CN100358865C - Sulfonamide phenylalkylamine compound, its preparation method and application - Google Patents
Sulfonamide phenylalkylamine compound, its preparation method and application Download PDFInfo
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- CN100358865C CN100358865C CNB021169012A CN02116901A CN100358865C CN 100358865 C CN100358865 C CN 100358865C CN B021169012 A CNB021169012 A CN B021169012A CN 02116901 A CN02116901 A CN 02116901A CN 100358865 C CN100358865 C CN 100358865C
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Abstract
The present invention provides a sulfamide phenylalkyl compound whose general formula as follows. The compound is prepared by adopting a preparation method whose reaction condition is moderate and raw material is easily available. Pharmacological tests show that the compound is a potassium ion channel inhibitor, has good therapeutic effect on rat heart reperfusion arrhythmia model in vitro and has activity for resisting arrhythmia so as to achieve the purpose of curing arrhythmia.
Description
Technical field
The present invention relates to the synthetic and purposes of sulfonamide phenyl alkylamide derivative.
Background technology
The mortality ratio of cardiovascular disorder has risen to first in China.Serious irregular pulse, as quick type ventricular tachycardia (VT), quiver (VF) in the chamber and cardiac sudden death (SCD) then is the major reason of cardiovascular disorder death.At present clinical use and develop in medicine can be divided into four big classes by Vanghan Williams classification: the I class is a sodium channel inhibitor, and the II class is a beta-blocker, and the III class is the potassium channel blocking agent; The IV class is a calcium channel blocker.The I class, the II class, IV class medicine all has the effect that reduces conduction of velocity even cause block, and these effects can increase the possibility of reciprocal excitation, thereby bring out irregular pulse.The effect characteristics of III class medicine are the blocking-up potassium-channels, even high selectivity ground suppresses I
KrThe electricity physiological effect is over reach current potential time-histories (APD) and effective refractory period (ERP) only, intracardiac conduction of velocity does not slow down, make that stream increases in the calcium of 2 phase plateaus, therefore slight positive inotropic action is arranged, simultaneously, the effect of prolongation often has reverse frequency/application dependency (reverse frequency/use dependence): the slow APD of heart rate prolongs obviously; The fast APD prolongation of heart rate effect reduces even disappears.They are used for the treatment of life-threatening re-entrant ventricular arrhythmia clinically, and atrial arrhythmia is also had certain curative effect.Research and development potassium channel antagonist has become the developing direction of present antiarrhythmic drug.The antiarrhythmic drug of report nearly all is the potassium channel antagonist since 1998, and they compare safer, wide spectrum, efficient with other antiarrhythmic drug, be expected to become first-selected antiarrhythmic drug.
Summary of the invention
The present invention seeks to seek a class has the inhibiting sulfonamide phenyl alkylamide compound of the high selection of potassium-channel.Another purpose of the present invention is to be the method for the synthetic sulfonamide phenyl alkylamide compound of raw material with β-phenylethylamine.A further object of the present invention provides sulfonamide phenyl alkylamide compound and uses in the medicine of treatment cardiovascular disorder.
Sulfonamide phenylalkylamine compound has following general structure:
In the formula: R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X, the substituting group of Y and alk is with following identical;
X is O, S or a singly-bound;
Y is ethylene, trimethylene or the tetramethylene that is replaced arbitrarily by methyl;
Alk is an ethylene, trimethylene or tetramethylene, and alk can be replaced arbitrarily by methyl.
When X is O, when Y is ethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X, the substituting group of Y and alk is with following identical;
Alk is an ethylene, trimethylene or tetramethylene, and alk can be replaced arbitrarily by methyl.
When X is S, when Y is ethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X, the substituting group of Y and alk is with following identical;
Alk is an ethylene, trimethylene or tetramethylene, and alk can be replaced arbitrarily by methyl.
When X is a singly-bound, when Y is ethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X, the substituting group of Y and alk is with following identical;
Alk is an ethylene, trimethylene or tetramethylene, and alk can be replaced arbitrarily by methyl.
When X is O, when Y is trimethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X, the substituting group of Y and alk is with following identical;
Alk is an ethylene, trimethylene or tetramethylene, and alk can be replaced arbitrarily by methyl.
When X is S, when Y is trimethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X, the substituting group of Y and alk is with following identical;
Alk is an ethylene, trimethylene or tetramethylene, and alk can be replaced arbitrarily by methyl.
When X is single key, when Y is trimethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X, the substituting group of Y and alk is with following identical;
Alk is an ethylene, trimethylene or tetramethylene, and alk can be replaced arbitrarily by methyl.
