CN101906085B - Compound and composition for treating cardiovascular and cerebrovascular diseases and preparation method and use thereof - Google Patents
Compound and composition for treating cardiovascular and cerebrovascular diseases and preparation method and use thereof Download PDFInfo
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- CN101906085B CN101906085B CN2009100691314A CN200910069131A CN101906085B CN 101906085 B CN101906085 B CN 101906085B CN 2009100691314 A CN2009100691314 A CN 2009100691314A CN 200910069131 A CN200910069131 A CN 200910069131A CN 101906085 B CN101906085 B CN 101906085B
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Abstract
The invention provides a 1-(3,4,5-trimethoxycinnamoyl)-4-alkylamide derived compound and pharmaceutically acceptable salts thereof. The invention also provides a method for preparing the compound. The invention simultaneously provides a medicinal composition for treating cardiovascular and cerebrovascular diseases. The invention also provides use of the compound or the pharmaceutically acceptable salts thereof for preparing medicaments for treating the cardiovascular and cerebrovascular diseases and/or dilating cerebral, peripheral and coronary vessels and/or anticoagulation and/or enhancing the effects of adenoside and cyclic adenosine monophosphate (cAMP).
Description
Technical field
The present invention relates to a kind of compound, its composition, Preparation method and use for the treatment of cardiovascular and cerebrovascular diseases, the invention belongs to the pharmaceutical chemistry technical field.
Background technology
Cardiovascular and cerebrovascular diseases is a kind of serious threat mankind, and particularly the healthy common disease of the elderly more than 50 years old, even apply most advanced, perfect at present treatment means, still can have the cerebrovascular accident survivor's life more than 50% not take care of oneself fully! Every year is died from the number of cardiovascular and cerebrovascular diseases up to 1,500 ten thousand people in the whole world, occupies various causes of the death first place.Cardiovascular and cerebrovascular diseases has become the No.1 killer that mankind's Death causes is the highest, is also " the noiseless demon " of health of people!
Cardiovascular and cerebrovascular diseases has the characteristics of " sickness rate is high, disability rate is high, mortality ratio is high, recurrence rate is high, and complication is many "-" four is high by more than one ",
Cardiovascular and cerebrovascular diseases is current primary Death causes, is common disease and the frequently-occurring disease of serious threat China people ' s health, and selecting effective and safe medicine is the important topic that the clinician faces.
Drug effect and the side effect of at present a lot of vasodilators are to be improved, and existing market marketed drug is represented as Cinepazide Maleate.
Summary of the invention
One object of the present invention is, a kind of 1-(3,4,5-trimethoxy cinnamoyl)-4-alkylamide derivative compound or its pharmacy acceptable salt is provided; Another object of the present invention is, a kind of method for preparing described compound is provided; Another object of the present invention is, a kind of pharmaceutical composition that is used for the treatment of cardiovascular and cerebrovascular diseases is provided; Another object of the present invention is, provides described compound or its pharmacy acceptable salt for the preparation of the treatment cardiovascular and cerebrovascular diseases and/or for expanding brain, tip, coronary vasodilator and/or anticoagulation and/or strengthening the application of medicine of the effect of adenosine and cyclic monophosphate (cAMP).
For the foregoing invention purpose, the invention provides following technical scheme:
On the one hand, the invention provides a kind of as shown in the formula the 1-shown in (1) (3,4,5-trimethoxy cinnamoyl)-4-alkylamide derivative compound or its pharmacy acceptable salt:
In formula, Me is methyl, and NH-R is selected from:
Preferably, according to foregoing compound, wherein, the acid salt that described pharmacy acceptable salt is formula (1) compound, be preferably nitrate, vitriol, hydrobromate, hydriodate, phosphoric acid salt, maleate, fumarate, Citrate trianion, oxalate or tartrate; Most preferably be maleate or fumarate.
On the other hand, the invention provides a kind of method for preparing foregoing compound, wherein, described method comprises by formula (3) compound and 3,4,5-trimethoxy cinnamyl chloride, under the existence of de-acidying agent, reaction obtains formula (1) compound, and synthetic route is as follows:
Wherein:
Me means methyl,
Substituent R in formula (1), (3) is selected from
temperature of reaction is that room temperature extremely refluxes, and is preferably room temperature.
Preferably, according to method of the present invention, wherein, the reaction solvent of described reaction is selected from: water, methylene dichloride, chloroform, acetone, normal hexane, hexanaphthene, sherwood oil, toluene, benzene, ether, ethanol, ethyl acetate and composition thereof; Be preferably anhydrous solvent; Most preferably be methylene dichloride.
Preferably, according to method of the present invention, wherein, two kinds of reactants: 3, the mole dosage proportioning of 4,5-trimethoxy cinnamic acid halides and formula (3) compound 1-alkane amide piperazidine thing in described reaction system be more than 1: 1, be preferably 1.01: 1～1.3: 1.
Preferably, according to method of the present invention, wherein, the de-acidying agent used is selected from: triethylamine, pyridine, sodium carbonate and sodium bicarbonate.
Preferably, according to method of the present invention, wherein, described formula (3) compound is by with following formula (2) compound and piperazine or piperazine list salt, in solvent, reacting and obtain:
Wherein, substituent R is selected from
Described reaction solvent is selected from: water, methylene dichloride, chloroform, acetone, normal hexane, hexanaphthene, sherwood oil, toluene, benzene, ether and ethyl acetate are preferably water.
