CN101798287A - [(4-methyl-2-propyl-N-methoxyl-substituted benzene alkyl-1H-benzimidazole-6-formamide)-1-yl] methyldiphenyl compound and preparation method thereof - Google Patents

[(4-methyl-2-propyl-N-methoxyl-substituted benzene alkyl-1H-benzimidazole-6-formamide)-1-yl] methyldiphenyl compound and preparation method thereof Download PDF

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CN101798287A
CN101798287A CN201010126447A CN201010126447A CN101798287A CN 101798287 A CN101798287 A CN 101798287A CN 201010126447 A CN201010126447 A CN 201010126447A CN 201010126447 A CN201010126447 A CN 201010126447A CN 101798287 A CN101798287 A CN 101798287A
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methyl
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周智明
章军
李志怀
汪进良
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Beijing Institute of Technology BIT
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Abstract

The invention relates to a [(4-methyl-2-propyl-N-methoxyl-substituted benzene alkyl-1H-benzimidazole-6-formamide)-1-group] methyldiphenyl compound and a preparation method thereof, belonging to the technical field of medicine. The general formula and the synthetic route of the compound are both shown in the specification of the invention. The compound can be used for preparing medicaments for treating cardiovascular and cerebrovascular diseases, and has favorable inhibition activity on angiotensin II AT1 receptors. The preparation method has the advantages of simple synthesis process and easy obtainment of raw materials and is beneficial for industrial production.

Description

[(4-methyl-2-propyl group-N-methoxyl group substituted benzene alkyl-1H-benzoglyoxaline-6-methane amide)-1-yl] methyl diphenyl compounds and preparation method
Technical field
The present invention relates to a kind of as Angiotensin II AT 1[(4-methyl-2-propyl group-N-methoxyl group substituted benzene alkyl-1H-benzoglyoxaline-6-methane amide)-1-yl] methyl diphenyl compounds and preparation method of receptor antagonist belongs to medical technical field.
Background technology
Hypertension is modal cardiovascular disorder, and its complication is to cause one of human main causes of death, is great public health problem in the global range.China is in the period of social economy's high speed development, along with the transition of society, adds the aggravation of aging population, and huge change has taken place for people's living standard and behavior, and hypertensive morbidity also presents swift and violent ascendant trend.Suffer from hypertensive people among China grownup and have 1.6 hundred million now, and annual newly-increased hyperpietic more than 600 ten thousand, thereby strengthen prevention and treat hypertension seeming particularly important.Non-peptide class Angiotensin II AT 1Receptor antagonist (ARB) is a class novel antihypertensive medicine that acts on renin-angiotensin system (RAS), and (ACEI) compares with angiotensin-convertion enzyme inhibitor, and hypotensive effect is more remarkable, more selectively block RAS, and side effect is little.At present, the existing a plurality of kind listings of ARB class medicine, as losartan, valsartan, telmisartan, irbesartan, Candesartan etc.Wherein, the telmisartan activity is the highest, but its complex structure, synthetic difficulty is relatively large, therefore, simplifies its structure, and synthetic new highly active compound has significance.
Summary of the invention
The objective of the invention is to solve problems such as complex structure, synthetic difficulty that ARB class antihypertensive drug telmisartan exists be relatively large, be synthetic new highly active compound, and a kind of [(4-methyl-2-propyl group-N-methoxyl group substituted benzene alkyl-1H-benzoglyoxaline-6-methane amide)-1-yl] methyl diphenyl compounds and preparation method is provided.
The objective of the invention is to be achieved through the following technical solutions:
[(4-methyl-2-propyl group-N-methoxyl group substituted benzene alkyl-1H-benzoglyoxaline-6-methane amide)-1-yl] of the present invention methyl diphenyl compounds, its general formula is as follows:
Wherein, n is 1 or 2; R 1Be 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 3,4-Dimethoxyphenyl, 2,5-Dimethoxyphenyl; R 2Be carboxylic acid, tetrazolium.
The preparation method of [(4-methyl-2-propyl group-N-methoxyl group substituted benzene alkyl-1H-benzoglyoxaline-6-methane amide)-1-yl] of the present invention methyl diphenyl compounds.Its synthetic route is as follows:
Wherein, P is methyl-formiate or triphenyltetrazolium.
Its concrete preparation process is as follows:
(1) 4-methyl-2-propyl group-1H-benzoglyoxaline-6-formic acid is added in the thionyl chloride, reflux is more than 1 hour, remove excessive thionyl chloride under reduced pressure, the solid that obtains is added in the methylene dichloride, add triethylamine after being cooled to 0～5 ℃, add the phenylalkylamine that the N-methoxyl group replaces again, add that the afterreaction mixture rises to room temperature naturally and more than reaction 5h under the room temperature; Again reacted solution is used saturated sodium bicarbonate solution and water washing successively, drying obtains the off-white color solid behind the concentrating under reduced pressure, obtain intermediate A through ethyl alcohol recrystallization.
Wherein the mol ratio of the phenylalkylamine of 4-methyl-2-propyl group-1H-benzoglyoxaline-6-formic acid, thionyl chloride, triethylamine and the replacement of N-methoxyl group is 1: 5～10: 1.5: 1;
The phenylalkylamine that described N-methoxyl group replaces is any one of following general formula representative;
Figure GSA00000047680900031
The general formula of described intermediate A is as follows:
Figure GSA00000047680900032
(II) and the n (III) be 1 or 2; R 1Be 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 3,4-Dimethoxyphenyl, 2,5-Dimethoxyphenyl;
(2) intermediate A that (1) step was obtained is added to solvent N, in N '-dimethylformamide, add after being cooled to 0～5 ℃ more than the potassium tert.-butoxide reaction 30min, add biphenol compound B again, add that the afterreaction mixture rises to room temperature naturally and more than reaction 8h under the room temperature; Again post reaction mixture is poured in the water, the solid ethyl acetate extraction of separating out, washing, drying, residual branch uses column chromatography behind the concentrating under reduced pressure, obtains white solid intermediate C.
