CN1125221A - 具有药理效果的1-苯基-3-二甲氨基丙烷化合物 - Google Patents

具有药理效果的1-苯基-3-二甲氨基丙烷化合物 Download PDF

Info

Publication number
CN1125221A
CN1125221A CN95108919A CN95108919A CN1125221A CN 1125221 A CN1125221 A CN 1125221A CN 95108919 A CN95108919 A CN 95108919A CN 95108919 A CN95108919 A CN 95108919A CN 1125221 A CN1125221 A CN 1125221A
Authority
CN
China
Prior art keywords
formula
alkyl
phenyl
represent
compound
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.)
Granted
Application number
CN95108919A
Other languages
English (en)
Other versions
CN1077566C (zh
Inventor
H·布施曼
W·施特拉斯堡格
E·弗里德里希斯
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.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=6524045&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN1125221(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Publication of CN1125221A publication Critical patent/CN1125221A/zh
Application granted granted Critical
Publication of CN1077566C publication Critical patent/CN1077566C/zh
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
    • C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C07C215/62—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • 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
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • 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
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
    • C07C217/72—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • 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
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/20—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C219/22—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/04—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
    • C07C225/08—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
    • C07C225/10—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings with doubly-bound oxygen atoms bound to carbon atoms not being part of rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/58—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • 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
    • C07C323/31—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 atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/33—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 atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring
    • C07C323/35—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 atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
    • C07C323/36—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 atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group the sulfur atom of the sulfide group being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pain & Pain Management (AREA)
  • Public Health (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (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)
  • Furan Compounds (AREA)
  • Steroid Compounds (AREA)
  • Adhesive Tapes (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

