CN101007791A - Amino acid diphenyl compound - Google Patents

Abstract

The invention discloses an amino acid biphenyl compound, which is formed by organically linking biphenyl, amino acid and oxadiazole, and is an angiotensin II receptor blocker. Drugs for blood pressure, coronary heart disease, cardiovascular and cerebrovascular diseases, migraine, pulmonary hypertension and other diseases.

Description

A kind of amino acid biphenyl compound

technical field

The invention relates to the field of medicinal chemistry, in particular to a class of amino acid biphenyl compounds capable of treating hypertension, other cardiovascular and cerebrovascular diseases, migraine, pulmonary hypertension and other diseases.

Background technique

Since the identification of hypertension in the 1940s, antihypertensive drugs have experienced the following development process. In the 1940s, malignant hypertension was first treated with the nerve blocker hexacarbonate quaternary ammonium, diuretics in the 1950s, anti-adrenaline blockers in the 1960s, further development of α-receptor blockers in the 1970s, and vascular tension in the 1980s In the 1990s, a new generation of antihypertensive drugs such as angiotensin-converting enzyme inhibitors, calcium channel blockers, and angiotensin receptor antagonists began to be used and developed vigorously.

In 1970, Marshall et al. synthesized the first receptor antagonist non-peptide compound Sarala-sin (Sarala-sin: Sarl-Ala8-Ang II), which is very similar to A II in structure and has specificity to isolated tissues antagonism. However, in clinical practice, it is limited due to oral ineffectiveness, unstable metabolism, and partial A II agonism. In 1982, when Japan’s Takeda Pharmaceutical Company was studying the diuretic and antihypertensive effects of imidazole acetic acid compounds, it first discovered that S-8307 could inhibit the rabbit arterial contraction and boosting effect induced by A II. Although the activity was weak, it belonged to the A II receptor Specific antagonist without the agonistic effect of Saralasin. In the late 1980s, researchers from Dupont (Med.Rev.1992, 12: 149-158) and Smithkline Beecham (Drugs of the fixture. 1992, 17: 575-593) companies used two of the putative A II active conformations. A different molecular model was used to compare the C-terminal region of A II with S-8307, and a series of structural modifications were made to S-8307 to enhance the affinity with the receptor. As a result, two different structural types, Dup-753 (Losartan) and SK&F-108566 (Eprosartan), both of which have relatively high activity, were listed in Sweden in 1994 by Losartan (Drngs of the Future.1997, 22: 1079-1085), and Eprosartan was launched in Germany in 1997 (Drugs of the future. 1996, 21(8): 794-798).

At present, non-peptide A II receptor antagonists are favored because of their strong affinity with A II receptors, high selectivity, oral efficacy, and long duration of action. They are promising antihypertensive drugs. Since the discovery of Losartan by Dupont, major pharmaceutical companies in the world have participated in the research of A II receptor antagonists, successively synthesized and screened out a large number of non-peptide AII receptor antagonists with strong antihypertensive activity, such as chlorine Losartan, Valsartan, Candesartan, Irbesartan, Olmesartan, Telmisartan, Eprosartan ) and Elisartan.

Most of the currently marketed drugs and compounds entering clinical trials contain tetrazole groups, but there are certain defects in the synthesis and metabolism of tetrazole, such as the synthesis of which requires the use of toxic and explosive azide compounds, It is easily metabolized in the form of glucuronidation in the body, resulting in a shortened existence time of the compound in the body (Drug Metab Dispos, 1993, 21: 792-799). And when containing 2 acid groups (tetrazolium and carboxyl) in the compound, because its polarity is big, general oral bioavailability is not high, needs to form prodrug to improve oral (Bioorg MedChem Lett, 1944,4:201 -206).

Contents of the invention

The technical problem to be solved by the present invention is to provide a class of amino acid biphenyl compounds to solve the defects in the prior art.

The principle of the present invention is to utilize 5-oxo-1,2,4-oxadiazole and carboxyl equipotentiality (AnnuRep Med Chem, 1986,21:283-291), better lipophilicity than tetrazole , higher oral bioavailability, and safe synthetic routes, organically link biphenyl with amino acids and oxadiazoles, and design and synthesize a series of compounds, which are compounds of structural formula (I):

Wherein, R ₁ is a normal alkyl group; R ₂ is an alkyl or heterocyclic group; R ₃ is an oxadiazole group, and the position is preferably an ortho position.

Wherein R ₁ is preferably n-propyl or n-butyl, namely: -CH ₂ CH ₂ CH ₂ CH ₃ ; -CH ₂ CH ₂ CH ₃ .

