WO1997025035A1 - Utilisation de 3,4-diphenylchromannes dans la fabrication d'une composition pharmaceutique servant au traitement ou a la prophylaxie des symptones menopausiques - Google Patents

Utilisation de 3,4-diphenylchromannes dans la fabrication d'une composition pharmaceutique servant au traitement ou a la prophylaxie des symptones menopausiques Download PDF

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Publication number
WO1997025035A1
WO1997025035A1 PCT/DK1997/000008 DK9700008W WO9725035A1 WO 1997025035 A1 WO1997025035 A1 WO 1997025035A1 DK 9700008 W DK9700008 W DK 9700008W WO 9725035 A1 WO9725035 A1 WO 9725035A1
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Prior art keywords
use according
com
phenyl
compound
treatment
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Ceased
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PCT/DK1997/000008
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English (en)
Inventor
Michael Shalmi
Niels Korsgaard
Birgitte Hjort Guldhammer
James Robertson Piggott
Virender Mohan Labroo
Steven Bain
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Novo Nordisk AS
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Novo Nordisk AS
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Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Priority to EP97900200A priority Critical patent/EP0873120A1/fr
Priority to AU13672/97A priority patent/AU1367297A/en
Priority to IL12488297A priority patent/IL124882A0/xx
Priority to BR9706967A priority patent/BR9706967A/pt
Priority to HU9902683A priority patent/HUP9902683A3/hu
Priority to JP9524768A priority patent/JP2000506505A/ja
Publication of WO1997025035A1 publication Critical patent/WO1997025035A1/fr
Priority to NO983178A priority patent/NO983178L/no
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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders

