WO2008086678A2 - Usage médical de lévophéncynonate comme agent neuroprotecteur - Google Patents

Usage médical de lévophéncynonate comme agent neuroprotecteur Download PDF

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WO2008086678A2
WO2008086678A2 PCT/CN2007/003159 CN2007003159W WO2008086678A2 WO 2008086678 A2 WO2008086678 A2 WO 2008086678A2 CN 2007003159 W CN2007003159 W CN 2007003159W WO 2008086678 A2 WO2008086678 A2 WO 2008086678A2
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pharmaceutically acceptable
acceptable salt
ester
phenyl
toxic pharmaceutically
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PCT/CN2007/003159
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WO2008086678A3 (fr
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Bohua Zhong
Shuangqing Peng
Zhenyu Ren
He Liu
Lanfu Chen
Keliang Liu
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Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D221/00Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22Bridged ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/08Antiepileptics; Anticonvulsants

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  • the present invention provides a neuroprotective levocyclic oxime ester and a non-toxic pharmaceutically usable salt thereof, a pharmaceutical composition containing the same as an active ingredient, and a levocyclononyl ester or a benzocyclone neuroprotective agent. use. Background technique
  • Phenylcyclodecyl HCl (phencynonate hydroc lor ide, 2'-cyclopentyl-2'-phenyl-2'-hydroxyacetic acid-9 ⁇ -[3-methyl-3-azabicyclo[3. 1) oxime ester hydrochloride] is a selective anticholinergic drug, which is clinically used for the prevention of various motion diseases such as motion sickness and seasickness.
  • Chinese Patent CN1089838A and US Patent (US6028198) disclose phencyclidine hydrochloride as an anti-motion disease ( The use of drugs for motion sickness, boat, machine, etc.; Chinese patent CN97125424.
  • the molecular structure of phencyclidine ester contains a chiral carbon atom and has a pair of optical isomers.
  • a pair of optical isomers of a chiral molecule have identical physical or chemical properties, such as melting point, solubility, chromatographic retention time, infrared spectroscopy, and nuclear magnetic resonance, in the absence of external chiral effects.
  • different optical isomers exhibit opposite optical activity, which enables plane-polarized light to rotate in a clockwise direction (right-handed) or counterclockwise (left-handed).
  • the absolute configuration of the optical isomer chiral center can be represented by the prefixes D and L or R and S.
  • the optical properties of the molecule can also be represented by the prefixes d and 1 or (+) and (-), such as d-tartaric acid or (+)-tartaric acid indicating that the isomer is dextrorotatory; and buckwort acid or (-)- Tartaric acid indicates that the isomer is left-handed.
  • the object of the present invention is to provide a neuroprotective levocyclononyl ester and a non-toxic pharmaceutically usable salt thereof, a pharmaceutical composition containing the same as an active ingredient, and a levothylidene or phencyclidine neuron
  • the use of protective agents is to provide a neuroprotective levocyclononyl ester and a non-toxic pharmaceutically usable salt thereof, a pharmaceutical composition containing the same as an active ingredient, and a levothylidene or phencyclidine neuron.
  • L-phenyl oxime ester (Structure I a ) has an action of antagonizing nerve damage caused by NMDA and can be used as a neuroprotective agent.
  • pharmaceutically acceptable salt in the present invention may be a pharmaceutically acceptable inorganic or organic salt.
  • the compound having a basic group in the formula I of the present invention may form a pharmaceutically acceptable salt with a mineral acid such as a sulfate, a hydrochloride, a hydrobromide or a phosphate; or may form a pharmaceutically acceptable salt with an organic acid, such as acetic acid. Salt, oxalate, citrate, gluconate, succinate, Tartrate, p-toluenesulfonate, methanesulfonate, benzoate, lactate, maleate, and the like.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can form a solvate such as a hydrate, an alcoholate or the like.
  • the above compounds may also be in the form of a prodrug or a form which can be released after metabolism in the body.
  • suitable prodrug derivatives are well known to those skilled in the art.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered alone or in the form of a pharmaceutical composition.
  • the pharmaceutical composition of the present invention can be formulated into various suitable dosage forms depending on the route of administration.
  • the use of one or more physiologically acceptable carriers, including excipients and auxiliaries, facilitates processing of the active compounds into preparations which can be used in pharmaceutical compositions.
  • the form of the preparation which is appropriate depends on the route of administration selected and can be produced according to common knowledge well known in the art.
