WO1995017383A1 - Derives d'indole diriges contre les oestrogenes - Google Patents

Derives d'indole diriges contre les oestrogenes Download PDF

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Publication number
WO1995017383A1
WO1995017383A1 PCT/EP1994/004250 EP9404250W WO9517383A1 WO 1995017383 A1 WO1995017383 A1 WO 1995017383A1 EP 9404250 W EP9404250 W EP 9404250W WO 9517383 A1 WO9517383 A1 WO 9517383A1
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WO
WIPO (PCT)
Prior art keywords
estrogen
cells
indole
indole derivative
indole derivatives
Prior art date
Application number
PCT/EP1994/004250
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English (en)
Inventor
Ulf Norinder
Original Assignee
Karo Bio Ab
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 Karo Bio Ab filed Critical Karo Bio Ab
Priority to EP95904514A priority Critical patent/EP0736008A1/fr
Priority to JP7517189A priority patent/JPH09510689A/ja
Priority to AU13169/95A priority patent/AU1316995A/en
Publication of WO1995017383A1 publication Critical patent/WO1995017383A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms

Definitions

  • the present invention relates to new indole derivatives and in particular to new indole derivatives which are useful as non-steroidal anti-estrogens.
  • Estrogen Replacement Therapy is effective in the prevention of osteoporosis and fracture.
  • Estrogen Replacement Therapy is effective in the prevention of osteoporosis and fracture.
  • it has recently become evident that it may also be valuable in the treatment of established osteoporosis and fractures C.W. Marx et al. , J. Bone and Mineral Res 11 (1992) 1275 and C. Christiansen et al. in Christiansen (ed) "Hormone replacement and its impact on osteoporosis” , Bailliere Tindall, London (1991) 853).
  • estrogen therapy includes endometrial cancer, breast cancer and venous thrombosis and associated pulmonary embolism.
  • Transdermal supply of estrogen which avoids the first hepatic passage occurring with oral formulations, may circumvent conditions favouring thrombosis.
  • the estrogen receptor antagonist, or anti-estrogen, tamoxifen used particularly today in the treatment of hormone-dependent breast cancer is one of the safest anti-cancer drugs on the market.
  • tamoxifen has number of disadvantages.
  • an improved anti-estrogen devoid of estrogenic activity would be desirable both as a drug and as a biochemical tool to investigate the mechanisms of action of estrogens.
  • estradiol estradiol
  • Non-steroidal compounds such as dihydronaphthalenes (Suarez and Jones, U.S. Patent 4,230,862) and benzothiophenes (Jones and Suarez, U.S. Patent 4,230,862) and benzothiophenes (Jones and Suarez, U.S. Patent 4,230,862) and benzothiophenes (Jones and Suarez, U.S. Patent 4,230,862) and benzothiophenes (Jones and Suarez, U.S. Patent
  • the present invention provides an indole derivative of the formula
  • Rl and R2 independently is/are hydroxy, methoxy or fluorine
  • n is an integer of between 9 and 12 inclusive;
  • X is CONR4R5, CSNR4R5, NR4COR5, NR4R5. SO : NR4R5. NR4SO 2 R5, or 1-
  • R4 and R5 are independently selected from hydrogen and lower alky Is, typically C1-C5, or R4 and R5 together form a bridge of the formula - (CH 2 )y- wherein y is 4 or 5 or a salt, preferably a physiologically-acceptable salt, thereof.
  • the indole derivative of the invention in addition to lacking or possessing a minimum of estrogenic activity in breast, the indole derivative of the invention also exhibits estrogenic activity in bone and/or in liver and/or lacks or possesses a minimum of estrogenic activity in endometrium.
  • One or more of the indole derivatives of the invention may be included in a pharmaceutical preparation as an active ingredient together with a pharmaceutically acceptable carrier(s) and/or diluent(s) in accordance with the skill of the average worker.
  • the indole derivatives of the invention may be used in the treatment, whether therapeutic or prophylactic, of an estrogen-related disorder or disease, such as breast cancer, or in estrogen replacement therapy.
  • the indole derivatives of the invention may be used in the manufacture of a medicament for the therapeutic or prophylactic treatment of an estrogen related disorder or disease comprising administering to an individual in need of such treatment a therapeutically or prophylactically effective amount of such indole derivatives.
  • the medicaments are especially suitable for use in estrogen replacement therapy and/or breast cancer therapy.
  • the preferred activity profiles make the indole derivative of the invention particularly suitable for use in the long term treatment of patients. This contrasts the worrying evidence emerging for the anti-estrogen Tamoxifen used presently.
  • Figs 1 - 14 illustrate the effect of compounds in accordance with the invention in the ZRAF cell line; a Breast carcinoma cell line; an endometrium carcinoma cell line: and a liver carcinoma cell line; and
  • Figs 15 and 16 illustrate the effect of prior art compounds ZK 119010 and Tamoxifen on the same cells .
  • the estrogen reporter cell line is an engineered, estrogen receptor (ER) expressing mammalian cell line containing an integrated artificial transcription unit comprising an estrogen response element (ERE) and core promoter sequences fused to a reporter gene encoding a secreted form of alkaline phosphatase.
  • ERE estrogen response element
  • the cells express only very low levels of the alkaline phosphatase reporter protein.
  • the ER gets activated resulting in transcriptional activation of the alkaline phosphatase reporter gene, mediated through the ERE.
  • the level of estrogen-dependent alkaline phosphatase protein expressed can be determined indirectly by an enzymatic chemiluminescence assay as previously described (Nilsson S.et al. (1993) in Advances in Steroid Analysis '93, Proceedings of the 5th Symposium on the Analysis of Steroids, Ed. Gor ⁇ g S. , Published by Akademia Kiad ⁇ . Budapest, Hungary, p. 57 - 67).
