CN1033580C - N-烷基-3-苯基-3-(2-烷硫基苯氧基)丙胺 - Google Patents

N-烷基-3-苯基-3-(2-烷硫基苯氧基)丙胺 Download PDF

Info

Publication number
CN1033580C
CN1033580C CN92111081A CN92111081A CN1033580C CN 1033580 C CN1033580 C CN 1033580C CN 92111081 A CN92111081 A CN 92111081A CN 92111081 A CN92111081 A CN 92111081A CN 1033580 C CN1033580 C CN 1033580C
Authority
CN
China
Prior art keywords
phenyl
compound
acid
compounds
norepinephrine
Prior art date
Legal status (The legal status 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 status listed.)
Expired - Fee Related
Application number
CN92111081A
Other languages
English (en)
Other versions
CN1071416A (zh
Inventor
D·R·格勒特
D·W·罗伯逊
王大维
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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 Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of CN1071416A publication Critical patent/CN1071416A/zh
Application granted granted Critical
Publication of CN1033580C publication Critical patent/CN1033580C/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/29—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/48—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing rings
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Urology & Nephrology (AREA)
  • Reproductive Health (AREA)
  • Anesthesiology (AREA)
  • Toxicology (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Addiction (AREA)
  • Hospice & Palliative Care (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

本发明提供了N-烷基-3-苯基-3-(2-取代的苯氧基)丙胺，它们适用于治疗与去甲肾上腺素失调有关的神经疾病。

Description

N-烷基-3-苯基-3-(2-烷硫基苯氧基)丙胺
本发明涉及新的N-烷基-3-苯基-3-(2-取代苯氧基)丙胺类化合物，它们是选择性的和有效的去甲肾上腺素摄取抑制剂。
在过去几十年中，人们对于神经细胞(神经元)的生物学作用的了解有了很大的提高。尤其是，特定的神经元与特定的疾病有关。本发明提供了能够在至少一种类型神经元即去甲肾上腺素神经元中抑制突触前生物胺摄取的化合物。
已经发现，去甲肾上腺素神经元存在于脑中各个部位，并且已知它们还存在于体内其他器官，例如膀胱中。本发明化合物通过抑制去甲肾上腺素摄取间接刺激神经元。此外，已知肾上腺会分泌出去甲肾上腺素以对应激反应作出响应。因此，去甲肾上腺素的英文又可称作“noradrenalin”。
患有阿尔茨海默综合症和科尔萨科夫综合症及抑郁症的患者可能缺乏去甲肾上腺素。本发明可用于治疗与去甲肾上腺素失调有关的疾病。Schildkraut的“Neuro-pharmacology of AffectiveDisorders”，427(1973)是很好的背景材料来源。
US4,018,895描述并要求保护一类  N-烷基-3-苯基-3-苯氧基丙胺化合物，这些胺与本发明所要求保护的那些化合物相似。特别是，实施例2描述了N-甲基-3-苯基-3-(2-甲氧基苯氧基)丙胺。本发明提供了式(I)化合物或其可药用的酸加成盐其中X是C1-C4烷硫基，Y是C1-C2烷基。
这些化合物的优点在于它们是比甲氧基取代的同属物(cogeners)更有效的去甲肾上腺素摄取抑制剂。
本发明还提供了含有式(I)化合物或其可药用的盐和供其使用的可药用载体、稀释剂或赋形剂的药物制剂。本发明的另一具体实施方案是选择性地抑制去甲肾上腺素摄取的方法以及治疗各种与哺乳动物中去甲肾上腺素神经传递下降有关的疾病的方法，这些疾病包括物质滥用(substance abuse)、抑郁、发作性睡病、恐慌症、贪食以及有关的精神失调。本发明的化合物适用于治疗这些精神疾病。此外，由于已知去甲肾上腺素与泌尿系统相互影响，因此本发明化合物适用于治疗尿失禁。
优选的化合物是其中Y是甲基的那些化合物。此系列最优选的化合物是N-甲基-3-苯基-3-(2-甲硫基苯氧基)丙胺。