Further preferably, according to method of the present invention, wherein, described formula (2) compound is by chloroacetyl chloride and NH
2-R reaction preparation is obtained in solvent:
Wherein, substituent R is selected from
Described reaction solvent is selected from: water, methylene dichloride, chloroform, acetone, normal hexane, hexanaphthene, sherwood oil, toluene, benzene, ether and ethyl acetate are preferably methylene dichloride.
On the other hand, the invention provides a kind of pharmaceutical composition that is used for the treatment of cardiovascular and cerebrovascular diseases, described composition comprises: 1) foregoing compound or its pharmacy acceptable salt; With 2) to learn upper acceptable carrier.
On the other hand, the invention provides described compound or its pharmacy acceptable salt for the preparation of the treatment cardiovascular and cerebrovascular diseases and/or for expanding brain, tip, coronary vasodilator and/or anticoagulation and/or strengthening adenosine and the application of the medicine of the effect of cyclic monophosphate (cAMP).
On the one hand, the invention provides a kind of as shown in the formula the 1-alkane amide piperazidine midbody compound shown in (3) again:
Wherein, Me means methyl, and R is selected from
According to the present invention one preferred embodiment, a kind of compound meaned by formula (1) and pharmacy acceptable salt and preparation method thereof are provided.
In formula, NH-R is
In formula, NH-R is
1-(3; 4,5-trimethoxy cinnamoyl)-derivative that the 4-alkylamide is replaced by piperazine and pharmacy acceptable salt are the salt that the organic acids such as the salt that forms such as formula (1) compound and nitric acid, sulfuric acid, hydrogen bromide, hydrogen iodide, phosphoric acid or toxilic acid, fumaric acid, citric acid, oxalic acid, tartrate form.Preferably maleate and fumarate.
According to the present invention, another preferred embodiment, provides a kind of compound and preparation method who is meaned by formula (2):
Chloroacetyl chloride and R reaction preparation are obtained formula (2) compound in organic solvent, and reaction solvent comprises water, methylene dichloride, chloroform, acetone, normal hexane, hexanaphthene, sherwood oil, toluene, benzene, ether, ethyl acetate etc.First-selected methylene dichloride.
In formula, NH-R is
According to the present invention, another preferred embodiment, provides a kind of compound and preparation method who is meaned by formula (3):
Formula (2) compound and piperazine or piperazine list salt react the formula that obtains (3) compound in solvent.
Reaction solvent comprises water, methylene dichloride, chloroform, acetone, normal hexane, hexanaphthene, sherwood oil, toluene, benzene, ether, ethyl acetate etc., first-selected water.
In formula, NH-R is
According to the present invention, another preferred embodiment, provides a kind of compound meaned by formula (1) and the preparation method of pharmacy acceptable salt:
The preparation of formula (1) compound is by formula (3) compound and 3,4,5-trimethoxy cinnamyl chloride, and under the existence of de-acidying agent alkali, reaction obtains for the reaction of feature.Reaction solvent comprises water, methylene dichloride, chloroform, acetone, normal hexane, hexanaphthene, sherwood oil, toluene, benzene, ether, ethyl acetate etc., first-selected methylene dichloride.
In formula, NH-R is
The salt that the organic acids such as the salt that formula (1) compound and pharmacy acceptable salt are the formation such as nitric acid, sulfuric acid, hydrogen bromide, hydrogen iodide, phosphoric acid or toxilic acid, fumaric acid, citric acid, oxalic acid wine, stone acid etc. form.Preferably toxilic acid and fumarate.
According to the present invention, another preferred embodiment, provides a kind of cardiovascular and cerebrovascular diseases medicine, and said a kind of cardiovascular and cerebrovascular diseases medicine has and at least is no less than the described compound of a kind of claim (1) as effective constituent.
The maleate that the compound 1-compound that (3,4,5-trimethoxy cinnamoyl)-the 4-alkylamide is replaced by piperazine and pharmacology are allowed and the manufacture method of hydrochloride.
More specifically, the compounds of this invention is as shown in following general formula:
In formula, R is as hereinbefore, and 1-(3,4,5-trimethoxy cinnamoyl)-4-alkylamide is replaced by piperazine and pharmacy acceptable salt etc.
In formula of the present invention (2) compound, NH-R means that amido is as cyclopropylamine, cyclopentamine, phenylethylamine, piperidines, bicyclo-propyl methylamine.More than in preparation process, the equivalence ratio of the consumption of chloroacetyl chloride and NH-R is no less than 1 equivalent, preferably 1.01～1.3 equivalents react in anhydrous solution medium, and the organic solvent of use is as ethanol, ether, toluene, chloroform, methylene dichloride, benzene, ethyl acetate etc.
In the preparation of formula of the present invention (3) compound, more than the equivalence ratio of the consumption of piperazine and formula (2) compound is no less than 1 equivalent, piperazine, than formula (2) compound, is preferably 2-3 equivalent.The organic solvent used is as water, ethanol, ether, toluene, chloroform, methylene dichloride, benzene, ethyl acetate etc.Room temperature, to back flow reaction, preferably refluxes.