  • the ZRAF cells show a stringent dependence on the presence of an agonist for expression of the alkaline phosphatase reporter protein the cells have to be stimulated by a low dose of reference agonist (1 nM moxestrol, New England Nuclear) in order to analyse compounds with antagonistic activity.
  • the synthesized indole derivatives of the invention were tested for their estrogenic/antiestrogenic activity and potency in regulating the expression of the alkaline phosphatase reporter gene, exerted by the human estrogen receptor.
  • the ZRAF cells were cultivated at 37 °C and 5% CO 2 in a humidified incubator under hormone free conditions, suspended in Coon's a) (w/o phenolred ) + 10 % FCS w (doublestripped from hormone by dextran coated charcoal (2xDCC)) in plastic petridishes (Costar.LabDesign, Sweden) for four days prior to the start of each experiment.
  • ZRAF cells were seeded at a density of 4xl0 4 cells per well in 96-well microtiterplates
  • the human breast tumor cell line ZR75-1 (ATCC CRL 1500) is highly dependent on estradiol E 2 for growth in vitro (half maximal proliferative response to Eo is already reached at approximately 50 pM and at a 1 nM concentration of ⁇ *2 a maximal response is obtained - in the absence of E these cells become quiescent) and therefore was selected as a tool for evaluation of the agonist/antagonist activity of compounds that mediate their effect through the human estrogen receptor.
  • Tamoxifen displays a very weak estrogenic activity in the breast tumour cell proliferation assay cells. However, in the presence of 1 nM E ⁇ tamoxifen shows a concentration dependent anti-estrogenic activity.
  • the partial estrogenic/ anti-estrogenic profile of Tamoxifen in the absence or presence of Ei respectively, is known from the literature (Br. J. Cancer 59 (1989) 727 and Cancer Res. 48 (1988) 3693).
  • the level of cellular ATP was chosen as a measure of cell growth rather than counting the number of cells as it has previously been shown that the level of cellular ATP, indirectly determined by a chemiluminescence assay, is a more reproducible way to study cell growth and cell number than traditional cell counting (Methods in
  • the effect of the indole derivatives of the present invention was determined on the ZR75-1 breast tumor cell line by monitoring their ability to stimulate or repress cell growth in the absence or presence of 1 nM estradiol, respectively (173-estradiol purchased from Sigma).
  • the ZR75-1 cells were cultivated under hormone free conditions in Coon's (w/o phenolred ) + 10 % FCS (2xDCC) in plastic petridishes for four days at 37°C and 5% CO 2 in a humidified incubator, prior to start of the experiment.
  • the cells were trypsinised and seeded at a density of 8 x 10 3 cells/well in 96-well microtiterplates.
  • the cells were seeded in Coon's (w/o phenolred) + 10 % FCS (2xDCC) and cultivated at 37 °C and 5% CO, in a humidified incubator.
  • Spent medium was exchanged for fresh Ham ' s (w/o phenolred ) + 5 % FCS (2xDCC) +/- hormone and test substances (see day 5).
  • the liver is another target organ for estrogens/antiestrogens.
  • the human liver cell line HepG2 ATCC # CRL HB 8065
  • the gene encoding sex hormone binding globulin (SHBG) is positively regulated by estrogen receptor binding hormones/compounds that have partial or full agonist properties. Therefore the effect of the indole derivatives, in the presence or absence of the reference agonist moxestrol (1 nM), on the transcriptional regulation of the SHGBG gene was used to assess their estrogenic/antiestrogenic activities.
  • the uterus is yet another target for effects induced by estrogenic compounds. It is well known that tamoxifen. a potent antiestrogen for treatment of breast cancer, has very high estrogenic activity in endometrial cells. The relatively high agonistic effect of tamoxifen in the endometrium is believed to be one reason for the increased incidence of new endometrial tumors formed during long-term tamoxifen treatment.
  • the endogenous alkaline phosphatase gene was used as the target gene for characterization of the agonistic/antagonistic effect of the indole compounds in the Ishikawa endometrial cell line. Their agonist/antagonist profile is assessed by determining the level of alkaline phosphatase expressed and secreted by the endometrial cells following exposure to the indole compounds in the presence or absence of 0.1 nM of the reference agonist moxestrol.
  • Dav 2 Change of medium to Coon's (w/o phenolred) supplemented with 2 mM L- glutamine and 5 % serum substitute +/- reference agonist and test substances (see below).
  • the cells were continued to be cultivated at 37 °C and 5% CO 2 in a humidified incubator.
  • Toxicity was monitored by the colorimetric MTS/PMS method (SDS. Sweden) following the supplier's recommendations.
  • the concentration range of the reference agonist used was IO "6 - IO" 11 M.
  • the concentration range of the indole derivatives, the Schering compound ZK 119010 and tamoxifen used in the experiments was IO "5 - IO "10 M (or as otherwise depicted in the dose response curves) ⁇ 0.1/1 nM reference agonist.
  • the cellular response to hormone/compound is expressed in the accompanying dose response curves as percent of the response elicited by the reference agonist. Background expression of the chosen cellular response was set at 0 % .
  • indole derivatives in accordance with the invention were able to suppress estradiol- dependent growth of the ZR75-1 breast cancer cells and estradiol-mediated transcriptional activation of the endogenous alkaline phosphatase gene in the Ishikawa endometrial cell line.
  • ER-28 displayed a significantly lower growth stimulatory effect of the breast cancer cell line ZR75-1 i.e. they elicited very low or no agonist function.
  • KB ER-1 KB-ER-14, KB ER -16, KB ER -22.
  • KB ER -26 and KB ER -27 also showed a more favourable agonist/antagonist profile in the endometrial cell line than the Schering compound ZK 119010.
  • Compounds KB ER-17, KB ER-18 andKB ER- 21 displayed a degree of agonism similar to ZK 119010 while the other indole derivatives, except KB ER-28, showed only a slightly higher relative agonism.
  • the invention thus provides anti-estrogens lacking or possessing a minium of estrogenic activity in breast.

