CN103012381B - Benzofuran compound, preparation method thereof and application of benzofuran compound in preparation of antiarrhythmic drugs - Google Patents
Benzofuran compound, preparation method thereof and application of benzofuran compound in preparation of antiarrhythmic drugs Download PDFInfo
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Abstract
The invention relates to a benzofuran compound, a preparation method thereof and an application of the benzofuran compound in preparation of antiarrhythmic drugs. The structural formula of the compound and substituent groups of the compound are described in the specification; and the preparation method comprises the following steps of: reacting R1-substituted phenylamine with sodium nitrite under an acidic condition firstly to generate diazonium salt, then carrying out coupled reaction with furfuryl amine in presence of copper chloride or titanium trichloride to generate an intermediate III, stirring the intermediate III and chloroacetyl chloride in K2CO3 and CH2Cl2 at room temperature and reacting to obtain an intermediate IV, carrying out refluxing of the intermediate IV and sodium azide in acetonitrile and stirring and reacting to obtain an intermediate V; and carrying out cycloaddition reaction on the intermediate V and a compound VII under the catalysis of sodium ascorbate and CuSO4 to obtain the target compound. The compound provided by the invention has the activity of inhibiting an hERG potassium ion channel and can be utilized as a leading compound of the antiarrhythmic drugs.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, relate to a kind of benzofurane compounds, the invention still further relates to the preparation method of this compound and the application in pharmacy thereof.
Background technology
Irregular pulse is that cardiovascular system diseases is common but fatefulue with illness, according to Vaughan Williams and Singh ' the s classification of classics, current antiarrhythmic drug can be divided into following four large class-I Na-like ions channel blockers, II class receptor,β blocker, III class potassium channel blocker, IV class calcium antagonist.Wherein, I Na-like ions channel blocker is the antiarrhythmic drug found the earliest, but show 1989 and the clinical experiment of large-scale twice carried out for 1992, such medicine is while the strong antiarrhythmic effect of generation, there is serious proarrhythmia side effect, compared with placebo, the mortality ratio of tested group raises.After this, the research focus of people has turned to the antiarrhythmic drug acting on other target spots.Wherein III class anti-arrhythmic develops a class medicine faster, is also the Main way of the research of current antiarrhythmic drug.
The major target class of III traditional class antiarrhythmic drug effect is that export-oriented quick active postpones to arrange potassium current (I
kr), but find that the antiarrhythmic effect of such medicine has reverse frequency-dependence through long-term clinical practice: slow heart rate or beta-adrenaline level lower time, excessively can extend APD(Action Potential Duration), the excessive prolongation of APD simultaneously makes action potential 2 phase plateau Ca
2+interior stream increases and causes early afterdepolarizations, can produce serious fatefulue torsades de pointes type irregular pulse in some cases; When heart rate is very fast or beta-adrenaline level is higher, anti-arrhythmia does declines, and this is mainly due to I
ksstrong upregulation caused by.Particularly the clinical experiment SWORD (SurvivalWith ORal D-sotalol) of large-scale twice and the result of DIAMOND (Danish Investigation of Arrhythmia and Mortality ON Dofetilide) show, selectivity I
krblocker makes the mortality ratio of tested group higher than placebo, and this makes people find selectivity I
krblocker reduces as the enthusiasm of antiarrhythmic drug, starts to find new for the dependent antiarrhythmic drug of negative chronotropic.
Current antiarrhythmic drug research direction mainly compound anti-arrhythmic---(1) blocks quick active potassium channel current (I simultaneously
kr) and slow active potassium channel current (I
ks) medicine; (2) block quick active potassium channel current (I simultaneously
kr) and the medicine of other ionic channel.Procter & Gamble company find Azimilide(SDUL-012-065) be first report can block I simultaneously
krand I
kscompound, it has the structural framework different from traditional anti-arrhythmia, i.e. benzofurane structure fragment.This medicine still can keep pharmacologically active when fast heart rate, and this point is particularly important, and this medicine has completed III clinical trial phase at present, is just applying for that being used for the treatment of room flutters and atrial fibrillation.
This patent utilizes Computer-Aided Drug Design technology to carry out multianalysis to lead compound Azimilide structure, utilizes the hERG(I that early stage builds
krmain adjustment subunit) and KCNQ1(I
ksmain adjustment subunit) homology model and their retarding agent Pharmacophore Model, from based on acceptor with based on part angle to the structure of benzofurane compounds carry out reasonably optimizing,
Synthesis and activity rating, have new framework structure, safer and more effective antiarrhythmic drug molecule to obtain.
Summary of the invention
The object of the invention is for overcoming above-mentioned the deficiencies in the prior art, a kind of benzofurane compounds, its preparation method being provided and preparing the application in antiarrhythmic drug.
For achieving the above object, the present invention adopts following technical proposals:
Benzofurane compounds, it is the following compound of structural formula and pharmaceutical salts thereof:
In formula, R
1be simultaneously-substituted electrophilic on 4 or 2,4-position, supplied for electronic or neutral group; R
2for the piperazine ring that nitrogenous hexa-member heterocycle or N-replace.
Preferably, wherein R
1be 2,4-dichloro, 4-methoxyl group, 4-methyl, 4-halogen, 4-nitro, R
2for piperidyl, morpholinyl, methylpiperazine base, piperazine, 1-(2-p-methoxy-phenyl) piperazine, 4-phenylpiperazine.
The pharmaceutical salts of described compound refers to the hydrochloride of this compound.
The preferred following compound of benzofurane compounds of the present invention:
N-[[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide (L1, SDUL-009-098);
N-[[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide (L2, SDUL-012-042);
N-[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-[4-[[4-(2-p-methoxy-phenyl) piperazine-1-base] methyl]-1H-1,2,3-triazole-1-base] ethanamide (L3, SDUL-009-099);
N-[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide (L4, SDUL-009-111);
N-[[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-[4-(piperidin-1-yl methyl)-1H-1,2,3-triazole-1-yl acetamide] (L6, SDUL-012-038);
N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide (L7, SDUL-009-075);
N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide (L8, SDUL-009-101);
N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-[[4-(2-p-methoxy-phenyl) piperazine-1-base] methyl]-1H-1,2,3-triazole-1-base] ethanamide (L9, SDUL-009-102);
N-[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide (L10, SDUL-009-116);
N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-(piperazine-1-ylmethyl)-1H-1,2,3-triazole-1-base] ethanamide (L11, SDUL-012-020);
N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-(piperidin-1-yl methyl)-1H-1,2,3-triazole-1-yl acetamide] (L12, SDUL-012-039);
N-[[5-(4-nitrophenyl) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide (L13, SDUL-012-043);
N-[[5-(4-nitrophenyl) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide (L14, SDUL-009-106);
N-[[5-(4-nitrophenyl) furans-2-base] methyl]-2-[4-[[4-(2-p-methoxy-phenyl) piperazine-1-base] methyl]-1H-1,2,3-triazole-1-base] ethanamide (L15, SDUL-009-107);
N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-[4-[4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide (L16, SDUL-009-054);
N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide (L17, SDUL-009-077);
N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-[4-[4-(2-p-methoxy-phenyl) piperazine-1-base] methyl]-1H-1,2,3-triazole-1-base] ethanamide (L18, SDUL-009-091);
N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide (L19, SDUL-009-110);
N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-[4-(piperazine-1-ylmethyl)-1H-1,2,3-triazole-1-base] ethanamide (L20, SDUL-012-017);
N-[[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide (L21, SDUL-012-022);
N-[[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide (L22, SDUL-012-025);
N-[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide (L23, SDUL-012-027);
N-[[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-[4-(piperazine-1-ylmethyl)-1H-1,2,3-triazole-1-base] ethanamide (L24, SDUL-012-052);
N-[[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-[4-(piperidin-1-yl methyl)-1H-1,2,3-triazole-1-yl acetamide] (L25, SDUL-012-028);
N-[[5-(p-tolyl) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide (L26, SDUL-012-035);
N-[[5-(p-tolyl) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide (L27, SDUL-012-034)
N-[5-(p-tolyl) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide (L28, SDUL-012-031);
N-[[5-(p-tolyl) furans-2-base] methyl]-2-[4-(piperazine-1-ylmethyl)-1H-1,2,3-triazole-1-base] ethanamide (L29, SDUL-012-051);
N-[[5-(p-tolyl) furans-2-base] methyl]-2-[4-(piperidin-1-yl methyl)-1H-1,2,3-triazole-1-yl acetamide] (L30, SDUL-012-030).
