WO2006029549A1 - Composes de quinuclidine a groupe ammonium quaternaire, procede d'elaboration et utilisation comme agents de blocage de l'acetycholine - Google Patents

Composes de quinuclidine a groupe ammonium quaternaire, procede d'elaboration et utilisation comme agents de blocage de l'acetycholine Download PDF

Info

Publication number
WO2006029549A1
WO2006029549A1 PCT/CN2004/001047 CN2004001047W WO2006029549A1 WO 2006029549 A1 WO2006029549 A1 WO 2006029549A1 CN 2004001047 W CN2004001047 W CN 2004001047W WO 2006029549 A1 WO2006029549 A1 WO 2006029549A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
compound according
preparation
quaternary ammonium
Prior art date
Application number
PCT/CN2004/001047
Other languages
English (en)
French (fr)
Inventor
Shuqiang Zhao
Original Assignee
Shuqiang Zhao
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shuqiang Zhao filed Critical Shuqiang Zhao
Priority to PCT/CN2004/001047 priority Critical patent/WO2006029549A1/zh
Priority to DK04762181.8T priority patent/DK1790643T3/da
Priority to EP04762181A priority patent/EP1790643B1/en
Priority to DE602004027555T priority patent/DE602004027555D1/de
Priority to ES04762181T priority patent/ES2344842T3/es
Priority to US11/575,384 priority patent/US7521559B2/en
Priority to JP2007531567A priority patent/JP4781362B2/ja
Priority to AT04762181T priority patent/ATE469898T1/de
Publication of WO2006029549A1 publication Critical patent/WO2006029549A1/zh
Priority to US12/400,053 priority patent/US8207192B2/en
Priority to US13/239,892 priority patent/US8394824B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the present invention relates to the field of medicine, and in particular to an anticholinergic drug, in particular to a quinine-based compound containing a quaternary ammonium group, a preparation method thereof, and a composition containing one or more of these compounds, and the compound is prepared for anti-cholestasis
  • an anticholinergic drug in particular to a quinine-based compound containing a quaternary ammonium group, a preparation method thereof, and a composition containing one or more of these compounds, and the compound is prepared for anti-cholestasis
  • alkalinity drugs The use of alkalinity drugs.
  • Acetylcholine is a neurotransmitter released from cholinergic nerve endings (including motor nerve fibers, autonomic ganglia fibers, parasympathetic ganglia fibers and partial sympathetic ganglia fibers) and has strong biological activity. It exerts an effect by acting on a cholinergic receptor, a muscarinic receptor (M receptor) and a nicotinic receptor (N receptor).
  • Cholinergic receptor blockers are a class of drugs that act by blocking choline receptors and are classified into M-choline receptor blockers and N-choline receptor blockers.
  • M-choline receptor blockers block choline receptors on the effectors of central and postganglionic cholinergic innervation, manifested by the central nervous system's pseudo-psychotic effects and smooth muscle relaxation, glandular secretion inhibition, and pupil dilation , increased heart rate, etc., has a wide range of pharmacological effects and clinical uses.
  • M-choline receptor blockers are basically tropine alkaloids and atropine synthetic substitutes. Due to its wide range of pharmacological effects, when it is applied in one of its aspects, other aspects of the effect will appear as side effects, especially psychotropic effects, which limits its clinical application, therefore, anticholinergic The drug should have a certain selectivity, that is, retain its anticholinergic effect and reduce the central mental side effects.
  • Another object of the present invention is to provide a novel quinine compound containing a quaternary ammonium group. Another object of the present invention is to provide a process for preparing a quinine-based compound containing a quaternary ammonium group. It is a further object of the invention to provide one or more pharmaceutical compositions comprising the compound and a pharmaceutically acceptable carrier. Such as: tablets, capsules, aerosols, sprays, injections, sustained release agents, etc.
  • a further object of the present invention is to provide a use of the compound as a medicament for anticholinergic diseases.
  • the present invention adopts the following technical proposal - the present invention relates to a novel compound having the general formula I:
  • It is selected from the group consisting of saturated linear alkanes and cycloalkanes having 1 to 12 carbon atoms.
  • R 2 is selected from the group consisting of saturated linear anthracene hydrocarbons having 1 to 12 carbon atoms and linear indole hydrocarbons.
  • X is selected from the group consisting of halide ions, organic and inorganic acid radicals and the like as a pharmaceutically acceptable acid radical.
  • the process of the invention comprises reacting a phenylalkyl oxirane with 2-quinol in an organic solvent with a strong base, further separating the diastereomers by chromatography The structure is then reacted with an alkyl halide.
  • a process for the preparation of a compound of formula I comprises the steps of:
  • step (B) reacting the product obtained in the step (A) with a halogenated hydrazine to prepare a racemic compound containing a quaternary ammonium group;
  • the product obtained in the step (C) is separately reacted with a halogenated hydrazine to prepare a stereoisomer compound containing a quaternary ammonium group.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
  • the compound of the formula I of the present invention has an activity of blocking cholinergic receptors; and for guinea pig-specific allergic asthma, the compound of the present invention has a significant inhibitory effect. More importantly, the invention is The N2004/001047 compound does not penetrate the blood-brain barrier and does not enter the central nervous system. There is no central mental side effect.
  • the compounds of the present invention are a class of cholinergic receptor blockers which do not enter the central nervous system and are useful for the treatment of bronchial asthma, chronic obstructive pulmonary disease, colds, rhinitis, peptic ulcers, dysentery, arrhythmias and the like.