Abstract

Dérivé d'indole de la formule (I) dans laquelle R1 et R2 représentent indépendamment hydroxy, méthoxy ou fluor, de préférence hydroxy; n représente un nombre entier compris entre 9 et 12; et X représente un élément du groupe consistant en CONR4R5, CSNR4R5, NR4COR5, NR4R5, SO2NR4R5, NR4SO2R5, 1-R4-5-tétrazole, où R4 et R5 sont choisis indépendamment dans le groupe d'hydrogène et des alcoyles inférieurs, ou bien R4 et R5 forment ensemble un pont pour la formule -(CH2)y- dans laquelle y représente un nombre entier qui peut être 4 ou 5. Cette invention se rapporte également à une préparation pharmaceutique comprenant un ou plusieurs de ces dérivés d'indole, ainsi qu'à l'utilisation desdits dérivés en tant que médicament. L'invention se rapporte encore à l'utilisation de ces dérivés d'indole dans la préparation d'un médicament destiné au traitement thérapeutique ou prophylactique d'un désordre ou d'une maladie associés à un oestrogène, comme dans la thérapie de remplacement d'oestrogènes et/ou dans le cancer du sein.
PCT/EP1994/004250 1993-12-23 1994-12-23 Derives d'indole diriges contre les oestrogenes WO1995017383A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP95904514A EP0736008A1 (fr) 1993-12-23 1994-12-23 Derives d'indole diriges contre les oestrogenes
JP7517189A JPH09510689A (ja) 1993-12-23 1994-12-23 抗エストロゲンとしてのインドール誘導体
AU13169/95A AU1316995A (en) 1993-12-23 1994-12-23 Indole derivatives as anti-estrogens