公开了1-苯基-3-二甲氨基丙烷化合物，其制备方法和这类化合物作为药物活性成分的用途。

Description

具有药理效果的1-苯基 -3-二甲氨基丙烷化合物
本发明涉及1-苯基-3-二甲氨基丙烷化合物、其制备方法和这类化合物作为药物活性成分的用途。
慢性和非慢性病痛的治疗在医学上具有极大的重要性。这反映在许多出版物中。例如，从EP176049可知1-萘基-3-氨基丙-1-醇具有止痛麻醉效果。J.Pharm.Sci.59，1038(1970)和J.Prakt.Chem.323，793(1981)叙述了具有γ-氨基基团的仲醇和叔醇；Chem.Abstr.54，20936c(1960)和Chem.Abstr.63.6912e(1965)叙述了含有对位取代苯基基团的苯基-二甲氨基丙醇。这些化合物也具有止痛性能。相反，DE3242922中叙述的含有2个苯基基团的3-二甲氨基丙-1-醇类则具有抗抑制效果。J.Pharm.Sci57，1487(1968)中所述的1-苯基-丙-1-醇类具有不同的药理效果，取决于γ-氨杂环。
类阿片尽管会产生一系列副作用，例如上瘾和依赖性、呼吸阻抑、胃肠抑制以及顽固便秘等，但它们多年来一直作治疗疼痛的止痛药。因此，它们只能在一个较长的时间周期或较高的剂量给药，还必须有特殊的预防措施，如特殊的规定条例(参见：Goodman，Gilman：“Pharmacological Basis of Therapeutics”，Pergamon出版社，纽约(1990)。
盐酸曲马多(Tramadol)-(1RS，2RS)-2-[(二甲氨基)甲基]-1-(3-甲氧基苯基)环己醇盐酸盐-在起中心作用的止痛药中具有特殊的地位，因为这种活性成分对疼痛会产生显著的抑制作用，而没有对类阿片而言是已知的副作用(I.Pharmacol.Exptl.Ther.267，331(1993)。曲马多是一种外消旋体，由等量的(+)和(-)对映体构成。活性成分在活体内形成代谢物O-脱甲基曲马多，它同样以对映体的混合物形式存在。研究表明，曲马多的对映体和曲马多代谢物的对映体都具有止痛效果(J.Pharmacol.Exp.Ther.260，275(1992))。
本发明的根本目的是开发具有止痛效果的物质，这类物质适用于治疗严重疼痛而不会产生类阿片通常所具有的副作用。本发明的目的也在于所开发的这类物质必须无副作用，例如在某些情况下用曲马多治疗时所产生的恶心和呕吐。
已经发现，某些1-苯基-3-二甲氨基丙烷化合物能满足对要开发的这类物质所提出的严格要求。这类物质的特点是其镇痛效果与曲马多相比明显提高。
因此，本发明涉及式I所示的1-苯基-3-二甲氨基丙烷化合物，其碱或生理上可配伍的酸加成盐形式的非对映体和对映体：
Figure A9510891900071
式中
X代表OH、F、Cl、H或OCOR6基团，其中R6是C1-3烷基，
R1是C1-4烷基，
R2代表H或C1-4烷基，R3代表H或直链的C1-4烷基，或者R2和R3一起构成C4-7环烷基，
当R5是H时，R4代表间位的O-Z，其中Z是H、C1-3烷基，PO(OC1-4烷基)2、CO(OC1-5烷基)、CONH-C6H4-(C1-3烷基)或CO-C6H4-R7，其中R7是邻位的-OCOC1-3烷基或者间位或对位的-CH2N(R8)2，这里R8是C1-4烷基或4-吗啉代，或者R4代表间位的-S-C1-3烷基、间位-Cl、间位-F或间位-CR9R10R11，这里R9、R10和R11代表H或F，邻位的OH，邻位的-O-C2-3烷基，对位的F或对位的CR9R10R11，或者
当R5代表对位的-Cl、-F、-OH或-O-C1-3烷基时，R4代表间位的-Cl、-F、-OH或-O-C1-3烷基，或者
R4和R5-起代表3，4-OCH＝CH-或3，4-OCH＝CHO-。
各基团按如下定义的式I化合物是优选的1-苯基-3-二甲氨基丙烷化合物：X代表OH、F、Cl、或H，R1代表C1-4烷基，R2代表H或CH3，R3代表H或CH3，当R5是H时，R4代表间位的-OC1-3烷基、-OH、-S-C1-3烷基、-F、-Cl、-CH3、-CF2H或-CF3，或对位的-CF3，或者
当R5是对位的-Cl或对位的-F时，R4代表间位的Cl或间位的F，或者
R4和R5一起代表3，4-OCH＝CH-。
当式I中R2和R3具有不同定义时，式I所示的1-苯基-3-二甲氨基丙烷化合物是特别优选的，其形式为下面构型Ia所示的非对映异构体：
Figure A9510891900081
本发明也涉及制备其中变量X代表OH的式I的1-苯基-3-二甲氨基丙烷化合物的方法，其特征在于使式II的β-二甲氨基酮与式III的有机金属化合物反应，以生成X＝OH的式I化合物：式III中Z代表MgCl、MgBr、MgI或Li。
β-二甲氨基酮与式III的格式试剂(式中Z代表MgCl；MgBr或MgI)或与式III的有机锂化合物的反应可在脂族醚中，例如在二乙醚和/或四氢呋喃中在-70—+60℃之间的温度下进行。式III的有机锂化合物可通过式III的化合物(式中Z代表Cl、Br或I)与正丁基锂在例如己烷中的溶液反应用锂取代卤素而制得。式II的β-二甲氨基酮可由通式IV的酮：与二甲胺盐酸盐和甲醛在冰醋酸或C1-4烷基醇中反应，或用乙酰氯作催化剂在乙腈中与二甲氨基氯乙烷反应而制得(Synthesis 1973，703)。
当式II的β-二甲氨基酮(式中可变基团R2和R3具有不同的意义)与式III的有机金属化合物反应时就得到具有相对式Ia构型的式Ia的1-苯基-3-二甲氨基丙烷化合物：
Figure A9510891900101
式中X和二甲氨基基团彼此以对映体关系配置。相反，如果制备1-苯基-1-羟基-3-氨基丙烷的反应是按DD124521所述方法进行的，即如果式V的β-氨基酮：
Figure A9510891900102
是与烷基格氏试剂R1MgHal反应，则会生成具有相对构型Ib的化合物：式中OH基和二甲氨基基团彼此以叠同关系配置。
其中R4和/或R5是OH基的式I的1-苯基-3-二甲氨基丙烷化合物可由相应的1-(4(5)-甲氧基苯基)-3-二甲氨基丙醇化合物在芳族烃类，如甲苯中，在60-130℃的温度下用氢化二异丁基铝进行选择性醚裂解反应来制备(Synthesis 1975，617)。
本发明也涉及制备其中X代表H的式I的1-苯基-3-二甲氨基丙烷化合物的方法，其特征在于使其中X代表Cl的式I化合物与氢硼化锌、氰基氢硼化锌和/或氰基氢硼化锡反应。
该反应通常在溶剂中，例如在二乙醚和/或四氢呋喃中，在0-30℃进行。
其中X是H，R4和/或R5是OH基的式I化合物可由相应的甲氧基苯基化合物与浓氢溴酸-起加热数小时而制备(Chem.Rev.54，615(1954)；J.Am.Chem.Soc.74，1316(1952))。
本发明还涉及制备其中X代表F的式I的1-苯基-3-二甲氨基丙烷化合物的方法，其特征在于使其中X代表OH的式I化合物与二甲氨基三氟化硫在溶剂中进行反应。
适用的溶剂包括二氯甲烷、1，1，2-三氯乙烷和/或甲苯。该反应通常在-50℃—+30℃的温度下进行(Org.React.35，513(1988))。如果使用X＝OH，R4和/或R5是OH基的式I化合物，则必须先将这些OH基保护起来，然后才能与含氟化合物反应，例如可通过与苯甲酰氯反应来保护。
本发明也涉及制备其中X代表Cl的式I的1-苯基-3-二甲氨基丙烷化合物的方法，其特征在于使其中X代表OH的式I化合物与硫酰氯反应。
该反应通常在0-20℃的温度，在没有溶剂的条件下进行。可以用Cl取代OH，而同时保持其构型。
本发明也涉及制备其中X代表OCOR6基团(R6是C1-3烷基)的式I的1-苯基-3-二甲氨基丙烷化合物的方法，其特征在于使其中X代表OH的式I化合物与酰氯Cl-COOR6反应。
该反应较好在溶剂中，例如在二氯甲烷、甲苯和/或四氢呋喃中，在-10℃—+30℃的温度下进行。
其中R5是H，R4是间位的磷酸酯基、碳酸酯基、氨基甲酸酯基或羧酸酯基的式I的1-苯基-3-二甲氨基丙烷化合物可通过使相应的式I的1-(3-羟基苯基)-3-二甲氨基丙烷化合物的碱金属盐与氯磷酸二烷基酯的碱金属盐、与氯甲酸烷酯、与异氰酸芳基酯或与羧酰基氯反应制得。这些反应通常在溶剂中，例如在甲苯、二氯甲烷、乙醚和/或四氢呋喃中，在-15℃—+110℃的温度下进行(Drugs of the Future 16，443(1991)；J.Med.Chem.30，2008(1987)和32，2503(1989)；J.Org.Chem.43，4797(1978)；Tetrahedron Lett.1977，1571；J.Pharm.Sci.57.774(1968))。
式I的化合物可按本技术中已知的方法用生理上可配伍的酸，例如盐酸、氢溴酸、硫酸、甲磺酸、甲酸、乙酸、草酸、琥珀酸、酒石酸、扁桃酸、富马酸、乳酸、柠檬酸、谷氨酸和/或天冬氨酸转化成其盐。盐的生成较好在溶剂中，例如在乙醚、二异丙醚、乙酸烷基酯、丙酮和/或2-丁酮中进行。此外，三甲基氯硅烷的水溶液适用于制备盐酸盐。
从毒理学上看式I的1-苯基-3-二甲氨基丙烷化合物是无害的，因此这类化合物适于用作药剂中的药物活性成分。
因此，本发明也涉及式I的1-苯基-3-二甲氨基丙烷化合物作为药物活性成分的用途。
式I的化合物较好是用来治疗疼痛。
本发明的镇静剂除含有至少一种式I的1-苯基-3-二甲氨基丙烷化合物外，还可含有载体、填料、溶剂、稀释剂、着色剂和/或粘结剂。辅助物质及其用量的选择取决于给药方式，如口服、静脉内、皮内、肌内、鼻内或局部给药，例如对于皮肤、粘膜或眼睛感染。片剂、糖衣丸、胶囊、粒剂、滴剂、液剂和浆剂均适于口服给药。溶液、悬浮液、易复原的干制剂和喷雾剂等适于非经肠的、局部的和吸入给药。按照本发明的式I化合物在溶解形式中或在斑点中的沉积，选择性地加上促进皮肤渗透的手段，就成为适合于经皮给药的制剂。可以口服或经皮给药的制剂形式可以实现本发明式I化合物的延迟释放。
给病人服用的活性成分的量依病人的体重、给药方式、病情的严重程度和指征的不同而改变。通常的给药量为50-500mg/kg至少一种式I的1-苯基-3-二甲氨基丙烷化合物。
实例
所制备的化合物的收率未经优化。
所有温度均未校正。
除非另有指明，否则所用石油醚的沸点为50-70℃。“醚”一词是指乙醚。
用E.Merck(Darmnstadt)公司生产的硅胶60(0.040-0.063mm)作为柱色谱的固定相。
用E.Merck(Darmstadt)公司生产的预制硅胶60F254 HPTLC板进行薄层色谱研究。
外消旋物的分离在Chiracel柱中进行。所有色谱研究用的流动相的混合物比例均以体积/体积表示。
RT表示室温，m.p.表示熔点。
实例1
Figure A9510891900141
(2RS，3RS)-1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇盐酸盐(1)
将溶解于400ml无水四氢呋喃中的207.63g(1.11摩尔)3-溴茴香醚溶液逐滴加入到26.99g(1.11摩尔)镁屑和1.50ml无水四氢呋喃的混合物中，使反应混合物慢慢沸腾。在加完3-溴茴香醚后，将混合物加热回流1小时，然后冷却至5-10℃。在此温度下加入溶解在400ml四氢呋喃中的128.30g(0.89摩尔)1-二甲氨基-2-甲基戊-3-酮。让反应混合物静置过夜，然后再冷却至5-10℃。加入300ml 20％氯化铵溶液使格氏溶液分解。反应混合物用400ml乙醚稀释，分离出有机相，水相用250ml乙醚萃取2次。合并后的有机相用硫酸钠干燥。通过蒸馏除去溶剂后，将残留物(212g)收集在3200ml2-丁酮中，并加入到由120.60g(1.11摩尔)三甲基氯硅烷和20ml水组成的混合物中。在4-5℃结晶出121.5g熔点为198-199℃的盐酸盐(1)(理论产率的38％)。
实例2(1)的对映体：
(-)-(2S，3S)-1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇盐酸盐(-1)，和
(+)-(2R，3R)-1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇盐酸盐(+1)。
用二氯甲烷/氢氧化钠溶液使碱从(1)中释出。该溶液经干燥后在真空下蒸出二氯甲烷。然后在手性HPLC柱上分离外消旋物。从在2-丁酮中与三甲基氯硅烷/水反应而得到的对映体制得熔点为150-151℃的盐酸盐。
(-1)：产率：理论的42％。
      [α]D RT＝-31.8°(c＝0.99；甲醇)
(+1)：产率：理论的41％
      [α]D RT＝+33.0°(c＝0.96：甲醇)。
实例3
(2RS，3RS)-3-(3，4-二氯苯基)-1-二甲氨基-2-二甲基戊-3-醇盐酸盐(2)
与实例1相似，从15g(105毫摩尔)1-二甲氨基-2-甲基戊-3-酮、35.5g(157毫摩尔)4-溴-1，2-二氯苯和3.8g(157毫摩尔)镁屑制备39g粗混合物。将该混合物引入到装有硅胶的7×40cm柱上并用4∶1的乙酸乙酯/甲醇洗脱。得到14.9g碱，在2-丁酮/二异丙醚中用三甲基氯硅烷/水处理该碱，得到11.2g熔点为183-184℃的盐酸盐(2)(理论产率的31％)。
实例4
Figure A9510891900171
(2RS，3RS)-3-(3-异丙氧苯基)-1-二甲氨基-2-二甲基戊-3-醇盐酸盐(3)
与实例1相似，从14.3g(100毫摩尔)1-二甲氨基-2-甲基戊-3-酮、20.0g(157毫摩尔)1-溴-3-异丙氧基苯和2.79g(115毫摩尔)镁屑制备25g粗混合物。将该混合物引入到装有硅胶的7×40cm柱上并用15∶1的乙酸乙酯/甲醇洗脱。得到9.0g碱，在2-丁酮中用三甲基氯硅烷/水处理该碱，得到8.3g熔点为133-134℃的盐酸盐(3)(理论产率的26％)。实例5
Figure A9510891900181
(2RS，3RS)-3-(3-氯苯基)-1-二甲氨基-2-二甲基戊-3-醇盐酸盐(4)
按实例1所述条件，从38.0g(270毫摩尔)1-二甲氨基-2-甲基戊-3-酮、74.7g(390毫摩尔)1-溴-3-氯苯和9.50g(390毫摩尔)镁屑制备63g粗混合物。将该混合物引入到装有硅胶的7×45cm柱上并用7∶1的二异丙醚/甲醇洗脱。得到12.8g碱，在2-丁酮/醚中用三甲基氯硅烷/水处理该碱，得到10.8g熔点为160-162℃的盐酸盐(4)(理论产率的14％)。
实例6
Figure A9510891900182
(2RS，3RS)-1-二甲氨基-2-甲基-3-(3-三氟甲基苯基)-戊-3-醇盐酸盐(5)
按实例1所述条件，从14.3g(100毫摩尔)1-二甲氨基-2-甲基戊-3-酮、29.3g(130毫摩尔)1-溴-3-三氟甲基苯和3.2g(130毫摩尔)镁屑制备21.2g粗混合物。将该混合物引入到装有硅胶的6×40cm柱上并用10∶1的二异丙醚/甲醇洗脱。得到9.1g碱，在2-丁酮中用三甲基氯硅烷/水处理该碱，得到7.8g熔点为189-190℃的盐酸盐(5)(理论产率的18.5％)。
实例7
(2RS，3RS)-1-二甲氨基-2-甲基-3-(3-间甲苯基)-戊-3-醇盐酸盐(6)
按实例1方法，从47.3g(330毫摩尔)1-二甲氨基-2-甲基戊-3-酮、64.6g(400毫摩尔)3-溴甲苯和9.72g(400毫摩尔)镁屑制备75g粗混合物。将该混合物引入到装有硅胶的7×50cm柱上并用7∶1的二异丙醚/甲醇洗脱。得到24.3g碱，在2-丁酮中用三甲基氯硅烷/水处理该碱，得到21.5g熔点为154-155℃的盐酸盐(6)(理论产率的24％)。实例8
Figure A9510891900201
(2RS，3RS)-1-二甲氨基-3-(3-氟苯基)-2-甲基戊-3-醇盐酸盐(7)
按实例1所述条件，从54.0g(380毫摩尔)1-二甲氨基-2-甲基戊-3-酮、82.5g(470毫摩尔)1-溴-3-氯苯和9.23g(470毫摩尔)镁屑制备70g粗混合物。将该混合物引入到装有硅胶的7×50cm柱上并用1∶1的乙酸乙酯/甲醇洗脱。得到13.0g碱，在2-丁酮中用三甲基氯硅烷/水处理该碱，得到11.2g熔点为145-146℃的盐酸盐(7)(理论产率的11.5％)。实例9
Figure A9510891900202
(2RS，3RS)-3-(3-二氟甲基苯基)-1-二甲氨基-2-甲基戊-3-醇盐酸盐(8)
将7.0g(34毫摩尔)按Org.React.35，513(1988)方法从3-溴苯甲醛和三氟化二乙氨基硫(溶于二氯甲烷中)制得的1-溴-3-二氟甲基苯溶解于110ml无水四氢呋喃中并冷却至-75℃。加入21.12ml(34毫摩尔)1.6M正丁基锂己烷溶液，然后在-75℃将该混合物搅拌1小时。然后逐滴加入由4.8g(34毫摩尔)1-二甲氨基-2-甲基戊-3-醇溶于15ml无水四氢呋喃而形成的溶液。在2.5小时内将反应混合物加温至室温。
进行后处理时可逐滴加入65ml 5％盐酸，并用冰浴冷却，使内部温度不超过15℃。相分离之后，有机相用40ml 5％盐酸萃取。合并后的水相用50ml醚洗涤两次。为使碱释出，可将该混合物加入到氢氧化钠浓溶液中，并用二氯甲烷萃取。用这种方法得到7.8g粗产品，将其引入到装有硅胶的7×40cm柱上。用1∶1的乙酸乙酯/甲醇洗脱得到4.89g碱。在2-丁酮中用三甲基氯硅烷/水处理得到4.6g熔点为194-195℃的盐酸盐(8)(理论产率的44％)。
实例10
Figure A9510891900211
(2RS，3RS)-1-二甲氨基-2-甲基-3-(3-甲磺酰基苯基)-戊-3-醇盐酸盐(9)
按实例1所述条件从17.6g(123毫摩尔)1-二甲氨基-2-甲基戊-3-酮、25.0g(123毫摩尔)1-溴-3-甲磺酰基苯和3.0g(123毫摩尔)镁屑制得38g粗混合物。将该混合物引入到装有硅胶的7×40cm柱上并用10∶1的乙酸乙酯/甲醇洗脱。得到8.35g碱，在2-丁酮中用三甲基氯硅烷/水处理该碱，得到7.2g熔点为159-160℃的盐酸盐(9)(理论产率的19％)。
实例11
Figure A9510891900221
(2RS，3RS)-3-苯并呋喃-6-基-1-二甲氨基-2-甲基戊-3-醇盐酸盐(10)