The preparation method of above-mentioned benzofurane compounds, comprises the following steps:
(1) with R
1the aniline replaced is starting raw material, acid dissolve is added to it, then under ice bath, slowly drip sodium nitrite solution, dropwise, continue reaction 20-30min, reaction generates diazonium salt, then add cupric chloride or titanous chloride makes catalyzer, add chaff amine, stirring at room temperature 12-36h, linked reaction occurs, and product separation is purified to obtain intermediate 5-substituted-phenyl-2-aminomethyl-furan;
(2) in 5-replacement-2-aminomethyl-furan, K is added
2cO
3and CH
2cl
2, then under ice bath, slowly drip chloroacetyl chloride CH
2cl
2solution, drips and finishes, and stirring at room temperature reaction detects without raw material midbody to TLC, and separating-purifying obtains the chloro-N-of intermediate 2-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide;
(3) chloro-for 2-N-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide and sodiumazide return stirring in acetonitrile are reacted 10-18h, obtain intermediate 2-azido--N-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide;
(4) by 2-azido--N-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide and structural formula if the compound of VII is in methyl alcohol, water mixed solvent, add sodium ascorbate and CuSO
4catalysis, there is ring-closure reaction, obtain benzofurane compounds in lucifuge stirring at room temperature 12-24h; Benzofurane compounds and ethanol solution hydrochloride react, must the hydrochloride of this benzofurane compounds
Wherein X is O, CH
2, NH; R
3for methyl, phenyl, N-(2-p-methoxy-phenyl).
Step (1) R in above-mentioned preparation method
1replace aniline and Sodium Nitrite, acid, catalyzer, chaff amine reaction mol ratio be 1:1:5-10:0.02-3:1-5, the concentration of sodium nitrite solution is 2mol/L.
In above-mentioned steps (2), 5-replaces-2-aminomethyl-furan and K
2cO
3and the reaction mol ratio of chloroacetyl chloride is 1:1-4:1-2.
In step (3), the reaction mol ratio of the chloro-N-of 2-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide and sodiumazide is 1:3-5.
2-azido--N-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide and structural formula are as the compound of VII, sodium ascorbate and CuSO in step (4)
4reaction mol ratio be 1:1:0.5-1:0.05-1, mixed solvent be first alcohol and water by volume 1-5:1 mixing.
Benzofurane compounds synthetic route is as follows:
1, the preparation of compound described in general formula III
Add distilled water and concentrated hydrochloric acid in substituted aniline II, heating is dissolved completely, and cryosel bath is cooled to 0 ° of below C, slow dropping sodium nitrite solution, drips and finishes, and continues reaction 20-30min, add chaff amine and cupric chloride or titanous chloride, stirring at room temperature 12-36h, separate out brown solid, suction filtration, obtains red brown solid, and filter cake is successively with a small amount of water and ethyl acetate washing, obtain light tan solid, solids with methanol/ethanol activated carbon decolorizing recrystallization, vacuum-drying, obtains solid intermediate III.
2, the preparation of compound described in general formula I V
Add in intermediate III and heavily steam CH
2cl
2and anhydrous K
2cO
3, in white casse liquid.Chloroacetyl chloride is dissolved in CH
2cl
2in, slowly drop in reaction solution under ice bath.Drip and finish, room temperature reaction detects without raw material midbody I II to TLC.By solvent under reduced pressure evaporate to dryness, add distilled water, with dichloromethane extraction, merge organic layer, anhydrous MgSO
4dried overnight, suction filtration, filtrate decompression evaporate to dryness, obtains brown solid, ethyl alcohol recrystallization, and activated carbon decolorizing obtains solid intermediate IV.
3, the preparation of compound described in general formula V
Intermediate compound IV adds DMF/ acetonitrile, and solid dissolves completely, then adds NaN
3, reaction solution is muddy, return stirring 10-18h, and reaction solution is orange-yellow, pressure reducing and steaming partial solvent, with dichloromethane extraction, merges organic layer, saturated NaCl solution washing, anhydrous Na
2sO
4dry.Suction filtration, filtrate decompression evaporate to dryness, obtains oily matter intermediate V, directly casts single step reaction.
4, the preparation of compound described in general formula VII
Add Anhydrous potassium carbonate (1.5eq) and acetone in the piperazine ring compound VI (1.5eq) that nitrogenous hexa-member heterocycle or N-replace, slowly add propargyl bromide (1eq) under nitrogen protection, stirring at room temperature 16-24h.Suction filtration, a small amount of washing with acetone of solid, merging filtrate, evaporated under reduced pressure solvent.Add distilled water in residue, use CH
2cl
2extraction, merges organic layer, uses saturated common salt water washing, anhydrous Na
2sO
4dry.Suction filtration, is spin-dried for solvent, obtains colorless oil.In above-mentioned oily matter, drip the saturated ethanolic soln of hydrogenchloride again produce to there being a large amount of white solid, suction filtration, obtains white powder solid intermediate VII.
5, the preparation of compound described in general formula I
Add methyl alcohol in intermediate V, then add intermediate VII, sodium ascorbate, CuSO successively
4solution, lucifuge stirring at room temperature, TLC monitoring reaction reacts completely to raw material (intermediate V), and stopped reaction, pressure reducing and steaming partial solvent, adds distilled water, and with dichloromethane extraction, organic layer saturated nacl aqueous solution washs, and anhydrous sodium sulfate drying spends the night.Suction filtration, evaporated under reduced pressure solvent, obtains brown solid, column chromatography, obtains target compound I.Or continue target compound to be dissolved in methyl alcohol, drip the saturated ethanolic soln of hydrogenchloride, obtain the hydrochloride of target compound.
