xenyl -4- base) -3- through column chromatographic purifying [(5- carbonyl -4,5- dihydro-[1,3,4] oxadiazoles -2- carbonyl)-amino] ethyl butyrate.
The 4th kind of technical solution that the present invention uses to solve above-mentioned technical problem is to provide a kind of 3- amide groups -4- (2 '-alkoxy -4- xenyl) butanoic acid derivative treats or prevents hypertension, pulmonary hypertension, heart failure and kidney in preparation Application in disease medicament.
The present invention comparison prior art has following the utility model has the advantages that 3- amide groups -4- (2 '-alkoxies-provided by the invention 4- xenyl) butanoic acid derivative and preparation method thereof, pharmaceutical composition and purposes, 3- amide groups -4- (2 '-alkoxy -4- biphenyl Base) butanoic acid derivative have NEP inhibitory activity, can be used as nep inhibitor, can be used to prepare treatment related disease medicine Object, such as hypertension, heart failure, pulmonary hypertension and kidney trouble.
Specific embodiment
The invention will be further described for following example, but does not limit the invention in any way.
Embodiment 1:4- (2'- difluoro-methoxy-xenyl -4- base) -3- [(dislikes two in dihydro-[1,3,4] 5- carbonyl -4,5- Azoles -2- carbonyl)-amino] ethyl butyrate
Step 1:(R) -3- tertbutyloxycarbonylamino -4- (2'- difluoro-methoxy-xenyl -4- base) ethyl butyrate's Preparation
(R) -4- (the bromo- phenyl of 4-) -3- tertbutyloxycarbonylamino ethyl butyrate (3.58g, 10mmol) and 2- difluoro first Oxygroup phenyl boric acid (2.82g, 15mmol) is dissolved in 30 milliliters of toluene, is added sodium carbonate (2.5g), 25 milliliters of water are added, and is added PdCl2(dppf)2(500mg), reaction system are heated to reflux 10 hours under nitrogen atmosphere, are cooled to room temperature, liquid separation, water phase warp Ethyl acetate extraction, merges organic phase, is dried, filtered with anhydrous sodium sulfate, steam filtrate, residue is purified by silica gel column chromatography It obtains light yellow solid (3.08g).
1HNMR(CDCl3, 400MHz) and δ 7.58 (s, 1H), 7.43 (d, J=8.4Hz, 2H), 7.37 (m, 1H), 7.20 (d, J =8.2Hz, 2H), 7.03 (s, 0.5H), 6.81-7.18 (m, 3H), 6.95 (s, 0.5H), 4.50-4.53 (m, 1H), 4.12 (q, J=7.2Hz, 2H), 2.91-3.10 (m, 2H), 2.58 (d, J=6.2Hz, 2H), 1.41 (s, 9H), 1.38 (t, J=6.8Hz, 3H)；LCMS:tR=3.27min, 450.34 [M+H+].
Step 2:(R) -4- (2'- difluoro-methoxy-xenyl -4- base) -3- (ethyoxyl oxalyl<oxalyl>- amino) Ethyl butyratePreparation
(R) -3- tertbutyloxycarbonylamino -4- (2'- difluoro-methoxy-xenyl -4- base) ethyl butyrate (2g, 10 milliliters of methylene chloride 4.4mmol) are dissolved in, ice water 2 milliliters of trifluoroacetic acids of cooling lower dropwise addition are stirred at room temperature 2 hours, are steamed with rotation Hair instrument steams solvent, and residue is dissolved in 10 milliliters of methylene chloride, and 1 milliliter of triethylamine, the cooling lower dropwise addition oxalyl chloride list of ice water is added Ethyl ester (0.8g, 5.8mmol) is added dropwise and is stirred at room temperature 1 hour, and 10 milliliters of saturated sodium bicarbonate aqueous solutions, stirring 10 is added Minute, liquid separation, water phase is extracted with 10 milliliters of methylene chloride, is merged methylene chloride phase, is dried, filtered, steamed with anhydrous sodium sulfate Filtrate, residue are purified by silica gel column chromatography to obtain (R) -4- (2'- difluoro-methoxy-xenyl -4- base) -3- (ethyoxyl grass Acyl<oxalyl>-amino) ethyl butyrate (1.96g).
1HNMR(CDCl3, 400MHz) and δ 7.53 (s, 1H), 7.43 (d, J=8.4Hz, 2H), 7.37 (m, 1H), 7.20 (d, J =8.2Hz, 2H), 7.03 (s, 0.5H), 6.81-7.18 (m, 3H), 6.95 (s, 0.5H), 4.50-4.53 (m, 1H), 4.32 (q, ), J=7.2Hz 4.17-4.27 (m, 2H), 3.78 (s, 3H), 2.91-3.10 (m, 2H), 2.58 (d, J=6.2Hz, 2H), 1.38 (t, J=6.8Hz, 3H), 1.30 (t, J=7.2Hz, 3H)；LCMS:tR=4.07min, 450.34 [M+H+].