When X is O, when Y is tetramethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X, the substituting group of Y and alk is with following identical;
Alk is an ethylene, trimethylene or tetramethylene, and alk can be replaced arbitrarily by methyl.
When X is S, when Y is tetramethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X, the substituting group of Y and alk is with following identical;
Alk is an ethylene, trimethylene or tetramethylene, and alk can be replaced arbitrarily by methyl.
When X is single key, when Y is tetramethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X, the substituting group of Y and alk is with following identical;
Alk is an ethylene, trimethylene or tetramethylene, and alk can be replaced arbitrarily by methyl.
Sulfonamide phenyl alkylamide compound of the present invention mainly makes through the following steps:
1. the preparation method of general formula (I):
(A) compound of general formula (II) is under alkyl sulfonyl chloride, alkyl sulfonyl bromine, the effect of alkylsulphonic acid acid anhydride, and (alkyl is C to the acylation reaction of generation
1-C
4), used alkali is organic bases such as pyridine, triethylamine, 4-dimethylamino pyridine (DMAP), diisopropylethylamine etc., mineral alkali such as yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide etc.Reaction is carried out between-40-40 ℃ usually.The product of gained can get pure products through purifications such as appropriate means such as column chromatography, recrystallizations.
In the formula, R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X, the substituting group of Y and alk is identical with the compound of general formula (I); X, Y, " alk " are identical with the compound of general formula (I).
2. the preparation method of general formula (II):
(B) compound of general formula (III) is in Pd/C, Pt/C, Raney nickel/hydrogen, Raney nickel/hydrazine hydrate system, reduction reaction takes place, used solvent has ethanol, methyl alcohol, ethyl acetate, tetrahydrofuran (THF) etc., and temperature of reaction can at room temperature be carried out between 0～60 ℃ usually; (C) reduction reaction particularly in iron powder/hydrochloric acid system, takes place in iron powder/acid in the compound of general formula (III), and the compound of gained can get pure products with purifications such as appropriate means such as column chromatography, recrystallizations;
In the formula, R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X, the substituting group of Y and alk is identical with the compound of general formula (I); X, Y, " alk " are identical with the compound of general formula (I).
3. the preparation method of general formula (III):
(D) compound of general formula (IV) is under the halides effect, base catalysis, substitution reaction takes place, used solvent has ethanol, methyl alcohol, second eyeball, propyl carbinol, water etc., used alkali has salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide etc., reaction is carried out between 20～100 ℃ usually, generally gets final product in room temperature.Used halides has 1,2-ethylene dichloride, glycol dibromide, 1,3-propylene dichloride, 1,3-dibromopropane, 1,4-dichlorobutane, 1,4-dibromobutane, ethyl bromoacetate, acid propyl bromide, bromoacetic acid butyl ester, ethyl bromide, bromo-propionic acid propyl ester, bromo-propionic acid butyl ester etc.;
In the formula, X, Y, " alk " are identical with the compound of general formula (I).
4. the preparation method of general formula (IV):
(E) condensation reaction takes place in the compound of the compound or its salt of logical formula V and general formula (VI) under alkaline condition, and reaction in inert solvent, is carried out under 20-100 ℃ usually.Used solvent has THF, Et
2O, DMF, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane etc.Used alkali has salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide etc., and the compound of gained can get pure products with purifications such as appropriate means such as column chromatography, recrystallizations;
In the formula, A is Cl, Br, I, and X, Y, " alk " are identical with the compound of general formula (I).
5. the preparation method of leading to formula V:
(F) deprotection base R takes place in the compound of general formula (VII) in acidic aqueous solution or alkaline aqueous solution
3Reaction;
In the formula, R
3Be R
4CO, wherein R
4Be C
1-C
4Alkyl, aryl, Y is identical with the compound of general formula (I).
6. the preparation method of general formula (VI):
(G) compound of general formula (VIII) is under the halides effect, substitution reaction takes place, used halohydrocarbon has 1,2-ethylene dichloride, glycol dibromide, 1,3-propylene dichloride, 1,3-dibromopropane, 1,4-dichlorobutane, 1,4-dibromobutane etc., used alkali has sodium hydrogen, amido sodium, potassium hydroxide, sodium hydroxide, potassium tert.-butoxide, sodium tert-butoxide etc., and used solvent has DMF, THF, EtOH etc.Reaction is carried out between-30～40 ℃ usually, generally carries out under 0-100 ℃, and the compound of gained can get pure products with purifications such as appropriate means such as column chromatography, recrystallizations.