The application in antiarrhythmic drug prepared by above-mentioned benzofurane compounds and salt thereof.
A kind of antiarrhythmic drug composition, comprises benzofurane compounds described above, and one or more pharmaceutically acceptable carriers or vehicle.
Can be that one is suitable for orally giving mammiferous pharmaceutical composition, comprise above-mentioned benzofurane compounds, and one or more pharmaceutically acceptable carriers or vehicle.
Also can be that one is suitable for parenteral and gives mammiferous pharmaceutical composition, comprise above-mentioned benzofurane compounds, and one or more pharmaceutically acceptable carriers or vehicle.
Benzofurane compounds provided by the invention has stronger antiarrhythmic activity, and be the hERG potassium channel inhibitors of novel structure, the lead compound that can be used as antiarrhythmic drug is used.Benzofurane compounds provided by the invention is with first report, be in III phase clinical study, safer and more effective I
krand I
ksdual retarding agent Azimilide(Archie Li Te) be lead compound, research completely likely finds the novel antiarrhythmic drug having independent intellectual property right further.Preparation method's reaction conditions provided by the invention is gentle, and raw material is cheaply easy to get, operation and aftertreatment simple.
Embodiment
The following examples can make the present invention of those skilled in the art comprehend, but do not limit the present invention in any way.
Embodiment 1:N-[[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide
(1) p-Chlorobenzoic acid amide (2.55g, distilled water 20mL and concentrated hydrochloric acid 14mL is added 20mmol), white opacity, be heated to 60 ° of C, to dissolving completely, cryosel bath is cooled to 0 ° of C, slow dropping sodium nitrite solution (1.38g is dissolved in 10mL distilled water), drip and finish, continue reaction 20min, add chaff amine (2.19g, 30mmol) and cupric chloride (0.54g, 4mmol), reaction solution is in green, stirring is spent the night, separate out brown solid, suction filtration, obtain red brown solid, filter cake is successively with a small amount of water and ethyl acetate washing, obtain off-white color solid, solids with methanol/ethanol activated carbon decolorizing recrystallization, vacuum-drying, obtain white solid intermediate 5-(4-chloro-phenyl-)-2-aminomethyl-furan 0.88g, yield is 18%.
1H-NMR(600MHz,DMSO-d6):δ=8.58(s,3H),7.77(m,2H),7.53(t,J＝7.8Hz,2H),7.02(d,J＝3.6Hz,1H),6.66(d,J＝3.0Hz,1H),4.14(d,J＝4.2Hz,2H);ESI-MS:[M-NH
2]
+:191.3,193.3。
(2) add in intermediate 5-(4-chloro-phenyl-)-2-aminomethyl-furan (1.17g, 4.79mmol) and heavily steam CH
2cl
235mL and dry K
2cO
3powder (2.00g, 14.4mmol), in white casse liquid.Chloroacetyl chloride (0.81g, 7.19mmol) is dissolved in 5mL CH
2cl
2in, slowly drop in reaction solution under ice bath.Drip and finish, room temperature reaction detects without raw material midbody 5-(4-chloro-phenyl-)-2-aminomethyl-furan to TLC.By solvent under reduced pressure evaporate to dryness, add 40mL distilled water, with dichloromethane extraction (40mL × 3), merge organic layer, use anhydrous MgSO
4dried overnight.Elimination MgSO
4, filtrate decompression evaporate to dryness, obtains brown solid, ethyl alcohol recrystallization, activated carbon decolorizing, and obtain the chloro-N-of white solid intermediate 2-[[5-(4-chloro-phenyl-)-2-furyl] methyl]-ethanamide 0.8g, yield is 58.8%.m.p:124-126°C，
1H-NMR(600MHz,DMSO-d6):δ=8.76(d,1H),7.68(d,J＝8.4Hz,2H),7.47(d,J＝8.4Hz,2H),6.94(d,J3Hz,1H),6.40(d,J＝3Hz,1H),4.36(d,J=6Hz,2H),4.12(s,2H);ESI-MS:[M+H]
+:283.8;[M+NH
4]
+:300.8,302.9。
(3) add DMF10mL and acetonitrile 10mL in the chloro-N-of intermediate 2-[[5-(4-chloro-phenyl-)-2-furyl] methyl]-ethanamide (0.49g, 1.5mmol), solid dissolves completely, then adds NaN
3(0.49g, 7.5mmol), reaction solution is muddy.Stir 12h, reaction solution is orange-yellow, pressure reducing and steaming partial solvent, with dichloromethane extraction (30mL × 3), merges organic layer, saturated NaCl solution washing (40mL × 2), anhydrous Na
2sO
4dry.Suction filtration, filtrate decompression evaporate to dryness, obtains orange-yellow oily matter intermediate 2-azido--N-[[5-(4-chloro-phenyl-)-2-furyl] methyl]-ethanamide.
(4) add Anhydrous potassium carbonate (4.18g, 30mmol) and acetone 40mL in 1-methylpiperazine (3.00g, 30mmol), slowly add propargyl bromide (3.38g, 20mmol) under nitrogen protection, stirring at room temperature 16h.Suction filtration, a small amount of washing with acetone of solid, merging filtrate, evaporated under reduced pressure solvent.Add 40mL distilled water in residue, use CH
2cl
2extraction (40mL × 3), merges organic layer, uses saturated common salt water washing, anhydrous Na
2sO
4dry.Suction filtration, is spin-dried for solvent, obtains colorless oil intermediate 1-methyl-4-proyl piperazine.In above-mentioned oily matter, dripping the saturated ethanolic soln of hydrogenchloride produce to there being a large amount of white solid, suction filtration, obtaining the hydrochloride 2.8g of 1-methyl-4-proyl piperazine, yield is 68%, m.p:210 ° of C,
1h-NMR (600MHz, D
2o): δ=3.96 (s, 2H), 3.69 (s, 4H), 3.35 (s, 4H), 2.98 (d, J=2.4Hz, 1H), 2.85 (s, 3H); ESI-MS:[M+H]
+: 139.1.
(5) 2-azido--N-[[5-(4-chloro-phenyl-)-2-furyl] methyl]-ethanamide (step (3) reaction gained, the clarification of 14mL dissolve with methanol is added 1.5mmol), add the hydrochloride (0.32g of intermediate 1-methyl-4-proyl piperazine more successively, 1.5mmol, be dissolved in 2mL methyl alcohol), sodium ascorbate (0.15g, 0.75mmol, be dissolved in 2mL distilled water), 0.5N CuSO
4(0.15mL, 0.075mmol), stirring at room temperature, TLC monitoring reaction reacts completely to raw material 2-azido--N-[[5-(4-chloro-phenyl-)-2-furyl] methyl]-ethanamide, stopped reaction, pressure reducing and steaming partial solvent, add 25mL distilled water, with dichloromethane extraction (40mL × 3), dichloromethane layer saturated nacl aqueous solution washs, and anhydrous sodium sulfate drying spends the night.Suction filtration, evaporated under reduced pressure solvent, obtains brown solid, column chromatography (CH
2cl
2: MeOH=30:1), obtain white solid 0.19g, yield is 29.6%, m.p:160-161 ° of C,
1h-NMR (300MHz, CDCl
3): δ=7.62 (s, 1H), 7.51 (d, J=8.4Hz, 2H); 7.32 (d, J=8.4Hz, 1H), 6.53 (m; 2H), 6.27 (d, J2.7Hz, 1H); 5.06 (s, 2H), 4.47 (d, J=5.7Hz; 2H), 3.68 (d, J=2.1Hz, 2H); 2.56-2.45 (br.d, 8H), 2.28 (s, 3H); ESI-HRMS:m/z calcd for C
21h
26clN
6o
2[(M+H)
+], 429.1806; Found, 429.1800.