Step 3:(R)-4-(2'-Difluoro-methoxyXenyl -4- base) -3- (diazanyl<hydrazino>oxalyl<oxalyl>- Amino) ethyl butyratePreparation
(R) -4- (2'- difluoro-methoxy-xenyl -4- base) -3- (ethyoxyl oxalyl<oxalyl>- amino) ethyl butyrate (6.12g, 13.6mmol) is dissolved in 10 milliliters of dehydrated alcohols, is added hydrazine hydrate (1ml, 85%), reaction system is stirred at room temperature 1 Hour, 5 milliliters of cold water are added, stir 10 minutes, the white solid filtering of precipitation obtains (R) -4- (2'- after collecting solid drying Difluoro-methoxy-xenyl -4- base) -3- (diazanyl<hydrazino>oxalyl<oxalyl>- amino) ethyl butyrate (5.26g).
1HNMR(CDCl3, 400MHz) and δ 7.42 (s, 1H), 7.23 (d, J=8.4Hz, 2H), 7.37 (m, 1H), 7.20 (d, J =8.2Hz, 2H), 7.00-7.05 (m, 3H), 7.03 (s, 0.5H), 6.81-7.18 (m, 3H), 6.95 (s, 0.5H), 4.50- 4.53 (m, 1H), 4.17-4.27 (m, 2H), 3.78 (s, 3H), 2.91-3.10 (m, 2H), 2.58 (d, J=6.2Hz, 2H), (1.30 t, J=7.2Hz, 3H)；LCMS:tR=2.03min, 436.04 [M+H+].
Step 4:(R) -4- (2'- difluoro-methoxy -Xenyl- 4- base) [(dihydro-[1,3,4] 5- carbonyl -4,5- -3- Oxadiazoles -2- carbonyl)-amino] ethyl butyratePreparation
(R) -4- (2'- difluoro-methoxy-xenyl -4- base) -3- (diazanyl<hydrazino>oxalyl<oxalyl>- amino) fourth Acetoacetic ester (4.35g, 10mmol) is dissolved in 50 milliliters of methylene chloride at room temperature, is added carbonyl dimidazoles (2.4g, 14mmol), instead It answers system to be stirred at room temperature overnight, steams solvent with Rotary Evaporators, residue obtains (R) -4- (2'- through column chromatographic purifying Difluoro-methoxy-xenyl -4- base) -3- [(5- carbonyl -4,5- dihydro-[1,3,4] oxadiazoles -2- carbonyl)-amino] butyric acid second Ester (4.05g).
1HNMR(MeOH-d4, 400MHz) and δ 7.44 (s, 1H), 7.37 (m, 1H), 7.20 (d, J=8.2Hz, 2H), 7.00- 7.05(m,3H),7.03(s,0.5H),6.97(s,1H),6.95(s,0.5H),4.50-4.53(m,1H),4.17-4.27(m, 2H), 3.78 (s, 3H), 2.91-3.10 (m, 2H), 2.58 (d, J=6.2Hz, 2H), 1.30 (t, J=7.2Hz, 3H)；LCMS: tR=2.23min, 462.14 [M+H+].
Embodiment 2:(R) -4- (5 '-chloro- 2 '-difluoro-methoxies-xenyl -4- base) -3- [(5- carbonyl -4,5- dihydro - [1,3,4] oxadiazoles -2- carbonyl)-amino] butyric acid
(R) -4- (2'- difluoro-methoxy-xenyl -4- base) -3- [(5- carbonyl -4,5- dihydro-[1,3,4] oxadiazoles - 2- carbonyl)-amino] ethyl butyrate (4.05g, 8.8mmol) is dissolved in 25 milliliter of 95% ethyl alcohol, sodium hydrate solid is added (1.5g), is stirred overnight at room temperature, and steams ethyl alcohol, and 5 milliliters of water are added, and 3N sulphur acid for adjusting pH value is added in 1-2, directly uses reversed-phase column Chromatographic purifying (acetonitrile/water system) obtains light yellow solid (3.483g).
