CN101058566A - Novel medicinal salt for cinepazide and preparation method thereof - Google Patents

Novel medicinal salt for cinepazide and preparation method thereof Download PDF

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CN101058566A
CN101058566A CN 200610110549 CN200610110549A CN101058566A CN 101058566 A CN101058566 A CN 101058566A CN 200610110549 CN200610110549 CN 200610110549 CN 200610110549 A CN200610110549 A CN 200610110549A CN 101058566 A CN101058566 A CN 101058566A
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cinepazide
pharmaceutical salts
acid
tartrate
preparation
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CN100584835C (en
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车冯升
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Jilin Huikang Pharmaceutical Co Ltd
Beijing Sihuan Pharmaceutical Co Ltd
Tonghua Jida Pharmaceutical Co Ltd
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Abstract

The invention discloses a new medicinal salt of (E)-1-{4-[(3',4',5'-trimethoxy cinnamon acyl]-1-piperazidine} acetopyrrole as cinprazole, especially for methanesulphonate, citrate, succinate and tartrate, which provides the making method and application to treat and/or prevent cardiovascular and cerebrovascular disease and peripheral vessel disease. The drug possesses good stability and superior solubility, which can be made into acceptable pharmacy agent.

Description

New pharmaceutical salts of cinepazide and preparation method thereof
1, technical field
The present invention relates to (E)-1-{4-[(3 ', 4 ', 5 '-the trimethoxy cinnamoyl)]-the 1-piperazine } the acetyl-pyrrole pyridine is new pharmaceutical salts of cinepazide and its production and use, belongs to medical technical field.
2, background technology
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 Cinepazide Maleate (Cinepazide Maleate) of external development is owing to determined curative effect, and untoward reaction is little, in developed country's widespread uses such as Europe, Japan.China is also successfully imitated and formally be used for clinical.
Cinepazide Maleate is by the exploitation of French Sanofi-Aventis company, and 1974 at first in France's listing, after this successively in listings such as European countries, Japan, goes on the market in China in 2002.Cinepazide Maleate has the dual vasodilation mechanism of adenosine, cAMP synergy and the retardance of weak calcium ion, and its pharmacological action is: (1) selectivity suppresses Ca 2+In the 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; (2) effect of enhancing adenosine and cyclic monophosphate (cAMP) reduces the oxygen consumption; (3) suppress the cAMP phosphodiesterase, cAMP quantity is increased; (4) improve erythrocytic snappiness and deformability, improve its ability, reduce the viscosity of blood, microcirculation improvement by minute blood vessel; (5) by improving cerebrovascular volume of blood flow, improve the metabolism of brain.Clinically be mainly used in following treatment of diseases: (1) cerebrovascular disease: cerebral arteriosclerosis, transient cerebral ischemic attack, cerebral thrombosis, cerebral embolism, apoplexy sequela and cerebral trauma sequela; (2) cardiovascular disorder: coronary heart disease, stenocardia, as be used for the treatment of myocardial infarction, should cooperate relevant comprehensive drug treatment; (3) peripheral vascular disease: artery of lower extremity atheromatosis, thromboangiitis obliterans, arteritis, Raynaud disease etc.
The chemistry of cinepazide is by name: (E)-and 1-{4-[(3 ', 4 ', 5 '-the trimethoxy cinnamoyl)]-the 1-piperazine } the acetyl-pyrrole pyridine, structural formula is as follows:
Figure A20061011054900031
The cinepazide maleate injection of present domestic listing needs shading, airtight preservation during storage, see that auroral poles easily decomposes; Often be dissolved in glucose injection or the physiological saline intravenous drip clinically.
3, summary of the invention
The purpose of this invention is to provide (E)-1-{4-[(3 '; 4 ', 5 '-the trimethoxy cinnamoyl)]-the 1-piperazine } the acetyl-pyrrole pyridine is new pharmaceutical salts of cinepazide and preparation method thereof and is used for the treatment of and/or prevents purposes in the medicine of cardiovascular and cerebrovascular and peripheral vascular disease in preparation.
For solubleness and the stability of better improving cinepazide, we have carried out a large amount of screening operations, the organic carboxylate and the alkylsulfonate that are surprised to find cinepazide now demonstrate solvability and the stability more excellent than maleate, especially the mesylate of cinepazide, citrate, succinate and tartrate more show beyond thought superiority, cinepazide and methylsulfonic acid in its molecular formula, Citric Acid, Succinic Acid, tartaric mole proportioning is 1: 0.5～1: 5, be preferably 1: 1,1: 2 or 1: 3, the best is 1: 1, preferred especially methanesulfonic acid cinepazide (C 22H 31N 3O 5CH 3SO 3H).
The preparation method of the above-mentioned salt of cinepazide of the present invention is: cinepazide and acid (as: methylsulfonic acid, Citric Acid, Succinic Acid, tartrate) in the water-containing organic solvent or organic solvent of lower alcohol, ketone, ester, are carried out to reactant salt, crude product.Wherein, cinepazide is 1: 0.5～1: 10 with the mole proportioning of acid.Reaction solution is preferably in-10～30 ℃ of temperature ranges and is stirred, and leaves standstill 0.1～10h then.In order to improve purity, the gained crude product also can be dissolved in the solvent again, further places crystallization, is preferably in to place 0.1～10h under low temperature or the normal temperature, gets highly finished product.Must notice that all operations must carry out under lucifuge.