在1.5小时内将溶解于60ml无水乙醚中的3.45g(18毫摩尔)6-溴苯并呋喃(按EP 355827制备)和6ml 1，2-二溴乙烷滴加到放在30ml无水乙醚中的2，12g(87毫摩尔)镁屑中；加完后将该混合物加热回流30分钟。然后在1.5小时内滴加由2.5g(18毫摩尔)1-二甲氨基-2-甲基戊-3-酮溶于7.5ml乙醚所形成的溶液，同时用冰浴冷却，以维持内部温度5-10℃。让反应混合物在室温下静置12小时，然后再冷却到5-10℃，并加入到35ml20％氯化铵水溶液中。相分离后，水相用50ml乙醚萃取2次。合并后的有机相用硫酸钠干燥。蒸馏除去溶剂后将残留物引入到装有硅胶的5×16cm柱上。用7∶1的二异丙醚/甲醇洗脱，得到0.95g碱。在乙酸乙酯/2-丁酮中用三甲基氯硅烷/水处理该碱，得到0.82g熔点为162℃盐酸盐(10)(理论产率的15.5％)。
实例12
Figure A9510891900231
(2RS，3RS)-1-二甲氨基-2-甲基-3-(4-三氟甲基苯基)-戊-3-醇盐酸盐(11)
按实例1的方法从20g(140毫摩尔)1-二甲氨基-2-甲基戊-3-酮、31.5g(140毫摩尔)1-溴-4-三氟甲基苯、16.5g(680毫摩尔)镁屑和47ml 1，2-二溴乙烷制得44g粗混合物。将该混合物引入到装有硅胶的7×50cm柱上并用5∶1的乙酸乙酯/甲醇洗脱。得到16.4g碱，在2-丁酮中用三甲基氯硅烷/水处理该碱，得到12.3g熔点为170-171℃的盐酸盐(11)(理论产率的27％)。
实例13
(3RS)-1-二甲氨基-3-(3-甲氧基苯基)-己-3-醇盐酸盐(12)
按实例1的方法从10g(70毫摩尔)1-二甲氨基-己-3-酮、18.7g(100毫摩尔)1-溴-3-甲氧基苯和2.3g(100毫摩尔)镁屑制得18.5g粗混合物。将该混合物引入到装有硅胶的6×50cm柱上，并用1∶1的乙酸乙酯/甲醇洗脱。得到6.84g碱，在2-丁酮中用三甲基氯硅烷/水处理该碱，得到6.15g熔点为179-180℃的盐酸盐(12)(理论产率的32％)。
实例14
(3RS)-1-二甲氨基-3-(3-甲氧基苯基)-庚-3-醇盐酸盐(13)
按实例1所述方法从10g(64毫摩尔)1-二甲氨基-庚-3-酮、15.9g(157毫摩尔)1-溴-3-甲氧基苯和2.06g(85毫摩尔)镁屑制得17.3g粗混合物。将该混合物引入到装有硅胶的6×40cm柱上，并用乙酸乙酯洗脱。得到5.4g碱，在2-丁酮中用三甲基氯硅烷/水处理该碱，得到4.1g熔点为150℃的盐酸盐(13)(理论产率的21％)。
实例15
(3RS)-1-二甲氨基-3-(3-甲氧基苯基)-4，4-二甲基-戊-3-醇盐酸盐(14)
按实例1所述方法从18.6g(118毫摩尔)1-二甲氨基-4，4-二甲基戊-3-酮、28.4g(152毫摩尔)1-溴-3-甲氧基苯和3.7g(152毫摩尔)镁屑制得37g粗混合物。将该混合物引入到装有硅胶的7×40cm柱上，并用5∶1的乙酸乙酯/甲醇洗脱。得到2.2g碱，在2-丁酮中用三甲基氯硅烷/水处理该碱，得到1.8g熔点为213℃的盐酸盐(14)(理论产率的5％)。
实例16
Figure A9510891900251
(2RS，3RS)-4-二甲氨基-2-(3-甲氧基苯基)-3-甲基丁-3-醇盐酸盐(15)
按实例1所述方法从5.3g(41毫摩尔)4-二甲氨基-3-甲基丁-3-酮、23.0g(123毫摩尔)1-溴-3-甲氧基苯和3.0g(123毫摩尔)镁屑制得21g粗混合物。将该混合物引入到装有硅胶的4.5×27cm柱上，并用4∶1的乙酸乙酯/甲醇洗脱。得到4.0g碱，在2-丁酮中用三甲基氯硅烷/水处理该碱，得到3.6g熔点为124℃的盐酸盐(15)(理论产率的32％)。实例17
Figure A9510891900261
(15)的对映体：
(-)-(2S，3S)-4-二甲氨基-2-(3-甲氧基苯基)-3-甲基丁-3-醇盐酸盐(-15)，和
(+)-(2R，3R)-4-二甲氨基-2-(3-甲氧基苯基)-3-甲基丁-3-醇盐酸盐(+15)。
用二氯甲烷/氢氧化钠溶液使碱从盐酸盐(15)(按实施例16制备的)中释出。经干燥后蒸馏除去二氯甲烷。然后在手性HPLC柱上将外消旋物分离成对映体。在2-丁酮中用三甲基氯硅烷/水处理该对映体，得到其盐酸盐。
(-15)：产率：理论的41％
       m.p.：117-118℃
       [α]D RT＝-38.6°(c＝1.05；甲醇)
(+15)：产率：理论的41％
       m.p.：118-119℃
      [α]D RT＝+41.0°(c＝1.01；甲醇)。实例18
Figure A9510891900271
(2RS，3RS)-3-(3-二甲氨基-1-乙基-1-羟基-2-甲基丙基)-苯酚盐酸盐(16)
用二氯甲烷/氢氧化钠溶液使碱从化合物(1)(按实例1制备)中释出。该溶液干燥后通过蒸馏除去二氯甲烷。将4.3g(17毫摩尔)碱溶解于25ml无水甲苯中并缓慢地将其滴加到71ml(85毫摩尔)1.2M氢化二异丁基铝的甲苯溶液中。加完之后，将混合物加热回流8小时，然后冷却至室温。反应混合物用25ml甲苯稀释。先后滴加9.4ml乙醇和9.4ml水，同时用冰浴冷却。在冰浴冷却下搅拌1小时后过滤除去铝盐，残留物用甲苯洗涤3次，每次用50ml。然后将合并的有机相干燥，并通过蒸馏除去甲苯。在丙酮中用盐酸水溶液处理该碱，得到3.95g熔点为213-214℃的盐酸盐(16)(理论产率的85％)。实例19
Figure A9510891900281
(16)的对映体：
(-)(2S，3S)-3-(3-二甲氨基-1-乙基-1-羟基-2-甲基丙基)-苯酚盐酸盐(-16)
和
(+)(2S，3S)-3-(3-二甲氨基-1-乙基-1-羟基-2-甲基丙基)-苯酚盐酸盐(+16)。
按实例2所述条件制备对映体(-16)和(+16)。
(-16)：产率：理论的85％
       m.p.：208-209℃
       [α]D RT＝-34.6°(c＝0.98；甲醇)；
(+16)：产率：理论的85％
       m.p.：206-207℃
       [α]D RT＝+34.4°(c＝1.06；甲醇)。实例20
Figure A9510891900291
(1RS，2RS)-3-(3-二甲氨基-1-羟基-1，2-二甲基丙基)苯酚盐酸盐(17)
按实例18所述条件从实例16得到的甲氧基化合物(15)制备化合物(17)。
产率：理论的85％
m.p.：232℃
实例21
(17)的对映体：
(-)-(1S，2S)-3-(3-二甲氨基-1-羟基-1，2-二甲基丙基)-苯酚盐酸盐(-17)，和
(+)-(1R，2R)-3-(3-二甲氨基-1-羟基-1，2-二甲基丙基)-苯酚盐酸盐(+17)。
按实例2所述条件制备对映体(-17)和(+17)。
(-17)：产率：理论的82％
       m.p.：204-205℃
       [α]D RT＝-42.0°(c＝0.94：甲醇)：
(+17)：产率：理论的83％
       m.p.：204-205℃
       [α]D RT＝+41.2°(c＝1.01；甲醇)。
实例22
(+)-(1R，2R)-3-(3-二甲氨基-1-乙基-1-氟-2-甲基丙基)-苯酚盐酸盐(+18)第一步
Figure A9510891900311
(+)-(1R，2R)-3-(3-苄氧基苯基)-1-二甲氨基-2-甲基戊-3-醇(+19)
用二氯甲烷/氢氧化钠溶液使该碱从实例19制得的对映体(+16)中释出，使溶液干燥后通过蒸馏除去二氯甲烷。将5.3g(22毫摩尔)碱溶于27ml无水二甲基甲酰胺中，并分成若干份加入到1.2g50％氢化钠中。在加入2.8ml(24毫摩尔)苄基氯后将该混合物在70℃加热3小时。然后使反应混合物冷却至室温并倒入到冰/水混合物中。用70ml(每次)乙醚萃取三次。用硫酸钠干燥合并后的有机相，蒸出溶剂，残留物引入到装有硅胶的4.5×30cm柱上。用二异丙醚/甲醇洗脱，得到6.8g浅黄色高粘度油状的碱(+19)(理论产率的92％)。
第二步
Figure A9510891900321
(+)-(2R，3R)-[3-(3-苄氧基苯基)-3-氟-2-甲基戊基]-二甲胺(+20)
将溶解在80ml二氯甲烷的6.8g(21毫摩尔)化合物(+19)在-20℃滴加到3.7g(23毫摩尔)三氟化二乙氨基硫在30ml无水二氯甲烷和溶液中。滴加完毕后，在此温度下将混合物搅拌30分钟，然后加温至室温。在室温下再搅拌1小时后使混合物冷却至0-5℃，并用50ml水进行水解。相分离后，水相用50ml二氯甲烷萃取2次。将合并后的有机相干燥，并在真空下蒸馏除去溶剂。得到的粗混合物(8.04g)引入到装有硅胶的6×50cm柱上，并用1∶1的乙酸乙酯/甲醇洗脱。得到3.04g浅黄色粘稠油状的碱(+20)(理论产率的40％)。
第三步：
(+)-(1R，2R)-3-(3-二甲氨基-1-乙基-1-氟-2-甲基丙基)-苯酚盐酸盐(+18)
将3.0g(91毫摩尔)(+20)溶解在15ml无水甲醇中，并加入到装有0.44g载于活性炭上的钯(10％ Pd)的加氢反应器中。在室温下搅拌3小时后消耗215ml氢气。过滤除去催化剂、甲醇通过蒸馏除去。得到2.22g碱，在2-丁酮中用三甲基氯硅烷处理该碱，得到2.0g盐酸盐(+18)(理论产率的79％)。
m.p.：174-176℃
[α]D RT＝+29.5°(c＝1.08；甲醇)
实例23
(-)-(1S，2S)-3-(3-二甲氨基-1-乙基-1-氟-2-甲基丙基)-苯酚盐酸盐(-18)
按实例22所述条件由实例19得到的对映体(-16)制得对映体(-18)，其产率为理论的29％。
m.p.：170-172℃
[α]D RT＝-28.4°(c＝1.03；甲醇)。实例24
Figure A9510891900341
(+)-(1R，2R)-3-(3-二甲氨基-1-乙基-2-甲基丙基)-苯酚盐酸盐(+21)
第一步：
(+)-(2R，3R)-[3-氯-3-(3-甲氧基苯基)-2-甲基戊基]-二甲胺盐酸盐(+22)
在室温下将10g(35毫摩尔)按实例2制备的(+1)加入到10ml亚硫酰氯中。随后在反应物上通氨2小时以除去过量的亚硫酰氯。重新加入10ml亚硫酰氯后让反应混合物静置12小时，然后再通氮2.5小时除去过量的亚硫酰氯。干燥后将残留物溶解在10ml冰冷的2-丁酮中，在搅拌下先后与200ml乙醚和140ml二异丙醚混合。将上层溶剂相倾出，剩下的油层再溶于10ml 2-丁酮中。在添加晶种后，滴加300ml二异丙醚，同时猛烈搅拌3小时以上，此时结晶出盐酸盐。得到9.8g(+22)(理论的91％)。
m.p.：120℃(分解)
[α]D RT＝+24.7°(c＝1.01；甲醇)。
第二步
Figure A9510891900351
(+)-(2R，3R)-[3-(3-甲氧基苯基)-2-甲基戊基]-二甲胺盐酸盐(+23)
46g经干燥的氯化锌溶于580ml无水乙醚中，然后滴加到31g硼氢化钠在1800ml乙醚的浆液中。搅拌12小时后从所得到的硼氢化锌悬浮液中倾析出500ml，并滴加到含有9.8g(32毫摩尔)(+22)的200ml无水乙醚中。在室温下将反应混合物搅拌72小时，然后在冰浴冷却下滴加到40ml饱和氯化铵溶液中。相分离后，醚相用饱和食盐水洗涤两次：用硫酸钠干燥后在真空下蒸出溶剂。得到7.3g胺-甲硼烷配合物，再将其溶于100ml无水甲醇中以离析出游离碱。加入7.5g三苯膦后将混合物加热回流18小时。通过蒸馏除去溶剂后残留物加入到100ml 5％的盐酸中，然后用50ml乙醚洗涤盐酸相2次。然后用氢氧化钠浓溶液使盐酸相变成碱性，同时用冰浴冷却，并用50ml二氯甲烷进行溶剂萃取2次。合并后的有机相用硫酸镁干燥后，在真空下蒸出溶剂，残留物(5.2g)收集在2-丁酮中。加入三甲基氯硅烷/水之后结晶出4.3g盐酸盐(+23)(理论的50％)。
m.p.：163-164℃
[α]D RT＝+25.2°(c＝0.95；甲醇)。
第三步
(+)-(1R，2R)-3-(3-二甲氨基-1-乙基-2-甲基丙基)-苯酚盐酸盐(+21)
将步骤2得到的4.3g(15毫摩尔)(+23)加入到100ml浓盐酸中。然后将该混合物加热回流2小时，冷却至室温后在水泵产生的真空下使混合物浓缩。残留物用碳酸氢钠浓溶液处理直至得到碱性反应为止。用二氯甲烷萃取2次(每次用50ml)后，合并的有机相用硫酸钠干燥。然后在真空下蒸出二氯甲烷，残留物(4g)收集在2-丁酮中。加入三甲基氯硅烷/水之后，结晶出3.8g盐酸盐(+21)(理论的98％)。
m.p.：194-196℃
[α]D RT＝+24.5°(c＝1.10；甲醇)。实例25
(-)-(1S，2S)-3-(3-二甲氨基-1-乙基-2-甲基丙基)-苯酚盐酸盐(-21)
按实例24所述条件从实例2制备的(-1)制得对映体(-21)，产率为45％。
m.p.：168-170℃
[α]D RT＝-27.5°(c＝0.97；甲醇)。
实例26
(+)-(1R，2R)-乙酸-3-二甲氨基-1-乙基-1-(3-甲氧基苯基)-2-甲基丙基酯盐酸盐(+24)
用二氯甲烷/氢氧化钠溶液使碱从按实例2制备的对映体(+1)中释出。将该溶液干燥后通过蒸馏除去二氯甲烷。在冰浴冷却下将3.0g(39毫摩尔)乙酰氯滴加到收集在150ml无水二氯甲烷中的所得到的10g(35毫摩尔)碱中。滴加完乙酰氯后，将混合物温热至室温，搅拌2小时后与100ml饱和碳酸氢钠溶液混合。有机相与水相分离，水相用50ml二氯甲烷萃取2次。将有机相合并后用硫酸钠干燥。蒸馏除去溶剂后，得到13.4g粗混合物，在2-丁酮/乙酸乙酯中用三甲基氯硅烷/水处理得到10.7g盐酸盐(+24)(理论的93％)。
m.p.：153℃
[α]D RT＝-17.3°(c＝1.04；甲醇)。
实例27
Figure A9510891900381
(1RS)-1-(1-二甲氨基甲基-环己基)-1-(3-甲氧基苯基)-丙-1-醇盐酸盐(25)
第一步：
Figure A9510891900391
(1RS)-1-(1-二甲氨基甲基-环己基)-(3-甲氧基苯基)-甲醇盐酸盐(26)
按实例1所述条件，从25g(150毫摩尔)1-二甲氨基甲基-环己烷甲醛、32.9g(180毫摩尔)1-溴-3-甲氧基苯和4.3g(180毫摩尔)镁屑制得44g粗混合物。将该混合物引入到装有硅胶的7×40cm柱上，并用4∶1的二异丙醚/甲醇洗脱。得到38g碱，在2-丁酮中用三甲基氯硅烷/水处理该碱，得到40g熔点为235℃的盐酸盐(26)(理论的85％)。
第二步：
(1RS)-(1-二甲氨基甲基-环己基)-(3-甲氧基苯基)-甲酮盐酸盐(27)
用二氯甲烷/氢氧化钠溶液使碱从(26)中释出，该溶液经干燥后通过蒸馏除去二氯甲烷。将8.3g(30毫摩尔)碱溶于30ml正己烷中并滴加到由吸附在中性氧化铝上的95g氯铬酸吡啶鎓(按Synthesis1980，223方法制备)组成的悬浮物中。在室温下搅拌72小时后将反应混合物与120ml二氯甲烷混合，再搅拌2小时，然后通过30g氧化铝过滤。过滤后的残留物用50ml二氯甲烷和乙醚(在每种情况下)用倾析法洗涤3次。有机相与滤液合并，通过蒸馏除去溶剂。得到的残留物收集在60ml 2N氢氧化钠溶液中并用乙酸乙酯萃取4次，每次用20ml。将合并后的有机相干燥后，通过蒸馏除去溶剂。得到4.8g粗混合物，将其引入到装有硅胶的6×30cm柱上，并先用乙酸乙酯、再用9∶1的乙酸乙酯/甲醇、最后用4∶1的乙酸乙酯/甲醇洗脱。得到3.8g碱，在2-丁酮中用三甲基氯硅烷/水处理该碱，得到3.1g熔点为174℃的盐酸盐(27)(理论的33％)。
第三步：
(1RS)-1-(1-二甲氨基甲基-环己基)-1-(3-甲氧基苯基)-丙-1-醇盐酸盐(25)
按实例1所述条件，用乙醚作溶剂从2.8g(10毫摩尔)碱形式的(27)、1.4g(13毫摩尔)溴乙烷和0.32g(13毫摩尔)镁屑制得3.0g粗混合物。将该混合物引入到装有硅胶的3×20cm柱上，并用19∶1二异丙醚/甲醇洗脱。得到2.1g碱，在2-丁酮/乙酸乙酯中用三甲基氯硅烷/水处理该碱，得到1.9g熔点为230℃的盐酸盐(25)(理论的55％)。实例28
Figure A9510891900411
(-)-(2R，3S)-{3[3-(对异丙基-苯基-氨基甲酰基)-氧-苯基]-2-甲基戊基-二甲胺盐酸盐(-28)
用二氯甲烷/氢氧化钠溶液使碱从按实例24制备的对映体(+21)中释出，使该溶液干燥后通过蒸馏除去二氯甲烷。将所得到的2.2g(10毫摩尔)碱溶于20ml无水甲苯中，并与1.8g(11毫摩尔)异氰酸4-异丙基苯基酯混合。在室温下搅拌20小时后通过蒸馏除去甲苯。残留物在乙酯正丙酯中与三甲基氯硅烷/水反应生成3.2g盐酸盐(-28)(理论的76％)。
m.p.：151-152℃
[α]D RT＝-5.2°(c＝1.11；甲醇)。
药理实验
对小鼠的扭动(Writhing)试验
按照本发明的化合物的镇痛效果用对小鼠进行的苯基苯醌诱发的扭动试验来研究，该试验是按照I.C.Hendershot，J.Forsaith在J.Pharmacol.Exptl.Ther.125，237(1959)中所述方法改进的。本试验使用体重为25-30g的雄性小鼠。对每种剂量的物质，各用10只动物，在口服给药本发明的化合物后30分钟，每只小鼠通过腹膜内给药0.3ml 0.02％苯基苯醌水溶液(苯基苯并苯醌由Sigma公司(Deisenhofen)生产；通过添加5％乙醇并保持在45℃水浴上而制成的溶液)。然后将这些小鼠分别关在观察笼中。用按钮计数器记录由疼痛诱发的伸展运动(扭动反应＝随后腿的伸展身体变直)的次数。与只服用苯基苯醌的平行试验小鼠相比，从扭动反应中剂量依赖的减少，用95％的置信界限通过回归分析(由Martens EDV-Service，Eckental提供的评估程序)计算出ED50值(50％抑制扭动反应的有效剂量)。
所有进行试验的本发明的化合物都显示出显著的镇痛效果。结果汇总于下表中。表：扭动抑制
   实例 本发明的化合物       ED50[mg/kg口服]     25mg/kg，口服时的抑制％
     12234567891011131516171819192021212224       (1)(-1)(+1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(12)(14)(15)(+15)(16)(-16)(+16)(17)(-17)(+17)(+18)(+21)        5.822.31.113.215.58.311.827.312.912.812.919.910.53.816.11.015.71.9 -81.3-95.2-100.0-87.0-58.3-97.2