本发明化合物可以以单独的立体异构体存在，也可以以外消旋混合物的形式存在。因此，本发明化合物不仅包括d，l-外消旋体，也包括其相应的光学活性d-和l-异构体。
正如上面所指明的，本发明包括上式所定义化合物的可药用的酸加成盐。由于本发明的化合物是胺，它们是碱性的，因此它们可以与许多无机酸和有机酸反应形成可药用的酸加成盐。由于本发明的游离胺在室温下通常为油状，因此最好将这些游离胺转化成其相应的可药用的酸加成盐，后者在室温通常为固体，易于处理。通常用于形成这类盐的酸包括无机酸例如盐酸、氢溴酸、氢碘酸、硫酸和磷酸，以及有机酸，例如对甲苯磺酸、甲磺酸、草酸、对溴苯磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸和乙酸，以及有关的无机酸和有机酸。
因此，这类可药用的盐包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1，4-二酸盐、己炔-1，6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、β-羟基丁酸盐、乙醇酸盐、苹果酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐等。优选的可药用的酸加成盐包括那些无机酸例如盐酸和氢溴酸形成的盐，和特别是那些与有机酸如草酸和马来酸形成的盐。
下列化合物进一步说明包括在本发明范围内的化合物：
N-乙基-3-苯基-3-(2-甲硫基苯氧基)丙胺磷酸盐，N-甲基-3-苯基-3-(2-叔丁硫基苯氧基)丙胺盐酸盐，N-乙基-3-苯基-3-(2-正丙硫基苯氧基)丙胺甲酸盐，N-甲基-3-苯基-3-(2-乙硫基苯氧基)丙胺琥珀酸盐，N-甲基-3-苯基-3-(2-异丙硫基苯氧基)丙胺盐酸盐。
本发明化合物的游离碱形式为高沸点的油状物，而其酸加成盐为白色结晶固体。这些化合物可以通过多种方法制备。一种有用的制备上式所示化合物的方法是基本上按照US 4,018,895所述方法进行。
根据本发明的进一步具体实施方案，它提供了制备式(I)化合物的方法，该方法包括使式(II)的3-苯基丙胺衍生物与式(III)化合物反应：
Figure C9211108100062
其中Q和J为羟基或卤素；P是氢、卤素或保护基；然后当其中P为保护基时将其脱保护，而当其中P为卤素时，用式YNH2的胺进行胺化，并且如果需要可随意地通过任何存在的游离碱的成盐作用形成可药用的酸加成盐。
                  实施例1
N-甲基-3-苯基-3-(2-甲硫基苯氧基)丙胺盐酸盐的制备
在500ml三颈圆底烧瓶中，将10.80g氯苯基·乙基酮溶于100ml甲醇中。该烧瓶装有氮气入口和温度计。通过磁搅拌棒搅拌反应混合物，并保持在氮气氛下。将混合物在冰浴中冷却，同时非常缓慢地加入2.03g硼氢化钠。撤去冰浴，然后将混合物在室温搅拌大约2小时。
然后将混合物蒸发得到黄色油状物，并用大约100ml水稀释。通过用乙醚洗涤三次从水中萃取混合物。然后用水洗涤该乙醚两次，并用饱和氯化钠溶液洗涤一次。所得混合物用硫酸钠干燥并蒸发，得到11.2g含有3-氯-1-苯基-1-丙醇的黄色中间体产物。
将4.99g上述制备的中间体3-氯-1-苯基-1-丙醇装入充满氮气的250ml三颈圆底烧瓶中。该烧瓶装有温度计、氮气入口和滴液漏斗，将该化合物、3.52g 2-甲硫基苯酚和7.69g三苯基膦在40ml四氢呋喃中磁搅拌。向该混合物中滴加4.61ml偶氮二羧酸二乙酯。用冰浴将反应混合物的温度保持在大约25℃，用四氢呋喃冲洗滴液漏斗，并将反应混合物在大约室温下搅拌过夜。加入偶氮二羧酸二乙酯过程中，该混合物变成稠的、不透明的黄色。大约1小时后，该混合物变成透明的黄色溶液。将反应混合物蒸发，得到黄色固体。向该固体中加入己烷并剧烈振摇该混合物。
然后吸滤出不溶的三苯基膦氧化物，再向该固体中加入己烷，振摇该混合物并再次过滤。将滤液蒸发，得到6.63g透明油状物。然后将此透明的油状物溶于乙醚中。加入2N氢氧化钠溶液。除去氢氧化钠层，将有机层用水洗涤一次，并用饱和氯化钠溶液洗涤一次。然后用硫酸钠干燥此溶液。所得化合物，即1-(3-氯-1-苯基丙氧基)-2-甲硫基苯通过在130℃在乙醇中与甲胺(40％水溶液)反应3小时进行胺化。蒸发掉乙醇后，向所得黄色油状物中加入水。将该混合物用乙醚萃取两次，并用水洗涤两次，用盐水洗涤一次。用硫酸钠干燥该产物。
采用100∶5∶1的二氯甲烷、甲醇和氨水体系，经湿法装料，通过闪式层析纯化该产物。得到870mg产品。
将此胺溶于甲醇中，加入1.05当量的12N HCL。重结晶后，得到850mg米色结晶。
该固体的熔点为143℃-144.5℃。
分析：
理论值：C，63.04；H，6.85；N，4.32；
实验值：C，63.08；H，6.94；N，4.23。
如上所述，本发明化合物适用于抑制去甲肾上腺素的摄取。因此，本发明另一个具体方案是抑制哺乳动物去甲肾上腺素摄取的方法，该方法包括给需要增加去甲肾上腺素神经传导的哺乳动物服用药学上有效量的本发明化合物。
本发明所用术语“药学上有效量”是指能够抑制去甲肾上腺素摄取的本发明化合物的量。当然，所用化合物的具体剂量要根据患者的具体情况来决定，这些情况包括所用的化合物、给药途径、受治患者的具体状况等类似情况。这些化合物可以通过各种途径给药，包括口服、直肠、经皮、皮下、静脉、肌肉或鼻内途径给药。优选口服。
本发明化合物以出人意料的选择性和有效方式抑制哺乳动物去甲肾上腺素的摄取。典型的日剂量包含约0.01mg/kg至约20mg/kg本发明的活性化合物。优选的日剂量是约0.05mg/kg至10mg/kg，理想的是约0.1mg/kg至5mg/kg。
