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WO1998033499A1 - Utilisation de chromanes de 3,4-diphenyle pour la fabrication d'une composition pharmaceutique destinee a augmenter la libido chez les femmes en phase de post-menopause - Google Patents

Utilisation de chromanes de 3,4-diphenyle pour la fabrication d'une composition pharmaceutique destinee a augmenter la libido chez les femmes en phase de post-menopause Download PDF

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Publication number
WO1998033499A1
WO1998033499A1 PCT/DK1998/000031 DK9800031W WO9833499A1 WO 1998033499 A1 WO1998033499 A1 WO 1998033499A1 DK 9800031 W DK9800031 W DK 9800031W WO 9833499 A1 WO9833499 A1 WO 9833499A1
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WO
WIPO (PCT)
Prior art keywords
use according
compound
post
phenyl
alkoxy
Prior art date
Application number
PCT/DK1998/000031
Other languages
English (en)
Inventor
Michael Shalmi
Malcolm Sheardown
Birgitte Hjort Guldhammer
Original Assignee
Novo Nordisk A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU55502/98A priority Critical patent/AU5550298A/en
Publication of WO1998033499A1 publication Critical patent/WO1998033499A1/fr

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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
    • 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
    • A61K31/352—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 condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin

Definitions

  • the present invention relates to the use of compounds of the general formula I for increasing libido in post-menopausal women.
  • the present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.
  • 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) 1 26 ( 1 992), 444 - 450; Grubb. Curr Opin Obstet Gynecol 3 (1 991 ), 491 - 495; Sankaran et al., Contraception 9 ( 1 974), 279 - 289; Indian Patent Specification No. 1 291 87).
  • 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 cholesterol lowering pharmaceutical expressed by a significant decrease of the serum concentrations (S.D. Bain et al., _ Min Ben Qss. 3 (1 994), S 394).
  • U.S. patent 5,453,442 describes methods of lowering serum cholesterol and inhibiting 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 increase libido in post-menopausal women. There remains a need in the art for compositions and methods useful for increasing libido in post-menopausal women.
  • This invention provides the use of a compound having the formula
  • R ⁇ R 4 and R 5 are individually hydrogen, hydroxy, halogen, tri- fluoromethyl, C,. 6 alkyl, C ⁇ alkoxy or (tertiary aminoXC, ⁇ alkoxy); and R 2 and R 3 are individually hydrogen or C . e alkyl, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for increasing li- bido in post-menopausal women.
  • the current invention concerns the discovery that the compounds of formula I are useful for increasing libido.
  • the methods of treatment provided by this invention are practiced by administering to a human in need a dose of a compound of formula I or a pharmaceutically acceptable salt thereof, that is effective to increase libido.
  • post-menopausal women is defined to include not only women of advanced age who have passed through menopause, but also women who have been oophorectomised, hysterectomized or oophorohysterectomised or for some other reason have suppressed estrogen production, such as those who have un- dergone long-term administration of corticosteroids, suffer from Cushions' syndromes or have gonadal dysgenesis.
  • libido refers to those aspects of the human psy- che which are related to sexual interest and drive. Additionally, the expression “libido” refers to related psychic attitudes concerned with mental well-being and which refer to such characteristics as mental alertness and activity, creativity, enthusiasm, sociability and an awareness of interpersonal relationships. Libido is generally recognized to be the result of a complex interaction of factors in which genetic, anatomic, neurologic, psychologic and biochemical factors all play prominent roles. The exact mechanism by which the compounds of the present invention achieve this effect is not understood except to the extent that it is attributable to a biochemical mechanism.
  • R , R ⁇ and R° are individually hydrogen, hydroxy, halogen, trifluoromethyl, C,. 6 alkyl, C,. 6 alkoxy or (tertiary ammoMC ⁇ alkoxy); and R ⁇ and
  • R ⁇ are individually hydrogen or a C, ⁇ 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.
  • 6 alkoxy 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 1 . 6 alkoxy) is a C 1-6 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 1 is C 1-6 alkoxy; R 2 and R 3 are C ⁇ alkyl, especially methyl; R 4 is hydrogen; and R 5 is (tertiary aminoMC ⁇ e alkoxy) of the polymethyleneimine type.
  • R ' is in the 7-position and is C,.
  • each of R 2 and R 3 is methyl, R ⁇ is hydrogen, and R ⁇ is in the 4- position and is a (tertiary aminoMC ⁇ e alkoxy) radical such as 2-(pyrrolidin-1 - yl)ethoxy with formula II
  • the compounds of formula I in the transconfiguration. These compounds may be used as racemic mixtures, or the isolated d- or I- enantiomers may be used. The trans-l-enantiomers are more preferred.
  • a particularly preferred compound for use within the present invention is cen- tchroman having the formula IV
  • 3,4-diarylchromans of formula I may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids.
  • salts include salts of organic acids such as formic acid, fumaric acid, maleic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like.
  • Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • a preferable salt is the hydrogen fumarate salt.
  • 3,4-diarylchromans of formula I and their salts are useful within human medicine in the treatment of patients suffering from a decline in libido.
  • 3,4-diarylchromans of formula I and their pharmaceutically acceptable salts are formulated with a pharmaceutically acceptable carrier to provide a medicament for parenteral, oral, nasal, 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 prepared in a form suitable for oral administration, such as a tablet or capsule.
  • a pharmaceutically acceptable salt of the compound of formula I is combined with a carrier and moulded into a tablet.
  • Suitable carriers include starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate and the like.
  • Such compositions may further include one or more auxiliary substances, such as wetting agents, emulsifiers, preservatives, stabilizers, colouring additives, etc.
  • compositions containing a compound of formula I may be admin- istered one or more times per day or week.
  • An effective amount of such a pharmaceutical composition is the amount required to increase libido, according to this invention. Such amounts will depend, in part, on the particular 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 dos- age 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 compound 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., _ Pharm Sci 7_3_ ( 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 incorporated herein by reference.
  • Examples of preferred compounds of formula I are centchroman as a racemic mixture and as isolated l-centchroman and d-centchroman enantiomers. Furthermore, 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 iso- lated 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.
  • the animals used are ovariectomized Sprague Dawley rats (M ⁇ llegaard Denmark) weighing 250-300 grams Food and water are available ad libitum.
  • a compound of the invention (or oestrogen) is administered to one group of rats, and the other group is maintained as a control.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des utilisations nouvelles de composés de formule générale (I) ou un sel pharmaceutiquement acceptable de ceux-ci, pour la fabrication d'une composition pharmaceutique destinée à augmenter la libido des femmes en phase de post-ménopause. Dans la dite formule (I), R?1, R4 et R5¿ représentent séparément hydrogène, hydroxy, halogène trifluorométhyle, alkyle C¿1-6?, alcoxy C1-6 ou (alcoxy C1-6)(amino tertiaire); et R?2 et R3¿ représentent individuellement hydrogène ou alkyle C¿1-6?.
PCT/DK1998/000031 1997-01-29 1998-01-28 Utilisation de chromanes de 3,4-diphenyle pour la fabrication d'une composition pharmaceutique destinee a augmenter la libido chez les femmes en phase de post-menopause WO1998033499A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55502/98A AU5550298A (en) 1997-01-29 1998-01-28 Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical compositionfor increasing libido in post-menopausal women