Claims (10)

1.式I所示的1-苯基-3-二甲氨基丙烷化合物，其碱或生理上可配伍的酸加成盐形式的非对映体和对映体：
Figure A9510891900021
式中
X代表OH、F、Cl、H或OCOR6基团，其中R6是C1-3烷基，
R1是C1-4烷基，
R2代表H或C1-4烷基，R3代表H或直链的C1-4烷基，或者R2和R3一起构成C4-7环烷基，
当R5是H时，R4代表间位的O-Z，其中Z是H、C1-3烷基，PO(OC1-4烷基)2、CO(OC1-5烷基)、CONH-C6H4-(C1-3烷基)或CO-C6H4-R7，其中R7是邻位的-OCOC1-3烷基或者间位或对位的-CH2N(R8)2，这里R8是C1-4烷基或4-吗啉代，或者R4代表间位的-S-C1-3烷基、间位-Cl、间位-F或间位-CR9R10R11，这里R9、R10和R11代表H或F，邻位的OH，邻位的-O-C2-3烷基，对位的F或对位的CR9R10R11，或者
当R5代表对位的-Cl、-F、-OH或-O-C1-3烷基时，R4代表间位的-Cl、-F、-OH或-O-C1-3烷基，或者
R4和R5一起代表3，4-OCH＝CH-或3，4-OCH＝CHO-。
2.按照权利要求1的化合物，其特征在于X代表OH、F、Cl或H，R1代表C1-4烷基，R2代表H或CH3，R3代表H或CH3，
当R5是H时，R4代表间位的OC1-3烷基、间位-OH、间位-S-C1-3烷基、间位-F、间位-Cl、间位-CH3、间位-CF2H、间位-CF3或对位-CF3，或当R5是对位-Cl时或对位-F时，R4代表间位-Cl或间位-F，或
R4和R5一起代表3，4-OCH＝CH-。
3.按照权利要求1或2的化合物，其特征在于式I的化合物中R2和R3具有不同的含义，该化合物以具有Ia构型的非对映体形式存在：
Figure A9510891900031
4.制备按照权利要求1-3的X＝OH的式I的1-苯基-3-二甲氨基丙烷化合物的方法，其特征在于使式II的β-二甲氨基酮与式III的有机金属化合物反应生成X代表OH的式I化合物
Figure A9510891900041
式III中Z代表MgCl、MgBr、MgI或Li。
5.制备按照权利要求1-3的X＝H的式I的1-苯基-3-二甲氨基丙烷化合物的方法，其特征在于使X代表Cl的式I化合物与硼氢化锌、氰基硼氢化锌和/或氰基硼氢化锡反应。
6.制备按照权利要求1-3的X＝F的式I的1-苯基-3-二甲氨基丙烷化合物的方法，其特征在于使X代表OH的式I化合物与三氟化二甲氨基硫在溶剂中反应。
7.制备按照权利要求1-3的X＝Cl的式I的1-苯基-3-二甲氨基丙烷化合物的方法，其特征在于使X代表OH的式I化合物与亚硫酰氯反应。
8.制备按照权利要求1-3的式I(式中X代表OCOR6基团，其中R6是C1-3烷基)的1-苯基-3-二甲氨基丙烷化合物的方法，其特征在于使X代表OH的式I化合物与酰氯Cl-COOR6反应。
9.按照权利要求1-3的式I的1-苯基-3-二甲氨基丙烷化合物作为药物活性成分的用途。
10.含有作为活性成分的按照权利要求1-3的至少一种式I的1-苯基-3-二甲氨基丙烷化合物的镇痛剂。
CN95108919A 1994-07-23 1995-07-21 具有药理效果的1－苯基－3－二甲氨基丙烷化合物 Expired - Lifetime CN1077566C (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4426245.0 1994-07-23
DE4426245A DE4426245A1 (de) 1994-07-23 1994-07-23 1-Phenyl-3-dimethylamino-propanverbindungen mit pharmakologischer Wirkung