Definitions

  • the present invention relates to the use of compounds of the general formula I for the prevention and treatment of menopausal symptoms.
  • the present inventi ⁇ on also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.
  • the menopause is defined as the final episode of menstrual bleeding in women. However, the term is used commonly to refer to the period of the female climac- teric that encompasses the transitional period between the reproductive years up to and beyond the last episode of menstrual bleeding. This period is also referred to as the peri-menopause or the climacterium. During this period there is a gra ⁇ dual but progressive loss of ovarian function and a variety of endocrine, somatic and psycological changes. The median age of the women at the time of cessati- on of menstrual bleeding is 50 to 51 years. Since the life expectancy of women in developed countries is now close to 80 years, approximately one-third of a woman's life-span occurs after cessation of reproductive function.
  • the symptoms associated with declining estrogen levels in the perimenopause include hot flashes and sweats, atrophic vaginitis, headache, dizziness, joint pain, sleeplessness, apathy, lassitude, muscular weakness, palpitations and psy ⁇ chological symptoms such as changes in mood, depression, memory and concen ⁇ tration deficits, irritability and problems related to sexual functioning. All of these symptoms are a direct consequence of the declining estrogen production.
  • the treatment of these disorders involves different regimens of estro ⁇ gen administration with or without concomitant progestin administration. Estro ⁇ gen alone and in different combinations is often associated with unacceptable side effects.
  • progestin are often poorly tolerated causing depressi- on and may even in some tissues negate the positive results of estrogen.
  • the hormone replacement theraphy often causes unpleasant effects such as water retention, frequently weight gain and prolonged therapy is associated with an in ⁇ creased risk of endometrial cancer.
  • a new compound which ameliorates the symptoms of the menopause, but which is safe and cau- ses less side effects, and preferably brings the woman into a stable post- menopausal state in a reduced period of time than known compounds.
  • Centchroman is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et al., U.S. Patent Specification No. 4,447,622; Singh et al., Acta Endocrinal ( Copenh ) 123 (1992), 444 - 450; Grubb, £un £ ⁇ i ⁇ £bsl ⁇ l Gyo ⁇ cfii 3. ( 1 991 ), 491 - 495; San- karan et al., Contraception 9 ( 1 974), 279 - 289; Indian Patent Specification No. 1 29187).
  • Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 43 (1 989), 781 - 783. Recently, centchroman as a racemate has been found as a potent choleste ⁇ rol lowering pharmaceutical expressed by a significant decrease of the serum concentrations (S.D. Bain et al., J Min Eon fi£S 2 ( 1 994), S 394).
  • U.S. patent 5,453,442 describes methods of lowering serum cholesterol and in- hibiting smoother muscle cell proliferation in humans and inhibiting uterine fibroid disease and endometriosis in women by administering compounds of formula I as shown therein.
  • US patent 5,280,040 describes methods and phar ⁇ maceutical compositions for reducing bone loss using 3,4-diaryl chromans and their pharmaceutically acceptable salts. There is no disclosure in the patents of using the compounds to treat or prevent menopausal symptoms.
  • One object of the present invention is to provide compounds which can effecti ⁇ vely be used in the treatment or prophylaxis of menopausal symptoms.
  • the present invention is based in part on the discovery that a representative 3,4- diarylchroman, centchroman (3,4-trans-2,2-dimethyl-3-phenyl-4-[p-(beta- pyrrolidinoethox ⁇ )phenyl]-7-methoxychroman) is a partial estrogen antago- nist/agonist and elicits similar actions as estrogen in a range of animal models and is useful in the treatment of climacteric symptoms and complaints without having the adverse effects associated with estrogen treatment.
  • compounds of formula I or their pharmaceutically acceptable salts are used for prevention and treatment of menopausal symptoms in a patient.
  • R 1 , R 4 and R 5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, C, .6 alkyl, C ⁇ alkoxy or (tertiary amino)(C 1 . 6 alkoxy); and R 2 and
  • R 3 are individually hydrogen or a C 1 -6 alkyl.
  • C ⁇ alkyl includes straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec- amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like.
  • C, ⁇ al ⁇ koxy includes straight and branched chain alkoxy radicals containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-amyloxy, sec-amyloxy, n-hexyloxy, 2-ethylbutoxy, 2,3- dimethylbutoxy and the like.
  • Hydrogen includes chloro, fluoro, bromo and iodo.
  • (tertiary amino)(C,. 6 alkoxy) is a C,. 6 alkoxy group which is substituted by a tertiary amino radical.
  • the tertiary amino radical may be a N,N- dialkylamine such as a N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino and N,N-dibutylamino or a polymethyleneimine, e.g., piperidine, pyrrolidine, N- methylpiperazine or morpholine.
  • Preferred compounds include those in which R ' is C,. 6 alkoxy; R 2 and R 3 are C,. 6 alkyl, especially methyl; R 4 is hydrogen; and R 5 is (tertiary amino)(C 1 . 6 alkoxy) of the polymethyleneimine type.
  • R 1 is in the 7-position and is C ⁇ alkoxy, particu ⁇ larly methoxy; each of R 2 and R 3 is methyl, R 4 is hydrogen, and R 5 is in the 4- position and is a (tertiary amino)(C,. 6 alkoxy) radical such as 2-(pyrrolidin-1 - yDethoxy with formula II
  • a particularly preferred compound for use within the present invention is cen ⁇ tchroman having the formula IV
  • 3,4-diarylchromans are prepared according to known methods, such as those di ⁇ sclosed in U.S. Patent Specification No. 3,340,276 to Carney et al., U.S. Patent Specification No. 3,822,287 to Bolger, and Ray et al., Med Chem 12 (1 976), 276 - 279, the contents of which are incorporated herein by reference.
  • Conver ⁇ sion of the cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrangement is disclosed in U.S. Patent Specification No. 3,822,287.
  • the optically active d- and l-enantiomers may be prepared as disclo ⁇ sed by Salman et al.
  • 3,4-diarylchromans of formula I may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, in- eluding salts of organic acids and mineral acids.
  • salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic a- cid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like.
  • Suitable inorga ⁇ nic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like.
  • the acid addition salts may be obtained as the di ⁇ rect products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isola ⁇ ted by evaporating the solvent or otherwise separating the salt and solvent.
  • 3,4-diarylchromans of formula I and their salts are useful within human and vete ⁇ rinary medicine, for example, in the treatment of patients suffering from meno ⁇ pausal symptoms.
  • 3,4-diarylchromans of formula I and their pharmaceutically acceptable salts are formulated with a phar ⁇ maceutically acceptable carrier to provide a medicament for parenteral, oral, na- sal, rectal, subdermal or intradermal or transdermal administration according to conventional methods.
  • Formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc.
  • the active compound of formula I is prepa- red in a form suitable for oral administration, such as a tablet or capsule.
  • a pharmaceutically acceptable salt of the compound of formula I is com ⁇ bined with a carrier and moulded into a tablet.
  • Suitable carriers in this regard in ⁇ clude starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate and the like.
  • Such compositions may further include one or more auxiliary sub- stances, such as wetting agents, emulsifiers, preservatives, stabilizers, colouring additives, etc.
  • compositions containing a compound of formula I may be admini ⁇ stered one or more times per day or week.
  • An effective amount of such a phar- maceutical composition is the amount that provides a clinically significant effect against menopausal symptoms. Such amounts will depend, in part, on the parti ⁇ cular condition to be treated, age, weight, and general health of the patient, and other factors evident to those skilled in the art.
  • a typical daily dose will contain a nontoxic dosage range of from about 0.001 to about 75 mg/kg patient per day of a compound of the present invention.
  • compositions containing a compound of formula I may be administered in unit dosage form one or more times per day or week.
  • they may be provided as controlled release formulations suitable for dermal implantation.
  • Implants are formulated to provide release of active com ⁇ pound over the desired period of time, which can be up to several years.
  • Con ⁇ trolled-release formulations are disclosed by, for example, Sanders et al., J Pharm Sci 73 ( 1 964), 1 294 - 1 297, 1 984; U.S: Patent Specification No. 4,489,056; and U.S. Patent Specification No. 4,210,644, which are incorpora- ted herein by reference.
  • the following examples are offered by way of illustration, not limitation.
  • Examples of preferred compounds of formula I are centchroman as a racemic mixture and as isolated l-centchroman and d-centchroman enantiomers. Further- more, 3,4-trans-2,2-dimethyl-3-phenyl-4- ⁇ 4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl]-7- hydroxychroman is a preferred compound. The more preferred compound is isola ⁇ ted l-centchroman (l-3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 - yl)ethoxy)phenyl]-7-methoxychroman).
  • Examples of pharmaceutically acceptable acid addition salts are salts with non- toxic acids, either inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid, or organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid.
  • inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid
  • organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid.
  • a compound of the invention is given in the amount of 0,001 to 75 mg/kg pa ⁇ tient per day and the frequency of vasomotor symptoms are closely monitored together with the variables laid down in the Green Scale or Kupperman Indeks monitoring systems. The dosing of the compound of the invention continues for a period of 4 weeks.
  • This test is ran as Test 1 , except the dosing period is for a period of 6 months.
  • Activity defined as either total cessation of one or more sequellae of the patient, or reduced severity or occurrence thereof, or a more rapid advancement to men ⁇ opausal state, in any of the above assays indicates that the compounds of the invention are useful in the treatment of menopausal symptoms.