The structural formula of the methanesulfonic acid cinepazide for preparing as stated above is listed below, and only limits to following invention but should not be construed as:
Methanesulfonic acid cinepazide (C 22H 31N 3O 5CH 3SO 3H) structural formula is as follows:
Figure A20061011054900041
Methanesulfonic acid cinepazide (C 22H 31N 3O 52CH 3SO 3H) structural formula is as follows:
Figure A20061011054900042
Methanesulfonic acid cinepazide (C 22H 31N 3O 53CH 3SO 3H) structural formula is as follows:
Figure A20061011054900043
The structural formula of the Citric Acid cinepazide for preparing as stated above is listed below, and only limits to following invention but should not be construed as:
Citric Acid cinepazide (C 22H 31N 3O 5C 6H 8O 7) structural formula as follows:
Citric Acid cinepazide (C 22H 31N 3O 52C 6H 8O 7) structural formula as follows:
Figure A20061011054900051
Citric Acid cinepazide (C 22H 31N 3O 53C 6H 8O 7) structural formula as follows:
Figure A20061011054900052
The structural formula of the Succinic Acid cinepazide for preparing as stated above is listed below, and only limits to following invention but should not be construed as:
Succinic Acid cinepazide (C 22H 31N 3O 5(CH 2COOH) 2) structural formula as follows:
Figure A20061011054900053
Succinic Acid cinepazide (C 22H 31N 3O 52 (CH 2COOH) 2) structural formula as follows:
Figure A20061011054900054
Succinic Acid cinepazide (C 22H 31N 3O 53 (CH 2COOH) 2) structural formula as follows:
Figure A20061011054900055
The structural formula of the tartrate cinepazide for preparing as stated above is listed below, and only limits to following invention but should not be construed as:
Tartrate cinepazide (C 22H 31N 3O 5C 4H 6O 6) structural formula as follows:
Tartrate cinepazide (C 22H 31N 3O 52C 4H 6O 6) structural formula as follows:
Figure A20061011054900062
Tartrate cinepazide (C 22H 31N 3O 53C 4H 6O 6) structural formula as follows:
Figure A20061011054900063
The new pharmaceutical salts of the further claimed cinepazide of the present invention is used for the treatment of and/or prevents application in the medicine of cardiovascular and cerebrovascular and peripheral vascular disease in preparation.The new pharmaceutical salts of cinepazide can be passed through hemato encephalic barrier, has unique endogenous adenosine synergism, gentle calcium antagonism, hemorheology be can improve, erythrocytic snappiness and blood viscosity lowering increased, anticoagulant, can block the ischemic cascade reaction by multipath, and blood pressure, heart rate had no adverse effects, safe in utilization, no obvious toxic-side effects.
The new pharmaceutical salts of cinepazide of the present invention can be made pharmaceutical composition with other active pharmaceutical ingredients, also can make pharmaceutical composition, be applied to the patient of this treatment of needs in the mode of parenteral or oral administration with one or more pharmaceutically acceptable carriers and/or thinner.
Contain in the aforementioned pharmaceutical compositions by (E)-1-{4-[(3 '; 4 '; 5 '-the trimethoxy cinnamoyl)]-the 1-piperazine } the acetyl-pyrrole pyridine is the active ingredient of cinepazide meter 10～500mg; for example can be 10mg; 20mg; 40mg; 60mg; 62.5mg; 62.6mg; 80mg; 100mg; 120mg; 125mg; 125.2mg; 150mg; 156.5mg; 160mg; 180mg; 200mg; 250mg; 300mg; 350mg; 400mg; 450mg; 500mg, preferred 60mg; 62.5mg; 62.6mg; 80mg; 100mg; 120mg; 125mg; 125.2mg; 150mg; 156.5mg; 160mg; 180mg; 200mg; 250mg; 300mg.
When being used for administered parenterally, can be made into injection, injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution, comprises injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, it indicates loading amount can be 0.5ml, 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and the large volume injection liquid of using for intravenous drip that generally is not less than 100ml also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension that sterilized powder can make with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When being used for oral administration, conventional solid preparation be can be made into, tablet, capsule, granule, pill and oral solution etc. comprised.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form; Tablet is based on oral ordinary tablet, and other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material; Capsule can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule according to its dissolving and release characteristics.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size; Granule can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Pill means medicine and suitable auxiliary material uniform mixing, the spherical or near-spherical solid preparation made from proper method; Pill comprises dripping pill, sugar-pill, piller etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.
The preparation of the new pharmaceutical salts of cinepazide of the present invention can adopt the ordinary method production in the existing pharmacy field, can add various pharmaceutically acceptable carriers when needing.Described carrier comprises osmotic pressure regulator, pH value conditioning agent, solubilizing agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent, weighting agent, tackiness agent, disintegrating agent, lubricant of pharmaceutical field routine etc.
The new pharmaceutical salts of cinepazide of the present invention is when making injection, solvent for use can be aqueous solvent and non-aqueous solvent, also can add suitable additives, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.The most frequently used aqueous solvent of aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; The non-aqueous solvent that non-aqueous solvent is commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid+sodium-acetate, lactic acid, Citric Acid+Sodium Citrate, sodium bicarbonate+sodium carbonate etc.; Expanding material commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Oxidation inhibitor commonly used comprises S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used comprises phenol, cresols, trichloro-butyl alcohol, phenylcarbinol etc.
The new pharmaceutical salts of cinepazide of the present invention can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc. when making oral preparations.Weighting agent comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Tackiness agent comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Lubricant comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
The aqueous solution of the mesylate of cinepazide of the present invention, citrate, succinate and tartrate under illumination 4500Lx condition, place 5 days with the aqueous solution of cinepazide maleate relatively, its stability to light has beyond thought improvement, the results are shown in Table 1.