1HNMR(DMSO-d6, 400MHz) and δ 11.85 (s, 1H), 7.54 (s, 1H), 7.37 (m, 1H), 7.20 (d, J= 8.2Hz,2H),7.00-7.05(m,3H),7.03(s,0.5H),6.97(s,1H),6.95(s,0.5H),4.50-4.53(m, 1H), 3.78 (m, 3H), 2.91-3.10 (m, 2H), 2.58 (d, J=6.2Hz, 2H)；LCMS:tR=2.03min, 422.18 [M- H]-.
Embodiment 3:4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- [(5- carbonyl -4,5- dihydro-[1,3, 4] oxadiazoles -2- carbonyl)-amino] ethyl butyrate
The preparation method is the same as that of Example 1.
1HNMR(MeOH-d4, 400MHz) and δ 7.34 (s, 1H), 7.27 (s, 1H), 7.20 (d, J=8.2Hz, 2H), 7.00- 7.05(m,3H),7.03(s,0.5H),6.95(s,0.5H),4.50-4.53(m,1H),4.17-4.27(m,2H),3.78(s, 3H), 2.91-3.10 (m, 2H), 2.58 (d, J=6.2Hz, 2H), 1.30 (t, J=7.2Hz, 3H)；LCMS:tR=2.30min, 480.04[M+H+].
Embodiment 4:4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- [(5- carbonyl -4,5- dihydro-[1,3, 4] oxadiazoles -2- carbonyl)-amino] butyric acid
Preparation method is the same as embodiment 2.
1HNMR(DMSO-d6, 400MHz) and δ 12.03 (s, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 7.20 (d, J= 8.2Hz,2H),7.00-7.05(m,3H),7.03(s,0.5H),6.95(s,0.5H),4.50-4.53(m,1H),3.78(m, 3H), 2.91-3.10 (m, 2H), 2.58 (d, J=6.2Hz, 2H)；LCMS:tR=2.13min, 450.18 [M-H]-.
Embodiment 5:4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- [(5- carbonyl -4,5- dihydro-[1,3, 4] oxadiazoles -2- carbonyl)-amino]-butyric acid -1- cyclohexyloxy carbon oxygroup ethyl ester
Step 1:(R) -3- { [5- (tert-butyl-dimethyl-silane oxygroup)-[1,3,4] oxadiazoles -2- carbonyl]-ammonia Base } -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) butyric acid preparation
(R) -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- [(is disliked dihydro-[1,3,4] 5- carbonyl -4,5- Diazole -2- carbonyl)-amino] butyric acid (2.856g, 6.3mmol) and DMAP (85mg) be dissolved in 10 milliliters of methylene chloride, it is added 0.5 Milliliter triethylamine, is added tert-butyl chloro-silicane (1.5g), is stirred overnight at room temperature, and 10 milliliters of water are added, and stirs 10 minutes, Liquid separation, water phase are extracted with 10 milliliters of methylene chloride, are merged methylene chloride phase, are dried, filtered with anhydrous sodium sulfate, use rotary evaporation Instrument is evaporated the pale yellowish oil thick liquid of filtrate, this liquid is directly used in the next step without being further purified.
Step 2:4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- [(5- carbonyl -4,5- dihydro-[1,3, 4] oxadiazoles -2- carbonyl)-amino]-butyric acid -1- cyclohexyloxy carbon oxygroup ethyl esterPreparation
(R) -3- { [5- (t-butyl-dimethyI-sila oxygroup)-[1,3,4] oxadiazoles -2- carbonyl]-amino } -4- (2'- Fluoro- xenyl -4- the base of difluoro-methoxy -5'-) butyric acid (0.865g, 1.53mmol) is dissolved in 15 milliliters of acetonitriles, potassium carbonate is added (800mg) and potassium iodide (1.2g) is added the chloro- ethyl ester carbonic acid cyclohexyl (1ml) of 1-, is stirred overnight at room temperature, filters, with rotation Turn evaporimeter and be evaporated filtrate, residue obtains thick pale yellow oily liquids (0.803g) through column chromatographic purifying.By this oily liquid Body is dissolved in 10 milliliters of tetrahydrofurans, and TBAF (3ml, 1M in THF) is added at room temperature, stirs 30 minutes, steams solvent, residue It is purified by silica gel column chromatography to obtain light yellow solid (563mg).
Embodiment 6:(R, R) -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- [(5- carbonyl -4,5- two Hydrogen-[1,3,4] oxadiazoles -2- carbonyl)-amino]-butyric acid -1- cyclohexyloxy carbon oxygroup ethyl ester
Embodiment 6 (338mg) is obtained by the chiral column chromatographic resolution of embodiment 5 (500mg).Chiral column type number: CHIRALPAK AD-H；Chiral column specification: 0.46cm X 15cm；Mobile phase: petroleum ether/isopropanol (80/20, volume ratio), it is different The acetic acid of addition 5% in propyl alcohol；Flow velocity: 2ml/min；Detection wavelength: 254nm.