  • the route of administration may be oral, parenteral or topical, preferably oral and injectable.
  • Pharmaceutical preparations which can be orally administered include capsules and tablets and the like. When the patient has difficulty swallowing, it can also be administered by sublingual tablets or other non-swallowing methods.
  • the compounds of the invention may also be formulated for parenteral administration or transdermal administration or transmucosal administration. Alternatively, it can be administered by suppository or implant.
  • DDS drug delivery system
  • the dosage and method of use of the compounds of the invention depend on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and the diagnosis and treatment. Subjective judgment of the physician.
  • the preferred dosage is between 0.01 and 100 rag/kg body weight per day.
  • L-Phenylcyclononyl ester can be prepared by resolution of racemic phenothylide with a known resolving agent or by the following synthetic method: using R mandelic acid as a chiral template, using the hydroxyl group in the mandelic acid molecule to first react with pivalaldehyde The condensation of the aldehyde, the formation of a hydroxyl group in the hemiacetal molecule Intramolecular condensation with a carboxyl group, stereoselectively obtaining a lactone product 11a; then, cyclopentanone and the enol form of Ila undergo a stereo-controlled Michael addition reaction, and the addition product Ilia is dehydrated, hydrogenated, and deprotected.
  • R-mandelic acid 20g (0.13mol) was dissolved in 200mL of n-pentane, and pivalaldehyde 21.2mL was added. (content 80%, 0.16 mol), then 0.5 mL of trifluoromethanesulfonic acid was added, a water separator was installed, and refluxed for 6 hours, and the water was removed by a water separator. After cooling to room temperature, 100 mL of 8% sodium hydrogencarbonate solution was added, n-pentane was distilled off under reduced pressure, and (2R, 5S) 2 -t-butyl-5-phenyl-1, 3-dioxane-4-one was obtained by filtration.
