CN101906085A - 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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- CN101906085A CN101906085A CN2009100691314A CN200910069131A CN101906085A CN 101906085 A CN101906085 A CN 101906085A CN 2009100691314 A CN2009100691314 A CN 2009100691314A CN 200910069131 A CN200910069131 A CN 200910069131A CN 101906085 A CN101906085 A CN 101906085A
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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 use 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 highest No.1 killer of the human dead cause of disease, also is " the noiseless demon " of health of people!
Cardiovascular and cerebrovascular diseases has the characteristics of " sickness rate height, disability rate height, mortality ratio height, recurrence rate height, complication is many "-" four is high by more than one ",
Cardiovascular and cerebrovascular diseases is the present primary dead cause of disease, is the 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.
The drug effect of at present a lot of vasodilators and side effect remain 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 to be used for the treatment of cardiovascular and cerebrovascular diseases and/or to be used for expanding brain, tip, coronary vasodilator and/or anticoagulation and/or the application of the medicine of the effect of enhancing adenosine and cyclic monophosphate (cAMP) in preparation.
At 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:
Me is a methyl in the formula, and NH-R is selected from:
Preferably, according to foregoing compound, wherein, described pharmacy acceptable salt is the acid salt of formula (1) compound, is 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, and reaction obtains formula (1) compound in the presence of de-acidying agent, and synthetic route is as follows:
Wherein:
Me represents 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: 3,4, the mole dosage proportioning of 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, employed de-acidying agent is selected from: triethylamine, pyridine, yellow soda ash and sodium bicarbonate.
Preferably, according to method of the present invention, wherein, described formula (3) compound obtains by reacting in solvent with following formula (2) compound and piperazine or piperazine list salt:
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 prepared in reaction obtains 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 acceptable carrier.
On the other hand, the invention provides described compound or its pharmacy acceptable salt is used for the treatment of cardiovascular and cerebrovascular diseases and/or is used for expanding brain, tip, coronary vasodilator and/or anticoagulation and/or the application of the medicine of the effect of enhancing adenosine and cyclic monophosphate (cAMP) in preparation.
On the one hand, the invention provides a kind of again as shown in the formula the 1-alkane amide piperazidine midbody compound shown in (3):
Wherein, Me represents methyl, and R is selected from
According to the present invention one preferred embodiment, a kind of compound and pharmacy acceptable salt and preparation method thereof by formula (1) expression is provided.
NH-R is in the formula
NH-R is in the formula
1-(3; 4,5-trimethoxy cinnamoyl)-derivative that the 4-alkylamide is replaced by piperazine and pharmacy acceptable salt are the salt that 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.
Another preferred embodiment provides a kind of compound and preparation method by formula (2) expression according to the present invention:
Chloroacetyl chloride and R prepared in reaction obtain formula (2) compound in organic solvent, reaction solvent comprises water, methylene dichloride, chloroform, acetone, normal hexane, hexanaphthene, sherwood oil, toluene, benzene, ether, ethyl acetate etc.First-selected methylene dichloride.
NH-R is in the formula
Another preferred embodiment provides a kind of compound and preparation method by formula (3) expression according to the present invention:
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.
NH-R is in the formula
Another preferred embodiment provides a kind of by the compound of formula (1) expression and the preparation method of pharmacy acceptable salt according to the present invention:
The preparation of formula (1) compound is by formula (3) compound and 3,4,5-trimethoxy cinnamyl chloride, and reaction obtains for the reaction of feature in the presence of de-acidying agent alkali.Reaction solvent comprises water, methylene dichloride, chloroform, acetone, normal hexane, hexanaphthene, sherwood oil, toluene, benzene, ether, ethyl acetate etc., first-selected methylene dichloride.
NH-R is in the formula
Formula (1) compound and pharmacy acceptable salt are the salt that organic acids such as the salt that forms 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.
Another preferred embodiment provides a kind of cardiovascular and cerebrovascular diseases medicine according to the present invention, and said a kind of cardiovascular and cerebrovascular diseases medicine has and is no less than the described compound of a kind of claim (1) at least as effective constituent.