1HNMR(DMSO-d6, 400MHz) and δ 7.44 (s, 1H), 7.27 (s, 1H), 7.20 (d, J=8.2Hz, 2H), 7.00- 7.05 (m, 3H), 7.03 (s, 0.5H), 6.95 (s, 0.5H), 6.60 (q, J=5.4Hz, 1H), 4.50-4.53 (m, 1H), 3.78-3.92 (m, 4H), 2.91-3.10 (m, 2H), 2.58 (d, J=6.2Hz, 2H), 1.61 (d, J=7.6Hz, 3H), 1.14- 1.27(m,10H),；LCMS:tR=2.13min, 622.18 [M+H]+.
Embodiment 7:(R, S) -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- [(5- carbonyl -4,5- two Hydrogen-[1,3,4] oxadiazoles -2- carbonyl)-amino]-butyric acid -1- cyclohexyloxy carbon oxygroup ethyl ester
Embodiment 7 (135mg) is obtained by the chiral column chromatographic resolution of embodiment 5 (500mg).Chiral column type number: CHIRALPAK AD-H；Chiral column specification: 0.46cm X 15cm；Mobile phase: petroleum ether/isopropanol (80/20, volume ratio), it is different The acetic acid of addition 5% in propyl alcohol；Flow velocity: 2ml/min；Detection wavelength: 254nm.
1HNMR(DMSO-d6, 400MHz) and δ 7.44 (s, 1H), 7.27 (s, 1H), 7.20 (d, J=8.2Hz, 2H), 7.00- 7.05 (m, 3H), 7.03 (s, 0.5H), 6.95 (s, 0.5H), 5.87 (q, J=5.4Hz, 1H), 4.50-4.53 (m, 1H), 3.78-3.92 (m, 4H), 2.91-3.10 (m, 2H), 2.58 (d, J=6.2Hz, 2H), 1.61 (d, J=7.6Hz, 3H), 1.14- 1.27(m,10H),；LCMS:tR=2.13min, 622.18 [M+H]+.
Embodiment 8:4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- [(5- carbonyl -4,5- dihydro-[1,3, 4] oxadiazoles -2- carbonyl)-amino]-butyric acid -1- isopropoxy carbon oxygroup ethyl ester
(R) -3- { [5- (t-butyl-dimethyI-sila oxygroup)-[1,3,4] oxadiazoles -2- carbonyl]-amino } -4- (2'- Fluoro- xenyl -4- the base of difluoro-methoxy -5'-) butyric acid (0.500g, 0.884mmol) is dissolved in 10 milliliters of acetonitriles, potassium carbonate is added (500mg) and potassium iodide (0.8g) is added the chloro- ethyl ester propylene carbonate (0.6ml) of 1-, is stirred overnight at room temperature, filters, and uses Rotary Evaporators are evaporated filtrate, and residue obtains thick pale yellow oily liquids (0.487g) through column chromatographic purifying.By this oily Liquid is dissolved in 10 milliliters of tetrahydrofurans, is added TBAF (2ml, 1M in THF), stirs 30 minutes, steams solvent, residue is through silicon It is gel column chromatography eluting to obtain light yellow solid (457mg).
Embodiment 9:4- (the chloro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- [(5- carbonyl -4,5- dihydro-[1,3, 4] oxadiazoles -2- carbonyl)-amino]-butyric acid -1- cyclohexyloxy carbon oxygroup ethyl ester
Preparation method is the same as embodiment 5.
Embodiment 10:4- (the chloro- 2'- difluoro-methoxy of 5'--xenyl -4- base) -3- [(5- carbonyl -4,5- dihydro-[1, 3,4] oxadiazoles -2- carbonyl)-amino]-butyric acid -1- isopropoxy carbon oxygroup ethyl ester
Preparation method is the same as embodiment 8.
Embodiment 11:(R)-amino) -4- (the chloro- xenyl -4- base of 2'- difluoro-methoxy -5'-)-butyric acid-cyclohexyloxy Carbon oxygroup ethyl ester
Step 1:(R) -3- t-butoxy carbonylamino -4- (the chloro- 2'- difluoro-methoxy of 5'--xenyl -4- base)-fourth Acid-cyclohexyloxy carbon oxygroup ethyl esterPreparation
(R) -3- t-butoxy carbonylamino -4- (the chloro- 2'- difluoro-methoxy of 5'--xenyl -4- base) butyric acid (0.650g, 1.43mmol) is dissolved in 15 milliliters of acetonitriles, and potassium carbonate (780mg) and potassium iodide (1.1g) is added, and the chloro- ethyl of 1- is added Ester carbonic acid cyclohexyl (0.85ml), is stirred overnight at room temperature, and filtering is evaporated filtrate with Rotary Evaporators, residue is chromatographed through column Purifying obtains thick pale yellow oily liquids (0.603g).