已知许多生理功能均受到体内去甲肾上腺素含量的影响。因此，确信本发明化合物能够治疗各种与体内去甲肾上腺素含量异常有关的哺乳动物疾病。
进行下列试验以说明本发明化合物抑制去甲肾上腺素摄取的能力。在Wong等人的6-Drug Development Research 397(1985)中给出了这种一般性方法步骤。
将重150-250g的雄性Sprague-Dawley鼠断头处死并立即取出脑。将大脑皮层在含有0.32M蔗糖和10mM葡萄糖的9倍体积介质中匀浆。在1000×g下差速离心10分钟并在17,000×g下差速离心28分钟后分离粗制的突触体(synaptosomal)制备物。将最终的沉积物悬浮于相同的介质中并保存在冰中，直到在当天使用时。
按下述方法测定3H-去甲肾上腺素(3H-NE)的突触体摄取。在37℃将皮质突触体(相当于1mg蛋白质)在1ml Krebs-碳酸氢盐介质中温育5分钟，其中介质还含有10mM葡萄糖、0.1mM异烟酰异丙肼、1mM抗坏血酸、0.17mM EDTA和50nM 3H-NE。将反应混合物立即用2ml冰冷却的Krebs-碳酸氢盐缓冲液稀释并用细胞收集器(Brandel，Gaithersburg，MD)真空过滤。将滤物用约5ml冰冷却的0.9％盐水漂洗两次，并通过液体闪烁计数器测定放射标记NE的摄取。以3H-NE在4℃的蓄积为本底，并且从所有测量中减去。通过线性回归分析测定抑制50％3H-NE蓄积所需试验化合物的浓度(IC50值)。
评估结果列于下面表I中。如表中所示，对此化合物进行评估以测定抑制50％去甲肾上腺素所需试验化合物的浓度，以IC50表示。化合物X                Y                                IC50 NE摄取(nM)CH3S          CH3                                    4.4CH3O          CH3                                    7.0
这些数据清楚地表明本发明的甲硫基衍生物的活性明显高于先有技术的甲氧基衍生物。
最好在使用本发明化合物之前对其进行配制。因此，本发明还有一个具体方案是含有本发明化合物及供其使用的可药用载体、稀释剂或赋形剂的药物制剂。
使用众所周知和易于得到的成分通过已知方法制备本发明的药物制剂。在本发明组合物的制备过程中，通常将活性成分与载体混合，载体可以是胶囊、香囊、纸或其他容器的形式。当载体用作稀释剂时，它可以是固体、半固体或液体材料，用作活性成分的载体、赋形剂或介质。因此，该组合物可以是片剂、丸剂、粉剂、锭剂、香囊、扁囊剂、酏剂、悬浮液、乳剂、溶液、糖浆、含有例如多达10％(重量)活性化合物的油膏、软和硬明胶胶囊、栓剂、无菌注射液和无菌包装粉末。
合适的载体、赋形剂和稀释剂的一些例子包括乳糖、葡萄糖、蔗糖、山梨醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯和丙酯、滑石、硬脂酸镁和矿物油。制剂中还可以包括润滑剂、湿润剂、乳化剂和悬浮剂、防腐剂、甜味剂或调味剂。通过采用本领域众所周知的方法可以配制本发明的组合物，使其在给患者服用后能迅速、持续或延持释放活性成分。
该组合物优选配制成单位剂量形式，每一剂量含有约5-500mg活性成分，更通常含有约25-300mg活性成分。术语“单位剂量形式”是指适宜用作人或其他哺乳动物单元剂量的物理上分离的单位，每一单位含有计算产生所需的治疗效果的预定量的活性物质，以及合适的药物载体。
下列制剂实施例仅用于说明本发明，而不是对本发明范围任何方面的限制。
                          制剂1用下列成分制备硬明胶胶囊：量(mg/胶囊)N-甲基-3-苯基-3-(2-甲硫基苯氧基)丙胺                    250干淀粉                                                  200硬脂酸镁                                                10总量                                                    460mg
将上述成分混合并填入硬明胶胶囊中，填充量为460mg。制剂2
按下述方法制备每片含60mg活性成分的片剂：N-甲基-3-苯基-3-(2-甲硫基苯氧基)丙胺                    60.0mg淀粉                                                    45.0mg微晶纤维素                                              35.0mg聚乙烯吡咯烷酮(10％的水溶液)                            4.0mg羧甲基淀粉钠                                            4.5mg硬脂酸镁                                                0.5mg滑石                                                    1.0mg总量                                                    150.0mg
将活性成分、淀粉和纤维素通过No.45筛目美国筛并彻底混合。将聚乙烯吡咯烷酮溶液与所得粉末混合，然后将其通过No.14筛目美国筛。将所得颗粒在50℃干燥并过No.18筛目美国筛。将羧甲基淀粉钠、硬脂酸镁和滑石预先过No.60筛目美国筛，然后加至颗粒中，混合后，将其在压片机上压片，得到每片重150mg的片剂。

