WO2005021481A1 - Sel n,n'-dibenzyl ethylenediamine d'acide benzoique 2-(alpha-hydroxypentyl) et procede de preparation et utilisation correspondante - Google Patents

Sel n,n'-dibenzyl ethylenediamine d'acide benzoique 2-(alpha-hydroxypentyl) et procede de preparation et utilisation correspondante Download PDF

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Publication number
WO2005021481A1
WO2005021481A1 PCT/CN2004/000102 CN2004000102W WO2005021481A1 WO 2005021481 A1 WO2005021481 A1 WO 2005021481A1 CN 2004000102 W CN2004000102 W CN 2004000102W WO 2005021481 A1 WO2005021481 A1 WO 2005021481A1
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WO
WIPO (PCT)
Prior art keywords
salt
hydroxypentyl
organic solvent
dibenzylethylenediamine
cerebral
Prior art date
Application number
PCT/CN2004/000102
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English (en)
Chinese (zh)
Inventor
Wenbin Yang
Hua Qin
Xingkai Zhao
Xisheng Ma
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Team Academy Of Pharmaceutical Science
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Publication of WO2005021481A1 publication Critical patent/WO2005021481A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains

Definitions

  • the present invention relates to a novel 1- ( ⁇ -hydroxypentyl) benzoic acid salt, in particular to 2_ ( ⁇ -hydroxypentyl) benzoic acid N, N, -dibenzylethylenediamine salt, and
  • the preparation method and the pharmaceutical composition using the salt as an active ingredient also relate to the application of the salt in the preparation of a medicament for treating cardio-cerebral ischemia, cardiac artery obstruction and the like.
  • Acute ischemic stroke, coronary heart disease, and myocardial infarction are all diseases that are caused by atherosclerosis until the formation of thrombus, which leads to ischemic injury. Such diseases bring great pain and even life threat to patients.
  • research on drugs for treating such diseases has been a hot spot and frontier of drug research and development.
  • -Hydroxypentyl benzoate and its preparation method and use, which relate to monovalent metal ions, divalent metal ions and salts of organic bases, and specifically disclose potassium, sodium, calcium, magnesium, zinc, aniline, benzylamine , Morpholine, diethylamine salt.
  • the specification only discloses the preparation of potassium salt, sodium salt, lithium salt, calcium salt, and benzylamine salt, but does not disclose specific preparation methods of zinc salt, aniline, morpholine, and diethylamine salt.
  • the specification also discloses the effects of potassium salts on cerebral infarction area in rats with ischemic cerebral ischemia, platelet aggregation in rats, and the protective effect of isolated heart ischemia-reperfusion arrhythmia in rats. The above experiments have played a beneficial role. Other salts have not been tested for efficacy.
  • Some bases are prepared according to the existing published preparation methods.
  • the solid obtained is amorphous, has no fixed melting point and good appearance and physical form, such as sodium salt, magnesium salt, lithium salt, and zinc salt.
  • After the dry solvent, it is a foamy solid or gel. It has no crystalline form, is very viscous, is difficult to pulverize, can not talk about fluidity, and is not suitable for processing by the pharmaceutical industry.
  • the purpose of the present invention is to provide a new 2- ( ⁇ -hydroxypentyl) phenyl sulfonate which can overcome the shortcomings of the prior art, which has obvious anti-platelet aggregation and improvement of cerebral circulation, and has good effects on the heart and brain.
  • Ischemia and cardio-cerebral artery occlusion have drug activity, have good appearance and physical form, have no hygroscopicity, and have excellent wet stability.
  • novel salt of the present invention is 2- ( ⁇ -hydroxypentyl) phenylarsinic acid N, N'-dibenzyl ethylenediamine salt, and its structural formula is as follows:
  • the salt of the present invention has the following excellent properties:
  • Another object of the present invention is to provide a method for preparing the above 2-( ⁇ -hydroxypentyl) phenylarsinic acid N, N, -dibenzylethylenediamine salt, which comprises the following steps:
  • the acidification operation is performed on 2-( ⁇ -hydroxypentyl) benzoate, and the temperature of the acidification process is controlled-10 ⁇ 1 (TC, pH 2-3, then extracted with an organic solvent, and the organic solvent layer is washed to neutrality Then, it is dried, and the organic solvent is removed under reduced pressure to obtain 2-( ⁇ -hydroxypentyl) phenylarsinic acid;
  • step (1) The 2- ( ⁇ -hydroxypentyl) phenylarsinic acid in step (1) is dissolved in an organic solvent, and a solution prepared by adding N, N, -dibenzylethylenediamine in an organic solvent is reacted to control,
  • the reaction temperature is-10 ⁇ 10 ° C;
