DK118655B - Analogifremgangsmåde til fremstilling af p-aminoalkoxyphenylalkenderivater. - Google Patents

Analogifremgangsmåde til fremstilling af p-aminoalkoxyphenylalkenderivater.

Info

Publication number
DK118655B
DK118655B DK433463AA DK433463A DK118655B DK 118655 B DK118655 B DK 118655B DK 433463A A DK433463A A DK 433463AA DK 433463 A DK433463 A DK 433463A DK 118655 B DK118655 B DK 118655B
Authority
DK
Denmark
Prior art keywords
aminoalkoxyphenylalkene
derivatives
preparation
analogous process
analogous
Prior art date
Application number
DK433463AA
Other languages
Danish (da)
English (en)
Inventor
M Harper
D Richardson
A Walpole
Original Assignee
Ici Ltd
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=26260578&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=DK118655(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from GB34989/62A external-priority patent/GB1013907A/en
Application filed by Ici Ltd filed Critical Ici Ltd
Publication of DK118655B publication Critical patent/DK118655B/da

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/64—Preparation of O-metal compounds with O-metal group bound to a carbon atom belonging to a six-membered aromatic ring
    • C07C37/66—Preparation of O-metal compounds with O-metal group bound to a carbon atom belonging to a six-membered aromatic ring by conversion of hydroxy groups to O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (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)
DK433463AA 1962-09-13 1963-09-13 Analogifremgangsmåde til fremstilling af p-aminoalkoxyphenylalkenderivater. DK118655B (da)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB34989/62A GB1013907A (en) 1962-09-13 1962-09-13 Alkene derivatives
GB30755/65A GB1064629A (en) 1962-09-13 1965-07-20 Alkene derivatives

Publications (1)

Publication Number Publication Date
DK118655B true DK118655B (da) 1970-09-21

Family

ID=26260578

Family Applications (3)

Application Number Title Priority Date Filing Date
DK433463AA DK118655B (da) 1962-09-13 1963-09-13 Analogifremgangsmåde til fremstilling af p-aminoalkoxyphenylalkenderivater.
DK432067AA DK117953B (da) 1962-09-13 1967-08-25 Analogifremgangsmåde til fremstilling af p-aminoalkoxyphenylalkenderivater.
DK355571AA DK127777B (da) 1962-09-13 1971-07-19 p-(Aminoalkoksy)fenyl-stilbenderivater til anvendelse som svangerskabsforebyggende midler.

Family Applications After (2)

Application Number Title Priority Date Filing Date
DK432067AA DK117953B (da) 1962-09-13 1967-08-25 Analogifremgangsmåde til fremstilling af p-aminoalkoxyphenylalkenderivater.
DK355571AA DK127777B (da) 1962-09-13 1971-07-19 p-(Aminoalkoksy)fenyl-stilbenderivater til anvendelse som svangerskabsforebyggende midler.

Country Status (8)

Country Link
US (1) US4536516A (en:Method)
BE (2) BE678807A (en:Method)
BR (2) BR6352734D0 (en:Method)
CH (3) CH441286A (en:Method)
DE (1) DE1568834A1 (en:Method)
DK (3) DK118655B (en:Method)
FR (1) FR1502607A (en:Method)
GB (1) GB1064629A (en:Method)