Claims (2)

1.制备药物制剂的方法，该方法包括将下述式I化合物或其可药用的盐与一种或多种供其使用的可药用载体、赋形剂或稀释剂混合，
Figure C9211108100021
其中X是C1-C4烷硫基，Y是C1-C2烷基。
2.权利要求1的方法，其中式I化合物中X是甲硫基，Y是甲基。
CN92111081A 1991-09-27 1992-09-26 N-烷基-3-苯基-3-(2-烷硫基苯氧基)丙胺 Expired - Fee Related CN1033580C (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US766,993 1991-09-27
US07/766,993 US5281624A (en) 1991-09-27 1991-09-27 N-alkyl-3-phenyl-3-(2-substituted phenoxy) propylamines and pharmaceutical use thereof

Publications (2)

Publication Number Publication Date
CN1071416A CN1071416A (zh) 1993-04-28
CN1033580C true CN1033580C (zh) 1996-12-18

Family

ID=25078150

Family Applications (1)

Application Number Title Priority Date Filing Date
CN92111081A Expired - Fee Related CN1033580C (zh) 1991-09-27 1992-09-26 N-烷基-3-苯基-3-(2-烷硫基苯氧基)丙胺

Country Status (23)

Country Link
US (1) US5281624A (zh)
EP (1) EP0534756A3 (zh)
JP (2) JPH05238996A (zh)
KR (1) KR100221180B1 (zh)
CN (1) CN1033580C (zh)
AT (1) ATE124934T1 (zh)
AU (1) AU655075B2 (zh)
BR (2) BR9203743A (zh)
CA (2) CA2079161C (zh)
CZ (1) CZ281817B6 (zh)
DE (1) DE69203424T2 (zh)
FI (1) FI111250B (zh)
HU (1) HU215519B (zh)
IL (1) IL103277A (zh)
MX (1) MX9205433A (zh)
MY (1) MY108304A (zh)
NO (1) NO178109C (zh)
NZ (1) NZ244460A (zh)
RU (1) RU2057120C1 (zh)
SK (1) SK280480B6 (zh)
TW (1) TW249225B (zh)
YU (1) YU87192A (zh)
ZA (1) ZA927240B (zh)