The comparison (10 days) of the pharmaceutical salts that table 1 cinepazide is new and the aqueous solution of Cinepazide Maleate stability under illumination 4500Lx condition
Title 0 day 10 days
Solution colour Content Solution colour Content
Cinepazide Maleate Colourless 99.3％ Colourless 17.2％
Methanesulfonic acid cinepazide (C 22H 31N 3O 5·CH 3SO 3H) Colourless 99.6％ Colourless 29.1％
Methanesulfonic acid cinepazide (C 22H 31N 3O 5·2CH 3SO 3H) Colourless 99.5％ Colourless 24.1％
Methanesulfonic acid cinepazide (C 22H 31N 3O 5·3CH 3SO 3H) Colourless 99.4％ Colourless 20.1％
Citric Acid cinepazide (C 22H 31N 3O 5·C 6H 8O 7) Little yellow 99.5％ Little yellow 26.5％
Succinic Acid cinepazide (C 22H 31N 3O 5·(CH 2COOH) 2) Little yellow 99.7％ Little yellow 24.3％
Succinic Acid cinepazide (C 22H 31N 3O 5·2(CH 2COOH) 2) Little yellow 99.1％ Little yellow 21.3％
Tartrate cinepazide (C 22H 31N 3O 5·C 4H 6O 6) Colourless 99.2％ Colourless 26.6％
Tartrate cinepazide (C 22H 31N 3O 5·2C 4H 6O 6) Colourless 99.4％ Colourless 23.5％
Tartrate cinepazide (C 22H 31N 3O 5·3C 4H 6O 6) Colourless 99.5％ Colourless 22.8％
Cinepazide mesylate of the present invention, citrate and the solubility property of succinate in water are far superior to the cinepazide maleate, the results are shown in Table 2.
Pharmaceutical salts that table 2 cinepazide of the present invention is new and the cinepazide maleate solubleness in water relatively
Solubleness Water (25 ℃, mg/ml)
Cinepazide Maleate 485
Methanesulfonic acid cinepazide (C 22H 31N 3O 5·CH 3SO 3H) 1320
Methanesulfonic acid cinepazide (C 22H 31N 3O 5·2CH 3SO 3H) 1250
Methanesulfonic acid cinepazide (C 22H 31N 3O 5·3CH 3SO 3H) 1200
Citric Acid cinepazide (C 22H 31N 3O 5·C 6H 8O 7) 1150
Succinic Acid cinepazide (C 22H 31N 3O 5·(CH 2COOH) 2) 1080
Tartrate cinepazide (C 22H 31N 3O 5·C 4H 6O 6) 550
Tartrate cinepazide (C 22H 31N 3O 5·2C 4H 6O 6) 520
Tartrate cinepazide (C 22H 31N 3O 5·3C 4H 6O 6) 500
The mesylate of cinepazide of the present invention, citrate, succinate and tartrate raw material under the condition of 60 ℃ of high temperature, place 5 days with cinepazide maleate raw material ratio, the result shows that mesylate, citrate, succinate and the tartrate resistance and high temperature resistance property of cinepazide are better than maleate.The results are shown in Table 3.
The comparison (10 days) of pharmaceutical salts that table 3 cinepazide is new and cinepazide maleate stability under 60 ℃ of conditions of high temperature
Title 0 day 10 days
Proterties Content Proterties Content
Cinepazide Maleate White powder 99.3％ White powder 94.2％
Methanesulfonic acid cinepazide (C 22H 31N 3O 5·CH 3SO 3H) White powder 99.6％ White powder 99.0％
Methanesulfonic acid cinepazide (C 22H 31N 3O 5·2CH 3SO 3H) White powder 99.2％ White powder 98.1％
Methanesulfonic acid cinepazide (C 22H 31N 3O 5·3CH 3SO 3H) White powder 99.4％ White powder 98.6％
Citric Acid cinepazide (C 22H 31N 3O 5·C 6H 8O 7) Micro-yellow powder 99.3％ Micro-yellow powder 98.0％
Succinic Acid cinepazide (C 22H 31N 3O 5·(CH 2COOH) 2) Micro-yellow powder 99.3％ Micro-yellow powder 97.4％
Tartrate cinepazide (C 22H 31N 3O 5·C 4H 6O 6) White powder 99.5％ White powder 98.8％
Tartrate cinepazide (C 22H 31N 3O 5·2C 4H 6O 6) White powder 99.6％ White powder 99.1％
Tartrate cinepazide (C 22H 31N 3O 5·3C 4H 6O 6) White powder 99.3％ White powder 98.7％
(E)-1-{4-[(3 ' of the present invention; 4 '; 5 '-the trimethoxy cinnamoyl)]-the 1-piperazine } the acetyl-pyrrole pyridine is that cinepazide new pharmaceutical salts, especially mesylate, citrate, succinate and tartrate are compared with the cinepazide maleate, has the following advantages:
(1) finds that first the organic carboxylate of cinepazide and alkylsulfonate show surprising solvability, especially its mesylate, citrate, succinate and tartrate.
(2) compare with the cinepazide maleate, cinepazide mesylate, citrate, succinate and tartrate were placed 5 days under the condition of 60 ℃ of high temperature, and the result shows that mesylate, citrate, succinate and the tartrate resistance and high temperature resistance property of cinepazide are better than maleate.
(3) compare with the aqueous solution of cinepazide maleate, the aqueous solution of cinepazide mesylate, citrate, succinate and tartrate was placed 5 days under illumination 4500Lx condition, its stability to light improves significantly, helps storing and improving the security of clinical application.
(4) compare with the cinepazide maleate, cinepazide mesylate, citrate and the succinate solubleness in water improves nearly 1 times, therefore can improve the bioavailability of this product greatly, the performance better therapeutic.
(5) provide the preferred preparation method of cinepazide mesylate, citrate, tartrate and succinate, technology is simple, and cost is low, and medicine purity height, yield height, steady quality are suitable for scale production.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
The preparation (1) of embodiment 1 methanesulfonic acid cinepazide
Get cinepazide 10g (24mmol), drop in the reaction flask, add 50ml ethanol, after the stirring and dissolving, under agitation drip 2.9g methylsulfonic acid (25mmol)/50ml ethanol then, leave standstill 1h after dropwising, with the freezing crystallization of reaction solution, obtain off-white color methanesulfonic acid cinepazide crude product then.Crude product is joined in the 90ml ethanol, be heated with stirring to backflow, treat the complete molten back of solid solution cooling crystallization, obtain white crystalline powder 9.5g, yield: 77.2%.