Families Citing this family (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE637389A (en:Method) * 1962-09-13
GB1560274A (en) * 1977-02-28 1980-02-06 Ici Ltd Phenylbut 1-ene derivatives having antiostrogenicactivity
EP0002097B1 (en) 1977-08-22 1981-08-05 Imperial Chemical Industries Plc Triphenylalkene derivatives, process for their preparation and pharmaceutical compositions containing them
US4206234A (en) * 1977-08-22 1980-06-03 Imperial Chemical Industries Limited Triphenylbut-1-ene derivatives and pharmaceutical compositions and uses thereof
HU178253B (en) * 1979-08-15 1982-04-28 Gyogyszerkutato Intezet Process for preparing 1,1,2-triphenyl-propane and -propane derivatives
DE3046719C2 (de) * 1980-12-11 1983-02-17 Klinge Pharma GmbH, 8000 München 1,1,2-Triphenyl-but-1-en-Derivate, Verfahren zu ihrer Herstellung und Arzneimittel
ATE25515T1 (de) * 1983-05-24 1987-03-15 Bristol Myers Co Verfahren zur umwandlung von 1,2-diphenyl-1-(4-(2-dimethylamino-ethoxy)-phen l>-1-buten-e-isomeren zu tamoxifen-hydrochlorid.
US4666885A (en) * 1985-02-08 1987-05-19 Fernand Labrie Combination therapy for treatment of female breast cancer
US4760053A (en) * 1984-08-02 1988-07-26 Fernand Labrie Combination therapy for selected sex steroid dependent cancers
US4775660A (en) * 1984-08-02 1988-10-04 Fernand Labrie Treatment of breast cancer by combination therapy
US4806685A (en) * 1985-08-05 1989-02-21 Gyogyszerkutato Inteezet/Pharmaceutical Research Institute 1,1,2-triphenylpropane and -propene derivatives
GB8604528D0 (en) * 1986-02-24 1986-04-03 Ici Plc Therapeutic agents
CA1289570C (en) * 1986-06-16 1991-09-24 Tetsuji Asao 1,1,2-triaryl-1-alkene derivatives
EP0287690B1 (de) * 1987-04-21 1992-09-02 HEUMANN PHARMA GMBH & CO Stabile Lösungsmitteladdukte von Z-1-(p-beta-Dimethylamino-ethoxyphenyl)-1-(p-hydroxyphenyl)-2-phenylbut-1-en
DE3736682A1 (de) * 1987-10-29 1989-05-11 Klinge Co Chem Pharm Fab Verfahren zur herstellung von trans-1,1,2-triphenyl-but-1-en-derivaten
US4895715A (en) * 1988-04-14 1990-01-23 Schering Corporation Method of treating gynecomastia
US5204337A (en) * 1988-10-31 1993-04-20 Endorecherche Inc. Estrogen nucleus derivatives for use in inhibition of sex steroid activity
US5364847A (en) * 1989-03-10 1994-11-15 Endorecherche Inhibitors of sex steroid biosynthesis and methods for their production and use
ZA924811B (en) * 1991-06-28 1993-12-29 Endorecherche Inc Controlled release systems and low dose androgens
US5811447A (en) 1993-01-28 1998-09-22 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US6515009B1 (en) 1991-09-27 2003-02-04 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US5446203A (en) * 1992-08-25 1995-08-29 New York University Synthesis of haloenones and aryl or alkyl substituted enones or alkenes
US6251920B1 (en) 1993-05-13 2001-06-26 Neorx Corporation Prevention and treatment of cardiovascular pathologies
US5770609A (en) * 1993-01-28 1998-06-23 Neorx Corporation Prevention and treatment of cardiovascular pathologies
US5354861A (en) * 1992-11-04 1994-10-11 National University Of Singapore 2-(benzyl)-3-arylbenzofurans as antitumour and hypocholesterolemic agents
US6491938B2 (en) 1993-05-13 2002-12-10 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
JPH08510451A (ja) * 1993-05-13 1996-11-05 ネオルックス コーポレイション 異常増殖性平滑筋細胞に関連した病因の予防及び治療
US6197789B1 (en) 1995-06-07 2001-03-06 Neorx Corporation Prevention and treatment of cardiovascular pathologies with tamoxifen analogues
CZ285522B6 (cs) * 1993-06-24 1999-08-11 Eli Lilly And Company Farmaceutický prostředek pro snížení koncentrace glukosy v krvi
US5451590A (en) * 1993-12-21 1995-09-19 Eli Lilly & Co. Methods of inhibiting sexual precocity
US6417198B1 (en) 1993-12-21 2002-07-09 Eli Lilly And Company Methods of inhibiting CNS problems in post-menopausal women
US5534526A (en) * 1993-12-21 1996-07-09 Eli Lilly And Company Methods for inhibiting vasomotor symptoms and attending psychological disturbances surrounding post-menopausal syndrome
US5462950A (en) * 1993-12-21 1995-10-31 Eli Lilly And Company Methods of treating menstrual symptoms and compositions therefore
GB9326255D0 (en) * 1993-12-23 1994-02-23 Roussel Lab Ltd Medical device for the prevention and treatment of cancer