The represented pharmacy acceptable salt of general expression shown in front of the present invention (1) is as salt that the organic acids such as the salt that nitric acid, sulfuric acid, hydrogen bromide, hydrogen iodide, phosphoric acid etc. form or toxilic acid, fumaric acid, citric acid, oxalic acid wine, stone acid form.Preferably maleate and fumarate.
The present invention is derivative and the preparation method that 1-shown in aforementioned new compound general expression (1) (3,4,5-trimethoxy cinnamoyl)-4-alkylamide piperazine replaces.
The preparation of formula of the present invention (1) compound, relative type motor (3) compound 1-alkane amide piperazidine thing and 3, more than the consumption of its halides of reaction of 4,5-trimethoxy cinnamic acid halides is no less than 1 equivalent, preferably 1.01～1.3 equivalents react in anhydrous solution medium.
The organic solvent that the present invention uses is as ethanol, ether, toluene, chloroform, methylene dichloride, benzene, ethyl acetate etc.De-acidying agent used in the present invention as triethylamine, pyridine, sodium carbonate, sodium bicarbonate, etc.Temperature of reaction is that room temperature is to backflow, preferably room temperature.
This reacts raw materials used formula (2) compound 1-alkane amide piperazidine thing and also has other new compounds, and its preparation method is as reference example J.Heterocyclic.Chem, and 31,297 (1994).The Journal oforganin chemistry.16,1283 (1951) also the record react preparation with 3-chlorine propionic acid amide.
The preparation method of intermediate new compound type of the present invention (3) can be with reference to US.4, and 278,796.
Compared with prior art, the present invention has following obvious advantage:
Formula of the present invention (1) compound is the outstanding expander to brain, tip, coronary vasodilator, and the present invention is medically strengthening drug effect and reducing aspect side effect very effective.
Formula (1) compound has wonderful cardiovascular and cerebrovascular diseases effect, for calcium ion channel blocker, by stoping in Ca2+ cross-film intravasation smooth muscle cell, make vascular smooth muscle relaxation, the cerebrovascular, coronary vasodilator and peripheral blood vessel expansion, thus the alleviating vascular spasm, reduce vascular resistance, increase volume of blood flow.
Formula (1) compound can strengthen the effect of adenosine and cyclic monophosphate (cAMP), reduces the oxygen consumption.This product can suppress the cAMP phosphodiesterase, and cAMP quantity is increased.
Formula (1) compound can also improve erythrocytic snappiness and deformability, improves it by the ability of minute blood vessel, reduces the viscosity of blood, improves microcirculation.
Formula of the present invention (1) compound has strong vasorelaxation action and anticoagulant drug effect.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Be not used in and limit the scope of the invention but these embodiment only limit to the present invention is described.The experimental technique of unreceipted concrete experiment condition in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
the chloro-N-cyclopropyl of embodiment 1:2-ethanamide
By cyclopropylamine 15 grams, 60 milliliters of mixing of toluene, under stirring, chloroacetyl chloride 18 grams and 120 milliliters of mixed solutions of toluene are splashed in cyclopropylamine solution, dropwise, room temperature reaction one hour, leach solid, and filtrate is concentrated into dry, ethyl alcohol recrystallization, obtain colourless crystallization 12.74 grams.Fusing point: 82-84 ℃.
embodiment 2:1-(cyclopropylamine ethanoyl) piperazine
After piperazine 13.1 grams, 70 milliliters of distilled water, 25 milliliters of mixing of concentrated hydrochloric acid, stir 10 minutes, add afterwards the chloro-N-cyclopropyl of 16.2 gram 2-ethanamide, 60 ℃ are reacted 2 hours, react in the complete 5%NaOH of using and PH9, use chloroform extraction, drying, steaming obtains colourless crystallization except solvent.The sherwood oil recrystallization, obtain colourless crystallization 12 grams.Fusing point 80-82 ℃.
Hydrogen spectrum detected result:
Solvent: deuterochloroform
Cyclopropyl δ 0.446～0.486ppm, m, 2H (J=7.2HZ) δ 0.733～0.781ppm, m, 2H (J=7.2HZ) δ 2.668～2.713ppm, m, 1H (J=7.2HZ)
Piperazinyl δ 2.420～2.443ppm, t, 4H (J=4.8HZ) δ 2.845～2.869ppm, t, 4H (J=4.8HZ) δ 2.085ppm, s, 1H
Acetyl CH
2δ 2.914ppm, s, 2H
Acylamino hydrogen δ 7.110ppm, s, 1H.
embodiment 3:1-(3,4,5-trimethoxy cinnamoyl)-4-(cyclopropylamine ethanoyl) piperazine
Product 5.5 grams that obtained by embodiment 2 and triethylamine 3.0 grams and 60 milliliters of solution that form of methylene dichloride are added to 3,4,5-trimethoxy cinnamic acid muriate is (by 3,4,5-trimethoxy cinnamic acid 5.36 grams and thionyl chloride 25.6 restrained standby) and 10 milliliters of methylene dichloride among, room temperature reaction 2 hours.React the complete water that adds, water layer adds sodium carbonate and chloroform extraction, the extracting solution drying, and steaming obtains colorless solid except solvent.Ethanol-Acetic Acid ethyl ester recrystallization obtains colourless crystallization 6.2 grams.
Fusing point: 194-196 ℃.