R is preferably ₂ -methylbutyl, 3-methylbutyl, 2-benzyl or 3-indolylmethyl, i.e.:

或

-CH( _CH3 ) _CH2CH3 ; _{-CH2CH ( CH3} ) _CH3 ;

or

where R3 is , the preferred position is ortho, ie 5-oxo-1,2,4-oxadiazole.

Wherein preferred compounds are:

(S)-N-n-butyryl N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylisoleucine;

(S)-N-n-pentanoyl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylisoleucine;

(S)-N-n-butyryl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylphenylalanine;

(S)-N-n-pentanoyl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylphenylalanine;

(S)-N-n-butyryl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzyl tryptophan;

(S)-N-n-pentanoyl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzyl tryptophan;

(S)-N-n-butyryl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylleucine;

(S)-N-n-pentanoyl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylleucine.

The present invention also provides the preparation method of this compound, the concrete steps of this method are:

Amino acid and methanol undergo esterification reaction under the action of thionyl chloride to generate amino acid methyl ester; the amino acid methyl ester undergoes alkylation reaction with 2'-cyano-4-bromomethylbiphenyl, and then undergoes acylation reaction with acid chloride , to generate (S)-N-n-alkanoyl-N-[4-(2-cyanophenyl)]benzyl amino acid methyl ester; after the acylation product reacts with hydroxylamine hydrochloride, it reacts with chloroformate, Then heat and cyclize to generate (S)-N-n-alkanoyl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzyl amino acid Methyl ester; Jier hydrolyzes methyl ester to obtain amino acid biphenyl compound.

Those skilled in the art can synthesize the compound according to the above description.

After further research, it is found that the above compounds have good preventive or therapeutic effects on diseases such as hypertension, cardiovascular and cerebrovascular diseases, migraine, pulmonary hypertension and the like. Therefore, the compound of the present invention can be used to prepare medicines for preventing or treating diseases such as hypertension, cardiovascular and cerebrovascular diseases, migraine, and pulmonary hypertension.

Experiments on the antihypertensive effect of the above compounds on the spontaneously hypertensive rat (SHR) model and the changes of nitric oxide (NO) and endothelin (ET) values show that the compounds have significant antihypertensive effects.

Detailed ways

[Example 1] (S)-N-n-butyryl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylisobright amino acid

Step 1: (L)-Isoleucine Methyl Ester Hydrochloride

Add 5 mL of anhydrous methanol to a 50 mL three-necked flask under ice-bath conditions, stir, slowly add 1 mL of thionyl chloride dropwise, after the dropwise addition, stir for 30 min, add 1 g (L)-isoleucine, and stir overnight, The solvent was evaporated under reduced pressure. Recrystallized from methanol-ether to obtain 1.4 g of a colorless needle-like solid, mp: 153-160°C.

Step 2: N-[4-(2-cyanophenyl)]benzyl-L-isoleucine methyl ester

Under _N2 protection conditions, dissolve 2.0g (L)-isoleucine methyl ester hydrochloride in 15mL DMF, cool in an ice bath, stir, add 5mL triethylamine dropwise, and then add 3.0g 2'-cyano Base-4-bromomethylbiphenyl. React at 70°C and monitor by TLC. After the reaction is complete, cool down rapidly, add 15 mL of distilled water, and extract with ethyl acetate. The organic phases were combined, washed with KHCO ₃ solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a yellow oil. Column separation gave 3.2 g of a colorless oily liquid. ¹ H-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- CH ₂ -), 3.72 (s, 3H, -OCH ₃ ), 3.03 (d, 1H, J=6.3Hz, -CO-CH-N-), 1.95 (m, 1H, -CH -CH ₃ ), 1.26 (m, 2H, -CH- CH ₂ CH ₃ ), 0.96, 0.97 (two d, 6H, J=6.6Hz, -CHCH 3 ); MS (m/z): 337.2[M+ ₁ ] ⁺ , 359.2[M+Na] ⁺ .

Step 3: Methyl N-n-butyryl-N-[4-(2-cyanophenyl)]benzyl-L-isoleucine

Dissolve 3.8g N-[4-(2-cyanophenyl)]benzyl-L-isoleucine methyl ester in 31mL toluene, add 5mL triethylamine dropwise, add 3.1g n-butyryl chloride dropwise, nitrogen After 1 hour, it was cooled, and 15 mL of distilled water was added. The organic phase was washed with hydrochloric acid, NaHCO ₃ solution, and water successively, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a yellow oil. The column layer was separated to obtain 3.8 g of white liquid. ¹ H-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 -, -CH CH ₃ ), 1.75-1.23 (m, 4H, -CH ₂ CH ₃ ), 1.05- 0.84(m, 9H); MS(m/z): 407.2[M+1] ⁺ , 429.2[M+Na] ⁺ .