Embodiment 2:N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide
(1) by step (1) method preparation in embodiment 1, unlike being obtained by reacting white solid 5-(4-bromophenyl)-2-aminomethyl-furan 1.18g with para-bromoaniline (3.44g, 20mmol) and chaff amine (2.91g, 30mmol), yield is 20.4%,
1h-NMR (600MHz, DMSO-d6): δ=8.61 (s, 3H), 7.66 (m, 4H), 7.03 (d, J=3.6Hz, 1H), 6.66 (d, J=3.6Hz, 1H), 4.13 (d, J=3.6Hz, 2H); ESI-MS:[M-NH
2]
+: 235.1,237.1.
(2) by step (2) method preparation in embodiment 1, unlike with 5-(4-bromophenyl)-2-aminomethyl-furan (2.16g, 8.5mmol) with chloroacetyl chloride (1.44g, 12.75mmol) be obtained by reacting the chloro-N-of yellow solid 2-[[5-(4-bromophenyl)-2-furyl] methyl]-ethanamide 0.65g, yield is 58%, m.p:131-133 ° of C
1h-NMR (600MHz, DMSO-d6): δ=8.77 (t, 1H), 7.62 (m, 4H), 6.95 (d; J=3Hz, 1H), 6.40 (d, J=3Hz, 1H); 4.36 (d, J=5.4Hz, 2H), 4.12 (s, 2H); ESI-MS:[M+H]
+: 327.7; [M+NH
4]
+: 344.7,346.8.
(3) by step (3) method preparation in embodiment 1, unlike with the chloro-N-of 2-[[5-(4-bromophenyl)-2-furyl] methyl]-ethanamide (0.49g, 1.5mmol) and NaN
3reaction, obtains oily matter 2-azido--N-[[5-(4-bromophenyl)-2-furyl] methyl]-ethanamide, directly casts single step reaction.
(4) by step (4) method preparation in embodiment 1, replace 1-methylpiperazine to react unlike with morpholine (2.61g, 30mmol), obtain white solid N-proyl morpholine hydrochloride 1.15g, yield is 46%, m.p:161-163 ° of C,
1h-NMR (600MHz, D
2o): δ=3.95-3.90 (m, 4H), 3.77 (s, 2H), 3.43 (s, 2H), 3.13 (s, 2H), 2.95 (t, J=2.4Hz, 1H); ESI-MS:[M+H]
+: 126.0.
(5) by step (5) method preparation in embodiment 1, unlike with 2-azido--N-[[5-(4-bromophenyl)-2-furyl] methyl]-ethanamide (1.5mmol) and N-proyl morpholine hydrochloride (0.24g, 1.5mmol) be obtained by reacting faint yellow solid 0.24g, solid is with dissolve with methanol, instillation HCl alcohol saturated solution salify, obtain pale yellow crystals solid, yield is 36.2%.
1H-NMR(300MHz,DMSO-d6):δ=11.40(br.s,1H),8.98(t,J＝5.4Hz,1H),7.62(m,4H),6.95(d,J＝3.3Hz,1H),6.43(d,J3.3Hz,1H),5.26(s,2H),4.46(s,2H),4.38(d,J=5.4Hz,2H),3.98-3.93(m,2H),3.78-3.70(m,2H),3.32-3.28(m,2H),3.10(s,2H);ESI-HRMS:m/z?calcd?forC
20H
23BrN
5O
2[(M+H)
+],460.0984;found,460.1052。
Embodiment 3:N-[[5-(4-nitrophenyl) furans-2-base] methyl]-2-[4-[[4-(2-p-methoxy-phenyl) piperazine-1-base] methyl]-1H-1,2,3-triazole-1-base] ethanamide
(1) by step (1) method preparation in embodiment 1, unlike with p-Nitroaniline (2.76g, 20mmol) be obtained by reacting yellow solid 5-(4-nitrophenyl)-2-aminomethyl-furan 1.10g with chaff amine (2.91g, 30mmol), yield is 21.6%.1H-NMR(600MHz,DMSO-d6):δ=8.65(s,3H),8.31(m,2H),8.00(m,2H),7.32(d,J=3Hz1H),6.76(d,J=3Hz,1H),4.19(s,2H);ESI-MS:[M-NH2]+:202.3。
(2) by step (2) method preparation in embodiment 1, unlike with 5-(4-nitrophenyl)-2-aminomethyl-furan (0.98g, 3.4mmol) and chloroacetyl chloride (0.77g, 6.8mmol) be obtained by reacting yellow solid 1.56g, yield is 63%, m.p:144-146 ° of C
1h-NMR (600MHz, CDCl
3): δ=8.24 (d, J=9Hz, 2H), 7.76 (d; J=8.4Hz, 2H), 6.96 (s; 1H), 6.82 (d, J3.6Hz; 1H), 6.43 (d, J=3.6Hz; 1H), 4.58 (d, J=5.4Hz; 2H), 4.12 (s, 2H); ESI-MS:[M+H]
+: 295.4, [M+Na]
+: 317.3.
(3) by step (3) method preparation in embodiment 1, unlike with the chloro-N-of 2-[[5-(4-nitrophenyl)-2-furyl] methyl]-ethanamide (0.44g, 1.5mmol) and NaN
3reaction, obtains oily matter 2-azido--N-[[5-(4-nitrophenyl)-2-furyl] methyl]-ethanamide, directly casts single step reaction.
(4) by step (4) method preparation in embodiment 1, unlike in order to 1-(2-p-methoxy-phenyl) piperazine (2.88g, 15mmol) with propargyl bromide (1.19g, 10mmol) react, column chromatography obtains white solid 1-(2-p-methoxy-phenyl)-4-proyl-piperazine 1.69g, yield is 73.5%, m.p:75-77 ° of C
1h-NMR (600MHz, CDCl
3): δ=7.01 (m, 1H), 6.96 (d, J=1.2Hz; 1H), 6.92 (t, J=7.2Hz, 1H); 6.86 (d, J=7.8Hz, 1H); 3.87 (s, 3H), 3.36 (d; J=1.8Hz, 4H), 2.79 (s; 4H), 2.27 (s, 1H); ESI-MS:[M+H]
+: 231.2.