Wherein, the mol ratio of intermediate A, potassium tert.-butoxide and biphenol compound B is 1: 1.1: 1.1;
The general formula of described biphenol compound B is as follows:
Figure GSA00000047680900041
The general formula of described intermediate C is as follows:
Figure GSA00000047680900042
(IV) and the n (V) be 1 or 2; R 1Be 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 3,4-Dimethoxyphenyl, 2,5-Dimethoxyphenyl; P is methyl-formiate or triphenyltetrazolium;
(3) when P represents methyl-formiate, Compound C adds in the solvent methanol, adds the 2mol/L aqueous sodium hydroxide solution again, more than the reflux 2h, be cooled to room temperature, filter, remove the methyl alcohol in the filtrate under reduced pressure, residual solution is used salt acid for adjusting pH value to 6～7 of 2mol/L, separate out white solid, filter, drying obtains target product;
Wherein the mol ratio of Compound C and aqueous sodium hydroxide solution is 1: 5:.
When P represented triphenyltetrazolium, Compound C added in solvents tetrahydrofurane and the methyl alcohol, adds 10% hydrochloric acid again, stirring reaction 12h under room temperature.Reaction mixture is regulated pH value to 12 with 2mol/L sodium hydroxide, removes tetrahydrofuran (THF) and methyl alcohol again under reduced pressure, filters, and filtrate is separated out white solid with salt acid for adjusting pH value to 6～7 of 2mol/L, filters, and drying obtains target product.
Wherein the mol ratio of Compound C and 10% hydrochloric acid is 1: 10.
The purposes of [(4-methyl-2-propyl group-N-methoxyl group substituted benzene alkyl-1H-benzoglyoxaline-6-methane amide)-1-yl] of the present invention methyl diphenyl compounds is that it can be used for preparing the medicine for the treatment of cardiovascular and cerebrovascular diseases.
Beneficial effect of the present invention is embodied in: the compound of being invented has good Angiotensin II AT 1It is active that acceptor suppresses, and can be used for preparing the medicine for the treatment of cardiovascular and cerebrovascular diseases, and its aqueous solution and sodium hydroxide or potassium hydroxide reaction directly obtain the sodium salt or the sylvite of this product, and structure of the present invention and synthesis technique are simple, and raw material is easy to get, and is fit to China's actual conditions.
Embodiment:
The invention will be further described below in conjunction with embodiment, but and can't help these examples and limit the scope of the invention.
Embodiment 1
(1) in the 100mL single port flask of stirring, reflux condensing tube and gas absorbing device is housed, add 2.18g (10.0mmol) 4-methyl-2-propyl group-1H-benzoglyoxaline-6-formic acid and 20mL thionyl chloride, stir reflux 1.5h down, remove excessive thionyl chloride then under reduced pressure, obtain the 2.40g light yellow solid, this solid is added in the 60mL methylene dichloride, add 2.1mL (15mmol) triethylamine after being cooled to 0 ℃, add 1.37g (10mmol) 2-methoxybenzylamine again, add the afterreaction mixture and rise to room temperature naturally and under room temperature, react 5h.Again reacted solution is used saturated sodium bicarbonate solution and water washing successively, drying obtains the off-white color solid behind the concentrating under reduced pressure, obtains 4-methyl-2-propyl group-N-(2-methoxybenzyl amido)-1H-benzoglyoxaline-6-methane amide 2.63g behind ethyl alcohol recrystallization.Two step total recoverys are 77.9%.129～131 ℃ of fusing points. 1H?NMR(400MHz，DMSO-d 6)δ：0.94(t，J＝7.26Hz，3H)，1.76(m，2H)，2.56(s，3H)，2.83(t，J＝7.12Hz，2H)，3.47(s，3H)，4.45(s，2H)，7.09～7.31(m，4H)，7.57(s，1H)，7.88(s，1H)，8.48(s，1H)。
(2) 1.69g (5.0mmol) (1) step product is added among the 20mL DMF, adds 0.62g (5.5mmol) potassium tert.-butoxide after being cooled to 0 ℃ with ice bath, add 1.68g (5.5mmol) 4 '-bromomethylbiphenyl-2-methyl-formiate again behind the reaction 30min.Add the recession deicing and bathe, reaction mixture rises to room temperature naturally, and under room temperature stirring reaction 8h.Reaction mixture is poured in the 200mL water, use ethyl acetate extraction, extracting solution washes with water after merging, dry, residual branch uses column chromatography behind the concentrating under reduced pressure, obtain white solid 4 '-[4-methyl-2-propyl group-N-(2-methoxybenzyl amido)-1H-benzoglyoxaline-6-methane amide)-1-yl] methyl diphenyl-2-methyl-formiate 2.37g, yield 84.7%.Fusing point: 163-164 ℃; IR (KBr), vmax/cm-1:3308,1727,1631,1590,1544,1458,1288,1244,1129; 1H NMR (400MHz, CDCl 3) δ: 0.97 (t, J=7.23Hz, 3H), 1.74 (m, 2H), 2.55 (s, 3H), 2.78 (t, J=7.16Hz, 2H), 3.47 (s, 3H), 3.69 (s, 3H), 4.45 (s, 2H), 5.55 (s, 2H), 7.12～7.86 (m, 14H), 8.45 (s, 1H); ESI-MS (m/z): 562.3 (M+H) +
(3) 1.12g (2.0mmol) (2) step product is added in the 50mL methyl alcohol, adds 5mL 2mol/L sodium hydroxide after the stirring and dissolving, reflux 2h.After being cooled to room temperature, filter, remove the methyl alcohol in the filtrate under reduced pressure, residual solution is separated out the white solid product with salt acid for adjusting pH value to 6～7 of 2mol/L, filters, be washed to neutrality, drying, obtain 4 '-[4-methyl-2-propyl group-N-(2-methoxybenzyl amido)-1H-benzoglyoxaline-6-methane amide)-the 1-yl] methyl diphenyl-2-formic acid (compound 1) 0.80g, yield 73.9%.
