CN102100695B - High-safety medicinal composition of cinepazide, and preparation method and application thereof - Google Patents
High-safety medicinal composition of cinepazide, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a high-safety medicinal composition of cinepazide, and a preparation method and application thereof. The medicinal composition comprises cinepazide or pharmaceutically acceptable salt thereof and compounds, of which the content is less than 0.5 and which have the structure shown in the formula III. The medicinal composition of cinepazide and the preparations thereof have higher safety, effectiveness and stability and can effectively reduce or avoid adverse reactions, such as decreasing hemogram, of patients caused by the cinepazide. Moreover, the invention also separates, purifies and characterizes new nitrogen oxides of cinepazide. Complete research on the new nitrogen oxides of cinepazide shows that the toxicity of nitrogen oxides of cinepazide is far higher than that of the cinepazide, and the nitrogen oxides of cinepazide have the insecticidal activity different from that of the cinepazide; moreover, the research shows that the nitrogen oxides of cinepazide can cause the reduction of leukocytes of animals, even affect the formation and the differentiation of granulocytes, which are possibly the main reason for the cinepazide causing adverse reactions such as the decreasing hemogram of patients.
Description
The application is dividing an application of CN200910180174.X safe cinepazide Pharmaceutical composition of submission on November 13rd, 2009 and preparation method thereof and its application.
Technical field
The invention belongs to cardiovascular and cerebrovascular vessel expansion medicine, be specifically related to a kind of safe cinepazide Pharmaceutical composition and preparation method thereof and its application.
Background technology
Cardiovascular and cerebrovascular disease is the same with cancer, has become the commonly encountered diseases and the frequently-occurring disease of serious threat people ' s health.Therefore, preparation and select more safely and effectively that the cardiovascular and cerebrovascular vessel medicine had become the field of medicaments important research project already.
Cinepazide (Cinepazide) belongs to the cardiovascular and cerebrovascular vessel dilator, because of its determined curative effect, extensive use once in countries in the world, its chemical name be (E)-1-{4-[(3 ', 4 ', 5 '-the trimethoxy cinnamoyl)]-the 1-piperazine acetyl pyrrole pyridine, have following structure:
formula (I).
Cinepazide is clinical to be mainly used in the following disease of control: 1. cerebrovascular accident: cerebral arteriosclerosis, TCIA, cerebral thrombosis, cerebral embolism, apoplexy sequela and cerebral trauma sequela; 2. cardiovascular disease: coronary heart disease, angina pectoris cooperates relevant medicine to carry out the Comprehensive Treatment myocardial infarction; 3. peripheral blood vessel: artery of lower extremity atheromatosis, thromboangiitis obliterans, arteritis, Raynaud disease etc.
Although the cinepazide medicine from 1974 since France listing, in the treatment heart, brain, peripheral blood vessel field, brought into play outstanding curative effect, yet; Because the untoward reaction of this medicine promptly can cause patient's leukopenia clinically, when serious; Even cause patient's agranulocytosis; From 1986, this medicine progressively withdrawed from European market (Agranulocytosisinduced by cinepazide.Eur J Clin Pharmacol 1990,38:387～388.).Though; China is also at the production and selling Cinepazide Maleate; But all in its medicine operation instructions, spell out, this medicine has the patient's of causing leukopenia and agranulocytic danger, and the suggestion patient is before using cinepazide; At first check hemogram, and suggestion leukocyte disorder patient perhaps there is the patient of leukopenia pharmacohistory to use.So big limitations the clinical scope of application of cinepazide, simultaneously, also bring potential safety hazard to the patient.
In order to reduce or avoid the untoward reaction of cinepazide; Domestic and international research scholar has made a lot of research work; Once attempted through control and improve the cinepazide raw material and effectiveness and safety that the quality of preparation improves cinepazide class medicine, for example, the content of controlling cinepazide in the raw material of cinepazide is not less than 98%; The content of cinepazide cis-isomer (structure is suc as formula shown in the II) must not surpass 1%, and the content of other related substances is no more than 1%.
But, aforementioned quality control method reduction still not yet in effect or avoid the caused patient's hemogram of cinepazide to descend.Therefore, the reason of further investigation cinepazide generation untoward reaction improves the drug safety and the effectiveness of cinepazide, brings into play its clinical efficacy better, avoids or reduces its untoward reaction or side reaction, becomes the research topic that is rich in practice significance.
Summary of the invention
For this reason; The present invention is separation, purification and characterized structure and the activity thereof of research cinepazide related substances further; Obtain surprising discovery; Pharmacological evaluation confirms that the pure article of cinepazide can not cause the leucocytes reduction of animal, causes leucocytes reduction or influences the granulocyte differentiation and the material that forms is the cinepazide oxynitride of structure shown in the formula III.
Itself there is unstability in cinepazide (claiming " cinepazide free alkali " again), and very easily oxidized, its nitrogen oxide increases along with the prolongation of standing time gradually.Therefore, need the amount of nitrogen oxide in the control cinepazide to improve its safety.
The object of the present invention is to provide a kind of safe pharmaceutical composition, said pharmaceutical composition contains cinepazide or its pharmaceutically acceptable salt and content and is not higher than structural compounds shown in 0.5% the formula III (claiming " cinepazide oxynitride ", " nitrogen oxide " or formula III chemical compound again).
Further, the content of cinepazide or its pharmaceutically-acceptable salts is not less than 90% in the said pharmaceutical composition, preferably is not less than 95%, more preferably is not less than 98%.
Further, the content of structural compounds is not higher than 0.4% shown in the formula (III), preferably is not higher than 0.3%, more preferably no higher than 0.2%.
Further, the weight ratio between cinepazide or its pharmaceutically acceptable salt and formula (III) chemical compound was not less than 200: 1, preferably was not less than 300: 1, more preferably was not less than 500: 1.
Further; Said Pharmaceutical composition contains content and is not less than 98% cinepazide or its pharmaceutically acceptable salt, content and is not higher than 0.20% cinepazide oxynitride, content and is not higher than 1.0% cinepazide cis-isomer, and surplus is other related substances.
Further, the content of cinepazide cis-isomer is not higher than 0.8% in the said Pharmaceutical composition.