(5) by step (5) method preparation in embodiment 1, unlike in order to 2-azido--N-[[5-(4-nitrophenyl)-2-furyl] methyl]-ethanamide (1.5mmol) and 1-(2-p-methoxy-phenyl)-4-proyl-piperazine (0.35g, 1.5mmol) be obtained by reacting yellow solid 0.28g, solid is with dissolve with methanol, instillation HCl alcohol saturated solution salify, obtain yellow solid, yield is 32.9%
1h-NMR (300MHz, DMSO-d6): δ=11.19 (br.s, 1H); 9.06 (t, J=5.4Hz, 1H); 8.39 (s, 1H), 8.39-8.27 (m; 2H), 7.94-7.91 (m, 2H); 7.26 (d, J=3.3Hz, 1H); 7.04-6.86 (m, 4H), 6.54 (d; J=3.3Hz, 1H), 5.30 (s; 2H), 4.53 (s, 2H); (4.44 d, J=5.4Hz, 2H); 3.78 (s, 3H), 3.52-3.44 (br.m; 4H), 3.19 (br.m, 2H); 3.05-3.01 (br.m, 2H); ESI-HRMS:m/z calcd for C
27h
30n
7o
5[(M+H)
+], 532.2308; Found, 532.2295.
Embodiment 4:N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide
(1) by step (1) method preparation in embodiment 1, unlike with 2,4 dichloro aniline (3.24g, 20mmol) with chaff amine (2.91g, 30mmol) be obtained by reacting white solid 5-(2,4 dichloro benzene base)-2-aminomethyl-furan 1.92g, yield is 34.5%.
1H-NMR(600MHz,DMSO-d6):δ=8.39(s,3H),7.96(d,J=8.4Hz,1H),7.76(d,J=1.8Hz,1H),7.59(dd,J
1=2.4,8.4Hz,1H),6.71(d,J=3.6Hz,1H),6.17(d,J＝3.6Hz,1H),4.17(s,2H);ESI-MS:[M+H]
+:225.3。
(2) by step (2) method preparation in embodiment 1, unlike with 5-(2,4-dichlorophenyl)-2-aminomethyl-furan (0.47g, 1.87mmol) and chloroacetyl chloride (0.31g, 2.72mmol) be obtained by reacting the chloro-N-of white solid 2-[[5-(2,4 dichloro benzene base)-2-furyl] methyl]-ethanamide 0.25g, yield is 46%, m.p:127-129 ° of C
1h-NMR (600MHz, DMSO-d6): δ=8.81 (s, 1H) 7.81 (d, J=9Hz, 1H), 7.73 (s, 1H), 7.55 (dd, J
1=8.4Hz, 1.2Hz, 1H), 7.10 (d, J=3Hz, 1H), 6.47 (d, J=3Hz, 1H), 4.39 (d, J=5.4Hz, 2H), 4.13 (s, 2H); ESI-MS:[M+H]
+: 317.8; [M+NH
4]
+: 334.8,336.8.
(3) by step (3) method preparation in embodiment 1, unlike with the chloro-N-of 2-[[5-(2,4-dichlorophenyl)-2-furyl] methyl]-ethanamide (0.48g, 1.5mmol) react with NaN3, obtain oily matter 2-azido--N-[[5-(4-nitrophenyl)-2-furyl] methyl]-ethanamide, directly cast single step reaction.
(4) by step (4) method preparation in embodiment 1, unlike being obtained by reacting white solid 1-phenyl-4-proyl piperazine 1.64g with 4-phenylpiperazine (1.95g, 12mmol) and propargyl bromide (1.19g, 10mmol), yield is 82%, m.p:46-48 ° of C,
1h-NMR (600MHz, DMSO-d6): δ=7.19 (dd, J
1=9.0,7.8Hz, 2H), 6.92 (d, J=7.8Hz, 2H), 6.76 (t, J=7.2Hz, 1H), 3.36 (s, 2H), 3.22 (s, 1H), 3.15 (s, 4H), 2.62 (s, 4H); ESI-MS:[M+H]
+: 201.4.
(5) by step (5) method preparation in embodiment 1, unlike with 2-azido--N-[[5-(4-nitrophenyl)-2-furyl] methyl]-ethanamide (1.5mmol) and 1-phenyl-4-proyl piperazine (0.3g, 1.5mmol) be obtained by reacting white solid 0.3g, solid is with dissolve with methanol, instillation HCl alcohol saturated solution salify, obtain white solid, yield is 38.1%
1h-NMR (300MHz, DMSO-d6): δ=11.07 (br.s, 1H), 9.03 (s, 1H), 8.34 (s, 1H), 7.81 (d, J=8.7Hz, 1H), 7.72 (m, 1H), 7.56-7.53 (dd, J=8.7Hz, 2.1Hz, 1H), 7.23 (m, 2H), 7.10 (d, J=3.3Hz, 1H), 6.96 (d, J=8.4Hz, 2H), 6.88-6.83 (t, J=7.2Hz, 1H), 6.50 (d, J=3.3Hz, 1H), 5.28 (s, 2H), 4.54 (s, 2H), 4.41 (d, J=5.1Hz, 2H), 3.85-3.81 (m, 2H), 3.50-3.39 (br.m, 2H), 3.17-3.06 (br.m, 4H), ESI-HRMS:m/z calcd for C
26h
27cl
2n
6o
2[(M+H)
+], 525.1573, found .525.1571.
Embodiment 5:N-[[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-[4-(piperidin-1-yl methyl)-1H-1,2,3-triazole-1-yl acetamide]
(1) diazonium salt is prepared: in P-nethoxyaniline (1.23g, 10mmol), add distilled water 10mL and concentrated hydrochloric acid 5mL, in the reddish-brown stillness of night, cryosel bath cooling, slowly drips Sodium Nitrite (0.69g is dissolved in 6mL distilled water), drips and finish, continue reaction 20min, elimination insolubles.
Under nitrogen protection, to Titanium Trichloride Solution (30ml, about 30mmol) and chaff amine (4.86g, 50mmol) slowly drip diazonium salt solution in solution, drip and finish, room temperature reaction 1h, regulate reaction solution pH to alkalescence (pH=9) with anhydrous sodium carbonate powder, reaction solution is mazarine, and have solid to separate out, elimination solid, filtrate with ethyl acetate washing after with extraction into ethyl acetate (30mL × 3), merge organic layer, anhydrous magnesium sulfate drying, elimination anhydrous magnesium sulfate, HCl alcohol saturated solution salify is added after filtrate is concentrated, refrigeration crystallization obtains brown solid 5-(4-p-methoxy-phenyl)-2-aminomethyl-furan 0.47g, yield is 19.6%,
1h-NMR (600MHz, DMSO-d6): δ=8.42 (s, 3H), 7.67 (d, J=8.4Hz, 2H), 7.01 (d, J=8.4Hz, 2H), 6.80 (d, J=3.0Hz, 1H), 6.60 (d, J=3.6Hz, 1H), 4.13 (s, 2H), 3.79 (d, J=8.4Hz, 3H), ESI-MS:[M-NH
2]
+: 187.4.
