CN101007791A - Amino acid diphenyl compound - Google Patents
Amino acid diphenyl compound Download PDFInfo
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- CN101007791A CN101007791A CN 200710036444 CN200710036444A CN101007791A CN 101007791 A CN101007791 A CN 101007791A CN 200710036444 CN200710036444 CN 200710036444 CN 200710036444 A CN200710036444 A CN 200710036444A CN 101007791 A CN101007791 A CN 101007791A
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- phenmethyl
- oxadiazole
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Abstract
The invention discloses an amino acid phenyl benzene, which is comprised of phenyl benzene, amino acid and oxdiazole organically. It is the receptor blocking agent for angiotensin II and can be used for preparing medicine for treating or preventing high blood pressure, coronary disease, cerebrovascular disease, cephalagra, pulmonary arterial hypertension and so on.
Description
Technical field
The present invention relates to the medical chemistry field, relate in particular to the amino-acid biphenyl compound that a class has diseases such as treatment hypertension and other heart brain and kidney blood vessel diseases, migraine, pulmonary hypertension.
Background technology
From the forties in 19th century essential hypertension be identified, antihypertensive drug has experienced following development course.The forties in 20th century is at first with nerve block medicine hexamethonium treatment malignant hypertension, the fifties hydragog(ue), the sixties adrenolytic blocking agent, further developing of the alpha-blocking agent seventies, the eighties angiotensin-convertion enzyme inhibitor, calcium channel blocker, the beginning of angiotensin receptor antagonist etc. nineties antihypertensive drug of new generation used, and obtained flourish.
People such as Marshall had synthesized first receptor antagonist non-peptide compound Saralasin (Sarala-sin:Sarl-Ala8-Ang II) in 1970, and the structure of it and A II is quite similar, and it has the specificity antagonistic action in vitro tissue.But in clinical practice is used since exist oral invalid, metabolism instability, and have part A II agonism and be restricted.Nineteen eighty-two, Japan military field drugmaker does the time spent at the diuretic antihypertensive of research imidazoleacetic acid compounds, find that at first S-8307 can suppress rabbit arterial contraction and pressor effect that A II brings out, though activity a little less than, but belong to A II acceptor specificity antagonist, and do not have the stirring effect of Saralasin.The latter stage eighties, (the Med.Rev.1992 of Dupont company, 12:149-158) with Smithkline Beecham (Drugs of the fixture.1992,17:575-593) the researchist of company, utilize two kinds of differing molecular models of the A II activity conformation of supposition, C-stub area and the S-8307 of A II are arranged relatively, S-8307 has been carried out serial structural modification, strengthening the avidity with acceptor, the result obtained respectively two kinds of different types of structure, all have the Compound D up-753 (Losartan) and a SK﹠amp of greater activity; F-108566 (Eprosartan), Losartan in 1994 at Sweden listing (Drngs of the Future.1997,22:1079-1085), Eprosartan in 1997 in Germany listing (Drugs of thefuture.1996,21 (8): 794-798).
At present, non-peptide class A II receptor antagonist is with it and A II receptor affinity is strong, selectivity is high, oral effectively, advantage such as long action time and being expected, be the up-and-coming depressor of a class.Since Dupont company finds Losartan, each big drugmaker of the world has all participated in the research work of A II receptor antagonist, synthetic in succession and filter out large quantities of non-peptide class aii receptor antagonists with strong antihypertensive activity, as losartan (Losartan), valsartan (Valsartan), Candesartan (Candesartan), Irb (Irbesartan), Olmesartan (Olmesartan), telmisartan (Telmisartan), Yi Pushatan (Eprosartan) and Ai Lishatan (Elisartan).