  • step (3) The reaction product in step (2) is stirred for several hours and then filtered, the filter cake is washed with an organic solvent, and the filter cake is dried to obtain 2-(c-hydroxypentyl) phenylarsinic acid N, N, -di Benzylethylenediamine salt.
  • the organic solvent may be diethyl ether, dichloromethane or ethyl acetate, and preferably diethyl ether.
  • the reaction temperature described in step (2) is preferably 0 to -5 ° C.
  • Another object of the present invention is to provide 2- ( ⁇ -hydroxypentyl) phenylarsinic acid N, N'-dibenzylethylenediamine salt for preparing and / or treating cardio-cerebral ischemia and / or cardio-cerebral artery Obstruction and improvement of the brain ⁇ : Application of drugs in circulation.
  • a further object of the present invention is to provide a pharmaceutical composition capable of preventing and / or treating cardio-cerebral ischemia and / or cardio-cerebral artery occlusion and improving cerebral microcirculation, which contains a therapeutically effective amount of 2-(a -Hydroxypentyl) phenylarsinic acid N, N,-Dibenzylethylenediamine salt is an active ingredient, and may also contain one or more pharmaceutically acceptable carriers.
  • the above pharmaceutically acceptable carriers refer to conventional pharmaceutical carriers in the pharmaceutical field, fillers such as starch, sucrose, etc .; binders such as cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; wetting agents such as ethanol, water Disintegrating agents such as starch and its derivatives, low-substituted hydroxypropyl cellulose, effervescent disintegrating agents; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and soap clay; Lubricants such as talc, calcium and magnesium stearate, and polyethylene glycol; in addition, other adjuvants such as flavoring agents, sweeteners, etc. may be added to the composition.
  • fillers such as starch, sucrose, etc .
  • binders such as cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone
  • wetting agents such as ethanol, water Disintegrating agents such
  • the various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional production methods in the pharmaceutical field.
  • the active ingredient is mixed with one or more carriers and then made into the desired dosage form, including tablets, capsules and granules. detailed description
  • Example 1 Preparation of 2- ( ⁇ -hydroxypentyl) benzoic acid N, N, -dibenzylethylenediamine salt
  • 2- (ex-hydroxypentyl) benzene was prepared according to the following four schemes, respectively.
  • the acetic acid N, N, -dibenzylethylenediamine salt, the specific operation process is as follows.
  • Option A
  • the solid After drying, the solid is transferred to a 2.5 L beaker, washed twice with 2.0 L of ethyl acetate, filtered, and the filter cake is placed. Dry in a vacuum dryer to obtain 78.7 g of a white solid, mp: 105-106 ° C, yield: 83.3%.
  • lithium salt, sodium salt, magnesium salt, and zinc salt are all foam-like or gel-like solids with no obvious melting point.
  • Morpholine and diethylamine salts are viscous liquids. None of them meet the requirements of the pharmaceutical industry. Potassium, calcium, benzylamine, N, N, -dibenzylethylenediamine and tert-butylamine salts have good physical appearance and fixed melting point. Aniline does not react at all.
  • Example 3 Comparison of wet stability
  • ICR mice male and female, weighing 18-20 g, were provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • the certificate number is: SCXK (Beijing) 2002-0003.
  • mice Sixty ICR mice were randomly divided into six groups according to body weight and sex, with ten in each group, half male and half female. Based on the pre-test results, the doses of each group were designed according to the group spacing 1: 0.8.
  • the oral administration volume is 0.2 ml / 10 g body weight (the potassium salt intravenous administration volume is 0.1 ml / l Og body weight), fasting and water ca n’t be avoided for 12 hours before the test, and conventional feeding after the administration, continuous Observe for 14 days, record the toxic reaction and death of the animals, necropsy was performed in the dead group, pathological changes were observed with the naked eye, and LD 5 was calculated by Bliss method. Value and 95% confidence limit.
  • Test drugs N, N,-dibenzylethylenediamine salt, potassium salt, calcium salt, all provided by Beijing Tianheng Pharmaceutical Research Institute, suspended with 0.5% carboxymethyl cellulose sodium solution, formulated different density.
  • Reagent FeC l 3 ⁇ 6H 2 0 (AR), produced by Beijing Chemical Plant, formulated with lmo l / L hydrochloric acid; red tetrazolium (TTC), produced by Beijing Chemical Plant.
  • Grouping and administration Animals were randomly divided into 14 groups, namely the operation group, the MCAT model group, N, N, -dibenzylethylenediamine salt 340mg / kg, 200mg / kg, 170mg / kg, 100mg / kg, 85mg / kg, 50mg / kg group, potassium salt 200mg / kg, 100mg / kg, 50mg / kg group, calcium salt 200mg / kg, 100mg / kg, 50mg / kg group.