(2) by step (2) method preparation in embodiment 1, unlike with 5-(4-p-methoxy-phenyl)-2-aminomethyl-furan (0.91g, 3.73mmol) and chloroacetyl chloride (0.84g, 7.46mmol) be obtained by reacting white needles 2-methoxyl group-N-[[5-(2,4-dichlorophenyl)-2-furyl] methyl]-ethanamide 0.8g, m.p:120-122 ° of C, yield is 74.5%.
1H-NMR(600MHz,DMSO-d6):δ=8.73(t,1H),7.60-7.58(m,2H),6.97-6.99(m,2H),6.70(d,J=3Hz,1H),6.34(d,J＝3Hz,1H),4.35(d,J=5.4Hz,2H),4.11(s,2H),3.78(s,3H);ESI-MS:[M+H]
+:280.3,282.5;[M+Na]
+:302.5,304.4。
(3) by step (3) method preparation in embodiment 1, unlike with 2-methoxyl group-N-[[5-(2,4-dichlorophenyl)-2-furyl] methyl]-ethanamide (0.28g, 1mmol) react with NaN3, obtain oily matter 2-azido--N-[[5-(4-p-methoxy-phenyl)-2-furyl] methyl]-ethanamide, directly cast single step reaction.
(4) by step (4) method preparation in embodiment 1, unlike being obtained by reacting white solid N-proyl piperidine hydrochlorate 1.12g with piperidines (1.92g, 22.5mmol) and propargyl bromide (1.78g, 15mmol), yield is 46.9%, m.p:178-180 ° of C,
1h-NMR (600MHz, D
2o-d6): δ=3.79 (s, 2H), 3.45-3.43 (m; 2H), 2.90-2.83 (m, 3H); 1.80-1.78 (m; 2H), 1.65-1.63 (m, 1H); 1.57-1.50 (m; 2H), 1.29-1.26 (m, 1H); ESI-MS:[M+H]
+: 124.3.
(5) by step (5) method preparation in embodiment 1, unlike with 2-azido--N-[[5-(4-p-methoxy-phenyl)-2-furyl] methyl]-ethanamide (1.5mmol) and N-proyl piperidine hydrochlorate (0.16g, 1mmol) be obtained by reacting white solid 0.08g, yield is 19.5%, m.p:147-148 ° of C
1h-NMR (300MHz, CDCl
3): δ=7.62 (s, 1H), 7.50 (d, J=8.7Hz; 2H), 1.39 (br.m, 2H); (6.88 d, J=8.7Hz, 2H); (6.53 br.s, 1H), 6.39 (d; J=3.3Hz, 1H), 6.23 (d; J=3.3Hz, 1H), 5.05 (s; 2H), 4.45 (d, J=5.7Hz; 2H), 3.82 (s, 2H); (3.64 s, 2H), 2.42 (br.s; 4H), 1.51 (br.s, 4H); ESI-HRMS:m/z calcd for C
22h
28n
5o
3[(M+H)
+], 410.2192; Found, 410.2199.
Embodiment 6:N-[[5-(p-tolyl) furans-2-base] methyl]-2-[4-(piperazine-1-ylmethyl)-1H-1,2,3-triazole-1-base] ethanamide
(1) by step (1) method preparation in embodiment 5, unlike with open-chain crown ether (0.54g, 5mmol) replace P-nethoxyaniline, chaff amine consumption is (2.48g, 25mmol), be obtained by reacting brown solid 5-(4-aminomethyl phenyl)-2-aminomethyl-furan 0.76g, yield is 34.1%
1h-NMR (600MHz, DMSO-d6): δ=8.43 (s, 3H), 7.67 (d; J=8.4Hz, 2H), 7.26 (d, J=8.4Hz; 2H), 6.88 (d, J=3.0Hz; 1H), 6.62 (d, J=3.6Hz; 1H), 4.13 (s, 2H); 2.32 (d, 3H, J=8.4H); ESI-MS:[M-NH
2]
+: 171.4.
(2) by step (2) method preparation in embodiment 1, be 5-(4-aminomethyl phenyl)-2-aminomethyl-furan (0.96g unlike intermediate, 4.25mmol), chloroacetyl chloride is (0.96g, 8.5mmol), white needles 2-methyl-N-[[5-(2,4 dichloro benzene base)-2-furyl] methyl]-ethanamide 0.85g is obtained by reacting, m.p:117-119 ° of C, yield is 71.2%.
1H-NMR(300MHz,DMSO-d6):δ=8.72(t,1H),7.55(d,J＝8.1Hz,2H),7.21(d,J＝8.1Hz,2H),6.70(d,J=3.3Hz,1H),6.34(d,J＝3.3Hz,1H),4.35(d,J=5.7Hz,2H),4.11(s,2H),2.31(s,3H);ESI-MS:[M+H]
+:264.3,266.3;[M+NH
4]
+:281.4,283.5;[M+Na]
+:286.3,288.3。
(3) by step (3) method preparation in embodiment 1, unlike with 2-methyl-N-[[5-(2,4-dichlorophenyl)-2-furyl] methyl]-ethanamide (0.26g, 1mmol) react with NaN3, obtain oily matter 2-azido--N-[[5-(4-aminomethyl phenyl)-2-furyl] methyl]-ethanamide, directly cast single step reaction.
(4) be dissolved in 20mL dehydrated alcohol by Piperazine anhydrous (1.72g, 20mol), stirring and dissolving is to achromaticity and clarification, slow dropping 4.05mL40%HBr solution (20mol), separate out a large amount of white solid, drip hydrobromic constant pressure dropping funnel with 4mL distilled water wash, room temperature continues to stir 5min.Propargyl bromide is dissolved in 5mL ethanol, then slowly drop in piperazine and hydrobromic reaction solution, dropwise, 76 ° of C oil bath reflux 5h, obtain achromaticity and clarification reaction solution, refrigeration, separate out white solid, suction filtration, filtrate revolves desolventizing, add 20mL distilled water, be extracted with ethyl acetate (40mL × 4), organic over anhydrous dried over sodium sulfate, leach, be spin-dried for, obtain pale yellow oil, drip the alcohol saturated solution of HCl, refrigeration, suction filtration, dry, obtain white solid 4-proyl piperazine hydrochloride 0.26g, yield is 13.3%, m.p:199 ° of C (dec),
1h-NMR (600MHz, D
2o-d6): δ=3.88 (d, J=2.4Hz, 2H), 3.41 (s, 8H), 2.94 (s, 1H), ESI-MS:[M+H]
+: 125.1.
(5) by step (5) method preparation in embodiment 1, with 2-azido--N-[[5-(4-aminomethyl phenyl)-2-furyl] methyl]-ethanamide and 4-proyl piperazine hydrochloride (0.20g, 1mmol) be obtained by reacting white solid 0.05g, yield is 12.7%
1h-NMR (300MHz, CDCl
3): δ=7.61 (s, 1H), 7.50-7.47 (d, J=8.1Hz, 2H); 7.18-7.15 (d, J=8.1Hz, 2H), 6.52-6.47 (br.m, 2H); 6.25 (d, J=3Hz, 1H), 5.05 (s, 2H); 4.46 (d, J=5.7Hz, 2H), 3.66 (s; 2H), 2.85 (t, J=4.5Hz, 4H); 2.46 (br.s, 4H), 2.35 (s, 3H); ESI-HRMS:m/z calcd for C
21h
27n
6o
2[(M+H)
+], 395.2195; Found, 395.2179.