  • PCI 2 cells were cultured in DMEM medium containing 5% FBS and 10% HS, seeded at a density of 2 x 10 4 cells / ml, and passaged every 5-7 days.
  • the medium was induced to differentiate by adding 6% FBS, 6% HS and 50 ng/ml NGF, and the solution was changed once every other day. After 7 days, more than 95% of the cells differentiated into neuronal cells.
  • Kunming mice ⁇ , 20 ⁇ 2g, were provided by the Animal Center of the Academy of Military Medical Sciences. They were exposed to light and darkness for 12h/12h every day, and they were fed freely. Kunming mice were randomly divided into groups of 9 each. Different doses of phencyclidine were injected intraperitoneally. After 30 minutes, all animals were given a lethal dose of NMDA (ip). The survival of the mice was observed within 2 hours, and the survival rate was calculated. Table 2 Protective effect of L-phenyl oxime ester on NMDA-induced death in mice

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Description

左旋苯环壬酯作为神经保护剂的医药用途 技术领域
本发明提供具有神经保护作用的左旋苯环壬酯及其非毒性的 药学上可用的盐、 含有这些化合物作为活性成分的药物组合物, 以及左旋苯环壬酯或苯环壬酯神经保护剂的用途。 背景技术
式 I盐酸苯环壬酯 ( phencynonate hydroc lor ide, 2' -环戊 基- 2'-苯基- 2'-羟基乙酸 -9α- [3-甲基- 3-氮杂双环( 3. 3. 1 )壬酯 盐酸盐]是一种选择性抗胆碱药物, 临床用于防治晕车、 晕船等各 种运动病。 中国专利 CN1089838A和美国专利 ( US6028198 )公开 了盐酸苯环壬酯作为抗运动病 (暈车、 船、 机等) 药物的用途; 中国专利 CN97125424. 9 , 英国专利 ( GB2297255 )和西班牙专利 ES549796A 公开了盐酸苯环壬酯的制备方法。 中国专利公开号为 CN01104881. 6 申请了盐酸苯环壬酯治疗帕金森氏病 /综合征的用 途;中国专利公开号为 CN01104881. 6申请了盐酸苯环壬酯治疗或 緩解美尼尔氏病及位置性眩晕等眩暈症急性发作的药物用途。
Figure imgf000003_0001
I
由结构 I可以看出, 苯环壬酯的分子结构中含有一个手性碳 原子, 具有一对光学异构体, 目前临床应用的是消旋体形式。 手性分子的一对光学异构体在不存在外部手性影响时, 具有 完全相同的物理或化学性质, 如熔点、 溶解度、 色谱保留时间、 . 红外光谱和核磁共振讲等。 但是, 不同的光学异构体表现出相反 的光学活性, 它们能够使平面偏振光按顺时针方向 (右旋)或逆 时针方向旋转 (左旋) 。
可以用前缀 D和 L或 R和 S来表示光学异构体手性中心的绝 对构型。也可以用前缀 d和 1或 (+)和(-)来表示分子的旋光性质, 如 d-酒石酸或(+) -酒石酸表明该异构体是右旋的;而卜酒石酸或 ( - ) -酒石酸表明该异构体是左旋的。 发明内容
本发明的目的是提供具有神经保护作用的左旋苯环壬酯及其 非毒性的药学上可用的盐、 含有这些化合物作为活性成分的药物 組合物, 以及左旋苯环壬酯或苯环壬酯神经保护剂的用途。
本发明意外发现, 左旋苯环壬酯 (结构 I a ) 具有拮抗 NMDA 所致的神经损伤的作用, 可以用作神经保护剂。
Figure imgf000004_0001