Further, described cinepazide pharmaceutically acceptable salt is selected from any or its combination of maleate, mesylate, sulfonate, sulfate, hydrochlorate, hydrobromate, phosphate, nitrate, tosilate, tartrate, fumarate, citrate, acetate, formates, benzoate, cinnamate, succinate, malonate.
Further, described formula III chemical compound is prepared by following method, cinepazide free alkali and peroxide is carried out oxidation reaction obtain.
Further, said oxidation reaction places cinepazide free alkali and peroxide in the solvent and takes place.
Further, said solvent is selected from any or its combination of alkyl halide, protonic solvent, aprotic polar solvent.
Further, described alkyl halide is selected from dichloromethane, chloroform, 1,1-dichloroethanes, 1, any or its combination of 2-dichloroethanes.
Further, described protonic solvent is water and alcohols, and preferred alcohols is selected from any or its combination of methanol, ethanol, isopropyl alcohol, normal propyl alcohol, n-butyl alcohol.
Further, described aprotic polar solvent is selected from any or its combination of DMF, DMSO, acetone.
Further, oxidation reaction takes place with cinepazide free alkali and peroxide through grinding in described oxidation reaction under condition of no solvent.
Further, said peroxide is selected from any or its combination of hydrogen peroxide, peracetic acid, benzoyl hydroperoxide, chloro-peroxy benzoic acid, Ammonium persulfate..
Further, the method for preparing of structural compounds shown in the formula III of the present invention comprises separation, the purification of oxidation reaction product, and preferred said purification process is selected from purified any or its combination that is separated of recrystallization, preparative liquid.
Further, the solvent that the present invention is used for recrystallization is an alcohols, and preferred said alcohols is selected from any or its combination of methanol, ethanol, isopropyl alcohol, normal propyl alcohol, n-butyl alcohol.
Further, the described preparative liquid purification condition that is separated does, mobile phase is any or its combination of methanol-water, acetonitrile-water, methanol-acetonitrile-water, and degree of grade or gradient elution are collected product stream part, and evaporate to dryness or lyophilization promptly get.
Adopt separation of the present invention, purification process, the content of gained cinepazide oxynitride is not less than 95%, preferably is not less than 98%, more preferably is not less than 99%.
Another object of the present invention is to provide a kind of preparation cinepazide method for compositions, it is characterized in that, in lucifuge, under the condition of anaerobic, intermediate, cinepazide or its pharmaceutically acceptable salt of preparation cinepazide.
In order clearly to explain content of the present invention, the present invention defines following term as follows:
" oxygen free condition " of the present invention is the reaction condition of starvation or isolated other oxidant, and described " oxygen free condition " is selected from nitrogen protection, inert gas shielding or adds any or its combination of Reducing agent.
" related substance " of the present invention is meant the impurity except that cinepazide; Cis-isomer, cinepazide oxynitride, 1-(3 like cinepazide; 4,5-trimethoxy cinnamoyl) other that contain in piperazine and the cinepazide detect less than material, " other related substances " is meant 1-(3; 4,5-trimethoxy cinnamoyl) other that contain in piperazine and the cinepazide detect less than material.
Except as otherwise noted, percentage composition of the present invention is the quality percentage composition.
Cinepazide oxynitride of the present invention can be used as the quality that reference substance is used to control cinepazide free alkali or its pharmaceutically-acceptable salts and preparation thereof, and is used to detect the effect duration of cinepazide free alkali or its pharmaceutically-acceptable salts and preparation thereof.Therefore, another object of the present invention is to provide cinepazide oxynitride to be used for preparing the application of the reference substance of cinepazide medicine or its preparation.
Another object of the present invention is to provide a kind of safe pharmaceutical preparation, said preparation is made up of pharmaceutical composition of the present invention and pharmaceutically acceptable carrier.
Pharmaceutical preparation of the present invention can be various dosage form well known in the art.Be suitable for dosage form of the present invention and be selected from oral formulations, external preparation or injection, be preferably oral formulations or injection, more preferably injection.Said oral formulations is selected from oral liquid, tablet, capsule, granule, pill, powder, syrup, mixture, distillate medicinal water, suspending agent, Emulsion or medicinal tea, and preferred said suspending agent is selected from does outstanding agent or suspension; Said tablet means medicine and disk shape or special-shaped flaky solid preparation that suitable auxiliary materials and mixing compacting forms, can be selected from oral ordinary tablet, buccal tablet, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet or enteric coatel tablets etc.; Said capsule is selected from hard capsule (being commonly referred to as capsule), soft capsule (soft gelatin capsule), slow releasing capsule, controlled release capsule or enteric coated capsule etc.; Said pill is selected from drop pill, sugar pill, piller etc.; Said granule is selected from soluble particles (being commonly referred to as granule), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules, controlled release granule etc.; Said external preparation is selected from gel, unguentum, liniment, lotion, liniment, and preferred said unguentum is selected from emplastrum, coagulates unguentum or ointment; Said injection is selected from injection (injection), transfusion, freeze-dried powder or sterile packaged preparation, is preferably injection.Can adopt preparation technique means well known in the art to prepare pharmaceutical preparation of the present invention.
Pharmaceutically acceptable carrier of the present invention is conventional excipients or the adjuvant that is used to prepare said preparation well known in the art.Excipient or adjuvant that oral formulations or external preparation are commonly used include but are not limited to filler (diluent), lubricant (fluidizer or antitack agent), dispersant, wetting agent, binding agent, regulator, solubilizing agent, antioxidant, antibacterial, emulsifying agent etc.Binding agent; For example syrup, arabic gum, gelatin, sorbitol, tragacanth, cellulose and derivant thereof, gelatine size, starch slurry, polyvinylpyrrolidone, PVP-K30, hydroxypropyl cellulose, starch slurry, methylcellulose, gelling starch, the preferred cellulose derivant is microcrystalline Cellulose, sodium carboxymethyl cellulose, ethyl cellulose or hydroxypropyl methylcellulose; Filler; For example lactose, Icing Sugar, dextrin, starch and derivant thereof, cellulose and derivant thereof, inorganic calcium salt, sorbitol, glycine, calcium sulfate two water things, microcrystalline Cellulose, pregelatinized Starch, mannitol, preferred inorganic calcium salt is calcium sulfate, calcium phosphate, calcium hydrogen phosphate or precipitated calcium carbonate; Lubricant, for example micropowder silica gel, magnesium stearate, Pulvis Talci, aluminium hydroxide, boric acid, hydrogenated vegetable oil, Polyethylene Glycol, sodium lauryl sulphate; Disintegrating agent; For example starch or derivatives thereof, polyvinylpyrrolidone, microcrystalline Cellulose, dried starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, the preferred starch derivant is carboxymethyl starch sodium, PRIMOGEL, pregelatinized Starch, modified starch, hydroxypropyl starch, corn starch; Wetting agent, for example sodium lauryl sulphate, water or alcohol etc.
