WO1995017383A1 - Indole derivatives as anti-estrogens - Google Patents
Indole derivatives as anti-estrogens Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- estrogen
- cells
- indole
- indole derivative
- indole derivatives
- Prior art date
Links
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
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU13169/95A AU1316995A (en) | 1993-12-23 | 1994-12-23 | Indole derivatives as anti-estrogens |
JP7517189A JPH09510689A (en) | 1993-12-23 | 1994-12-23 | Indole derivatives as antiestrogens |
EP95904514A EP0736008A1 (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 (en) | 1995-06-29 |
Family
ID=10747121
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1994/004250 WO1995017383A1 (en) | 1993-12-23 | 1994-12-23 | Indole derivatives as anti-estrogens |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0736008A1 (en) |
JP (1) | JPH09510689A (en) |
AU (1) | AU1316995A (en) |
CA (1) | CA2187296A1 (en) |
GB (1) | GB9326332D0 (en) |
WO (1) | WO1995017383A1 (en) |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996003375A1 (en) * | 1994-07-27 | 1996-02-08 | Schering Aktiengesellschaft | 2-phenyl indoles as anti-oestrogen drugs |
EP0802183A1 (en) * | 1996-04-19 | 1997-10-22 | American Home Products Corporation | Estrogenic agents |
KR970069986A (en) * | 1996-04-19 | 1997-11-07 | 버그 이곤 이 | Estrogen preparations |
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 (en) * | 1998-05-15 | 1999-11-25 | American Home Products Corporation | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole in combination with estrogens |
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 (en) * | 1999-09-13 | 2001-03-22 | American Home Products Corporation | Glucopyranosides conjugates of 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 (en) | 1997-10-15 | 2007-04-25 | Wyeth | Novel aryloxy-alkyl-dialkylamines |
WO2013130832A1 (en) | 2012-02-29 | 2013-09-06 | Repros Therapeutics Inc. | Combination therapy for treating androgen deficiency |
EP2826475A1 (en) | 2007-10-16 | 2015-01-21 | Repros Therapeutics Inc. | Trans-clomiphene for treating diabetes in hypogonadal men |
CN105732465A (en) * | 2016-04-06 | 2016-07-06 | 沈阳药科大学 | Phenylindole compound and preparation method and application thereof |
CN105859606A (en) * | 2016-04-06 | 2016-08-17 | 沈阳药科大学 | Piperazinyl-containing indole derivatives, and preparation method and application thereof |
WO2017081171A1 (en) | 2015-11-10 | 2017-05-18 | Paracrine Therapeutics Ab | Treatment of er-negative breast cancer with an pdgf-cc inhibitor and an anti estrogen |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022070483A1 (en) * | 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 | Pharmaceutical composition for treatment of prostate cancer or breast cancer |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0348341A2 (en) * | 1988-06-23 | 1989-12-27 | Schering Aktiengesellschaft | Aminoalkyl indoles, process for their preparation and pharmaceutical compositions thereof |
WO1993010741A2 (en) * | 1991-12-02 | 1993-06-10 | Endorecherche Inc. | Sex steroid activity inhibitors |
-
1993
- 1993-12-23 GB GB939326332A patent/GB9326332D0/en active Pending
-
1994
- 1994-12-23 WO PCT/EP1994/004250 patent/WO1995017383A1/en not_active Application Discontinuation
- 1994-12-23 CA CA002187296A patent/CA2187296A1/en not_active Abandoned
- 1994-12-23 AU AU13169/95A patent/AU1316995A/en not_active Abandoned
- 1994-12-23 JP JP7517189A patent/JPH09510689A/en active Pending
- 1994-12-23 EP EP95904514A patent/EP0736008A1/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0348341A2 (en) * | 1988-06-23 | 1989-12-27 | Schering Aktiengesellschaft | Aminoalkyl indoles, process for their preparation and pharmaceutical compositions thereof |
WO1993010741A2 (en) * | 1991-12-02 | 1993-06-10 | Endorecherche Inc. | Sex steroid activity inhibitors |
Non-Patent Citations (2)
Title |
---|
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." * |
J. STEROID BIOCHEM. MOL. BIOL. 1994,49(1),51-62 * |
Cited By (46)
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---|---|---|---|---|
WO1996003375A1 (en) * | 1994-07-27 | 1996-02-08 | Schering Aktiengesellschaft | 2-phenyl indoles as anti-oestrogen drugs |
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 (en) * | 1996-04-19 | 2003-03-26 | 惠氏公司 | 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 |
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 (en) * | 1996-04-19 | 1997-10-22 | American Home Products Corporation | Estrogenic agents |
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 (en) * | 1996-04-19 | 1997-11-07 | 버그 이곤 이 | Estrogen preparations |
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 |
US6326367B1 (en) | 1996-04-19 | 2001-12-04 | American Home Products Corporation | 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 |
US7449455B2 (en) | 1996-04-19 | 2008-11-11 | Wyeth | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents |
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US6242605B1 (en) | 1997-10-15 | 2001-06-05 | American Home Products Corporation | Aryloxy-alkyl-dialkylamines |
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US6005102A (en) * | 1997-10-15 | 1999-12-21 | American Home Products Corporation | Aryloxy-alkyl-dialkylamines |
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US6107292A (en) * | 1998-05-12 | 2000-08-22 | American Home Products Corporation | Indenoindoles and benzocarbazoles as estrogenic agents |
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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 |
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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 |
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CZ298862B6 (en) * | 1999-09-13 | 2008-02-27 | Wyeth | Estrogen compound |
EA005371B1 (en) * | 1999-09-13 | 2005-02-24 | Уайт | Glucopyranosides conjugates of 2-(4-hydroxy phenyl)-1-[4-(2-amin-1yl-ethoxy)-benzyl]-1h-indol-5-ols |
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 |
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WO2013130832A1 (en) | 2012-02-29 | 2013-09-06 | Repros Therapeutics Inc. | Combination therapy for treating androgen deficiency |
WO2017081171A1 (en) | 2015-11-10 | 2017-05-18 | Paracrine Therapeutics Ab | Treatment of er-negative breast cancer with an pdgf-cc inhibitor and an anti estrogen |
CN105859606A (en) * | 2016-04-06 | 2016-08-17 | 沈阳药科大学 | Piperazinyl-containing indole derivatives, and preparation method and application thereof |
CN105732465A (en) * | 2016-04-06 | 2016-07-06 | 沈阳药科大学 | Phenylindole compound and preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
EP0736008A1 (en) | 1996-10-09 |
AU1316995A (en) | 1995-07-10 |
JPH09510689A (en) | 1997-10-28 |
GB9326332D0 (en) | 1994-02-23 |
CA2187296A1 (en) | 1995-06-29 |
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