  • Rats are anesthetized by intraperitoneal injection of 12% chloral hydrate solution (350mg / kg). Refer to the method of Tanrnra et al. (Tamura A, Graham DI, McCulluoch J et al. Focal cerebral ischemia in the rat. 1. Description of technique and early neuropathological consequences following middle Cerebral artery occlusion.
  • the rat was placed in the right lateral position, and an arc-shaped incision was made at the midpoint of the conjunctiva of the eye and the external auditory canal, approximately 1.5 cm long.
  • the temporal muscle was clipped and cut away to expose the temporal bone.
  • a dental drill was used.
  • a bone window with a diameter of 2.5 mm was made at the confluence of the zygomatic bone and the temporal squamium to the mouth 1 to clear the residue and expose the middle cerebral artery (located between the olfactory tract and the inferior cerebral vein).
  • a small quantitative filter paper sucked with 50% ferric chloride solution 10 ⁇ l was applied to this middle cerebral artery. After the color of the blood vessels became black for about 30 minutes, the filter paper was removed, and the local tissue was washed with physiological saline, sutured layer by layer, and returned to the cage for feeding.
  • the neurological symptoms of rats in the N, N, -dibenzylethylenediamine salt 100-340mg / kg group were significantly improved at 6 hours after operation.
  • N, N, -dibenzylethylenediamine salt 50-340mg / kg group, potassium and calcium salts 100mg / kg, 200mg / kg group Neurological symptoms in rats were significantly improved, and there was a significant dose-effect relationship. There was no significant improvement in the potassium and calcium 50 mg / kg group (P> 0.05).
  • the significant therapeutic dose of N, N, -dibenzylethylenediamine salt to improve neurological symptoms in MCAT rats is 50mg / kg, which is lower than potassium and calcium salts (100mg / kg). At the same dose, N, N, -dibenzylethylenediamine salt improved the neurological symptoms of MCAT rats more than potassium and calcium salts.
  • B the effect on cerebral infarction range in MCAT rats
  • the animals were decapitated and brain removed after the last behavioral score. Remove the olfactory bulb, cerebellum and lower brainstem, and cut the remaining part into 5 pieces at 4 ° C. Quickly place the brain slices in TTC staining solution (4% TTC 1.5ml, 1M K 2 HP0 4 0.1ml per 5ml), incubate at 37 ° C in the dark for 30 minutes, then remove and place in 10 Store in dark solution in% formaldehyde solution. The non-ischemic area was rose red and the infarcted area was white after staining. The white tissue was carefully mined and weighed, and the percentage of infarcted tissue weight to total brain weight was used as the range of cerebral infarction. The t-test was used to compare the results between the groups. The results are shown in Table 5.
  • N, N, -Dibenzylethylenediamine salt inhibits the cerebral infarction range of MCAT rats at a significant therapeutic dose of 50 mg / kg, which is lower than potassium and calcium salts (100 mg / kg). O At the same dose, N, ⁇ ' -The inhibitory effect of dibenzylethylenediamine salt on cerebral infarct size in MCAT rats is stronger than that of potassium and calcium salts.
  • Example 6 Effect on platelet aggregation in rats
  • N, N, -dibenzylethylenediamine salt, potassium salt and calcium salt are provided by Beijing Tianheng Pharmaceutical Research Institute.
  • Adenosine diphosphate (ADP) was purchased from Sigma.
  • Rats were randomly divided into 11 groups, namely: solvent control group, ASA 100mg / kg, N, N,-dibenzylethylenediamine salt 200mg / kg, 100mg / kg, 50mg / kg group, bell salt 200mg / kg , 100mg / kg, 50mg / kg group, calcium salt 200mg / kg, 100mg / kg, 50mg / kg group.
  • Oral administration was performed once a day for three consecutive days, and the solvent control group was given the same amount of solvent.
  • Aggregation inhibition rate (aggregation rate of the solvent control group-aggregation rate of the administration group) / aggregation rate of the solvent control group ⁇ 100 ° /.
  • Preparation method According to the formula in Table 7, N, N, -dibenzylethylenediamine salt, starch, micro The crystalline cellulose and sodium carboxymethylcellulose are mixed uniformly, wetted with water uniformly, granulated, dried, and whole granulated, magnesium stearate and talc are added, and the mixture is compressed to obtain tablets of this product.
  • N, N, -dibenzylethylenediamine salt and excipients are mixed uniformly, granules are made by wet method, dried and whole granules, and then the mixture is charged into gastric hard gelatin capsules in a certain amount, that is, Get this product.
  • Preparation method According to the formula in Table 9, N, N, -dibenzylethylenediamine salt and auxiliary materials are mixed and then wet granulated, dried, whole and classified, and divided into packages to obtain the granules of this product.