In the formula, X is identical with the compound of general formula (I).
10. the preparation method of general formula (VII):
(H) compound of general formula (IX) is at nitrating agent, as nitrosonitric acid, and nitric acid/sulfuric acid, the nitration reaction in nitric acid/hydrochloric acid system;
In the formula, R
3Be R
4CO, wherein R
4Be C
1-C
4Alkyl, aryl, Y is identical with the compound of general formula (I).
Advantages such as sulfonamide phenyl alkylamide compound of the present invention has very strong antiarrhythmic activity, can be used as antiarrhythmic drug, and its preparation method has the reaction conditions gentleness, and abundant raw material is easy to get, and operation and aftertreatment are simple.
Biological activity determination:
Experiment title: isolated rat heart reperfusion arrhythmia model
Experimental technique: the SD rat body weight is 220-250kg, and rat was tapped the head to dusk.Open chest rapidly, on the dirty Langendoff of the placing perfusion device of coring, adopt the retrograde constant current perfusion of K-H liquid row aorta, Ppa pulmonary artery pressure is constant in 50-60mmHg, and perfusate passes to 95%O
2+ 5%CO
2Mixed gas, the moiety of K-H liquid (mmol/L): NaCl 118; KCl 4.74; MgSO
41.2; NaHCO
325; KH
2PO
40.93; CaCl
22.5; Glucose 10.PH 7.4, and temperature is 37 ℃.Control group stops to irritate 30min then and irritates again with K-H liquid perfusion 10min, observes the incidence of quivering in ventricular premature contraction, ventricular tachycardia and chamber.The administration group is carried out perfusion with the K-H liquid that contains medicine, and experiment condition is identical with control group in fact.
Experimental result:
| Group | The mouse number | Dosage (μ mol/l) | PVS | VT | VF |
| Contrast | 19 | K-H | 10 | 18 | 19 |
| 1 | 3 | 10 | 1 | 2 | 1 |
| 2 | 3 | 10 | 2 | 2 | 1 |
| 3 | 3 | 10 | 1 | 2 | 2 |
| 4 | 6 | 10 | 0 | 4 | 0 |
| 5 | 3 | 10 | 0 | 2 | 1 |
| 7 | 3 | 10 | 0 | 2 | 1 |
| 8 | 3 | 10 | 1 | 2 | 2 |
| 9 | 3 | 10 | 0 | 3 | 1 |
| 10 | 3 | 10 | 0 | 3 | 0 |
| 11 | 3 | 10 | 1 | 3 | 2 |
| 13 | 3 | 10 | 0 | 2 | 3 |
| 14 | 3 | 10 | 1 | 3 | 1 |
| 15 | 3 | 10 | 0 | 3 | 1 |
| 17 | 3 | 10 | 0 | 1 | 1 |
| 18 | 3 | 10 | 0 | 3 | 3 |
PVS: the chamber early; VT: chamber speed; VF: quiver in the chamber.
The present invention has following advantage:
1, expressing sulfonamide phenyl alkylamide compound from experimental result has very strong antiarrhythmic activity, can be used as antiarrhythmic drug,
Advantages such as 2, its preparation method has the reaction conditions gentleness, and abundant raw material is easy to get, and operation and aftertreatment are simple.
Specific implementation method:
Further use the preparation of embodiment formula (I) compound below, it does not limit the present invention, and all temperature all are ℃.
Nuclear magnetic resonance spectrum is measured on Bruker AM-400, and mass spectrum carries out on MAT-95 type mass spectrograph.Ultimate analysis is finished by analyzer room, institute of materia medica, Chinese Academy of Sciences Shanghai.Fusing point is measured on electric heating melting point tube or b type melting point tube, and thermometer is not calibrated; Thin layer chromatography (tlc) (TLC) adopts silica gel G F
254(Haiyang Chemical Plant, Qingdao's production) and concentration are that 0.8% Xylo-Mucine distilled water solution fully stirs evenly the back bed board, dry, behind 100～110 ℃ of activation 1～2h, in moisture eliminator, preserve standby, ultraviolet lamp (λ: 254nm) colour developing; Column chromatography adopts 100 orders～200 order column chromatography silica gels (Haiyang Chemical Plant, Qingdao's production).
1 pair of nitro acetyl of embodiment β-phenylethylamine
In 1000 milliliters of β-phenylethylamines, drip 1000 milliliters of aceticanhydrides in the ice-water bath, reacted 30 minutes, standby.
