CN103242214B - A kind of indole derivatives and preparation method thereof - Google Patents
A kind of indole derivatives and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of indole derivatives, as following general formula (I) represents, this derivative is the selective antagonist of mAChR:
wherein, R
1represent hydrogen atom or the straight or branched alkyl containing 1 to 3 carbon atom, R
2and R
3each straight or branched alkyl representing hydrogen atom independently or contain 1 to 3 carbon atom, R
4represent hydrogen atom or halogen.In addition, the invention also discloses the preparation method of this derivative and the purposes as muscarinic acetylcholine receptor antagonist.<!--1-->
Description
Technical field
Technical solution of the present invention relates to a kind of preparation method and purposes of anticholinergic indole derivatives, belongs to medical art.
Background technology
Anticholinergic shows anti-convulsion effect and secretion inhibitor effect, as the handicapped medicine such as enteron aisle, bladder.The amino alkane alkoxides such as the alkaloids such as current known coromegine, Oxybutynin and propantheline bromide, their quaternary ammonium salt etc. are anticholinergics, and they are antagonists of mAChR.But due to their antagonistic action Organic selection poor, even be greater than ileum, tracheae mAChR to the effect of heart mAChR is similar, comparatively severe side effect can be caused like this, such as dizzy, heart rate acceleration etc., this can badly influence the clinical application of this type of medicine.Though novel muscarinic acceptor blocker darifenacin, Suo Feinaxin, imidafenacin etc. have higher selectivity, reduce side effect, but its curative effect is still not ideal enough, therefore, require that exploitation has high selectivity and the anticholinergic of better efficacy clinically.
Summary of the invention
The object of this invention is to provide and there is high selectivity and the anticholinergic agents of better efficacy, in order to above-mentioned purpose, present inventor have developed a kind of indole derivatives of brand new, as shown in following general formula (I), medicine provided by the invention for the mAChR of unstriated muscle than to heart mAChR, there is higher selectivity and stronger antagonistic activity.
Wherein, R
1represent hydrogen atom or the straight or branched alkyl containing 1 to 3 carbon atom, R
2and R
3each straight or branched alkyl representing hydrogen atom independently or contain 1 to 3 carbon atom, R
4represent hydrogen atom or halogen.
At the compound described in logical formula I of the present invention, preferably R
1for methyl or hydrogen atom.
At the compound described in logical formula I of the present invention, preferably R
2for methyl, ethyl, sec.-propyl, R
3for hydrogen atom.
At the compound described in logical formula I of the present invention, preferably R
4for Cl, Br.
The synthetic method of the compounds of this invention
In order to complete object of the present invention, the present invention adopts following technical scheme:
When the R of compound described in formula I is led in the present invention
4during for hydrogen atom, following technical scheme is adopted to synthesize:
First, by bromo-for 4-2,2-diphenylbutanenitrile, substituted or unsubstituted indoles, triethylamine (Et
3n), dimethyl formamide (DMF) mixing, in 150 DEG C of heated and stirred, with thin-layer chromatography (TLC) monitoring reaction, after question response is complete, this solution is injected water, with dichloromethane extraction, the organic phase that extraction obtains, with dried over anhydrous sodium carbonate, is then filtered, filtrate decompression evaporate to dryness, solid evaporated under reduced pressure obtained is separated through silica gel column chromatography, then uses re-crystallizing in ethyl acetate.The compound upper step obtained mixes with 70% sulfuric acid, heated and stirred at 140 DEG C, after reacting completely, this solution 6NNaOH is adjusted to pH=8, and with dichloromethane extraction, extracts the organic phase dried over anhydrous sodium carbonate obtained, then filter, filtrate decompression evaporate to dryness, solid evaporated under reduced pressure obtained is separated through silica gel column chromatography, then uses re-crystallizing in ethyl acetate.By the compound that obtains and alkylating reagent (alkylatingagents, preferred halohydrocarbon) under the existence of NaH, 0-5 DEG C of ice bath reaction conditions reaction, solvent is DMF.After reacting completely, reaction soln is injected water, with dichloromethane extraction, extract the organic phase dried over anhydrous sodium carbonate obtained, then filter, filtrate decompression evaporate to dryness.The solid that this evaporated under reduced pressure obtains is separated through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtain the compound described in logical formula I.
When the R of compound described in formula I is led in the present invention
4during for halogen, following technical scheme is adopted to synthesize:
First, by phenyl ring with bromo-2, the 2-diphenyl butanamides of substituent 4-, substituted or unsubstituted indoles, triethylamine (Et
3n), dimethyl formamide (DMF) mixes, in 150 DEG C of heated and stirred, with thin-layer chromatography (TLC) monitoring reaction, after question response is complete, this solution is injected water, with dichloromethane extraction, the organic phase that extraction obtains, with dried over anhydrous sodium carbonate, is then filtered, filtrate decompression evaporate to dryness.The solid that this evaporated under reduced pressure obtains is separated through silica gel column chromatography, then uses re-crystallizing in ethyl acetate.Compound previous step obtained and alkylating reagent (preferred halohydrocarbon) are under the existence of NaH, and 0-5 DEG C of ice bath reaction conditions reaction, solvent is DMF.After reacting completely, reaction soln is injected water, with dichloromethane extraction, extract the organic phase dried over anhydrous sodium carbonate obtained, then filter, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains the compound described in logical formula I.