Biological activity determination:
Active testing selects radioligand binding assay, measures its inhibit activities to hERG potassium-channel, calculates IC
50.
Table one: benzofurane compound is to the inhibit activities of hERG potassium-channel
Note: IC
50for with hERG potassium-channel in conjunction with 50% concentration.
Screening active ingredients is carried out to above-mentioned 30 compounds, they the inhibit activities of hERG potassium-channel is listed in table one.
As shown in Table 1, L8, L9, L10, L22, L2, L12, L6, L16, L11 has good inhibit activities, and wherein L8 activity is best, its IC
50for 518nM, compound L 7, L20, L30 activity are medium.This shows, phenyl ring R
1when substituting group is bromine, activity is better than other substituting groups, and halogenic substituent is better than the substituting group of other types, R
2substituting group small volume is conducive to activity, when piperazine ring 4 has large phenyl ring to replace, phenyl ring has during methoxy substitution base and is conducive to activity.
Activity research shows, above-mentioned benzofurane compounds has the activity suppressing hERG potassium-channel, and be the hERG potassium channel inhibitors of novel structure, the lead compound that can be used as antiarrhythmic drug is used.
Benzofurane compounds of the present invention as the application of anti-arrhythmia inhibitor, specifically, as treatment ARR medicine.
A kind of antiarrhythmic drug composition, comprises benzofurane compounds of the present invention.
Preparation, pharmaceutical composition, dosage and taking:
Benzofurane derivative of the present invention can exist in a free form or in the form of salts.Those skilled in the art oneself know pharmacy acceptable salt of chemical compound lot type and preparation method thereof.Pharmacy acceptable salt comprises conventional avirulent salt, comprises season that such compound alkali and inorganic or organic acid formed by salt.
Compound of the present invention can form hydrate or solvate.The hydrate that one skilled in the art is known to be formed compound during freeze-drying together with water or form the method for solvate when concentrating with suitable organic solvent in the solution.
The present invention comprises the medicine containing therapeutic dose the compounds of this invention, and the pharmaceutical composition of one or more pharmaceutically acceptable carriers and/or vehicle.Carrier comprises as salt solution, buffer saline, glucose, water, glycerine, and ethanol and their binding substances, hereafter discuss in more detail.If needed, said composition can also comprise wetting agent or the emulsifying agent of comparatively a small amount of, or pH buffer reagent.Said composition can be liquid, suspension, emulsion, tablet, pill, capsule, extended release preparation or powder.Said composition can be mixed with suppository with traditional firewood mixture and carrier such as triglyceride.Oral preparations can comprise the mannitol of standard vector as medicine grade, lactose, starch, Magnesium Stearate, soluble saccharin, Mierocrystalline cellulose and magnesiumcarbonate etc.Optionally preparation and determining, preparation can design mixing, granulates and compression or solvent components.In another approach, said composition can be mixed with nano particle.
The pharmaceutical carrier used can be, such as, and solid or liquid.
Typical solid carrier comprises lactose, terra alba, sucrose, talcum, gel, agar, pectin, gum arabic, Magnesium Stearate, stearic acid etc.Solid carrier can comprise one or more may simultaneously as sweetener, lubricant, solubilizing agent, suspension agent, filler, glidant, compression aid, the material of tackiness agent or tablet-disintegrating agents; It can also be encapsulating material.In the powder, carrier is pulverizing solid, and it mixes with pulverizing activeconstituents.Activeconstituents mixes with suitable ratio with the carrier with necessary compression property in tablets, with the shape needed and size compression.Powder and tablet preferably comprise 99% activeconstituents at the most.Suitable solid carrier comprises, such as, and calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gel, Mierocrystalline cellulose, methylcellulose gum, sodium carboxymethyl-cellulose, polyvinylpyrrolidone alkane ketone, low melt wax and ion exchange resin.
Typical liquid vehicle comprises syrup, peanut oil, sweet oil, water, etc.Liquid vehicle for the preparation of solution, suspension, emulsion, syrup, the composition of tincture and sealing.Activeconstituents can dissolve or be suspended in pharmaceutically acceptable liquid vehicle as water, organic solvent, the mixture of the two or pharmaceutically acceptable oils or fat.Liquid vehicle can comprise other suitable medicated premixs as solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweetener, sweetener, suspension agent, thickening material, pigment, and viscosity modifier, stablizes shape or osmo-regulators.Suitable example for the liquid vehicle of oral and administered parenterally comprises water and (partly comprises as above-mentioned additive, such as derivatived cellulose, preferably carboxymethyl cellulose sodium salt solution), alcohol (comprises monohydroxy-alcohol and polyvalent alcohol, such as ethylene glycol) and their derivative, and oils (such as fractionated coconut oil and peanut oil).Carrier for administered parenterally can also be that grease is as ethyl oleate and isopropyl myristate.Aseptic liquid vehicle is used for the aseptic fluid composition of administered parenterally.Liquid vehicle for pressurized compositions can be halohydrocarbon or other pharmaceutically acceptable propelling agents.Sterile solution or aaerosol solution composition of liquid medicine can be used for, such as, and intravenously, intramuscular, intraperitoneal or subcutaneous injection.Can push or inject gradually by single during injection, entering the interior perfusion of passages through which vital energy circulates of 30 minutes.This compound can also with the form oral administration of liquid or solids composition.
Carrier or vehicle can comprise time lag material known in the art, as glyceryl monostearate or distearin, also can comprise wax, ethyl cellulose, light propyl methocel, methyl methacrylate etc.When preparation is used for oral, generally acknowledges that 0.01% tween 80 in PHOSALPG-50 is used for the preparation of the acceptable oral preparations of other compounds, the preparation of the various compound of the present invention can be adapted to.Medicament forms miscellaneous can be used when giving the compounds of this invention.If use solid carrier, preparation can be tablet, is placed into powder in hard capsule or piller form or lozenge or Lozenge forms.The amount of solid carrier changes to a great extent, but preferably from about 25mg to about 1.0g.If use liquid vehicle, preparation can be syrup, emulsion, soft capsule, the aseptic injectable solution in the liquid suspension of ampulla or bottle or non-water or suspension.
In order to obtain stable water miscible formulation, compound or its pharmacy acceptable salt can be dissolved in organic or inorganic aqueous acid, 0.3M succsinic acid or citric acid solution.Optionally, acid derivative can be dissolved in suitable basic solution.If can not get soluble form, compound can be dissolved in suitable cosolvent or their combination.The example of suitable cosolvent like this includes but are not limited to, concentration range from the ethanol of 0-60% cumulative volume, propylene glycol, Liquid Macrogol, polysorbate 80, glycerine, polyoxyethylene fatty acid ester, fatty alcohol or the light fatty acid ester of glycerine etc.