Excipient or adjuvant that said injection is commonly used include but are not limited to: antioxidant; For example phenols such as BHA (BHA), fourth hydroxy-methylbenzene (BHT), NDGA (NDGA); Sulfur-containing compound such as thiodipropionic acid, sulphite, bisulfites, MGD, sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate; Organic acid/alcohol/esters such as ascorbic acid, citric acid, malic acid, sorbitol, glycerol, propylene glycol, ascorbyl palmitate; Esters such as hydroquinone, Hydroxycoumarin, vitamin E; Amine such as ethanolamine, fabaceous lecithin, cephalin, plant phospholipid or animal phospholipid, mineral acid or its salt, phosphoric acid or its salt, phosphorous acid or its salt; Osmotic pressure regulator, for example sodium chloride, glucose, potassium chloride, magnesium chloride, calcium chloride, sorbitol, mannitol etc. are preferably sodium chloride or glucose; Antibacterial, for example 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol; PH regulator agent, for example hydrochloric acid, tartaric acid, citric acid, potassium hydroxide, sodium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, acetic acid, sodium acetate, lactic acid, citric acid, sodium citrate, sodium bicarbonate, sodium carbonate any or its combination; Emulsifying agent, for example Tween-80, do not have that sour Pyrusussuriensis is smooth, Pu Luonike F-68, lecithin, fabaceous lecithin; Solubilizing agent, for example tween 80, bile, glycerol, propylene glycol, lecithin, polyoxyethylene castor oil etc.; Filler or excipient, for example lactose, mannitol, sorbitol, dextran etc.
Said injection is selected from injection, injectable sterile powder and concentrated solution for injection, can be used for intramuscular injection, intravenous injection, intravenous drip etc.The specification of injection of the present invention has been selected from 1mL, 2mL, 5mL, 10mL, 20mL, 50mL, 100mL, 200mL, 250mL or 500mL.
In addition; Also can active component be mixed by its preparation requirement with pharmaceutically acceptable slow controlled release carrier; Again according to the method for preparing of sustained-release preparation well known in the art, as adding the blocker coating or with processing micropill after the active principle microcapsulesization again, like slow-release micro-pill or controlled release micro pill; Described slow controlled release carrier includes but are not limited to oil agent, hydrophilic colloid or the coating blocker etc. of mixing, and described oil to mix agent be glyceryl monostearate, castor oil hydrogenated, Dormant oils, polysiloxanes, dimethyl siloxane; Described hydrophilic colloid is cellulose derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, or PVP, arabic gum, tragcanth or carbopol etc.; Described coating blocker is ethyl cellulose (EC), hydroxypropyl methylcellulose (HMPC), polyvinylpyrrolidone (PVP), cellulose acetate-phthalate (CAP), acrylic resin etc.
Pharmaceutical preparation of the present invention can be unit formulation; In cinepazide; The pharmaceutical composition of the present invention that contains 0.01g～5g is as essential active component; Be preferably 0.01～3g, more preferably 0.04g, 0.08g, 0.1g, 0.16g, 0.2g, 0.25g, 0.32g, 0.4g, 0.5g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g or 2.5g.
Another object of the present invention is to provide a kind of method for preparing injection, it is characterized in that,, under the anaerobic protective condition, pharmaceutical composition of the present invention and pharmaceutically acceptable injection carrier are mixed in lucifuge.
Further, described pharmaceutically acceptable injection carrier is selected from any or its combination of antioxidant, antibacterial, pH regulator agent.
Further; Described antioxidant is selected from phenols such as BHA (BHA), fourth hydroxy-methylbenzene (BHT), NDGA (NDGA); Sulfur-containing compound such as thiodipropionic acid, sulphite, bisulfites, MGD, sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate; Organic acid/alcohol/esters such as ascorbic acid, citric acid, malic acid, sorbitol, glycerol, propylene glycol, ascorbyl palmitate; Esters such as hydroquinone, Hydroxycoumarin, vitamin E; Amine such as ethanolamine, fabaceous lecithin, cephalin, plant phospholipid or animal phospholipid, mineral acid or its salt, phosphoric acid or its salt, phosphorous acid or its salt.
Further, described pH regulator agent is selected from any or its combination of hydrochloric acid, tartaric acid, citric acid, potassium hydroxide, sodium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, acetic acid, sodium acetate, lactic acid, citric acid, sodium citrate, sodium bicarbonate, sodium carbonate.
Further, described antibacterial is selected from any or its combination of 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol.
Another object of the present invention is to the application that provides pharmaceutical composition of the present invention or its pharmaceutical preparation to be used for preparing the medicine of controlling cardiovascular and cerebrovascular disease in advance.
Further, described cardiovascular and cerebrovascular disease is selected from any or its combination of cerebrovascular accident, cardiovascular disease, peripheral blood vessel.
Further, described cerebrovascular accident is selected from any or its combination of cerebral arteriosclerosis, TCIA, cerebral thrombosis, cerebral embolism, apoplexy sequela, cerebral trauma sequela.
Further, described cardiovascular disease is selected from any or its combination of coronary heart disease, angina pectoris, myocardial infarction.
Further, described peripheral blood vessel be selected from that artery of lower extremity is atherosis, any or its combination of thromboangiitis obliterans, arteritis, Raynaud disease.
