CN101798300B - N-phenylindole methyl substituted bis-benzimidazole derivative and application thereof in reducing blood pressure and the like - Google Patents
N-phenylindole methyl substituted bis-benzimidazole derivative and application thereof in reducing blood pressure and the like Download PDFInfo
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Abstract
The invention discloses an N-phenylindole methyl substituted bis-benzimidazole derivative which is prepared by organically connecting periphery substituted benzpyrole and bis-benzimidazole as well as benzoic acid. The derivative is an angiotensin II receptor antagonist, and can be used for preventing or treating diseases of hypertension, cardiovascular disease, renal vascular diseases, pulmonary hypertension and the like.
Description
Technical field
The present invention relates to the new methyl substituted bis-benzimidazole derivative of N-Phenylindole of a class and the preparation method of this compounds.This compound can effectively prevent and treat diseases such as hypertension and other heart brain and kidney blood vessel diseases, pulmonary hypertension.
Background technology
People such as Marshall had synthesized first Angiotensin II (Angiotensin II in 1970, A II) receptor antagonist--peptides Saralasin (Saralasin:Sarl-Ala8-Ang II), the structure of it and Angiotensin II is quite similar, and it has the specificity antagonistic action in vitro tissue.But in clinical practice is used since oral invalid, metabolism is unstable and part A II generation agonism is restricted.Nineteen eighty-two, Japan military field drugmaker does the time spent at the diuretic antihypertensive of research imidazoleacetic acid compounds, finds that S-8307 can suppress the rabbit arterial that A II brings out and shrink and pressor effect, 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 (the Drugs of the fixture.1992 of Smithkline Beecham company, researchist 17:575-593), C-stub area and the S-8307 of AII are arranged relatively, S-8307 has been carried out serial structural modification, the result obtained respectively two kinds of different types of structure, all have Compound D up-753 (Losartan, losartan) and a SK ﹠amp of greater activity; F-108566 (Eprosartan, Yi Pushatan), losartan in 1994 Sweden listing (Drugs of the Future.1997,22:1079-1085).Yi Pushatan in 1997 in Germany listing (Drugs of the future.1996,21 (8): 794-798).
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.The non-peptide class A II receptor antagonist of listing has valsartan (Valsartan), losartan, Yi Pushatan, Irb (Irbesartan), telmisartan (Telmisartan) etc. at present.
On May 20th, 1998, European patent EP 0502314 discloses the new drug telmisartan, and goes on the market in the U.S. in March, 1999, its structural formula (compound VI) as follows:
Telmisartan has following pharmacological action characteristics:
(1) selectivity height: with the avidity of angiotensin-ii receptor 1 be more than 3000 times of acceptor 2; (2) long-acting: the curative of " 1 time on the 1st "; (3) efficient: the diastolic pressure hypotensive effect to the hyperpietic is more better than LOSARTAN POTASSIUM or amlodipine; (4) mainly be combined into the glcuronide of non-activity by liver, by defecate, minimum to the renal function influence by bile; (5) can effectively protect target organ such as cardiovascular, renal blood vessels, be applicable to tolerate or irritated various hyperpietic other depressor; (6) tolerance is good, and untoward reaction is lighter, and the drug withdrawal rate is low.Telmisartan is compared with losartan, the valsartan of listing at home, has the advantage of bioavailability height, long half time.
Telmisartan but is the antihypertensive class medicine the most rapidly of market development in recent years.
2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzoglyoxaline (compound I I c) is the important intermediate of synthetic telmisartan; this compound is, and to be starting raw material with 3-methyl-4-Methyl anthranilate get (Ries U through acidylate, nitrated, reduction, cyclization, ester hydrolysis, condensation reaction; Mihm G; Narr B; et al.J Med Chem; 1993,36:4040-4051).The compound of present patent application protection just with compound I I c and analog thereof as starting raw material.
