WO1999045886A2 - Nouveau kit de contraception - Google Patents

Nouveau kit de contraception Download PDF

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Publication number
WO1999045886A2
WO1999045886A2 PCT/EP1999/001404 EP9901404W WO9945886A2 WO 1999045886 A2 WO1999045886 A2 WO 1999045886A2 EP 9901404 W EP9901404 W EP 9901404W WO 9945886 A2 WO9945886 A2 WO 9945886A2
Authority
WO
WIPO (PCT)
Prior art keywords
contraceptive
steroid compound
formula
structural formula
pharmaceutically acceptable
Prior art date
Application number
PCT/EP1999/001404
Other languages
English (en)
Other versions
WO1999045886A3 (fr
Inventor
Helenius Jan Kloosterboer
Godefridus Hermanus Johanna Deckers
Johannes Antonius Maria Hamersma
Pieter Michiel Verbost
Herman Jan Tijmen Coelingh Bennink
Original Assignee
Akzo Nobel N.V.
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
Priority to PL99343428A priority Critical patent/PL343428A1/xx
Application filed by Akzo Nobel N.V. filed Critical Akzo Nobel N.V.
Priority to BR9908605-0A priority patent/BR9908605A/pt
Priority to JP2000535302A priority patent/JP2002506014A/ja
Priority to IL13754199A priority patent/IL137541A0/xx
Priority to HU0101007A priority patent/HUP0101007A3/hu
Priority to AU31437/99A priority patent/AU756882B2/en
Priority to NZ506115A priority patent/NZ506115A/en
Priority to EP99939157A priority patent/EP1061928A2/fr
Priority to KR1020007009917A priority patent/KR20010041698A/ko
Priority to CA002319765A priority patent/CA2319765A1/fr
Publication of WO1999045886A2 publication Critical patent/WO1999045886A2/fr
Publication of WO1999045886A3 publication Critical patent/WO1999045886A3/fr
Priority to NO20004492A priority patent/NO20004492D0/no

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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61P15/18—Feminine contraceptives