  • compositions containing an effective amount of a compound of the invention can be prepared using pharmaceutical carriers well known to those skilled in the art.
  • the compounds of the invention or compositions thereof may be administered orally or parenterally.
  • the oral administration may be a tablet, a capsule, a coating, a powder, an oral solution, a parenteral dosage form, an aerosol, a spray, a drop, an injection, and a suppository. These formulations are prepared according to methods well known to those skilled in the art.
  • Dressings for the manufacture of tablets, capsules, coatings, powders are conventional auxiliaries such as starch, dextrin, microcrystalline cellulose, pregelatinized starch, gelatin, gum arabic, methylcellulose, B Cellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, silica, polyethylene glycol, solvents for liquid dosage forms are water, ethanol, propylene glycol, vegetable oils such as corn oil, peanut oil, olive oil, and the like.
  • Other auxiliaries such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, pigments and the like may also be present in the preparation containing the compound of the present invention.
  • the dose of the compound of formula I of the present invention in a tablet, capsule, coating, aerosol, spray, injection or suppository is calculated as the amount of the compound present in the unit dosage form.
  • the compound of formula I of the present invention is typically present in a unit dosage form in an amount of from 1 to 5000 g.
  • the dose of the compound of the present invention sprayed to an adult patient is generally from 1 to 1000 g per day, preferably from 1 to 100 ⁇ g, and can be administered once or in divided doses; detailed description
  • the invention is further illustrated by the following examples, without limiting the scope of the invention.
  • the measuring instruments used in this paper XRC-1 type micro melting point apparatus for melting point measurement, uncorrected by thermometer; Bmker ARX500 type nuclear magnetic resonance apparatus for nuclear magnetic resonance spectroscopy, TMS for internal standard; and Nicoler FTMS-2000G type instrument for mass spectrometry.
  • Example 1 Preparation of 3-quinuclidinyl-(2'-phenyl-2'-cyclopentyl-2'-hydroxy)ethyl ether (1) 1-Phenyl-1-cyclopentyl epoxy Ethyl ruthenium 9.3 g was dissolved in DMSO.
  • Example 1 The compound (1) obtained in Example 1 was dissolved in absolute ethanol, and excess bromoformamide was added thereto to react overnight. After evaporating the solvent, it was recrystallized from acetone to give a white solid (yield: 75%). Melting point 166-168 ⁇ ;
  • the compound (1) was taken and separated by a self-made silica gel plate.
  • the developing solvent was chloroform: methanol: ammonia water (4:0.8:0.15), and a chromatographic band having a high R f value was collected. After elution, the product obtained was passed through excess methyl bromide and reacted overnight. . After evaporating the solvent, it was recrystallized from acetone to give a white solid. Melting point 149-151 ° C.
  • Example 4 3-(N-methylquinuclidinyl)-(2'-phenyl-2'-cyclopentyl-2'-hydroxy) ethyl ether bromide type II diastereomer (4 Preparation
  • the compound (1) was taken and separated with a self-made silica gel plate, and the developing solvent was chloroform: methanol: ammonia water (4:0.8:0.15), and a chromatographic band having a low R f value was collected. After elution, the obtained product was passed through excess methyl bromide and allowed to react overnight. . After evaporating the solvent, it was recrystallized from acetone to give a white solid. Melting point 160-162 ° C ; Example 5 in vitro anti-acetylcholine effect of the compound of the present invention
  • the isolated ileal specimens were prepared and suspended in a bath (30 ml) filled with Tyrode's solution.
  • the nutrient solution was passed through a mixture of 95% of 0 2 and 5% CO 2 , kept at a constant temperature of 37 ° C, and fitted with a stimulating electrode. Stimulation was performed with a square wave with a frequency of 0.1 times/second and a duration of 1 millisecond. For one stimulation, a transient contraction of the ileum occurred.
  • the propellant is trichlorofluoromethane, dichlorodifluoromethane, dichlorofluoromethane, chlorodifluoromethane, dichlorotetrafluoromethane, chloropentafluoroformamide, chlorodifluoroethane, Fluorine or octafluorocyclobutane or the like or a mixture of the above compounds.
  • Example 7
  • Each guinea pig was intraperitoneally injected with 10% of ovalbumin physiological saline solution 1.0 ml (ovalbumin albumin 100 mg), and randomly divided into a blank control group and a positive control group [Ai Quan Le (Isotropium bromide aerosol), 10ml / bottle, 204g / spray, produced by Boehringer lngelheim, Germany, batch number: 104015, date of manufacture: 06 2001, valid until: 06 2004], this compound example 2 aerosol group, the compound Example 3 Aerosol group, present compound Example 4 aerosol group, 10 per group.
  • the aliquot of the albumin physiological saline solution was homogenized by an ultrasonic nebulizer. The animal was placed in a closed bell jar.
  • the ground was sprayed into the bell jar for 30 s, and the time between the injection of the physiological saline solution of the ovalbumin to the contraction of the abdominal muscles was observed and recorded, which is the incubation period of asthma.
  • the measured data were compared by t test to compare differences between groups.
  • Positive control group 10 100 235. 40 ⁇ 45. 15**
  • Example 2 Compound Aerosol 10 100 248. 90 ⁇ 38. 24**
  • Example 3 Compound Aerosol 10 100 243. 50 ⁇ 42. 13**
  • Example 4 Compound Aerosol 10 100 231. 60 ⁇ 37. 30**
  • the compounds of the present invention have a blocking effect on mammalian M-choline receptors. Moreover, the compounds of the present invention have good promise in the preparation of medicaments for mammals including human M choline receptor blockers.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Otolaryngology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicinal Preparation (AREA)

