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WO2010054758A1 - Combinaison pharmaceutique synergique contenant un antagoniste du récepteur des oestrogènes et une progestine - Google Patents

Combinaison pharmaceutique synergique contenant un antagoniste du récepteur des oestrogènes et une progestine Download PDF

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Publication number
WO2010054758A1
WO2010054758A1 PCT/EP2009/007801 EP2009007801W WO2010054758A1 WO 2010054758 A1 WO2010054758 A1 WO 2010054758A1 EP 2009007801 W EP2009007801 W EP 2009007801W WO 2010054758 A1 WO2010054758 A1 WO 2010054758A1
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WO
WIPO (PCT)
Prior art keywords
estrogen receptor
receptor antagonist
acetate
bazedoxifene
hydroxyphenyl
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.)
Ceased
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PCT/EP2009/007801
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English (en)
Inventor
Tim Wintermantel
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Bayer Pharma AG
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Bayer Schering Pharma AG
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Filing date
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Publication of WO2010054758A1 publication Critical patent/WO2010054758A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens

Definitions

  • Synergistic pharmaceutical combination comprising an estrogen receptor antagonist and a progestin
  • the present invention relates to the coadministration of an estrogen receptor antagonist and a progestin to treat gynecological diseases resulting from abnormal growth of uterine tissue, such as endometriosis or uterine fibroids.
  • Endometriosis is a disease in women of reproductive age characterized by the ectopic growth of uterine tissue in the abdominal cavity. This uterine tissue remains hormone responsive, such as cyclical bleeding and estrogen-dependent growth. The ectopic growth triggers abdominal pain leading to a loss in quality of life, and immune system activation. Frequently, endometriosis leads to infertility in affected women.
  • Uterine fibroids or uterine leiomyomata is a disease in women of reproductive age characterized by benign tumor-like growth of the myometrial layer of the uterus, and deposition of fibroid tissue on the uterine wall.
  • estrogen receptor antagonist e.g. antiestrogens (e.g. WO2003/045972 and W01998/007740) or selective estrogen receptor modulators (SERMs, e.g. WO2001 /68634).
  • SERMs selective estrogen receptor modulators
  • SERMs have a tissue-specific partial agonism that allows beneficial estrogen agonist effects on bone with estrogen antagonistic effects on the uterus.
  • the SERM raloxifene ([6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl] 4-(2- piperidinoethoxy)phenyl] ketone) which is a uterine antagonist, has been shown to be efficacious in treating uterine leiomymata in postmenopausal women (Palomba, S., Sammartino, A., Di Carlo, C, Affinito, P., ZuIIo, F., and Nappi, C. (2001 ). Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women. Fertil Steril 76, 38-43).
  • Progestins have been shown to effectively reduce endometriotic symptoms, be it by local application of levonorgestrel in an intrauterine device (Bahamondes, L., Petta, C. A., Femandes, A., and Monteiro, I. (2007).
  • levonorgestrel-releasing intrauterine system in women with endometriosis, chronic pelvic pain and dysmenorrhea. Contraception 75, S134-139) or by systemic application of the progestin dienogest (Schindler, A. E., Christensen, B., Henkel, A., Oettel, M., and Moore, C. (2006).
  • hormone-dependent gynecological diseases e.g. endometriosis or uterine fibroids
  • hormone-dependent gynecological diseases e.g. endometriosis or uterine fibroids
  • progestin can be treated by the combination of an estrogen receptor antagonist with a progestin.
  • the estrogen receptor antagonist to be used can be Fulvestrant, Raloxifene, Tamoxifene, Toremifene, Arzoxifene, CHF-4227, Lasofoxifene, LY-2066948, LY- 2120310, Ospemifene, Sivifene, TAS-108, Bazedoxifene acetate (1- ⁇ 4-[2-(Azepan-1- yl)ethoxy]benzyl ⁇ -2-(4-hydroxyphenyl)-3-methyl-1 H-indol-5-ol acetate), Afimoxifene, Enclomiphene, Fispemifene, Acolbifene, EM-652, Droloxifene, GW-7603, Centchromane, Levormeloxifene, ICI-164384, A-007, PSK-3471 , BL-3040, CH- 4893237, SRI-16158, SRI 16137, Rad-1901 , i
  • any compound can be used that interacts with the progesterone receptor and shows agonistic activity on biological endpoints of the natural hormone, progesterone (P4) ' s action.