1H-NMR(600MHz，DMSO)δ：1.94[m，4H]，1.98[brs，1H]，2.57[m，4H]，2.75[s，3H]，3.01[m，4H]，3.19[s，2H]，3.42[m，4H]，3.69[s，9H]，6.23[s，2H]，6.94[d，1H]，7.47[d，1H]
IR(KBr)cm -1：3442，2951，2868，2585，1657，1448，1425，1271，1232，1035，765，557，531
Ultimate analysis (C 22H 31N 3O 5CH 3SO 3H): C, 53.70%; H, 6.94%; N, 8.17%; S, 6.23% (theory: C, 53.79%; H, 6.87%; N, 8.18%; S, 6.24%)
The preparation (2) of embodiment 2 methanesulfonic acid cinepazides
Get cinepazide 10g (24mmol), drop in the reaction flask, add 50ml ethanol, after the stirring and dissolving, Dropwise 5 .8g methylsulfonic acid (50mmol)/80ml ethanol under agitation dropwises back 40 ℃ and leaves standstill 1h then, with the freezing crystallization of reaction solution, obtain off-white color methanesulfonic acid cinepazide crude product then.Crude product is joined in the 100ml ethanol, be heated with stirring to backflow, treat the complete molten back of solid solution cooling crystallization, obtain white crystalline powder 11.1g, yield: 76.0%.
1H-NMR(600MHz，DMSO)δ：1.92[m，4H]，1.96[brs，2H]，2.55[m，4H]，2.78[s，6H]，3.04[m，4H]，3.22[s，2H]，3.43[m，4H]，3.71[s，9H]，6.24[s，2H]，6.95[d，1H]，7.48[d，1H]
IR(KBr)cm -1：3440，2940，2877，2583，1653，1453，1421，1276，1224，1037，772，552，535
Ultimate analysis (C 22H 31N 3O 52CH 3SO 3H): C:47.21%, H:6.48%, N:6.82%, S:10.49% (theory: C, 47.28%; H, 6.45%; N, 6.89%; S, 10.52%)
The preparation (3) of embodiment 3 methanesulfonic acid cinepazides
Get cinepazide 10g (24mmol), drop in the reaction flask, add 50ml ethanol then, after the stirring and dissolving, under agitation drip 8.7g methylsulfonic acid (75mmol)/120ml ethanol then, dropwise post-heating backflow 1h, leave standstill 1h, with the freezing crystallization of reaction solution, obtain off-white color methanesulfonic acid cinepazide crude product then.Crude product is joined in the 120ml ethanol, be heated with stirring to backflow, treat the complete molten back of solid solution cooling crystallization, obtain white crystalline powder 12.5g, yield: 73.9%.
1H-NMR(600MHz，DMSO)δ：1.99[m，4H]，2.05[brs，3H]，2.64[m，4H]，2.82[s，9H]，3.08[m，4H]，3.26[s，2H]，3.48[m，4H]，3.76[s，9H]，6.27[s，2H]，7.03[d，1H]，7.57[d，1H]
IR(KBr)cm -1：3435，2946，2875，2581，1651，1458，1427，1274，1229，1042，775，557，528
Ultimate analysis (C 22H 31N 3O 53CH 3SO 3H): C, 42.48%; H, 6.22%; N, 5.93%; S, 13.61% (theory: C, 42.54%; H, 6.14%; N, 5.95%; S, 13.63%)
The preparation (1) of embodiment 4 Citric Acid cinepazides
Get cinepazide 10g (24mmol), drop in the reaction flask, add 50ml ethanol then, after the stirring and dissolving, under agitation drip 4.8g Citric Acid (25mmol)/40ml ethanol then, leave standstill 1h after dropwising, with the freezing crystallization of reaction solution, obtain little yellow Citric Acid cinepazide crude product then.Crude product is joined in the 50ml ethanol, be heated to dissolving slightly, the solution cooling crystallization obtains little yellow solid powder 9.7g, yield: 66.4%.
1H-NMR(600MHz，DMSO)δ：2.02[m，4H]，2.05[m，1H]，2.62[m，4H]，2.65[m，4H]，3.09[m，4H]，3.29[s，2H]，3.52[m，4H]，3.78[s，9H]，6.33[s，2H]，7.05[d，1H]，7.56[d，1H]，11.33[brs，3H]
IR(KBr)cm -1：3434，2938，2867，2561，1775，1705，1648，1440，1422，1274，1222，1032，762，555，528
Ultimate analysis (C 22H 31N 3O 5C 6H 8O 7): C, 55.11%; H, 6.50%; N, 6.87% (theory: C, 55.17%; H, 6.45%; N, 6.89%)
The preparation (2) of embodiment 5 Citric Acid cinepazides
Get cinepazide 10g (24mmol), drop in the reaction flask, add 50ml ethanol then, after the stirring and dissolving, under agitation drip 9.6g Citric Acid (50mmol)/60ml ethanol then, leave standstill 1h after dropwising, with the freezing crystallization of reaction solution, obtain little yellow Citric Acid cinepazide crude product then.Crude product is joined in the 70ml ethanol, be heated to dissolving slightly, the solution cooling crystallization obtains little yellow solid powder 12.3g, yield: 64.1%.