Publications (2)

Publication Number Publication Date
CN1125221A true CN1125221A (zh) 1996-06-26
CN1077566C CN1077566C (zh) 2002-01-09

Family

ID=6524045

Family Applications (1)

Application Number Title Priority Date Filing Date
CN95108919A Expired - Lifetime CN1077566C (zh) 1994-07-23 1995-07-21 具有药理效果的1－苯基－3－二甲氨基丙烷化合物

Country Status (31)

Country Link
US (3) US6248737B1 (zh)
EP (1) EP0693475B1 (zh)
JP (2) JP4034366B2 (zh)
KR (1) KR100364465B1 (zh)
CN (1) CN1077566C (zh)
AT (1) ATE163176T1 (zh)
AU (1) AU685644B2 (zh)
BR (1) BR9502390A (zh)
CA (1) CA2154424C (zh)
CO (1) CO4410179A1 (zh)
CZ (1) CZ286441B6 (zh)
DE (3) DE4426245A1 (zh)
DK (1) DK0693475T3 (zh)
ES (1) ES2115298T3 (zh)
FI (1) FI114704B (zh)
FR (1) FR12C0016I2 (zh)
GR (1) GR3026326T3 (zh)
HK (1) HK1005062A1 (zh)
HU (1) HU218481B (zh)
IL (1) IL113901A (zh)
LT (1) LTPA2011007I1 (zh)
LU (1) LU91793I2 (zh)
MY (1) MY114889A (zh)
NZ (1) NZ272623A (zh)
PE (1) PE34896A1 (zh)
PL (1) PL181169B1 (zh)
RU (1) RU2150465C1 (zh)
SI (1) SI0693475T1 (zh)
UA (1) UA41345C2 (zh)
UY (1) UY23992A1 (zh)
ZA (1) ZA956118B (zh)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100421654C (zh) * 2000-11-30 2008-10-01 格吕伦塔尔有限公司 1-苯基-3-二甲基氨基丙烷化合物用于治疗尿失禁的用途
WO2011080756A1 (en) * 2009-12-29 2011-07-07 Ind-Swift Laboratories Limited Process for the preparation of 1-phenyl-3-dimethylaminopropane derivatives
CN101431990B (zh) * 2006-04-28 2011-08-03 格吕伦塔尔有限公司 包含3-（3-二甲基氨基-1-乙基-2-甲基-丙基）-酚和对乙酰氨基酚的药物结合
CN101495446B (zh) * 2006-07-24 2012-12-05 格吕伦塔尔有限公司 3-[(1r,2r)-3-(二甲氨基)-1-乙基-2-甲基丙基]苯酚的制备
CN103108631A (zh) * 2010-06-15 2013-05-15 格吕伦塔尔有限公司 用于治疗疼痛的联合药物
CN101495447B (zh) * 2006-07-24 2013-05-29 詹森药业有限公司 (2r,3r)-3-(3-甲氧苯基)-n,n,2-三甲基戊胺的制备
CN103298463A (zh) * 2007-04-23 2013-09-11 格吕伦塔尔有限公司 用于治疗关节炎引起的疼痛的他喷他多
CN101495445B (zh) * 2006-07-24 2013-10-30 格吕伦塔尔有限公司 (1r,2r)-3-(3-二甲胺基-1-乙基-2-甲基丙基)苯酚的制备方法
WO2014005546A1 (zh) * 2012-07-06 2014-01-09 江苏恩华药业股份有限公司 他喷他多的制备方法及用于制备他喷他多的化合物
CN104803861A (zh) * 2014-01-27 2015-07-29 上海博邦医药科技有限公司 一种合成盐酸他喷他多的方法
CN102675136B (zh) * 2006-04-28 2016-01-20 格吕伦塔尔有限公司 包含3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚和nsaid的药物组合物
CN111056961A (zh) * 2019-11-13 2020-04-24 李晓强 3-((1s,2s)-3-二甲氨基-1-乙基-2-甲基丙基)苯酚盐酸盐的制备方法