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7087765B2 (en) * 1995-06-07 2006-08-08 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
US6071970A (en) * 1993-02-08 2000-06-06 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
US6017965A (en) * 1993-02-08 2000-01-25 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
TW344661B (en) * 1993-11-24 1998-11-11 Lilly Co Eli Pharmaceutical composition for treatment of incontinence
JPH11510143A (ja) * 1995-07-24 1999-09-07 イーライ・リリー・アンド・カンパニー 注意不足／活動亢進障害の処置
AU4421697A (en) * 1996-09-19 1998-04-14 American Home Products Corporation Method of treating urinary incontinence
US6586427B2 (en) 1998-04-09 2003-07-01 Pharmacia & Upjohn Company Treatments for nervous disorders
CA2321157A1 (en) * 1998-04-09 1999-10-21 Pharmacia & Upjohn Company New treatments for nervous disorders
US6342533B1 (en) 1998-12-01 2002-01-29 Sepracor, Inc. Derivatives of (−)-venlafaxine and methods of preparing and using the same
DE60039132D1 (de) 1999-04-06 2008-07-17 Sepracor Inc O-Desmethylvenlafaxin-Succinat
NZ516111A (en) 1999-05-24 2003-05-30 Mitsubishi Pharma Corp Phenoxypropylamine compounds useful to treat depression
ES2246485T3 (es) 1999-07-01 2006-02-16 PHARMACIA & UPJOHN COMPANY LLC (s,s)-reboxetina para tratar la incontinencia.
US20040034106A1 (en) * 2001-11-06 2004-02-19 Read Holly Ann Treatment of anxiety disorders
AU2002347984A1 (en) * 2001-11-30 2003-06-17 Eli Lilly And Company Use of norepinephrine reuptake inhibitors for the treatment of tic disorders
CN1713900A (zh) * 2001-12-11 2005-12-28 伊莱利利公司 去甲肾上腺素再摄取抑制剂在治疗认知障碍中的应用
EP1539181B1 (en) * 2003-04-04 2007-06-27 Dynogen Pharmaceuticals Inc. Method of treating lower urinary tract disorders
WO2005020976A2 (en) * 2003-08-27 2005-03-10 Eli Lilly And Company Treatment of pervasive developmental disorders with norepinephrine reuptake inhibitors
CA2548304A1 (en) * 2003-12-12 2005-07-07 Eli Lilly And Company Selective norepinephrine reuptake inhibitors for the treatment of hot flashes, impulse control disorders and personality change due to a general medical condition
ITMI20061987A1 (it) 2006-10-16 2008-04-17 Archimica Srl Processo per la sintesi di arilossipropilammine ed eteroarilossipropilammine.
CN111225901B (zh) * 2017-10-16 2023-07-04 埃斯特韦制药股份公司 用于治疗疼痛和与疼痛相关的病症的丙胺衍生物
CN113121394B (zh) * 2019-12-30 2022-11-08 中国药科大学 一种苯氧乙酸类衍生物的制备方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4194009A (en) * 1974-01-10 1980-03-18 Eli Lilly And Company Aryloxyphenylpropylamines for obtaining a psychotropic effect
US4313896A (en) * 1974-01-10 1982-02-02 Eli Lilly And Company Aryloxyphenylpropylamines
US4018895A (en) * 1974-01-10 1977-04-19 Eli Lilly And Company Aryloxyphenylpropylamines in treating depression
US4314081A (en) * 1974-01-10 1982-02-02 Eli Lilly And Company Arloxyphenylpropylamines
US4584404A (en) * 1974-01-10 1986-04-22 Eli Lilly And Company Substituted phenoxyphenylproply dimethylamines
US4626549A (en) * 1974-01-10 1986-12-02 Eli Lilly And Company Treatment of obesity with aryloxyphenylpropylamines
IL89854A (en) * 1988-04-08 1994-02-27 Lilly Co Eli Phenoxypropanamines, the process for their preparation and medicinal preparations containing them