Its structural formula is as follows:
Figure GSA00000047680900071
Fusing point: 243-245 ℃.IR(KBr)，v max/cm -1：3395，1655，1598，1540，1490，1459，1358，1243，1122，1026，870，818，764； 1H?NMR(400MHz，CDCl 3)δ：0.97(t，J＝7.23Hz，3H)，1.74(m，2H)，2.55(s，3H)，2.78(t，J＝7.16Hz，2H)，3.47(s，3H)，4.45(s，2H)，5.56(s，2H)，7.12～7.86(m，14H)，8.45(s，1H)，12.718(br，1H)； 13C?NMR(100MHz，CDCl 3)δ：13.98，16.64，18.71，20.69，28.90，46.01，55.48，56.18，107.56，110.58，110.25，121.30，126.19，127.27，127.50，127.61，127.97，128.12，128.89，129.24，130.60，131.00，132.36，134.85，136.08，140.22，140.57，143.98，156.71，156.77，166.92，169.62；HRMS?calcd?for?C 34H 34N 3O 4[M+H] +548.2544，found?548.2533。
Embodiment 2
(1) phenylalkylamine of methoxyl group replacement adopts 10mmol 4-methoxybenzylamine, other feed intake and implementation method goes on foot with embodiment 1 (1), product is white solid 4-methyl-2-propyl group-N-(4-methoxybenzyl amido)-1H-benzoglyoxaline-6-methane amide, yield 71.4%, 133～135 ℃ of fusing points. 1H?NMR(400MHz，DMSO-d 6)δ：0.94(t，J＝7.18Hz，3H)，1.79(m，2H)，2.56(s，3H)，2.87(t，J＝7.16Hz，2H)，3.78(s，3H)，4.47(s，2H)，6.82～7.29(m，4H)，7.55(s，1H)，7.82(s，1H)，8.46(s，1H)。
(2) condition is with embodiment 1 (2) step, product be white solid 4 '-[4-methyl-2-propyl group-N-(4-methoxybenzyl amido)-1H-benzoglyoxaline-6-methane amide)-1-yl] methyl diphenyl-2-methyl-formiate, yield 91.5%.Fusing point: 147-148 ℃; IR (KBr), v Max/ cm -1: 3312,1732,1635,1595,1515,1455,1429,1248,1131; 1H NMR (400MHz, CDCl3) δ: 0.96 (t, J=7.21Hz, 3H), 1.75 (m, 2H), 2.55 (s, 3H), 2.79 (t, J=7.16Hz, 2H), 3.69 (s, 3H), 3.77 (s, 3H), 4.46 (s, 2H), 5.56 (s, 2H), 7.09～7.90 (m, 14H), 8.44 (s, 1H); ESI-MS (m/z): 562.3 (M+H) +
(3) condition is with embodiment 1 (3) step, product be white solid 4 '-[4-methyl-2-propyl group-N-(4-methoxybenzyl amido)-1H-benzoglyoxaline-6-methane amide)-1-yl] methyl diphenyl-2-formic acid (compound 2), yield 79.3%.
Its structural formula is as follows:
Figure GSA00000047680900081
Fusing point:＞250 ℃.IR(KBr)，v max/cm -1：3357，1652，1593，1533，1511，1454，1293，1245，1041，880，818，756； 1H?NMR(400MHz，CDCl3)δ：0.96(t，J＝7.21Hz，3H)，1.75(m，2H)，2.55(s，3H)，2.79(t，J＝7.16Hz，2H)，3.77(s，3H)，4.46(s，2H)，5.56(s，2H)，7.09～7.90(m，14H)，8.44(s，1H)，12.716(br，1H)； 13C?NMR(100MHz，CDCl3)δ：13.98，16.63，20.67，28.89，42.30，46.00，55.20，56.18，107.51，113.81，121.25，126.17，127.47，127.58，128.14，128.79，128.89，129.24，130.69，131.00，132.03，132.36，134.85，136.07，140.21，140.57，143.95，156.76，158.31，166.64，169.63；HRMS?calcd?for?C 34H 34N 3O 4[M+H] +?548.2544，found?548.2533。
Embodiment 3
(1) phenylalkylamine of methoxyl group replacement adopts 10mmol 3, the 4-dimethoxybenzylamine, other conditions and implementation method are with (1) step of embodiment 1, product is white solid 4-methyl-2-propyl group-N-(3,4-dimethoxybenzylamine base)-1H-benzoglyoxaline-6-methane amide, yield 75.0%, 128～130 ℃ of fusing points. 1H?NMR(400MHz，DMSO-d 6)δ：0.81(t，J＝7.29Hz，3H)，1.72(m，2H)，2.50(s，3H)，2.81(t，J＝7.16Hz，2H)，3.71(s，3H)，3.79(s，3H)，4.43(s，2H)，6.99～7.01(m，3H)，7.68(s，1H)，7.81(s，1H)。
(2) condition is with (2) step of embodiment 1, product be white solid 4 '-[4-methyl-2-propyl group-N-(3,4-dimethoxybenzylamine base)-1H-benzoglyoxaline-6-methane amide)-1-yl] methyl diphenyl-2-methyl-formiate, yield 78.3%.。Fusing point: 126-127 ℃; IR (KBr), v Max/ cm -1: 3375,1715,1645,1596,1513,1448,1264,1127; 1H NMR (400MHz, CDCl 3) δ: 0.96 (t, J=7.21Hz, 3H), 1.75 (m, 2H), 2.55 (s, 3H), 2.79 (t, J=7.19Hz, 2H), 3.67 (s, 3H), 3.72 (s, 3H), 3.80 (s, 3H), 4.42 (s, 2H), 5.55 (s, 2H), 7.07～7.93 (m, 13H), 8.43 (s, 1H); ESI-MS (m/z): 592.3 (M+H) +
(3) condition is with (3) step of embodiment 1, product be white solid 4 '-[4-methyl-2-propyl group-N-(3,4-dimethoxybenzylamine base)-1H-benzoglyoxaline-6-methane amide)-1-yl] methyl diphenyl-2-formic acid (compound 3), yield 71.7%.