Present marketed drug and enter that great majority have all comprised the tetrazole group in the compound of clinical trial, but because there is certain defective in the synthetic and metabolism of tetrazole, synthetic need use toxic and explosive triazo-compound as it, in vivo it easily with the form of glucoside acidifying by metabolism, cause chemical combination object internal memory to shorten (Drug Metab Dispos in the time, 1993,21:792-799).And when containing 2 acidic-groups in the compound (tetrazole and carboxyl), because its polarity is big, general oral administration biaavailability is not high, need to form prodrug with improve oral property (Bioorg MedChem Lett, 1944,4:201-206).
Summary of the invention
Technical problem to be solved by this invention is to provide the class of amino acid biphenol compound, to solve defective of the prior art.
Principle of the present invention is to utilize 5-oxo-1,2,4-oxadiazole and carboxyl tool equipotentiality (AnnuRep Med Chem, 1986,21:283-291), have than tetrazole that better lipotropy, oral administration biaavailability are higher, the characteristics of synthetic route safety, biphenyl and amino acid, oxadiazole are organically coupled together, and series compound has been synthesized in design, and this compound is the compound of structural formula (I):
Wherein, R
1Be positive alkyl; R
2Be alkyl or heterocyclic radical; R
3Wei oxadiazole group, optimum seeking site is the ortho position.
R wherein
1Be preferably n-propyl or normal-butyl, that is :-CH
2CH
2CH
2CH
3-CH
2CH
2CH
3
R
2Be preferably 2-methyl butyl, 3-methyl butyl, 2-phenmethyl or 3-indyl methyl, that is:
-CH (CH
3) CH
2CH
3-CH
2CH (CH
3) CH
3 
Or
Wherein R3 is
, preferred positions is an adjacent, i.e. 5-oxo-1,2,4-oxadiazole.
Wherein preferred compound is:
(S)-and the positive butyryl radicals N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl Isoleucine;
(S)-and the positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl Isoleucine;
(S)-and the positive butyryl radicals-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl phenylalanine;
(S)-and the positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl phenylalanine;
(S)-and the positive butyryl radicals-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl tryptophane;
(S)-and the positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl tryptophane;
(S)-and the positive butyryl radicals-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl leucine;
(S)-and the positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl leucine.
The present invention also provides the preparation method of this compound, and the concrete steps of this method are:
Esterification takes place and generates amino acid methyl ester in amino acid and methyl alcohol under the sulfur oxychloride effect; This amino acid methyl ester and 2 '-cyano group-4-bromomethylbiphenyl generation alkylated reaction thereafter with acyl chlorides generation acylation reaction, generates the positive alkyloyl-N-[4-of (S)-N-(2-cyano-phenyl)] the phenmethyl amino acid methyl ester; After this acylate and the oxammonium hydrochloride reaction,, heat cyclization then, generate the positive alkyloyl-N-[4-of (S)-N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl) with the chloro-formic ester reaction] the phenmethyl amino acid methyl ester; Continue you with the methyl esters hydrolysis, make amino-acid biphenyl compound.
Those skilled in the art can synthesize this compound according to foregoing description.
Through further discovering, above-claimed cpd has prevention or therapeutic action preferably to diseases such as hypertension, heart brain and kidney blood vessel diseases, migraine, pulmonary hypertensions.Therefore, compound of the present invention can be used for preparing the medicine that prevents or treat diseases such as hypertension, heart brain and kidney blood vessel diseases, migraine, pulmonary hypertension.
Above-claimed cpd shows that with the experiment that endothelin (ET) value changes this compounds has significant hypotensive effect to the hypotensive effect and the nitrogen protoxide (NO) of spontaneous hypertensive rat (SHR) model.
Embodiment
[embodiment 1] (S)-the positive butyryl radicals-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl Isoleucine
Step 1:(L)-the Isoleucine methyl ester hydrochloride
Add the 5mL anhydrous methanol under condition of ice bath, stir in the 50mL three-necked flask, slowly drip the 1mL sulfur oxychloride, after dropwising, stir 30min, add 1g (L)-Isoleucine, stirring is spent the night, and removes solvent under reduced pressure.With methyl alcohol-ether recrystallization, get colourless needle-like solid 1.4g, mp:153-160 ℃.
