EP0873119A1 - Utilisation de l'enantiomere-l de centchromanne dans la fabrication d'une composition pharmaceutique servant au traitement ou a la prophylaxie du cancer du sein - Google Patents

Utilisation de l'enantiomere-l de centchromanne dans la fabrication d'une composition pharmaceutique servant au traitement ou a la prophylaxie du cancer du sein

Info

Publication number
EP0873119A1
EP0873119A1 EP97900199A EP97900199A EP0873119A1 EP 0873119 A1 EP0873119 A1 EP 0873119A1 EP 97900199 A EP97900199 A EP 97900199A EP 97900199 A EP97900199 A EP 97900199A EP 0873119 A1 EP0873119 A1 EP 0873119A1
Authority
EP
European Patent Office
Prior art keywords
breast cancer
enantiomer
treatment
phenyl
pharmaceutically acceptable
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.)
Withdrawn
Application number
EP97900199A
Other languages
German (de)
English (en)
Inventor
Michael Shalmi
Ved Prakash Kamboj
Omkar Prasad Asthana
Suprabhat Ray
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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 AS filed Critical Novo Nordisk AS
Publication of EP0873119A1 publication Critical patent/EP0873119A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of the isolated l-enantiomer of centchro ⁇ man (3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl]-7- methoxychroman) or pharmaceutically acceptable salts thereof for the treatment of patients suffering from breast cancer and prophylaxis hereof.
  • the present in- vention also embraces pharmaceutical compositions comprising the l-enantiomer of centchroman or pharmaceutically acceptable salts thereof and methods of using above mentioned compounds and their pharmaceutical compositions.
  • breast cancer is the most common malignant tumor and the leading cause of cancer death in women. It causes approximately 20% of the cancer deaths among women. However, in spite of many years of intensive research and new types of treatment the age-adjusted death rate from breast cancer in the western world has virtually remained stable over the past 30 years.
  • the term " breast cancer” implies a carcinoma arising in the ductal and glandular structures of the breast. Breast cancer is rare in women who have been castrated; oophorectomy before 35 years of age reduces the risk to one third. Women who have their first child before the age of 1 8 years have only one third the risk compared with those whose first child is delayed until age 30. Growth of breast cancer is associated with the presence of estrogen.
  • a course of treatment of breast cancer is, therefore, ablation of the estrogen source by ovariectomy or hysterectomy.
  • An alternative to this surgical approach is endocrine therapy whereby an estrogen antagonist is used to deplete estrogen concentration at the target site.
  • 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 Endocrinol.
  • Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., ]ni. 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., J.Min.Bon.Res. 9. (1 994), 394). However, it has never been disclosed that the isolated l-enantiomer of centchroman is use ⁇ ful for treatment of breast cancer.
  • compositions and methods that are useful and safe in the treatment or prophylaxis of breast cancer.
  • One object of the present invention is to provide compounds which can effecti ⁇ vely be used in the treatment or prophylaxis of breast cancer.
  • the present invention relates to the use of the isolated l-enantiomer of centchro- man (3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl]-7- methoxychroman) or pharmaceutically acceptable salts thereof for the manufac ⁇ ture of a pharmaceutical composition for the treatment or prophylaxis of breast cancer.
  • 3,4-diarylchromans are prepared according to known methods, such as those disclosed 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., J. ed.Chem. 1_ ⁇ ( 1 976), 276 - 279, the contents of which are incorporated herein by reference. Conversion of the cis isomer to the trans configuration by means of an organo- metallic 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 disclosed by Salman et al. in U.S. Patent Specification No. 4,447,622
  • the l-enantiomer of centchroman may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, in ⁇ cluding salts of organic acids and mineral acids.
  • salts include salts of organic acids such as formic acid, fumaric 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 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 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.
  • the l-enantiomer of centchroman and its salts are useful within human and vete ⁇ rinary medicine, for example, in the treatment of patients suffering from breast cancer.
  • the l-enantiomer of centchroman or its 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, emulsi ⁇ fiers, preservatives, buffers, excipients, etc.
  • centchroman may be provided in such forms as liquids, powders, emulsions, suppositories, liposomes, transdermal patches, controlled release, dermal implants, tablets, etc.
  • One skilled in this art may for ⁇ mulate the l-enantiomer of centchroman or a pharmaceutically acceptable salt thereof in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences. Gennaro, ed., Mack Publishing Co., Easton, PA, 1 990
  • the active l-enantiomer of centchroman or a pharmaceutically acceptable salt thereof is prepared in a form suitable for oral administration, such as a tablet or capsule.
  • a pharmaceutically acceptable salt of the l-enantiomer of centchroman 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 the l-enantiomer of centchroman or a pharmaceutically acceptable salt thereof is administered one or more times per day or week.
  • An effective amount of such a pharmaceutical composition is the amount that provides a clinically significant effect against breast cancer. Such amounts will depend, in part, on the particular condition to be treated, age, weight, and general health of the patient, and other factors evi ⁇ dent to those skilled in the art.
  • a typical daily dose will contain a non-toxic dosage range of from about 0 001 to about 75 mg/kg patient per day of a compound of the present invention
  • compositions containing the l-enantiomer of centchroman or a pharmaceutically acceptable salt thereof may be administered in unit dosage form one or more times per day or week.
  • they may be pro ⁇ vided as controlled release formulations suitable for dermal implantation.
  • Im ⁇ plants are formulated to provide release of active compound over the desired period of time, which can be up to several years.
  • Controlled-release formulations are disclosed by, for example, Sanders et al., J.Pharm.Sci. 23. ( 1 964), 1 294 - 1 297, 1 984; U.S. Patent Specification No 4,489,056; and U.S. Patent Specifi ⁇ cation No. 4,21 0,644, which are incorporated herein by reference.
  • the present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protection.
  • mice Between 1 5 and 45 nude (thymus deficient) mice are ovariectomized under phe- nobarbital anaesthesia. After one week recovery an estrogen sensitive human tumor cell line (MCF7, mammary cancer fibroblast 7) is serially transplanted to each of these animals. Subsequently the mice are treated with either placebo (negative control), 1 7-beta-estradiol (positive control), or the test compound. Oestrogen stimulated tumor growth is assessed by measurement of tumor size twice weekly for a dosing period of approximately 8 weeks.
  • MCF7 estrogen sensitive human tumor cell line