本发明中的术语 "可药用盐" 可以是药用无机或有机盐。 本 发明式 I中具有碱性基团的化合物可以与无机酸形成药用盐, 例 如硫酸盐、 盐酸盐、 氢溴酸盐、 磷酸盐; 也可与有机酸形成药用 盐, 例如乙酸盐、 草酸盐、 柠檬酸盐、 葡萄糖酸盐、 琥珀酸盐、 酒石酸盐、 对曱苯磺酸盐、 甲磺酸盐、 苯甲酸盐、 乳酸盐、 马来 酸盐等。
本发明化合物或其可药用盐可以形成溶剂化物,例如水合物、 醇合物等。 上述化合物还可以是前药或可在体内代谢后释放出所 述活性成分的形式。 选择和制备适当的前药衍生物是本领域技术 人员公知技术。
本发明化合物或其可药用盐可以单独或以药物组合物的形式 给药。 本发明药物组合物可根据给药途径配成各种适宜的剂型。 使用一种或多种生理学上可接受的载体, 包含赋形剂和助剂, 它 们有利于将活性化合物加工成可以在药学上使用的制剂。 适当的 制剂形式取决于所选择的给药途径, 可以按照本领域熟知的常识 进行制造。
给药途径可以是口服、 非肠道或局部给药, 优选口服和注射 形式给药。 可以口服的药物制剂包括胶嚢剂和片剂等。 病人吞咽 有困难时, 也可以采用舌下片或者其他非吞咽的方式给药。 本发 明化合物也可以配制用于肠胃外给药或者透皮给药或者经粘膜给 药。 或者采用栓剂或者埋植剂的方式给药。 本领域技术人员可以 理解, 本发明化合物可以采用合适的药物释放系统(DDS )以得到 更有利的效果。
另外需要指出, 本发明化合物使用剂量和使用方法取决于诸 多因素, 包括患者的年龄、 体重、 性别、 自然健康状况、 营养状 况、 化合物的活性强度、 服用时间、 代谢速率、 病症的严重程度 以及诊治医师的主观判断。优选的使用剂量介于 0. 01 ~ 100 rag/kg 体重 /天。
左旋苯环壬酯可以通过用已知拆分试剂拆分消旋苯环壬酯或 下列合成方法制备: 以 R扁桃酸为手性模板, 利用扁桃酸分子中 的羟基先与特戊醛进行醇醛缩和, 形成的半缩醛分子中的羟基再 与羧基进行分子内的缩合, 立体选择性得到内酯产物 Ila; 然后, 环戊酮与烯醇形式的 Ila进行立体控制性的 Michael加成反应, 加成产物 Ilia脱水、 氢化、 脱保护可方便地得到光学纯度 99% 以上的 R-α-苯基 -α-环戊基 -α-羟基乙酸(Via); 后者曱酯化 后, 与 9"-[1^-曱基-3-氮杂双环(3, 3,1)壬]醇 (VIII)进行酯交 换反应即得目标化合物。 具体合成路线如下:
Figure imgf000006_0001
具体实施方式
下面用实施例具体说明本发明, 这些实施例不应理解为任何 意义上的对本发明的限制。 实施例 1、 (2R,5S)- 2-特丁基 - 5-苯基- 1,3-二噁烷 - 4-酮(Ila) 的制备
R-扁桃酸 20g(0.13mol)溶于 200mL正戊烷,加入特戊醛 21· 2mL (含量 80%, 0.16mol), 然后加入三氟甲磺酸 0.5mL, 安装分水器, 回流 6小时, 以分水器去水。 冷却到室温, 加入 8%碳酸氢钠溶液 lOOmL, 减压蒸去正戊烷, 过滤得到(2R, 5S)_2-特丁基 -5-苯基 - 1, 3-二噁烷 -4-酮(IIa)27.1g, 熔点 100-102°C, 产率 95%, 元素 分析 理论值% C 70.89 H 7.32 实验值 C 70.81 H 7.39。 核磁 共振氢谱: δ (ppm, CDC13),1.10 (s, 9H) , 5.25 (s, 1H) , 5.38 (s, 1H), 7.47 (m, 5H)。 实施例 2、 (2S, 5R)- 2-特丁基 -5-苯基- 1, 3-二噁烷 -4-酮 (lib) 的制备
参照实施例 1的方法, 以(S)-扁桃酸为原料,合成(2R,5R)-2 - 特丁基 -5-苯基- 1, 3-二噁烷 -4-酮(lib), 熔点 100- 102° (:, 产率 97%, 元素分析 理论值%C 70.89 H 7.32 实验值 C 70.83 H 7.300 核磁共振氢谱: δ (ppm, CDC13) , 1.12 (s, 9H), 5.23 (s, 1H), 5.36 (s, 1H), 7.49 (in, 5H)。 实施例 3、 (2R,5R)-2-特丁基 -5-苯基 -5- (环戊基 -1-羟 基) -1, 3-二噁烷 -4-酮(Ilia)的制备
10g(45mmol) (2R, 5S) -2-特丁基 -5-苯基 -1, 3-二噁烷 -4-酮 溶于 70mL干燥四氢呋喃, 冷却到 - 78°C, 加入 60mL二(三甲硅基) 氨基锂(四氢呋喃溶液, 1.0M)。 搅拌下滴加环戊酮 65讓 ol, 搅拌 反应 2小时,滴加 15mL饱和磷酸氢钠溶液和 20 OmL饱和氯化铵溶液, 分出有机层, 水层用乙酸乙酯萃取, 合并有机层, 千燥, 蒸出溶 剂得到(2R, 5R) -2-特丁基 -5-苯基- 5- (环戊基- 1-羟基) -1, 3-二噁 烷- 4-酮(Ilia) 10· 5g, 产率 74%。 核磁共振氢谱: δ (ppm, CDC13), 0.88 (s, 9H), 1.52-2.06 (m, 8H) , 5.52 (s, 1H), 7.31 (m, 3H), 7.78 (dd, / = 1.5, 8.3 Hz, 2H)。 实施例 4、 (2S,5S)-2-特丁基 - 5-苯基- 5- (环戊基- 1-羟 基)- 1, 3-二噁烷 -4-酮(Illb)的制备