In the mixed solution of 1500 milliliters of vitriol oils and 1500 milliliters of nitric acid, 0 ℃ drips above-mentioned reserve liquid, drips and finishes, and continues reaction 5 hours, pour in the frozen water, with ethyl acetate extraction three times, merge the ester layer, washing and drying, be concentrated into dried, use acetone recrystallization, get title compound 600 grams, fusing point 138-141 ℃.
2 pairs of nitro β-phenylethylamine hydrobromates of embodiment
In to nitro acetyl β-phenylethylamine (600 gram), add 47%HBr (1000 milliliters), reflux 6 hours, cooling is separated out title compound (650 gram), fusing point 218-220 ℃.
Embodiment 3 1-bromo-2-(naphthalene-1-base oxygen base) ethane
In the 20g naphthyl alcohol, 5.7g NaOH, 50ml ethanol, among a little TBA, stirring heating refluxed 3 hours, disposable adding 34.5ml glycol dibromide, slowly the temperature rising reflux reaction is 20 hours, and filtered while hot is used ethyl acetate extraction three times, merges the ester layer, anhydrous MgSO
4Drying, column chromatography for separation get colorless oil 16.5g, yield 47.4%, developping agent, ethyl acetate: sherwood oil=1: 4, R
f=0.8.
MS(SCI，m/z)252(MH
+)，157，143，115(base peak)
Embodiment 4 N-[2-(naphthalene-1-base oxygen base) ethyl] p-nitrophenyl ethamine
In free to nitro β-phenylethylamine 10g, 12.97g K
2CO
3In the 40ml ethanol, stirring heating refluxes and drips 12.95g 1-bromo-2-(naphthalene-1-base oxygen base) ethane that the 30ml alcohol dilution is crossed, reflux after 5 hours, boil off behind the ethanol with ethyl acetate extraction, the saturated common salt water washing is to neutral, anhydrous magnesium sulfate drying concentrates the dry method upper prop and gets object 14.16g, productive rate: 81.6%.Developping agent, ethyl acetate: sherwood oil=4: 1, R
f=0.24.
1HNMR(CDCl
3)ppm：δ＝3.04～3.12(2s，4H，-
CH 2 CH 2N)，3.25(t，2H，-N
CH 2)，4.30(t，2H，-O
CH 2)，6.75～6.80(q，1H，o-O-
ArH)，7.0～7.4(m，6H，
ArH)，7.55～7.70(m，2H，
ArH)，8.0～8.2(m，2H，
ArH)
Anal Calcd for C
20H
30O
3N
2：C 71.43，H 5.95，N 8.33；Found：C 69.73，H 5.731，N 8.27
MS(SCI，m/z)：336(MH
+)，193(base peak)
Embodiment 5 N-acetyl oxygen ethyl-N-[2-(naphthalene-1-base oxygen base) ethyl] p-nitrophenyl ethamine
In compound N-[2-(naphthalene-1-base oxygen base) ethyl] p-nitrophenyl ethamine 2.4g, add K
2CO
31.00g, second eyeball 30ml, 2.4ml BrCH
2COOC
2H
5, temperature of reaction is 20 ℃, stirring reaction 3-40 hour, boil off the second eyeball, and ethyl acetate extraction merges the ester layer, and saturated common salt is washed to neutrality, anhydrous MgSO
4Drying, column chromatography for separation get product 2.653g, yield 88%, developping agent, ethyl acetate: sherwood oil=1: 2, R
f=0.90
1HNMR(CDCl
3)ppm：δ＝1.21(s，3H，-CH
2 CH 3)，2.95(s，2H，-
CH 2CH
2N)，3.15(s，2H，-CH
2 CH 2N)，3.30(s，2H，-
CH 2N)，3.60(s，2H，
CH 2CO)，4.10(q，2H，CH
3 CH 2)，4.30(t，2H，-O
CH 2)，6.70～6.80(q，1H，o-O-
ArH)，7.20～7.45(m，6H，
ArH)，7.70～7.80(m，2H，
ArH)，7.95～8.20(m，2H，
ArH)
MS(SCI，m/z)：422(MH
+)，286(base peak)
Embodiment 6 N-(2-bromotrifluoromethane)-N-[2-(naphthalene-1-base oxygen base) ethyl] p-nitrophenyl ethamine
In compound N-[2-(naphthalene-1-base oxygen base) ethyl] p-nitrophenyl ethamine 1.19g, add 1.5ml1,2-ethylene dibromide, 0.489g K
2CO
3, 20ml second eyeball, 50 ℃ of reactions of temperature of reaction 4 hours boil off the second eyeball, ethyl acetate extraction, the saturated common salt water washing concentrates behind the anhydrous magnesium sulfate drying to neutral, and column chromatography for separation gets faint yellow title compound 0.978g, yield 63.72%, developping agent, ethyl acetate: sherwood oil=1: 1, R
f=0.35.