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

Abstract

Cette invention se rapporte à de nouvelles utilisations de composés représentés par la formule générale (I), où R?1, R4 et R5¿ représentent séparément hydrogène, hydroxy, halogène, trifluorométhyle, C¿1-6? alkyle, C1-6 alkoxy ou (C1-6 alkoxy)(amino tertiaire); et R?2 et R3¿ représentent séparément hydrogène ou C¿1-6? alkyle; ou d'un sel pharmaceutiquement acceptable de ces composés, combinés à un excipient pharmaceutiquement acceptable, dans la fabrication d'une composition pharmaceutique servant au traitement ou à la prophylaxie des symptômes ménopausiques.
PCT/DK1997/000008 1996-01-11 1997-01-09 Utilisation de 3,4-diphenylchromannes dans la fabrication d'une composition pharmaceutique servant au traitement ou a la prophylaxie des symptones menopausiques Ceased WO1997025035A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP97900200A EP0873120A1 (fr) 1996-01-11 1997-01-09 Utilisation de 3,4-diphenylchromannes dans la fabrication d'une composition pharmaceutique servant au traitement ou a la prophylaxie des symptones menopausiques
AU13672/97A AU1367297A (en) 1996-01-11 1997-01-09 Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical comp osition for the treatment or prophylaxis of menopausal symptoms
IL12488297A IL124882A0 (en) 1996-01-11 1997-01-09 Use of 3, 4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of menopausal symptoms
BR9706967A BR9706967A (pt) 1996-01-11 1997-01-09 Utilização de compostos e processo para tratamento e profilaxia de sintomas relacionados à menopausa
HU9902683A HUP9902683A3 (en) 1996-01-11 1997-01-09 Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of menopausal symptoms
JP9524768A JP2000506505A (ja) 1996-01-11 1997-01-09 閉経期の症状の治療又は予防のための医薬組成物の製造のための３，４―ジフェニルクロマンの使用
NO983178A NO983178L (no) 1996-01-11 1998-07-10 Anvendelse av 3,4-difenylkromaner til fremstilling av et farmasaytisk preparat for behandling eller profylakse av menopausesymptomer