Step 2:N-[4-(2-cyano-phenyl)] phenmethyl-L-Isoleucine methyl esters
At N
2Under the protective condition, 2.0g (L)-Isoleucine methyl ester hydrochloride is dissolved among the 15mL DMF, the ice bath cooling is stirred, and Dropwise 5 mL triethylamine adds 3.0g 2 '-cyano group-4-bromomethylbiphenyl then.70 ℃ of reactions, the TLC monitoring, after reacting completely, cooling rapidly adds 15mL distilled water, ethyl acetate extraction.Merge organic phase, KHCO
3Solution washing, anhydrous sodium sulfate drying removes solvent under reduced pressure, gets yellow oil.The post layer separates, and gets colourless oil liquid 3.2g.
1H-NMR(CDCl
3，500.12MHz)δ：7.78-7.23(m，8H，Ph-H)，3.89，3.62(two?d，2H，J＝13.5Hz，J＝13.7Hz，-NH-C
H 2-)，3.72(s，3H，-OCH
3)，3.03(d，1H，J＝6.3Hz，-CO-CH-N-)，1.95(m，1H，-C
H-CH
3)，1.26(m，2H，-CH-C
H 2CH
3)，0.96，0.97(two?d，6H，J＝6.6Hz，-CHC
H 3)；MS(m/z)：337.2[M+1]
+，359.2[M+Na]
+.
Positive butyryl radicals-the N-[4-of step 3:N-(2-cyano-phenyl)] phenmethyl-L-Isoleucine methyl esters
With 3.8g N-[4-(2-cyano-phenyl)] phenmethyl-L-Isoleucine methyl esters is dissolved in 31mL toluene, and Dropwise 5 mL triethylamine drips the 3.1g n-butyryl chloride, nitrogen protection, behind the 1h, cooling adds 15mL distilled water, and organic phase is used hydrochloric acid, NaHCO successively
3Solution, washing, anhydrous sodium sulfate drying removes solvent under reduced pressure, gets yellow oil.The post layer separates, and gets white liquid 3.8g.
1H-NMR(CDCl
3，500.12MHz，doubling?due?to?amide?rotamers)δ：7.71-7.25(m，8H，Ph-H)，5.03(d，J＝15.3Hz)，4.92(d，1H，J＝10.5Hz，-CO-CH-N-)，4.63(m)，4.28(d，J＝15.6Hz)，4.07(d，2H，J＝10.6Hz，-N-CH
2-)，3.43(s)，3.38(s，3H，-OCH
3)，2.58-2.23(m，3H，-COCH
2-，-C
HCH
3)，1.75-1.23(m，4H，-C
H 2CH
3)，1.05-0.84(m，9H)；MS(m/z)：407.2[M+1]
+，429.2[M+Na]
+.
Step 4:(S)-and the positive butyryl radicals-N-[4-of N-(2-(N-hydroxyl) amidino groups) phenyl] phenmethyl Isoleucine methyl esters
3.9g N-butyryl radicals-N-[4-(2-cyano-phenyl)] phenmethyl-L-Isoleucine methyl esters is dissolved among the 60mL DMSO; add 2.76g oxammonium hydrochloride and 10.1mL triethylamine; 90 ℃ of reaction 1h; cooling back dilute with water; ethyl acetate extraction; anhydrous sodium sulfate drying removes solvent under reduced pressure, gets yellow oil.The post layer separates, and gets white solid 1.96g.mp：97.5-99.7℃。
1H-NMR(CDCl
3，500.12MHz，doubling?due?to?amide?rotamers)δ：7.77-7.25(m，8H，Ph-H)，5.01(d，J＝15.3Hz)，4.93(d，1H，J＝10.3Hz，-CO-CH-N-)，4.67(m)，4.30(d，J＝15.3Hz)，4.07(d，2H，J＝10.8Hz，-N-CH
2-)，4.43(s，2H，-NH
2)，3.45(s，3H，-OCH
3)，2.53-2.27(m，3H，-CO-CH
2-，-C
HCH
3)，1.61-1.54(m，2H，-CH
2C
H 2CH
3)，1.31-1.28(m，2H，-CHC
H 2CH
3)，0.97-0.94(m，9H)；MS(m/z)：426.2[M+1]
+，448.2[M+Na]
+.