Families Citing this family (159)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1088585C (zh) * 1994-02-08 2002-08-07 Nps药物有限公司 在受体操纵性钙通道上的新位点具有活性的可用于治疗神经障碍和其他疾病的化合物
FR2745815B1 (fr) * 1996-03-08 1998-06-26 Synthelabo Derives de benzofurane, leur preparations et compositions pharmaceutiques les comprenant
WO1997032870A1 (fr) * 1996-03-08 1997-09-12 Synthelabo Derives de 2-aminoethyl-benzofurane, leur preparation et leur application en therapeutique
DE19609847A1 (de) * 1996-03-13 1997-09-18 Gruenenthal Gmbh Dimethyl-(3-aryl-but-3-enyl)-aminverbindungen als pharmazeutische Wirkstoffe
DE19732928C2 (de) * 1997-07-31 2000-05-18 Gruenenthal Gmbh Verwendung substituierter Imidazolidin-2,4-dion-Verbindungen als Schmerzmittel
DE19933421A1 (de) 1999-07-16 2001-01-25 Gruenenthal Gmbh 2-Benzyl-3-dimethylamino-1-phenyl-propanderi- vate
PE20010623A1 (es) * 1999-10-05 2001-07-07 Gruenenthal Chemie Uso de (+)-tramadol y/o o-demetiltramadol para tratamiento de urgencia urinaria incrementada y/o incontinencia urinaria
DE10000312A1 (de) * 2000-01-05 2001-07-12 Gruenenthal Gmbh Substituierte Aminomethyl-Phenyl-Cyclohexanderivate
DE10109763A1 (de) * 2001-02-28 2002-09-05 Gruenenthal Gmbh Pharmazeutische Salze
US20050176790A1 (en) * 2001-02-28 2005-08-11 Johannes Bartholomaus Pharmaceutical salts
DE10146275A1 (de) * 2001-09-18 2003-04-24 Gruenenthal Gmbh Kombination ausgewählter Opioide mit Muscarin-Antagonisten zur Therapie der Harninkontinenz
PE20030527A1 (es) * 2001-10-24 2003-07-26 Gruenenthal Chemie Formulacion farmaceutica con liberacion retardada que contiene 3-(3-dimetilamino-1-etil-2-metil-propil) fenol o una sal farmaceuticamente aceptable del mismo y tabletas para administracion oral que la contienen
US20080057011A1 (en) * 2001-12-12 2008-03-06 L'oreal S.A., Composition structured with a polymer containing a heteroatom and an Organogelator
DE10161644A1 (de) * 2001-12-14 2003-06-26 Gruenenthal Gmbh N,N'-disubstituierte Piperazin-Verbindungen
DE10161809A1 (de) * 2001-12-14 2003-06-26 Gruenenthal Gmbh Arzneimittel enthaltend N,N'-disubstituierte Piperazin-Verbindungen
DE10163421A1 (de) * 2001-12-21 2003-07-31 Gruenenthal Gmbh Verwendung von (+)-(1S,2S)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)phenol als Antiemetikum
US20050137194A1 (en) * 2002-05-29 2005-06-23 Gruenenthal Gmbh Combination of selected opioids with other active compounds for treatment of urinary incontinence
DE10224108A1 (de) * 2002-05-29 2004-01-29 Grünenthal GmbH 1-Dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol enthaltendes Arzneimiitel mit verzögerter Wirkstofffreisetzung
US7410965B2 (en) * 2002-05-29 2008-08-12 Gruenenthal Gmbh Delayed release pharmaceutical composition containing 1-dimethyl-amino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol
US20050137145A1 (en) * 2002-05-30 2005-06-23 Gruenenthal Gmbh Metabolites of 1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol and their use in the treatment of urinary incontinence
DE10224624A1 (de) * 2002-05-30 2003-12-11 Gruenenthal Gmbh Metabolite und Prodrugs von 1-Dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol
DE10224556A1 (de) * 2002-05-31 2004-01-08 Grünenthal GmbH 1-Dimethylamino- 3-(3-methoxy-phenyl)2-methyl-pentan-3-ol entaltendes Arzneimittel in verschiedenen Formulierungen
DE10225315A1 (de) * 2002-06-06 2003-12-24 Gruenenthal Gmbh Wirkstoffsalze und Ester von 1-Dimethylamino-3-(3-methoxy-phenyl)-2-methyl- pentan-3-ol und 3-(3-Dimethylamino-1-ethyl-1-hydroxy-2-methyl- propyl)-phenol
US7550624B2 (en) * 2002-06-06 2009-06-23 Gruenenthal Gmbh Pharmaceutically active salts and esters of 1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and 3- (3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol and methods of using same
US7776314B2 (en) 2002-06-17 2010-08-17 Grunenthal Gmbh Abuse-proofed dosage system
DE10228192A1 (de) * 2002-06-24 2004-01-15 Grünenthal GmbH Darreichungsform zur oralen Verabreichung von Wirkstoffen, Vitaminen und/oder Nährstoffen
US20060106106A1 (en) * 2002-09-24 2006-05-18 Glennon Richard A Beta-hydroxyphenylalkylamines and their use for treating glaucoma
SI1685829T1 (sl) 2002-11-22 2008-08-31 Gruenenthal Gmbh Uporaba (1RS,3RS,6RS)-6-dimetilaminometil-1- (3-metoksi-fenil)-cikloheksan-1, 3-diola za zdravljenje vnetne bolečine
DE10326097A1 (de) * 2003-06-06 2005-01-05 Grünenthal GmbH Verfahren zur Herstellung von Dimethyl-(3-aryl-butyl)-aminverbindungen
DE10328316A1 (de) 2003-06-23 2005-01-20 Grünenthal GmbH Verfahren zur Herstellung von Dimethyl-(3-aryl-buthyl)-aminverbindungen als pharmazeutische Wirkstoffe
DE10361596A1 (de) 2003-12-24 2005-09-29 Grünenthal GmbH Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform
US20070048228A1 (en) * 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
US8075872B2 (en) * 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
DE10336400A1 (de) 2003-08-06 2005-03-24 Grünenthal GmbH Gegen Missbrauch gesicherte Darreichungsform
DE102004020220A1 (de) * 2004-04-22 2005-11-10 Grünenthal GmbH Verfahren zur Herstellung einer gegen Missbrauch gesicherten, festen Darreichungsform
DE102005005446A1 (de) * 2005-02-04 2006-08-10 Grünenthal GmbH Bruchfeste Darreichungsformen mit retardierter Freisetzung
DE102004032051A1 (de) * 2004-07-01 2006-01-19 Grünenthal GmbH Verfahren zur Herstellung einer gegen Missbrauch gesicherten, festen Darreichungsform
DE102004019916A1 (de) * 2004-04-21 2005-11-17 Grünenthal GmbH Gegen Missbrauch gesichertes wirkstoffhaltiges Pflaster
MXPA06013270A (es) * 2004-05-14 2007-04-23 Johnson & Johnson Compuestos de opioide carboxamido.
PT1612203E (pt) * 2004-06-28 2007-08-20 Gruenenthal Gmbh ''formas cristalinas de cloridrato de (-) - (1r,2r) - 3 -(3-dimetilamino-l-etil - 2 - metilpropil) fenol''
DE102004032049A1 (de) 2004-07-01 2006-01-19 Grünenthal GmbH Gegen Missbrauch gesicherte, orale Darreichungsform
WO2006078239A1 (en) * 2005-01-18 2006-07-27 University Of Florida Compositions and methods for inhibiting pain
US20060160905A1 (en) * 2005-01-18 2006-07-20 Bergeron Raymond J Jr Compositions and methods for inhibiting pain
DE102005005449A1 (de) 2005-02-04 2006-08-10 Grünenthal GmbH Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform
DE102005033732B4 (de) 2005-05-27 2014-02-13 Grünenthal GmbH Trennung stereoisomerer N,N-Dialkylamino-2-alkyl-3-hydroxy-3-phenyl-alkane
DE202005014347U1 (de) * 2005-09-09 2007-01-18 Grünenthal GmbH Applikationssystem für ein wirkstoffhaltiges Pflaster und Wirkstoffabgaberegulierungsmittel
US20090104266A1 (en) * 2005-09-15 2009-04-23 Tobias Jung 3-(2-dimethylaminomethylcy clohexyl)phenol retard formulation
DE102005052588A1 (de) * 2005-11-02 2007-05-10 Grünenthal GmbH Verfahren zur Herstellung substituierter Dimethyl-(3-aryl-butyl)-amin-Verbindungen mittels homogener Katalyse
US20070254960A1 (en) * 2006-04-28 2007-11-01 Gruenenthal Gmbh Pharmaceutical combination
SA07280459B1 (ar) 2006-08-25 2011-07-20 بيورديو فارما إل. بي. أشكال جرعة صيدلانية للتناول عن طريق الفم مقاومة للعبث تشتمل على مسكن شبه أفيوني
DE102007011485A1 (de) 2007-03-07 2008-09-11 Grünenthal GmbH Darreichungsform mit erschwertem Missbrauch
DE102007012165A1 (de) * 2007-03-12 2008-09-18 Grünenthal GmbH Verwendung von 1-Phenyl-3-dimethylamino-propanverbindungen zur Therapie des Neuropathieschmerzes
EP1985292A1 (en) * 2007-04-23 2008-10-29 Grünenthal GmbH Titration of tapentadol
US20090076164A1 (en) * 2007-09-15 2009-03-19 Protia, Llc Deuterium-enriched tapentadol
DK2596784T3 (en) * 2007-11-23 2017-03-06 Gruenenthal Gmbh Tapentadol compositions
SI2240431T1 (sl) 2007-12-07 2017-05-31 Gruenenthal Gmbh Kristalinične modifikacije (1R,2R)-3-(3-dimetilamino-1-etil-2-metil-propil)-fenola
BRPI0906467C1 (pt) 2008-01-25 2021-05-25 Gruenenthal Gmbh forma de dosagem farmacêutica com formato exterior modificado resistente à ruptura e com liberação controlada
LT2273983T (lt) 2008-05-09 2016-10-25 Grünenthal GmbH Tarpinės miltelių kompozicijos gamybos būdas ir galutinė kieta dozavimo forma naudojant purškalo kietinimo stadija
US20100063148A1 (en) 2008-09-05 2010-03-11 Gruenenthal Gmbh Pharmaceutical Combination
US20100190752A1 (en) * 2008-09-05 2010-07-29 Gruenenthal Gmbh Pharmaceutical Combination
CN104257600A (zh) 2008-10-30 2015-01-07 格吕伦塔尔有限公司 新型有效的他喷他多剂型
US20100272815A1 (en) * 2009-04-28 2010-10-28 Actavis Group Ptc Ehf Amorphous form of tapentadol hydrochloride
KR20210027513A (ko) * 2009-04-30 2021-03-10 그뤼넨탈 게엠베하 류마티스성 통증을 치료하기 위한 １―페닐―３―디메틸아미노프로판 화합물의 용도
KR101747156B1 (ko) 2009-07-22 2017-06-27 그뤼넨탈 게엠베하 산화-안정화된 탬퍼-내성 용량형
TW201105316A (en) 2009-07-22 2011-02-16 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
CN102002065B (zh) * 2009-09-02 2014-09-10 上海特化医药科技有限公司 他喷他多的制备方法及其中间体
US8288592B2 (en) 2009-09-22 2012-10-16 Actavis Group Ptc Ehf Solid state forms of tapentadol salts
IT1397189B1 (it) 2009-12-01 2013-01-04 Archimica Srl Nuovo processo per la preparazione di tapentadol e suoi intermedi.
PL2519100T3 (pl) 2009-12-29 2017-09-29 Mapi Pharma Limited Związki pośrednie i sposoby wytwarzania tapentadolu i pokrewnych związków
WO2011092719A2 (en) * 2010-02-01 2011-08-04 Ind-Swift Laboratories Limited Process for the preparation of l-phenyl-3-dimethylaminopropane derivatives
CN102821757B (zh) 2010-02-03 2016-01-20 格吕伦塔尔有限公司 通过挤出机制备粉末状药物组合物
WO2011107876A2 (en) 2010-03-05 2011-09-09 Actavis Group Ptc Ehf Improved resolution methods for isolating desired enantiomers of tapentadol intermediates and use thereof for the preparation of tapentadol
CA2793948A1 (en) 2010-04-05 2011-10-20 Actavis Group Ptc Ehf Novel process for preparing highly pure tapentadol or a pharmaceutically acceptable salt thereof
JP5905872B2 (ja) 2010-04-07 2016-04-20 ルピン・リミテッド タペンタドールの制御放出医薬組成物
EP2383255A1 (en) 2010-04-28 2011-11-02 Lacer, S.A. New compounds, synthesis and use thereof in the treatment of pain
US20130116333A1 (en) 2010-05-05 2013-05-09 Ratiopharm Gmbh Solid tapentadol in non-crystalline form
ITMI20100924A1 (it) * 2010-05-21 2011-11-22 Fidia Farmaceutici Nuovo metodo di sintesi delle due forme enantiomeriche del tapentadol
CN104725245A (zh) 2010-06-15 2015-06-24 格吕伦塔尔有限公司 用于制备取代的3-(1-氨基-2-甲基戊烷-3-基)苯基化合物的方法
ES2591354T3 (es) 2010-06-30 2016-11-28 Grünenthal GmbH Tapentadol para su uso en el tratamiento del síndrome de intestino irritable
IT1401109B1 (it) 2010-07-02 2013-07-12 Archimica Srl Nuovo processo per la preparazione di tapentadol e suoi intermedi.
MX341072B (es) * 2010-07-23 2016-08-05 Grünenthal Gmbh * Sales o co-cristales de 3-(3-dimetilamino-1-etil-2-metil-propil)-f enol.
EP2606030B1 (en) 2010-08-16 2016-05-18 Indoco Remedies Limited Process for the preparation of tapentadol
MX2013002377A (es) 2010-09-02 2013-04-29 Gruenenthal Gmbh Forma de dosificacion resistente a manipulacion que comprende una sal inorganica.
RU2607499C2 (ru) 2010-09-02 2017-01-10 Грюненталь Гмбх Устойчивая к разрушению лекарственная форма, которая содержит анионный полимер
CN101948397A (zh) * 2010-09-07 2011-01-19 天津泰普药品科技发展有限公司 镇痛药他喷他多重要中间体的制备方法
WO2012038974A1 (en) 2010-09-20 2012-03-29 Ind-Swift Laboratories Limited Process for preparing l-phenyl-3-dimethylaminopropane derivative
WO2012051246A1 (en) 2010-10-12 2012-04-19 Ratiopharm Gmbh Tapentadol hydrobromide and crystalline forms thereof
CZ303115B6 (cs) * 2010-12-30 2012-04-11 Zentiva, K.S. Zpusob výroby (2R,3R)-N,N-dimethyl-3-(3-hydroxyfenyl)-2-methylpentylaminu
CZ302992B6 (cs) * 2010-12-30 2012-02-08 Zentiva, K.S. Zpusob výroby (2R,3R)-N,N-dimethyl-3-(3-hydroxyfenyl)-2-methylpentylaminu (tapentadolu)
US20130296608A1 (en) 2011-01-27 2013-11-07 Symed Labs Limited Novel stereospecific synthesis of (-) (2s, 3s)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl pentan-3-ol
CN102617501A (zh) 2011-01-31 2012-08-01 中国科学院上海药物研究所 取代正戊酰胺类化合物、其制备方法及用途
CN103501773A (zh) 2011-03-04 2014-01-08 格吕伦塔尔有限公司 用于口服给予的他喷他多含水药物制剂
DK2680833T3 (en) 2011-03-04 2016-05-23 Gruenenthal Gmbh PARENTERAL SUBMISSION OF TAPENTADOL
PT2680834T (pt) 2011-03-04 2018-01-25 Gruenenthal Gmbh Composição farmacêutica aquosa semissólida contendo tapentadol
JP2014510759A (ja) 2011-04-05 2014-05-01 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 疼痛の慢性化を予防するためのタペンタドール
WO2012136351A1 (en) 2011-04-05 2012-10-11 Grünenthal GmbH Tapentadol for treating pain associated with trigeminal neuralgia
CN102206164A (zh) * 2011-04-11 2011-10-05 中国药科大学 一种他喷他多中间体的制备方法
WO2012146978A2 (en) 2011-04-28 2012-11-01 Actavis Group Ptc Ehf A novel process for the preparation of tapentadol or a pharmaceutically acceptable salt thereof
ES2788548T3 (es) 2011-04-29 2020-10-21 Gruenenthal Gmbh Tapentadol para la prevención y el tratamiento de la depresión y la ansiedad
EP2530072A1 (en) 2011-06-03 2012-12-05 Lacer, S.A. New compounds, synthesis and use thereof in the treatment of pain
EP2753302B1 (en) 2011-07-20 2018-11-28 Torrent Pharmaceuticals Ltd. Pharmaceutical composition of tapentadol
SI2736501T1 (en) * 2011-07-29 2018-03-30 Gruenenthal Gmbh Intrathecal or epidural administration of 3 - ((1S, 2S) -3- (dimethylamino) -1-ethyl-2-methylpropyl) phenol
WO2013016840A1 (zh) 2011-07-29 2013-02-07 安徽省新星药物开发有限责任公司 用于合成他喷他多或其类似物的新中间体
EA201400172A1 (ru) 2011-07-29 2014-06-30 Грюненталь Гмбх Устойчивая к разрушению таблетка, которая обеспечивает немедленное высвобождение лекарственного средства
EA201400173A1 (ru) 2011-07-29 2014-06-30 Грюненталь Гмбх Устойчивая к разрушению таблетка, которая обеспечивает немедленное высвобождение лекарственного средства
WO2013105109A1 (en) 2011-11-09 2013-07-18 Indoco Remedies Limited Process for the preparation of tapentadol
WO2013090161A1 (en) 2011-12-12 2013-06-20 Boehringer Ingelheim International Gmbh Stereoselective synthesis of tapentadol and its salts
CN102557851B (zh) * 2011-12-13 2014-03-26 安徽省新星药物开发有限责任公司 一种盐酸他喷他多及其类似物的合成方法
WO2013111161A2 (en) * 2012-01-10 2013-08-01 Msn Laboratories Limited Process for the preparation of 3-aryl-2-methyl-propanamine derivatives and polymorphs thereof
WO2013120466A1 (en) 2012-02-17 2013-08-22 Zentiva, K.S. A new solid form of tapentadol and a method of its preparation
JP6117249B2 (ja) 2012-02-28 2017-04-19 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 薬理学的に活性な化合物および陰イオン性ポリマーを含むタンパーレジスタント剤形
JP6282261B2 (ja) 2012-04-18 2018-02-21 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 不正使用防止および過量放出防止医薬剤形
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
EP2674414A1 (en) 2012-06-15 2013-12-18 Siegfried AG Method for the preparation of 1-aryl-1-alkyl-3-dialkylaminopropane compounds
WO2014012653A1 (en) 2012-07-16 2014-01-23 Grünenthal GmbH Pharmaceutical patch for transdermal administration of tapentadol
CZ304576B6 (cs) * 2012-07-24 2014-07-16 Zentiva, K.S. Oxalát TAPENTADOLU a způsob jeho přípravy
KR20150075408A (ko) 2012-11-01 2015-07-03 토렌트 파마슈티칼스 리미티드 비경구용 타펜타돌의 약학 조성물
US9090539B2 (en) 2013-05-24 2015-07-28 Ampac Fine Chemicals Llc Compounds and methods for preparing substituted 3-(1-amino-2-methylpentane-3-yl)phenyl compounds
AU2014273227B2 (en) 2013-05-29 2019-08-15 Grunenthal Gmbh Tamper-resistant dosage form containing one or more particles
AR096439A1 (es) 2013-05-29 2015-12-30 Gruenenthal Gmbh Forma de dosificación resistente al uso indebido que contiene una o más partículas
EP2808319A1 (en) 2013-05-31 2014-12-03 Arevipharma GmbH 3-[3-(Dimethylamino)-1-ethyl-2-methylpropyl]phenol resin complex
CA2917136C (en) 2013-07-12 2022-05-31 Grunenthal Gmbh Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
EP2845625A1 (en) 2013-09-04 2015-03-11 Grünenthal GmbH Tapentadol for use in the treatment of fibromyalgia and chronic fatigue syndrome
RU2016120002A (ru) * 2013-11-01 2017-12-04 Сан Фарма Адвансед Ресёрч Компани Новое промежуточное соединение тапентадола
WO2015071248A1 (en) 2013-11-15 2015-05-21 Synthon B.V. Abuse-proofed extended release pharmaceutical composition comprising tapentadol
WO2015075678A1 (en) 2013-11-21 2015-05-28 Unimark Remedies Ltd. A novel process for the preparation of 1-phenyl-3-aminopropane derivatives
JP6480936B2 (ja) 2013-11-26 2019-03-13 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング クライオミリングによる粉末状医薬組成物の調製
EP3083551B1 (en) 2013-12-16 2018-02-14 Farma GRS, d.o.o. Crystalline form of tapentadol intermediate
CZ307492B6 (cs) 2014-02-04 2018-10-17 Zentiva, K.S. Pevná forma maleátu tapentadolu a způsob její přípravy
GB2523089A (en) * 2014-02-12 2015-08-19 Azad Pharmaceutical Ingredients Ag Stable polymorph form B of tapentadol hydrochloride
EP2942054A1 (en) 2014-05-09 2015-11-11 G.L. Pharma GmbH Slow-release pharmaceutical formulation
AU2015261060A1 (en) 2014-05-12 2016-11-03 Grunenthal Gmbh Tamper resistant immediate release capsule formulation comprising Tapentadol
EA201692388A1 (ru) 2014-05-26 2017-05-31 Грюненталь Гмбх Лекарственная форма в виде множества частиц, защищенная от вызываемого этанолом сброса дозы
EP3166923B1 (en) 2014-07-10 2023-03-15 SpecGx LLC Process for preparing substituted phenylalkanes
SI3273953T1 (sl) 2015-03-27 2019-03-29 Gruenenthal Gmbh Stabilna oblika za parenteralno dovajanje tapentadola
MX2017013637A (es) 2015-04-24 2018-03-08 Gruenenthal Gmbh Forma de dosificacion resistente a alteraciones con liberacion inmediata y resistencia contra la extraccion por solventes.
US10421050B2 (en) * 2015-05-22 2019-09-24 Digi-Star, Llc Utilization of a mobile agricultural weighing system to monitor and store ancillary operational data for diagnostic purposes on trailed and truck-mounted equipment
PT3302454T (pt) 2015-05-26 2021-04-01 Technophage Investig E Desenvolvimento Em Biotecnologia Sa Composições para utilização no tratamento da doença de parkinson e distúrbios associados
PL3319941T3 (pl) 2015-07-10 2022-05-02 SpecGx LLC Dwuetapowy sposób wytwarzania 3-podstawionych fenyloalkiloamin
CA2998259A1 (en) 2015-09-10 2017-03-16 Grunenthal Gmbh Protecting oral overdose with abuse deterrent immediate release formulations
DK3377049T3 (en) 2015-11-17 2021-04-12 Msn Laboratories Private Ltd Crystalline forms of tapentadol salts and process for preparation thereof
DK3819287T3 (da) 2016-04-19 2023-12-18 Ratiopharm Gmbh Amorft tapentadolphosphat
EA201990744A1 (ru) 2016-09-23 2019-08-30 Грюненталь Гмбх Стабильная лекарственная форма для парентерального введения тапентадола
PT3568126T (pt) 2017-01-11 2023-12-19 Torrent Pharmaceuticals Ltd Composição nasal de tapentadol
US10292948B2 (en) 2017-01-11 2019-05-21 Torrent Pharmaceuticals Limited Tapentadol nasal composition
WO2019195775A1 (en) * 2018-04-06 2019-10-10 Flex Pharma, Inc. Tolperisone analogs and methods of use
US20210253513A1 (en) 2018-06-15 2021-08-19 Pharmathen S.A. A novel process for the preparation of tapentadol
GR1009751B (el) 2019-03-22 2020-05-29 "Φαρματεν Α.Β.Ε.Ε." Σκευασμα παρατεταμενης αποδεσμευσης που περιλαμβανει οξαλικη ταπενταδολη και μεθοδος παρασκευης αυτου
GR1009791B (el) 2019-03-26 2020-08-03 Φαρματεν Α.Β.Ε.Ε. Σκευασμα παρατεταμενης αποδεσμευσης που περιλαμβανει ταπενταδολη και μεθοδος παρασκευης αυτου
KR102297806B1 (ko) * 2019-11-11 2021-09-03 한국생산기술연구원 탄탈륨-구리 합금의 제조방법 및 이로부터 제조된 탄탈륨-구리 합금
HRP20240081T1 (hr) 2020-03-02 2024-05-24 Grünenthal GmbH Oblik doziranja koji pruža produljeno oslobađanje soli tapentadol-fosforne kiseline
WO2021175773A1 (en) 2020-03-02 2021-09-10 Grünenthal GmbH Dosage form providing prolonged release of tapentadol phosphoric acid salt
EP3875079A1 (en) 2020-03-02 2021-09-08 Grünenthal GmbH Dosage form providing prolonged release of tapentadol phosphoric acid salt
DE202020104285U1 (de) 2020-07-24 2020-12-18 Grünenthal GmbH Ethylcellulose-beschichtete Partikel enthaltend ein Salz aus Tapentadol und Phosphorsäure
DE202020005470U1 (de) 2020-11-10 2022-01-25 Grünenthal GmbH Darreichungsformen mit verlängerter Freisetzung eines Salzes von Tapentadol mit L-(+)-Weinsäure
DK3995135T3 (da) 2020-11-10 2022-08-22 Gruenenthal Gmbh Doseringsform med forlænget afgivelse af et salt af tapentadol med l-(+)-vinsyre
WO2022101247A1 (de) 2020-11-10 2022-05-19 Grünenthal GmbH Darreichungsformen mit verlängerter freisetzung eines salzes von tapentadol mit l-(+)-weinsäure
EP4011369A1 (en) 2020-12-14 2022-06-15 G.L. Pharma GmbH Aqueous pharmaceutical composition comprising tapentadol tartrate
EP4269384A1 (en) 2022-04-26 2023-11-01 KRKA, d.d., Novo mesto Method for crystallizing tapentadol intermediate, tapentadol intermediate of high purity, method of making tapentadol and tapentadol of high purity