Description

一种含有季铵基团的奎宁类化合物及其制法和药物用途 技术领域
本发明涉及医药领域， 特别涉及一种抗胆碱能药物， 具体涉及含有季铵基团 的奎宁类化合物及其制备方法， 以及含有一个或多个这些化合物的组合物， 和该 化合物在制备抗胆碱能药物中的应用。
Figure imgf000003_0001
背景技术
乙酰胆碱（acetylcholine,ACh)是胆碱能神经末梢（包括运动神经纤维、 植物 神经节前纤维、副交感神经节后纤维和部分交感神经节后纤维）释放的神经递质， 具有很强的生物活性， 通过作用于胆碱能受体即毒蕈碱受体（M受体）和烟碱受 体（N受体）发挥效应。 胆碱能受体阻断药是一类通过阻断胆碱受体而发挥作用. 的药物， 分为 M-胆碱受体阻断药和 N-胆碱受体阻断药。 M-胆碱受体阻断药能阻 断中枢及节后胆碱能神经支配的效应器上的胆碱受体， 表现为中枢神经的拟精神 作用及平滑肌松弛、 腺体分泌抑制、 瞳孔放大、 心律增快等， 具有广泛的药理作 用和临床用途。
目前， M-胆碱受体阻断药基本都是托品类生物碱及阿托品合成代用品。 由于 其药理作用广泛， 在应用其某一方面的作用时， 其它方面的作用就会表现为副作 用， 尤其是拟精神性作用， 这就限制了其在.临床上的应用， 因此， 抗胆碱能药应 有一定的选择性， 即保留其抗胆碱作用， 减少其中枢拟精神性副作用。
在现有文献中，迄今尚未见到本发明之含有季铵基团的奎宁类化合物的报道， 以及它用于阻断胆碱能受体而作为抗胆碱能药物的用途。 发明内容
为了克服现有药物及技术的不足， 本发明的目的在于提供一种含有季铵基团 的奎宁类新型化合物。 本发明的另一目的在于提供一种制备含有季铵基团的奎宁类化合物的方法。 本发明的又一目的在于提供一种或多种含有该化合物与药学上可接受的载体 的药物组合物。 如： 片剂、 胶囊剂、 气雾剂、 喷雾剂、 注射剂、 缓释剂等。
本发明的再一目的在于提供一种该化合物作为抗胆碱能相关疾病药物的用 途。
为了实现本发明之目的， 本发明采取如下技术方案- 本发明是涉及具有通式 I的新型化合物： .
Figure imgf000004_0001
R2
( i ) 式中，
选自含 1至 12个碳原子的饱和直链烷烃和环烷烃。
R2选自含 1至 12个碳原子的饱和直链垸烃和直链垸烃。
X选自卤离子， 有机和无机酸根等可作为药用的酸根。
为制备本发明通式 I所述的化合物， 本发明方法包括， 将苯基烷基环氧乙烷 与 2-奎宁醇在有机溶剂中与强碱反应， 进一步用色谱法分离非对映异构体， 再与 卤代烷反应。
具体地讲， 制备通式 I所述的化合物的方法， 包括如下步骤：
(A)、 将苯基烷基环氧乙烷与 2-奎宁醇在 DMSO溶剂中和强碱反应；
(B)、 将（A) 步所得产物与卤代垸反应， 制备含季铵基团的外消旋化合物；
(C)、 将（A) 步所得产物用色谱法分离， 制备一对非对映体化合物和相应纯 光学异构体化合物；
(D)、 将（C)步所得产物分别与卤代垸反应， 制备含季铵基团的立体异构体 化合物。
本发明还涉及一种含有药物有效剂量的如通式 I所述的化合物和药学上可接 受的载体的药物组合物。
药理学 究表明， 本发明的通式 I化合物具有阻断胆碱能受体的活性； 对豚 鼠特异性过敏性哮喘， 本发明化合物有明显的抑制作用。 更重要的是， 本发明化 N2004/001047 合物不能透过血脑屏障， 不能进入中枢神经系统， 没有中枢拟精神性副作用。
本发明化合物是一类不能进入中枢神经系统的胆碱能受体阻断药， 它可用于 治疗支气管哮喘， 慢性阻塞性肺病， 感冒， 鼻炎， 消化性溃疡， 痢疾， 心律失常 等疾病。
选用本领域技术人员熟知的药物载体可以制成含有效剂量的本发明化合物的 药物组合物。