In December, 1994, US Patent No. 5374615 was reported following compound (compound VI I) with indole structure, and this compound has antihypertensive activity (Michael A.Poss, Denis E.Ryono, et al.Bioorganic preferably; MedicinalChemistry Letters, 1994,4:145-150).As shown in the figure:
R
2=-CH
2OH or-CHO or-COOH
R
3=C
1-10Alkyl or C
3-10Thiazolinyl
R
4=-COOH
Summary of the invention
Easy to prepare for seeking, and have better AT
1The new drug of receptor antagonist effect, the present invention is on the telmisartan architecture basics, replaced the biphenyl structural of telmisartan with substituted indole, the new methyl substituted bis-benzimidazole derivative I of N-Phenylindole of a class has been synthesized in design, and the preparation method of this compound is provided.This compound is better than Irb, valsartan etc. aspect blood pressure lowering effect.
Wherein R is methyl, ethyl, n-propyl, normal-butyl and n-pentyl.
The compound of protecting is:
(compound I a) for phenylformic acid for 2-(4-((2,4-dimethyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl)
2-(4-((2-ethyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compounds ib)
2-(4-((2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compound I c)
2-(4-((2-normal-butyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compound I d)
2-(4-((2-n-pentyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compound I e)
Compound provided by the invention, can be by the preparation of following method (be that n-propyl be example with R):
Substitution reaction is taken place with the 4-brooethyl indoles of being protected by benzoyl in bisbenzimidazole compound IIc generate compound III c under alkaline condition; the hydrolysis in aqueous sodium hydroxide solution of this compound is sloughed protecting group and is obtained compound IV c; compound IV c and adjacent fluorobenzonitrile generation substitution reaction generate Vc, and last hydrolysis obtains the bisbenzimidazole compound Ic that the N-Phenylindole replaces.The synthetic method of the target compound that other is cited and compound I c are similar.
Those skilled in the art can synthesize this compounds according to foregoing description.
Through further discovering, above-claimed cpd has prevention or therapeutic action preferably to hypertension, heart brain and kidney blood vessel diseases, pulmonary hypertension.Therefore, compound of the present invention can be used for preparing the medicine of diseases such as prevention or treatment hypertension.
Embodiment
[embodiment 1]
The preparation method of 2-(4-((2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compound I c) specifically may further comprise the steps:
Step 1:(4-((2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) (phenyl) ketone (compound III c) is synthetic
With 2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzoglyoxaline (IIc) (455mg, 1.49mmol) and 60% sodium hydride (NaH) (39.42mg, 1.64m mol) be dissolved in the 20mL tetrahydrofuran (THF) (THF).Nitrogen (N
2) protect down, stir 20min in 50 ℃.Be cooled to room temperature, slowly Dropwise 5 0mL is dissolved with the THF solution of 10~20m mol (4-(brooethyl)-1H-indoles-1-yl) phenyl ketone, continues heated and stirred 3h.Reaction solution is poured in the 15mL frozen water.With ethyl acetate extraction three times (30mL * 3), merge organic phase, wash once (50mL) with saturated common salt.The organic phase anhydrous magnesium sulfate drying filters, and removes solvent under reduced pressure, and the gained residue is carried out column chromatography, and (elutriant is methylene dichloride: methyl alcohol=100: 1).Get faint yellow solid 579mg, yield 72.0%.