US5650425A (en) * 1994-04-04 1997-07-22 Pharmos Corporation Permanently ionic derivatives of steroid hormones and their antagonists
US5681835A (en) * 1994-04-25 1997-10-28 Glaxo Wellcome Inc. Non-steroidal ligands for the estrogen receptor
UA41909C2 (uk) 1994-07-22 2001-10-15 Елі Ліллі Енд Компані Використання комбінації сполук для інгібірування остеопорозу, фармацевтичний препарат
DE19526146A1 (de) * 1995-07-07 1997-01-09 Schering Ag Triphenylethylene, Verfahren zu deren Herstellung, diese Triphenylethylene enthaltene pharmazeutische Präparate sowie deren Verwendung zur Herstellung von Arzneimitteln
CA2243330A1 (en) 1996-01-20 1997-07-24 Ioana Popa Tamoxifen and analogues thereof
HN1996000101A (es) 1996-02-28 1997-06-26 Inc Pfizer Terapia combinada para la osteoporosis
WO1998034583A2 (en) * 1997-02-09 1998-08-13 Pharmos Corporation Enhanced anti-angiogenic activity of permanently charged derivatives of steroid hormones
US6083990A (en) 1997-04-02 2000-07-04 Pharmos Corporation Enhanced anti-angiogenic activity of permanently charged derivatives of steroid hormones
WO1998037892A1 (en) * 1997-02-27 1998-09-03 Pharmacia & Upjohn Company Tamoxifen as a therapy to reduce irinotecan hydrochloride-induced diarrhea
GB9715479D0 (en) * 1997-07-23 1997-10-01 Univ Bradford Tamoxifen and analogues thereof
HUP0002852A3 (en) 1997-08-15 2001-11-28 Univ Durham A method of preventing or treating estrogen-dependent diseases and disorders using triphenil-ethylene derivatives
UA66370C2 (en) 1997-12-16 2004-05-17 Lilly Co Eli Arylpiperazines having activity to setotonin 1 receptors
GB9824207D0 (en) * 1998-11-04 1998-12-30 Zeneca Ltd Neurological disorders
TW593256B (en) 1999-11-16 2004-06-21 Hormos Medical Oy Ltd Triphenylalkene derivatives and their use as selective estrogen receptor modulators
US20020013327A1 (en) * 2000-04-18 2002-01-31 Lee Andrew G. Compositions and methods for treating female sexual dysfunction
GB0012291D0 (en) * 2000-05-23 2000-07-12 Astrazeneca Ab Pharmaceutical combination
US6613083B2 (en) 2001-05-02 2003-09-02 Eckhard Alt Stent device and method
RU2188000C1 (ru) * 2001-09-27 2002-08-27 Нестерук Владимир Викторович Лекарственное средство на основе тамоксифена
AU2003230691A1 (en) * 2002-03-20 2003-10-08 Elan Pharma International Ltd. Nanoparticulate compositions of angiogenesis inhibitors
CN1678296A (zh) * 2002-07-30 2005-10-05 卡里凯昂公司 依泽替米贝的组合物和治疗胆固醇有关的良性与恶性肿瘤的方法
US7332525B2 (en) * 2003-01-17 2008-02-19 Castle Erik P Method of treatment of prostate cancer and composition for treatment thereof
US20040248989A1 (en) 2003-06-05 2004-12-09 Risto Santti Method for the treatment or prevention of lower urinary tract symptoms
WO2005027924A1 (en) * 2003-09-19 2005-03-31 Pfizer Products Inc. Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin d derivatives and an estrogen agonist/antagonist
EP1689383B1 (en) 2003-11-19 2012-10-31 Metabasis Therapeutics, Inc. Novel phosphorus-containing thyromimetics
US7456149B2 (en) 2004-03-02 2008-11-25 Acceleron Pharma, Inc. ALK7 and myostatin inhibitors and uses thereof
US20050203086A1 (en) * 2004-03-04 2005-09-15 Pfizer Inc. Methods of treatment using an EP2 selective receptor agonist
EP1819681B1 (en) * 2004-11-23 2009-08-12 Warner-Lambert Company LLC 7-(2h-pyrazol-3-yl)-3,5-dihydroxy-heptanoic acid derivatives as hmg co-a reductase inhibitors for the treatment of lipidemia
ES2552338T3 (es) 2005-01-21 2015-11-27 Astex Therapeutics Limited Compuestos farmacéuticos
CA2615374A1 (en) 2005-07-18 2007-01-25 Ernest Kun Kun Treatment of cancer
US7741317B2 (en) 2005-10-21 2010-06-22 Bristol-Myers Squibb Company LXR modulators
US7888376B2 (en) 2005-11-23 2011-02-15 Bristol-Myers Squibb Company Heterocyclic CETP inhibitors
ES2551690T3 (es) 2006-05-22 2015-11-23 Hormos Medical Ltd. Método de tratamiento de la prostatitis crónica no bacteriana con moduladores selectivos del receptor de estrógeno o inhibidores de aromatasa
BRPI0711525A2 (pt) 2006-06-02 2011-11-01 Pear Tree Women S Health Care composição farmacêutica e método para tratar sintomas de vaginite atrófica
US20100160442A1 (en) * 2006-07-18 2010-06-24 Ossovskaya Valeria S Formulations for cancer treatment