Step 2:(R)-amino) -4- (the chloro- xenyl -4- base of 2'- difluoro-methoxy -5'-) butyric acid-cyclohexyloxy carbon oxygen Base ethyl esterPreparation
(R) -3- t-butoxy carbonylamino -4- (the chloro- 2'- difluoro-methoxy of 5'--xenyl -4- base)-butyric acid-hexamethylene Oxygroup carbon oxygroup ethyl ester (0.603g, 1.32mmol) is dissolved in 10 milliliters of methylene chloride, and 1 milliliter of trifluoroacetic acid is added, stirs at room temperature It mixes 1 hour, solvent evaporated, residue is dissolved in 10 milliliters of acetonitriles, and 1 milliliter of triethylamine is added, and succinic acid tertiary butyl ester -5- two is added Carbonyl-pyrrolidin-1-yl ester (1g), is stirred overnight at room temperature, solvent evaporated, residue obtains a clear yellow viscous through column chromatographic purifying Liquid, this liquid are dissolved in 10 milliliters of methylene chloride, and 1 milliliter of trifluoroacetic acid is added, and stir 1 hour at room temperature, solvent evaporated, residual The inverted column chromatographic purifying of object obtains white solid (0.439g).
1HNMR(DMSO-d6, 400MHz) and δ 11.78 (br s, 1H), 8.05 (d, J=8.4Hz, 1H), 7.58 (dd, J= 6.8,2.8Hz, 1H), 7.50 (dd, J=8.4,1.6Hz, 2H),
7.44 (s, 1H), 7.20 (d, J=8.2Hz, 2H), 7.03 (s, 0.5H), 6.95 (s, 0.5H), 6.61 (0.6H), 5.87 (0.4H), 4.50-4.53 (m, 1H), 3.78-3.92 (m, 4H), 2.91-3.10 (m, 2H), 2.58 (d, J=6.2Hz, 2H), 2.5-2.45 (m, 4H), 1.61 (d, J=7.6Hz, 3H), 1.14-1.27 (m, 10H),；LCMS:tR=3.13min, 625.18[M-H]-.
Embodiment 12,(R) -3- (3- carboxyl-propionamido) -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) - Butyric acid 1- cyclohexyloxy carbon oxygroup ethyl ester
The preparation method is the same as that of Example 11.
Embodiment 13,(R) -3- (3- carboxyl-propionamido) -4- (the chloro- 2'- difluoro-methoxy of 5'--xenyl -4- base) - Butyric acid-isopropoxy carbon oxygroup ethyl ester
The preparation method is the same as that of Example 11.
Embodiment 14,(R) -3- (3- carboxyl-propionamido) -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) Ethyl butyrate
(R) -3- tertbutyloxycarbonylamino -4- (the fluoro- 2'- difluoro-methoxy of 5--xenyl -4- base) ethyl butyrate (1.2g, 2.57mmol) is dissolved in 10 milliliters of methylene chloride, and ice water 2 milliliters of trifluoroacetic acids of cooling lower dropwise addition are stirred at room temperature 2 hours, Solvent is steamed with Rotary Evaporators, residue is dissolved in 10 milliliters of methylene chloride, and 1 milliliter of triethylamine, the cooling lower addition of ice water is added Succinic acid tertiary butyl ester -5- dicarbapentaborane-pyrrolidin-1-yl ester (1.27g), is stirred overnight at room temperature, and 10 milliliters of unsaturated carbonates are added Hydrogen sodium water solution stirs 10 minutes, and liquid separation, water phase is extracted with 10 milliliters of methylene chloride, merges organic phase, solvent evaporated, residual Object is dissolved in 10 milliliters of methylene chloride, and 2 milliliters of trifluoroacetic acids are added, and is stirred at room temperature 1 hour, and 10 milliliters of water, liquid separation are added, and water phase is used 10 milliliters of methylene chloride extractions, merge organic phase, are evaporated, the inverted column chromatographic purifying of residue (acetonitrile/water system) obtains white Solid (0.764g).