本发明化合物或其组合物可用口服方法或非肠胃道用药。 口服用药可以是片 剂、 胶囊剂、 包衣剂、 散剂、 口服液， 非经胃肠用药剂型有气雾剂、 喷雾剂、 滴 剂、 注射剂和栓剂等。 这些制剂是按照本领域的技术人员所熟知的方法制备的。 为制造片剂、 胶囊剂、 包衣剂、 散剂所用的敷料是常规用的助剂， 例如淀粉， 糊 精， 微晶纤维素， 预胶化淀粉， 明胶， 阿拉伯胶， 甲基纤维素， 乙基纤维素， 羟 丙基纤维素， 羧甲基纤维素钠， 硅石， 聚乙二醇， 液体剂型所用的溶剂有水， 乙 醇， 丙二醇， 植物油类如玉米油， 花生油， 橄榄油等。 含有本发明化合物的制剂 中还可有其它助剂， 例如表面活性剂， 润滑剂， 崩解剂， 防腐剂， 矫味剂， 色素 等。
在片剂， 胶囊剂， 包衣剂， 气雾剂， 喷雾剂， 注射剂或栓剂中含有本发明式 I 化合物的剂量是以单元剂型中存在的化合物量计算的。 在单元剂型中本发明式 I 化合物一般含量为 1-5000 g。
为治疗支气管哮喘， 慢性阻塞性肺病， 感冒， 鼻炎等疾病， 成人患者喷雾给 予的本发明化合物的剂量一般每日为 1-1000 g，优选为 1-100 y g， 可一次或分次 给药； 具体实施方式
以下将结合实施例对发明作进一步说明， 但并不限制本发明的范围。 本文中 使用的测定仪器： 熔点测定用 XRC-1型显微熔点仪， 温度计未校正； 核磁共振光 谱测定用 Bmker ARX500 型核磁共振仪， TMS 为内标； 质谱测定用 Nicoler FTMS-2000G型仪器。 实施例 1 3-奎宁环基- (2' -苯基 -2' -环戊基 -2' -羟基） 乙基醚（1 ) 的制备 将 1-苯基 -1-环戊基环氧乙垸 9.3g溶于 DMSO中。取奎宁醇 6.35g，溶于 64ml DMSO 中， 加氢化钠 2.5g， 搅拌 1 小时， 冷至室温， 滴加苯基环戊基环氧乙垸 一 DMSO溶液， 再搅拌 3小时。 冷至室温， 乙醚提取， 将醚层用 6N HC1提取， 酸 T N2004/001047 水层用 20%NaOH碱化， 再用乙醚提取， 无水硫酸钠干燥过夜。 蒸除溶剂， 产物经 蒸镏纯化后待用。 收率 54%。 实施例 2 3- (N-甲基奎宁环基） - (2' -苯基 -2' -环戊基 -2' -羟基） 乙基醚 溴化物 （2) 的制备
将实施例 1所得化合物（1 )， 用无水乙醇溶解， 通入过量溴甲垸， 反应过夜。 蒸除溶剂后， 用丙酮重结晶， 得白色固体， 收率 75%。 熔点 166-168 Ό ;
,3.70(m,4H),3.30(d,lH),3.22(s,3H),3. ll(m,2H),2.25(m,2H), 1.96(m,2H),1.63(m,4H),1.4 4(m，4H),1.26(m,2H)。 MS(m/z): 410(1^); 175,726(B)。 实施例 3 3- (N-甲基奎宁环基） - (2' -苯基 -2' -环戊基 -2' -轻基） 乙基醚 溴化物 I型非对映异构体 （3 ) 的制备
取化合物（1 )， 用自制硅胶板分离， 展开剂为氯仿： 甲醇： 氨水（4:0.8:0.15 )， 收集 Rf值高的色谱带， 经洗脱后所得产物通入过量溴甲烷， 反应过夜。 蒸除溶剂 后， 用丙酮重结晶， 得白色固体， 收率 30%。 熔点 149-151°C。 实施例 4 3- (N-甲基奎宁环基） - (2' -苯基 -2' -环戊基 -2' -羟基） 乙基醚 溴化物 II型非对映异构体 （4) 的制备
