CN101003521A - A compound valeryl biphenyl of valine - Google Patents
A compound valeryl biphenyl of valine Download PDFInfo
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- CN101003521A CN101003521A CN 200710036452 CN200710036452A CN101003521A CN 101003521 A CN101003521 A CN 101003521A CN 200710036452 CN200710036452 CN 200710036452 CN 200710036452 A CN200710036452 A CN 200710036452A CN 101003521 A CN101003521 A CN 101003521A
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Abstract
This invention discloses a valine valeryl biphenyl compound, which is prepared by connecting biphenyl, valine and furodiazole. The compound is a receptor blocker of angiotensin II, thus can be used to manufacture drugs that can prevent or treat hypertension, coronary artery disease, cardiovascular, cerebrovascular and nephric vascular diseases, migraine and pulmonary artery hypertension.
Description
Technical field
The present invention relates to the medical chemistry field, relate in particular to a kind of compound valeryl biphenyl of valine with diseases such as prevention and treatment hypertension and other heart brain and kidney blood vessel diseases, migraine, pulmonary hypertensions.
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 AII 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 AII brings out, though activity a little less than, but belong to aii receptor 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 AII activity conformation of supposition, C-stub area and the S-8307 of AII 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 (Drugs 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 aii receptor antagonist is with it and aii receptor avidity 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 aii 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 Med Chem Lett, 1944,4:201-206).
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of compound valeryl biphenyl of valine, 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 Wei oxadiazole group;
The R preferred positions is the ortho position, i.e. 5-oxo-1,2, and the 4-oxadiazole, structure is
The preferred compound of the present invention is:
(S)-and the positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl Xie Ansuan.
The present invention also provides the preparation method of this compound, and the concrete steps of this method are:
Esterification takes place and generates valine methyl ester in L-Xie Ansuan 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 pentanoyl-N-[4-of (S)-N-(2-cyano-phenyl)] the phenmethyl valine methyl ester; After this acylate and the oxammonium hydrochloride reaction,, heat cyclization then, generate the positive pentanoyl-N-[4-of (S)-N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl) with the chloro-formic ester reaction] the phenmethyl valine methyl ester; Continue you with the methyl esters hydrolysis, make compound valeryl biphenyl of valine.
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 pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl Xie Ansuan
Step 1:(L)-valine 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)-Xie Ansuan, stirring is spent the night, and removes solvent under reduced pressure.With methyl alcohol-ether recrystallization, get colourless needle-like solid 1.35g, mp:128-132 ℃.
Step 2:N-[4-(2-cyano-phenyl)] phenmethyl-L-valine methyl ester
At N
2Under the protective condition, 2.0g (L)-valine 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 3.28g.
1H-NMR(CDCl
3，300.75MHz)δ：7.78-7.25(m，8H，Ph-H)，3.90，3.65(two?d，2H，J＝13.5Hz，-NH-CH
2-)，3.74(s，3H，-OCH
3)，3.05(d，1H，J＝6.3Hz，-CO-CH-N-)，1.94(m，1H，-CO-CH-)，0.96，0.97(two?d，6H，J＝6.6Hz，-CH-CH
3)；MS(m/z)：323.2[M+1]
+，345.2[M+Na]
+。
Positive pentanoyl-the N-[4-of step 3:N-(2-cyano-phenyl)] phenmethyl-L-valine methyl ester
With 3.8g N-[4-(2-cyano-phenyl)] phenmethyl-L-valine methyl ester is dissolved in 31mL toluene, and Dropwise 5 mL triethylamine drips the 3.5g n-amyl 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 4.0g.