Hydrogen spectrum detected result:
Solvent: deuterated methanol
Cyclopropyl δ 0.514～0.554ppm, m, 2H (J=7.2HZ) δ 0.717～0.765ppm, m, 2H (J=7.2HZ) δ 2.651～2.707ppm, m, 1H (J=7.2HZ)
Piperazinyl δ 2.535ppm, s, 4H δ 3.684ppm, s, 2H δ 3.829ppm, s, 2H
Acetyl CH
2δ 3.025ppm, s, 2H
4-methoxyl group δ 3.777ppm, s, 3H
3,5-dimethoxy δ 3.867ppm, s, 6H
Phenyl ring hydrogen δ 6.935ppm, s, 2H
Trans double bond δ 7.053～7.091ppm, d, 1H (J=15.2HZ) δ 7.470～7.508ppm, d, 1H (J=15.2HZ).
embodiment 4:1-(3,4,5-trimethoxy cinnamoyl)-4-(cyclopropylamine ethanoyl) piperazine toxilic acid
salt
1-(3; 4; 5-trimethoxy cinnamoyl)-4-(cyclopropylamine ethanoyl) piperazine 2.3 grams are dissolved in 11 milliliters of dehydrated alcohols; toxilic acid 1.0 grams are dissolved in 4 milliliters of dehydrated alcohols, by 1-(3,4; 5-trimethoxy cinnamoyl)-4-(cyclopropylamine ethanoyl) piperazine solution is added in maleic acid solution; room temperature is standing, and crystallization filters and obtains colourless crystallization 3.0 grams.
Fusing point: 86-89 ℃
Hydrogen spectrum detected result:
Solvent: deuterated methanol
Cyclopropyl δ 0.514～0.554ppm, m, 2H (J=7.2HZ) δ 0.732～0.780ppm, m, 2H (J=7.2HZ) δ 2.701～2.737ppm, m, 1H (J=7.2HZ)
[δ 1.150～1.185ppm and δ 3.570～3.623ppm are the alcohol solvent peak]
Piperazinyl δ 3.085ppm, s, 4H δ 3.908～3.960ppm, m, 4H
Acetyl CH2 δ 3.584ppm, s, 2H
4-methoxyl group δ 3.782ppm, s, 3H
3,5-dimethoxy δ 3.869ppm, s, 6H
Phenyl ring hydrogen δ 6.951ppm, s, 2H
Trans double bond δ 7.062～7.101ppm, d, 1H (J=15.2HZ) δ 7.519～7.557ppm, d, 1H (J=15.2HZ)
Toxilic acid δ 6.263ppm, s, 2H.
the chloro-N-cyclopentyl of embodiment 5:2-ethanamide
By cyclopentamine 17 grams, 60 milliliters of mixing of toluene, under stirring, chloroacetyl chloride 18 grams and 120 milliliters of reference examples 1 of toluene are obtained to colourless crystallization 12.74 grams.Fusing point: 80-82 ℃.
embodiment 6:1-(cyclopentamine ethanoyl) piperazine
Piperazine 13.1 grams, 85 milliliters of distilled water, 32 milliliters of concentrated hydrochloric acids, the chloro-N-cyclopentyl of 16.4 gram 2-ethanamide, reference example 2, colourless crystallization 16.2 grams.
Fusing point 64-66 ℃
Hydrogen spectrum detected result:
Solvent: deuterochloroform
Cyclopentyl δ 1.320～1.401ppm, m, 2H δ 1.548～1.692ppm, m, 4H δ 1.91701～1.978ppm, m, 2H δ 4.149～4.236ppm, m, 1H (J=6.8HZ)
Piperazinyl δ 2.442～2.466ppm, s, 4H (J=4.8HZ) δ 2.864～2.889ppm, s, 4H (J=4.8HZ) δ 2.184ppm, s, 1H
Acetyl CH
2δ 2.936ppm, s, 2H
Acylamino hydrogen δ 7.024ppm, s, 1H.
embodiment 7:1-(3,4,5-trimethoxy cinnamoyl)-4-(cyclopentamine ethanoyl) piperazine
Product 7.7 grams that embodiment 6 obtains, triethylamine 4.0 grams, 3,4,5-trimethoxy cinnamic acid muriate (restraining standby by 3,4,5-trimethoxy cinnamic acid, 7.36 grams and thionyl chloride 15.6) reference example 3 obtains colorless solid.Ethanol-Acetic Acid ethyl ester recrystallization obtains colourless crystallization 4.28 grams.
Fusing point: 164-166 ℃
Hydrogen spectrum detected result:
Solvent: deuterochloroform
Cyclopentyl δ 1.347～1.394ppm, m, 2H (J=6.8HZ) δ 1.565～1.684ppm, m, 4H (J=6.8HZ) δ 1.917～1.998ppm, m, 2H (J=6.8HZ) δ 4.178～4.231ppm, m, 1H (J=6.8HZ)
Piperazinyl δ 2.551ppm, s, 4H δ 3.695ppm, s, 4H
Acetyl CH
2δ 3.008ppm, s, 2H
4-methoxyl group δ 3.833ppm, s, 3H
3,5-dimethoxy δ 3.852ppm, s, 6H
Phenyl ring hydrogen δ 6.695ppm, s, 2H
Trans double bond δ 6.673～6.711ppm, d, 1H (J=15.2HZ) δ 7.531～7.570ppm, d, 1H (J=15.2HZ)
Acylamino hydrogen δ 6.925ppm, s broad peak, 1H.
embodiment 8:1-(3,4,5-trimethoxy cinnamoyl)-4-(cyclopentamine ethanoyl) piperazine toxilic acid
salt
1-(3,4,5-trimethoxy cinnamoyl)-4-(cyclopentamine ethanoyl) piperazine 3.0 gram toxilic acid 1.0 gram reference examples 4 obtain colourless crystallization 2.82 grams.