Compared with prior art, the present invention has following advantage:
1) separation of the present invention, purification and characterized new cinepazide oxynitride; And the activity of this chemical compound carried out abundant research, the toxicity of finding this chemical compound is much larger than cinepazide, and has the insecticidal activity that is different from cinepazide; Simultaneously; Finding that cinepazide oxynitride can cause the leukopenia of animal, even influence granulocytic formation and differentiation, possibly be the main cause that cinepazide class medicine causes degradation side reaction under patient's hemogram or untoward reaction.
2) separation of the present invention, purification cinepazide issuable related substances in depositing process; Obtain nitrogen oxide, the 1-(3 of cinepazide; 4; 5-trimethoxy cinnamoyl) cis-isomer of piperazine, cinepazide and other related substanceses, and, find that the cinepazide oxynitride of certain content can cause leukopenia or the agranulocytosis of animal through the active of these related substanceses of comparative experiments research and to the influence that quantity of leucocyte, granulocyte form and break up; It is the cause a disease main cause of side reaction such as people's hemogram decline or untoward reaction of cinepazide; And the cis-isomer of 1-(3,4,5-trimethoxy cinnamoyl) piperazine, cinepazide and other related substances are to a few nothing influences of animal hemogram.
3) the present invention passes through further investigation, surprising discovery, and cinepazide oxynitride is not higher than at 0.5% o'clock at its content, to animal leukocyte count or granulocytic formation and differentiation existence influence, but not remarkable; Be not higher than at 0.2% o'clock at its content, then to animal leukocyte count or granulocytic formation and not influence of differentiation.Therefore, the present invention provides a kind of safe cinepazide pharmaceutical composition, and said pharmaceutical composition contains cinepazide or its pharmaceutically acceptable salt and content and is not higher than 0.5% formula III chemical compound.
4) the present invention is through further investigation; Tentatively inquired into the reason that the pathogenic people's hemogram of cinepazide descends; And obtained a kind of safe cinepazide pharmaceutical composition; And through effectively controlling the content of cinepazide oxynitride in cinepazide raw material or its preparation, to improve safety, effectiveness and the stability of cinepazide product and preparation thereof.
5) the present invention also provides a kind of method for preparing safe cinepazide pharmaceutical composition; Each link that is about to prepare cinepazide or its pharmaceutically acceptable salt and preparation thereof is controlled at operation under the oxygen free condition; With the content of the cinepazide oxynitride in effective reduction or minimizing cinepazide or its pharmaceutically acceptable salt and the preparation thereof, thereby improve its safety, effectiveness and stability.
6) the present invention also provides the method for preparing of multiple cinepazide oxynitride, and the cinepazide oxynitride that will prepare gained is used for controlling the content of cinepazide pharmaceutically acceptable salt and preparation oxynitride thereof as reference substance.
Description of drawings
The figure of the HPLC of structural compounds shown in Fig. 1 formula (III);
The H of structural compounds shown in Fig. 2 formula (III)
1-NMR figure;
The mass spectrum of structural compounds shown in Fig. 3 formula (III).
The specific embodiment
Through embodiment the present invention is described further below.It should be understood that the embodiment of the invention is only used for explaining the present invention, rather than limitation of the present invention, under design prerequisite of the present invention, simple modifications of the present invention is all belonged to the scope that requirement of the present invention is protected.
The preparation of embodiment 1 cinepazide oxynitride
2 gram cinepazides are dissolved in the 100ml dichloromethane, add peracetic acid 10 grams, stir, accomplish to reaction, filter, revolve and do filtrating, use ethyl alcohol recrystallization, lyophilization then promptly gets the 0.52g cinepazide oxynitride.HPLC peak area normalization method records its content and is not less than 98%.
1H?NMR(300MHz，CDCl
3)δ(ppm)：7.615(d，1H)6.731(d，1H)6.610(s，2H)3.801(m，1H)、4.012(m，2H)、4.131(m，1H)4.674(d，1H)、4.278(d，1H)3.907(s，6H)3.882(s，3H)3.251(d，2H)、3.589(d，2H)3.504(t，2H)4.137(t，2H)1.914(m，2H)、2.015(m，2H)
The preparation of embodiment 2 cinepazide oxynitrides
2 gram cinepazides are dissolved in the 100ml methanol, add 5 gram benzoyl hydroperoxides, stir, extremely reaction is accomplished; Filter, revolve and do filtrating, separate with preparation type high performance liquid chromatogram, mobile phase is methanol-water; Gradient elution receives product stream part, promptly gets the 0.3g cinepazide oxynitride.HPLC peak area normalization method records its content and is not less than 99%.
1H?NMR(600MHz，DMSO)δ(ppm)：7.492(d，1H)7.238(d，1H)7.060(s，2H)4.306(dd，2H)、4.090(s，2H)、3.913(m，1H)3.835(s，6H)、3.723(m，1H)3.689(s，3H)3.641(m，3H)、3.489(s，1H)3.311(t，2H)3.186(m，2H)1.853(m，2H)、1.776(m，2H)
The preparation of embodiment 3 cinepazide oxynitrides
Come cinepazide maleate to be dissolved in the 25ml water 5 KEMA, adding 25ml concentration is 25% hydrogen peroxide, stirring at room reaction 5 days; Separate with preparation type high performance liquid chromatogram, mobile phase is acetonitrile-water, gradient elution; Receive product stream part, promptly get the 500mg cinepazide oxynitride.HPLC peak area normalization method records its content and is not less than 99%.
MS(LC-MS)＝434.2(M+H
+)，867.5(2M+H
+)。
The preparation of embodiment 4 cinepazide oxynitrides
2.5g cinepazide and 2.5g metachloroperbenzoic acid are ground, grind the back and separate with preparation type high performance liquid chromatogram, mobile phase is methanol-acetonitrile-water, and gradient elution is accepted product stream part, promptly gets the 210mg cinepazide oxynitride.HPLC peak area normalization method records its content and is not less than 99%.