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9326332.5 1993-12-23
GB939326332A GB9326332D0 (en) 1993-12-23 1993-12-23 Indole derivatives

Publications (1)

Publication Number Publication Date
WO1995017383A1 true WO1995017383A1 (fr) 1995-06-29

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PCT/EP1994/004250 WO1995017383A1 (fr) 1993-12-23 1994-12-23 Derives d'indole diriges contre les oestrogenes

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Country Link
EP (1) EP0736008A1 (fr)
JP (1) JPH09510689A (fr)
AU (1) AU1316995A (fr)
CA (1) CA2187296A1 (fr)
GB (1) GB9326332D0 (fr)
WO (1) WO1995017383A1 (fr)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996003375A1 (fr) * 1994-07-27 1996-02-08 Schering Aktiengesellschaft 2-phenylindoles utilises comme medicaments antiestrogenes
EP0802183A1 (fr) * 1996-04-19 1997-10-22 American Home Products Corporation Composés oestrogènes
KR970069986A (ko) * 1996-04-19 1997-11-07 버그 이곤 이 에스트로겐 제제
US5780497A (en) * 1996-04-19 1998-07-14 American Home Products Corporation 2-phenyl-1- 4-(amino-1-yl-alk-1-ynyl)-benzyl!-1H-indol-5-ols as estrogenic agents
US5880137A (en) * 1996-04-19 1999-03-09 American Home Products Corporation 2-phenyl-1- 4-(amino-1-yl-alk-1-ynyl)-benzyl!-1H-indol-5-ols as estrogenic agents
US5985910A (en) * 1996-04-19 1999-11-16 American Home Products Corporation 3- [4- (2- Phenyl-Indole-1-ylmethyl) Phenyl]- Acrylamides as estrogenic agents
WO1999059581A1 (fr) * 1998-05-15 1999-11-25 American Home Products Corporation 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole en combinaison avec des oestrogenes
US5998402A (en) * 1996-04-19 1999-12-07 American Home Products Corporation 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
US6005102A (en) * 1997-10-15 1999-12-21 American Home Products Corporation Aryloxy-alkyl-dialkylamines
US6069153A (en) * 1998-05-12 2000-05-30 American Home Products Corporation Indenoindoles and benzocarbazoles as estrogenic agents
US6159959A (en) * 1999-05-06 2000-12-12 American Home Products Corporation Combined estrogen and antiestrogen therapy
WO2001019839A1 (fr) * 1999-09-13 2001-03-22 American Home Products Corporation Conjugues glucopyranosides de 2-(4-hydroxy-phenyl)-1-[4-(2-amin-1-yl-ethoxy)-benzyl]-1h-indol-5-ols
US6326392B1 (en) 1997-11-06 2001-12-04 American Home Products Corporation Anti-estrogen plus progestin containing oral contraceptives
US6380185B1 (en) 1999-03-04 2002-04-30 American Home Products Corporation N-substituted benzoyl indoles as estrogenic agents
US6380166B1 (en) 1999-09-13 2002-04-30 American Home Products Corporation Glucopyranosides conjugates of 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-amin-1-yl-ethoxy)-benzyl]-1H-indol-5-ols
US6479535B1 (en) 1998-05-15 2002-11-12 Wyeth 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole and estrogen formulations
EP1777214A2 (fr) 1997-10-15 2007-04-25 Wyeth Nouveaux dialkylamines-alkyl-aryloxyx
WO2013130832A1 (fr) 2012-02-29 2013-09-06 Repros Therapeutics Inc. Polythérapie pour le traitement d'une carence en androgène
EP2826475A1 (fr) 2007-10-16 2015-01-21 Repros Therapeutics Inc. Trans-clomphène pour le traitement du diabète chez les hommes atteints d'hypogonadisme
CN105732465A (zh) * 2016-04-06 2016-07-06 沈阳药科大学 苯基吲哚类化合物及其制备方法和应用
CN105859606A (zh) * 2016-04-06 2016-08-17 沈阳药科大学 含有哌嗪基的吲哚类衍生物及其制备方法和应用
WO2017081171A1 (fr) 2015-11-10 2017-05-18 Paracrine Therapeutics Ab Traitement d'un cancer du sein négatif pour er à l'aide d'un inhibiteur du pdgf-cc et d'un anti-œstrogène