Fusing point: 96-99 ℃
Hydrogen spectrum detected result:
Solvent: deuterated methanol
Cyclopentyl δ 1.437～1.518ppm, m, 2H (J=6.8HZ) δ 1.583～1.641ppm, m, 2H (J=6.8HZ) δ 1.645～1.745ppm, m, 2H (J=6.8HZ) δ 1.904～1.984ppm, m, 2H (J=6.8HZ) δ 4.124～4.191ppm, m, 1H (J=6.8HZ)
Piperazinyl δ 3.164ppm, s, 4H δ 4.970ppm, s broad peak, 4H
Acetyl CH
2δ 3.667ppm, s, 2H
4-methoxyl group δ 3.781ppm, s, 3H
3,5-dimethoxy δ 3.867ppm, s, 6H
Phenyl ring hydrogen δ 6.949ppm, s, 2H
Trans double bond δ 7.063～7.101ppm, d, 1H (J=15.2HZ) δ 7.521～7.559ppm, d, 1H (J=15.2HZ)
Toxilic acid δ 6.258ppm, s, 2H.
the chloro-N-styroyl of embodiment 9:2-ethanamide
By phenylethylamine 9.7 grams, chloroacetyl chloride 13 grams, reference example 1 obtains colourless crystallization 4.18 grams.
Fusing point: 67-68 ℃.
embodiment 10:1-(phenylethylamine ethanoyl) piperazine
After piperazine 6.2 grams, 40 milliliters of distilled water, 12.9 milliliters of mixing of concentrated hydrochloric acid, the chloro-N-styroyl of 7.9 gram 2-ethanamide, reference example 2, obtain colourless crystallization 9.3 grams.
Fusing point 68-69 ℃
Hydrogen spectrum detected result:
Solvent: deuterochloroform
Piperazine δ 2.328～2.351ppm, t, 4H (J=4.8HZ) δ 2.713～2.737ppm, t, 4H (J=4.8HZ) δ 2.002ppm, s, 1H
Ph-CH
2 δ2.800～2.834ppm，t，2H(J＝6.8HZ)
HN-CH
2 δ3.526～3.575ppm，q，2H(J＝6.8HZ)
O=C-NH δ 7.130ppm, s, 1H acetyl CH22.892, s, 2H
Phenyl ring hydrogen δ 7.165～7.299ppm, m, 5H.
embodiment 11:1-(3,4,5-trimethoxy cinnamoyl)-4-(phenylethylamine ethanoyl) piperazine
Embodiment 10 product 6.18 grams and triethylamine 4.0 grams and 3,4,5-trimethoxy cinnamic acid muriate (by 3,4,5-trimethoxy cinnamic acid, 6.36 grams and thionyl chloride 15.6, restraining standby), reference example 3 obtains colourless crystallization 3.28 grams.
Fusing point: 152-153 ℃
Hydrogen spectrum detected result:
Solvent: deuterated methanol
Piperazine δ 2.397～2.464ppm, two broad peaks, 4H δ 3.623～3.734ppm, two broad peaks, 4HPh-CH
2δ 2.825～2.861ppm, t, 2H (J=7.2HZ)
HN-CH
2 δ3.497～3.532ppm，t，2H(J＝7.2HZ)
Acetyl CH
2δ 2.984, s, 2H
3,5-dimethoxy δ 3.869ppm, s, 6H
Phenyl ring hydrogen δ 7.181～7.312ppm, m, 5H
4-methoxyl group δ 3.779ppm, s, 3H
Trimethoxy phenyl ring δ 6.937ppm, s, 2H
Trans double bond δ 7.035～7.073ppm, d, 1H (J=15.6HZ) δ 7.469～7.508ppm, d, 1H (J=15.6HZ).
embodiment 12:1-(3,4,5-trimethoxy cinnamoyl)-4-(phenylethylamine ethanoyl) piperazine Malaysia
hydrochlorate
1-(3,4,5-trimethoxy cinnamoyl)-4-(phenylethylamine ethanoyl) piperazine 2.75 gram toxilic acid 0.7 gram reference examples 4 obtain colourless crystallization 3.1 grams.