Specific embodiment
Below the specific embodiment of content of the present invention, for set forth in present specification want the concrete technical scheme of technical solution problem, but realization of the present invention is not limited to these embodiments, and these embodiments not limit scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, the reaction raw materials in unreceipted source and reagent are commercially available.
In following embodiment:
The structure of compound is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS).NMR displacement (δ) provides with the unit of 1,000,000/(ppm).The mensuration of NMR is that measuring solvent is deuterochloroform (CDC by Varian-Inova-400 type nuclear magnetic resonance analyser
l3), be inside designated as trimethyl silane (TMS), chemical shift is with 10
-6(ppm) provide as unit.
The mensuration MAT212 magnetic-type mass spectrograph of MS.
Thin-layer chromatography (TLC): silica gel H SGF254 (Yantai City's Zhifu Huang business silica gel develop sequence factory)
Column chromatography silica gel: tlc silica gel H (Qingdao Marine Chemical Co., Ltd.'s product)
Embodiment 14-indyl-2,2-diphenylbutanenitrile (intermediate 1)
Bromo-for 4-2,2-diphenylbutanenitrile (3.00g, 10.0mmol), indoles (3.51g, 30.0mmol), triethylamine (1.40ml, 10.0mmol) and dimethyl formamide (50ml) are mixed, in 150 DEG C of heated and stirred 40 hours.After reacting completely, this reaction soln is injected water, with dichloromethane extraction, the organic phase that extraction obtains, with dried over anhydrous sodium carbonate, is then filtered, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: methylene dichloride: methyl alcohol=20:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 2.52g, yield 75%.
MS(ESI+，m/e)：337.17[M+H]
+
Embodiment 24-indyl-2,2-diphenyl butanamide (compound 1)
By intermediate 1(6.72g, 20mmol) and 70% sulfuric acid (50ml) mixing, stir 40 minutes in 140 DEG C.This solution 6NNaOH is adjusted to pH=8, and with dichloromethane extraction, extracts the organic phase dried over anhydrous sodium carbonate obtained, then filter, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: trichloromethane: methyl alcohol=25:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 2.40g, yield 68%.
Molecular formula: C
24h
22n
2o
Molecular weight: 354
MS(ESI+，m/e)：355.18[M+H]
+
1H-NMR(400MHz,CDCl3)δ(ppm)：7.04-7.59(m,4H),6.41(d,1H),7.33(d,1H),4.16(t,2H),2.63(t,2H),7.16(s,2H),7.09-7.40(m,10H)
Embodiment 34-indyl-2,2-phenylbenzene-N-methylbutyryl amine (compound 2)
By compound 1(3.54g, 10mmol), methyl iodide (2.12g, 15mmol), NaH(0.24,10mmol), dimethyl formamide (50ml) mixing, under 0-5 DEG C of ice bath reaction conditions stir 4 hours.This solution is injected water, with dichloromethane extraction, extracts the organic phase dried over anhydrous sodium carbonate obtained, then filter, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: trichloromethane: methyl alcohol=18:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 1.76g, yield 48%.
Molecular formula: C
25h
24n
2o
Molecular weight: 368
MS(ESI+，m/e)：369.19[M+H]
+
1H-NMR(400MHz,CDCl3)δ(ppm)：7.04-7.59(m,4H),6.41(d，1H),7.33(d,1H),4.16(t,2H),2.63(t,2H),8.03(m,1H),3.05(d,3H),7.09-7.40(m,10H)
Embodiment 44-indyl-2,2-phenylbenzene-N-ethyl butyramide (compound 3)
By compound 1(3.54g, 10mmol), monobromethane (1.63g, 15mmol), NaH(0.24,10mmol), dimethyl formamide (50ml, commercially available) mixing, under 0-5 DEG C of ice bath reaction conditions stir 6 hours.This solution is injected water, with dichloromethane extraction, extracts the organic phase dried over anhydrous sodium carbonate obtained, then filter, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: trichloromethane: methyl alcohol=20:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 1.52g, yield 40%.