Its structural formula is as follows:
Figure GSA00000047680900091
Fusing point:＞250 ℃.IR(KBr)，v max/cm -1：3346，1653，1593，1513，1462，1418，1257，1215，1149，1034，1012，814，754； 1H?NMR(400MHz，CDCl 3)δ：0.96(t，J＝7.21Hz，3H)，1.75(m，2H)，2.55(s，3H)，2.79(t，J＝7.19Hz，2H)，3.72(s，3H)，3.80(s，3H)，4.42(s，2H)，5.55(s，2H)，7.07～7.93(m，13H)，8.43(s，1H)，12.721(br，1H)；13C?NMR(100MHz，CDCl 3)δ：13.98，16.64，18.71，20.68，28.89，30.09，45.98，55.38，55.95，56.18，107.35，111.73，111.80，116.38，121.19，126.16，127.48，128.44，128.73，128.90，129.25，130.60，131.00，132.36，134.80，136.07，140.22，140.58，143.84，151.55，152.37，157.54，166.70，169.63；HRMS?calcd?for?C 35H 36N 3O 5[M+H] +578.2650，found?578.2638。
Embodiment 4
(1) phenylalkylamine of methoxyl group replacement adopts 10mmol 2, the 5-dimethoxy-phenylethylamine, other feed intake and implementation method goes on foot with (1) of embodiment 1, product is white solid 4-methyl-2-propyl group-N-(2,5-dimethoxy-phenylethylamine base)-1H-benzoglyoxaline-6-methane amide, yield 72.4%, 145～147 ℃ of fusing points. 1H?NMR(400MHz，DMSO-d 6)δ：0.95(t，J＝7.24Hz，3H)，1.76(m，2H)，2.55(s，3H)，2.78(t，J＝7.16Hz，2H)，2.86(t，J＝7.19Hz，2H)，3.48(m，2H)，3.70(s，3H)，3.76(s，3H)，6.94～7.12(m，3H)，7.70(s，1H)，7.86(s，1H)。
(2) condition is with (2) step of embodiment 1, product be white solid 4 '-[4-methyl-2-propyl group-N-(2,5-dimethoxy-phenylethylamine base)-1H-benzoglyoxaline-6-methane amide)-1-yl] methyl diphenyl-2-methyl-formiate, yield 90.7%.Fusing point: 130-132 ℃; IR (KBr), v Max/ cm -1: 3305,1716,1643,1595,1539,1449,1246,1126,1046; 1H NMR (400MHz, CDCl 3) δ: 0.96 (t, J=7.25Hz, 3H), 1.75 (m, 2H), 2.55 (s, 3H), 2.80 (t, J=7.16Hz, 2H), 2.85 (t, J=7.18Hz, 2H), 3.48 (m, 2H), 3.60 (s, 3H), 3.71 (s, 3H), 3.77 (s, 3H), 5.55 (s, 2H), 7.07～7.87 (m, 13H), 8.43 (s, 1H); ESI-MS (m/z): 606.3 (M+H) +
(3) condition is with (3) step of embodiment 1, product be white solid 4 '-[4-methyl-2-propyl group-N-(2,5-dimethoxy-phenylethylamine base)-1H-benzoglyoxaline-6-methane amide)-1-yl] methyl diphenyl-2-formic acid (compound 4), yield 82.0%.
Its structural formula is as follows:
Figure GSA00000047680900111
Fusing point: 231-233 ℃.IR(KBr)，v max/cm -1：3361，1654，1597，1536，1501，1465，1355，1291，1244，1039，809，764； 1H?NMR(400MHz，CDCl 3)δ：0.96(t，J＝7.25Hz，3H)，1.75(m，2H)，2.55(s，3H)，2.80(t，J＝7.16Hz，2H)，2.85(t，J＝7.18Hz，2H)，3.48(m，2H)，3.71(s，3H)，3.77(s，3H)，5.56(s，2H)，7.07～7.87(m，13H)，8.43(s，1H)，12.727(br，1H)； 13CNMR(100MHz，CDCl 3)δ：13.98，16.64，18.71，20.68，28.89，30.09，45.98，55.38，55.95，56.18，107.35，111.73，111.80，116.38，121.19，126.16，127.48，128.44，128.73，128.90，129.25，130.60，131.00，132.36，134.80，136.07，140.22，140.58，143.84，151.55，153.14，156.67，166.70，169.63；HRMS?calcd?for?C 36H 38N 3O 5[M+H] +592.2806，found?592.2795。
Embodiment 5
(1) condition and result obtain 4-methyl-2-propyl group-N-(2-methoxybenzyl amido)-1H-benzoglyoxaline-6-methane amide with (1) step of embodiment 1.