1H-NMR(600MHz，DMSO)δ：1.99[m，4H]，2.06[m，2H]，2.63[m，8H]，2.68[m，4H]，3.12[m，4H]，3.28[s，2H]，3.53[m，4H]，3.78[s，9H]，6.35[s，2H]，7.06[d，1H]，7.58[d，1H]，11.38[brs，6H]
IR(KBr)cm -1：3433，2921，2867，2562，1774，1693，1640，1438，1427，1264，1224，1033，764，551，521
Ultimate analysis (C 22H 31N 3O 52C 6H 8O 7): C, 50.87%; H, 5.97%; N, 5.23% (theory: C, 50.93%; H, 5.91%; N, 5.24%)
The preparation (3) of embodiment 6 Citric Acid cinepazides
Get cinepazide 10g (24mmol), drop in the reaction flask, add 50ml ethanol then, after the stirring and dissolving, under agitation drip 14.4g Citric Acid (75mmol)/80ml ethanol then, dropwise post-heating backflow 1h, leave standstill 1h, with the freezing crystallization of reaction solution, obtain little yellow Citric Acid cinepazide crude product then.Crude product is joined in the 80ml ethanol, be heated to dissolving slightly, the solution cooling crystallization obtains little yellow solid powder 14.5g, yield: 60.9%.
1H-NMR(600MHz，DMSO)δ：2.02[m，4H]，2.09[m，3H]，2.63[m，12H]，2.67[m，4H]，3.14[m，4H]，3.32[s，2H]，3.54[m，4H]，3.77[s，9H]，6.34[s，2H]，7.06[d，1H]，7.54[d，1H]，11.42[brs，9H]
IR(KBr)cm -1：3438，2931，2857，2557，1765，1691，1634，1430，1422，1264，1215，1027，751，540，525
Ultimate analysis (C 22H 31N 3O 53C 6H 8O 7): C, 48.29%; H, 5.63%; N, 4.23% (theory: C, 48.34%; H, 5.58%; N, 4.23%)
The preparation (1) of embodiment 7 Succinic Acid cinepazides
Get cinepazide 10g (24mmol), drop in the reaction flask, 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 crystallization of reaction solution, obtain off-white color Succinic Acid cinepazide crude product then.Crude product is joined in the 60ml ethanol, be heated with stirring to backflow, treat the complete molten back of solid solution cooling crystallization, obtain little yellow crystalline powder 6.8g, yield: 53.0%.
1H-NMR(600MHz，DMSO)δ：2.03[m，4H]，2.56[s，4H]，2.68[m，4H]，3.13[m，4H]，3.31[s，2H]，3.50[m，4H]，3.77[s，9H]，6.30[s，2H]，7.03[d，1H]，7.64[d，1H]，11.42[brs，2H]
IR(KBr)cm -1：3434，2935，2866，2576，1782，1705，1643，1444，1423，1273，1219，1031，769，556，532
Ultimate analysis (C 22H 31N 3O 5(CH 2COOH) 2): C:58.28%, H:7.02%, N:7.83% (theory: C, 58.31%; H, 6.96%; N, 7.85%)
The preparation (2) of embodiment 8 Succinic Acid cinepazides
Get cinepazide 10g (24mmol), drop in the reaction flask, add 50ml ethanol then, after the stirring and dissolving, Dropwise 5 .8g Succinic Acid (49mmol)/40ml ethanol under agitation leaves standstill 1h after dropwising then, with the freezing crystallization of reaction solution, obtain off-white color Succinic Acid cinepazide crude product then.Crude product is joined in the 80ml ethanol, be heated with stirring to backflow, treat the complete molten back of solid solution cooling crystallization, obtain little yellow crystalline powder 8.2g, yield: 52.4%.
1H-NMR(600MHz，DMSO)δ：2.05[m，4H]，2.57[s，8H]，2.66[m，4H]，3.11[m，4H]，3.32[s，2H]，3.52[m，4H]，3.78[s，9H]，6.33[s，2H]，7.05[d，1H]，7.56[d，1H]，11.45[brs，4H]
IR(KBr)cm -1：3447，2928，2861，2566，1786，1700，1634，1458，1432，1264，1231，1038，764，552，538
Ultimate analysis (C 22H 31N 3O 52 (CH 2COOH) 2): C, 55.09%; H, 6.67%; N, 6.42% (theory: C, 55.12%; H, 6.63%; N, 6.43%)
The preparation (3) of embodiment 9 Succinic Acid cinepazides
Get cinepazide 10g (24mmol), drop in the reaction flask, add 50ml ethanol then, after the stirring and dissolving, under agitation drip 8.7g Succinic Acid (74mmol)/50ml ethanol then, dropwise post-heating backflow 1h, leave standstill 1h, with the freezing crystallization of reaction solution, obtain off-white color Succinic Acid cinepazide crude product then.Crude product is joined in the 100ml ethanol, be heated with stirring to backflow, treat the complete molten back of solid solution cooling crystallization, obtain little yellow crystalline powder 9.7g, yield: 52.5%.
1H-NMR(600MHz，DMSO)δ：2.04[m，4H]，2.59[s，12H]，2.68[m，4H]，3.14[m，4H]，3.33[s，2H]，3.54[m，4H]，3.78[s，9H]，6.33[s，2H]，7.06[d，1H]，7.59[d，1H]，11.45[brs，6H]
IR(KBr)cm -1：3424，2924，2854，2561，1774，1717，1640，1441，1427，1273，1214，1035，772，565，535
Ultimate analysis (C 22H 31N 3O 53 (CH 2COOH) 2): C, 52.88%; H, 6.44%; N, 5.43% (theory: C, 52.91%; H, 6.40%; N, 5.44%)
The preparation (1) of embodiment 10 tartrate cinepazides
Get cinepazide 10g (24mmol), drop in the reaction flask, add 50ml ethanol then, after the stirring and dissolving, under agitation drip 3.8g tartrate (25mmol)/50ml ethanolic soln then, dropwise post-heating backflow 1h, leave standstill 1h, with the freezing crystallization of reaction solution, obtain off-white color tartrate cinepazide crude product then.Crude product is joined in the 80ml ethanol, be heated with stirring to backflow, treat the complete molten back of solid solution cooling crystallization, obtain white crystalline powder 8.7g, yield: 64.0%.