Molecular formula: C
26h
26n
2o
Molecular weight: 382
MS(ESI+，m/e)：383.21[M+H]
+
1H-NMR(400MHz,CDC
l3)δ(ppm)：7.04-7.59(m,4H),6.41(d，1H),7.33(d,1H),4.16(t,2H),2.63(t,2H),8.03(t,1H),3.11(m,2H),1.04(t,3H),7.09-7.40(m,10H)
Embodiment 54-indyl-2,2-phenylbenzene-N-butanamide (compound 4)
By compound 1(3.54g, 10mmol), 2-N-PROPYLE BROMIDE (1.85g, 15mmol), NaH(0.24,10mmol), dimethyl formamide (50ml) mixing, under 0-5 DEG C of ice bath reaction conditions stir 6 hours.This solution is injected water, with dichloromethane extraction, extracts the organic phase dried over anhydrous sodium carbonate obtained, then filter, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: trichloromethane: methyl alcohol=15:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 1.78g, yield 45%.
Molecular formula: C
27h
28n
2o
Molecular weight: 396
MS(ESI+，m/e)：397.22[M+H]
+
1H-NMR(400MHz,CDC
l3)δ(ppm)：7.04-7.59(m,4H),6.41(d，1H),7.33(d,1H),4.16(t,2H),2.63(t,2H),8.03(d,1H),3.81(m,1H),1.00(d,6H),7.09-7.40(m,10H)
Embodiment 64-indyl-2 phenyl-2-rubigan butyramide (compound 5)
By bromo-for 4-2-phenyl-2-to chlorobenzene butyramide (3.52g, 10.0mmol, prepares by US Patent No. 3790581), indoles (3.51g, 30.0mmol), triethylamine (1.40ml, 10.0mmol) and dimethyl formamide (50ml) mixing, in 150 DEG C of heated and stirred 35 hours.This solution is injected water, and with dichloromethane extraction, the organic phase that extraction obtains, with dried over anhydrous sodium carbonate, is then filtered, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: methylene dichloride: methyl alcohol=25:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 1.59g, yield 41%.
Molecular formula: C
24h
21clN
2o
Molecular weight: 388.5
MS(ESI+，m/e)：389.14[M+H]
+
1H-NMR(400MHz,CDCl3)δ(ppm)：7.04-7.59(m,4H),6.41(d,1H),7.33(d,1H),4.02(t,2H),2.63(t,2H),7.16(s,2H),7.09-7.40(m,5H),7.23-7.44（m，4H）
Embodiment 74-indyl-2 phenyl-2-is to bromophenyl butyramide (compound 6)
By bromo-for 4-2-phenyl-2-to bromobenzene butyramide (3.97g, 10.0mmol, prepare by US Patent No. 3790581), indoles (3.51g, 30.0mmol, commercially available), triethylamine (1.40ml, 10.0mmol, commercially available) and dimethyl formamide (50ml) mixing, in 150 DEG C of heated and stirred 38 hours.This solution is injected water, and with dichloromethane extraction, the organic phase that extraction obtains, with dried over anhydrous sodium carbonate, is then filtered, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: methylene dichloride: methyl alcohol=25:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 3.25g, yield 75%.
Molecular formula: C
24h
21brN
2o
Molecular weight: 433
MS(ESI+，m/e)：434.08[M+H]
+
1H-NMR(400MHz,CDCl3)δ(ppm)：7.04-7.59(m,4H),6.41(d,1H),7.33(d,1H),4.02(t,2H),2.63(t,2H),7.16(s,2H),7.09-7.40(m,5H),7.18-7.92（m，4H）
Embodiment 84-indyl-2 phenyl-2-rubigan-N-methylbutyryl amine (compound 7)
By compound 5(3.88g, 10mmol), methyl iodide (2.12g, 15mmol), NaH(0.24,10mmol), dimethyl formamide (50ml) mixing, under 0-5 DEG C of ice bath reaction conditions stir 4 hours.This solution is injected water, with dichloromethane extraction, extracts the organic phase dried over anhydrous sodium carbonate obtained, then filter, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: trichloromethane: methyl alcohol=18:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 1.81g, yield 45%.
Molecular formula: C
25h
23clN
2o
Molecular weight: 403
MS(ESI+，m/e)：404.16[M+H]
+
1H-NMR(400MHz,CDCl3)δ(ppm)：7.04-7.59(m,4H),6.41(d，1H),7.33(d,1H),4.02(t,2H),2.63(t,2H),8.03(m,1H),3.05(d,3H),7.23-7.44(m,10H)
Embodiment 94-indyl-2 phenyl-2-is to bromophenyl-N-butanamide (compound 8)
By compound 6(4.33g, 10mmol), methyl iodide (2.12g, 15mmol), NaH(0.24,10mmol), dimethyl formamide (50ml) mixing, under 0-5 DEG C of ice bath reaction conditions stir 4 hours.This solution is injected water, with dichloromethane extraction, extracts the organic phase dried over anhydrous sodium carbonate obtained, then filter, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: trichloromethane: methyl alcohol=18:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 1.81g, yield 45%.