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  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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Abstract

L'invention concerne un sel N,N'-dibenzyl éthylènediamine d'acide benzoïque 2-(alpha-hydroxypentyl), lequel sel a un effet notoire sur l'inhibition de l'agrégation des plaquettes sanguines et sur l'amélioration de la circulation cérébrale. Ce sel présente une activité pharmaceutique contre l'ischémie cardiaque, l'ischémie cérébrale, l'embolie artérielle cérébrale et l'embolie artérielle cardiaque. Le sel susmentionné permet de conserver une bonne apparence, un bon état physique et il est stable à l'humidité. Cette invention concerne également le procédé permettant de préparer ce sel, la composition pharmaceutique contenant ce sel en tant que principe actif et son utilisation dans la préparation d'un médicament contre l'ischémie cardiaque, l'ischémie cérébrale, l'embolie artérielle cérébrale et l'embolie artérielle cardiaque.
PCT/CN2004/000102 2003-09-01 2004-02-09 Sel n,n'-dibenzyl ethylenediamine d'acide benzoique 2-(alpha-hydroxypentyl) et procede de preparation et utilisation correspondante WO2005021481A1 (fr)

Applications Claiming Priority (2)

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CN03156495.X 2003-09-01
CNB03156495XA CN100422133C (zh) 2003-09-01 2003-09-01 2-（α-羟基戊基）苯甲酸盐及其制法和用途

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012055014A1 (fr) * 2010-10-27 2012-05-03 Prometic Biosciences Inc. Composés de carboxylate de phénylcétone et leurs utilisations pharmaceutiques

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103113210A (zh) * 2013-02-19 2013-05-22 石药集团中奇制药技术（石家庄）有限公司 羟戊基苯甲酸钾晶体及其制备方法
CN105616375B (zh) * 2013-03-06 2018-08-28 贵州贵安新区协生元医药科技有限公司 消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法
CN103142513B (zh) * 2013-03-25 2016-01-20 石家庄鸯星科技有限公司 一种注射用消旋2-(α-羟基戊基)苯甲酸盐冻干粉针及其制备方法
CN104086399B (zh) * 2013-07-17 2016-08-24 浙江奥翔药业股份有限公司 5-溴-2-（α-羟基戊基）苯甲酸钠盐的不同晶型及其制备方法
WO2021185356A1 (fr) 2020-03-20 2021-09-23 石药集团恩必普药业有限公司 Utilisation de butylphtalide et dérivé associé

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1382682A (zh) * 2002-05-09 2002-12-04 中国医学科学院药物研究所 2－(α－羟基戊基)苯甲酸盐及其制法和用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1382682A (zh) * 2002-05-09 2002-12-04 中国医学科学院药物研究所 2－(α－羟基戊基)苯甲酸盐及其制法和用途

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012055014A1 (fr) * 2010-10-27 2012-05-03 Prometic Biosciences Inc. Composés de carboxylate de phénylcétone et leurs utilisations pharmaceutiques
JP2013545729A (ja) * 2010-10-27 2013-12-26 プロメティック・バイオサイエンシーズ・インコーポレイテッド カルボン酸フェニルケトン化合物およびその薬学的使用
EA022988B1 (ru) * 2010-10-27 2016-04-29 Прометик Биосайнсиз Инк. Соединения фенилкетонкарбоксилата и их фармацевтическое применение
EA022988B9 (ru) * 2010-10-27 2016-08-31 Прометик Биосайнсиз Инк. Соединения фенилкетонкарбоксилата и их фармацевтическое применение
US9475750B2 (en) 2010-10-27 2016-10-25 Prometic Biosciences Inc. Phenylketone carboxylate compounds and pharmaceutical uses thereof

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CN1523003A (zh) 2004-08-25
CN100422133C (zh) 2008-10-01

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