1H?NMR(400MHz,CDCl
3):δ8.35(d,1H,J=8.32Hz,N-C
2-H),7.80(s,1H,Ph-H),7.78(d,2H,J=7.48Hz,Ph-H),7.60(t,2H,J
1=7.84Hz,J
2=7.08Hz,Ph-H),7.54(t,2H,J
1=7.52Hz,J
2=7.64Hz,Ph-H),7.43(s,2H,Ph-H),7.34(d,2H,J=3.8Hz,Ph-H),7.31(t,2H,J
1=4.04Hz,J
2=3.6Hz,Ph-H),7.28(d,1H,J=8.24Hz,Ph-H),6.73(d,1H,J=7.48Hz,N-C
3-H),5.68(s,2H,N-CH
2-Ph),3.74(s,3H,N-CH
3),2.94(t,2H,J
1=7.84Hz,J
2=7.92Hz,C
H 2CH
2CH
3),2.78(s,3H,Ph-CH
3),1.85(m,2H,CH
2C
H 2CH
3),1.04(t,3H,J
1=7.36Hz,J
2=7.36Hz,CH
2CH
2C
H 3)。MS(ESI)m/z:538.3[M+H]
+。
Synthesizing of step 2:4-((2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl) indoles (compound IV c)
With (4-((2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenyl ketone (compound III c) (579mg, 1.34m mol) with behind the 20mL dissolve with methanol, at the NaOH solution 20mL that adds 2mol/L, stirring and refluxing reaction 3h.Remove methyl alcohol under reduced pressure, use CH
2Cl
2Extraction, the organic phase anhydrous magnesium sulfate drying filters, and removes solvent under reduced pressure, and the gained residue is carried out column chromatography, and (elutriant is methylene dichloride: methyl alcohol=100: 1).Get faint yellow solid 547mg, yield 94.2%.
1HNMR(400MHz,CDCl
3):δ8.5(s,1H,NH),7.78(d,1H,J=4.88Hz,Ph-H),7.45(d,2H,J=9Hz,Ph-H),7.38(d,2H,J=7.84Hz,Ph-H),7.30(s,1H,Ph-H),7.27(d,1H,J=4.56Hz,Ph-H),7.02(t,1H,J
1=7.64,J
2=7.92Hz,N-C
2-H),6.50(d,2H,J=7.92Hz,N-C
3-H),5.73(s,1H,N-CH
2-Ph),3.69(s,3H,N-CH
3),2.95(t,3H,J
1=7.56Hz,J
2=7.28Hz,C
H 2CH
2CH
3)2.77(s,3H,Ph-CH
3),1.86(m,2H,CH
2C
H 2CH
3),1.04(t,3H,J
1=7.32Hz,J
2=7.36Hz,CH
2CH
2C
H 3)。MS(ESI)m/z:434.3[M+H]
+。
Synthesizing of step 3:2-(4-((2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) cyanophenyl (compound Vc)
With 4-((2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl) indoles (compound IV c) (547mg, 1.26m mol) and adjacent fluorobenzonitrile (0.21mL, 1.90m mol), K
2CO
3(350mg, 2.52m mol) is dissolved among the 15mL DMF, stirring heating backflow 5h.Add ethyl acetate in the reaction solution, wash with water five times (30mL * 5), the saturated common salt water washing is (30mL) once.The organic phase anhydrous magnesium sulfate drying filters, and removes solvent under reduced pressure, and the gained residue is carried out column chromatography, and (elutriant is methylene dichloride: methyl alcohol=100: 1).Get faint yellow solid 540mg, yield 80.2%.