Molecular formula: C
27h
27brN
2o
Molecular weight: 475
MS(ESI+，m/e)：476.13[M+H]
+
1H-NMR(400MHz,CDC
l3)δ(ppm)：7.04-7.59(m,4H),6.41(d，1H),7.33(d,1H),4.16(t,2H),2.63(t,2H),8.03(d,1H),3.81(m,1H),1.00(d,6H),7.18-7.92(m,4H)，7.09-7.40（m，4H）
Embodiment 104-(3-methyl-indolyl)-2,2-diphenylbutanenitrile (intermediate 2)
Bromo-for 4-2,2-diphenylbutanenitrile (3.00g, 10.0mmol), 3-skatole (3.93g, 30.0mmol), triethylamine (1.40ml, 10.0mmol) and dimethyl formamide (50ml) are mixed, in 150 DEG C of heated and stirred 42 hours.This solution is injected water, and with dichloromethane extraction, the organic phase that extraction obtains, with dried over anhydrous sodium carbonate, is then filtered, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: methylene dichloride: methyl alcohol=22:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 2.73g, yield 78%.
MS(ESI+，m/e)：351.26[M+H]
+
Embodiment 114-(3-methyl-indolyl)-2,2-diphenyl butanamides (compound 9)
By intermediate 2(7.00g, 20mmol) and 70% sulfuric acid (60ml) mixing, stir 55 minutes in 140 DEG C.This solution 6NNaOH is adjusted to pH=8, and uses dichloromethane extraction.Organic phase dried over anhydrous sodium carbonate, then filters, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: trichloromethane: methyl alcohol=24:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 2.58g, yield 70%.
Molecular formula: C
25h
24n
2o
Molecular weight: 368
MS(ESI+，m/e)：369.19[M+H]
+
1H-NMR(400MHz,CDCl3)δ（ppm）：7.02-7.55(m,4H),2.29(s,3H),6.35(s,1H),4.16(t,2H),2.63(t,2H),7.16(s,2H),7.09-7.40(m,10H)
Embodiment 124-(3-methyl-indolyl)-2,2-phenylbenzene-N-methylbutyryl amine (compound 10)
By compound 9(3.68g, 10mmol), methyl iodide (2.12g, 15mmol), NaH(0.24,10mmol), dimethyl formamide (50ml) mixing, under 0-5 DEG C of ice bath reaction conditions stir 4 hours.This solution is injected water, with dichloromethane extraction, extracts the organic phase dried over anhydrous sodium carbonate obtained, then filter, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: trichloromethane: methyl alcohol=20:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 1.72g, yield 45%.
Molecular formula: C
26h
26n
2o
Molecular weight: 382
MS(ESI+，m/e)：383.21[M+H]
+
1H-NMR(400MHz,CDCl3)δ(ppm)：7.02-7.55(m,4H),2.29（s,3H）,6.35(s，1H),4.16(t,2H),2.63(t,2H),8.03(m,1H),3.05(d,3H),,7.09-7.40(m,10H)
Embodiment 134-(3-methyl-indolyl)-2,2-phenylbenzene-N-ethyl butyramides (compound 11)
By compound 9(3.68g, 10mmol), monobromethane (1.63g, 15mmol, commercially available), NaH(0.24,10mmol, commercially available), dimethyl formamide (50ml, commercially available) mixing, under 0-5 DEG C of ice bath reaction conditions stir 6 hours.This solution is injected water, uses dichloromethane extraction.Extract the organic phase dried over anhydrous sodium carbonate obtained, then filter, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: trichloromethane: methyl alcohol=20:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 1.58g, yield 40%.
Molecular formula: C
27h
28n
2o
Molecular weight: 396
MS(ESI+，m/e)：397.22[M+H]
+
1H-NMR(400MHz,CDC
l3)δ(ppm)：7.02-7.55(m,4H),2.29(s,3H),6.35(s，1H),4.16(t,2H),2.63(t,2H),8.03(t,1H),3.11(m,2H),1.04(t,3H),7.09-7.40(m,10H)
Embodiment 144-(3-methyl-indolyl)-2,2-phenylbenzene-N-butanamide (compound 12)
By compound 9(3.68g, 10mmol), 2-N-PROPYLE BROMIDE (1.85g, 15mmol), NaH(0.24,10mmol), dimethyl formamide (50ml) mixing, under 0-5 DEG C of ice bath reaction conditions stir 6 hours.This solution is injected water, uses dichloromethane extraction.Extract the organic phase dried over anhydrous sodium carbonate obtained, then filter, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: trichloromethane: methyl alcohol=18:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 1.72g, yield 42%.