MS(LC-MS)＝434.2(M+H
+)，867.5(2M+H
+)。
The toxicity research of experimental example 5 cinepazide oxynitrides
Experimental animal: 100 of SD rats, body weight 200g ± 20g; 100 of Kunming kind white mice, body weight 20g ± 2g.The animal tail vein injection gives cinepazide oxynitride (calling " nitrogen oxide " in the following text), and the administration volume is: rat is the 1.0ml/100g body weight, and mice is the 0.1mL/10g body weight, and be administered once every day.After the administration, observed for 2 weeks continuously.
Observation index:
(1) behind the injectable drug, observes death time of animal and dead quantity thereof, and calculate LD
50Value;
(2) poisoning symptom and persistent period after the administration;
(3) the upright row of dead animal is dissected inspection; When observing end, surviving animals is dissected inspection.
The LD of table 1 cinepazide and nitrogen oxide thereof
50Value
Can find out the LD of cinepazide in SD rat and mice by table 1
50Value is about 90 times and 60 times of cinepazide oxynitride, and the toxicity that cinepazide oxynitride is described infers thus that much larger than cinepazide the untoward reaction of cinepazide maybe be relevant with nitrogen oxide.
Related substances is to murine interleukin and granulocytic influence in experimental example 6 cinepazides
130 of female Kunming kind white mice; Body weight 20 ± 2 grams; After adapting to raising, be divided into the high, normal, basic dose groups of solvent control group, cinepazide, the high, normal, basic dose groups of cinepazide cis-isomer, the high, normal, basic dose groups and the related substances 1-(3,4 of cinepazide oxynitride at random; 5-trimethoxy cinnamoyl) the high, normal, basic dose groups of piperazine, totally 13 groups.
Receive the reagent thing: purity is 99.9% Cinepazide Maleate, white odorless powder; Purity is 98.3% cinepazide cis-isomer, off-white color or faint yellow odorless crystalline powder; Purity is 98.5% cinepazide oxynitride, off-white color or little yellow crystalline powder; Purity is 98% 1-(3,4,5-trimethoxy cinnamoyl) piperazines (structure is suc as formula shown in the IV), light yellow crystalline powder, its
1H NMR (400MHz, DMSO) δ: 7.457 (d, 1H) 7.182 (d, 1H) 7.044 (s, 2H) 2.826 (d, 4H) 3.819 (s, 6H) 3.671 (s, 3H) 3.722 (m, 2H), 3.574 (m, 2H) 8.275 (s, 1H).
Medication: mouse tail vein injection administration, administration volume are the 0.1ml/10g body weight, 4 weeks of successive administration.Before the administration, dissolved through water for injection by the reagent thing, and according to dosage require to be diluted to desired concn.
The dosage design
Human clinical dosage (320mg/ people/sky) according to Cinepazide Maleate; Be equivalent to cinepazide 250mg/ people/sky; Set the height (312mg/kg of cinepazide; Be equivalent to 10 times of human dosage), in (156mg/kg is equivalent to 5 times of human dosage), low (78mg/kg is equivalent to 2.5 times of human dosage) dosage group.
The dosage setting of cinepazide cis-isomer is the same.
The high dose of cinepazide oxynitride and 1-(3,4,5-trimethoxy cinnamoyl) piperazine administration is 32mg/kg, and middle dosage is 16mg/kg, and low dosage is 8mg/kg.
Matched group gives isopyknic normal saline.
Observation index
Hemogram detects: the tail vein is got blood 20 μ l, detects with daily output hemogram detector.Each organize mice before administration, during the administration weekly, administration finishes a week each detects once.The result sees table 2 and table 3.
Related substances is to the influence of mice PBL in table 2 cinepazide
* represent to compare p＜0.05 with matched group
Visible by table 2, compare cinepazide group, cinepazide cis-isomer, 1-(3 with matched group; 4; 5-trimethoxy cinnamoyl) leukocyte count of piperazine treated animal is more stable, and all within normal range, and the peripheral white blood cell amount of respectively organizing mice does not have obvious change; And the leukocyte count of each dose groups animal of cinepazide oxynitride decline is all bigger, compares with matched group to present significant difference.Explain that cinepazide oxynitride can cause the leukocyte count minimizing of mice peripheral blood, and cinepazide itself, cinepazide cis-isomer and 1-(3,4,5-trimethoxy cinnamoyl) piperazine is to the not influence of mice peripheral white blood cell.
Related substances is to the granulocytic influence of mice in table 3 cinepazide
Visible by table 3; Compare with matched group; The bone marrow of cinepazide group, cinepazide cis-isomer group, 1-(3,4,5-trimethoxy cinnamoyl) piperazine group mice all is the active proliferation state; The total ratio of granulocyte system changes little, and grain is that notable difference does not also appear in the proportion of composing of variant differential period; And the bone marrow of cinepazide oxynitride group mice all is the state of being suppressed, and grain is that notable difference also appears in the proportion of composing of variant differential period.Explain that cinepazide oxynitride can have a strong impact on granulocytic generation of mice and differentiation generation, and cinepazide itself, cinepazide cis-isomer and 1-(3,4,5-trimethoxy cinnamoyl) piperazine does not influence granulocytic generation of mice and differentiation.
Because 1-(3 is not seen in the present invention's research; 4; 5-trimethoxy cinnamoyl) toxic and side effects and the related activity of piperazine, but in order to control and improve the quality of cinepazide product or its preparation, the present invention is with 1-(3; 4,5-trimethoxy cinnamoyl) piperazine is as " other related substances " control of limiting the quantity of.
Experimental example 7 cinepazides and compositions thereof are to murine interleukin and granulocytic influence
80 of female Kunming kind white mice, body weight 20 ± 2 grams, adaptation is divided into solvent control group, cinepazide group, cinepazide and cinepazide oxynitride compositions group, totally 8 groups after raising at random.
Receive the reagent thing: purity is 99.9% cinepazide, white odorless powder; The weight ratio of cinepazide and cinepazide oxynitride is respectively the compositions group (calling " compositions " in the following text) of 1: 0.1%, 1: 0.2%, 1: 0.3%, 1: 0.4%, 1: 0.5% and 1: 0.6%.
Before the administration, dissolved through water for injection by the reagent thing, and according to dosage require to be diluted to desired concn.
Medication
Mouse tail vein injection administration, administration volume are the 0.1ml/10g body weight, 4 weeks of successive administration.