1H-NMR(CDCl
3，300.75MHz，doubling?due?to?amide?rotamers)δ：7.75-7.67(m，1H，Ph-H)，7.63-7.58(m，1H，Ph-H)，7.54-7.37(m，4H，Ph-H)，7.34-7.28(m，2H，Ph-H)，5.08(d，J＝15.7Hz)，4.97(d，1H，J＝10.3Hz，-CO-CH-N-)，4.72(d，J＝17.9Hz)，4.26(d，J＝15.4Hz)，4.11(d，2H，J＝11.1Hz，-N-CH
2-)，3.40(s)，3.35(s，3H，-OCH
3)，2.58-2.18(m，3H，-CO-CH
2-，-C
HCH
3)，1.85-1.13(m，4H，-CH
2CH
2CH
3)，0.83-0.99(m，9H)；MS(m/z)：407.3[M+1]
+，429.3[M+Na]
+.
Step 4:(S)-and the positive pentanoyl-N-[4-of N-(2-(N-hydroxyl) amidino groups) phenyl] the phenmethyl valine methyl ester
3.9g N-pentanoyl-N-[4-(2-cyano-phenyl)] phenmethyl-L-valine methyl ester 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 1.94g.mp：96.8-98.9℃。。
1H-NMR(CDCl
3，500.12MHz，doubling?due?to?amide?rotamers)δ：7.71(m，1H，Ph-H)，7.49-7.31(m，5H，Ph-H)，7.20(m，2H，Ph-H)，5.02(d，J＝15.3?Hz)，4.92(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)，3.40(s，3H，-OCH
3)，2.55-2.24(m，3H，-CO-CH
2-，-C
HCH
3)，1.82-1.58(m，2H，-C
H 2CH
2CH
3)，1.48-1.25(m，2H，-CH
2CH
H 2CH
3)，1.03-0.82(m，9H)；MS(m/z)：440.3[M+1]
+.
Step 5:(S)-and the positive pentanoyl-N-[4-of N-(2-(N-isobutyl oxygen carbonyl oxygen base) amidino groups) phenyl] the phenmethyl valine methyl ester
1.9g (S)-and the positive pentanoyl-N-[4-of N-(2-(N-hydroxyl) amidino groups) phenyl] the phenmethyl valine methyl ester 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 colorless solid 2.15g.
1H-NMR(CDCl
3，δ，ppm，doubling?due?toamide?rotamers)：7.78-7.20(m，8H，Ph-H)，5.02(d，J＝15.3Hz)，4.97(d，1H，J＝10.8Hz，-N-CH-)，4.65-4.61(m)，4.07-4.04(m，2H，-N-CH
2-)，4.02(d，2H，J＝6.8Hz，-OCH
2-)，3.60(s)，3.39(s，3H，-OCH
3)，2.48-2.02(m，4H，-CO-CH
2-，-C
HCH
3)，1.78-1.60(m，2H，-CH
2C
H 2CH
2-)，1.32(m，2H，-CH
2C
H 2CH
3)，1.03-0.82(m，15H)；MS(m/z)：540.5[M+1]
+，562.4[M+Na]
+.
Step 6:(S)-and the positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl valine methyl ester
1.5g (S)-and the positive pentanoyl-N-[4-of N-(2-(N-isobutyl oxygen carbonyl oxygen base) amidino groups) phenyl] the phenmethyl valine methyl ester 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 solid 1.3g.
1H-NMR(CDCl
3，500.12MHz，doubling?due?to?amide?rotamers)δ：7.78-7.31(m，8H，Ph-H)，5.08(d，J＝15.4Hz)，4.96(d，1H，J＝10.4Hz，-CO-CH-N-)，4.72(d，J＝7.9Hz)，4.27(d，J＝15.4Hz)，4.12(d，J＝10.1Hz，-N-CH
2-)，3.49(s)，3.43(s，3H，-OCH
3)，2.40-2.34(m，3H，-CO-C
H 2-，-C
HCH
3)，1.67-1.58(m，2H，-C
H 2CH
2CH
3)，1.34-1.25(m，2H，-CH
2C
H 2CH
3)，1.03-0.82(m，9H)；
13C-NMR
1(CDCl
3，500.12MHz，doubling?due?to?amide?rotamers)δ：174.8，174.6，170.9，170.1，159.6，159.5，157.9，157.7，141.2，141.0，137.9，137.8，137.1，131.8，130.9，129.7，129.0，128.6，127.8，127.6，127.5，126.1，121.9，65.9，61.8，51.9，51.6，48.1，45.4，33.2，27.6，27.5，27.4，27.1，22.3，22.2，19.7，18.5，13.7；MS(m/z)：466.5[M+1]
+，488.4[M+Na]
+.