1H?NMR(400MHz,CDCl3):δ7.87(d,1H,J=7.68Hz,Ph-H),7.77(q,1H,J
1=4.36Hz,J
2=4.4Hz,Ph-H),7.73(s,1H,Ph-H),7.58(d,1H,J=8.08Hz,N-C2-H),7.53(t,1H,J
1=7.64Hz,J
2=7.64Hz,Ph-H),7.48(s,1H,Ph-H),7.45(t,2H,J
1=3.44Hz,J
2=4.08Hz,Ph-H),7.35(t,1H,J
1=1.48Hz,J
2=5.2Hz,Ph-H),7.28(t,1H,J
1=5.4Hz,J
2=4.36Hz,Ph-H),7.21(s,1H,Ph-H),7.08(s,1H,N-C3-H),6.73(d,1H,J=3.36Hz,Ph-H),6.56(d,1H,J=7.32,Ph-H),5.68(s,2H,N-CH
2-Ph),3.74(s,3H,N-CH3),2.94(t,2H,J
1=7.84Hz,J
2=7.92Hz,C
H 2CH
2CH
3),2.78(s,3H,Ph-CH
3),1.85(m,2H,CH
2C
H 2CH
3),1.04(t,3H,J
1=7.36Hz,J
2=7.36Hz,CH
2CH
2C
H 3)。MS(ESI)m/z:535.1[M+H]
+。
Synthesizing of step 4:2-(4-((2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compound I c)
With 2-(4-((2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) cyanophenyl (compound Vc) (540mg, 1.01m mol) use the 20mL dissolve with methanol, at the NaOH solution 20mL that adds 5mol/L, stirring and refluxing 18h, screw out methyl alcohol, hydrochloric acid transfers to PH=5-6, uses CH
2Cl
2Extractive reaction liquid, organic phase washes with water, the saturated common salt washing.The organic phase anhydrous magnesium sulfate drying filters, and removes solvent under reduced pressure, and the gained residue is carried out column chromatography, and (elutriant is methylene dichloride: methyl alcohol=100: 1).Get faint yellow solid 347mg, yield 62.1%.
1H?NMR(400MHz,CDCl
3):δ8.23(d,1H,J=7.86Hz,Ph-H),8.10(d,1H,J=7.56Hz,Ph-H),7.73(d,1H,J=4Hz,Ph-H),7.60(t,1H,J
1=4.98Hz,J
2=4.46Hz,Ph-H),7.50(t,2H,J
1=2.88Hz,J
2=6.32Hz,N-C
2’-H),7.24(d,4H,J=7.68Hz,Ph-H),7.10(t,2H,J
1=10.52Hz,J
2=9.12Hz,Ph-H),6.94(d,2H,J=15.4Hz,Ph-H),6.58(s,1H,N-C
3’-H),5.23(s,2H,N-CH
2-Ph),3.74(s,3H,N-CH
3),2.94(t,2H,J
1=7.84Hz,J
2=7.92Hz,C
H 2CH
2CH
3),2.78(s,3H,Ph-CH
3),1.85(m,2H,CH
2C
H 2CH
3),1.04(t,3H,J
1=7.36Hz,J
2=7.36Hz,CH
2CH
2C
H 3)。MS(ESI)m/z:554.1[M+H]
+。
[embodiment 2]
2-(4-((2,4-dimethyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compound I preparation method a):
Experimental procedure is as described in the embodiment 1, yield 32.7%.
1H?NMR(400MHz,DMSO)δ:11.98(brs,1H,COO-H),7.92(d,1H,J=7.68Hz,Ph-H),7.81(m,4H,Ph-H),7.55(t,1H,J
1=7.64Hz,J
2=7.64Hz,Ph-H),7.49(s,1H,Ph-H),7.43(s,1H,Ph-H),7.34(m,4H,Ph-H),7.28(d,1H,J=8.24Hz,Ph-H),7.02(t,1H,J
1=7.64,J
2=7.92Hz,N-C
2-H),6.50(d,2H,J=7.92Hz,N-C
3-H),5.73(s,1H,N-CH
2-Ph),3.74(s,3H,N-CH
3),2.78(s,3H,Ph-CH
3),2.04(s,3H,C-C
H 3)。MS(ESI)m/z:526.3[M+H]
+。
[embodiment 3]
The preparation method of 2-(4-((2-ethyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compounds ib):
Experimental procedure is as described in the embodiment 1, yield 29.1%.