Step 5:(S)-and the positive butyryl radicals-N-[4-of N-(2-(N-isobutyl oxygen carbonyl oxygen base) amidino groups) phenyl] phenmethyl Isoleucine methyl esters
1.9g (S)-and the positive butyryl radicals-N-[4-of N-(2-(N-hydroxyl) amidino groups) phenyl] phenmethyl Isoleucine methyl esters is in 20mL DMF, and adding 0.43mL pyridine stirs; the ice bath cooling; dropwise add the 0.53mL isobutyl chlorocarbonate, ice bath stirs 2h; reaction solution is poured in the 15mL water; ethyl acetate extraction, water washing, anhydrous sodium sulfate drying; the evaporated under reduced pressure solvent gets yellow oil.The post layer separates, and gets white solid 2.15g.
1H-NMR(CDCl
3，500.12MHz，doubling?dueto?amide?rotamers)δ：7.86-7.29(m，8H，Ph-H)，5.01(d，J＝15.3Hz)，4.95(d，1H，J＝10.8Hz，-N-CH-)，4.67-4.62(m)，4.08-4.03(m，2H，-N-CH
2-)，4.05(d，2H，J＝6.8Hz，-OCH
2-)，3.58(s)，3.43(s，3H，-OCH
3)，2.50-2.04(m，4H，-CO-CH
2-，-C
HCH
3)，1.68-1.20(m，4H，-C
H 2CH
3)，0.97-0.77(m，15H)；MS(m/z)：540[M+1]
+，562[M+Na]
+.
Step 6:(S)-and the positive butyryl radicals-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] phenmethyl Isoleucine methyl esters
1.5g (S)-and the positive butyryl radicals-N-[4-of N-(2-(N-isobutyl oxygen carbonyl oxygen base) amidino groups) phenyl] phenmethyl Isoleucine methyl esters is dissolved in 10mL dimethylbenzene, stirs reflux 5h; the evaporated under reduced pressure solvent; get yellow liquid, the petroleum ether-ethyl acetate recrystallization gets white crystals thing 1.29g.
1H-NMR(CDCl
3，500.12MHz，doubling?due?to?amide?rotamers)δ：7.75-7.17(m，8H，Ph-H)，5.01(d，J＝15.4Hz)，4.79(d，1H，J＝10.4Hz，-CO-CH-N-)，4.66(s)，4.42(d，J＝15.6Hz)，4.12(d，2H，J＝10.1Hz，-N-CH
2-)，3.48(s)，3.42(s，3H，-OCH
3)，2.52-2.03(m，3H，-CO-CH
2-，-C
HCH
3)，1.65-1.23(m，4H，-C
H 2CH
3)，0.97-0.78(m，9H)；
13C-NMR
1(CDCl
3，500.12MHz，doubling?due?to?amide?rotamers)δ：174.7，174.5，171.2，170.3，159.6，159.4，157.8，157.7，141.2，140.9，138.4，137.7，137.6，137.0，131.9，130.9，129.8，129.1，128.7，128.0，127.8，127.6，126.1，121.9，65.2，60.5，52.0，51.6，47.8，45.6，35.5，35.4，33.9，33.8，24.9，24.8，18.7，18.5，15.9，15.8，13.8，13.7，11.0，10.9；MS(m/z)：466.4[M+1]
+，488.4[M+Na]
+.