参照实施例 3的方法,(2S, 5R)- 2-特丁基 -5-苯基- 1, 3-二噁烷 -4-酮(lib)与环戊酮反应,得到(2S, 5S) -2-特丁基 -5-苯基 -5- (环 戊基- 1-羟基) -1, 3-二噁烷 -4-酮(Illb) ,产率 71%。核磁共振氢谱: δ ( pm, CDC13), 0.89 (s, 9H), 1.51-2.07 (m, 8H), 5.54 (s, 1H): 7.30 (m, 3H), 7.76 (dd, / = 1.5, 8.3 Hz, 2H)。 实施例 5、 (2R,5S)- 2-特丁基 -5-苯基- 5- (1-环戊烯基) -1, 3- 二噁烷 -4-酮(I Va)的制备
将 3.6g (lOramol) (2R, 5R) - 2-特丁基 - 5-苯基 -5- (环戊基 -1- 羟基) - 1, 3-二噁烷 -4-酮溶于 70mL干燥四氢呋喃溶液中, 冷却下 到 0°C, 加入 2raL氯化亚砜和 3mL吡啶, 搅拌反应 1小时, 加入 60mL饱和氯化铵溶液, 分出有机层, 水层用乙酸乙酯萃取, 合并 有机层, 干燥, 蒸出溶剂得到(2R,5S )-2-特丁基 - 5-苯基 -5-(1- 环戊烯基)- 1, 3-二噁烷 -4-酮(IVa)3.7g, 产率 95%。 核磁共振氢 谱: δ (ppm, CDCh), 1.07 (s, 9H), 1.92-2.50 (m, 6H), 5.22 (s, 1H), 6.03 (m, 1H), 7.25 (m, 4H) , 7.59 (m, 1H)。 实施例 6、 (2S,5R)-2-特丁基 -5-苯基 -5-(1-环戊烯基) -1, 3- 二噁烷 -4-酮(IVb)的制备
参照实施例 5的方法, 由 Illb得到(2S, 5R)-2-特丁基 -5 -苯 基 -5- (1-环戊烯基) -1, 3-二噁烷 -4-酮(IVb), 产率 92%。 核磁共 振氢谱: δ (ppm, CDCI3), 1.05 (s, 9H) , 1.90-2.51 (m, 6Η) , 5.23 (s, 1Η), 6.01 (ra, 1Η), 7.28 (m, 4H) , 7.57 (ra, 1H)。 实施例 7、 (R)- α-苯基 -α-环戊基 -α-羟基乙酸(Via)的制 备
将 2.8 g (lOmraol) (2R, 5S) -2 -特丁基- 5 -苯基 -5- (1-环戊烯 基) -1, 3-二噁烷 -4 -酮 (IVa)溶于 50raL甲醇, 加入 0.2g 10 Pd/C, 1个大气压 H2还原 8个小时。 过滤, 将滤液减压蒸除溶剂, 得到 (2R, 5S )-2-特丁基 -5-苯基 -5-环戊基 -1, 3-二噁烷 -4-酮(Va)。将 (Va)溶于曱醇和水混合溶液, 加入 K0H, 搅拌回流反应 3小时。 冷却至室温, 正庚烷萃取, 干燥, 蒸出溶剂得到 00- α-苯基- α- 环戊基 -α-羟基乙酸(Via), 1.3g, 产率 60%, [ ] o = -2.4 ( MeOH, c = 4), 熔点: 118-120° ( 。 实施例 8、 (R)- α-苯基 -α-环戊基 - α-羟基乙酸甲酯(Vila)的 合成
将 2.2g( 0. Olraol ) (R) -α-苯基- α -环戊基- α -羟基乙酸(Via) 溶解于 20mL乙醚中, 导入重氮甲烷至溶液呈浅黄色。 蒸干乙醚。 残余物减压蒸馏, 收集 85-87°C/35醒 Hg 的馏分, 得无色油状 (R)-oc -苯基 - α-环戊基 -oc-羟基乙酸甲酯(VIIa)2. lg, 收率 89.6°/oo [ ] ^= +9.4 (MeOH, c = 5)。 实施例 9 (ΙΟ-2'-环戊基 -2'-苯基- 2'-羟基乙酸 -9oc-[3 -甲 基 -3-氮杂双环 (3.3.1)壬]酯盐酸盐 (la)的制备