1HNMR(CD
3COCD
3)ppm：δ＝2.95(s，8H，-
CH 2 CH 2N，-
CH 2 CH 2Br)，3.05(t，2H，-
CH 2N)，4.15(t，2H，-O
CH 2)，6.65～6.80(q，1H，o-O-
ArH)，7.10～7.50(m，11H，
ArH)，7.70～8.0(m，3H，
ArH)，8.10～8.25(m，1H，
ArH)
Embodiment 7 N, N '-{ two [2-(naphthalene-1-base oxygen base) ethyl] }-N, N '-{ two [2-(p-oil of mirbane) ethyl] }-1
In the 35ml glycol dibromide, 8g K
2CO
3, in the 150ml second eyeball, add compound N-[2-(naphthalene-1-base oxygen base) ethyl] p-nitrophenyl ethamine 17g, 50 ℃ of reactions of temperature of reaction 10 hours boil off the second eyeball, ethyl acetate extraction, the saturated common salt water washing is to neutral, concentrate behind the anhydrous magnesium sulfate drying,, column chromatography for separation gets faint yellow title compound 12.71g, yield 72%, developping agent, ethyl acetate: sherwood oil=2: 1, R
f=0.35.
1HNMR(CD
3COCD
3)ppm：δ＝2.88(s，4H，-N
CH 2 CH 2N)，2.93～3.02(m，8H，2×p-ph-(
CH 2 CH 2N)，3.15(t，4H，2×-
CH 2N)，4.19(t，4H，2×-O
CH 2)，6.81(d，2H，2×o-O-
ArH)，7.33～7.50(m，12H，
ArH)，7.83(d，2H，
ArH)，7.98(d，4H，
ArH)，8.21(d，2H，ArH)
Embodiment 8 N-acetyl oxygen ethyl-N-[2-(naphthalene-1-base oxygen base) ethyl] to (amino) phenylethylamine
(a) in the presence of room temperature and normal pressure and Raney nickel, with N-acetyl oxygen ethyl-N-[2-(naphthalene-1-base oxygen base) ethyl] p-nitrophenyl ethamine 3.0 grams, the logical hydrogen of solution in acetone 20ml stirred 1-48 hour, temperature of reaction can be between 0～60 ℃, reaction mixture is filtered, be concentrated into dried, title compound 1.4 gram.
1HNMR(CDCl
3)ppm：δ＝1.21(s，3H，-CH
2 CH 3)，2.79(t，2H，-
CH 2CH
2N)，3.05(t，2H，-CH
2 CH 2N)，3.32(s，2H，-
CH 2N)，3.60(s，2H，
CH 2CO)，4.10(q，2H，CH
3 CH 2)，4.30(t，2H，-O
CH 2)，6.70～6.80(q，1H，o-O-
ArH)，7.20～7.45(m，6H，
ArH)，7.70～7.80(m，2H，
ArH)，7.95～8.20(m，2H，
ArH)
MS(SCI，m/z)：392(MH
+)，286(base peak)
(b) hydrazine hydrate 5ml is slowly splashed into N-acetyl oxygen ethyl n-[2-(naphthalene-1-base oxygen base) ethyl] p-nitrophenyl ethamine 5 grams and Raney nickel 2ml in the suspension of acetone 100ml, stir backflow 30min down, filter, filtrate is concentrated into dried, use ether dissolution, filter, after concentrating, use recrystallization from ethyl acetate/petroleum ether, get title compound.
(c) in 50ml ethanol, 1ml hydrochloric acid adds N-acetyl oxygen ethyl-N-[2-(naphthalene-1-base oxygen base) ethyl that a small amount of ammonium chloride stirring heating drips dissolve with ethanol in the 4.38g reduced iron powder] p-nitrophenyl ethamine 3.3g, dripped Bi Fanying 1 hour, temperature is at 20 ℃, and cooling adds 20%NaOH and transfers pH=10, heating, suction filtration boils off ethanol while hot, ethyl acetate extraction, saturated common salt is washed to neutrality, anhydrous MgSO
4Dry concentrate 3.03g, productive rate 97.9%.Developping agent, ethyl acetate: sherwood oil=1: 2, R
f=0.42.