Step 7:(S)-and the positive butyryl radicals-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl Isoleucine
1.0g (S)-the positive butyryl radicals-N-[4-of N-(2-(5-oxo-1; 2; 4-oxadiazole-3) phenyl)] phenmethyl Isoleucine methyl esters is dissolved among the 0.5mLDMF, adds the 6mL 6mol/LNaOH aqueous solution, and 70 ℃ are stirred 5h; regulate pH to 3 with hydrochloric acid; ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying; the evaporated under reduced pressure solvent gets the light red solid.The post layer separates, and gets white solid 0.81g.mp：78-82℃。
1H-NMR(CDCl
3，500.12MHz，doubling?due?to?amiderotamers)δ：7.92-7.18(m，8H，Ph-H)，4.72(d，J＝16.2Hz)，4.56(d，1H，J＝16.7Hz，-CO-CH-N-)，4.27-4.06(m，2H，-N-CH
2-)，2.67-2.12(m，3H，-CO-CH
2-，-C
HCH
3)，1.54-1.26(m，4H，-C
H 2CH
3)，1.04-0.90(m，9H)；
13C-NMR(CDCl
3，500.12MHz，doubling?due?to?amide?rotamers)δ：175.7，174.7，172.2，161.3，160.1，157.6，157.3，140.9，140.3，139.4，137.9，136.6，136.4，132.4，132.2，130.6，130.5，129.8，129.6，129.3，129.1，128.9，128.3，128.2，127.8，121.1，65.2，60.5，52.0，51.6，47.8，45.6，36.2，35.5，32.6，32.4，29.6，24.8，24.4，21.0，18.8，18.7，16.0，15.4，14.1，13.9，13.8，11.0，10.7；MS(m/z)：452.3[M+1]
+，474.3[M+Na]
+.
[embodiment 2] (S)-the positive butyryl radicals-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl phenylalanine
Experimental procedure is as described in the embodiment 1, yield 89.4%.
1H-NMR(CDCl
3，500.12MHz，doubling?due?to?amide?rotamers)δ：7.61-7.41(13H，m，Ph-H)，4.43(d，1H，J＝14.2Hz，-N-CH-)，4.30-4.27(m)，3.63(d，J＝16.3Hz，-CH
2-N-)，3.27(d，2H，J＝7.8Hz，-CH-C
H 2-Ph)，2.31-2.27(m，2H，-CO-CH
2-)，1.31-1.28(m，2H，-CH
2-C
H 2-CH
3)，0.91-0.85(m，3H，-CH3)；MS(m/z)：486.1[M+1]
+，508.2[M+Na]
+.
[embodiment 3] (S)-the positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl phenylalanine
Experimental procedure is as described in the embodiment 1, yield 89.1%.
1H-NMR(CDCl
3，500.12MHz，doubling?due?to?amide?rotamers)δ：7.77-7.16(13H，m，Ph-H)，4.42(d，J＝16.3Hz)，4.28(m，-N-CH
2-)，3.64(d，1H，J＝17.1Hz，-CH-N-)，3.31-3.24(m，2H，-CH-C
H 2-Ph)，2.34-2.24(m，2H，-CO-CH
2-)，1.58-1.53(m，2H，-CH
2-C
H 2-CH
2)，1.39-132(m，2H，-CH
2-C
H 2-CH
3)，0.91-0.84(m，3H，-CH
3)；MS(m/z)：500.1[M+1]
+，522.1[M+Na]
+.
[embodiment 4] (S)-the positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl Isoleucine
Experimental procedure is as described in the embodiment 1, and yield is 78.6%, mp:79-82 ℃.