  • the progestin used in this invention can be any progestin from the group of Desogestrel, Dienogest, Drospirenone, Gestodene, Levonorgestrel, Medroxyprogesterone, Medroxyprogesterone acetate, Megestrol acetate, Nomegestrol, Norethindrone acetate, Norethynodrel, Norethisterone, Norethisterone acetate, Norgestimate, Norgestrel, NorLevo, Progesterone, SH-329, SH-461 , SH- 543, Tibolone, Trimegestone, Cyproterone, Nestorone , Nomegestrol acetat, Org- 201745, Org-42669, Org-47241 , Org-32818, Tanaproget, AP-1081 , ETI-411 , FPMA, NSP-808, Eltanolone, Etonorgestrel, Tosagestin, TX
  • Combinations preferably comprises of drospirenon and apeledoxifene acetate (1- ⁇ 4- [2-(Azepan-1 -yl)ethoxy]benzyl ⁇ -2-(4-hydroxyphenyl)-3-methyl-1 H-indol-5-ol acetate), drospirenon and (+)-3-(4-Hydroxyphenyl)-2-[4-(2-piperidin-1 -ylethoxy)phenyl]-4- (trifluoromethyl)-2H-chromen-7-ol, drospirenon and a steroidal estrogen receptor antagonist, levonorgestrel and apeledoxifen, levonorgestrel and (+)-3-(4- Hydroxyphenyl ⁇ - ⁇ -piperidin-i-ylethoxyJphenyll ⁇ - ⁇ rifluoromethyl ⁇ H-chromen- 7-ol, levonorgestrel and a steroidal estrogen receptor antagonist, dienogest and apeledoxifen, die
  • This combination is able to
  • the combination shows a synergistic effect as it is superior to antiestrogens and SERMs that cause ovarian stimulation, to SERMs devoid of ovarian stimulation as described in WO2004/009086 because it harnesses the proven effects of the progestin on endometriotic lesions, and is superior to progestin-only treatments because of the anti-uterotrophic effect of the antiestrogen.
  • This combination can also be used to treat leiomyomata of the uterus.
  • the progestin and the estrogen receptor antagonist can be administered simultaneously, consecutively and partly simultaneaously and partly consecutively. It is also possible, that there are application free days between the administration of the progestin and the estrogen receptor antagonist.
  • a simultaneous application means an application of both active ingredients in a fixed combination as well as an application in separated dosage forms as long as both active ingredients are administered at the same day.
  • a consecutive administration means the administration of both active ingredients in different dosage forms and on different days.
  • the number of administration free days can be between 1 and 28, especially 7, 14 and 21.
  • Raloxifene, Bazedoxifene, and compounds A, B and C were tested in this assay and found to elevate estrogen levels by a factor of 2 or higher. This is indicative of ovarian stimulation, an effect which is unwanted.
  • Addition of the progestin gestoden alleviated the antiestrogen-evoked rise in estradiol levels.
  • To control for antiestrogenic activity in vivo uteri are prepared and weighed after necropsy (after 10 days). The experiment shows that the addition of gestodene alleviates the stimulation of E2 levels, but does not impair antiuterotrophic activity of the SERM or antiestrogen.
  • Table 2 Restoration of estrogen levels to baseline evoked by a 10-day-treatment with SERMs and Antiestrogens by a progestin.
  • Premenopausal women suffering from endometriosis are treated with a daily dose of 1-100 mg of (+)-3-(4-Hydroxyphenyl)-2-[4-(2-piperidin-1-ylethoxy)phenyl]-4- (trifluoromethyl)-2H-chromen-7-ol, and a daily dose of 2-4 mg Dienogest for three to six months.
  • women show amenorrhea and improved pelvic pain sensation.
  • Laparoscopic examination of endometriotic lesions will show atrophy/ shrinking of lesions.
  • Premenopausal women suffering from endometriosis are treated for several treatment cycles first for twentyfour days with a daily dose of 1 -100 mg of 11£-Fluoro- 17 ⁇ -methyl-7 ⁇ -5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentylestra-1 ,3,5(10)- triene-3,17£-diol (compound B), combined with a daily dose of 0,1-0,3 mg Levonorgestrel, followed by a 4 day interval without treatment.
  • This treatment cycle is repeated three to six times.
  • women show amenorrhea and improved pelvic pain sensation. Laparoscopic examination of endometriotic lesions will show atrophy/ shrinking of lesions.
  • Premenopausal women suffering from endometriosis are treated for several treatment cycles first for six days with a daily dose of between 1 and 100 mg of apeledoxifene acetate, combined with a daily dose of 0,05 mg gestodene, followed by a 5 day treatment with the same dose of apeledoxifene acetate combined with 0,07 mg Gestodene, followed by treatment for 10 days with the same dose of apeledoxifene acetate combined with 0,1 mg Gestodene.
  • This treatment cycle is repeated three to six times.
  • women show amenorrhea and improved pelvic pain sensation. Laparoscopic examination of endometriotic lesions will show atrophy/shrinking of lesions.
  • Fig. 1 Estrogen increase by Bazedoxifene, and alleviation by gestoden