1H-NMR(600MHz，DMSO)δ：2.03[m，4H]，2.08[brs，2H]，2.67[m，4H]，3.12[m，4H]，3.32[s，2H]，3.51[m，4H]，3.82[s，9H]，4.65[s，4H]，6.37[s，2H]，7.13[d，1H]，7.65[d，1H]，11.48[brs，2H]
IR(KBr)cm -1：3350，2973，2875，2563，1731，1650，1425，1308，1259，1135，1073，684
Ultimate analysis (C 22H 31N 3O 5C 4H 6O 6): C:54.92%, H:6.61%, N:7.36% (theory: C:55.02%, H:6.57%, N:7.40%)
The preparation (2) of embodiment 11 tartrate cinepazides
Get cinepazide 10g (24mmol), drop in the reaction flask, add 50ml ethanol then, after the stirring and dissolving, under agitation drip 7.6g tartrate (50mmol)/80ml ethanolic soln then, dropwise post-heating backflow 1h, leave standstill 1h, with the freezing crystallization of reaction solution, obtain off-white color tartrate cinepazide crude product then.Crude product is joined in the 100ml ethanol, be heated with stirring to backflow, treat the complete molten back of solid solution cooling crystallization, obtain white crystalline powder 11.4g, yield: 66.3%.
1H-NMR(600MHz，DMSO)δ：2.04[m，4H]，2.10[brs，4H]，2.69[m，4H]，3.13[m，4H]，3.33[s，2H]，3.53[m，4H]，3.79[s，9H]，4.63[s，8H]，6.35[s，2H]，7.05[d，1H]，7.58[d，1H]，11.42[brs，4H]
IR(KBr)cm -1：3342，2968，2871，2567，1734，1655，1422，1307，1251，1132，1078，687
Ultimate analysis (C 22H 31N 3O 52C 4H 6O 6): C, 50.17%; H, 6.08%; N, 5.85% (theory: C, 50.21%; H, 6.04%; N, 5.86%)
The preparation (3) of embodiment 12 tartrate cinepazides
Get cinepazide 10g (24mmol), drop in the reaction flask, add 50ml ethanol then, after the stirring and dissolving, under agitation drip 11.4g tartrate (75mmol)/100ml ethanolic soln then, dropwise post-heating backflow 2h, leave standstill 1h, with the freezing crystallization of reaction solution, obtain off-white color tartrate cinepazide crude product then.Crude product is joined in the 120ml ethanol, be heated with stirring to backflow, treat the complete molten back of solid solution cooling crystallization, obtain white crystalline powder 13.2g, yield: 63.5%.
1H-NMR(600MHz，DMSO)δ：2.02[m，4H]，2.06[brs，6H]，2.68[m，4H]，3.10[m，4H]，3.28[s，2H]，3.52[m，4H]，3.77[s，9H]，4.58[s，12H]，6.31[s，2H]，7.02[d，1H]，7.57[d，1H]，11.45[brs，6H]
IR(KBr)cm -1：3346，2965，2877，2566，1735，1658，1424，1301，1255，1132，1071，687
Ultimate analysis (C 22H 31N 3O 53C 4H 6O 6): C, 47.01%; H, 5.74%; N, 4.83% (theory: C, 47.06%; H, 5.69%; N, 4.84%)
The new pharmaceutical salts of used cinepazide is cinepazide mesylate, citrate, succinate or tartrate in following examples, is derived from the foregoing description 1-12.
The preparation of embodiment 13 cinepazide pharmaceutical salts injection liquids
1, prescription:
Prescription 1
The new pharmaceutical salts 62.6g (in cinepazide) of cinepazide
Sodium-chlor 45g
Water for injection 5000ml
Prepare 1000 altogether
Prescription 2
The new pharmaceutical salts 62.5g (in cinepazide) of cinepazide
Sodium-chlor 45g
Water for injection 5000ml
Prepare 1000 altogether
Prescription 3
The new pharmaceutical salts 125g (in cinepazide) of cinepazide
Sodium-chlor 45g
Water for injection 5000ml
Prepare 1000 altogether
Prescription 4
The new pharmaceutical salts 250g (in cinepazide) of cinepazide
Sodium-chlor 45g
Water for injection 5000ml
Prepare 1000 altogether
Prescription 5
Methanesulfonic acid cinepazide (C 22H 31N 3O 5CH 3SO 3H) 62.5g～250g (in cinepazide)
Sodium-chlor 45g
Water for injection 5000ml
Prepare 1000 altogether
2, preparation technology:
(1) will produce with the ampoule dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation;
(2) take by weighing raw material and auxiliary material by prescription;
(3) get the water for injection that sodium-chlor adds dosing amount 80%, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal;
(4) the new pharmaceutical salts of adding cinepazide in solution, stirring and dissolving;
(5) the pH value of survey solution is used anhydrous Na in case of necessity 2HPO 4Adjust pH;
(6) benefit adds to the full amount of water for injection constant volume;
(7) soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m;
(8) inspection of semifinished product;
(9) soup is loaded in the ampoule;
(10) 100 ℃ of flowing steam sterilization 30min;
(11) leak detection, the lamp inspection;
(12) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 14 cinepazide pharmaceutical salts powder injection
1, prescription:
Prescription 1
The new pharmaceutical salts 62.6g (in cinepazide) of cinepazide
Dextran 200g
Water for injection 2000ml
Prepare 1000 altogether
Prescription 2
The new pharmaceutical salts 62.5g (in cinepazide) of cinepazide
Dextran 200g
Water for injection 2000ml
Prepare 1000 altogether
Prescription 3
The new pharmaceutical salts 125g (in cinepazide) of cinepazide
Dextran 100g
Water for injection 2000ml
Prepare 1000 altogether
Prescription 4
The new pharmaceutical salts 250g (in cinepazide) of cinepazide
Dextran 100g
Water for injection 3000ml
Prepare 1000 altogether
Prescription 5
Methanesulfonic acid cinepazide (C 22H 31N 3O 5CH 3SO 3H) 62.5g～250g (in cinepazide)
Dextran 100g
Water for injection 2000ml
Prepare 1000 altogether
2, preparation technology:
(1) will produce used cillin bottle, plug and dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation;
(2) take by weighing raw material and auxiliary material by prescription;
(3) dextran is added dosing amount 80% water for injection, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% then stirs 15min, filters, and takes off charcoal;
(4) the new pharmaceutical salts of adding cinepazide in solution, stirring and dissolving;
(5) the pH value of survey solution is used anhydrous Na in case of necessity 2HPO 4Adjust pH;
(6) benefit adds to the full amount of water for injection constant volume;