取化合物（1 )， 用自制硅胶板分离， 展开剂为氯仿： 甲醇： 氨水 (4:0.8:0.15), 收集 Rf值低的色谱带， 经洗脱后所得产物通入过量溴甲烷， 反应过夜。 蒸除溶剂 后， 用丙酮重结晶， 得白色固体， 收率 30%。 熔点 160-162°C ; 实施例 5 本发明化合物体外抗乙酰胆碱作用
本试验采用本领域技术人员熟知的方法进行。 制备离体回肠标本， 悬挂于充 满台氏液的浴曹 （30ml) 中， 营养液通以 95%的 02和 5%CO2的混合气体， 保持 恒温 37°C， 装上刺激电极。用频率 0.1次 /秒、持续时间为 1毫秒的方波进行刺激， 对于一次刺激， 回肠将发生一次一过性的收缩。 置换含不同药物的台氏夜时需用 台氏液清洗三次并作空白剌激。 结果， 在分别含有硫酸阿托品 （10_7g/ml) 和本发 明化合物实施例 2、 实施例 3和实施例 4 ( 10-7g/ml) 的台氏液中， 电刺激引起的 回肠收缩反应被完全阻断。 04 001047 本发明化合物气雾剂的制备：
实施例 6
本发明化合物 0.28g
丙二醇 35g
乙醇 382g
抛射剂 983g
灌封于定量阔门容器中， 每瓶 10g， 每喷 100mg、 含本发明化合物 20 g。 抛 射剂为三氯一氟甲烷、 二氯二氟甲烷、 二氯一氟甲垸、 一氯二氟甲垸、 二氯四氟 甲烷、 一氯五氟甲垸、 一氯二氟乙烷、 二氟乙烷或八氟环丁烷等或上述化合物的 混合物。 . 实施例 7
本发明化合物 0.28g
丙二醇 42g
无水乙醇 210g
二氯二氟甲烷 231g
二氯四氟乙垸 971g
灌封于定量阀门容器 实施例 8 本发明化合物气雾剂对豚鼠特异性过敏性哮喘的治疗作用 本试验采用本领域技术人员熟知的方法进行。 选用 30只体重在 200- 220g的 健康豚鼠进行试验。 给每只豚鼠腹腔注射 10%的卵清白蛋白生理盐水溶液 1. 0ml (卵清白蛋白 100mg)， 随机分为空白对照组、 阳性对照组 [爱全乐（异丙托溴铵气 雾剂）， 10ml /瓶， 204g /喷， 德国勃林格林格翰 （Boehringer lngelheim) 公司生 产， 批号： 104015, 生产日期： 06 2001， 有效期至： 06 2004]、 本化合物实施例 2 气雾剂组、本化合物实施例 3气雾剂组、本化合物实施例 4气雾剂组，每组 10只。 于注射后第 6天开始每日经呼吸道喷雾给药一次， 连续给药 5天后， 将动物单独 置密闭的钟罩内，用超声雾化器将 0. 5 %的卵清白蛋白生理盐水溶液均匀地喷入钟 罩内 30s， 观察并记录自喷入卵清白蛋白生理盐水溶液至产生腹肌收缩之间的时 间， 即为哮喘潜伏期。 所测数据经 t检验比较组间差异。
结果： 当给豚鼠腹腔注射卵清白蛋白 10天后， 再次接触同一抗原时， 便出现 了以呼吸道的水肿和痉挛为主的抗原抗体反应， 称之为特异性过敏性哮喘。 试验 证明， 本化合物气雾剂对此特异性反应具有明显的抑制作用， 哮喘潜伏期较空白 对照组显著延长， P 〈0. 01。 结果见表 1。
表 1. 本化合物气雾剂对豚鼠过敏性哮喘的影响 （s 土 SD )
组 别 n 剂量 潜伏期 （s )
g · kg.
空白对照组 10 - 124. 00±21. 66
阳性对照组 10 100 235. 40±45. 15**
实施例 2化合物气雾剂 10 100 248. 90 ±38. 24**
实施例 3化合物气雾剂 10 100 243. 50 ±42. 13**
实施例 4化合物气雾剂 10 100 231. 60±37. 30**
与空白对照组相比较 ** P<0. 01 ; 工业应用性
经过上述试验结果， 本领域技术人员熟知， 本发明化合物对哺乳动物 M-胆碱 受体具有阻断作用。 而且本发明化合物在制备哺乳动物包括人 M胆碱受体阻断剂 药物的应用上具有良好的前景。