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US983496P 1996-01-11 1996-01-11
US67826196A 1996-07-11 1996-07-11
US08/678,261 1996-07-11
US60/009,834 1996-07-11

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WO1997025035A1 true WO1997025035A1 (fr) 1997-07-17

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PCT/DK1997/000008 Ceased WO1997025035A1 (fr) 1996-01-11 1997-01-09 Utilisation de 3,4-diphenylchromannes dans la fabrication d'une composition pharmaceutique servant au traitement ou a la prophylaxie des symptones menopausiques

Country Status (12)

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EP (1) EP0873120A1 (fr)
JP (1) JP2000506505A (fr)
KR (1) KR19990077156A (fr)
AU (1) AU1367297A (fr)
BR (1) BR9706967A (fr)
CA (1) CA2241623A1 (fr)
CZ (1) CZ217298A3 (fr)
HU (1) HUP9902683A3 (fr)
IL (1) IL124882A0 (fr)
NO (1) NO983178L (fr)
PL (1) PL327831A1 (fr)
WO (1) WO1997025035A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6465445B1 (en) 1998-06-11 2002-10-15 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
JP2003519219A (ja) * 1999-12-30 2003-06-17 シグナル ファーマシューティカルズ， インコーポレイテッド エストロゲン受容体をモジュレートするための化合物および方法
US7601855B2 (en) 2004-09-21 2009-10-13 Novogen Research Pty Ltd Substituted chroman derivatives, medicaments and use in therapy
US8080675B2 (en) 2004-09-21 2011-12-20 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US8268806B2 (en) 2007-08-10 2012-09-18 Endorecherche, Inc. Pharmaceutical compositions
US8389548B2 (en) 1998-06-11 2013-03-05 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
WO2013130832A1 (fr) 2012-02-29 2013-09-06 Repros Therapeutics Inc. Polythérapie pour le traitement d'une carence en androgène
US8835413B2 (en) 2004-10-20 2014-09-16 Endorecherche, Inc. Sex steroid precursors alone or in combination with a selective estrogen receptor modulator and/or with estrogens and/or a type 5 cGMP phosphodiesterase inhibitor for the prevention and treatment of vaginal dryness and sexual dysfunction in postmenopausal women
EP2826475A1 (fr) 2007-10-16 2015-01-21 Repros Therapeutics Inc. Trans-clomphène pour le traitement du diabète chez les hommes atteints d'hypogonadisme
WO2015135061A1 (fr) 2014-03-10 2015-09-17 Endorecherche, Inc. Traitement des symptômes ou des maladies de carence en androgènes par des précurseurs de stéroïdes sexuels en combinaison avec des serm
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
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
EP3178480A1 (fr) 2009-06-16 2017-06-14 Endorecherche, Inc. Traitement de bouffées de chaleur, de symptômes vasomoteurs et de sueurs nocturnes par des précurseurs de stéroïdes sexuels en combinaison avec des modulateurs sélectifs du récepteur de l' strogène
US9701655B2 (en) 2014-02-07 2017-07-11 Novogen Limited Functionalised benzopyran compounds and use thereof
US10980774B2 (en) 2015-02-02 2021-04-20 Mei Pharma, Inc. Combination therapies
US11576891B2 (en) 2010-06-16 2023-02-14 Endorecherche, Inc. Methods of treating or preventing estrogen-related diseases