1H?NMR(400MHz,DMSO)δ:11.88(brs,1H,COO-H),7.84(d,1H,J=7.68Hz,Ph-H),7.80(s,1H,Ph-H),7.76(m,3H,Ph-H),7.51(m,3H,Ph-H),7.34(d,2H,J=3.8Hz,Ph-H),7.28(m,3H,Ph-H),7.02(t,1H,J
1=7.64,J
2=7.92Hz,N-C
2-H),6.50(d,2H,J=7.92Hz,N-C
3-H),5.73(s,1H,N-CH
2-Ph),3.74(s,3H,N-CH
3),2.46(m,2H,C
H 2CH
3),2.30(s,3H,Ph-CH
3),1.27(t,3H,J=15.04Hz,CH
2C
H 3)。MS(ESI)m/z:540.2[M+H]
+。
[embodiment 4]
The preparation method of 2-(4-((2-normal-butyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compound I d):
Experimental procedure is as described in the embodiment 1, yield 26.3%.
1H?NMR(400MHz,DMSO)δ:11.98(brs,1H,COO-H),7.89(d,1H,J=7.68Hz,Ph-H),7.81(m,4H,Ph-H),7.51(m,3H,Ph-H),7.31(m,5H,Ph-H),7.02(t,1H,J
1=7.64,J
2=7.92Hz,N-C
2-H),6.50(d,2H,J=7.92Hz,N-C
3-H),5.73(s,1H,N-CH
2-Ph),3.74(s,3H,N-CH
3),2.41(t,2H,C
H 2CH
2CH
2CH
3),2.17(s,3H,Ph-CH
3),1.73(m,2H,CH
2C
H 2CH
2CH
3),1.43(m,2H,CH
2CH
2C
H 2CH
3),0.97(t,3H,J=7.32Hz,CH
2CH
2CH
2C
H 3)。MS(ESI)m/z:568.3[M+H]
+。
[embodiment 5]
The preparation method of 2-(4-((2-n-pentyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compound I e):
Experimental procedure is as described in the embodiment 1, yield 22.1%.
1H?NMR(400MHz,DMSO)δ:12.01(brs,1H,COO-H),7.97(d,1H,J=7.68Hz,Ph-H),7.85(s,1H,Ph-H),7.73(m,3H,Ph-H),7.48(m,3H,Ph-H),7.34(m,4H,7.28(d,1H,J=8.24Hz,Ph-H),7.02(t,1H,J
1=7.64,J
2=7.92Hz,N-C
2-H),6.50(d,2H,J=7.92Hz,N-C
3-H),5.73(s,1H,N-CH
2-Ph),3.74(s,3H,N-CH
3),2.45(t,2H,J=15.24Hz,C
H 2CH
2CH
2CH
2CH
3),2.36(s,3H,Ph-CH
3),1.73(m,2H,CH
2C
H 2CH
2CH
2CH
3),1.37(m,4H,CH
2CH
2C
H 2C
H 2CH
3),0.94(t,3H,J=7.32Hz,CH
2CH
2CH
2CH
2C
H 3)。MS(ESI)m/z:582.3[M+H]
+。
The experiment of [embodiment 6] antihypertensive drugs screening active ingredients
Laboratory animal: 30 of spontaneous hypertensive rats (SHR), health, male, 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 2-(4-((2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compound I c).
Positive control drug: Irb, clinical consumption are 150mg/ people, valsartan, clinical consumption is 80mg/ people, establishing body weight for humans is 60kg, be scaled rat dosage after, Irb is 15mg/kg, valsartan is 8mg/kg.Test is got 15mg/kg and is contrast concentration.
Experimental technique: select 40 spontaneous hypertensive rats (SHR) model for use, be divided into blank group, the Irb group, the valsartan group, compound I c administration group does not have the wound blood pressure transducer with animalcule and be connected to the clear-headed free moving animals blood pressure recording analytical system (Shanghai, Alcott) of MPA-HBBS type after carrier wave amplifies, the subcutaneous insertion needle electrode of four limbs is connected to alternating current amplifier and is used for monitoring standard two lead electrocardiogram.The femoral arteriography method is measured clear-headed rat aorta mean arterial pressure (MAP), systolic pressure (SAP), diastolic pressure (DAP), heart rate (HR) and electrocardiogram(ECG (ECG).