Claims

权利要求
1、 如通式 I的含有季铵基团的奎宁类化合物-
Figure imgf000009_0001
R2
( I )
式中：
选自含有 1至 12个碳原子的饱和直链烷烃和环烷烃；
选自含有 1至 12个碳原子的饱和直链垸烃和直链垸烃；
X选自卤离子、 有机和无机酸根。
2、 如权利要求 1所述的化合物， 其特征在于所述化合物中 是环丙基、环戊基、 或环己基； R2是甲基、 乙基、 丙基、 异丙基、 正丁基、 异丁基、 或叔丁基； X 是氟、 氯、 溴、 碘、 甲磺酸根、 或对甲苯磺酸根及其它可作为药用的酸根。
3、 如权利要求 1或 2所述的化合物， 其特征是 代表环戊基， R2代表甲基， X 代表溴。
4、 如权利要求 3所述的化合物， 其特征是化合物构型是非对映异构体。
5、 如权利要求 4所述的化合物， 其特征是化合物构型是纯光学异构体。
6、 如权利要求 1至 5任一所述的化合物的合成方法， 其特征包括如下步骤：
(A)、 将苯基烷基环氧乙烷与 2-奎宁醇在有机溶剂中和碱反应；
(B)、 将（A)步所得产物与卤代烷反应， 制备含季铵基团的外消旋化合物；
(C)、 将（A)步所得产物用色谱法分离， 制备一对非对映异构体化合物和相 应纯光学异构体化合物；
(D)、将（C)步所得产物分别与卤代垸反应， 制备含季铵基团的立体异构体。
7、 如权利要求 1至 5任一所述的化合物在制备阻断胆碱能受体的药物中的应用。
8、 如权利要求 1至 5任一所述的化合物的应用，其特征在于可将其应用于制备治 疗哺乳动物呼吸系统疾病的药物， 如慢性阻塞性肺病、 支气管哮喘、 鼻炎和感
9、 如权利要求 1至 5任一所述的化合物的应用，其特征在于可将其应用于制备治 疗哺乳动物消化系统疾病的药物， 如消化性溃疡、 痢疾等。 、 、 一种含有药物有效剂量的如权利要求 1至 5任一所述的化合物的应用， 其 特征在于可将其应用于制备该化合物与药学上可接受的载体的药物组合物， 如 片剂、 胶囊剂、 气雾剂、 喷雾剂、 口服液、 注射剂、 缓释剂等。
PCT/CN2004/001047 2004-09-15 2004-09-15 Composes de quinuclidine a groupe ammonium quaternaire, procede d'elaboration et utilisation comme agents de blocage de l'acetycholine WO2006029549A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
PCT/CN2004/001047 WO2006029549A1 (fr) 2004-09-15 2004-09-15 Composes de quinuclidine a groupe ammonium quaternaire, procede d'elaboration et utilisation comme agents de blocage de l'acetycholine
DK04762181.8T DK1790643T3 (da) 2004-09-15 2004-09-15 Quinuclidinforbindelser med kvaternær ammoniumgruppe, fremgangsmåde til fremstilling heraf og anvendelse som blokeringsmidler for acetylcholin
EP04762181A EP1790643B1 (en) 2004-09-15 2004-09-15 Quinuclidine compounds having quaternary ammonium group, it's preparation method and use as blocking agents of acetycholine
DE602004027555T DE602004027555D1 (de) 2004-09-15 2004-09-15 Chinuclidinverbindungen mit quaternärer ammoniumgruppe, verfahren zu ihrer herstellung und ihre verwendung als acetylcholinblockierende mittel
ES04762181T ES2344842T3 (es) 2004-09-15 2004-09-15 Compuestos de quinuclidina que tienen un grupo amonio cuaternario, su metodo de preparacion y uso como agentes bloqueantes de la acetilcolina.
US11/575,384 US7521559B2 (en) 2004-09-15 2004-09-15 Quinuclidine compounds having quaternary ammonium group, its preparation method and use as blocking agents of acetylcholine
JP2007531567A JP4781362B2 (ja) 2004-09-15 2004-09-15 ４級アンモニウム基を有するキヌクリジン化合物とその調製方法、およびアセチルコリン遮断剤としての用途
AT04762181T ATE469898T1 (de) 2004-09-15 2004-09-15 Chinuclidinverbindungen mit quaternärer ammoniumgruppe, verfahren zu ihrer herstellung und ihre verwendung als acetylcholinblockierende mittel
US12/400,053 US8207192B2 (en) 2004-09-15 2009-03-09 Quinuclidine compounds having quaternary ammonium group, its preparation method and use as blocking agents of acetylcholine
US13/239,892 US8394824B2 (en) 2004-09-15 2011-09-22 Quinuclidine compounds having quaternary ammonium group, its preparation method and use as blocking agents of acetylcholine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2004/001047 WO2006029549A1 (fr) 2004-09-15 2004-09-15 Composes de quinuclidine a groupe ammonium quaternaire, procede d'elaboration et utilisation comme agents de blocage de l'acetycholine

