EP0873119A1 - Use of the l-enantiomer of centchroman for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of breast cancer - Google Patents

Use of the l-enantiomer of centchroman for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of breast cancer

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Withdrawn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)
French (fr)
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/en
Withdrawn legal-status Critical Current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

Abstract

The present invention provides a novel use of the l-enantiomer of centchroman or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of breast cancer.

Description

Use of the l-enantiomer of centchroman for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of breast cancer
FIELD OF THIS INVENTION
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.
BACKGROUND OF THIS INVENTION
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. (Copenh) 1__ ( 1 9921, 444 - 450; Grubb, 2 (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., ]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.
There remains today a need in the art for 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.
DETAILED DESCRIPTION OF THIS INVENTION
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
(incorporated herein by reference) by forming an optically active acid salt which is subjected to alkaline hydrolysis to produce the desired enantiomer.
Within the present invention 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. Examples of such 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. In the alternative, 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. For use within the present invention, 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. and 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
Oral administration is preferred. Thus, 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. Typically, a pharmaceutically acceptable salt of the l-enantiomer of centchroman is combined with a carrier and moulded into a tablet. Suitable carriers in this regard 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.
Pharmaceutical 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
The pharmaceutical 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. In the alternative, 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.
The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realising the invention in diverse forms thereof.
EXAMPLES
Test
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.

Claims

1 . The use of the l-enantiomer of 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2- (pyrrolidin-1 -yl)ethoxy)phenyl]-7-methoxychroman or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of breast cancer.
2. The use according to claim 1 wherein said composition is in a form suitable for oral administration.
3. The use according to any one of the preceding claims wherein said compound is administered as a dose in a range from about 0.001 to 75 mg/kg patient per day.
4. The use according to any one of the preceding claims wherein said composi¬ tion is administered one or more times per day or week.
5. The use according to any one of the preceding claims wherein said composi¬ tion is in the form of a dermal implant.
6. Method for treatment and prophylaxis of breast cancer comprising administer¬ ing to a patient a clinically effective amount of the l-enantiomer of 3,4-trans-2,2- dimethyl-3-phenyl-4-[4-(2-(pyrrolidin- 1 -yl)ethoxy)phenyl]-7-methoxychroman stated to be used in any one of the preceding use claims, or a pharmaceutically acceptable salt thereof in an amount sufficient to treat or prevent breast cancer.
7. A method of treating or preventing breast cancer which method comprises administering a clinically effective amount of a compound of the l-enantiomer of
3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl]-7- methoxychroman or a salt thereof and pharmaceutically acceptable compositions containing such a compound, to a patient in need of such a treatment.
EP97900199A 1996-01-11 1997-01-09 Use of the l-enantiomer of centchroman for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of breast cancer Withdrawn EP0873119A1 (en)

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 (en) 1996-01-11 1997-01-09 Use of the l-enantiomer of centchroman for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of breast cancer

Publications (1)

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

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP97900199A Withdrawn EP0873119A1 (en) 1996-01-11 1997-01-09 Use of the l-enantiomer of centchroman for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of breast cancer

Country Status (12)

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

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Publication number Priority date Publication date Assignee Title
WO1999024032A1 (en) * 1997-11-10 1999-05-20 Novo Nordisk A/S Transdermal delivery of 3,4-diarylchromans
US6465445B1 (en) 1998-06-11 2002-10-15 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
AU2011253842B2 (en) * 1998-06-11 2014-08-14 Endorecherche Inc. Medical Uses of a Selective Estrogen Receptor Modulator in Combination with Sex Steroid Precursors
US7005428B1 (en) 1998-06-11 2006-02-28 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
BRPI0516243C1 (en) 2004-10-20 2021-05-25 Endorecherche Inc use of a sex steroid precursor selected from the group consisting of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-ene-3b,17b-diol and 4-androsten-3,17-dione, use of said precursor in association with a selective estrogen receptor modulator for uterine and mammary gland protection against cancer, pharmaceutical composition and kit
US8268806B2 (en) 2007-08-10 2012-09-18 Endorecherche, Inc. Pharmaceutical compositions
BRPI0818637A2 (en) 2007-10-16 2015-04-07 Repros Therapeutics Inc Methods of treating symptom of impaired fasting glucose, metabolic syndrome, metabolic syndrome, and impaired fasting glucose in subjects with secondary or idiopathic hypogonadotropic hypogonadism
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
EP2582371B1 (en) 2010-06-16 2019-10-16 Endorecherche, Inc. Methods of treating or preventing estrogen-related diseases
CN104244953A (en) 2012-02-29 2014-12-24 利普生物药剂公司 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
JP7048505B2 (en) 2015-11-10 2022-04-05 パラクリン セラピューティクス エービー Treatment of ER-negative breast cancer with PDGF-CC inhibitors and antiestrogens

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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)

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See references of WO9725034A1 *

Also Published As

Publication number Publication date
IL124881A0 (en) 1999-01-26
KR19990077157A (en) 1999-10-25
HUP9901633A2 (en) 1999-10-28
HUP9901633A3 (en) 2000-02-28
BR9706966A (en) 1999-05-04
WO1997025034A1 (en) 1997-07-17
PL328135A1 (en) 1999-01-18
CA2241462A1 (en) 1997-07-17
JP2001500101A (en) 2001-01-09
CZ217198A3 (en) 1998-11-11
AU1367197A (en) 1997-08-01
NO983177L (en) 1998-07-10

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