Fusing point: 138-140 ℃
Hydrogen spectrum detected result:
Solvent: deuterated methanol
Piperazine δ 2.943ppm, broad peak, 4H δ 3.870ppm, broad peak (with the methoxyl group peak overlapping), 4H
Ph-CH
2 δ2.818～2.853ppm，t，2H(J＝7.2HZ)
HN-CH
2δ 3.505～3.537ppm, t, 2H (J=7.2HZ) (with acetyl CH2 peak overlapping)
Acetyl CH
2δ 3.505, s, 2H
3,5-dimethoxy δ 3.870ppm, s, 6H
Phenyl ring hydrogen δ 7.179～7.306ppm, m, 5H
4-methoxyl group δ 3.806ppm, s, 3H
Trimethoxy phenyl ring δ 6.952ppm, s, 2H
Toxilic acid δ 6.267ppm, s, 2H
Trans double bond δ 7.053～7.092ppm, d, 1H (J=15.6HZ) δ 7.515～7.554ppm, d, 1H (J=15.6HZ).
the chloro-N-piperidyl of embodiment 13:2-ethanamide
By piperidinyl-1 7.4 grams, 40 milliliters of mixing of toluene, under stirring, chloroacetyl chloride 18 grams and 60 milliliters of mixed solutions of toluene are splashed in piperidine solution, reference example 1 obtains light brown oily thing 25.14 grams.Boiling point 128-131 ℃/6mmHg
embodiment 14:1-(piperidines ethanoyl) piperazine
After piperazine 15.1 grams, 150 milliliters of distilled water, 42 milliliters of mixing of concentrated hydrochloric acid, stir 10 minutes, add afterwards 25.14 gram 2-chlorine N-piperidyl ethanamides, reference example 2 obtains colourless crystallization 12 grams.
Fusing point 64-66 ℃
Hydrogen spectrum detected result:
Solvent: deuterochloroform
Piperidyl: δ 1.475～1.532ppm, m, 4H δ 1.566～1.610ppm, m, 2H δ 3.436～3.492ppm, m, 4H
Piperazinyl: δ 2.422～2.433ppm, t, 4H (J=4.8HZ) δ 2.840～2.864ppm, t, 4H (J=4.8HZ) δ 2.128ppm, s, 1H (N-H)
Ethanoyl CH
2δ 3.096ppm, s, 2H.
embodiment 15:1-(3,4,5-trimethoxy cinnamoyl)-4-(piperidines ethanoyl) piperazine
Be added to 3 by embodiment 14 product 8.45 grams and triethylamine 2.0 grams and 29 milliliters of solution that form of methylene dichloride, 4,5-trimethoxy cinnamic acid muriate is (by 3,4,5-trimethoxy cinnamic acid 9.36 grams and thionyl chloride 15.6 restrained standby) and 10 milliliters of methylene dichloride among, reference example 3 obtains colourless crystallization 14.2 grams.
Fusing point: 170-172 ℃
Hydrogen spectrum detected result:
Solvent: deuterated methanol
Piperidyl: δ 1.533～1.543ppm, m, 2H δ 1.609～1.618ppm, m, 2H δ 1.647～1.673ppm, m, 2H δ 3.512～3.551ppm, m, 4H
Piperazinyl: δ 2.542ppm, broad peak, 4H δ 3.714～3.734ppm, m, 2H δ 3.775ppm, (with 4-methoxyl group peak overlapping), 2H
4-methoxyl group δ 3.775ppm, s overlapping (with the piperazine base peak), 3H,
3,5 dimethoxy δ 3.865ppm, s, 6H,
Ethanoyl CH
2δ 3.253ppm, s, 2H,
Phenyl ring hydrogen δ 6.936ppm, s, 2H
Trans double bond hydrogen δ 7.059～7.090ppm, d, 1H (J=15.6HZ) δ 7.469～7.508ppm, d, 1H (J=15.6HZ).
embodiment 16:1-(3,4,5-trimethoxy cinnamoyl)-4-(piperidines ethanoyl) piperazine toxilic acid
salt
1-(3,4,5-trimethoxy cinnamoyl)-4-(piperidines ethanoyl) piperazine 2.37 grams, toxilic acid 0.7 gram reference example 4 obtains colourless crystallization .2.7 gram.
Fusing point: 156-157.5 ℃
Hydrogen spectrum detected result:
Solvent: deuterated methanol
Piperidyl: δ 1.570～1.598ppm, m, 2H δ 1.625～1.634ppm, m, 2H δ 1.681～1.692ppm, m, 2H δ 3.376～3.403ppm, m, 2H δ 3.561～3.588ppm, m, 2H
Piperazinyl: δ 3.300ppm, broad peak, 4H (overlapping with the deuterated methanol solvent peak) δ 4.021ppm, m, 4H
4-methoxyl group δ 3.785ppm, s, 3H
3,5 dimethoxy δ 3.873ppm, s, 6H
Toxilic acid δ 6.249ppm, s, 2H
Ethanoyl CH2 δ 4.115ppm, S, 2H
Phenyl ring hydrogen δ 6.962ppm, s, 2H
Trans double bond hydrogen δ 7.079～7.118ppm, d, 1H (J=15.6HZ) δ 7.544～7.582ppm, d, 1H (J=15.6HZ).
the chloro-N-bicyclo-propyl of embodiment 17:2-methylacetamide
By bicyclo-propyl methylamine 25 grams, chloroacetyl chloride 22 grams, reference example 1 obtains colourless crystallization 33.02 grams.Fusing point: 119-121 ℃
embodiment 18:1-(bicyclo-propyl methylamine ethanoyl) piperazine
Piperazine 6.88 grams, the chloro-N-bicyclo-propyl of 9.4 gram 2-methylacetamide, reference example 2 obtains colourless crystallization 12 grams.