1HNMR(CDCl3, 400MHz) δ 11.38 (br s, 1H), 7.65 (d, J=8.4Hz, 1H), 7.58 (dd, J=6.8, 2.8Hz, 1H), 7.50 (dd, J=8.4,1.6Hz, 2H), 7.44 (s, 1H), 7.20 (d, J=8.2Hz, 2H), 7.03 (s, 0.5H),6.95(s,0.5H),6.61(0.6H),5.87(0.4H),4.50-4.53(m,1H),3.78-3.92(m,4H), 2.91-3.10 (m, 2H), 2.58 (d, J=6.2Hz, 2H), 2.5-2.45 (m, 4H), 1.61 (d, J=7.6Hz, 3H)；LCMS: tR=2.73min, 466.18 [M-H]-.
Embodiment 15:3- (3- carboxyl-propionamido) -4- (2'- difluoro-methoxy-xenyl -4- base) butyric acid-hexamethylene oxygen Base carbon oxygroup ethyl ester
The preparation method is the same as that of Example 11.LCMS:tR=3.53min, 590.18 [M-H]-.
Embodiment 16:3- (3- carboxyl-propionamido) -4- (2'- difluoro-methoxy-xenyl -4- base) butyric acid 1- isopropyl Oxygroup carbon oxygroup-ethyl ester
Preparation method is the same as embodiment 9.LCMS:tR=3.12min, 550.21 [M-H]-.
Embodiment 17:3- (3- carboxyl-propionamido) -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) butyric acid Isopropoxy carbon oxygroup methyl esters
Step 1:(R) -3- tertbutyloxycarbonylamino -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) butyric acid Isopropoxy carbon oxygroup methyl estersPreparation
(R) -3- tertbutyloxycarbonylamino -4- (the fluoro- 2'- difluoro-methoxy of 5--xenyl -4- base) butyric acid (500mg, 10 milliliters of acetonitriles 1.138mmol) are dissolved in, potassium carbonate (300mg) and potassium iodide (250mg) is added, chloromethyl isobutyl carbonate third is added Ester (695mg), is stirred overnight at room temperature, filtering, is evaporated filtrate, and residue is directly used in react in next step.
Step 2:3- (3- carboxyl-propionamido) -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) butyric acid is different Propoxyl group carbon oxygroup methyl estersPreparation
Previous step to crude product be dissolved in 10 milliliters of methylene chloride, 1.5 milliliters of trifluoroacetic acids are added, are stirred at room temperature 2 hours, With Rotary Evaporators solvent evaporated, residue is dissolved in 10 milliliters of acetonitriles, and 1 milliliter of triethylamine is added, and succinic acid tertiary butyl ester-is added 5- dicarbapentaborane-pyrrolidin-1-yl ester (300mg), is stirred overnight at room temperature, and filtering is evaporated filtrate, residue is dissolved in 10 milliliters of dichloros Methane, is added 1.5 milliliters of trifluoroacetic acids, solvent evaporated, and residue obtains pale yellow viscous liquid through column chromatographic purifying (218mg)。
LCMS:tR=3.09min, 554.21 [M-H]-.
Embodiment 18:3- (3- carboxyl-propionamido) -4- (the chloro- 2'- difluoro-methoxy of 5'--xenyl -4- base)-butyric acid Isopropoxy carbon oxygroup methyl esters
The preparation method is the same as that of Example 17.
Embodiment 19:(R) -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- (3- phosphorus carboxyl-propionyl ammonia Base) ethyl butyrate
(R) -3- tertbutyloxycarbonylamino -4- (the fluoro- 2'- difluoro-methoxy of 5--xenyl -4- base) ethyl butyrate (250mg, 0.5mmol) is dissolved in 5 milliliters of methylene chloride, and the Isosorbide-5-Nitrae-epoxy dioxane solution of 2.5 milliliters of hydrogen chloride is added, is stirred at room temperature 1 hour, solvent evaporated, residue was dissolved in 5 milliliters of methylene chloride, was added HATU (450mg), and 3- phosphonopropionic acid is added (175mg) is added 1 milliliter of triethylamine, is stirred at room temperature 3 hours, steams solvent, the inverted column chromatographic purifying (acetonitrile/water of residue System) obtain white solid (196mg).
1HNMR(MeOH-d4, 400MHz) and δ 7.37 (m, 1H), 7.20 (d, J=8.2Hz, 2H), 7.00-7.05 (m, 3H), 7.03(s,0.5H),6.97(s,1H),6.95(s,0.5H),4.50-4.53(m,1H),3.08-2.87(m,3H),2.91- 3.10 (m, 4H), 2.58 (d, J=6.2Hz, 2H), 1.47-1.39 (m, 3H)；LCMS:tR=1.93min, 502.18 [M-H]-.