Embodiment 9 N-(2-bromotrifluoromethane)-N-[2-(naphthalene-1-base oxygen base) ethyl] right-(amino) phenylethylamine
Title compound is by compound N-(2-bromotrifluoromethane)-N-[2-(naphthalene-1-base oxygen base) ethyl] p-nitrophenyl ethamine 0.829g press embodiment 7 operation preparations, must title compound 0.575g, yield 74.4%, developping agent, ethyl acetate: sherwood oil=4: 1, R
f=0.36.
1HNMR(CD
3COCD
3)ppm：δ＝2.80(t，2H，
CH 2CH
2Br)，2.95(s，4H，-
CH 2 CH 2N)，3.18(t，2H，-
CH 2N)，3.57(t，2H，CH
2 CH 2Br)，4.21(t，2H，-O
CH 2)，6.65～6.80(q，1H，o-O-
ArH)，7.10～7.50(m，11H，
ArH)，7.70～8.0(m，3H，
ArH)，8.10～8.25(m，1H，
ArH)
Embodiment 10 N, N '-{ two [2-(naphthalene-1-base oxygen base) ethyl] }-N, N '-{ two [2-(p-amino-benzene) ethyl] }-1
Title compound is by compound N, N '-{ two [2-(naphthalene-1-base oxygen base) ethyl] }-N, N '-{ two [2-(p-oil of mirbane) ethyl] }-1,2-quadrol 2.5g presses embodiment 8 operation preparations, gets title compound 1.83g, yield 80%, developping agent, ethyl acetate: sherwood oil=4: 1, R
f=0.36.
Embodiment 11 N-acetyl oxygen ethyl-N-[2-(naphthalene-1-base oxygen base) ethyl] to methylsalfonamido phenethylamine
In compound N-acetyl oxygen ethyl-N-[2-(naphthalene-1-base oxygen base) ethyl] 3.03g in right-(amino) phenylethylamine, 20ml CH
2Cl
2The middle stirring, slowly drip 1.08ml triethylamine and 0.903ml methylsulfonyl chloride simultaneously, reaction is carried out between 40 ℃ usually, and stirring is spent the night, and reaction solution washes with water repeatedly, concentrate behind the anhydrous magnesium sulfate drying, column chromatography for separation gets faint yellow title compound 2.984g, yield 82.0%, developping agent, ethyl acetate: sherwood oil=1: 2, R
f=0.35.
1HNMR(CDCl
3)ppm：δ＝1.21(s，3H，-CH
2 CH 3)，2.95(t，5H，-
CH 2CH
2N，
CH 3SO
2NH-)，3.15(t，2H，-CH
2 CH 2N)，3.42(s，2H，-
CH 2N)，3.72(s，2H，
CH 2CO)，4.15(q，2H，CH
3 CH 2)，4.20(t，2H，-O
CH 2)，6.70～6.80(q，1H，o-O-
ArH)，7.20～7.45(m，6H，
ArH)，7.70～7.80(m，2H，
ArH)，7.95～8.20(m，2H，
ArH)
MS(SCI，m/z)：470(MH
+)，286(base peak)
Embodiment 12 N-(2-bromotrifluoromethane)-N-[2-(naphthalene-1-base oxygen base) ethyl] to methylsalfonamido phenethylamine
Title compound is by compound N-(2-bromotrifluoromethane)-N-[2-(naphthalene-1-base oxygen base) ethyl] right-(amino) phenylethylamine 0.433g press embodiment 9 operation preparations, must 0.072g, yield 15.0%, developping agent, chloroform: acetone=3: 1, R
f=0.33.
1HNMR(CD
3COCD
3)ppm：δ＝2.80(t，2H，
CH 2CH
2Br)，2.95(s，7H，-
CH 2 CH 2N，
CH 3SO
2NH-)，3.18(t，2H，-
CH 2N，3.57(t，2H，CH
2 CH 2Br)，4.21(t，2H，-O
CH 2)，6.65～6.80(q，1H，o-O-
ArH)，7.10～7.50(m，11H，
ArH)，7.70～8.0(m，3H，
ArH)，8.10～8.25(m，1H，
ArH)
Embodiment 13 N, N '-{ two [2-(naphthalene-1-base oxygen base) ethyl] }-N, N '-{ two [2-(p-methylsulfonyl amido benzene) ethyl] }-1
Title compound is by compound N, N '-{ two [2-(naphthalene-1-base oxygen base) ethyl] }-N, and N '-{ two [2-(p-amino-benzene) ethyl] }-1 1.683g press embodiment 11 operation preparations, must 0.2g, yield 10.0%, developping agent, chloroform: acetone=3: 1, R
f=0.33.