(2) condition is with (2) step of embodiment 1, and product is white solid 4-methyl-2-propyl group-N-(2-methoxybenzyl amido)-1-[2 '-(1-trityl tetrazole-5-yl) biphenyl-4-yl] tolimidazole-6-methane amide, yield 86.3%.Fusing point: 107-109 ℃; IR (KBr), v Max/ cm -1: 3427,1646,1599,1513,1492,1448,1355,1247,1120,1028; 1H NMR (400MHz, CDCl 3) δ: 0.94 (t, J=7.40Hz, 3H), 1.72-1.80 (m, 2H), 2.70 (s, 3H), 2.74 (t, J=7.80Hz, 2H), 3.84 (s, 3H), 4.60 (d, J=5.6Hz, 2H), 5.22 (s, 2H), 6.58 (t, J=5.6Hz, 1H), 6.75-7.61 (m, 28H), 7.91-7.93 (m, 1H); ESI-MS (m/z): 814.4 (M+H) +
(3) product with (2) step of 0.81g (1mmol) is added in the 40mL tetrahydrofuran (THF), adds 40mL methyl alcohol and 9mL10%HCl, stirring reaction 12h under room temperature after the stirring and dissolving.Reaction mixture is regulated pH value to 12 with 2mol/L NaOH, remove tetrahydrofuran (THF) and methyl alcohol again under reduced pressure, filter, filtrate is used 2mol/L salt acid for adjusting pH value to 6～7, separate out white solid, filter dry 4-methyl-2-propyl group-N-(2-methoxybenzyl amido)-1-[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl that gets] tolimidazole-6-methane amide (compound 5) 0.51g, yield is 88.7%.
Its structural formula is as follows:
Figure GSA00000047680900121
Fusing point: 192-193 ℃; IR (KBr), v Max/ cm -1: 3263,1635,1591,1536,1492,1458,1392,1275,1240,1119,1026,877,754; 1H NMR (400MHz, CDCl 3) δ: 0.95 (t, J=7.40Hz, 3H), 1.71-1.80 (m, 2H), 2.57 (s, 3H), 2.80 (t, J=7.40Hz, 2H), 3.81 (s, 3H), 4.45 (d, J=5.6Hz, 2H), 5.47 (s, 2H), 6.87-7.52 (m, 12H), 7.62 (s, 1H), 7.95 (s, 1H), 8.71 (t, J=5.60Hz, 1H); 13CNMR (400MHz, CDCl 3) δ: 13.99,14.27,16.68,20.69,20.95,28.90,46.02,55.49,59.94,107.36,110.57,120.29,121.49,125.60,127.01,127.32,127.53,127.62,127.97,128.07,129.63,130.29,130.67,134.84,135.08,140.19,140.93,143.98,156.72,156.78,166.93; HRMS calcd forC 34H 34N 7O 2[M+H] +572.2768 found 572.2757.
Embodiment 6
(1) phenylalkylamine of methoxyl group replacement adopts 10mmol 3-anisole ethamine, other feed intake and implementation method goes on foot with (1) of embodiment 1, product is white solid 4-methyl-2-propyl group-N-(3-anisole ethylamino-)-1H-benzoglyoxaline-6-methane amide, yield 75.7%.148～150 ℃ of fusing points. 1H?NMR(400MHz，DMSO-d 6)δ：0.81(t，J＝7.23Hz，3H)，1.71(m，2H)，2.49(s，3H)，2.79(t，J＝7.22Hz，2H)，2.89(t，J＝7.16Hz，2H)，3.65(m，2H)，3.77(s，3H)，6.77～7.20(m，4H)，7.67(s，1H)，7.78(s，1H)。
(2) condition is with (2) step of embodiment 5, and product is white solid 4-methyl-2-propyl group-N-(3-anisole ethylamino-)-1-[2 '-(1-trityl tetrazole-5-yl) biphenyl-4-yl] tolimidazole-6-methane amide, yield 73.1%.Fusing point: 94-97 ℃; IR (KBr), v Max/ cm -1: 3388,1652,1596,1538,1488,1352,1272,1215,1190,1033; 1H NMR (400MHz, CDCl 3) δ: 0.95 (t, J=7.40Hz, 3H), 1.75-1.81 (m, 2H), 2.69 (s, 3H), 2.75 (t, J=8.0Hz, 2H), 2.87 (t, J=7.0Hz, 2H), 3.61-3.66 (m, 2H), 3.76 (s, 3H), 5.22 (s, 2H), 6.12 (d, J=4.80Hz, 1H), 6.76-7.52 (m, 28H), 7.90-7.92 (m, 1H); ESI-MS (m/z): 828.4 (M+H) +
(3) condition is with (3) step of embodiment 5, and product is white solid 4-methyl-2-propyl group-N-(3-anisole ethylamino-)-1-[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] tolimidazole-6-methane amide (compound 6), yield 80.1%.
Its structural formula is as follows:
Figure GSA00000047680900141
Fusing point: 164-166 ℃; IR (KBr), v Max/ cm -1: 3427,1637,1593,1541,1457,1352,1262,1215,1149,1093,875,757; 1H NMR (400MHz, CDCl 3) δ: 0.95 (t, J=7.40Hz, 3H), 1.71-1.78 (m, 2H), 2.55 (s, 3H), 2.78-2.84 (m, 4H), 3.45-3.52 (m, 2H), 3.70 (s, 3H), 5.47 (s, 2H), 6.74-7.56 (m, 13H), 7.84 (s, 1H), 8.44 (t, J=5.60Hz, 1H); 13C NMR (100MHz, CDCl 3) δ: 13.99,14.27,16.67,20.70,20.95,28.89,35.43,46.00,55.03,59.94,107.21,111.76,114.38,121.09,121.34,125.66,127.14,127.55,128.35,129.49,129.62,130.34,130.69,134.77,135.17,140.26,140.75,141.43,143.87,156.72,159.44,159.53,166.77; HRMScalcd for C35H36N7O2[M+H]+586.2925, found 586.2915.
