JP6433785B2 - トランス−クロミフェン代謝物およびその使用 - Google Patents
トランス−クロミフェン代謝物およびその使用 Download PDFInfo
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- JP6433785B2 JP6433785B2 JP2014524097A JP2014524097A JP6433785B2 JP 6433785 B2 JP6433785 B2 JP 6433785B2 JP 2014524097 A JP2014524097 A JP 2014524097A JP 2014524097 A JP2014524097 A JP 2014524097A JP 6433785 B2 JP6433785 B2 JP 6433785B2
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- clomiphene
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- metabolite
- administration
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Emergency Medicine (AREA)
- Neurology (AREA)
- Pregnancy & Childbirth (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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| PCT/US2012/049451 WO2013020017A1 (en) | 2011-08-04 | 2012-08-03 | Trans-clomiphene metabolites and uses thereof |
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| US20120284764A1 (en) * | 2011-05-05 | 2012-11-08 | Keith Ball | Method and system for requesting services by a media device |
| UA113291C2 (xx) | 2011-08-04 | 2017-01-10 | Метаболіти транскломіфену і їх застосування | |
| CA2872644A1 (en) | 2012-05-31 | 2013-12-05 | Allergan Pharmaceuticals International Limited | Formulations and methods for vaginal delivery of antiprogestins |
| HK1216502A1 (zh) * | 2012-11-02 | 2016-11-18 | Repros Therapeutics Inc. | 用於癌症治療的反式-克羅米芬 |
| US9545411B2 (en) | 2012-11-02 | 2017-01-17 | Repros Therapeutics Inc. | Methods and compositions for treating progesterone-dependent conditions |
| WO2017123577A1 (en) * | 2016-01-12 | 2017-07-20 | Repros Therapeutics Inc. | Trans-clomiphene and progesterone receptor antagonist combination therapy for treating hormone-dependent conditions |
| RU2018133603A (ru) * | 2016-02-25 | 2020-03-25 | Эспен Парк Фармасьютикалз, Инк. | Пероральная дозированная форма двух изомеров кломифена и способ ее использования для лечения вторичного гипогонадизма и минимизации побочных эффектов лекарственного препарата у мужчин |
| EP3368506B1 (en) | 2016-04-22 | 2023-09-06 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Process for the preparation of enclomiphene citrate having needle shaped crystal habit. |
Family Cites Families (69)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2914563A (en) | 1957-08-06 | 1959-11-24 | Wm S Merrell Co | Therapeutic composition |
| IT951631B (it) | 1971-03-18 | 1973-07-10 | Richardson Merrell Spa | Composti utili per la separazione di isomeri ottici geometrici e strutturali e relativo procedimen to di sintesi |
| US4061733A (en) | 1976-10-15 | 1977-12-06 | Narayan Vishwanath Gunjikar | Veterinary compositions for inducing estrus in animals and method |
| US4729999A (en) | 1984-10-12 | 1988-03-08 | Bcm Technologies | Antiestrogen therapy for symptoms of estrogen deficiency |
| ATE36312T1 (de) | 1985-06-08 | 1988-08-15 | Asta Pharma Ag | Neue derivate des 1,1,2,2-tetramethyl-1,2-bis-(2fluor-4-hydroxyphenyl)-ethans. |
| US4820736A (en) * | 1987-03-20 | 1989-04-11 | Yale University | Use of clomiphene to predict fertility in a human female |
| GB8926171D0 (en) | 1989-11-20 | 1990-01-10 | Applied Research Systems | Treatment of infertility |
| JPH04312522A (ja) | 1991-04-08 | 1992-11-04 | Yoshiaki Kawashima | 徐放性錠剤の製造方法 |