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US10/575,384 A-371-Of-International US20070249711A1 (en) 2003-10-10 2004-10-11 Triterpene Compounds which are Effective on Improvement of Brain Function
US12/400,053 Division US8207192B2 (en) 2004-09-15 2009-03-09 Quinuclidine compounds having quaternary ammonium group, its preparation method and use as blocking agents of acetylcholine

Publications (1)

Publication Number Publication Date
WO2006029549A1 true WO2006029549A1 (fr) 2006-03-23

Family

ID=36059691

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2004/001047 WO2006029549A1 (fr) 2004-09-15 2004-09-15 Composes de quinuclidine a groupe ammonium quaternaire, procede d'elaboration et utilisation comme agents de blocage de l'acetycholine

Country Status (8)

Country Link
US (3) US7521559B2 (zh)
EP (1) EP1790643B1 (zh)
JP (1) JP4781362B2 (zh)
AT (1) ATE469898T1 (zh)
DE (1) DE602004027555D1 (zh)
DK (1) DK1790643T3 (zh)
ES (1) ES2344842T3 (zh)
WO (1) WO2006029549A1 (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007045151A1 (fr) * 2005-10-20 2007-04-26 Cachet Pharmaceutical Co., Ltd. Composes et compositions pharmaceutiques les comprenant pour le traitement de l'hypersecretion de la cavite nasale et de la bronchopneumopathie chronique obstructive
CN103724298A (zh) * 2012-10-15 2014-04-16 天津药物研究院 一种1-苯基-1-环戊基环氧乙烷的制备方法
CN109776521A (zh) * 2019-03-30 2019-05-21 山东博洛德生物科技有限公司 一种含有季铵基团的奎宁类化合物及其制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2836113T3 (es) 2016-12-14 2021-06-24 Beijing Showby Pharmaceutical Co Ltd Clase de compuestos bifuncionales con estructura de sal de amonio cuaternario

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1938546A1 (de) 1968-08-01 1970-03-26 Rech S Et D Applic Scient Sorg Neue Chinuclidinderivate und Verfahren zu ihrer Herstellung
GB1490659A (en) 1974-03-05 1977-11-02 Vni Khim Farma I Im S Ordzhoni Quinuclidin-3-yl carbinols
EP0383281A1 (en) * 1989-02-14 1990-08-22 Toyama Chemical Co., Ltd. 1,2-ethanediol derivative and salt thereof, process for producing the same, and cerebral function-improving agent comprising the same
CN1475214A (zh) * 2002-08-16 2004-02-18 成都力思特制药有限公司 盐酸戊乙奎醚的应用
WO2004016590A1 (fr) 2002-08-16 2004-02-26 Chengdu List Pharmaceutical Co.,Ltd Sels de derives de quinuclidine, elaboration et applications
CN1519239A (zh) * 2003-01-23 2004-08-11 成都力思特制药股份有限公司 一种药物化合物的衍生物及其制备方法和应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1164227B (it) * 1983-05-13 1987-04-08 Angeli Inst Spa Composizione farmaceutica atta alla somministrazione nasale di sali quaternari d'ammonio ed attivita' anticolinergica
ES2204295B1 (es) * 2002-07-02 2005-08-01 Almirall Prodesfarma, S.A. Nuevos derivados de quinuclidina-amida.