在 250mL三口烧瓶中,加入 2.28g( 0. Olraol ) (R) - ot-苯基 环戊基 -α-羟基乙酸甲酯和 1.4g ( 0. Olmol ) 9α- [ Ν-甲基- 3 -氮 杂双环(3.3.1)壬 ]醇(VIII) , 50ml无水正庚烷和 0. lg氢化钠(含 量 80%) 。 油浴加热搅拌, 使液体緩緩蒸出,不断补充正庚垸。 反 应 3h。 减压抽出大部分溶剂, 冷却下滴入 2N盐酸溶液 5 ml, 搅 拌, 析出白色固体。 将固体过滤并移置于烧杯内, 加浓氨水碱化, 醚提取。 将醚层冷却, 加入 2N盐酸溶液 5ml, 搅拌析出固体。 滤 集固体, 水水洗涤, 用 95%乙醇重结晶, 得产品 la 2.3g, 产率 65%, 熔点: 209-210°C。 [α]^。=-11.9 (CH3C1, c - 0· 3)。 核 磁共振氢谱: S(ppm,CD3Cl), 10.87(s, 1H), 7.64 (ra, 2H), 7.35 (m, 3H), 5.00(s, 1H), 3.73-3.82 (ra, 2H) , 2.97-3.01 (ra, 4H) , 2.89 (s, 3H), 2.27 (s, 1H), 2.06 (s, 1H), 2.00 (ra, 2H) , 1.33-1.70 (m, 12H)。 实施例 10 对 NMDA所致细胞毒性的保护作用
PCI 2 细胞培养于含 5%FBS和 10%HS的 DMEM培养基中, 接 种密度 2x l04cells / ml, 每 5~7天传代一次。 培养基中加 6 %的 FBS、 6 %的 HS和 50ng/ml的 NGF诱导分化, 隔日换液一次。 7天后, 超过 95 %的细胞分化为神经性细胞。
吸弃培养液,换为含不同浓度 NMDA的新鲜培养基。将细胞先 用不同浓度的苯环壬酯或左旋苯环壬酯预处理 10min, 然后加入 损伤剂量的 NMDA 共同孵育 24h。 吸弃培养液, 加入含 MTT(0.5mg/ml)的无血清培养液, 37。C孵育 4h后, 小心吸弃培养 液, 每孔加入 150ml二甲基亚砜(DMS0)避光震荡 15min,用酶标 仪(Wellscans MK3) 测定其 570nm处 0D值, 计算细胞存活率。 表 1 左旋苯环壬酯对 NMDA所致小鼠死亡的保护作用 分 组 药物浓度(μΜ) 细胞存活率 (% ) 正常对照组 100 + 6.84
NMDA对照组 0 63.55 ±8.42
1 66.58 ±7.42
5 77.94 ±9.87 苯环壬酯 10 62.50 ±5.92
20 37.34 ±6.71 1 72.58 + 5.13 5 80.48 ±6.20 左旋苯环壬酯 1Q 73.41 ±6.00
20 54.05 ±6.34
实施例 11 对 NMDA所致小鼠死亡的保护作用
昆明小鼠, δ, 20±2g, 由军事医学科学院动物中心提供, 每天 12h/12h光照、 黑暗交替, 自由饮水摄食。 昆明小鼠随机分 组, 每组 9只。 腹腔注射不同剂量的苯环壬酯或, 30min后动物 全部均给予致死剂量的 NMDA(ip) , 观察小鼠 2h 内存活状况, 计 算存活率。 表 2 左旋苯环壬酯对 NMDA所致小鼠死亡的保护作用
分 组 剂量 (mg/kg
Figure imgf000011_0001
存活率% 溶剂 0 0 (0/9)
3 11.1 (1/9)
6 33.3 (3/9) 苯环壬酯 12 55.6* (5/9)
24 33.3 (3/9)
3 11.1 (1/9)
6 55.6* (5/9) 左旋苯环壬酯 12 22.2 (2/9)
24 11.1 (1/9) 实施例 12 小鼠急性毒性实验
昆明种小鼠 18- 22g, 雌雄各半, 随机分组, 腹腔注射给药, 观察给药后 24 h内动物反应及死亡数, Bliss法计算苯环壬酯 LD5。 为 332.00 士 48.72 rag/Kg, 左旋苯环壬酯 LDS。为 490.50 士 36.46 mg/Kg。

Claims

权 利 要 求
1. 由结构式 I a所示的左旋苯环壬酯及其非毒性的可药用盐
Figure imgf000013_0001
2. 根据权利要求 1的左旋苯环壬酯, 其中所述非毒性可药用 盐, 包括与无机酸形成药用盐, 例如硫酸盐、 盐酸盐、 氢溴酸盐、 磷酸盐; 也可与有机酸形成药用盐, 例如乙酸盐、 草酸盐、 柠檬 酸盐、 葡萄糖酸盐、 琥珀酸盐、 酒石酸盐、 对甲苯磺酸盐、 甲磺 酸盐、 苯曱酸盐、 乳酸盐、 马来酸盐等。
3. 根据权利要求 1或 2其中左旋苯环壬酯及其非毒性的可药 用盐可以形成溶剂化物, 例如水合物、 醇合物等。
5. 药物组合物,其包括根据权利要求 1― 4任一的左旋苯环壬 酯及其非毒性的可药用盐作为活性成分以及药用赋型剂。
4. 根据权利要求 1或 2, 其中的左旋苯环壬酯及其非毒性的 可药用盐还是其前药或可在体内代谢代谢后释放出所述活性成分 的形式。
6. 根据权利要求 1 - 4之一的左旋苯环壬酯,其非毒性的可药 用盐或苯环壬酯或盐酸苯环壬酯在制备神经保护剂中的用途。
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