Embodiment 20:4- (the chloro- 2'- difluoro-methoxy of 5'--xenyl -4- base) -3- (3- phosphorus carboxyl-propionamido) fourth Acetoacetic ester
The preparation method is the same as that of Example 19.
1HNMR(MeOH-d4, 400MHz) and δ 7.37 (m, 1H), 7.20 (d, J=8.2Hz, 2H), 7.00-7.05 (m, 3H), 7.03(s,0.5H),6.97(s,1H),6.95(s,0.5H),4.50-4.53(m,1H),3.08-2.87(m,3H),2.91- 3.10 (m, 4H), 2.58 (d, J=6.2Hz, 2H), 1.47-1.39 (m, 3H)；LCMS:tR=2.03min, 518.48 [M-H]-.
Embodiment 21:4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- (3- phosphorus carboxyl-propionamido)-fourth Acid -5- base -2- carbonyl-[1,3] dioxazole -4- base methyl esters
Step 1:(R) -3- t-butoxy carbonylamino -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-)-fourth Acid -5- methyl -2- carbonyl-[1,3] dioxazole -4- base methyl estersPreparation
(R) -3- tertbutyloxycarbonylamino -4- (the fluoro- 2'- difluoro-methoxy of 5--xenyl -4- base) ethyl butyrate (150mg, 0.34mmol) and 4- methylol -5- methyl-[1,3] dioxazole -2- ketone (75mg) are dissolved in 5 milliliters of methylene chloride, add Enter HATU (250mg), 0.5 milliliter of triethylamine is added, is stirred at room temperature 3 hours, solvent evaporated, residue is obtained through column chromatographic purifying Pale yellowish oil liquid (147mg).
Step 2:4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- (3- phosphorus carboxyl-propionamido)-fourth Acid -5- base -2- carbonyl-[1,3] dioxazole -4- base methyl estersPreparation
(R) -3- t-butoxy carbonylamino -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-)-butyric acid -5- first Base -2- carbonyl-[1,3] dioxazole -4- base methyl esters (147mg) is dissolved in 5 milliliters of methylene chloride, and 0.3 milliliter of trifluoroacetic acid, room is added Temperature stirring 1 hour, solvent evaporated, residue is dissolved in 5 milliliters of methylene chloride, 3- phosphonopropionic acid (85mg) is added, HATU is added (250mg) is added 0.5 milliliter of triethylamine, is stirred at room temperature 3 hours, solvent evaporated, and the inverted column chromatographic purifying of residue obtains shallowly Yellow oily liquid (87mg).
1HNMR(MeOH-d4, 400MHz) and δ 7.37 (m, 1H), 7.20 (d, J=8.2Hz, 2H), 7.00-7.05 (m, 3H), 7.03(s,0.5H),6.97(s,1H),6.95(s,0.5H),4.76(s,2H),4.50-4.53(m,1H),3.08-2.87(m, 2H), 2.91-3.10 (m, 2H), 2.58 (d, J=6.2Hz, 2H), 2.47 (d, J=6.4Hz, 2H), 1.87 (s, 3H)；LCMS: tR=2.03min, 586.48 [M-H]-.
Embodiment 22:(R) -4- (the chloro- 2'- difluoro-methoxy of 5'--xenyl -4- base) -3- (3- phosphorus carboxyl-propionyl ammonia Base)-butyric acid -5- methyl -2- carbonyl-[1,3] dioxazole -4- base methyl esters
Preparation method is the same as embodiment 21.1HNMR(MeOH-d4, 400MHz) and δ 7.37 (m, 1H), 7.20 (d, J=8.2Hz, 2H),7.00-7.05(m,3H),7.03(s,0.5H),6.97(s,1H),6.95(s,0.5H),4.76(s,2H),4.50-4.53 (m, 1H), 3.08-2.87 (m, 2H), 2.91-3.10 (m, 2H), 2.58 (d, J=6.2Hz, 2H), 2.47 (d, J=6.4Hz, 2H),1.87(s,3H)；LCMS:tR=2.14min, 602.48 [M-H]-.
Embodiment 23:(R) -4- (the fluoro- 2'- trifluoromethoxy of 5'--xenyl -4- base) -3- [(5- carbonyl -4,5- dihydro - [1,3,4] oxadiazoles -2- carbonyl)-amino] ethyl butyrate
The preparation method is the same as that of Example 1.
1HNMR(MeOH-d4, 400MHz) and δ 7.34 (s, 1H), 7.37 (m, 1H), 7.20 (d, J=8.2Hz, 2H), 7.00- 7.05(m,3H),6.97(s,1H),4.50-4.53(m,1H),4.17-4.27(m,2H),3.78(s,3H),2.91-3.10(m, 2H), 2.58 (d, J=6.2Hz, 2H), 1.30 (t, J=7.2Hz, 3H)；LCMS:tR=2.38min, 498.14 [M+H+].