Molecular formula: C
28h
30n
2o
Molecular weight: 410
MS(ESI+，m/e)：411.24[M+H]
+
1H-NMR(400MHz,CDC
l3)δ(ppm)：7.02-7.55(m,4H),2.29(s,3H),6.35(s，1H),4.16(t,2H),2.63(t,2H),8.03(d,1H),3.81(m,1H),1.00(d,6H),7.09-7.40(m,10H)
Embodiment 154-(3-methyl-indolyl)-2-phenyl-2-rubigan butyramide (compound 13)
By bromo-for 4-2-phenyl-2-to chlorobenzene butyramide (3.52g, 10.0mmol, prepares by US Patent No. 3790581), 3-skatole (3.93g, 30.0mmol), triethylamine (1.40ml, 10.0mmol) and dimethyl formamide (50ml) mixing, in 150 DEG C of heated and stirred 35 hours.This solution is injected water, and with dichloromethane extraction, the organic phase that extraction obtains, with dried over anhydrous sodium carbonate, is then filtered, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: methylene dichloride: methyl alcohol=24:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 1.65g, yield 41%.
Molecular formula: C
25h
23clN
2o
Molecular weight: 403
MS(ESI+，m/e)：404.16[M+H]
+
1H-NMR(400MHz,CDCl3)δ（ppm）：7.02-7.55(m,4H),2.29(s,3H),6.35(s,1H),4.02(t,2H),2.63(t,2H),7.16(s,2H),7.09-7.40(m,5H),7.23-7.44（m,4H）
Embodiment 164-(3-methyl-indolyl)-2 phenyl-2-are to bromophenyl butyramide (compound 14)
By bromo-for 4-2-phenyl-2-to bromobenzene butyramide (3.97g, 10.0mmol, prepares by US Patent No. 3790581), 3-skatole (3.93g, 30.0mmol), triethylamine (1.40ml, 10.0mmol) and dimethyl formamide (50ml) mixing, in 150 DEG C of heated and stirred 38 hours.This solution is injected water, and with dichloromethane extraction, the organic phase that extraction obtains, with dried over anhydrous sodium carbonate, is then filtered, filtrate decompression evaporate to dryness.This solid is separated (eluent: trichloromethane: methyl alcohol=25:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtain white solid 2.14g, yield 48%.
Molecular formula: C
25h
23brN
2o
Molecular weight: 447
MS(ESI+，m/e)：447.10[M+H]
+
1H-NMR(400MHz,CDCl3)δ（ppm）：7.02-7.55(m,4H),2.29（s,3H）,6.35(s,1H),4.02(t,2H),2.63(t,2H),7.16(s,2H),7.09-7.40(m,5H),7.18-7.92（m,4H）
Embodiment 174-(3-methyl-indolyl)-2 phenyl-2-rubigan-N-methylbutyryl amine (compound 15)
By compound 13(4.03g, 10mmol), methyl iodide (2.12g, 15mmol), NaH(0.24,10mmol), dimethyl formamide (50ml) mixing, under 0-5 DEG C of ice bath reaction conditions stir 4 hours.This solution is injected water, with dichloromethane extraction, extracts the organic phase dried over anhydrous sodium carbonate obtained, then filter, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: trichloromethane: methyl alcohol=20:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 1.79g, yield 43%.
Molecular formula: C
26h
25clN
2o
Molecular weight: 417
MS(ESI+，m/e)：418.17[M+H]
+
1H-NMR(400MHz,CDCl3)δ(ppm)：7.02-7.55(m,4H),2.29（s，3H）,6.35(s，1H),4.02(t,2H),2.63(t,2H),8.03(m,1H),3.05(d,3H),7.09-7.40(m,5H),7.23-7.44(m,4H)
Embodiment 184-(3-methyl-indolyl)-2 phenyl-2-are to bromophenyl-N-butanamide (compound 16)
By compound 14(4.47g, 10mmol), 2-N-PROPYLE BROMIDE (1.85g, 15mmol), NaH(0.24,10mmol), dimethyl formamide (50ml) mixing, under 0-5 DEG C of ice bath reaction conditions stir 4 hours.This solution is injected water, with dichloromethane extraction, extracts the organic phase dried over anhydrous sodium carbonate obtained, then filter, filtrate decompression evaporate to dryness.Solid evaporated under reduced pressure obtained is separated (eluent: trichloromethane: methyl alcohol=25:1) through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains white solid 2.00g, yield 41%.
Molecular formula: C
28h
29brN
2o
Molecular weight: 489
MS(ESI+，m/e)：490.14[M+H]
+
1H-NMR(400MHz,CDC
l3)δ(ppm)：7.02-7.55(m,4H),2.29(s,3H),6.35(s，1H),4.02(t,2H),2.63(t,2H),8.03(d,1H),3.81(m,1H),1.00(d,6H),7.09-7.40（m,5H）7.18-7.92(m,4H)
In order to further illustrate the beneficial effect of technical solution of the present invention, we are verified by pharmacological evaluation, and pharmacological evaluation is as follows:
(1) to the anticholinergic effect of guinea pig ileum and heart
1. material
1.1 laboratory animal 114 Hartley cavys, body weight is 300 ~ 400g.