Step 7:(S)-and the positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl Xie Ansuan
1.0g (S)-the positive pentanoyl-N-[4-of N-(2-(5-oxo-1; 2; 4-oxadiazole-3) phenyl)] the phenmethyl valine methyl ester is dissolved among the 0.5mL DMF, 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 0.85 g.
1H-NMR(CDCl
3，500.12MHz，doubling?due?to?amide?rotamers)δ：7.64-7.22(m，8H，Ph-H)，4.70，4.58(two?d，1H，J＝16.0Hz，-N-CH
2-，COCHN-)，，4.22-4.10(m)，4.02-3.72(m，2H，-N-CH
2-)，2.75-2.38(m，3H，-C
HCH
3，-CO-CH
2-)，1.78-1.68(m，2H，-CH
2C
H 2CH
2)，1.49-1.25(m，2H，-CH
2CH
2CH
3)，1.01-0.87(m，9H)；
13C-NMR(CDCl
3，500.12MHz，doublingdue?to?amide?rotamers)δ：176.0，174.9，172.4，171.8，160.7，157.8，157.7，140.9，140.7，138.5，137.9，136.5，136.3，132.1，131.9，130.7，130.5，129.7，129.4，129.2，128.6，128.3，127.9，127.8，127.0，127.8，127.0，121.9，121.4，68.0，65.2，60.3，38.6，33.6，33.2，29.5，28.7，27.2，27.1，26.8，22.8，22.3，22.2，19.6，19.5，18.7，18.4，14.0，13.7，13.6；MS(m/z)：452.4[M+1]+，474.3[M+Na]
+.
The experiment of [embodiment 2] 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: antihypertensive activity compound (the S)-positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] phenmethyl Xie Ansuan (compound 1).
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, compound 1 administration group, 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 compound 1 is mixed with the aqueous solution that concentration is 3.72mol/L.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 are 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, 1 group of compound and positive control and blank group relatively have utmost point significant difference (P＜0.01), illustrate that compound 1 has better hypotensive effect again.
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, compound obviously is better than blank group (P＜0.01) for 1 group.
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, compound obviously is better than other groups (P＜0.05) for 1 group.
Respectively organize blood pressure, nitrogen protoxide (NO) and endothelin (ET) value relatively after table 1. experiment
| 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 |
| 1 group of compound | 45.55±10.33** | 56.52±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 (5)
1, a kind of compound valeryl biphenyl of valine, as structural formula (1):
R Wei oxadiazole group wherein.
2, compound valeryl biphenyl of valine according to claim 1 is characterized in that described R is a 5-oxo-1,2, the 4-oxadiazole.
3, amino-acid biphenyl compound according to claim 1 is characterized in that this compound is: (S)-the positive pentanoyl-N-[4-of N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl)] the phenmethyl Xie Ansuan.
4, a kind of method for preparing each described compound of claim 1-3, this method comprises the steps:
Esterification takes place and generates valine methyl ester in L-Xie Ansuan 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 pentanoyl-N-[4-of (S)-N-(2-cyano-phenyl)] the phenmethyl valine methyl ester; After this acylate and the oxammonium hydrochloride reaction,, heat cyclization then, generate the positive pentanoyl-N-[4-of (S)-N-(2-(5-oxo-1,2,4-oxadiazole-3) phenyl) with the chloro-formic ester reaction] the phenmethyl valine methyl ester; Continue you with the methyl esters hydrolysis, make compound valeryl biphenyl of valine.
5, the application of each described compound of claim 1-3 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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|---|---|---|---|
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