JP5528807B2 (ja) 2006-10-12 2014-06-25 アステックス、セラピューティックス、リミテッド 複合薬剤
JP5528806B2 (ja) 2006-10-12 2014-06-25 アステックス、セラピューティックス、リミテッド 複合薬剤
ATE547394T1 (de) 2006-12-01 2012-03-15 Bristol Myers Squibb Co N-((3-benzyl)-2,2-(bis-phenyl)-propan-1- aminderivate als cetp-hemmer für die behandlung von atherosklerose und herz-kreislauf- erkrankungen
CL2008002279A1 (es) 2007-08-03 2009-11-27 Summit Corp Plc Combinacion farmaceutica que comprende un compuesto heteroarilbiciclico o arilbiciclico y un agente auxiliar; proceso de preparacion; y envase farmaceutico, util en el tratamiento y/o profilaxis de la distrofia muscular de duchenne, distrofia muscular de becker y caquexia.
GB0715087D0 (en) 2007-08-03 2007-09-12 Summit Corp Plc Drug combinations for the treatment of duchenne muscular dystrophy
ES2718912T3 (es) 2007-10-16 2019-07-05 Repros Therapeutics Inc Trans-clomifeno para el tratamiento de la diabetes en hombres hipogonadales
US20120046364A1 (en) 2009-02-10 2012-02-23 Metabasis Therapeutics, Inc. Novel Sulfonic Acid-Containing Thyromimetics, and Methods for Their Use
RU2014135436A (ru) 2012-01-31 2016-03-27 Новартис Аг Комбинация ингибитора rtk с антиэстрогеном и ее применение для лечения рака
CA2865234A1 (en) 2012-02-29 2013-09-06 Repros Therapeutics Inc. Combination therapy for treating androgen deficiency
US9353132B2 (en) 2012-03-05 2016-05-31 Xavier University Of Louisiana Boron-based 4-hydroxytamoxifen and endoxifen prodrugs as treatment for breast cancer
CN103992234B (zh) * 2014-06-11 2016-05-18 扬子江药业集团江苏海慈生物药业有限公司 一种枸橼酸他莫昔芬e异构体的制备方法
CN108348605B (zh) 2015-11-10 2023-06-09 帕拉卡林治疗公司 用pdgf-cc抑制剂和抗雌激素治疗er阴性乳癌
EP3400009A2 (en) 2016-01-05 2018-11-14 The U.S.A. As Represented By The Secretary, Department Of Health And Human Services Combination of histone deacetylase inhibitor and immunotherapy
WO2017136342A1 (en) 2016-02-02 2017-08-10 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Fulvestrant for inducing immune-mediated cytotoxic lysis of cancer cells
US12059403B2 (en) 2016-08-04 2024-08-13 University Of Iowa Research Foundation Use of SWELL1 inhibitors and modulators to treat type 2 diabetes and obesity
EP3484463B1 (en) 2016-08-19 2020-02-12 The United States of America, as Represented by The Secretary, Department of Health and Human Services Office of Technology Transfer Selective estrogen-receptor modulators (serms) confer protection against photoreceptor degeneration
WO2019164861A1 (en) 2018-02-21 2019-08-29 AI Therapeutics, Inc. Combination therapy with apilimod and glutamatergic agents
WO2020252018A1 (en) * 2019-06-10 2020-12-17 University Of Iowa Research Foundation Swell 1 modulators for treatment of non-alcoholic fatty liver disease, immune deficiencies, male infertility and vascular diseases
CN114133334B (zh) * 2021-11-09 2024-07-19 北京京丰制药(山东)有限公司 枸橼酸他莫昔芬的工业化制备工艺
EP4230196A1 (en) 2022-02-21 2023-08-23 Som Innovation Biotech, S.A. Compounds for use in the treatment of dystrophinopathies
EP4311546A1 (en) 2022-07-26 2024-01-31 Dynacure Combination therapy for myopathies
WO2024254189A1 (en) 2023-06-06 2024-12-12 Daré Bioscience, Inc. Compositions and methods for treating vulvar and vaginal atrophy (vva)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1013907A (en) * 1962-09-13 1965-12-22 Ici Ltd Alkene derivatives
BE637389A (en:Method) * 1962-09-13
GB1029221A (en) * 1963-09-02 1966-05-11 Ici Ltd Triarylalkane derivatives
US3288806A (en) * 1964-03-23 1966-11-29 Parke Davis & Co Alpha-(aminoethoxyphenyl)-alpha-alkylstilbenes
GB1099093A (en) * 1965-09-03 1968-01-17 Ici Ltd Alkene derivatives
GB1560274A (en) * 1977-02-28 1980-02-06 Ici Ltd Phenylbut 1-ene derivatives having antiostrogenicactivity

Also Published As

Publication number Publication date
DE1568834A1 (de) 1970-11-26
CH441286A (de) 1967-08-15
BE637389A (en:Method)
CH446289A (de) 1967-11-15
DE1468088A1 (de) 1969-07-31
US4536516A (en) 1985-08-20
FR1502607A (fr) 1967-11-24
BR6678265D0 (pt) 1973-09-18
GB1064629A (en) 1967-04-05
BR6352734D0 (pt) 1973-09-18
DK117953B (da) 1970-06-22
BE678807A (en:Method) 1966-09-30
DK127777B (da) 1974-01-07
CH538447A (de) 1973-06-30

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