1.2 medicines and reagent are using compound 1-16 of the present invention as tested medicine, and coromegine, Oxybutynin, imidafenacin are positive reference substance.Tested medicine, positive reference substance and vagusstoff are all dissolved in dehydrated alcohol and are mixed with finite concentration and test.Wherein 16 tested medicines and 3 positive reference substances all make the solution for standby that concentration is respectively 0.01g/L, 0.05g/L, 0.1g/L, 0.5g/L tetra-concentration; And the solution for standby of 0.01g/L made by vagusstoff; TyrodeShi solution for standby.
The double-deck organ baths of 1.3 key instruments, thermostatted, etc. transmodulator, RM6240C microcomputer bio signal treatment system.
2. method
114 cavys are divided into 19 groups by 2.1 experiment groupings at random, and often organize 6, often group same medicine is tested.
The preparation mallet of 2.2 Ileum From A Whites hits cavy head and causes and faint, cut abdominal cavity open immediately, find ileocecus, then cutting off from ileocecus 1cm place, take out ileum, be placed in oxygen-saturated TyrodeShi water culture ware, along intestines wall removing mesentery, then ileum is cut into the intestines sheet of about 3cm, draws TyrodeShi solution with syringe and intestinal contents is rinsed well.
The preparation mallet of 2.3 isolated hearts hits cavy head and causes and faint, and takes out heart, is placed in oxygen-saturated TyrodeShi solution, and heart can self-propelled bouncing, is beneficial to and gets rid of residual blood in the chambers of the heart.
It is 1 gram that intestines sheet is suspended in tension force by 2.4 experimental techniques (1), and temperature is the 95%O of 36 DEG C
2and 5%CO
2in the organ bath of the TyrodeShi solution of process, treat that Ileum From A White stablizes 10 minutes, after waiting transmodulator record one section of normal contraction curve, add the vagusstoff solution that 10ml prepares, observe and record its shrinkage curve, with when the duration of contact of 5 minutes, mensuration did not add test agent, to the dose-response curve of vagusstoff, until obtain maximum value.Liquid in venting organ bath, with TyrodeShi solution continuous flushing twice, add the TyrodeShi solution of same volume again, drip the test agent compound 1 that 10ml concentration is 0.01g/L inwards, balance 20 minutes, then dose-response curve is redeterminated, until obtain maximum reaction, liquid in venting organ bath, with TyrodeShi solution continuous flushing twice, reload the TyrodeShi solution adding same volume, drip the test agent compound 1 that 10ml concentration is 0.05g/L inwards, repeat above-mentioned steps, in like manner, evaluate 0.1g/L, during the compound 1 of 0.5g/L concentration, repeat the experimental procedure identical with 0.05g/L concentration.
(2) isolated heart is measured dose-effect curve according to the identical method of above-mentioned intestines sheet, namely wherein involved parameters is all identical.
With mensuration guinea pig ileum and heart, to the method for the dose-effect curve of vagusstoff, measure the vagusstoff dose-effect curve of test agent compound 2-16, coromegine, Oxybutynin and imidafenacin respectively above.
According to Schild method (Arunlakshana, O. and Schild, H.O. (1959), Brit.J.Pharmacol., 14; 48 ~
58) test compound is measured to the avidity (pA of muscarinic receptor
2).
3. experimental result
As mentioned above, the affinity of test compound is measured.Experimental data represents with mean number, the results are shown in table 1.
The anticholinergic effect of table 1 pair guinea pig ileum and heart
As can be seen from Table 1, the M-ChR of compound of the present invention to guinea pig ileum has high-affinity, and to heart receptor, then affinity is much lower, reduces side effect.And coromegine and the effect of Oxybutynin to heart mAChR is similar is even greater than ileum mAChR, comparatively severe side effect can be caused like this.Although the effect of imidafenacin to ileum mAChR is greater than heart mAChR, the affinity of compound of the present invention to the M-ChR of guinea pig ileum is higher than imidafenacin, reaches object of the present invention.
(2) to the anticholinergic effect of guinea pig trachea and heart
1. material
1.1 laboratory animal 108 Hartley cavys, body weight is 300 ~ 400g.
1.2 medicines and reagent are using compound 1-16 of the present invention as tested medicine, and ipratropium bromide, imidafenacin are positive reference substance.Tested medicine, positive reference substance and vagusstoff are all dissolved in dehydrated alcohol and are mixed with finite concentration and test.Wherein 16 tested medicines and 2 positive reference substances all make the solution for standby that concentration is respectively 0.01g/L, 0.05g/L, 0.1g/L, 0.5g/L tetra-concentration; And the solution for standby of 0.01g/L made by vagusstoff; TyrodeShi solution for standby.
The double-deck organ baths of 1.3 key instruments, thermostatted, etc. transmodulator, RM6240C microcomputer bio signal treatment system.
2. method
108 cavys are divided into 18 groups by 2.1 experiment groupings at random, and often organize 6, often group same medicine is tested.