The dosage design
According to the human clinical dosage (the 320mg/ man day is equivalent to the cinepazide 250mg/ man day) of Cinepazide Maleate, setting cinepazide is 32mg/kg at the dosage of mice, and matched group gives isopyknic normal saline.
Observation index
Hemogram detects: the tail vein is got blood 20 μ l, detects with daily output hemogram detector.Each organize mice before administration, during the administration weekly, administration finishes a week each detects once.The result sees table 4 and table 5.
Table 4 cinepazide and compositions thereof are to the influence of mice PBL
* represent to compare p＜0.05 with matched group
Visible by table 4, to compare with matched group, the leukocyte count of cinepazide group and control animals is more stable, all within normal range; And the compositions group is at cinepazide oxynitride content≤0.20% o'clock; Each organizes the peripheral white blood cell amount of mice does not have obvious change; And, compare remarkable minimizing murine interleukin the 3rd week after administration with matched group when cinepazide amount of nitrogen oxides during in 0.4% dose groups; When the content of cinepazide nitrogen oxide reaches 0.5%; Murine interleukin second week after administration is compared remarkable minimizing with matched group, when the content of cinepazide nitrogen oxide reached 0.6%, murine interleukin first week after administration just significantly reduced; It is thus clear that; Along with the increase of cinepazide oxynitride content in the compositions, the degree of murine interleukin decreased number is big more, and leukopenic time also shifts to an earlier date.Because be 7～14 days clinical administration course of treatment of cinepazide, and the ratio of compositions reaches the untoward reaction that week occurs leukopenia in 1: 0.5% o'clock second, visible amount of nitrogen oxides is not higher than at 0.5% o'clock, is relatively safe.
Table 5 cinepazide and compositions thereof are to the influence of mouse bone marrow cells smear cell divide count results
Visible by table 5, the bone marrow of cinepazide group mice all is the active proliferation state, and the total ratio of granulocyte system changes little, and grain is that notable difference does not also appear in the proportion of composing of variant differential period; And the performance of compositions group is different; When the content of cinepazide oxynitride in the compositions≤0.20%; Each bone marrow of organizing mice all is the active proliferation state, and the total ratio of granulocyte system changes little, and grain is that notable difference does not also appear in the proportion of composing of variant differential period; The content of cinepazide oxynitride reaches 0.3%, 0.4%, 0.5% and 0.6% in compositions; Increase along with cinepazide oxynitride content; The bone marrow of mice all is the state of being suppressed to be aggravated all the more; And grain is that the difference that the proportion of composing of variant differential period also occurs increases gradually, explain that cinepazide oxynitride can have a strong impact on granulocytic generation and differentiation generation.Therefore, in order to guarantee the safety of medication, the content of cinepazide oxynitride should not be higher than 0.20% in cinepazide or its salt.
The preparation of embodiment 8 cinepazides (calling " compositions 1 " in the following text)
1) lucifuge under the condition of nitrogen protection, is got 1000g Anhydrous potassium carbonate, 1800g Piperazine anhydrous, joins in the 4000ml dehydrated alcohol; Stirring and refluxing adds 620g chloracetyl Pyrrolizidine in ethanol solution, finishes stirring reaction 2.5 hours; Leave standstill, filter, collect filtrating, decompression steams solvent; It is an amount of to add water, distilling under reduced pressure, and purified product gets 1-[(1-nafoxidine carbonyl) methyl] piperazine;
2) lucifuge is under the condition of nitrogen protection, with 3 of 800g; 4,5-trimethoxy cinnamoyl chloride adds in the 4000ml dichloromethane, stirring and dissolving; Under 15-20 ℃, progressively add 1-[(the 1-nafoxidine carbonyl) methyl] piperazine of 562g again, finish, continued stirring reaction 4 hours; Add 2000ml water shake well, leave standstill, divide water-yielding stratum; Add 2000 milliliter of 5% dilute hydrochloric acid solution in the organic layer and extract, set acid, aqueous solution slowly are added dropwise to 20% sodium hydroxide; Be neutralized to pH8-9, with 2000ml dichloromethane extraction three times, the set dichloromethane solution; With 200ml water washing dichloromethane solution 2 times, anhydrous sodium sulfate drying, decompression steams solvent to doing; Get 1-[(1-nafoxidine alkyl carbonyl) methyl]-4-(3,4,5-trimethoxy cinnamoyl)-piperazine;
3) lucifuge under the condition of nitrogen protection, is got the 200g cinepazide, adds anhydrous acetonitrile 4000ml, heating; After making material dissolution, backflow 15min, the room temperature cooling is placed after the 24h; Filter, collect crystal, reduced pressure at room temperature 10h gets cinepazide compositions 1 of the present invention.
The preparation of embodiment 9 cinepazide mesylates (calling " compositions 2 " in the following text)
1) lucifuge under the condition of nitrogen protection, is got the cinepazide chemical compound 10g (24mmol) that makes among the embodiment 1; Drop in the reaction bulb, add 50ml ethanol, stirring and dissolving; Under agitation drip then in 2.9g methanesulfonic acid (25mmol)/50ml ethanol; Leave standstill 1h after dropwising, the freezing crystallize of reactant liquor obtains off-white color methanesulfonic acid cinepazide bullion; Bullion is joined in the 90ml ethanol, be heated with stirring to backflow, treat that solid dissolves back solution cooling crystallization entirely, obtains the white crystalline powder of cinepazide mesylate;
2) lucifuge under the condition of nitrogen protection, is got the 20g methanesulfonic acid cinepazide, adds anhydrous propanone 30ml; Reflux slowly drips methanol then, to the 15min that refluxes again after solid just dissolves; The room temperature cooling is placed after the 24h, filters; Collect crystal, reduced pressure at room temperature 10h promptly gets cinepazide mesylate of the present invention.
The preparation of embodiment 10 cinepazide maleates (calling " compositions 3 " in the following text)
1) lucifuge under the condition of nitrogen protection, is got the cinepazide chemical compound 10g that makes referring to method for preparing among the embodiment 1, drops in the reaction bulb, adds 50ml ethanol then, after the stirring and dissolving, and Dropwise 5 g under agitation then.Maleic acid leaves standstill 1h after dropwising in 30ml ethanol, with the freezing crystallize of reactant liquor, obtain the off-white color bullion then.Bullion is joined in the 60ml ethanol, be heated with stirring to backflow, treat that solid dissolves back solution cooling crystallization entirely, obtains little yellow cinepazide maleate powder.