Biological experiment: NEP enzyme inhibits test
Following in vitro test can be used to measure the compounds of this invention for the inhibitory activity of NEP enzyme in rat plasma, Activity can use IC50Value indicates.The half-inhibitory concentration IC of compound50(by certain density inhibition of enzyme activity to 50% when institute The compound concentration needed) it is by will be after the untested compound hybrid reaction of a certain amount of enzyme and specific substrate and various concentration What tester calculated.This experiment NEP enzyme system used is taken from the new blood of normal SD rats, is placed in anticoagulant containing heparin sodium In the pipe of agent, after 5000rpm, 4 DEG C of centrifugation 10min, blood plasma is collected；Prepare the nep inhibitor of various concentration, wherein NEP inhibits The final concentration of 100uM of the highest of agent, and successively diluted 10 times with 3 times of gradients；The rat plasma that every hole adds 60ul fresh is in 384 holes Plate；Then, every hole adds the nep inhibitor of 10ul gradient dilution；37 DEG C, after being incubated for 30min, 10ul 10uM is added in every hole Substrate (SenoLyte 520Neprilysin Activity Assay Kit, AnaSpec, 72223)；In 37 DEG C of incubation 18h (±1h)；Under the wavelength of exciting light 490nm and transmitting light 520nm, fluorescence signal is measured；And it is asked using 5.0 software of Prism Obtain IC50。
The NEP enzyme inhibition activity of the compounds of this invention is measured by above test, the IC measured50Value see the table below.
Conclusion: compound of the embodiment of the present invention has significantly inhibiting effect to NEP enzyme in SD rat plasma.
Although the present invention is disclosed as above with preferred embodiment, however, it is not to limit the invention, any this field skill Art personnel, without departing from the spirit and scope of the present invention, when can make a little modification and perfect therefore of the invention protection model It encloses to work as and subject to the definition of the claims.

Claims (6)

1. (2'- alkoxy -4- xenyl) butanoic acid derivative of 3- amide groups -4- shown in the following general formula (I) and its racemic modification, Corresponding isomers, non-corresponding isomers, chiral optically pure isomer:
Wherein R1For hydrogen, C1-C8Alkyl, C3-C6Naphthenic base, alkali metal, alkaline-earth metal, R5For hydrogen, C1-C3Alkyl or C3-C6Naphthenic base；R6For C1-C6Alkyl, C3-C6Naphthenic base；R2For hydrogen atom, halogen Plain atom, C3-C6Naphthenic base, C1-C6Alkyl；R3For hydrogen；R4For
2. 3- amide groups -4- (2 '-alkoxy -4- xenyl) butanoic acid derivative as described in claim 1, which is characterized in that The derivative is (R) -4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- (3- phosphorus carboxyl-propionamido) butyric acid Ethyl ester；4- (the chloro- 2'- difluoro-methoxy of 5'--xenyl -4- base) -3- (3- phosphorus carboxyl-propionamido)
Ethyl butyrate；4- (the fluoro- xenyl -4- base of 2'- difluoro-methoxy -5'-) -3- (3- phosphorus carboxyl-propionamido)-butyric acid - 5- methyl -2- carbonyl-[1,3] dioxazole -4- base methyl esters；(R) -4- (the chloro- 2'- difluoro-methoxy of 5'--xenyl -4- base) -3- (3- phosphorus carboxyl-propionamido)-butyric acid -5- methyl -2- carbonyl-[1,3] dioxazole -4- base methyl esters.
3. a kind of pharmaceutical composition, which is characterized in that the 3- amide groups -4- of any of claims 1 or 2 containing therapeutically effective amount (2'- alkoxy -4- xenyl) butanoic acid derivative, pharmaceutically acceptable carrier and pharmaceutically acceptable salt.
4. pharmaceutical composition as claimed in claim 3, which is characterized in that in described pharmaceutical composition containing angiotensins by Body retarding agent or angiotensin converting enzyme inhibitors.
5. pharmaceutical composition as claimed in claim 4, which is characterized in that the angiotensin receptor blocker is that figured silk fabrics is husky Smooth, Aomei sandy beach or Losartan；The angiotensin converting enzyme inhibitors are enalapril or lisinopril.
6. prepared by a kind of 3- amide groups -4- as claimed in claim 1 or 2 (2 '-alkoxy -4- xenyl) butanoic acid derivative Treat or prevent hypertension, pulmonary hypertension, the application in heart failure and kidney trouble drug.
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