The maleate that compound that compound 1-(3,4,5-trimethoxy cinnamoyl)-4-alkylamide is replaced by piperazine and pharmacology are allowed and the manufacture method of hydrochloride.
More specifically, The compounds of this invention is shown in following general formula:
R is as hereinbefore in the formula, and 1-(3,4,5-trimethoxy cinnamoyl)-4-alkylamide is replaced by piperazine and pharmacy acceptable salt etc.
NH-R represents amido such as cyclopropylamine, cyclopentamine, phenylethylamine, piperidines, bicyclo-propyl methylamine in formula of the present invention (2) compound.The equivalence ratio of the consumption of chloroacetyl chloride and NH-R is no less than more than 1 equivalent in the preparation process, and preferably 1.01～1.3 equivalents react in anhydrous solution medium, the organic solvent of use such as ethanol, ether, toluene, chloroform, methylene dichloride, benzene, ethyl acetate etc.
In the preparation of formula of the present invention (3) compound, the equivalence ratio of the consumption of piperazine and formula (2) compound is no less than more than 1 equivalent, and piperazine is preferably 2-3 equivalent than formula (2) compound.Organic solvent that uses such as water, ethanol, ether, toluene, chloroform, methylene dichloride, benzene, ethyl acetate etc.Room temperature preferably refluxes to back flow reaction.
The represented pharmacy acceptable salt of general expression shown in the front of the present invention (1) is as salt that organic acids such as 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 the 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 formula (3) compound 1-alkane amide piperazidine thing and 3,4, the consumption of its halides of reaction of 5-trimethoxy cinnamic acid halides is no less than more than 1 equivalent, and preferably 1.01～1.3 equivalents react in anhydrous solution medium.
Organic solvent that the present invention uses such as ethanol, ether, toluene, chloroform, methylene dichloride, benzene, ethyl acetate etc.De-acidying agent used in the present invention such as triethylamine, pyridine, yellow soda ash, sodium bicarbonate, etc.Temperature of reaction is that room temperature is to backflow, preferably room temperature.
Raw materials used formula (2) the compound 1-alkane amide piperazidine thing of this reaction also has other new compounds, its preparation method such as reference example J.Heterocyclic.Chem, 31,297 (1994).The Journal oforganin chemistry.16,1283 (1951) also the record with 3-chlorine propionic acid amide prepared in reaction.
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 the side effect very effective.
Formula (1) compound has wonderful cardiovascular and cerebrovascular diseases effect, be calcium ion channel blocker, by stoping Ca2+ to stride in the 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, blood flow increasing.
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 its ability by minute blood vessel, reduces the viscosity of blood, microcirculation improvement.
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 but these embodiment only limit to the present invention is described and limit the scope of the invention.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.
Embodiment 1:2-chloro-N-cyclopropyl ethanamide
With cyclopropylamine 15 grams, 60 milliliters of mixing of toluene, under stirring chloroacetyl chloride 18 grams are splashed in the cyclopropylamine solution with 120 milliliters of mixed solutions of toluene, dropwise, room temperature reaction one hour leaches solid, and filtrate is concentrated into dried, ethyl alcohol recrystallization obtains 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, stirred 10 minutes, add 16.2 gram 2-chloro-N-cyclopropyl ethanamides afterwards, 60 ℃ were reacted 2 hours, and reaction finishes and uses among the 5%NaOH and PH9, uses chloroform extraction, drying, steaming removes solvent and obtains colourless crystallization.The sherwood oil recrystallization obtains 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)δ2.668～2.713ppm，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)δ2.085ppm，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 of forming of methylene dichloride are added to 3,4,5-trimethoxy cinnamic acid muriate is (by 3,4,5-trimethoxy cinnamic acid 5.36 gram and thionyl chloride 25.6 are restrained fully) and 10 milliliters of methylene dichloride among, room temperature reaction 2 hours.Reaction finishes and adds entry, and water layer adds yellow soda ash and chloroform extraction, the extracting solution drying, and steaming removes solvent and obtains colorless solid.Ethanol-re-crystallizing in ethyl acetate 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 gram is dissolved in 11 milliliters of dehydrated alcohols; toxilic acid 1.0 grams are dissolved in 4 milliliters of dehydrated alcohols, with 1-(3,4; 5-trimethoxy cinnamoyl)-4-(cyclopropylamine ethanoyl) piperazine solution is added in the maleic acid solution; room temperature leaves standstill, and separates out crystallization, filters to obtain 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.