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention se rapporte à une nouvelle utilisation de l'énantiomère-l de centchromanne ou d'un sel pharmaceutiquement acceptable de celui-ci, combiné à un excipient pharmaceutiquement acceptable, dans la fabrication d'une composition pharmaceutique servant au traitement ou à la prophylaxie du cancer du sein.
EP97900199A 1996-01-11 1997-01-09 Utilisation de l'enantiomere-l de centchromanne dans la fabrication d'une composition pharmaceutique servant au traitement ou a la prophylaxie du cancer du sein Withdrawn EP0873119A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US1000096P 1996-01-11 1996-01-11
US10000P 1996-01-11
DK77696 1996-07-11
DK77696 1996-07-11
PCT/DK1997/000007 WO1997025034A1 (fr) 1996-01-11 1997-01-09 Utilisation de l'enantiomere-l de centchromanne dans la fabrication d'une composition pharmaceutique servant au traitement ou a la prophylaxie du cancer du sein

Publications (1)

Publication Number Publication Date
EP0873119A1 true EP0873119A1 (fr) 1998-10-28

Family

ID=26064631

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97900199A Withdrawn EP0873119A1 (fr) 1996-01-11 1997-01-09 Utilisation de l'enantiomere-l de centchromanne dans la fabrication d'une composition pharmaceutique servant au traitement ou a la prophylaxie du cancer du sein

Country Status (12)

Country Link
EP (1) EP0873119A1 (fr)
JP (1) JP2001500101A (fr)
KR (1) KR19990077157A (fr)
AU (1) AU1367197A (fr)
BR (1) BR9706966A (fr)
CA (1) CA2241462A1 (fr)
CZ (1) CZ217198A3 (fr)
HU (1) HUP9901633A3 (fr)
IL (1) IL124881A0 (fr)
NO (1) NO983177L (fr)
PL (1) PL328135A1 (fr)
WO (1) WO1997025034A1 (fr)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU1143899A (en) * 1997-11-10 1999-05-31 Novo Nordisk A/S Transdermal delivery of 3,4-diarylchromans
US7005428B1 (en) 1998-06-11 2006-02-28 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
AU2011253842B2 (en) * 1998-06-11 2014-08-14 Endorecherche Inc. Medical Uses of a Selective Estrogen Receptor Modulator in Combination with Sex Steroid Precursors
AU2004200099B2 (en) * 1998-06-11 2006-11-02 Endorecherche, Inc. Medical Uses of A Selective Estrogen Receptor Modulator in Combination with Sex Steroid Precursors
CA2749235C (fr) 2004-10-20 2014-08-12 Endorecherche, Inc. Precurseurs de steroide sexuel, seuls ou combines a un modulateur de recepteur d'oestrogene selectif et/ou a des oestrogenes et/ou a un inhibiteur de phosphodiesterase de type 5 cgmp, pour prevenir et traiter la secheresse vaginale et les dysfonctionnements sexuels chez la femme postmenopausee
US8268806B2 (en) 2007-08-10 2012-09-18 Endorecherche, Inc. Pharmaceutical compositions
ME00996B (fr) 2007-10-16 2012-10-20 Repros Therapeutics Inc Traitement d'un syndrome métabolique par trans-clomiphène
US20100317635A1 (en) 2009-06-16 2010-12-16 Endorecherche, Inc. Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
MX2012014579A (es) 2010-06-16 2013-05-22 Endorech Inc Procedimientos de tratamiento o pevencion de enfermedades relacionadas con estrogenos.
US20150031656A1 (en) 2012-02-29 2015-01-29 Repros Therapeutics Inc. Combination therapy for treating androgen deficiency
US9744177B2 (en) 2014-03-10 2017-08-29 Endorecherche, Inc. Treatment of male androgen deficiency symptoms or diseases with sex steroid precursor combined with SERM
US11633382B2 (en) 2015-11-10 2023-04-25 Paracrine Therapeutics Ab Treatment of ER-negative breast cancer with an PDGF-CC inhibitor and anti-estrogen

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4447622A (en) * 1981-09-22 1984-05-08 Council Of Scientific And Industrial Research Rafi Marg Preparation of l- and d-isomers of dl-3,4-trans-2,2-disubstituted-3,4-diarylchromans and derivatives thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9725034A1 *

Also Published As

Publication number Publication date
CZ217198A3 (cs) 1998-11-11
NO983177L (no) 1998-07-10
PL328135A1 (en) 1999-01-18
HUP9901633A2 (hu) 1999-10-28
BR9706966A (pt) 1999-05-04
AU1367197A (en) 1997-08-01
HUP9901633A3 (en) 2000-02-28
IL124881A0 (en) 1999-01-26
CA2241462A1 (fr) 1997-07-17
WO1997025034A1 (fr) 1997-07-17
JP2001500101A (ja) 2001-01-09
KR19990077157A (ko) 1999-10-25

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