The preparation mallet of 2.2 isolated tracheals hits cavy head and causes and faint, and rapidly in outside of belly medisection skin of neck, is separated tracheae, and cuts whole tracheae from thyroid cartilage down to tracheae crotch, be placed in oxygen-saturated TyrodeShi solution at once
The preparation mallet of 2.3 isolated hearts hits cavy head and causes and faint, and takes out heart, is placed in oxygen-saturated TyrodeShi solution, and heart can self-propelled bouncing, is beneficial to and gets rid of residual blood in the chambers of the heart.
It is 1 gram that isolated tracheal is suspended in tension force by 2.4 experimental techniques (1), and temperature is the 95%O of 36 DEG C
2and 5%CO
2in the organ bath of the TyrodeShi solution of process, treat that isolated tracheal stablizes 10 minutes, after waiting transmodulator record one section of normal contraction curve, add the vagusstoff solution that 10ml prepares, observe and record its shrinkage curve, with when the duration of contact of 5 minutes, mensuration did not add test agent, to the dose-response curve of vagusstoff, until obtain maximum value.Liquid in venting organ bath, with TyrodeShi solution continuous flushing twice, add the TyrodeShi solution of same volume again, drip the test agent compound 1 that 10ml concentration is 0.01g/L inwards, balance 20 minutes, then dose-response curve is redeterminated, until obtain maximum reaction, liquid in venting organ bath, with TyrodeShi solution continuous flushing twice, reload the TyrodeShi solution adding same volume, drip the test agent compound 1 that 10ml concentration is 0.05g/L inwards, repeat above-mentioned steps, in like manner, evaluate 0.1g/L, during the compound 1 of 0.5g/L concentration, repeat the experimental procedure identical with 0.05g/L concentration.
(2) isolated heart is measured dose-effect curve according to the identical method of above-mentioned isolated tracheal, namely wherein involved parameters is all identical.
With mensuration guinea pig trachea and heart, to the method for the dose-effect curve of vagusstoff, measure the vagusstoff dose-effect curve of test agent compound 2-16, ipratropium bromide and imidafenacin respectively above.
According to Schild method (Arunlakshana, O. and Schild, H.O. (1959), Brit.J.Pharmacol., 14; 48 ~
58) test compound is measured to the avidity (pA of muscarinic receptor
2).
3. experimental result
As mentioned above, the affinity of test compound is measured.Experimental data represents with mean number, the results are shown in table 2.
The anticholinergic effect of table 2 pair guinea pig trachea
As can be seen from Table 2, the affinity of compound of the present invention to the affinity comparison heart receptor of the M-ChR of guinea pig trachea is much higher, improves selectivity, reduces side effect.And be widely used in the ipratropium bromide for the treatment of chronic obstructive bronchitis and light moderate bronchial asthma clinically, to the effect of heart mAChR and close to tracheae mAChR, comparatively severe side effect can be caused like this, as increased heart rate, palpitaition etc.Although the effect of imidafenacin to tracheae mAChR is greater than heart mAChR, but the affinity of compound of the present invention to the M-ChR of guinea pig ileum is higher than imidafenacin, thus improve curative effect, reach object of the present invention.
In sum, because general formula compound (I) introduces indole structure in the structure, improve the affinity to enteron aisle, tracheae acceptor on the whole; And work as R
2for alkyl, R
3during for hydrogen atom, further increase again the activity of compound, especially work as R
2during for sec.-propyl, it is more that activity improves; When the substituent R in phenyl ring
4during for halogen, can make again active raising further, therefore the activity of compound 8 and compound 16 is the highest.Investigator thinks the activity improving compound further on this basis, therefore introduces substituent R on indole ring
1, to improving the bonding force to acceptor, but sorry discovery, indole ring is introduced substituting group can not improve activity.
What beneficial effect of the present invention was outstanding shows as compared with the existing technology, and the compound structure that compound of the present invention and prior art relate to is not quite similar, particularly R
2and R
4substituent introducing on position, is all greatly improved to the activity and selectivity of this compounds.In general, compound of the present invention exclusively can be used for the treatment of irritable bowel syndrome, misnicturition clinically as frequent micturition and the urinary incontinence, and chronic obstructive airway disease.
Claims (5)
1. an indole derivatives, is characterized in that being represented by following logical formula I
Wherein, R
1for methyl, R
2represent hydrogen atom or the straight or branched alkyl containing 1 to 3 carbon atom, R
3for methyl, ethyl or sec.-propyl, R
4represent hydrogen atom, Cl or Br.
2. indole derivatives as claimed in claim 1, is characterized in that it is 4-(3-methyl-indolyl)-2 benzene
Base-2-is to bromophenyl-N-butanamide.