Embodiment 7
(1) phenylalkylamine of methoxyl group replacement adopts 10mmol 4-anisole ethamine, other feed intake and implementation method goes on foot with (1) of embodiment 1, product is white solid 4-methyl-2-propyl group-N-(4-anisole ethylamino-)-1H-benzoglyoxaline-6-methane amide, yield 76.6%, 149～151 ℃ of fusing points. 1H?NMR(400MHz，DMSO-d 6)δ：0.98(t，J＝7.26Hz，3H)，1.81(m，2H)，2.57(s，3H)，2.77(t，J＝7.20Hz，2H)，2.88(t，J＝7.12Hz，2H)，3.40(m，2H)，3.67(s，3H)，6.84～7.32(m，4H)，7.45(s，1H)，7.84(s，1H)。
(2) condition is with (2) step of embodiment 5, and product is white solid 4-methyl-2-propyl group-N-(4-anisole ethylamino-)-1-[2 '-(1-trityl tetrazole-5-yl) biphenyl-4-yl] tolimidazole-6-methane amide, yield 70.9%.Fusing point: 105-107 ℃; IR (KBr), v Max/ cm -1: 3327,1653,1595,1539,1470,1357,1240,1215,1033; 1H NMR (400MHz, CDCl 3) δ: 0.95 (t, J=7.40Hz, 3H), 1.75-1.81 (m, 2H), 2.69 (s, 3H), 2.75 (t, J=7.80Hz, 2H), 2.83 (t, J=7.0Hz, 2H), 3.58-3.63 (m, 2H), 3.77 (s, 3H), 5.22 (s, 2H), 6.08 (t, J=5.60Hz, 1H), 6.77-7.52 (m, 28H), 7.90-7.92 (m, 1H); ESI-MS (m/z): 828.4 (M+H) +
(3) condition is with (3) step of embodiment 5, and product is white solid 4-methyl-2-propyl group-N-(4-anisole ethylamino-)-1-[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] tolimidazole-6-methane amide (compound 7), yield 76.4%.
Its structural formula is as follows:
Figure GSA00000047680900151
Fusing point: 180-182 ℃; IR (KBr), v Max/ cm -1: 3274,1637,1593,1544,1511,1459,1352,1297,1245,1176,1034,877,820,757; 1H NMR (400MHz, CDCl 3) δ: 0.91 (t, J=7.40Hz, 3H), 1.68-1.74 (m, 2H), 2.54 (s, 3H), 2.75-2.80 (m, 4H), and 3.40-3.45 (m, 2H), 3.68 (s, 3H), 5.49 (s, 2H), 6.81-7.15 (m, 8H), and 7.48-7.66 (m, 5H), 7.83 (s, 1H), 8.38 (t, J=5.20Hz, 1H); 13C NMR (100MHz, CDCl 3) δ: 13.97,16.67,20.69,28.87,34.56,45.92,55.13,59.94,107.37,113.94,121.22,123.68,126.39,127.54,128.00,128.42,129.41,129.77,130.77,131.21,131.67,134.78,136.42,138.68,141.12,143.78,156.71,157.83,166.72; HRMS calcd forC 35H 36N 7O 2[M+H] +586.2925 found 586.2912.
Embodiment 8
(1) phenylalkylamine of methoxyl group replacement adopts 10mmol 3, the 4-dimethoxy-phenylethylamine, other feed intake and implementation method goes on foot with (1) of embodiment 1, product is white solid 4-methyl-2-propyl group-N-(3,4-dimethoxy-phenylethylamine base)-1H-benzoglyoxaline-6-methane amide, yield 78.7%, 147～149 ℃ of fusing points. 1H?NMR(400MHz，DMSO-d 6)δ：0.96(t，J＝7.21Hz，3H)，1.78(m，2H)，2.56(s，3H)，2.77(t，J＝7.18Hz，2H)，2.87(t，J＝7.21Hz，2H)，3.47(m，2H)，3.72(s，3H)，3.78(s，3H)，6.98～7.15(m，3H)，7.72(s，1H)，7.89(s，1H)。
(2) condition is with (2) step of embodiment 5, and product is white solid 4-methyl-2-propyl group-N-(3,4-dimethoxy-phenylethylamine base)-1-[2 '-(1-trityl tetrazole-5-yl) biphenyl-4-yl] tolimidazole-6-methane amide, yield 78.0%.Fusing point: 127-128 ℃; IR (KBr), v Max/ cm -1: 3356,1652,1594,1540,1490,1357,1262,1236,1155,1028; 1HNMR (400MHz, CDCl 3) δ: 0.94 (t, J=7.40Hz, 3H), 1.73-1.88 (m, 3H), 2.68 (s, 3H), 2.74 (t, J=7.80Hz, 2H), 2.83 (t, J=7.0Hz, 2H), 3.59-3.64 (m, 2H), 3.811 (s, 3H), 3.843 (s, 3H), 5.22 (s, 2H), 6.10-6.25 (br, 1H), 6.73-7.55 (m, 27H), 7.89-7.91 (m, 1H); ESI-MS (m/z): 858.4 (M+H) +
(3) condition is with (3) step of embodiment 5, and product is white solid 4-methyl-2-propyl group-N-(3,4-dimethoxy-phenylethylamine base)-1-[2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl] tolimidazole-6-methane amide (compound 8), yield 73.6%.