1H-NMR(CDCl
3，500.12MHz，doubling?due?to?amide?rotamers)δ：7.66-7.18(m，8H，Ph-H)，4.72(d，1H，J＝16.4Hz，-CH-N-)，4.56(d，1H，J＝9.6Hz)，4.07(d，J＝11.2Hz，-N-CH
2-)，2.59-2.03(m，3H，-CO-CH
2-，-C
H-CH
3)，1.61-1.25(m，6H，-CH
2-C
H 2C
H 2-，-C
H 2-CH
3)，0.94-0.82(m，9H，-CH
2-C
H 3)；MS(m/z)：466.4[M+1]
+，488.4[M+Na]
+.
The experiment of [embodiment 5] antihypertensive drugs screening active ingredients
Laboratory animal: 30 of spontaneous hypertensive rats (SHR), health, ♀ ♂ half and half (female unpregnancy), available from Shanghai must be triumphant laboratory animal company limited, conformity certification number: Shanghai is moving closes card card word No. 152;
Be subjected to the reagent product: the compound of embodiment 1-4.
Positive control drug: losartan, clinical consumption is 50mg/kg, if body weight for humans is 60kg, human dosage is 5/6mg/kg, be scaled rat dosage 5mg/kg, the losartan molecular weight is 461, and being converted into volumetric molar concentration is 1.86mol/L, positive control drug is equivalent to dosage in the effect experiment (ratio of basic, normal, high dosage is 1: 2: 4), is set at 3.72mol/L.
Experimental technique: select 30 spontaneous hypertensive rats (SHR) model for use, be divided into blank group, positive controls, experimental group (the compound administration group of the embodiment of the invention), do not have the wound blood pressure transducer with animalcule and after carrier wave amplifies, be connected to the clear-headed free moving animals blood pressure recording analytical system (Shanghai of MPA-HBBS type, Alcott), the subcutaneous insertion needle electrode of four limbs is connected to alternating current amplifier and is used for monitoring standard two lead electrocardiogram.Tail sleeve method is measured clear-headed rat caudal artery mean arterial pressure (MAP), systolic pressure (SBP), diastolic pressure (DBP), heart rate (HR) and electrocardiogram(ECG (ECG).
During test the experimental group compound is mixed with the aqueous solution that concentration is 3.72mol/L respectively.Positive control drug losartan sheet is mixed with the aqueous solution that concentration is 3.72mol/L during test.Each treated animal is pressed above-mentioned dosage gastric infusion 1 time every day, and blank group is given the physiological saline with volume, 2 weeks of continuous use.
The caudal artery of the non-invasive measurement rat blood pressure method of beating is adopted in blood pressure determination, all rats respectively at administration before and 1 month each measuring blood pressure 1 time after the administration, each blood pressure is got the mean value of measuring for 3 times.
The mensuration of blood plasma ET, NO: blood sampling 2ml, inject and to contain 10% the EDTA disodium 30 and the test tube of Trypsin inhibitor,Trasylol 40, mixing, 4 ℃, the centrifugal 10min of 3000r/min, separated plasma is put in one 20 ℃ the refrigerator and is preserved.Make sample place room temperature to melt again before the mensuration, 4 ℃ once more, the centrifugal 5min of 3000r/min gets supernatant and measures, then by the strict operation of reagent specification sheets separately.
Data processing: all experimental datas all with mean ± standard deviation (
) expression, the variance analysis that blood pressure, NO and ET relatively design with completely random between each group after the medication does not wait as each group population mean, uses the multiple comparisons between a plurality of sample averages again, i.e. and q check is handled.
Experimental result:
Blood pressure result: to treat front and back blood pressure difference as variable, each class mean relatively has utmost point significant difference (P＜0.01), through the q of multiple sample mean testing identity, experimental group and positive control and blank group relatively have utmost point significant difference (P＜0.01) again, and the illustrative experiment group has remarkable hypotensive effect.
Endothelin (ET) result: the ET value is through variance analysis (P＜0.01) after the medication, and illustrating between each group relatively has utmost point significant difference, and again through the q of multiple sample mean testing identity, experimental group obviously is better than other groups (P＜0.01).