3. the preparation method of indole derivatives as claimed in claim 1, is characterized in that it is made up of following steps: when the R of the compound described in formula I is led in the present invention
4during for hydrogen atom, carry out according to the following steps:
(1) by bromo-for 4-2,2-diphenylbutanenitrile, substituted or unsubstituted indoles, triethylamine (Et3N), dimethyl formamide (DMF) mix, in 150 DEG C of heated and stirred, with thin-layer chromatography (TLC) monitoring reaction, after question response is complete, this solution is injected water, with dichloromethane extraction, organic phase is with dried over anhydrous sodium carbonate, then filter, filtrate decompression evaporate to dryness, solid evaporated under reduced pressure obtained is separated through silica gel column chromatography, then uses re-crystallizing in ethyl acetate; (2) compound previous step obtained mixes with 70% sulfuric acid, heated and stirred at 140 DEG C, after reacting completely, this solution 6NNaOH is adjusted to pH=8, then dichloromethane extraction is used, organic phase dried over anhydrous sodium carbonate, then filters, filtrate decompression evaporate to dryness, solid evaporated under reduced pressure obtained is separated through silica gel column chromatography, then uses re-crystallizing in ethyl acetate; (3) compound previous step obtained and alkylating reagent (alkylatingagents) are under the existence of NaH, 0-5 DEG C of ice bath reaction conditions reaction, solvent is DMF, after reacting completely, reaction soln is injected water, with dichloromethane extraction, organic phase dried over anhydrous sodium carbonate, then filters, filtrate decompression evaporate to dryness, solid evaporated under reduced pressure obtained is separated through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains target compound; When the R of the compound described in formula I is led in the present invention
4during for halogen, carry out according to the following steps:
By on bromo-for 4-2,2-diphenyl butanamides or phenyl ring with bromo-2, the 2-diphenyl butanamides of substituent 4-, substituted or unsubstituted indoles, triethylamine (Et
3n), dimethyl formamide (DMF) mixing, in 150 DEG C of heated and stirred, with thin-layer chromatography (TLC) monitoring reaction, after question response is complete, this solution is injected water, with dichloromethane extraction, organic phase, with dried over anhydrous sodium carbonate, is then filtered, filtrate decompression evaporate to dryness, solid evaporated under reduced pressure obtained is separated through silica gel column chromatography, then uses re-crystallizing in ethyl acetate; (2) compound previous step obtained and alkylating reagent (alkylatingagents) are under the existence of NaH, ice bath reaction conditions reacts, and solvent is DMF, after reacting completely, reaction soln is injected water, with dichloromethane extraction, organic phase dried over anhydrous sodium carbonate, then filters, filtrate decompression evaporate to dryness, solid evaporated under reduced pressure obtained is separated through silica gel column chromatography, then uses re-crystallizing in ethyl acetate, obtains target compound.
4. the preparation method of indole derivatives as claimed in claim 3, is characterized in that described alkylating reagent is halohydrocarbon.
5. indole derivatives as claimed in claim 1 is used as the application in cholinergic receptor antagonist medicine in preparation.
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Citations (4)
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|---|---|---|---|---|
| US6103747A (en) * | 1993-12-10 | 2000-08-15 | Kyorin Pharmaceutical Co., Ltd. | Imidazole derivatives and process for preparing the same |
| WO2003027060A1 (en) * | 2001-09-20 | 2003-04-03 | Kyorin Pharmaceutical Co., Ltd. | Diphenylbutane amide derivatives |
| JP2003201281A (en) * | 2001-10-31 | 2003-07-18 | Kyorin Pharmaceut Co Ltd | Method for producing 4-(2-methyl-1-imidazolyl)-2,2- diphenylbutane amide |
| CN101268046A (en) * | 2005-09-21 | 2008-09-17 | 辉瑞有限公司 | Carboxamide derivatives as muscarinic receptor antagonists |
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2013
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6103747A (en) * | 1993-12-10 | 2000-08-15 | Kyorin Pharmaceutical Co., Ltd. | Imidazole derivatives and process for preparing the same |
| WO2003027060A1 (en) * | 2001-09-20 | 2003-04-03 | Kyorin Pharmaceutical Co., Ltd. | Diphenylbutane amide derivatives |
| JP2003201281A (en) * | 2001-10-31 | 2003-07-18 | Kyorin Pharmaceut Co Ltd | Method for producing 4-(2-methyl-1-imidazolyl)-2,2- diphenylbutane amide |
| CN101268046A (en) * | 2005-09-21 | 2008-09-17 | 辉瑞有限公司 | Carboxamide derivatives as muscarinic receptor antagonists |
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| Title |
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| "Synthesis and Antimuscarinic Activity of a Series of 4-(1-Imidazolyl)-2,2-diphenylbutyramides: Discovery of Potent and Subtype-selective Antimuscarinic Agents";Hiroyuki Miyachi等;《Bioorganic & Medicinal Chemistry》;19990630;第7卷;第1155-1156页, 表2-5 * |
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