1HNMR(CD
3COCD
3)ppm：δ＝2.82(m，2H，-N
CH 2CH
2N)，2.90-3.0(2s+m，12H，2×
CH 3SO
2NH，2×-N
CH 2CH
2ph，-NCH
2 CH 2N)，3.15(t，4H，2×-N
CH 2CH
2O)，3.22(t，4H，2×-NCH
2 CH 2ph，)，4.22(t，4H，2×-O
CH 2)，6.92(d，2H，2×o-O-
ArH)，7.28～7.50(m，12H，
ArH)，7.83(d，2H，
ArH)，7.98(d，4H，
ArH)，8.21(d，2H，ArH)；ESI 795(M+1)
+
Claims (13)
1, a class has the sulfonamide phenyl alkylamide compound of following general structure:
In the formula, R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X, the substituting group of Y and alk is with following identical;
X is O, S or a singly-bound;
Y is ethylene, trimethylene or the tetramethylene that is replaced arbitrarily by methyl;
" alk " is ethylene, trimethylene or tetramethylene, and " alk " replaced arbitrarily by methyl.
2, sulfonamide phenyl alkylamide compound according to claim 1 is characterized in that:
When X is O, when Y is ethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl or C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X are O, and Y is an ethylene, and the substituting group of alk is with following identical; " alk " is ethylene, trimethylene or tetramethylene, and " alk " replaced arbitrarily by methyl.
3, sulfonamide phenyl alkylamide compound according to claim 1 is characterized in that:
When X is S, when Y is ethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl or C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X are S, and Y is an ethylene, and the substituting group of alk is with following identical;
" alk " is ethylene, trimethylene or tetramethylene, and " alk " replaced arbitrarily by methyl.
4, sulfonamide phenyl alkylamide compound according to claim 1 is characterized in that:
When X is a singly-bound, when Y is ethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl or C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NH
SO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X are a singly-bound, and Y is an ethylene, and the substituting group of alk is with following identical;
" alk " is ethylene, trimethylene or tetramethylene, and " alk " replaced arbitrarily by methyl.
5, sulfonamide phenyl alkylamide compound according to claim 1 is characterized in that:
When X is O, when Y is trimethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl or C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X are O, and Y is a trimethylene, and the substituting group of alk is with following identical;
" alk " is ethylene, trimethylene or tetramethylene, and " alk " replaced arbitrarily by methyl.
6, sulfonamide phenyl alkylamide compound according to claim 1 is characterized in that:
When X is S, when Y is trimethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X are S, and Y is a trimethylene, and the substituting group of alk is with following identical;
" alk " is ethylene, trimethylene or tetramethylene, and " alk " replaced arbitrarily by methyl.
7, sulfonamide phenyl alkylamide compound according to claim 1 is characterized in that:
When X is a singly-bound, when Y is trimethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X are a singly-bound, and Y is a trimethylene, and the substituting group of alk is with following identical;
" alk " is ethylene, trimethylene or tetramethylene, and " alk " replaced arbitrarily by methyl.
8, sulfonamide phenyl alkylamide compound according to claim 1 is characterized in that:
When X is O, when Y is tetramethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X are O, and Y is a tetramethylene, and the substituting group of alk is with following identical;
" alk " is ethylene, trimethylene or tetramethylene, and " alk " replaced arbitrarily by methyl.
9, sulfonamide phenyl alkylamide compound according to claim 1 is characterized in that:
When X is S, when Y is four butylidenes,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X are a singly-bound, and Y is a trimethylene, and the substituting group of alk is with following identical;
" alk " is ethylene, trimethylene or tetramethylene, and " alk " replaced arbitrarily by methyl.
10, sulfonamide phenyl alkylamide compound according to claim 1 is characterized in that:
When X is a singly-bound, when Y is tetramethylene,
R
1Be H or C
1-C
4Alkyl;
R
2Be H, C
1-C
4Haloalkyl, C
nH
2nCOOC
mH
2m+1, n, m=1-4 or-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p), n=1-4; R
1Be H or C
1-C
4Alkyl, X are a singly-bound, and Y is that X is S, and Y is a tetramethylene, and the substituting group of alk is with following identical); " alk " is ethylene, trimethylene or tetramethylene, and " alk " replaced arbitrarily by methyl.