2) lucifuge under the condition of nitrogen protection, is got the 20g Cinepazide Maleate, adds anhydrous propanone 30ml; Reflux slowly drips water then, to the 15min that refluxes again after solid just dissolves; The room temperature cooling is placed after the 24h, filters; Collect crystal, reduced pressure at room temperature 10h gets cinepazide maleate of the present invention.
The phosphatic preparation of embodiment 11 cinepazides (calling " compositions 4 " in the following text)
1) lucifuge under the condition of nitrogen protection, is got the cinepazide chemical compound 15g (36mmol) that makes referring to method for preparing among the embodiment 1; Drop in the reaction bulb, add 50ml ethanol then, after the stirring and dissolving; Under agitation drip 4.2g phosphoric acid (36mmol)/10ml ethanol then; Leave standstill 1h after dropwising, with the freezing crystallize of reactant liquor, obtain the off-white color bullion then.Bullion is joined in the 60ml ethanol, be heated with stirring to backflow, treat that solid dissolves back solution cooling crystallization entirely, obtains little yellow cinepazide phosphate powder.
2) lucifuge under the condition of nitrogen protection, is got 20g phosphoric acid cinepazide, adds anhydrous propanone 30ml; Reflux slowly drips water then, to the 15min that refluxes again after solid just dissolves; The room temperature cooling is placed after the 24h, filters; Collect crystal, reduced pressure at room temperature 10h gets cinepazide phosphate of the present invention.
The preparation of embodiment 12 cinepazide tartrates (calling " compositions 5 " in the following text)
1) lucifuge under the condition of nitrogen protection, is got the cinepazide chemical compound 10g (24mmol) that makes referring to method for preparing among the embodiment 1; Drop in the reaction bulb, add 50ml ethanol then, after the stirring and dissolving; Under agitation drip 3.8g tartaric acid (25mmol)/50ml alcoholic solution then; Leave standstill 1h after dropwising, with the freezing crystallize of reactant liquor, obtain the off-white color bullion then.Bullion is joined in the 60ml ethanol, be heated with stirring to backflow, treat that solid dissolves back solution cooling crystallization entirely, obtains little yellow cinepazide tartrate powder.
2) lucifuge under the condition of nitrogen protection, is got 20g tartaric acid cinepazide, adds anhydrous propanone 30ml; Reflux slowly drips water then, to the 15min that refluxes again after solid just dissolves; The room temperature cooling is placed after the 24h, filters; Collect crystal, reduced pressure at room temperature 10h gets the cinepazide tartrate.
The preparation of embodiment 13 cinepazide sulfate (calling " compositions 6 " in the following text)
1) lucifuge under the condition of nitrogen protection, is got the cinepazide chemical compound 15g that makes referring to method for preparing among the embodiment 1; Drop in the reaction bulb, add 50ml ethanol then, after the stirring and dissolving; Under agitation drip then in 3.8g sulphuric acid (about 36mmol)/10ml ethanol; Leave standstill 1h after dropwising, with the freezing crystallize of reactant liquor, obtain the off-white color bullion then.Bullion is joined in the 60ml ethanol, be heated with stirring to backflow, treat that solid dissolves back solution cooling crystallization entirely, obtains little yellow cinepazide sulfate powder.
2) lucifuge under the condition of nitrogen protection, is got 20g sulphuric acid cinepazide, adds anhydrous propanone 30ml; Reflux slowly drips water then, to the 15min that refluxes again after solid just dissolves; The room temperature cooling is placed after the 24h, filters; Collect crystal, reduced pressure at room temperature 10h gets cinepazide sulfate.
The preparation of embodiment 14 cinepazide succinates (calling " compositions 7 " in the following text)
1) lucifuge under the condition of nitrogen protection, is got the cinepazide chemical compound 10g (24mmol) that makes referring to method for preparing among the embodiment 1; Drop in the reaction bulb, add 50ml ethanol then, after the stirring and dissolving; Under agitation drip 2.9g succinic acid (25mmol)/30ml ethanol then; Leave standstill 1h after dropwising, with the freezing crystallize of reactant liquor, obtain the off-white color bullion then.Bullion is joined in the 60ml ethanol, be heated with stirring to backflow, treat that solid dissolves back solution cooling crystallization entirely, obtains little yellow cinepazide succinate powder.
2) lucifuge under the condition of nitrogen protection, is got 20g succinic acid cinepazide, adds anhydrous propanone 30ml; Reflux slowly drips water then, to the 15min that refluxes again after solid just dissolves; The room temperature cooling is placed after the 24h, filters; Collect crystal, reduced pressure at room temperature 10h gets the cinepazide succinate.
The study on the stability of embodiment 15 pharmaceutical compositions of the present invention
Test method
Get pharmaceutical composition 1-7 of the present invention and existing raw material (the cinepazide raw material that promptly makes), add mobile phase, be made into the need testing solution of 0.5mg/1ml without the inventive method; Get 100 times of part need testing solution dilutions again, as contrast solution; It is an amount of that other gets cinepazide oxynitride reference substance, adds mobile phase, its dilution processed the reference substance solution of 5 μ g/ml; Carry out high performance liquid chromatogram and detect, the result sees table 6.
The study on the stability of table 6 pharmaceutical composition of the present invention
Visible by table 6; Pharmaceutical composition of the present invention was deposited 24 months; Can the content of related substance be controlled in the safety range; Especially can the cinepazide oxynitride content in the pharmaceutical composition be controlled in 0.20%, with effective reduction or avoid untoward reaction such as leukopenia or the agranulocytosis of cinepazide due to clinical, realize safe medication.
The activity research of embodiment 16 cinepazide oxynitrides
1, supply the examination insecticide: 3 ages are armyworm larvae in earlier stage, is provided by insectary, Xibei Univ. of Agricultural & Forest Science & Technology public nuisance-free agricultural chemicals research center;
2, test sample: get chemical compound shown in the 5mg formula III of the present invention, add 5mL water, be made into the medicinal liquid of 1mg/mL; Reference substance is a water.