Step 4: (S)-Methyl N-n-butyryl-N-[4-(2-(N-hydroxy)amidino)phenyl]benzylisoleucine

Dissolve 3.9g of N-butyryl-N-[4-(2-cyanophenyl)]benzyl-L-isoleucine methyl ester in 60mL of DMSO, add 2.76g of hydroxylamine hydrochloride and 10.1mL of triethylamine , React at 90°C for 1 h, dilute with water after cooling, extract with ethyl acetate, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a yellow oil. Column separation gave 1.96 g of white solid. mp: 97.5-99.7°C. ¹ H-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 -, -CH CH ₃ ), 1.61-1.54 (m, 2H, -CH ₂ CH ₂ CH ₃ ), 1.31-1.28 (m, 2H, -CHCH ₂ CH ₃ ), 0.97-0.94 (m, 9H); MS (m/z): 426.2[M+1] ⁺ , 448.2[ M+Na] ⁺ .

Step 5: (S)-Methyl N-n-butyryl-N-[4-(2-(N-isobutoxycarbonyloxy)amidino)phenyl]benzylisoleucine

1.9g (S)-N-n-butyryl-N-[4-(2-(N-hydroxy)amidino)phenyl]benzylisoleucine methyl ester in 20mL DMF, add 0.43mL pyridine, Stir, cool in an ice bath, add 0.53mL isobutyl chloroformate dropwise, stir in an ice bath for 2h, pour the reaction solution into 15mL water, extract with ethyl acetate, wash with water, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure , a yellow oil was obtained. Column separation gave 2.15 g of white solid. ¹ H-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=10.8 Hz, -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 -, -CH CH ₃ ), 1.68-1.20 (m, 4H, -CH ₂ CH ₃ ), 0.97-0.77(m, 15H); MS(m/z): 540[M+1] ⁺ , 562[M+Na] ⁺ .

Step 6: (S)-N-n-butyryl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylisoleucine methyl ester

1.5g (S)-N-n-butyryl-N-[4-(2-(N-isobutoxycarbonyloxy)amidino)phenyl]benzylisoleucine methyl ester was dissolved in 10mL xylene , stirred, heated to reflux for 5h, evaporated the solvent under reduced pressure to obtain a yellow liquid, and recrystallized from petroleum ether-ethyl acetate to obtain 1.29g of white crystals. ¹ H-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 -, -CH CH ₃ ), 1.65-1.23 (m, 4H, -CH ₂ CH ₃ ), 0.97-0.78(m, 9H); ¹³ C-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, 33.4, 38 , 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)-N-n-butyryl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylisoleucine

1.0g (S)-N-n-butyryl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylisoleucine Dissolve the ester in 0.5mL DMF, add 6mL 6mol/L NaOH aqueous solution, stir at 70°C for 5h, adjust the pH to 3 with hydrochloric acid, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain shallow red solid. Column separation gave 0.81 g of white solid. mp: 78-82°C. ¹ H-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=16.7 Hz, -CO-CH-N-), 4.27-4.06 (m, 2H, -N-CH ₂ -), 2.67-2.12 (m, 3H, -CO-CH ₂ -, -CH CH ₃ ), 1.54 -1.26 (m, 4H, -CH ₂ CH ₃ ), 1.04-0.90 (m, 9H); ¹³ C-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, 2, 127.8 , 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] ⁺ .

[Example 2] (S)-N-n-butyryl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylbenzenepropane amino acid

The experimental procedure is as described in Example 1, and the yield is 89.4%. ¹ H-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- CH ₂ -Ph), 2.31-2.27(m , 2H, -CO-CH ₂ -), 1.31-1.28 (m, 2H, -CH ₂ -CH 2 _{-CH 3} ), 0.91-0.85 (m, 3H, -CH3); MS (m/z): 486.1[M+1] ⁺ , 508.2[M+Na] ⁺ .

[Example 3] (S)-N-n-pentanoyl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylbenzenepropane amino acid

The experimental procedure is as described in Example 1, and the yield is 89.1%. ¹ H-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- CH ₂ -Ph), 2.34-2.24 (m, 2H, -CO -CH ₂ -), 1.58-1.53 (m, 2H, -CH ₂ -CH ₂ -CH ₂ ), 1.39-132 (m, 2H, -CH ₂ -CH 2 _{-CH 3} ), 0.91-0.84 ( m, 3H, -CH ₃ ); MS (m/z): 500.1[M+1] ⁺ , 522.1[M+Na] ⁺ .