During test testing compound is mixed with the aqueous suspension that concentration is 15mg/kg.Positive control drug Irb and valsartan all are mixed with the aqueous suspension that concentration is 15mg/kg during test.
SHR takes femoral arteriography operation, the recovery of spending the night before the test.SHR connected the multi-path physiology signalling system in second day, and on-line continuous detects blood pressure, recorded before the administration and blood pressure after the administration.
Data processing: all experimental datas are all with mean ± standard deviation (x ± SD) expression, the variance analysis that blood pressure relatively designs with completely random between each group after the medication, do not wait as each group population mean, use the multiple comparisons between a plurality of sample averages again, i.e. q check is handled.
Experimental result: blood pressure test result (seeing Table 1): to treat front and back blood pressure reduction value as variable, relatively there were significant differences with blank group to find compound I c group, again through the q of multiple sample mean testing identity, compound I c group has remarkable antihypertensive effect during 4h, the step-down value is greater than 20mmhg, there were significant differences (P<0.05) with the blank group, relatively has utmost point significant difference (P<0.01) step-down maximum value to reach 33.5mmhg with the blank group behind the 6h.
This compound is compared with Irb, and antihypertensive effect was close in preceding 6 hours, but the antihypertensive effect of this compound significantly is better than Irb (P<0.05) behind the 7h, has lasting step-down trend, still has remarkable antihypertensive effect in the time of 10 hours.
This compound is compared with valsartan, remarkable difference is arranged during 1~5h, because compound I c rate of pressure reduction is slow, the uncomfortable phenomenons such as dizziness that can avoid quick step-down to cause, and both step-down data do not have remarkable difference when 6h, and compound I c still has tangible step-down trend, and the hypotensive effect of valsartan slightly gos up, both step-down data are close when 7h, and the step-down value of compound I c has good step-down trend a little more than the step-down value of valsartan behind the 8h.
This compound antihypertensive effect obviously is better than the Irb positive controls in a word, and the step-down time length is also long than Irb; Antihypertensive effect and the valsartan of this compound are close, but antihypertensive effect is better than valsartan behind the 8h, are a kind of compounds of efficient, long-acting, steady step-down, are worth very much further research and development.
Respectively organize blood pressure reduction value relatively (x ± SD N=10) after table 1. experiment
Annotate: compare with the blank group: * P<0.01, * * P<0.01; Compare with the valsartan group: #P<0.05, ##P<0.01; Compare with the Irb group :+P<0.01, ++ P<0.01
Claims (8)
2. the methyl substituted bis-benzimidazole derivative of N-Phenylindole according to claim 1 is characterized in that described R is methyl, ethyl, n-propyl, normal-butyl or n-pentyl, and this compounds is:
(compound I a) for phenylformic acid for 2-(4-((2,4-dimethyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl);
2-(4-((2-ethyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compounds ib);
2-(4-((2-n-propyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compound I c);
2-(4-((2-normal-butyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compound I d);
2-(4-((2-n-pentyl-4-methyl-6 (1-tolimidazole-2-yl) benzimidazolyl-) methyl)-1H-indoles-1-yl) phenylformic acid (compound I e).