Embodiment 5:2-chloro-N-cyclopentyl ethanamide
With cyclopentamine 17 grams, 60 milliliters of mixing of toluene, stir down chloroacetyl chloride 18 grams and 120 milliliters of reference examples 1 of toluene are obtained 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, 16.4 gram 2-chloro-N-cyclopentyl ethanamides, 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 (by 3,4,5-trimethoxy cinnamic acid 7.36 grams and thionyl chloride 15.6 are restrained fully) reference example 3 obtains colorless solid.Ethanol-re-crystallizing in ethyl acetate 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 acids 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.
Embodiment 9:2-chloro-N-styroyl ethanamide
With 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, 7.9 gram 2-chloro-N-styroyl ethanamides, reference example 2 obtains 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
2δ2.800～2.834ppm，t，2H(J＝6.8HZ)
HN-CH
2δ3.526～3.575ppm，q，2H(J＝6.8HZ)
O=C-NH δ 7.130ppm, s, 1H acetyl CH22.892, s, 2H
Phenyl ring hydrogen δ 7.1657.299ppm, m, 5H.
Embodiment 11:1-(3,4,5-trimethoxy cinnamoyl)-4-(phenylethylamine ethanoyl) piperazine
Embodiment 10 products, 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 are restrained fully), 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, 4H
Ph-CH
2δ2.825～2.861ppm，t，2H(J＝7.2HZ)
HN-CH
2δ3.497～3.532ppm，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 acids 0.7 gram reference example 4 obtains 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
2δ2.818～2.853ppm，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).
Embodiment 13:2-chloro-N-piperidyl ethanamide
With piperidinyl-1 7.4 grams, 40 milliliters of mixing of toluene, under stirring chloroacetyl chloride 18 grams are splashed in the piperidine solution with 60 milliliters of mixed solutions of toluene, 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, stirred 10 minutes, add 25.14 gram 2-chloro-N-piperidyl ethanamides afterwards, 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
δ3.436～3.492ppm，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 products 8.45 gram and triethylamine 2.0 grams and 29 milliliters of solution of forming of methylene dichloride, 4,5-trimethoxy cinnamic acid muriate is (by 3,4,5-trimethoxy cinnamic acid 9.36 gram and thionyl chloride 15.6 restrain be equipped with) and 10 milliliters of methylene dichloride among, reference example 3 obtains colourless crystallization 14.2 and restrains.
Fusing point: 170-172 ℃
Hydrogen spectrum detected result:
Solvent: deuterated methanol
Piperidyl: δ 1.533～1.543 ppm, 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) δ 4.021ppm, m, 4H with the deuterated methanol solvent peak
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).
Embodiment 17:2-chloro-N-bicyclo-propyl methylacetamide
With 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, 9.4 gram 2-chloro-N-bicyclo-propyl methylacetamides, 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 the 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
By embodiment 18 products, 5.93 grams and triethylamine 1.25 grams and 3,4,5-trimethoxy cinnamic acid muriate (by 3,4,5-trimethoxy cinnamic acid 5.36 grams and thionyl chloride 25.6 are restrained fully) reference example 3 obtains light brown oily thing 3.8 grams.
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 acids 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 stripped carotid diastole effect research of rabbit
Present embodiment provides typical compound of the present invention to the stripped carotid diastole effect of rabbit.
Wherein, the concrete structure of 3#＞6#＞four kinds of samples of 1#＞4# is as follows:
The 1# structure is the maleate of following formula structure:
The 3# structure is the maleate of following formula structure:
The 4# structure is the maleate of following formula structure:
6# is contrast medicine Cinepazide Maleate.