(7) soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m;
(8) inspection of semifinished product;
(9) soup is sub-packed in the cillin bottle, half tamponade;
(10) sample is put in the Freeze Drying Equipment, adopted following freeze-dry process freeze-drying :-40 ℃ of pre-freezes 4 hours ,-30～0 ℃ of low-temperature vacuum drying 18 hours, 0～30 ℃ heated up dry 2 hours, 30 ℃ of freeze-day with constant temperature 2 hours;
(11) freeze-drying finishes tamponade, Zha Gai;
(12) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 15 cinepazide pharmaceutical salts sodium chloride injections
1, prescription:
Prescription 1
The new pharmaceutical salts 125.2g (in cinepazide) of cinepazide
Sodium-chlor 2250g
Water for injection 250000ml
Prepare 1000 bottles altogether
Prescription 2
The new pharmaceutical salts 250g (in cinepazide) of cinepazide
Sodium-chlor 2250g
Water for injection 250000ml
Prepare 1000 bottles altogether
Prescription 3
The new pharmaceutical salts 62.5g (in cinepazide) of cinepazide
Sodium-chlor 2250g
Water for injection 250000ml
Prepare 1000 bottles altogether
Prescription 4
The new pharmaceutical salts 62.6g (in cinepazide) of cinepazide
Sodium-chlor 2250g
Water for injection 250000ml
Prepare 1000 bottles altogether
Prescription 5
Methanesulfonic acid cinepazide (C 22H 31N 3O 5CH 3SO 3H) 62.5g～250g (in cinepazide)
Sodium-chlor 2250g
Water for injection 250000ml
Prepare 1000 bottles altogether
2, preparation technology:
(1) with dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation;
(2) take by weighing raw material and auxiliary material by prescription;
(3) get the water for injection that sodium-chlor adds dosing amount 80%, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal;
(4) the new pharmaceutical salts of adding cinepazide in solution, stirring and dissolving;
(5) the pH value of survey solution is used anhydrous Na in case of necessity 2HPO 4Adjust pH;
(6) benefit adds to the full amount of water for injection constant volume;
(7) soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m;
(8) inspection of semifinished product;
(9) soup is loaded in the infusion bottle;
(10) 115 ℃ of pressure sterilizing 30min;
(11) leak detection, the lamp inspection;
(12) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 16 cinepazide pharmaceutical salts glucose injections
1, prescription:
Prescription 1
The new pharmaceutical salts 125g (in cinepazide) of cinepazide
Glucose 25000g
Water for injection 250000ml
Prepare 1000 bottles altogether
Prescription 2
The new pharmaceutical salts 250g (in cinepazide) of cinepazide
Glucose 25000g
Water for injection 250000ml
Prepare 1000 bottles altogether
Prescription 3
The new pharmaceutical salts 62.5g (in cinepazide) of cinepazide
Glucose 25000g
Water for injection 250000ml
Prepare 1000 bottles altogether
Prescription 4
The new pharmaceutical salts 62.6g (in cinepazide) of cinepazide
Glucose 25000g
Water for injection 250000ml
Prepare 1000 bottles altogether
Prescription 5
Methanesulfonic acid cinepazide (C 22H 31N 3O 5CH 3SO 3H) 62.5g～250g (in cinepazide)
Glucose 25000g
Water for injection 250000ml
Prepare 1000 bottles altogether
2, preparation technology:
(1) with dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation;
(2) take by weighing raw material and auxiliary material by prescription;
(3) get the water for injection that glucose adds dosing amount 80%, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal;
(4) the new pharmaceutical salts of adding cinepazide in solution, stirring and dissolving;
(5) the pH value of survey solution is used anhydrous Na in case of necessity 2HPO 4Adjust pH;
(6) benefit adds to the full amount of water for injection constant volume;
(7) soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m;
(8) inspection of semifinished product;
(9) soup is loaded in the infusion bottle;
(10) 115 ℃ of pressure sterilizing 30min;
(11) leak detection, the lamp inspection;
(12) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 17 cinepazide pharmaceutical salts tablets
1, prescription:
Prescription 1
The new pharmaceutical salts 62.5g (in cinepazide) of cinepazide
Microcrystalline Cellulose 50g
Starch 35g
2%HPMC% ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 2
The new pharmaceutical salts 125g (in cinepazide) of cinepazide
Microcrystalline Cellulose 50g
Starch 125g
2%HPMC% ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 3
The new pharmaceutical salts 62.6g (in cinepazide) of cinepazide
Microcrystalline Cellulose 50g
Starch 35g
2%HPMC% ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 4
The new pharmaceutical salts 250g (in cinepazide) of cinepazide
Microcrystalline Cellulose 50g
Starch 100g
2%HPMC% ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 5
Methanesulfonic acid cinepazide (C 22H 31N 3O 5CH 3SO 3H) 62.5g～250g (in cinepazide)
Microcrystalline Cellulose 50g
Starch 125g
2%HPMC% ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
2, preparation technology:
(1) to cross 80 mesh sieves standby for raw material and auxiliary material separated pulverizing;
(2) granulation solution preparation: getting 2%HPMC, to add concentration be that 30～95% medicinal alcohols are made 5～10% solution, promptly;
(3) get raw material and auxiliary materials and mixing, add granulation solution and make softwood in right amount, 20 orders are granulated, 50～70 ℃ of dryings;
(4) behind the particle drying, the whole grain of 18 orders adds the Magnesium Stearate mixing;
(5) particle content measuring;
(6) compressing tablet, detection lug is heavy at random;
(7) finished product is examined entirely, the packing warehouse-in.