Fusing point 63-65 ℃
Hydrogen spectrum detected result:
Solvent: deuterochloroform
Bicyclo-propyl δ 0.237～0.397ppm, m, 4H (J=7.6HZ) δ 0.346～0.397ppm, m, 2H (J=7.6HZ) δ 0.455～0.506ppm, m, 2H (J=7.6HZ) δ 0.849～0.934ppm, m, 2H (J=7.6HZ)
Methyne δ 3.043～3.104ppm, q, 1H (J=7.6HZ)
Piperazinyl δ 2.473～2.496ppm, t, 4H (J=4.8HZ) δ 2.984～2.918ppm, t, 4H (J=4.8HZ) δ 2.128ppm, s, 1H (hydrogen on piperazine nitrogen)
Acetyl CH
2δ 2.945ppm, s, 2H
Acylamino hydrogen δ 7.082～7.102ppm, d, 1H (J=8.0HZ).
embodiment 19:1-(3,4,5-trimethoxy cinnamoyl)-4-(bicyclo-propyl methylamine ethanoyl) piperazine
piperazine
Obtain light brown oily thing 3.8 grams by embodiment 18 product 5.93 grams and triethylamine 1.25 grams and 3,4,5-trimethoxy cinnamic acid muriate (restraining standby by 3,4,5-trimethoxy cinnamic acid, 5.36 grams and thionyl chloride 25.6) reference example 3.
Hydrogen spectrum detected result:
Solvent: deuterated methanol
Bicyclo-propyl δ 0.241～0.344ppm, m, 4H δ 0.371～0.433ppm, m, 2H δ 0.509～0.573ppm, m, 2H δ 0.991～1.065ppm, m, 2H
Methyne δ 2.877～2.918ppm, t, 1H (J=8.0HZ)
Piperazinyl δ 2.587ppm, s, 4H δ 3.780～3.842ppm, d, 4H (with the methoxyl group peak overlapping)
Acetyl CH
2δ 3.070ppm, s, 2H
4-methoxyl group δ 3.780ppm, s, 3H
3,5-dimethoxy δ 3.873ppm, s, 6H
Trimethoxy phenyl ring hydrogen δ 6.947ppm, s, 2H
Trans double bond δ 7.073～7.111ppm, d, 1H (J=15.2HZ) δ 7.483～7.522ppm, d, 1H (J=15.2HZ).
embodiment 20:1-(3,4,5-trimethoxy cinnamoyl)-4-(bicyclo-propyl methylamine ethanoyl) piperazine
the piperazine maleate
1-(3,4,5-trimethoxy cinnamoyl)-4-(bicyclo-propyl methylamine ethanoyl) piperazine 3.8 gram toxilic acid 1.0 gram reference examples 4 obtain colourless crystallization 3.7 grams.
Fusing point: 162-164 ℃
Hydrogen spectrum detected result:
Solvent: deuterated methanol
Bicyclo-propyl δ 0.275～0.339ppm, m, 4H δ 0.351～0.434ppm, m, 2H δ 0.522～0.577ppm, m, 2H δ 0.970～1.031ppm, m, 2H
Methyne δ 2.917～2.957ppm, t, 1H (J=8.0HZ)
Piperazinyl δ 3.128ppm, s, 4H δ 3.961ppm, s, 4H
Acetyl CH
2δ 3.660ppm, s, 2H
4-methoxyl group δ 3.782ppm, s, 3H
3,5-dimethoxy δ 3.870ppm, s, 6H
Toxilic acid δ 6.263ppm, s, 2H
Trimethoxy phenyl ring hydrogen δ 6.953ppm, s, 2H
Trans double bond δ 7.070～7.108ppm, d, 1H (J=15.2HZ) δ 7.524～7.563ppm, d, 1H (J=15.2HZ).
embodiment 21: the compounds of this invention is to the in vitro carotid diastole effect research of rabbit
The present embodiment provides typical compound of the present invention to the in vitro carotid diastole effect of rabbit.
Wherein, the concrete structure of 3#>6#>tetra-kinds of samples of 1#>4# is as follows:
The maleate that the 1# structure is the following formula structure:
The maleate that the 3# structure is the following formula structure:
The maleate that the 4# structure is the following formula structure:
6# is contrast medicine Cinepazide Maleate.
The IC of above-mentioned four kinds of compounds to the in vitro carotid diastole effect of rabbit
50size is 3#>6#>1#>4#, and this is also four kinds of orders that sample vasodilator effect grows from weak to strong.Wherein the 3# effect is equivalent to contrast 67% of medicine Cinepazide Maleate (6#), and 1#, 4# are equivalent to respectively 1.2 and 1.3 times of reference substance.
Table Cinepazide Maleate and homologue thereof are to the in vitro carotid diastole effect of rabbit (x ± s, n=5, unit: %)
| Final concentration (mol/L) | 0.0003 | 0.001 | 0.003 | 0.01 | 0.03 | IC 50(mol/L) |
| 1# | 9.3± 4.1 | 20.7± 7.7 | 43.5± 14.2 | 71.7± 13.7 | 95.4± 3.3 | 0.00337 |
| 3# | 5.8± 3.8 | 18.2± 7.2 | 38.8± 18.3 | 59.2± 18.6 | 74.1± 9.5 | 0.00613 |
| 4# | 14.9± 7.3 | 28.5± 9.2 | 47.0± 14.9 | 69.0± 15.8 | 87.6± 9.7 | 0.00318 |
| 6# | 8.2± 4.8 | 20.6± 6.9 | 41.7± 11.8 | 66.2± 4.4 | 87.3± 8.2 | 0.00409 |
Claims (18)
1. one kind as shown in the formula the 1-(3 shown in (1), 4,5-trimethoxy cinnamoyl)-4-alkylamide derivative compound or its pharmacy acceptable salt:
In formula, Me is methyl, and NH-R is selected from:
2. compound according to claim 1, wherein, the acid salt that described pharmacy acceptable salt is formula (1) compound.