Family Cites Families (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE124521C (zh)
US2662886A (en) 1949-01-28 1953-12-15 Winthrop Stearns Inc Substituted phenylpropylamines
DE1051281B (de) * 1955-07-05 1959-02-26 Bayer Ag Verfahren zur Herstellung von Derivaten der 1-Aryl-3-aminopropan-1-ole
US3328249A (en) 1965-06-21 1967-06-27 Sterling Drug Inc Process for counteracting depressive states
NL7403348A (zh) * 1973-03-19 1974-09-23
DD124521A1 (zh) 1976-03-16 1977-03-02
US4608391A (en) 1977-07-05 1986-08-26 Cornell Research Foundation Inc. Catecholamine derivatives, a process for their preparation and pharmaceutical compositions thereof
DE2732750A1 (de) * 1977-07-20 1979-02-08 Merck Patent Gmbh Basische thioaether und verfahren zu ihrer herstellung
US4404222A (en) 1980-08-25 1983-09-13 American Cyanamid Company Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and improving the efficiency of feed utilization thereby
US4336269A (en) 1979-12-10 1982-06-22 Eli Lilly And Company Para-nitrophenylalkylamines
DE3242922A1 (de) 1982-11-20 1984-05-24 Basf Ag, 6700 Ludwigshafen Phenylpropanolamine, ihre herstellung und verwendung
IT1213219B (it) 1984-09-28 1989-12-14 Consiglio Nazionale Ricerche Derivati amminoalchilnaftalenici ad attivita' farmacologica.
US4843160A (en) 1984-10-01 1989-06-27 The Dow Chemical Company Preparation of alpha-aminoalkylphenols
US5169633A (en) 1985-07-29 1992-12-08 American Cyanamid Company Continuous release phenylethanolamine derivative compositions
US5059422A (en) 1985-07-29 1991-10-22 American Cyanamid Company Continuous release phenylethanolamine derivative compositions
US4857553A (en) 1987-08-06 1989-08-15 A. H. Robins Company, Incorporated Method of treating nausea and vomiting with certain substituted-phenylalkylamino (and aminoacid) derivatives and other serotonin depleting agents
SE8800207D0 (sv) * 1988-01-22 1988-01-22 Kabivitrum Ab Nya aminer, deras anvendning och framstellning
US5135955A (en) 1988-04-25 1992-08-04 Eli Lilly And Company Propanamine derivatives
WO1990002126A1 (en) 1988-08-24 1990-03-08 Mochida Pharmaceutical Co., Ltd. Hydantoin derivatives
DK258389D0 (da) * 1989-05-26 1989-05-26 Ferrosan As Aryloxyphenylpropylaminer, deres fremstilling og anvendelse
EP0507863A4 (en) 1989-12-28 1993-07-07 Virginia Commonwealth University Sigma receptor ligands and the use thereof
US5281623A (en) 1990-08-27 1994-01-25 Eli Lilly And Company Method for treating inflammation
ZA916555B (en) 1990-08-27 1993-04-28 Lilly Co Eli Method of treating inflammatory bowel disease
US5280046A (en) 1991-02-22 1994-01-18 The University Of Colorado Foundation, Inc. Method of treating type I diabetes
US6011068A (en) * 1991-08-23 2000-01-04 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US6031003A (en) * 1991-08-23 2000-02-29 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US6001884A (en) * 1991-08-23 1999-12-14 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US5419993A (en) 1991-11-01 1995-05-30 Canon Kabushiki Kaisha Polyamide, electrophotographic photosensitive member employing the polyamide, and electrophotographic apparatus, device unit and facsimile machine employing the member
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
US5322859A (en) 1993-02-08 1994-06-21 University Of Iowa Research Foundation Antiglaucoma drug composition and method
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
US5387614A (en) 1993-07-27 1995-02-07 University Of Iowa Research Foundation Use of sigma receptor ligands as salivary gland stimulants
CN1088585C (zh) * 1994-02-08 2002-08-07 Nps药物有限公司 在受体操纵性钙通道上的新位点具有活性的可用于治疗神经障碍和其他疾病的化合物
ATE199829T1 (de) 1994-06-03 2001-04-15 Thejmde Trust Meta substituierte arylalkylamine und therapeutische und diagnostische verwendung davon
PT1203761E (pt) 1994-10-21 2005-04-29 Nps Pharma Inc Compostos activos do receptor de calcio
DE19525137C2 (de) 1995-07-11 2003-02-27 Gruenenthal Gmbh 6-Dimethylaminomethyl-1-phenyl-cyclohexanverbin -dungen als Zwischenprodukte zur Herstellung pharmazeutischer Wirkstoffe
US5648541A (en) 1995-09-28 1997-07-15 Nps Pharmaceuticals, Inc. Chiral reductions of imines leading to the syntheses of optically active amines
US5830509A (en) 1996-02-07 1998-11-03 West; Daniel David Microparticle complexes with 2-amino-1-phenylpropanol materials
DE19609847A1 (de) * 1996-03-13 1997-09-18 Gruenenthal Gmbh Dimethyl-(3-aryl-but-3-enyl)-aminverbindungen als pharmazeutische Wirkstoffe
CN1254465C (zh) * 1996-04-09 2006-05-03 Nps医药公司 钙代谢化合物
AU731146C (en) * 1996-05-01 2005-02-03 Nps Pharmaceuticals, Inc. Inorganic ion receptor-active compounds
US6052610A (en) * 1998-01-09 2000-04-18 International Business Machines Corporation Magnetic catheter tracker and method therefor
US6011066A (en) 1998-02-02 2000-01-04 Veterans General Hospital-Taipei Method for treating septic shock
DE19915601A1 (de) 1999-04-07 2000-10-19 Gruenenthal Gmbh 3-Amino-3-arylpropan-1-ol-Derivate, deren Herstellung und Verwendung
AU2002239464B2 (en) 2000-11-01 2007-01-04 Cognition Pharmaceuticals Llc Methods and compositions for regulating memory consolidation