| US5681585A (en) | 1991-12-24 | 1997-10-28 | Euro-Celtique, S.A. | Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer |
| US5580578A (en) | 1992-01-27 | 1996-12-03 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
| FI951193L (fi) | 1992-09-15 | 1995-03-14 | Merrell Pharma Inc | Ei-metabolisoituvat klomifeenianalogit tamoksifeeniresistenttien kasvainten hoitamiseksi |
| US5776923A (en) | 1993-01-19 | 1998-07-07 | Endorecherche, Inc. | Method of treating or preventing osteoporosis by adminstering dehydropiandrosterone |
| GB9405304D0 (en) | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
| EP0802787A4 (en) | 1994-06-17 | 1998-09-02 | Univ Nebraska | VECTOR FOR DELIVERY OF BIO-EFFECTIVE SUBSTANCES WITH GELLIFICATION -i (IN SITU) AND METHOD OF USE |
| DE4435368A1 (de) | 1994-09-22 | 1996-03-28 | Schering Ag | Verwendung von Aromatasehemmern zur Herstellung eines Arzneimittels zur Behandlung eines relativen Androgenmangels beim Mann |
| DE69617245T2 (de) | 1995-08-17 | 2002-07-25 | Csir, Pretoria | Produkte mit gesteuerter freisetzung |
| US5773031A (en) | 1996-02-27 | 1998-06-30 | L. Perrigo Company | Acetaminophen sustained-release formulation |
| IL120262A (en) | 1996-02-28 | 2001-01-28 | Pfizer | Droloxifene and derivatives thereof for use in increasing serum testosterone levels |
| CA2269806C (en) | 1996-10-28 | 2006-01-24 | Bernhard H. Van Lengerich | Embedding and encapsulation of controlled release particles |
| BR9809064A (pt) | 1997-04-03 | 2002-01-02 | Guilford Pharm Inc | Polìmeros biodegradáveis de poliéster de tereftalato-polifosfato, composições, artigos e métodos para fazer e usar os mesmos |
| US6653297B1 (en) | 1997-07-03 | 2003-11-25 | Medical College Of Hampton Roads | Control of selective estrogen receptor modulators |
| US6342250B1 (en) | 1997-09-25 | 2002-01-29 | Gel-Del Technologies, Inc. | Drug delivery devices comprising biodegradable protein for the controlled release of pharmacologically active agents and method of making the drug delivery devices |
| US20040176470A1 (en) | 1998-05-07 | 2004-09-09 | Steiner Mitchell S. | Method for treatment and chemoprevention of prostate cancer |
| US6413533B1 (en) | 1998-05-07 | 2002-07-02 | The University Of Tennessee Research Corporation | Method for chemoprevention of prostate cancer |
| TR200100309T2 (tr) | 1998-07-30 | 2001-05-21 | Stoller Enterprises, Inc | Bitkilerin salisilik asit ve organik aminler ile muamelesi. |
| WO2000007996A2 (en) | 1998-08-07 | 2000-02-17 | Chiron Corporation | Pyrazoles as estrogen receptor modulators |
| US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
| US6583129B1 (en) | 1999-06-11 | 2003-06-24 | Watson Pharmaceuticals, Inc. | Administration of non-oral androgenic steroids to women |
| CA2321321A1 (en) | 1999-09-30 | 2001-03-30 | Isotis B.V. | Polymers loaded with bioactive agents |
| US6258802B1 (en) | 1999-10-06 | 2001-07-10 | Medical College Of Hampton Roads | Corticoid therapy |
| AU3104301A (en) | 2000-01-20 | 2001-07-31 | Noven Pharmaceuticals, Inc. | Compositions and methods to effect the release profile in the transdermal administration of active agents |
| BR0108107A (pt) | 2000-01-28 | 2003-03-11 | Endorech Inc | Moduladores seletivos dos receptores de estrogênio em combinação com estrogênios; kits e composições farmacêuticas para praticar tal combinação; bem como a administração da referida combinação |