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DK0112/97 1997-01-29
DK11297 1997-01-29
DK17097 1997-02-18
DK0170/97 1997-02-18

Publications (1)

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WO1998033499A1 true WO1998033499A1 (fr) 1998-08-06

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1106179A2 (fr) * 1996-02-28 2001-06-13 Pfizer Inc. Utilisation d'antagonistes et d'agonistes estrogéniques pour traiter des conditions pathologiques
WO2003070253A1 (fr) * 2002-02-21 2003-08-28 Pantarhei Bioscience B.V. Composant oestrogenique pour traiter la diminution de la libido chez les femmes
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
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
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

Citations (1)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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 (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1106179A2 (fr) * 1996-02-28 2001-06-13 Pfizer Inc. Utilisation d'antagonistes et d'agonistes estrogéniques pour traiter des conditions pathologiques
US6613796B2 (en) 1996-02-28 2003-09-02 Pfizer Inc. Use of estrogen antagonists and estrogen agonists in inhibiting pathological conditions
EP1106179A3 (fr) * 1996-02-28 2004-01-07 Pfizer Inc. Utilisation d'antagonistes et d'agonistes estrogéniques pour traiter des conditions pathologiques
US6911456B2 (en) 1996-02-28 2005-06-28 Pfizer Inc Use of estrogen antagonists and estrogen agonists in inhibiting pathological conditions
WO2003070253A1 (fr) * 2002-02-21 2003-08-28 Pantarhei Bioscience B.V. Composant oestrogenique pour traiter la diminution de la libido chez les femmes
US9198895B2 (en) 2004-09-21 2015-12-01 Mei Pharma, Inc. 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
US8084628B2 (en) 2004-09-21 2011-12-27 Marshall Edwards, Inc. Substituted 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
US8957109B2 (en) 2004-09-21 2015-02-17 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
US7601855B2 (en) 2004-09-21 2009-10-13 Novogen Research Pty Ltd 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
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US9708283B2 (en) 2010-11-01 2017-07-18 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US9981936B2 (en) 2010-11-01 2018-05-29 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US10105346B2 (en) 2010-11-01 2018-10-23 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10369132B2 (en) 2010-11-01 2019-08-06 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US10973799B2 (en) 2010-11-01 2021-04-13 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US11583514B2 (en) 2010-11-01 2023-02-21 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US11723893B2 (en) 2010-11-01 2023-08-15 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US9701655B2 (en) 2014-02-07 2017-07-11 Novogen Limited Functionalised benzopyran compounds and use thereof
US10370349B2 (en) 2014-02-07 2019-08-06 Kazia Therapeutics Limited Functionalised benzopyran compounds and use thereof
US10980774B2 (en) 2015-02-02 2021-04-20 Mei Pharma, Inc. Combination therapies

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Publication number Publication date
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