Its structural formula is as follows:
Figure GSA00000047680900171
Fusing point: 185-186 ℃; IR (KBr), v Max/ cm -1: 3235,1640,1593,1548,1514,1458,1351,1261,1139,1025,877,760; 1H NMR (400MHz, CDCl 3) δ: 0.95 (t, J=7.40Hz, 3H), 1.69-1.79 (m, 2H), 2.55 (s, 3H), 2.76-2.81 (m, 4H), 3.40-3.51 (m, 2H), 3.69 (d, J=2.0Hz, 6H), 5.48 (s, 2H), 6.72-7.08 (m, 7H), and 7.37-7.59 (m, 5H), 7.84 (s, 1H), 8.40 (t, J=5.60Hz, 1H); 13C NMR (100MHz, CDCl 3) δ: 13.98,14.27,16.67,20.69,20.95,28.88,34.95,41.34,45.97,55.48,107.25,112.08,112.72,120.63,121.29,125.90,127.44,127.54,128.23,128.40,129.3155.48,55.68,59.95,129.54,130.49,130.71,132.31,134.78,135.60,140.04,140.55,143.84,147.36,148.76,156.72,156.72,158.04,166.75; HRMS calcd forC 36H 38N 7O 3[M+H] +616.3031 found 616.3021.
To Angiotensin II AT of the present invention 1Acceptor suppresses determination of activity:
(COSTAR adds following reagent: AT in U.S.A) to 96 well culture plates successively 1Receptor150 μ L/ hole (is diluted to 2.0 μ g/ holes with the experiment damping fluid, 37 ℃ of pre-temperature of damping fluid), 10 μ L 0.1%DMSO, what add different concns in the testing tube is subjected to reagent thing 10 μ L, add deionized water 10 μ L in summary and the pipe, add 1mg/mLAngiotensin II standard substance 10 μ L (55 μ M/ hole) in non-specific knot and the pipe, 37 ℃ hatch 30min after, add in each hole [ 125I]-Sar 1, Ile 8-Angiotensin II 10 μ L (50 μ Ci/mL, 4 times of time spent dilutions, 0.27 μ M/ hole), hatch 2h for 37 ℃, in conjunction with and the free radioactive ligand simultaneously by cell harvestor and coupled glass fiber filter paper (filter paper is used the moistening 1h of 0.3%Poly (ethyleneimine) in advance), the lavation buffer solution of 4 ℃ of precoolings (50mM Tris-HCl, 500mM NaCl, pH7.4) flushing filter paper is 9 times, each every hole 200 μ L, drain filter paper, film is taken off, put and exempt from Guan Zhongyong HH6003 gamma counter mensuration CPM number.Calculate and suppress percentage, obtain the IC of each compound 50
Determination of activity the results list of The compounds of this invention among the gained embodiment is as follows:
??IC 50(nM)
Compound 1 ??2.4
??IC 50(nM)
Compound 2 ??4.2
Compound 3 ??1.3
Compound 4 ??3.6
Compound 5 ??3.7
Compound 6 ??2.6
Compound 7 ??2.2
Compound 8 ??1.9
??Losartan ??16.2
The active result of table 1 part of compounds
As can be seen from Table 1, these compounds all have very strong Angiotensin II AT 1It is active that acceptor suppresses, and is 4～12 times of existing clinical application losartan (Losartan).

Claims (3)

1.[(4-methyl-2-propyl group-N-methoxyl group substituted benzene alkyl-1H-benzoglyoxaline-6-methane amide)-and the 1-yl] the methyl diphenyl compounds, it is characterized in that general formula is as follows:
Wherein, n is 1 or 2; R 1Be 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 3,4-Dimethoxyphenyl, 2,5-Dimethoxyphenyl; R 2Be carboxylic acid, tetrazolium.
2.[(4-methyl-2-propyl group-N-methoxyl group substituted benzene alkyl-1H-benzoglyoxaline-6-methane amide)-and the 1-yl] preparation method of methyl diphenyl compounds, it is characterized in that concrete preparation process is as follows:
(1) 4-methyl-2-propyl group-1H-benzoglyoxaline-6-formic acid is added in the thionyl chloride, reflux is more than 1 hour, remove excessive thionyl chloride under reduced pressure, the solid that obtains is added in the methylene dichloride, add triethylamine after being cooled to 0～5 ℃, add the phenylalkylamine that the N-methoxyl group replaces again, add that the afterreaction mixture rises to room temperature naturally and more than reaction 5h under the room temperature; Again reacted solution is used saturated sodium bicarbonate solution and water washing successively, drying obtains the off-white color solid behind the concentrating under reduced pressure, obtain intermediate A through ethyl alcohol recrystallization;
Wherein the mol ratio of the phenylalkylamine of 4-methyl-2-propyl group-1H-benzoglyoxaline-6-formic acid, thionyl chloride, triethylamine and the replacement of N-methoxyl group is 1: 5～10: 1.5: 1;
The phenylalkylamine that described N-methoxyl group replaces is any one of following general formula representative;
Figure FSA00000047680800012
The general formula of described intermediate A is as follows:
Figure FSA00000047680800021
(II) and the n (III) be 1 or 2; R 1Be 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 3,4-Dimethoxyphenyl, 2,5-Dimethoxyphenyl;
(2) intermediate A that (1) step was obtained is added to solvent N, in N '-dimethylformamide, add after being cooled to 0～5 ℃ more than the potassium tert.-butoxide reaction 30min, add biphenol compound B again, add that the afterreaction mixture rises to room temperature naturally and more than reaction 8h under the room temperature; Again post reaction mixture is poured in the water, the solid ethyl acetate extraction of separating out, washing, drying, residual branch uses column chromatography behind the concentrating under reduced pressure, obtains white solid intermediate C;
Wherein, the mol ratio of intermediate A, potassium tert.-butoxide and biphenol compound B is 1: 1.1: 1.1;
The general formula of described biphenol compound B is as follows:
Figure FSA00000047680800022
The general formula of described intermediate C is as follows:
Figure FSA00000047680800023
(IV) and the n (V) be 1 or 2; R 1Be 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 3,4-Dimethoxyphenyl, 2,5-Dimethoxyphenyl; P is methyl-formiate or triphenyltetrazolium;
(3) when P represents methyl-formiate, Compound C adds in the solvent methanol, adds the 2mol/L aqueous sodium hydroxide solution again, more than the reflux 2h, be cooled to room temperature, filter, remove the methyl alcohol in the filtrate under reduced pressure, residual solution is used salt acid for adjusting pH value to 6～7 of 2mol/L, separate out white solid, filter, drying obtains target product;
Wherein Compound C and aqueous sodium hydroxide solution mol ratio are 1: 5.