| WO2001091744A1 (en) | 2000-05-26 | 2001-12-06 | Harry Fisch | Methods of treating androgen deficiency in men using selective antiestrogens |
| US7067557B2 (en) | 2000-05-26 | 2006-06-27 | Harry Fisch | Methods of treating androgen deficiency in men using selective antiestrogens |
| JP2004507465A (ja) | 2000-08-11 | 2004-03-11 | ワイス | エストロゲン受容体陽性癌腫の治療方法 |
| US6503894B1 (en) | 2000-08-30 | 2003-01-07 | Unimed Pharmaceuticals, Inc. | Pharmaceutical composition and method for treating hypogonadism |
| US20040192598A1 (en) | 2000-10-11 | 2004-09-30 | Laura Kragie | Composition and method of alleviating adverse side effects and/or enhancing efficacy of agents that inhibit aromatase |
| WO2002055020A2 (en) | 2000-12-11 | 2002-07-18 | Testocreme Llc | Topical testosterone formulations and associated methods |
| US7173064B2 (en) | 2001-07-09 | 2007-02-06 | Repros Therapeutics Inc. | Methods and compositions with trans-clomiphene for treating wasting and lipodystrophy |
| AU2002318225B2 (en) | 2001-07-09 | 2007-12-13 | Repros Therapeutics Inc. | Methods and materials for the treatment of testosterone deficiency in men |
| US6645974B2 (en) | 2001-07-31 | 2003-11-11 | Merck & Co., Inc. | Androgen receptor modulators and methods for use thereof |
| EP1429779A2 (en) | 2001-09-21 | 2004-06-23 | Merck & Co., Inc. | Androstanes as androgen receptor modulators |
| US20060269611A1 (en) | 2001-11-29 | 2006-11-30 | Steiner Mitchell S | Prevention and treatment of androgen-deprivation induced osteoporosis |
| US7105679B2 (en) | 2001-12-19 | 2006-09-12 | Kanojia Ramesh M | Heteroatom containing tetracyclic derivatives as selective estrogen receptor modulators |
| US7135575B2 (en) | 2003-03-03 | 2006-11-14 | Array Biopharma, Inc. | P38 inhibitors and methods of use thereof |
| US20050042268A1 (en) | 2003-07-16 | 2005-02-24 | Chaim Aschkenasy | Pharmaceutical composition and method for transdermal drug delivery |
| US20080242726A1 (en) | 2004-07-14 | 2008-10-02 | Podolski Joseph S | Trans-Clomiphene for the Treatment of Benign Prostate Hypertrophy, Porstate Cancer, Hypogonadism Elevated Triglycerides and High Cholesterol |
| US20060293294A1 (en) | 2004-09-03 | 2006-12-28 | Hormos Medical Corporation | Method for treatment or prevention of androgen deficiency |
| CN101115709B (zh) * | 2004-12-13 | 2011-04-13 | 小野药品工业株式会社 | 氨基羧酸衍生物及其医药用途 |
| NZ556499A (en) * | 2005-02-04 | 2011-02-25 | Repros Therapeutics Inc | Methods and materials with trans-clomiphene for the treatment of male infertility |
| EP1853298A2 (en) | 2005-02-11 | 2007-11-14 | Regeneron Pharmaceuticals, Inc. | Therapeutic combination of a vegf antagonist (vegf trap) and an anti-hypertensive agent |
| BRPI0609389A2 (pt) * | 2005-03-22 | 2010-03-30 | Repros Therapeutics Inc | tablete, composição e respectivos usos |
| JP2008543855A (ja) | 2005-06-13 | 2008-12-04 | ライジェル ファーマシューティカルズ， インコーポレイテッド | 変形性骨疾患を処置するための方法および組成物 |
| CA2617905A1 (en) | 2005-08-05 | 2007-02-15 | Repros Therapeutics Inc. | Methods and compositions for treating female infertility using clomiphene |
| US7613937B2 (en) | 2005-10-31 | 2009-11-03 | Hewlett-Packard Development Company, L.P. | Method and apparatus for utilizing a microcontroller to provide an automatic order and timing power and reset sequencer |