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WO2022070483A1 (fr) * 2020-09-30 2022-04-07 地方独立行政法人東京都健康長寿医療センター Composition pharmaceutique pour le traitement du cancer de la prostate ou du cancer du sein

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EP0348341A2 (fr) * 1988-06-23 1989-12-27 Schering Aktiengesellschaft Aminoalkylindoles, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO1993010741A2 (fr) * 1991-12-02 1993-06-10 Endorecherche Inc. Inhibiteurs de l'activite des steroides sexuels

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Publication number Priority date Publication date Assignee Title
EP0348341A2 (fr) * 1988-06-23 1989-12-27 Schering Aktiengesellschaft Aminoalkylindoles, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO1993010741A2 (fr) * 1991-12-02 1993-06-10 Endorecherche Inc. Inhibiteurs de l'activite des steroides sexuels

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CHEMICAL ABSTRACTS, vol. 121, no. 25, 19 December 1994, Columbus, Ohio, US; abstract no. 292961u, VON ANGERER,E. ET AL.: "1-Carbamoylalkyl-2-phenylindoles: relationship between side chain structure and estrogen antagonism." *
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WO1996003375A1 (fr) * 1994-07-27 1996-02-08 Schering Aktiengesellschaft 2-phenylindoles utilises comme medicaments antiestrogenes
US7132417B2 (en) 1996-04-19 2006-11-07 Wyeth 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
US6835729B2 (en) 1996-04-19 2004-12-28 Wyeth 2-phenyl-1-[4(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
US5780497A (en) * 1996-04-19 1998-07-14 American Home Products Corporation 2-phenyl-1- 4-(amino-1-yl-alk-1-ynyl)-benzyl!-1H-indol-5-ols as estrogenic agents
CN1103756C (zh) * 1996-04-19 2003-03-26 惠氏公司 雌激素剂
US5985910A (en) * 1996-04-19 1999-11-16 American Home Products Corporation 3- [4- (2- Phenyl-Indole-1-ylmethyl) Phenyl]- Acrylamides as estrogenic agents
US7138392B2 (en) 1996-04-19 2006-11-21 Miller Chris P 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
US5998402A (en) * 1996-04-19 1999-12-07 American Home Products Corporation 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
EP0802183A1 (fr) * 1996-04-19 1997-10-22 American Home Products Corporation Composés oestrogènes
US7041663B2 (en) 1996-04-19 2006-05-09 Wyeth 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
US6951852B2 (en) 1996-04-19 2005-10-04 Wyeth 2-Phenyl-1-[4-(2-Aminoethoxy)-Benzyl]-Indoles as estrogenic agents
US6127404A (en) * 1996-04-19 2000-10-03 American Home Products Corporation Tissue selective compounds in the treatment of endometrial proliferation
US6924281B2 (en) 1996-04-19 2005-08-02 Wyeth 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
KR970069986A (ko) * 1996-04-19 1997-11-07 버그 이곤 이 에스트로겐 제제
US6232307B1 (en) 1996-04-19 2001-05-15 American Home Products Corporation Tissue selective compounds in the treatment of ovarian cancer
US7247624B2 (en) 1996-04-19 2007-07-24 Wyeth 2-Phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
US7449455B2 (en) 1996-04-19 2008-11-11 Wyeth 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
US6291451B1 (en) 1996-04-19 2001-09-18 American Home Products Corporation 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
US6787538B2 (en) 1996-04-19 2004-09-07 Wyeth 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
US6326367B1 (en) 1996-04-19 2001-12-04 American Home Products Corporation 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