[Example 4] (S)-N-n-pentanoyl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzyl isobrilliant amino acid

The experimental procedure is as described in Example 1, the yield is 78.6%, mp: 79-82°C. ¹ H-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 -, -CH -CH ₃ ), 1.61-1.25 (m, 6H _, -CH ₂ -CH 2 CH ₂ -, -CH 2 _{-CH 3} ), 0.94-0.82 (m, 9H, -CH _{2 -CH} 3 ); MS ( m/z): 466.4[M+1] ⁺ , 488.4[M+Na] ⁺ .

[Example 5] Antihypertensive drug activity screening experiment

Experimental animals: 30 spontaneously hypertensive rats (SHR), healthy, half ♀♂ (female not pregnant), purchased from Shanghai Bikai Experimental Animal Co., Ltd., certificate number: Shanghai Dynamic Hezheng Zi No. 152 ;

Drugs tested: the compounds of Examples 1-4.

Positive control drug: losartan, the clinical dosage is 50mg/kg, assuming that the body weight is 60kg, the human dosage is 5/6mg/kg, converted to a rat dosage of 5mg/kg, the molecular weight of losartan is 461, converted into moles The concentration is 1.86mol/L, and the positive control drug is equivalent to the dose in the efficacy experiment (the ratio of low, medium and high doses is 1:2:4), which is set at 3.72mol/L.

Experimental method: select 30 spontaneously hypertensive rats (SHR) model, be divided into blank group, positive control group, experimental group (compound administration group of the embodiment of the present invention), use small animal non-invasive blood pressure transducer After the carrier is amplified, it is connected to the MPA-HBBS blood pressure recording and analysis system for conscious free-moving animals (Alcott, Shanghai). Needle-shaped electrodes are inserted subcutaneously in the limbs and connected to an AC amplifier for monitoring the standard two-lead electrocardiogram. The tail cuff method was used to measure mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) and electrocardiogram (ECG) in the tail artery of conscious rats.

During the test, the compounds of the experimental group were respectively prepared into aqueous solutions with a concentration of 3.72 mol/L. The positive control drug losartan tablet was prepared into an aqueous solution with a concentration of 3.72mol/L during the test. Animals in each group were intragastrically administered the above dose once a day, and the blank group was given the same volume of normal saline for 2 weeks.

Blood pressure was measured by tail artery pulse method of non-invasive measurement of blood pressure in rats. All rats were measured blood pressure once before administration and one month after administration, and the average value of three measurements was taken for each blood pressure.

Determination of plasma ET and NO: take 2ml of blood, inject it into a test tube containing 10% disodium EDTA 30 and aprotinin 40, mix well, centrifuge at 3000r/min at 4°C for 10min, separate the plasma, and put it in a refrigerator at 20°C save. Before the measurement, the samples were rethawed at room temperature, centrifuged again at 4°C, 3000r/min for 5min, and the supernatant was taken for measurement, and then strictly operated according to the instructions of the respective reagents.

)表示，用药后各组间血压、NO及ET比较用完全随机设计的方差分析，如各组总体均数不等，再用多个样本均数间的多重比较，即q检验进行处理。Data processing: All experimental data are presented as mean ± standard deviation (

) indicates that the comparison of blood pressure, NO, and ET among the groups after the treatment is performed by a fully randomized analysis of variance, and if the overall means of each group are not equal, multiple comparisons between the means of multiple samples, that is, the q test, are used for processing.

Experimental results:

Blood pressure results: Taking the difference in blood pressure before and after treatment as a variable, there is a very significant difference in the mean value of each group (P<0.01), and then it is proved by the q test of the multi-sample mean that the experimental group and the positive control group have a very significant difference compared with the blank group (P<0.01), indicating that the experimental group has a significant antihypertensive effect.

Endothelin (ET) results: the ET value after the drug was analyzed by variance (P<0.01), indicating that there was a very significant difference between the groups, and then proved by the q test of the multi-sample mean that the experimental group was significantly better than the other groups ( P<0.01).

Nitric oxide (NO) results: the NO value after medication was analyzed by variance (P<0.05), indicating that there were significant differences between the groups, and then proved by the q test of the multi-sample mean that the experimental group was significantly better than the other groups ( P<0.05).

Table 1. Comparison of blood pressure, nitric oxide (NO) and endothelin (ET) values in each group after the experiment ( 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 test group 47.55±10.33** 46.52±13.51**## 15.01±6.33#

Note: Compared with the blank group: **P<0.01; compared with the positive control group: #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.