3. compound according to claim 2, wherein, described acid salt is nitrate, vitriol, hydrobromate, hydriodate, phosphoric acid salt, maleate, fumarate, Citrate trianion, oxalate or tartrate.
4. compound according to claim 2, wherein, described acid salt is maleate or fumarate.
5. a method for preparing the described compound of any one in claim 1-4, wherein, described method comprises by formula (3) compound and 3,4,5-trimethoxy cinnamyl chloride, and under the existence of de-acidying agent, reaction obtains formula (1) compound, and synthetic route is as follows:
Wherein, Me means methyl,
Substituent R in formula (1), (3) is selected from
with
temperature of reaction is that room temperature is to refluxing.
6. method according to claim 5, wherein, described temperature is room temperature.
7. method according to claim 5, wherein, the reaction solvent of described reaction is selected from: water, methylene dichloride, chloroform, acetone, normal hexane, hexanaphthene, sherwood oil, toluene, benzene, ether, ethanol, ethyl acetate and composition thereof.
8. method according to claim 7, wherein, the reaction solvent of described reaction is anhydrous solvent.
9. method according to claim 7, wherein, the reaction solvent of described reaction is methylene dichloride.
10. method according to claim 5, wherein, two kinds of reactants: the mole dosage proportioning of 3,4,5-trimethoxy cinnamic acid halides and formula (3) compound 1-alkane amide piperazidine thing in described reaction system is 1.01:1～1.3:1.
11., according to the described method of any one in claim 5-9, wherein, the de-acidying agent used is selected from: triethylamine, pyridine, sodium carbonate and sodium bicarbonate.
12., according to the described method of any one in claim 5-9, wherein, described formula (3) compound is by with following formula: compound (2) and piperazine or piperazine list salt, in solvent, reacting and obtain:
Wherein, substituent R is selected from
with
Described reaction solvent is selected from: water, methylene dichloride, chloroform, acetone, normal hexane, hexanaphthene, sherwood oil, toluene, benzene, ether and ethyl acetate.
13. method according to claim 12, wherein, described reaction solvent is water.
14. method according to claim 12, wherein, described formula (2) compound is by chloroacetyl chloride and NH
2-R reaction preparation is obtained in solvent:
Wherein, substituent R is selected from
with
Described reaction solvent is selected from: water, methylene dichloride, chloroform, acetone, normal hexane, hexanaphthene, sherwood oil, toluene, benzene, ether and ethyl acetate.
15. method according to claim 14, wherein, described reaction solvent is methylene dichloride.
16. a pharmaceutical composition that is used for the treatment of cardiovascular and cerebrovascular diseases, is characterized in that, described composition comprises: 1) the described compound of any one or its pharmacy acceptable salt in claim 1-4; With 2) pharmaceutically acceptable carrier.
17. in claim 1-4, the described compound of any one or its pharmacy acceptable salt are for the preparation of the treatment cardiovascular and cerebrovascular diseases and/or for expanding brain, tip, coronary vasodilator and/or anticoagulation and/or strengthening adenosine and the application of the medicine of cyclic monophosphate effect.
18. one kind as shown in the formula the 1-alkane amide piperazidine midbody compound shown in (3):
Wherein, R is selected from
with
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| US4029650A (en) * | 1974-11-20 | 1977-06-14 | Delalande S. A. | Novel derivatives of N-(3,4,5-trimethoxy cinnamoyl)piperazine and the process for preparing them |
| CN101155784A (en) * | 2005-03-16 | 2008-04-02 | 霍夫曼-拉罗奇有限公司 | Cis-2,4,5-triaryl-imidazolines and their use as anti-cancer medicaments |
| CN101365699A (en) * | 2004-12-30 | 2009-02-11 | 4阿扎Ip股份有限公司 | Pyrido(3,2-D)pyrimidines and pharmaceutical compositions useful for medical treatment |
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| FR2522325B1 (en) * | 1982-02-26 | 1985-08-09 | Delalande Sa | NOVEL ARYLIC DERIVATIVES OF PIPERAZINE, HOMOPIPERAZINE AND N, N'-DIALKYL DIAMINO-1,2 ETHANE, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION |
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| US4029650A (en) * | 1974-11-20 | 1977-06-14 | Delalande S. A. | Novel derivatives of N-(3,4,5-trimethoxy cinnamoyl)piperazine and the process for preparing them |
| CN101365699A (en) * | 2004-12-30 | 2009-02-11 | 4阿扎Ip股份有限公司 | Pyrido(3,2-D)pyrimidines and pharmaceutical compositions useful for medical treatment |
| CN101155784A (en) * | 2005-03-16 | 2008-04-02 | 霍夫曼-拉罗奇有限公司 | Cis-2,4,5-triaryl-imidazolines and their use as anti-cancer medicaments |
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