Nitrogen protoxide (NO) result: the NO value illustrates that through variance analysis (P＜0.05) relatively there were significant differences between each group after the medication, and again through the q of multiple sample mean testing identity, experimental group obviously is better than other groups (P＜0.05).
Respectively organize after table 1. experiment blood pressure, nitrogen protoxide (NO) and the comparison of endothelin (ET) value (
N=10)
| Group | Blood pressure difference (mmHg) | ET(pg/ml)) | ?NO(μmol/L) |
| Blank group | 5.88±4.62 | 94.25±34.24 | ?11.57±2.35 |
| Positive control (losartan) group | 44.52±25.48** | 58.11±20.45 | ?11.36±4.23 |
| Experimental group | 47.55±10.33** | 46.52±13.51**## | ?15.01±6.33# |
Annotate: compare with the blank group: * * P＜0.01; Compare with positive controls: #P＜0.05, ##P＜0.01
Claims (7)
1, a kind of amino-acid biphenyl compound, as structural formula (I):
R wherein
1Be positive alkyl, R
2Be alkyl or heterocyclic radical, R
3Wei oxadiazole group.
2, amino-acid biphenyl compound according to claim 1 is characterized in that described R
1Be n-propyl or normal-butyl.
3, amino-acid biphenyl compound according to claim 1 is characterized in that described R
2Be 2-methyl butyl, 3-methyl butyl, phenmethyl or 3-indyl methyl.
4, amino-acid biphenyl compound according to claim 1 is characterized in that described R
3Be 5-oxo-1,2, the 4-oxadiazole.
5, amino-acid biphenyl compound according to claim 1 is characterized in that this compound is:
(S)-and the positive butyryl radicals-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl Isoleucine;
(S)-and the positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl Isoleucine;
(S)-and the positive butyryl radicals-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl phenylalanine;
(S)-and the positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl phenylalanine;
(S)-and the positive butyryl radicals-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl tryptophane;
(S)-and the positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl tryptophane;
(S)-and the positive butyryl radicals-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl leucine;
(S)-and the positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl leucine.
6, a kind of method for preparing each described compound of claim 1-5, this method comprises the steps:
Esterification takes place and generates amino acid methyl ester in amino acid and methyl alcohol under the sulfur oxychloride effect; This amino acid methyl ester and 2 '-cyano group-4-bromomethylbiphenyl generation alkylated reaction thereafter with acyl chlorides generation acylation reaction, generates the positive alkyloyl-N-[4-of (S)-N-(2-cyano-phenyl)] the phenmethyl amino acid methyl ester; After this acylate and the oxammonium hydrochloride reaction,, heat cyclization then, generate the positive alkyloyl-N-[4-of (S)-N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl) with the chloro-formic ester reaction] the phenmethyl amino acid methyl ester; Continue you with the methyl esters hydrolysis, make amino-acid biphenyl compound.
7, the application of each described compound of claim 1-5 in the medicine for preparing prevention and treatment hypertension, coronary heart disease, heart brain and kidney blood vessel diseases, migraine, pulmonary hypertension.
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| CN 200710036444 CN101007791A (en) | 2007-01-12 | 2007-01-12 | Amino acid diphenyl compound |
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| CN 200710036444 CN101007791A (en) | 2007-01-12 | 2007-01-12 | Amino acid diphenyl compound |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102770442A (en) * | 2010-01-14 | 2012-11-07 | 阿佩普蒂科研究和开发有限责任公司 | Cyclic peptides for the regulation of vectorial ion channels |
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2007
- 2007-01-12 CN CN 200710036444 patent/CN101007791A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102770442A (en) * | 2010-01-14 | 2012-11-07 | 阿佩普蒂科研究和开发有限责任公司 | Cyclic peptides for the regulation of vectorial ion channels |
| CN102770442B (en) * | 2010-01-14 | 2015-09-23 | 阿佩普蒂科研究和开发有限责任公司 | For regulating the organic compound of carrier ion passage |
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