Also Published As

Publication number Publication date
DE69203424T2 (de) 1996-01-11
JPH05238996A (ja) 1993-09-17
CA2079161A1 (en) 1993-03-28
CZ281817B6 (cs) 1997-02-12
FI924305A0 (fi) 1992-09-25
TW249225B (zh) 1995-06-11
KR100221180B1 (ko) 1999-09-15
NZ244460A (en) 1994-10-26
HU215519B (hu) 1999-01-28
MY108304A (en) 1996-09-30
NO178109C (no) 1996-01-24
HUT65375A (en) 1994-05-02
EP0534756A3 (en) 1993-06-16
CA2079161C (en) 2004-02-17
BR9203743A (pt) 1993-04-20
SK290892A3 (en) 2000-02-14
ATE124934T1 (de) 1995-07-15
FI111250B (fi) 2003-06-30
IL103277A0 (en) 1993-02-21
NO923710L (no) 1993-03-29
US5281624A (en) 1994-01-25
NO178109B (no) 1995-10-16
CA2079162A1 (en) 1993-03-28
CZ290892A3 (en) 1993-04-14
NO923710D0 (no) 1992-09-24
YU87192A (sh) 1995-10-24
IL103277A (en) 1997-11-20
RU2057120C1 (ru) 1996-03-27
SK280480B6 (sk) 2000-02-14
BR1100384A (pt) 1999-08-31
DE69203424D1 (de) 1995-08-17
MX9205433A (es) 1993-03-01
JPH05201961A (ja) 1993-08-10
EP0534756A2 (en) 1993-03-31
KR930005972A (ko) 1993-04-20
AU655075B2 (en) 1994-12-01
ZA927240B (en) 1994-03-22
CN1071416A (zh) 1993-04-28
HU9203051D0 (en) 1992-12-28
AU2537092A (en) 1993-04-01
JP3256291B2 (ja) 2002-02-12
FI924305A (fi) 1993-03-28

Similar Documents

Publication Publication Date Title
CN1033580C (zh) N-烷基-3-苯基-3-(2-烷硫基苯氧基)丙胺
DE69513708T2 (de) Verwendung von 3,4-diphenyl chroman Derivaten zur Herstellung eines Medikaments zur Absinkung des Cholesterolspiegels
DE60220188T2 (de) Hemmer des phosphattransports
CN1028024C (zh) 四唑类兴奋性氨基酸受体拮抗剂的制备方法
CS227019B2 (en) Method of preparing (-)-n-methyl-3-(2-methylphenyloxy)-3-phenylpropylamine
JPH07188008A (ja) 骨減少を抑制するための方法
IE901790L (en) Aryloxyphenylpropylamines their preparation and use
JPH07215871A (ja) 血清コレステロールを減少させるための方法
HUT71327A (en) Pharmaceutical compositions for inhibition of autoimmune diseases containing 2-phenyl-3-aroyl-benzothiophene derivatives and process for their preparation
DE69724733T2 (de) Substituierte Benzo(b)thiophene als selektive Östrogenrezeptormodulatoren
CN116724023A (zh) 作为药物活性化合物的大麻素衍生物及其制备方法
CN1042704A (zh) 氟苯氧丙胺类似物
DE69714504T2 (de) Benzothiopene, diese enthaltende Zubereitungen und Verfahren
DE69730796T2 (de) Naphthylverbindungen, Zusammensetzungen und Verfahren
DE69719640T2 (de) Amorphe Benzothiophen, Verfahren zur Herstellung und Verwendung
JPH11501929A (ja) 新規ナフチル医薬化合物
CN1036562A (zh) 对丙胺衍生物或与丙胺衍生物有关的改进方法
DE69612686T2 (de) Phosphor-enthaltende Benzothiophene
KR20120081120A (ko) 뉴로키닌 2 수용체 활성과 관련된 장애 또는 질환을 치료하기 위한 화합물
DE69628606T2 (de) 3-Benzyl-benzothiophene
HUT72297A (en) Pharmaceutical compositions for inhibiting the effects of amyloidogenic proteins containing benzotiophene derivatives and process for their preparation
JP2001516770A (ja) ｔｒｋＡ発現の調節方法
EP0537915B1 (en) N-alkyl-3-phenyl-3-(2-alkylthiophenoxy)propylamines as norepinephrine inhibitors
DE69711529T2 (de) Tetra-Hydrobenzo(a)fluorenverbindungen und ihre Anwendungen
DE69721358T2 (de) Benzothiophene, deren Zusammensetzungen und Verfahren

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C15 Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993)
OR01 Other related matters
C19 Lapse of patent right due to non-payment of the annual fee
CF01 Termination of patent right due to non-payment of annual fee