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Reproductive Health (AREA)
  • Diabetes (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne l’administration conjointe d’un antagoniste du récepteur des œstrogènes et d’une progestine pour traiter des maladies gynécologiques résultant du développement anormal du tissu utérin, telles qu’une endométriose ou un léiomyome utérin.
PCT/EP2009/007801 2008-11-11 2009-10-31 Combinaison pharmaceutique synergique contenant un antagoniste du récepteur des oestrogènes et une progestine Ceased WO2010054758A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102008057230A DE102008057230A1 (de) 2008-11-11 2008-11-11 Synergistische pharmazeutische Kombination mit einem Estrogenrezeptorantagonisten und einem Progestin
DE102008057230.6 2008-11-11

Publications (1)

Publication Number Publication Date
WO2010054758A1 true WO2010054758A1 (fr) 2010-05-20

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PCT/EP2009/007801 Ceased WO2010054758A1 (fr) 2008-11-11 2009-10-31 Combinaison pharmaceutique synergique contenant un antagoniste du récepteur des oestrogènes et une progestine

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Country Link
AR (1) AR074297A1 (fr)
DE (1) DE102008057230A1 (fr)
PA (1) PA8847901A1 (fr)
TW (1) TW201022251A (fr)
UY (1) UY32235A (fr)
WO (1) WO2010054758A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011029782A1 (fr) * 2009-09-11 2011-03-17 Bayer Schering Pharma Aktiengesellschaft Thiohydantoïnes à substitution hétéroarylméthyle, en tant que médicaments anticancer
WO2013131105A1 (fr) * 2012-03-02 2013-09-06 Sri International Activité synergique anti-prolifération du tas-108 associé à des inhibiteurs du mtor contre des cellules cancéreuses
CN104370796A (zh) * 2014-11-21 2015-02-25 扬子江药业集团有限公司 一种醋酸巴多昔芬多晶型b的制备方法
WO2017010515A1 (fr) * 2015-07-14 2017-01-19 ノーベルファーマ株式会社 Agoniste partiel du récepteur bêta aux œstrogènes possédant une activité inhibitrice du récepteur alpha aux œstrogènes, et agent thérapeutique contre les troubles gynécologiques utilisant ces derniers
JP2017522375A (ja) * 2014-07-02 2017-08-10 ザビエル・ユニバーシティ・オブ・ルイジアナＸａｖｉｅｒ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｌｏｕｉｓｉａｎａ 少なくとも１つのフェノール（または芳香族ヒドロキシル）基を含有する薬物分子に関する増大された生物学的利用能及びより低い必要用量のためのホウ素系プロドラッグ戦略

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WO1999024027A2 (fr) * 1997-11-06 1999-05-20 American Home Products Corporation Contraceptifs oraux a base d'anti-oestrogenes associes a un progestatif
WO2000007599A1 (fr) * 1998-08-07 2000-02-17 William Leroy Heinrichs Prevention de signes ou symptomes d'endometriose
GB2352716A (en) * 1999-07-29 2001-02-07 Lilly Co Eli Crystalline form of arzoxifene
WO2001068634A1 (fr) * 2000-03-15 2001-09-20 Schering Aktiengesellschaft 4-fluoroalkyl-2h-benzopyrannes a activite anti-oeoestrogenique
WO2003045972A1 (fr) * 2001-11-27 2003-06-05 Schering Aktiengesellschaft 17α-ALKYL-17β-OXY-ESTRATRIENES ET INTERMEDIAIRES NECESSAIRES A LEUR PRODUCTION, UTILISATION DE 17α-ALKYL-17β-OXY-ESTRATRIENES POUR PRODUIRE DES MEDICAMENTS ET PREPARATIONS PHARMACEUTIQUES
WO2003063859A1 (fr) * 2002-01-14 2003-08-07 Nordic Bioscience A/S Suppression de la degradation du cartilage a l'aide du recepteur des oestrogenes
WO2003099292A1 (fr) * 2002-05-24 2003-12-04 Akzo Nobel N.V. Traitement des symptomes post-menopausiques chez des patientes atteintes du cancer du sein, ce traitement comprenant la tibolone et un oestrogene de confection
WO2004009086A1 (fr) * 2002-07-22 2004-01-29 Eli Lilly And Company Modulateurs selectifs des recepteurs oestrogeniques contenant un groupe phenylsulfonyle
WO2007144151A1 (fr) * 2006-06-13 2007-12-21 Bayer Schering Pharma Aktiengesellschaft Schéma posologique décroissant d'œstrogène pour des femmes recevant une thérapie par œstrogène

Patent Citations (10)