When P represented triphenyltetrazolium, Compound C added in solvents tetrahydrofurane and the methyl alcohol, adds 10% hydrochloric acid again, stirring reaction 12h under room temperature; Reaction mixture is regulated pH value to 12 with 2mol/L sodium hydroxide, removes tetrahydrofuran (THF) and methyl alcohol again under reduced pressure, filters, and filtrate is separated out white solid with salt acid for adjusting pH value to 6～7 of 2mol/L, filters, and drying obtains target product;
Wherein the mol ratio of Compound C and 10% hydrochloric acid is 1: 10.
3. [(4-methyl-2-propyl group-N-methoxyl group substituted benzene alkyl-1H-benzoglyoxaline-6-methane amide)-1-yl] as claimed in claim 1 methyl diphenyl compounds is characterized in that: can be used for preparing the medicine for the treatment of cardiovascular and cerebrovascular diseases.
CN201010126447A 2010-03-18 2010-03-18 [(4-methyl-2-propyl-N-methoxyl-substituted benzene alkyl-1H-benzimidazole-6-formamide)-1-yl] methyldiphenyl compound and preparation method thereof Pending CN101798287A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011113351A1 (en) * 2010-03-18 2011-09-22 北京理工大学 [(4-methyl-2-propyl-n-methoxy-substituted phenylalkyl-1h-benzimidazol-6-formamide)-1-yl]-methyl biphenyl compounds and their preparation methods
CN102491971A (en) * 2011-12-19 2012-06-13 北京理工大学 Chiral ((4-methyl-2-propyl-1H-benzimidazole-6-amide)-1-radical) methyl diphenyl compound, as well as preparation method and application thereof
CN110105338A (en) * 2019-05-31 2019-08-09 东华大学 6 '-replace amine formyl benzimidazole -4- substituent methyl indole derivatives
CN112745302A (en) * 2019-10-31 2021-05-04 上海中医药大学附属龙华医院 Benzimidazole compound and medical application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101675036A (en) * 2007-06-05 2010-03-17 施万制药 dual-acting benzoimidazole antihypertensive agents
CN101921265A (en) * 2009-11-25 2010-12-22 北京理工大学 Biphenylacylamine tetrazole compounds, synthetic method and application

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4224752A1 (en) * 1992-04-11 1994-02-03 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
WO2009004064A1 (en) * 2007-07-03 2009-01-08 Krka, Tovarna Zdravil, D.D., Novo Mesto Process for preparing telmisartan
WO2009116089A2 (en) * 2008-03-14 2009-09-24 Ipca Laboratories Limited Novel intermediates and method for synthesis of 4'-[(1,4'-dimethyl-2'-propyl-[2,6'- bi-1hbenzimidazol]-l-yl)methyl]-1,1-biphenyl]-2-carboxylic acid.
CN101798287A (en) * 2010-03-18 2010-08-11 北京理工大学 [(4-methyl-2-propyl-N-methoxyl-substituted benzene alkyl-1H-benzimidazole-6-formamide)-1-yl] methyldiphenyl compound and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101675036A (en) * 2007-06-05 2010-03-17 施万制药 dual-acting benzoimidazole antihypertensive agents
CN101921265A (en) * 2009-11-25 2010-12-22 北京理工大学 Biphenylacylamine tetrazole compounds, synthetic method and application

Cited By (5)

* Cited by examiner, † Cited by third party
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WO2011113351A1 (en) * 2010-03-18 2011-09-22 北京理工大学 [(4-methyl-2-propyl-n-methoxy-substituted phenylalkyl-1h-benzimidazol-6-formamide)-1-yl]-methyl biphenyl compounds and their preparation methods
CN102491971A (en) * 2011-12-19 2012-06-13 北京理工大学 Chiral ((4-methyl-2-propyl-1H-benzimidazole-6-amide)-1-radical) methyl diphenyl compound, as well as preparation method and application thereof
CN102491971B (en) * 2011-12-19 2017-03-01 北京理工大学 Chiral [(4- methyl-2-propyl -1H- benzimidazole -6- amide) -1- base] methyl biphenyl class compound and its production and use
CN110105338A (en) * 2019-05-31 2019-08-09 东华大学 6 '-replace amine formyl benzimidazole -4- substituent methyl indole derivatives
CN112745302A (en) * 2019-10-31 2021-05-04 上海中医药大学附属龙华医院 Benzimidazole compound and medical application thereof

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Open date: 20100811