3. the preparation method of the methyl substituted bis-benzimidazole derivative I of N-Phenylindole according to claim 1 comprises the steps:
The compound I I of 1~10m mol and the alkali of 1~20m mol are dissolved in the organic solvent nitrogen (N
2) protection down, react 0.5~5h down at 50 ℃, be cooled to room temperature, slowly add 1~20m mol (4-(brooethyl)-1H-indoles-1-yl) phenyl ketone, continue heated and stirred 1~5h, reaction solution is poured in the frozen water, used ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous magnesium sulfate drying, filter, remove solvent under reduced pressure, the gained residue is carried out column chromatographic isolation and purification;
2) compound IV is synthetic
With the compound III of 1~20m mol with 1~50mL organic solvent dissolution after, add the alkaline solution of 1~10mol/L, stirring and refluxing reaction 1~10h, reaction mixture is with methylene dichloride (CH
2Cl
2) extraction, the organic phase anhydrous magnesium sulfate drying filters, and removes solvent under reduced pressure, and the gained residue is carried out column chromatographic isolation and purification;
3) compound V's is synthetic
The compound IV of 1~20m mol and the adjacent fluorobenzonitrile of 1~20m mol are dissolved in the organic solvent, add the salt of wormwood (K of 1~30mmol
2CO
3), stirring heating backflow 2~7h adds ethyl acetate in the reaction solution, washes with water, and the saturated common salt water washing, the organic phase anhydrous magnesium sulfate drying filters, and removes solvent under reduced pressure, and the gained residue is carried out column chromatographic isolation and purification;
4) compound I is synthetic
With the compound V organic solvent dissolution of 1~15m mol, add the alkaline solution of 1~10mol/L, stirring and refluxing 10~50h screws out organic solvent, and hydrochloric acid is transferred pH to 5~6, uses CH
2Cl
2Extractive reaction liquid washes with water, the saturated common salt water washing, and the organic phase anhydrous magnesium sulfate drying filters, and removes solvent under reduced pressure, and the gained residue is carried out column chromatography.
4. the methyl substituted bis-benzimidazole derivative I of N-Phenylindole according to claim 3 preparation method, it is characterized in that: in the described step 1), used alkali is sodium hydride, salt of wormwood, lithium hydroxide, potassium tert.-butoxide, lithium diisopropyl amido; Organic solvent is acetone, tetrahydrofuran (THF), chloroform, 1, the 4-dioxane; Weighting agent in the column chromatography is silica gel, and eluent is sherwood oil: ethyl acetate or sherwood oil: the mixed solvent of methylene dichloride, blending ratio scope are 50: 1~200: 1.
5. the methyl substituted bis-benzimidazole derivative I of N-Phenylindole according to claim 3 preparation method, it is characterized in that: described step 2), used organic solvent is methyl alcohol, ethanol, methylene dichloride, chloroform, tetrahydrofuran (THF); Alkaline solution is sodium hydroxide solution, potassium hydroxide solution, barium hydroxide solution; Weighting agent in the column chromatography is silica gel, and eluent is sherwood oil: ethyl acetate or sherwood oil: the mixed solvent of methylene dichloride, blending ratio scope are 50: 1~150: 1.
6. the methyl substituted bis-benzimidazole derivative I of N-Phenylindole according to claim 3 preparation method, it is characterized in that: in the described step 3), used organic solvent is N, dinethylformamide (DMF), 1,4-dioxane, ethylene glycol; Weighting agent in the column chromatography is silica gel, and eluent is methylene dichloride: the mixed solvent of methyl alcohol, blending ratio scope are 50: 1~150: 1.
7. the methyl substituted bis-benzimidazole derivative I of N-Phenylindole according to claim 3 preparation method, it is characterized in that: in the described step 4), used organic solvent is methyl alcohol, ethanol, methylene dichloride, chloroform, tetrahydrofuran (THF); Alkaline solution is sodium hydroxide solution, potassium hydroxide solution, barium hydroxide solution; Weighting agent in the column chromatography is silica gel, and eluent is methylene dichloride: the mixed solvent of methyl alcohol, blending ratio scope are 100: 1~350: 1.
8. each described compound of claim 1-2 is in preparation prevention with treat application in the hypertensive medicine.
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EP0502314A1 (en) * | 1991-02-06 | 1992-09-09 | Dr. Karl Thomae GmbH | Benzimidazol, medicaments containing them and process for their preparation |
US5374615A (en) * | 1990-10-31 | 1994-12-20 | E. R. Squibb & Sons, Inc. | Indole- and benzimidazole-substituted imidazole and benzimidazole derivatives |
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