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100421654C (zh) * 2000-11-30 2008-10-01 格吕伦塔尔有限公司 1-苯基-3-二甲基氨基丙烷化合物用于治疗尿失禁的用途
CN102675136B (zh) * 2006-04-28 2016-01-20 格吕伦塔尔有限公司 包含3-(3-二甲基氨基-1-乙基-2-甲基-丙基)-苯酚和nsaid的药物组合物
CN101431990B (zh) * 2006-04-28 2011-08-03 格吕伦塔尔有限公司 包含3-（3-二甲基氨基-1-乙基-2-甲基-丙基）-酚和对乙酰氨基酚的药物结合
CN101495446B (zh) * 2006-07-24 2012-12-05 格吕伦塔尔有限公司 3-[(1r,2r)-3-(二甲氨基)-1-乙基-2-甲基丙基]苯酚的制备
CN101495445B (zh) * 2006-07-24 2013-10-30 格吕伦塔尔有限公司 (1r,2r)-3-(3-二甲胺基-1-乙基-2-甲基丙基)苯酚的制备方法
CN101495447B (zh) * 2006-07-24 2013-05-29 詹森药业有限公司 (2r,3r)-3-(3-甲氧苯基)-n,n,2-三甲基戊胺的制备
CN103298463A (zh) * 2007-04-23 2013-09-11 格吕伦塔尔有限公司 用于治疗关节炎引起的疼痛的他喷他多
CN106619589A (zh) * 2007-04-23 2017-05-10 格吕伦塔尔有限公司 用于治疗关节炎引起的疼痛的他喷他多
WO2011080756A1 (en) * 2009-12-29 2011-07-07 Ind-Swift Laboratories Limited Process for the preparation of 1-phenyl-3-dimethylaminopropane derivatives
CN103108631A (zh) * 2010-06-15 2013-05-15 格吕伦塔尔有限公司 用于治疗疼痛的联合药物
CN103108631B (zh) * 2010-06-15 2015-08-26 格吕伦塔尔有限公司 用于治疗疼痛的联合药物
WO2014005546A1 (zh) * 2012-07-06 2014-01-09 江苏恩华药业股份有限公司 他喷他多的制备方法及用于制备他喷他多的化合物
CN104803861A (zh) * 2014-01-27 2015-07-29 上海博邦医药科技有限公司 一种合成盐酸他喷他多的方法
CN104803861B (zh) * 2014-01-27 2017-05-24 上海博邦医药科技有限公司 一种合成盐酸他喷他多的方法
CN111056961A (zh) * 2019-11-13 2020-04-24 李晓强 3-((1s,2s)-3-二甲氨基-1-乙基-2-甲基丙基)苯酚盐酸盐的制备方法

Also Published As

Publication number Publication date
ES2115298T3 (es) 1998-06-16
HUT74100A (en) 1996-11-28
SI0693475T1 (en) 1998-06-30
AU2713895A (en) 1996-02-08
CZ190495A3 (en) 1996-05-15
KR100364465B1 (ko) 2003-02-05
FI953523A (fi) 1996-01-24
EP0693475B1 (de) 1998-02-11
IL113901A (en) 1999-05-09
ZA956118B (en) 1996-05-31
DE4426245A1 (de) 1996-02-22
EP0693475A1 (de) 1996-01-24
KR960004315A (ko) 1996-02-23
PE34896A1 (es) 1996-09-07
LTPA2011007I1 (lt) 2018-08-10
JP2007084574A (ja) 2007-04-05
CZ286441B6 (en) 2000-04-12
JP4846552B2 (ja) 2011-12-28
JPH0899939A (ja) 1996-04-16
FR12C0016I1 (zh) 2012-04-06
UA41345C2 (uk) 2001-09-17
RU2150465C1 (ru) 2000-06-10
US6344558B1 (en) 2002-02-05
USRE39593E1 (en) 2007-04-24
UY23992A1 (es) 1995-08-02
CN1077566C (zh) 2002-01-09
CO4410179A1 (es) 1997-01-09
DE122011000007I1 (de) 2011-06-16
LU91793I2 (fr) 2011-05-02
RU95113154A (ru) 1997-06-27
DK0693475T3 (da) 1998-09-23
GR3026326T3 (en) 1998-06-30
JP4034366B2 (ja) 2008-01-16
FR12C0016I2 (fr) 2013-01-11
FI953523A0 (fi) 1995-07-21
BR9502390A (pt) 1996-02-27
CA2154424C (en) 2008-04-15
NZ272623A (en) 1996-02-27
CA2154424A1 (en) 1996-01-24
HU218481B (hu) 2000-09-28
HU9502146D0 (en) 1995-09-28
PL309734A1 (en) 1996-02-05
AU685644B2 (en) 1998-01-22
HK1005062A1 (en) 1998-12-18
DE59501431D1 (de) 1998-03-19
US20020010178A1 (en) 2002-01-24
MY114889A (en) 2003-02-28
IL113901A0 (en) 1995-08-31
ATE163176T1 (de) 1998-02-15
FI114704B (fi) 2004-12-15
PL181169B1 (pl) 2001-06-29
US6248737B1 (en) 2001-06-19

Similar Documents

Publication Publication Date Title
CN1077566C (zh) 具有药理效果的1－苯基－3－二甲氨基丙烷化合物
CN1157366C (zh) 作为药物有效成分的二甲基-(3-芳基-丁-3-烯基)-胺化合物
CN1071309C (zh) 用作药物活性成分的1－苯基－2－二甲氨基甲基－环己－1－醇化合物
USRE37355E1 (en) 6-dimethylaminomethyl-1-phenyl-cyclohexane compounds as pharmaceutical active ingredients
JP6298766B2 (ja) てんかんの予防または治療に使用するためのフェニルカルバメート化合物
CN1245376C (zh) 取代的2－二烷基氨基烷基联苯衍生物
US7612210B2 (en) Process for selective synthesis of enantiomers of substituted 1-(2-amino-1-phenyl-ethyl)-cyclohexanols
CN1946679A (zh) 氨基－丙醇衍生物
CN1914202A (zh) 1－(2s,3s)－2－二苯甲基－n－(5－叔丁基－2－甲氧基苄基)奎宁环－3－胺的制备方法
CN1437576A (zh) 取代的氨甲基－苯基－环己烷衍生物
CN1466567A (zh) 取代的1-氨基丁-3-醇衍生物
US6503942B2 (en) Ethers of O-Desmethyl venlafaxine
CN1373745A (zh) 3－氨基－2－苄基－1－苯基丙烷衍生物
CN1437575A (zh) 氨甲基－苯基－环己酮衍生物
CN1147461C (zh) 3-氨基-3-芳基丙-1-醇衍生物、其制备及用途
CN1278249A (zh) 用作药物的联苯基衍生物
US7291646B2 (en) Ethers of O-desmethyl venlafaxine
EP1232141B1 (en) Ethers of o-desmethyl venlafaxine
CN1179958C (zh) 环状被取代氨基甲基类化合物和含有这些化合物的药物
CN1324011C (zh) 用于治疗疼痛的氮杂－螺环化合物
CN1403456A (zh) 具有心血管活性的异喹啉类手性化合物及其合成方法
CN114656391A (zh) 多羟基吡咯烷类化合物及其制备方法和应用

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
CX01 Expiry of patent term

Expiration termination date: 20150721

Granted publication date: 20020109

EXPY Termination of patent right or utility model