Citations (1)

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Publication number Priority date Publication date Assignee Title
EP0178862A2 (fr) * 1984-10-12 1986-04-23 BCM Technologies, INC. Thérapie antioestrogène pour symptômes de déficience d'oestrogène

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
EP0178862A2 (fr) * 1984-10-12 1986-04-23 BCM Technologies, INC. Thérapie antioestrogène pour symptômes de déficience d'oestrogène

Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2399582A1 (fr) 1998-06-11 2011-12-28 Endorecherche Inc. Modulateur sélectif de récepteur d'ýstrogène combiné avec déhydroépiandrostérone (DHEA) ou des analogues
US6670346B1 (en) 1998-06-11 2003-12-30 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US7429576B2 (en) 1998-06-11 2008-09-30 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US6465445B1 (en) 1998-06-11 2002-10-15 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US7943603B2 (en) 1998-06-11 2011-05-17 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
EP2386304A2 (fr) 1998-06-11 2011-11-16 Endorecherche Inc. Modulateur sélectif de récepteur d'ýstrogène combiné avec déhydroépiandrostérone (DHEA) ou des analogues
EP2386305A2 (fr) 1998-06-11 2011-11-16 Endorecherche Inc. Modulateur sélectif de récepteur d'ýstrogène combiné avec déhydroépiandrostérone (DHEA) ou des analogues
US8389548B2 (en) 1998-06-11 2013-03-05 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US8188066B2 (en) 1998-06-11 2012-05-29 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
JP2003519219A (ja) * 1999-12-30 2003-06-17 シグナル ファーマシューティカルズ， インコーポレイテッド エストロゲン受容体をモジュレートするための化合物および方法
US9198895B2 (en) 2004-09-21 2015-12-01 Mei Pharma, Inc. Chroman derivatives, medicaments and use in therapy
US9138478B2 (en) 2004-09-21 2015-09-22 Mei Pharma, Inc. Substituted chroman derivatives, medicaments and use in therapy
US8084628B2 (en) 2004-09-21 2011-12-27 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
US8080675B2 (en) 2004-09-21 2011-12-20 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US8461361B2 (en) 2004-09-21 2013-06-11 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US8697891B2 (en) 2004-09-21 2014-04-15 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
US9381186B2 (en) 2004-09-21 2016-07-05 Mei Pharma, Inc. Substituted chroman derivatives, medicaments and use in therapy
US8957109B2 (en) 2004-09-21 2015-02-17 Mei Pharma, Inc. Chroman derivatives, medicaments and use in therapy
US7601855B2 (en) 2004-09-21 2009-10-13 Novogen Research Pty Ltd Substituted chroman derivatives, medicaments and use in therapy
US10478443B2 (en) 2004-10-20 2019-11-19 Endorecherche, Inc. Sex steroid precursors alone or in combination with selective estrogen receptor modulators for the prevention and treatment of sexual dysfunction in postmenopausal women
US10076525B2 (en) 2004-10-20 2018-09-18 Endorecherche, Inc. Sex steroid precursors alone or in combination with selective estrogen receptor modulators for the prevention and treatment of dyspareunia in postmenopausal women
US8835413B2 (en) 2004-10-20 2014-09-16 Endorecherche, Inc. Sex steroid precursors alone or in combination with a selective estrogen receptor modulator and/or with estrogens and/or a type 5 cGMP phosphodiesterase inhibitor for the prevention and treatment of vaginal dryness and sexual dysfunction in postmenopausal women
US10881650B2 (en) 2007-08-10 2021-01-05 Endorecherche, Inc. Pharmaceutical compositions
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KR19990077156A (ko) 1999-10-25
CA2241623A1 (fr) 1997-07-17
HUP9902683A2 (hu) 2001-04-28
CZ217298A3 (cs) 1999-01-13
IL124882A0 (en) 1999-01-26
JP2000506505A (ja) 2000-05-30
BR9706967A (pt) 1999-05-04
EP0873120A1 (fr) 1998-10-28
HUP9902683A3 (en) 2001-08-28
AU1367297A (en) 1997-08-01
PL327831A1 (en) 1999-01-04
NO983178L (no) 1998-07-10

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