Above-mentioned four kinds of compounds are to the IC of the stripped carotid diastole effect of rabbit
50Size is 3#＞6#＞1#＞4#, and this also is 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 1.2 and 1.3 times of reference substance respectively.
Table Cinepazide Maleate and homologue thereof to rabbit exsomatize carotid diastole effect (
N=5, unit: %)
Claims (11)
1. one kind as shown in the formula the 1-shown in (1) (3,4,5-trimethoxy cinnamoyl)-4-alkylamide derivative compound or its pharmacy acceptable salt:
Me is a methyl in the formula, and NH-R is selected from:
2. compound according to claim 1, wherein, described pharmacy acceptable salt is the acid salt of formula (1) compound, is preferably nitrate, vitriol, hydrobromate, hydriodate, phosphoric acid salt, maleate, fumarate, Citrate trianion, oxalate or tartrate; Most preferably be maleate or fumarate.
3. method for preparing claim 1 or 2 described compounds, wherein, described method comprises by formula (3) compound and 3,4,5-trimethoxy cinnamyl chloride, reaction obtains formula (1) compound in the presence of de-acidying agent, and synthetic route is as follows:
Wherein, Me represents methyl,
Substituent R in formula (1), (3) is selected from
Temperature of reaction is that room temperature extremely refluxes, and is preferably room temperature.
4. method according to claim 3, 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.
5. according to claim 3 or 4 described methods, wherein, two kinds of reactants: 3,4, the mole dosage proportioning of 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.
6. according to each described method among the claim 3-5, wherein, employed de-acidying agent is selected from: triethylamine, pyridine, yellow soda ash and sodium bicarbonate.
7. according to each described method among the claim 3-6, wherein, described formula (3) compound obtains by reacting in solvent with following formula: compound (2) and piperazine or piperazine list salt:
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.
8. method according to claim 7, wherein, described formula (2) compound is by chloroacetyl chloride and NH
2-R prepared in reaction obtains 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.
9. a pharmaceutical composition that is used for the treatment of cardiovascular and cerebrovascular diseases is characterized in that, described composition comprises: 1) claim 1 or 2 described compounds or its pharmacy acceptable salt; With 2) to learn acceptable carrier.
10. claim 1 or 2 described compounds or its pharmacy acceptable salt are used for the treatment of cardiovascular and cerebrovascular diseases and/or are used for expanding brain, tip, coronary vasodilator and/or anticoagulation and/or the application of the medicine of enhancing adenosine and cyclic monophosphate effect in preparation.
11. one kind as shown in the formula the 1-alkane amide piperazidine midbody compound shown in (3):
Wherein, Me represents methyl, and R is selected from
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| CN110498761A (en) * | 2018-05-18 | 2019-11-26 | 上海医药工业研究院 | Acetyl amantadine piperazine (pyridine) class compound is as neuroprotection agent application |
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| US4639452A (en) * | 1982-02-26 | 1987-01-27 | Delalande S.A. | Arylic derivatives of piperazine, the method of preparing same and their application in therapeutics |
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| GB1473262A (en) * | 1974-11-20 | 1977-05-11 | Delalande Sa | Derivatives of n-3,4,5-trimethoxy cinnamoyl-piperazine their process of preparation and their therapeutic application |
| GB0428475D0 (en) * | 2004-12-30 | 2005-02-02 | 4 Aza Bioscience Nv | Pyrido(3,2-D)pyrimidine derivatives and pharmaceutical compositions useful as medicines for the treatment of autoimmune disorders |
| MX2007011151A (en) * | 2005-03-16 | 2007-10-17 | Hoffmann La Roche | Cis-2,4,5-triaryl-imidazolines and their use as anti-cancer medicaments. |
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| CN110498761A (en) * | 2018-05-18 | 2019-11-26 | 上海医药工业研究院 | Acetyl amantadine piperazine (pyridine) class compound is as neuroprotection agent application |
| CN110498761B (en) * | 2018-05-18 | 2022-09-13 | 上海医药工业研究院 | Application of acetyl amantadine piperazine (pyridine) compound as cerebral nerve protective agent |
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