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1938546A1 (de) 1968-08-01 1970-03-26 Rech S Et D Applic Scient Sorg Neue Chinuclidinderivate und Verfahren zu ihrer Herstellung
GB1490659A (en) 1974-03-05 1977-11-02 Vni Khim Farma I Im S Ordzhoni Quinuclidin-3-yl carbinols
EP0383281A1 (en) * 1989-02-14 1990-08-22 Toyama Chemical Co., Ltd. 1,2-ethanediol derivative and salt thereof, process for producing the same, and cerebral function-improving agent comprising the same
CN1475214A (zh) * 2002-08-16 2004-02-18 成都力思特制药有限公司 盐酸戊乙奎醚的应用
WO2004016590A1 (fr) 2002-08-16 2004-02-26 Chengdu List Pharmaceutical Co.,Ltd Sels de derives de quinuclidine, elaboration et applications
CN1519239A (zh) * 2003-01-23 2004-08-11 成都力思特制药股份有限公司 一种药物化合物的衍生物及其制备方法和应用

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ACTA PHARMACEUTICA SINICA, vol. 22, no. 9, 1987, pages 708 - 710, XP008098215 *
ACTA PHARMACEUTICA SINICA, vol. 24, no. 3, 1989, pages 194 - 199, XP008098217 *
ACTA PHARMACEUTICA SINICA, vol. 25, no. 12, 1990, pages 891 - 897, XP008098214 *
ACTA PHARMACEUTICA SINICA, vol. 28, no. 8, 1993, pages 633 - 638, XP008098216 *
ACTA PHARMACEUTICA SINICA, vol. 48, no. 3, 1990, pages 302 - 306, XP008098220 *
D.S. FRIES ET AL.: "Synthesis and Preliminary Pharmacological Activity of Aminoalkoxy Isosteres of Glycolate Ester Anticholinergics", J MED. CHEM., vol. 20, no. 10, 1977, pages 1250 - 1254
JOURNAL OF MEDICINAL CHEMISTRY, vol. 20, no. 10, 1977, pages 1250 - 1254, XP008098223 *
NIU W.Z. ET AL, ARCHIVES INTERNATIONALES DE PHARMACODYNAMIE ET DE THERAPIE, vol. 304, 1990, pages 64 - 74, XP008098226 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007045151A1 (fr) * 2005-10-20 2007-04-26 Cachet Pharmaceutical Co., Ltd. Composes et compositions pharmaceutiques les comprenant pour le traitement de l'hypersecretion de la cavite nasale et de la bronchopneumopathie chronique obstructive
CN103724298A (zh) * 2012-10-15 2014-04-16 天津药物研究院 一种1-苯基-1-环戊基环氧乙烷的制备方法
CN109776521A (zh) * 2019-03-30 2019-05-21 山东博洛德生物科技有限公司 一种含有季铵基团的奎宁类化合物及其制备方法

Also Published As

Publication number Publication date
EP1790643A4 (en) 2008-09-24
DK1790643T3 (da) 2010-08-16
JP2008513380A (ja) 2008-05-01
US7521559B2 (en) 2009-04-21
DE602004027555D1 (de) 2010-07-15
US8394824B2 (en) 2013-03-12
ATE469898T1 (de) 2010-06-15
EP1790643B1 (en) 2010-06-02
ES2344842T3 (es) 2010-09-08
JP4781362B2 (ja) 2011-09-28
EP1790643A1 (en) 2007-05-30
US20090163541A1 (en) 2009-06-25
US8207192B2 (en) 2012-06-26
US20080247963A1 (en) 2008-10-09
US20120010236A1 (en) 2012-01-12

Similar Documents

Publication Publication Date Title
RU2314306C2 (ru) Производные хинуклидинамида, способ их получения и их применение, фармацевтическая композиция, комбинированный продукт и способ ингибирования мускариновых рецепторов
JP2656702B2 (ja) ペプチド性キヌクリジン
JP4295985B2 (ja) 新規なキヌクリジン誘導体およびそれを含む医薬組成物
US8071639B2 (en) Soft anticholinergic zwitterions
EP1725552B1 (en) New quaternized quinuclidine esters
AU2006315657B2 (en) Soft anticholinergic esters
US20100234333A1 (en) Novel quinuclidine derivatives and medicinal compositions containing the same
RU2193557C2 (ru) Бензоциклогептатиофеновые соединения, способы профилактики или лечения, фармацевтическая композиция
HU211889A9 (en) Quaternary basic amides, method of preparing them and pharmaceutical compositions in which they are present
WO1998043640A9 (en) Benzocycloheptathiophene compounds
JPH01131178A (ja) ケトン誘導体
US20060106055A1 (en) Novel quinuclidine derivatives and medicinal compositions containing the same
US8394824B2 (en) Quinuclidine compounds having quaternary ammonium group, its preparation method and use as blocking agents of acetylcholine
JP2877231B2 (ja) スピロキヌクリジン誘導体の光学異性体、それらの製造法、それらからなる薬剤組成物およびそれらを使用した治療法
CN1257903C (zh) 一种含有季铵基团的奎宁类化合物及其制法和药物用途
JPH02218614A (ja) 痴呆または認識障害に関する疾患の治療薬

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2007531567

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 11575384

Country of ref document: US

Ref document number: 2004762181

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

WWP Wipo information: published in national office

Ref document number: 2004762181

Country of ref document: EP