10, sulfonamide phenyl alkylamide compound according to claim 1 is characterized in that working as X is a singly-bound, when Y is tetramethylene,
R
1Be H, C
1-C
4Alkyl;
R
2Be H, C
1-C
4Substituted alkyl, C
nH
2nCOOC
mH
2m+1(n, m=1-4) ,-(CH
2)
nN (alk-X-naphthyl) (Y-phenyl-NHSO
2R
1-p) (n=1-4, R
1Be H, C
1-C
4Alkyl, X are a singly-bound, and Y is a tetramethylene, and the substituting group of alk is with following identical); " alk " is ethylene, trimethylene or tetramethylene, and " alk " replaced arbitrarily by methyl.
11, sulfonamide phenylalkylamine compound preparation method according to claim 1 is characterized in that:
(1) with naphthols etc. be starting raw material under the halides effect, substitution reaction takes place, with 1,2-ethylene dichloride, glycol dibromide, 1,3-propylene dichloride, 1,3-dibromopropane, 1,4-dichlorobutane, 1,4-dibromobutane synthetic intermediate compound VI class;
(2) β-phenylethylamine, γ-amphetamine is used nitrosonitric acid under the ethanoyl protection, nitric acid/sulfuric acid, nitrated in nitric acid/hydrochloric acid is to nitro-compound VII class;
(3) the VII compounds is under acidity or alkaline condition, the deprotection base;
(4) condensation reaction takes place and generates the compound IV class under alkaline condition in V compounds and VI compounds, and reaction in inert solvent, is carried out under-78～0 ℃ usually, and used solvent has THF, Et
2O, DMF, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, used alkali has butyllithium, phenyl lithium, diisopropylamine lithium, potassium tert.-butoxide, sodium tert-butoxide;
(5) under the halides effect, substitution reaction takes place and generates the compound III class compound VI class in base catalysis respectively;
(6) the compound III class is reduced to Compound I I class under following condition:
(5) under the halides effect, substitution reaction takes place and generates compound III compound IV in base catalysis respectively;
(6) compound III is reduced to Compound I I under following condition:
1. reduction reaction takes place in Pd/C, Pt/C, Raney nickel/hydrogen or Raney nickel/hydrazine hydrate system in compound III;
2. reduction reaction takes place in compound III in iron powder/acid system;
(7) Compound I I is under alkyl sulfonyl chloride, alkyl sulfonyl bromine or the effect of alkylsulphonic acid acid anhydride, and the acylation reaction alkyl of generation is C
1-C
4, generate Compound I.
12, the application of sulfonamide phenylalkylamine compound as claimed in claim 1 in the medicine of preparation treatment cardiovascular disorder.
Priority Applications (3)
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|---|---|---|---|
| CNB021169012A CN100358865C (en) | 2001-07-30 | 2002-04-26 | Sulfonamide phenylalkylamine compound, its preparation method and application |
| AU2002357560A AU2002357560A1 (en) | 2002-04-26 | 2002-12-30 | Sulfamidophenylalkylamines and their production and use |
| PCT/CN2002/000927 WO2003091205A1 (en) | 2002-04-26 | 2002-12-30 | Sulfamidophenylalkylamines and their production and use |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN01126366 | 2001-07-30 | ||
| CN01126366.0 | 2001-07-30 | ||
| CNB021169012A CN100358865C (en) | 2001-07-30 | 2002-04-26 | Sulfonamide phenylalkylamine compound, its preparation method and application |
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| CN107759477A (en) * | 2017-11-20 | 2018-03-06 | 阿里化学(常州)有限公司 | A kind of preparation method of p-nitrophenyl ethylamine hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1019801B (en) * | 1986-05-01 | 1992-12-30 | 菲泽有限公司 | Antiarrhythmic and preparation method thereof |
| CN1055679C (en) * | 1995-12-06 | 2000-08-23 | 中国药科大学 | Phenethylamine derivative with cardiovascular activity |
| CN1055682C (en) * | 1995-12-06 | 2000-08-23 | 中国药科大学 | Process for preparing mesylamido-phenethylamine derivative |
-
2002
- 2002-04-26 CN CNB021169012A patent/CN100358865C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1019801B (en) * | 1986-05-01 | 1992-12-30 | 菲泽有限公司 | Antiarrhythmic and preparation method thereof |
| CN1055679C (en) * | 1995-12-06 | 2000-08-23 | 中国药科大学 | Phenethylamine derivative with cardiovascular activity |
| CN1055682C (en) * | 1995-12-06 | 2000-08-23 | 中国药科大学 | Process for preparing mesylamido-phenethylamine derivative |
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