Claims (13)

1, (E)-1-{4-[(3 ', 4 ', 5 '-the trimethoxy cinnamoyl)]-the 1-piperazine } the acetyl-pyrrole pyridine is the pharmaceutical salts of cinepazide, comprises its organic carboxylate and alkylsulfonate, wherein except the maleate.
2, the pharmaceutical salts of cinepazide as claimed in claim 1 is mesylate, citrate, succinate or tartrate, and cinepazide and methylsulfonic acid, Citric Acid, Succinic Acid, tartaric mole proportioning are 1: 0.5～1: 5 in its molecular formula.
3, the mesylate of cinepazide as claimed in claim 2, citrate, succinate or tartrate, cinepazide and methylsulfonic acid, Citric Acid, Succinic Acid, tartaric mole proportioning are 1: 1,1: 2 or 1: 3 in its molecular formula.
4, the mesylate of cinepazide as claimed in claim 3, citrate, succinate or tartrate, cinepazide and methylsulfonic acid, Citric Acid, Succinic Acid, tartaric mole proportioning are 1: 1 in its molecular formula.
5, the mesylate of cinepazide as claimed in claim 4, the mole proportioning of cinepazide and methylsulfonic acid is 1: 1 in its molecular formula.
6, as the preparation method of the pharmaceutical salts of the described arbitrary cinepazide of claim 1-5, it is characterized in that, with cinepazide and acid in the water-containing organic solvent or organic solvent of lower alcohol, ketone, ester, be carried out to reactant salt, get crude product, also can further make with extra care in case of necessity, get highly finished product.
7, the preparation method of the pharmaceutical salts of cinepazide as claimed in claim 6, wherein said cinepazide is 1: 0.5～1: 10 with the mole proportioning of acid, described organic acid is methylsulfonic acid, Citric Acid, Succinic Acid or tartrate.
8, be used for the treatment of and/or prevent purposes in the medicine of cardiovascular and cerebrovascular and peripheral vascular disease in preparation as the pharmaceutical salts of the described arbitrary cinepazide of claim 1-5.
9, comprise the pharmaceutical salts of the described arbitrary cinepazide of claim 1-5 and the composition of other active pharmaceutical ingredients.
10, comprise the pharmaceutical salts of the described arbitrary cinepazide of claim 1-5 and the composition of one or more pharmaceutically acceptable carriers and/or thinner.
11, the composition that comprises the pharmaceutical salts of the described cinepazide of claim 10 is oral preparations or injection.
12, the composition of the pharmaceutical salts of the described cinepazide of claim 11 contains the active ingredient by cinepazide 10～500mg.
13, the composition of the pharmaceutical salts of the described cinepazide of claim 12 contains the active ingredient by cinepazide 50mg, 62.5mg, 62.6mg, 125mg or 250mg.
CN200610110549A 2006-04-21 2006-08-08 Novel medicinal salt for cinepazide and preparation method thereof Active CN100584835C (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102060808A (en) * 2010-12-16 2011-05-18 沈阳亿灵医药科技有限公司 Cinepazide acid addition salt and preparation method thereof
CN102336724A (en) * 2011-06-03 2012-02-01 辽宁中海康生物药业有限公司 Novel cinepazide salt and its preparation method, and pharmaceutical composition based on cinepazide salt
CN101747295B (en) * 2008-12-01 2012-04-25 北京四环制药有限公司 Methanesulfonic acid cinepazide crystal form and preparation method
CN102391209B (en) * 2008-12-01 2013-09-25 北京四环制药有限公司 Mesylate cinepazide crystal form II and preparation method thereof
CN102351812B (en) * 2008-12-01 2013-12-18 北京四环制药有限公司 Methanesulfonic acid cinepazide crystal form III and preparation method thereof
CN107224569A (en) * 2016-03-26 2017-10-03 复旦大学 Water-soluble Pharmaceutical composition of a kind of bortezomib and its production and use

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101747295B (en) * 2008-12-01 2012-04-25 北京四环制药有限公司 Methanesulfonic acid cinepazide crystal form and preparation method
CN102391209B (en) * 2008-12-01 2013-09-25 北京四环制药有限公司 Mesylate cinepazide crystal form II and preparation method thereof
CN102351812B (en) * 2008-12-01 2013-12-18 北京四环制药有限公司 Methanesulfonic acid cinepazide crystal form III and preparation method thereof
CN102060808A (en) * 2010-12-16 2011-05-18 沈阳亿灵医药科技有限公司 Cinepazide acid addition salt and preparation method thereof
CN102060808B (en) * 2010-12-16 2013-06-26 沈阳亿灵医药科技有限公司 Cinepazide acid addition salt and preparation method thereof
CN102336724A (en) * 2011-06-03 2012-02-01 辽宁中海康生物药业有限公司 Novel cinepazide salt and its preparation method, and pharmaceutical composition based on cinepazide salt
CN107224569A (en) * 2016-03-26 2017-10-03 复旦大学 Water-soluble Pharmaceutical composition of a kind of bortezomib and its production and use

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