US5880137A (en) * 1996-04-19 1999-03-09 American Home Products Corporation 2-phenyl-1- 4-(amino-1-yl-alk-1-ynyl)-benzyl!-1H-indol-5-ols as estrogenic agents
US6242605B1 (en) 1997-10-15 2001-06-05 American Home Products Corporation Aryloxy-alkyl-dialkylamines
EP1777214A2 (fr) 1997-10-15 2007-04-25 Wyeth Nouveaux dialkylamines-alkyl-aryloxyx
US6005102A (en) * 1997-10-15 1999-12-21 American Home Products Corporation Aryloxy-alkyl-dialkylamines
US6268504B1 (en) 1997-10-15 2001-07-31 American Home Products Corporation Aryloxy-alkyl-dialkylamines
US6326392B1 (en) 1997-11-06 2001-12-04 American Home Products Corporation Anti-estrogen plus progestin containing oral contraceptives
US6107292A (en) * 1998-05-12 2000-08-22 American Home Products Corporation Indenoindoles and benzocarbazoles as estrogenic agents
US6069153A (en) * 1998-05-12 2000-05-30 American Home Products Corporation Indenoindoles and benzocarbazoles as estrogenic agents
CZ299334B6 (cs) * 1998-05-15 2008-06-25 Wyeth Farmaceutický prostredek
AP1424A (en) * 1998-05-15 2005-06-06 Wyeth Corp 2-Phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole in combination with estrogens.
US8815934B2 (en) 1998-05-15 2014-08-26 Wyeth Llc 2-Phenyl-1-[4-(2-Aminoethoxy)-Benzyl]-Indole and estrogen formulations
BG64783B1 (bg) * 1998-05-15 2006-04-28 American Home Products Corporation Комбинация на 2-фенил-1-[4-(2-аминоетокси)-бензил]-индол с естрогени
WO1999059581A1 (fr) * 1998-05-15 1999-11-25 American Home Products Corporation 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole en combinaison avec des oestrogenes
US6479535B1 (en) 1998-05-15 2002-11-12 Wyeth 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole and estrogen formulations
US6380185B1 (en) 1999-03-04 2002-04-30 American Home Products Corporation N-substituted benzoyl indoles as estrogenic agents
US6159959A (en) * 1999-05-06 2000-12-12 American Home Products Corporation Combined estrogen and antiestrogen therapy
WO2001019839A1 (fr) * 1999-09-13 2001-03-22 American Home Products Corporation Conjugues glucopyranosides de 2-(4-hydroxy-phenyl)-1-[4-(2-amin-1-yl-ethoxy)-benzyl]-1h-indol-5-ols
CZ298862B6 (cs) * 1999-09-13 2008-02-27 Wyeth Estrogenová sloucenina
EA005371B1 (ru) * 1999-09-13 2005-02-24 Уайт Глюкопиранозидные конъюгаты 2-(4-гидроксифенил)-1-[4-(2-амин-1-илэтокси)бензил]-1h-индол-5-олов
US6380166B1 (en) 1999-09-13 2002-04-30 American Home Products Corporation Glucopyranosides conjugates of 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-amin-1-yl-ethoxy)-benzyl]-1H-indol-5-ols
US6537971B2 (en) 1999-09-13 2003-03-25 Wyeth Glucopyranosides conjugates of 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-amin-1-yl-ethoxy)-benzyl]-1H-indol-5-ols
EP2826475A1 (fr) 2007-10-16 2015-01-21 Repros Therapeutics Inc. Trans-clomphène pour le traitement du diabète chez les hommes atteints d'hypogonadisme
WO2013130832A1 (fr) 2012-02-29 2013-09-06 Repros Therapeutics Inc. Polythérapie pour le traitement d'une carence en androgène
WO2017081171A1 (fr) 2015-11-10 2017-05-18 Paracrine Therapeutics Ab Traitement d'un cancer du sein négatif pour er à l'aide d'un inhibiteur du pdgf-cc et d'un anti-œstrogène
CN105859606A (zh) * 2016-04-06 2016-08-17 沈阳药科大学 含有哌嗪基的吲哚类衍生物及其制备方法和应用
CN105732465A (zh) * 2016-04-06 2016-07-06 沈阳药科大学 苯基吲哚类化合物及其制备方法和应用

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JPH09510689A (ja) 1997-10-28
AU1316995A (en) 1995-07-10
CA2187296A1 (fr) 1995-06-29
EP0736008A1 (fr) 1996-10-09
GB9326332D0 (en) 1994-02-23

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