| EP1991241A4 (en) | 2006-02-23 | 2009-07-08 | Iomedix Sleep Internat Srl | COMPOSITIONS AND METHODS FOR INTRODUCING AND MAINTAINING HIGH-QUALITY SLEEPING |
| EP1829534A1 (en) | 2006-03-02 | 2007-09-05 | Laboratorios Del Dr. Esteve, S.A. | Use of compounds binding to the sigma receptor for the treatment of metabolic syndrome |
| WO2008005469A2 (en) | 2006-06-30 | 2008-01-10 | Schering Corporation | Igfbp2 biomarker |
| ES2381175T3 (es) | 2007-06-26 | 2012-05-23 | Media Patents, S. L. | Dispositivo para gestionar grupos multidifusión |
| US8106037B2 (en) | 2007-08-03 | 2012-01-31 | The Brigham And Women's Hospital, Inc. | Identification and treatment of estrogen responsive prostate tumors |
| BRPI0818637A2 (pt) | 2007-10-16 | 2015-04-07 | Repros Therapeutics Inc | Métodos de tratamento de sintoma da síndrome metabólica, de glicose em jejum prejudicada, da síndrome metabólica e de redução de níveis de glicose em, jejum em sujeito com hipogonadismo hipogonadotrófico secundário ou idiopático |
| US20100111901A1 (en) | 2008-11-03 | 2010-05-06 | Auspex Pharmaceuticals, Inc. | Triazole inhibitors of aromatase |
| TW201500041A (zh) | 2008-11-07 | 2015-01-01 | Repros Therapeutics Inc | 用於代謝症候群與第２型糖尿病的反式氯米芬 |
| US20100144687A1 (en) | 2008-12-05 | 2010-06-10 | Glaser Rebecca L | Pharmaceutical compositions containing testosterone and an aromatase inhibitor |
| UA113291C2 (xx) | 2011-08-04 | 2017-01-10 | Метаболіти транскломіфену і їх застосування | |
| WO2013020215A1 (en) | 2011-08-09 | 2013-02-14 | Adams Kenneth W | Use of aromatase inhibitor or estrogen blocker for increasing spermatogenesis or testosterone levels in males |
| JP2015508825A (ja) | 2012-02-29 | 2015-03-23 | レプロス セラピューティクス インコーポレイティド | アンドロゲン欠乏症を治療するための併用療法 |
| KR20150041793A (ko) | 2012-08-21 | 2015-04-17 | 레프로스 쎄라피우틱스 아이엔씨. | 트랜스-클로미펜 제형 및 그의 용도 |
| CN103351304B (zh) | 2013-07-01 | 2015-12-09 | 暨明医药科技（苏州）有限公司 | 一种克罗米芬的合成方法 |
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| MY170718A (en) | 2019-08-27 |
| CN103702975A (zh) | 2014-04-02 |
| HK1196349A1 (zh) | 2014-12-12 |
| BR112014000908A2 (pt) | 2017-02-21 |
| UA113291C2 (xx) | 2017-01-10 |
| EP3351527A1 (en) | 2018-07-25 |
| CN103702975B (zh) | 2016-03-16 |
| WO2013020017A1 (en) | 2013-02-07 |
| MX2014000825A (es) | 2014-02-27 |
| EP2744777A1 (en) | 2014-06-25 |
| ZA201400406B (en) | 2014-11-26 |
| SG10201606425WA (en) | 2016-09-29 |
| US9981906B2 (en) | 2018-05-29 |
| CA2841572A1 (en) | 2013-02-07 |
| MX355316B (es) | 2018-04-16 |
| CL2014000268A1 (es) | 2014-11-14 |
| PH12014500144A1 (en) | 2014-02-24 |
| CO6862154A2 (es) | 2014-02-10 |
| AU2017204171A1 (en) | 2017-07-13 |
| JP2014529584A (ja) | 2014-11-13 |
| AU2012289964A1 (en) | 2014-01-30 |
| KR20140054110A (ko) | 2014-05-08 |
| MY191802A (en) | 2022-07-15 |
| CR20140124A (es) | 2014-05-13 |
| IL230287B (en) | 2019-07-31 |
| AU2012289964B2 (en) | 2017-03-23 |
| NZ621892A (en) | 2016-03-31 |
| JP2019023210A (ja) | 2019-02-14 |
| CA2841572C (en) | 2020-10-13 |
| NI201400008A (es) | 2015-12-10 |
| EA201490416A1 (ru) | 2014-11-28 |
| US20140163114A1 (en) | 2014-06-12 |
| IL230287A0 (en) | 2014-03-06 |
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