* Cited by examiner, † Cited by third party
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WO1999024027A2 (fr) * 1997-11-06 1999-05-20 American Home Products Corporation Contraceptifs oraux a base d'anti-oestrogenes associes a un progestatif
WO2000007599A1 (fr) * 1998-08-07 2000-02-17 William Leroy Heinrichs Prevention de signes ou symptomes d'endometriose
GB2352716A (en) * 1999-07-29 2001-02-07 Lilly Co Eli Crystalline form of arzoxifene
WO2001068634A1 (fr) * 2000-03-15 2001-09-20 Schering Aktiengesellschaft 4-fluoroalkyl-2h-benzopyrannes a activite anti-oeoestrogenique
WO2003045972A1 (fr) * 2001-11-27 2003-06-05 Schering Aktiengesellschaft 17α-ALKYL-17β-OXY-ESTRATRIENES ET INTERMEDIAIRES NECESSAIRES A LEUR PRODUCTION, UTILISATION DE 17α-ALKYL-17β-OXY-ESTRATRIENES POUR PRODUIRE DES MEDICAMENTS ET PREPARATIONS PHARMACEUTIQUES
WO2003063859A1 (fr) * 2002-01-14 2003-08-07 Nordic Bioscience A/S Suppression de la degradation du cartilage a l'aide du recepteur des oestrogenes
WO2003099292A1 (fr) * 2002-05-24 2003-12-04 Akzo Nobel N.V. Traitement des symptomes post-menopausiques chez des patientes atteintes du cancer du sein, ce traitement comprenant la tibolone et un oestrogene de confection
WO2004009086A1 (fr) * 2002-07-22 2004-01-29 Eli Lilly And Company Modulateurs selectifs des recepteurs oestrogeniques contenant un groupe phenylsulfonyle
WO2007144151A1 (fr) * 2006-06-13 2007-12-21 Bayer Schering Pharma Aktiengesellschaft Schéma posologique décroissant d'œstrogène pour des femmes recevant une thérapie par œstrogène

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PALOMBA STEFANO ET AL: "Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women", FERTILITY AND STERILITY, vol. 76, no. 1, July 2001 (2001-07-01), pages 38 - 43, XP002567171, ISSN: 0015-0282 *
PALOMBA STEFANO ET AL: "Raloxifene administration in premenopausal women with uterine leiomyomas: A pilot study", JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM, vol. 87, no. 8, August 2002 (2002-08-01), pages 3603 - 3608, XP002567170, ISSN: 0021-972X *
SPRITZER P M ET AL: "Effects of norethisterone acetate and tamoxifen on serum prolactin levels, uterine growth and on the presence of uterine immunoreactive prolactin in estradiol-treated ovariectomized rats", BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH, vol. 28, no. 1, 1995, pages 125 - 130, XP009129124, ISSN: 0100-879X *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011029782A1 (fr) * 2009-09-11 2011-03-17 Bayer Schering Pharma Aktiengesellschaft Thiohydantoïnes à substitution hétéroarylméthyle, en tant que médicaments anticancer
WO2013131105A1 (fr) * 2012-03-02 2013-09-06 Sri International Activité synergique anti-prolifération du tas-108 associé à des inhibiteurs du mtor contre des cellules cancéreuses
JP2017522375A (ja) * 2014-07-02 2017-08-10 ザビエル・ユニバーシティ・オブ・ルイジアナＸａｖｉｅｒ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｌｏｕｉｓｉａｎａ 少なくとも１つのフェノール（または芳香族ヒドロキシル）基を含有する薬物分子に関する増大された生物学的利用能及びより低い必要用量のためのホウ素系プロドラッグ戦略
CN104370796A (zh) * 2014-11-21 2015-02-25 扬子江药业集团有限公司 一种醋酸巴多昔芬多晶型b的制备方法
CN104370796B (zh) * 2014-11-21 2016-09-14 扬子江药业集团有限公司 一种醋酸巴多昔芬多晶型b的制备方法
WO2017010515A1 (fr) * 2015-07-14 2017-01-19 ノーベルファーマ株式会社 Agoniste partiel du récepteur bêta aux œstrogènes possédant une activité inhibitrice du récepteur alpha aux œstrogènes, et agent thérapeutique contre les troubles gynécologiques utilisant ces derniers
US10369159B2 (en) 2015-07-14 2019-08-06 Nobelpharma Co., Ltd. Estrogen receptor β partial agonist having estrogen receptor α inhibitory effect, and gynecological disease therapeutic agent using same
AU2016294185B2 (en) * 2015-07-14 2021-10-14 National University Corporation Tottori University Estrogen receptor β partial agonist having estrogen receptor α inhibitory effect, and therapeutic agent for gynecological disorders using same

Also Published As

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PA8847901A1 (es) 2010-06-28
DE102008057230A1 (de) 2010-05-12
TW201022251A (en) 2010-06-16
UY32235A (es) 2010-06-30
AR074297A1 (es) 2011-01-05

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