3, give birth to the survey method: adopt lobule butterfly additive process
At diameter is culture dish bottom shop one deck filter paper of 9 centimetres, and adds water and preserve moisture.The armyworm larvae in early stage in 3 ages that 10 sizes of every ware picking are consistent, healthy and strong.Leaf of Semen Maydis is cut into 1 * 1 centimetre little leaf butterfly, in medicinal liquid to be measured, soaked 3 seconds, dry the back and feed the examination worm.With water is the blank group.10 of every processing repeat 3 times.In under the room temperature (about 25 ℃), humidity 65%-80%, light application time raise under 12 hours/12 hours the condition.After 48 hours, feed with normal leaf butterfly until emergence.The food ingestion of periodic logging insect, survivor of a murder attempt's number, reveal any symptoms etc., and according to formula calculating examination worm 24 hours, 48 hours refusing to eat rate and mortality rate.
Refusing to eat rate (%)=(the average food ingestion of the average food ingestion-processed group of matched group)/(the average food ingestion of matched group) * 100%;
Final mortality rate (%)=(the dead number of examination worm)/(the total number of examination worm) * 100%;
Correct mortality rate (%)=(handling mortality rate-contrast mortality rate)/(1-contrasts mortality rate) * 100%
The result sees table 7.
Table 7 formula III chemical compound to 3 age mythimna separata the refusing to eat toxic effect
Visible by table 7, formula III chemical compound of the present invention has insecticidal activity preferably, can be used for preparing insecticide.
The preparation of embodiment 17 injection of the present invention
1, prescription:
Prescription 1
2, preparation technology
(1) will produce with the ampoule dosing with vessel, instrument and equipment etc. clear up, degerming, depyrogenation;
(2) take by weighing raw material and adjuvant by prescription;
(3) get the water for injection that antioxidant adds dosing amount 80%, stirring and dissolving;
(4) in solution, add compositions 2 or 3, stirring and dissolving, the needle-use activated carbon of adding dosing amount 0.05% stirs 15min, filters, and takes off charcoal;
(5) add an amount of Na
2HPO
4, the pH value of regulator solution;
(6) benefit adds to the full amount of water for injection standardize solution;
(7) medicinal liquid is checked clarity through the microporous filter membrane fine straining of 0.22 μ m;
(8) inspection of semifinished product;
(9) medicinal liquid is loaded in the ampoule;
(10) 121 ℃ of sterilization 15min;
(11) leak detection, lamp inspection;
(12) packing warehouse-in, finished product is examined entirely.
The study on the stability of table 8 injection of the present invention
Visible by table 8; Injection of the present invention was deposited 24 months; Can the content of related substance be controlled in the safety range; Especially can be controlled in 0.20% by cinepazide oxynitride content, with effective reduction or avoid untoward reaction such as leukopenia or the agranulocytosis of cinepazide due to clinical, realize safe medication.
Claims (10)
1. safe pharmaceutical composition, said pharmaceutical composition contain cinepazide or its pharmaceutically acceptable salt and content and are not higher than structural compounds shown in 0.5% the formula III,
2. pharmaceutical composition according to claim 1, the content of said formula III chemical compound is not higher than 0.4%.
3. pharmaceutical composition according to claim 2, the content of said formula III chemical compound is not higher than 0.3%.
4. pharmaceutical composition according to claim 3, the content of said formula III chemical compound is not higher than 0.2%.
5. according to each described pharmaceutical composition of claim 1-4; Said Pharmaceutical composition contains content and is not less than 98% cinepazide or its pharmaceutically acceptable salt; Content is not higher than 0.20% cinepazide oxynitride; Content is not higher than 1.0% cinepazide cis-isomer, and surplus is other related substances.
6. pharmaceutical composition according to claim 5, described cinepazide pharmaceutically acceptable salt are selected from any or its combination of maleate, mesylate, sulfonate, sulfate, hydrochlorate, hydrobromate, phosphate, nitrate, tosilate, tartrate, fumarate, citrate, acetate, formates, benzoate, cinnamate, succinate, malonate, citrate.
7. a method for preparing each said pharmaceutical composition of claim 1-6 is characterized in that, in lucifuge, and under the condition of anaerobic, intermediate, cinepazide or its pharmaceutically acceptable salt of preparation cinepazide.
8. safe pharmaceutical preparation, said preparation is made up of each described pharmaceutical composition of claim 1-6 and pharmaceutically acceptable carrier.
9. a method for preparing the cinepazide injection is characterized in that, in lucifuge, under the anaerobic protective condition, each described pharmaceutical composition of claim 1-6 and pharmaceutically acceptable injection carrier is mixed.
10. each described pharmaceutical composition of claim 1-6 or the described pharmaceutical preparation of claim 8 application that is used for preparing the medicine of controlling cardiovascular and cerebrovascular disease in advance.
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| CN1631877A (en) * | 2004-11-22 | 2005-06-29 | 北京四环制药有限公司 | Synthesis method of cinepazide maleate |
| CN101204372A (en) * | 2007-12-17 | 2008-06-25 | 车冯升 | Cinepazide maleate injection and preparation method thereof |
| CN101260092A (en) * | 2008-04-14 | 2008-09-10 | 罗军 | Method for preparing cinepazide maleate |
| CN101376648A (en) * | 2008-02-01 | 2009-03-04 | 北京四环制药有限公司 | Cinepazide maleate crystal form and preparation thereof |
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| CN1631877A (en) * | 2004-11-22 | 2005-06-29 | 北京四环制药有限公司 | Synthesis method of cinepazide maleate |
| CN101204372A (en) * | 2007-12-17 | 2008-06-25 | 车冯升 | Cinepazide maleate injection and preparation method thereof |
| CN101376648A (en) * | 2008-02-01 | 2009-03-04 | 北京四环制药有限公司 | Cinepazide maleate crystal form and preparation thereof |
| CN101260092A (en) * | 2008-04-14 | 2008-09-10 | 罗军 | Method for preparing cinepazide maleate |
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