Various release system is known and may be used for the administration of compound or other various preparations, and these preparations comprise tablet, capsule, injectable solution, the capsule in liposome, particulate, microcapsule, etc.The method introduced includes, but are not limited to skin, intracutaneous, and intramuscular is endoperitoneal, intravenous, subcutaneous, nasal cavity, lung, peridural, eyes and (usually preferred) oral route.Compound can pass through easily any or other suitable administration, such as by injecting or bolus injection, by epithelium or mucous membrane circuit (such as, oral mucosa, rectum and intestinal mucosa, etc.) to absorb or by the support of carrying medicament and can in other biological promoting agent together administration.Can whole body or topical.For nose, when the treatment of segmental bronchus or lung disease or prevention, preferred route of administration is oral, nasal administration or segmental bronchus smoke substance or atomizer.
Claims (9)
1. benzofurane compounds, it is the following compound of structural formula and pharmaceutical salts thereof:
In formula,
R
1be 2,4-dichloro, 4-methoxyl group, 4-methyl, 4-halogen, 4-nitro, R
2for piperidyl, morpholinyl, methylpiperazine base, piperazine, 1-(2-p-methoxy-phenyl) piperazine, 4-phenylpiperazine.
2. benzofurane compounds according to claim 1, is characterized in that, compound is:
N-[[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide;
N-[[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-[4-[[4-(2-p-methoxy-phenyl) piperazine-1-base] methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-[4-(piperidin-1-yl methyl)-1H-1,2,3-triazole-1-yl acetamide];
N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide;
N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-[[4-(2-p-methoxy-phenyl) piperazine-1-base] methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-(piperazine-1-ylmethyl)-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-(piperidin-1-yl methyl)-1H-1,2,3-triazole-1-yl acetamide];
N-[[5-(4-nitrophenyl) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(4-nitrophenyl) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide;
N-[[5-(4-nitrophenyl) furans-2-base] methyl]-2-[4-[[4-(2-p-methoxy-phenyl) piperazine-1-base] methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-[4-[4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide;
N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-[4-[4-(2-p-methoxy-phenyl) piperazine-1-base] methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-[4-(piperazine-1-ylmethyl)-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide;
N-[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-[4-(piperazine-1-ylmethyl)-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-[4-(piperidin-1-yl methyl)-1H-1,2,3-triazole-1-yl acetamide];
N-[[5-(p-tolyl) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(p-tolyl) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide;
N-[5-(p-tolyl) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(p-tolyl) furans-2-base] methyl]-2-[4-(piperazine-1-ylmethyl)-1H-1,2,3-triazole-1-base] ethanamide;
N-[[5-(p-tolyl) furans-2-base] methyl]-2-[4-(piperidin-1-yl methyl)-1H-1,2,3-triazole-1-yl acetamide].
3. the preparation method of benzofurane compounds according to claim 1, is characterized in that, comprise the following steps:
(1) with R
1the aniline replaced is starting raw material, acid dissolve is added to it, then under ice bath, slowly drip sodium nitrite solution, dropwise, continue reaction 20-30min, reaction generates diazonium salt, then add cupric chloride or titanous chloride makes catalyzer, add chaff amine, stirring at room temperature 12-36h, linked reaction occurs, and product separation is purified to obtain intermediate 5-substituted-phenyl-2-aminomethyl-furan;
(2) in 5-replacement-2-aminomethyl-furan, K is added
2cO
3and CH
2cl
2, then under ice bath, slowly drip chloroacetyl chloride CH
2cl
2solution, drips and finishes, and stirring at room temperature reaction detects without raw material midbody to TLC, and separating-purifying obtains the chloro-N-of intermediate 2-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide;
(3) chloro-for 2-N-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide and sodiumazide return stirring in acetonitrile are reacted 10-18h, obtain intermediate 2-azido--N-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide;
(4) by 2-azido--N-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide and structural formula if the compound of VII is in methyl alcohol, water mixed solvent, add sodium ascorbate and CuSO
4catalysis, there is ring-closure reaction, obtain benzofurane compounds in lucifuge stirring at room temperature 12-24h; Benzofurane compounds and ethanol solution hydrochloride react, must the hydrochloride of this benzofurane compounds
Wherein X is O, CH
2, NH; R
3for methyl, phenyl, N-(2-p-methoxy-phenyl).
4. the preparation method of benzofurane compounds according to claim 3, is characterized in that, step (1) R
1replace aniline and Sodium Nitrite, acid, catalyzer, chaff amine reaction mol ratio be 1:1:5-10:0.02-3:1-5, the concentration of sodium nitrite solution is 2mol/L; In step (2), 5-replaces-2-aminomethyl-furan and K
2cO
3and the equivalence ratio of chloroacetyl chloride is 1:1-4:1-2.
5. the preparation method of benzofurane compounds according to claim 3, is characterized in that, in step (3), the equivalence ratio of the chloro-N-of 2-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide and sodiumazide is 1:3-5.
6. the preparation method of benzofurane compounds according to claim 3, it is characterized in that, 2-azido--N-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide and structural formula are as the compound of VII, sodium ascorbate and CuSO in step (4)
4equivalence ratio be 1:1:0.5-1-0.05-1, mixed solvent be first alcohol and water by volume 1-5:1 mixing.
7. benzofurane compounds according to claim 1 is preparing the application in antiarrhythmic drug.
8. an antiarrhythmic pharmaceutical composition, comprises benzofurane compounds according to claim 1, one or more pharmaceutically acceptable carriers or vehicle.
9. the antiarrhythmic pharmaceutical composition of one according to claim 8, is characterized in that, acceptable carrier comprises solid or liquid vehicle, and solid carrier is selected from starch, lactose, sucrose, dextrin, Magnesium Stearate; Liquid vehicle is selected from syrup, peanut oil, sweet oil, water.
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| CN104910894B (en) * | 2015-05-05 | 2017-05-03 | 山东大学 | Benzimidazole hERG potassium ion channel small-molecular fluorescent probe and preparation method and applications thereof |
| CN105778896B (en) * | 2016-04-08 | 2018-01-12 | 山东大学 | Phenyl（4 piperidyls）The small-molecule fluorescent probe of ketone class hERG potassium-channels |
| CN111568894B (en) * | 2020-05-18 | 2021-07-27 | 中国医学科学院肿瘤医院 | Use of 2- (ethylaminomethyl) -5- (phenyl) furan for the preparation of a medicament for inhibiting TLR7/8 |
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| WO1996027595A1 (en) * | 1995-03-08 | 1996-09-12 | Smithkline Beecham Laboratoires Pharmaceutiques | Heterocyclycarboxamides and other compounds for the treatment of the cardiac arrhythmias |
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| WO1996027595A1 (en) * | 1995-03-08 | 1996-09-12 | Smithkline Beecham Laboratoires Pharmaceutiques | Heterocyclycarboxamides and other compounds for the treatment of the cardiac arrhythmias |
| CN1479734A (en) * | 2000-12-12 | 2004-03-03 | ���ĵ�˹ҩ��¹�����˾ | Arylated furane and thenoyl amine with potassium channel blocking effect |
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