Definitions

  • the invention is in the field of hormonal contraception and pertains to a contraceptive kit comprising means for the daily administration of a contraceptive agent.
  • the invention also pertains to certain steroid compounds having an outstanding profile of biological properties with respect to use as contraceptive agents. More particularly, the invention pertains to compounds having such a profile as to make them suitable for use in anticonception by "monotherapy,” i.e. by administering to a female of child- bearing age a single active substance which on its own possesses the required activity for preventing pregnancy.
  • kits for the administration to a female of child-bearing age of two different agents, usually a progestagen and an estrogen. Depending on the specific kit, these agents can be administered in various ways and according to various regimens. Most customary are kits providing a contraceptive regimen of the so-called “combined contraceptive" type, in which daily dosage units comprising both the progestagen and the estrogen are administered for usually 21 consecutive days, in one or more phases distinguished by different amounts and ratio's of both active substances, while in the remaining days of the 28 days' cycle placebo's are administered or a "pill-free" interval is provided.
  • Contraceptive kits in which a single active substance is provided, are known. These are usually of the "progestagen only” type. While such "progestagen-only-pills” (POPs) have the advantage of avoiding the administration of an estrogen, they have a drawback in that cycle control frequently is unsatisfactory, as can be seen from irregular bleeding as well as from inherent amenorrhoe. Hence, it is desired to include an estrogenic component, for which usually ethinyl estradiol is taken. In the art, several less-desired properties (on haemostasis and a risk of cancer) of combined contraceptives are mainly attributed to this estrogenic component.
  • estrogenic receptor binding is usually described in relation to steroids which, just as estradiol, have an aromatic A-ring.
  • steroids which, just as estradiol, have an aromatic A-ring.
  • Anstead et al. in Steroids. 1997, vol. 62, pages 269-303 describes the in vitro estrogen receptor binding of a great many of such steroid structures, carrying various substituents.
  • Such a disclosure apart from not relating to in vivo activity, does not allow making any prediction on the estrogenic receptor binding of other, non-aromatic structures, let alone with respect to mixed estrogenic/progestagenic activity.
  • the present invention now provides a contraceptive kit comprising means for the daily administration of a contraceptive agent, characterised in that the single contraceptive agent is a steroid compound having an activity profile inherently combining progestagenic and estrogenic activity.
  • the invention also resides in the use of a steroid compound having an activity profile inherently combining progestagenic and estrogenic activity for the manufacture of a contraceptive pharmaceutical preparation in which said compound is the single contraceptive agent. More particularly, the invention is in the use of a steroid compound selected from the group consisting of steroids satisfying structural formula I given below, prodrugs thereof, and pharmaceutically acceptable salts thereof for the manufacture of a contraceptive pharmaceutical preparation.
  • the present invention is made possible in particular by the unexpected finding of a type of compounds which possess a rare activity profile in that they are at the same time progestagenic (P) and estrogenic (E), and both activities are at a relatively high level.
  • the single contraceptive agent to be used in the kit according to the invention is a steroid compound having an activity profile inherently combining progestagemc and estrogenic activity to such an extent that the Minimum Active Dose (MAD) in both the Allen-Doisy test for estrogenic activity and the McPhail test for progestagenic activity is ⁇ 250 ⁇ g/kg.
  • MAD Minimum Active Dose
  • single contraceptive agent does not preclude said steroids from being combined with any other progestogen and/or estrogen, in a minor amount that is not contraceptively active, to the extent that such is desired for fine-tuning of the activity profile. It is preferred that the mixed-profile steroid is the only active compound present.
  • Suitable compounds according to the invention include those satisfying the following structural formula I:
  • the invention pertains to the use of these compounds for the manufacture of a contraceptive pharmaceutical preparation.
  • the invention is a contraceptive kit comprising means for the daily administration of any one of the above steroids as a contraceptive agent.
  • the invention provides a method of contraception comprising administering, to a female of child-bearing age, an effective amount of a steroid compound as described above. It is intended to include in the invention the compounds of formula I, as well as prodrugs thereof, i.e. related compounds the substituents of which are easily metabolised to the active compound according to formula I, or are readily cleaved to such a compound upon being administered. Together with the most regular prodrugs, the invention thus pertains to the compounds satisfying formula II, and pharmaceutically acceptable salts thereof.
  • the 3-keto compounds, i.e. with Y being (O), are preferred.
  • the other possibilities for the substituent at carbon atom number 3 have as their main property according to the invention that they are precursors (prodrugs) of the preferred 3-keto compounds. Similar considerations hold for the X substituent, in which the optional ester group is a precursor for the preferred active compound, in which the OX group is OH.
  • the invention is described hereinafter with reference to the active compounds according to formula I, but is intended to include at least the prodrugs described with reference to formula II.
  • the compound used in the present invention is (l l ⁇ ,17 ⁇ )- 11 -ethyl- 17-hydroxy- 19-norpregn-4-en-20-yn-3-one (Org 4060), which has the following structural formula III:
  • This compound which is known from US 3,325,520 as a component of a mixture, from US 5,710,144 as a medicament in the treatment of menopausal complaints, and from GB 1,190,240 as a starting compound for the synthesis of other steroids, surprisingly has properties which make it highly favourable for use in contraception.
  • a yet further preferred embodiment of the invention is the compound satisfying the structural formula IV.
  • This compound ( 11 ⁇ , 17 ⁇ )- 11 -Ethenyl- 17-hydroxy- 19-norpregn-4-en-20-yn-3-one is within a class of steroid compounds known in general from US 4,292,251.
  • This document describes a group of compounds with a range of possible properties. The document does not pertain to compounds having a specific mixed E P profile, nor to monotherapy contraception.
  • the invention now provides a compound which shows a marked difference with respect to the profile of biological properties compared with structurally related compounds known from US 4,292,251. This very difference, i.e.
  • the unexpected mixed E/P profile makes Org 4325, as well as prodrugs thereof and pharmaceutically acceptable salts thereof, highly suitable for use in monotherapy contraception.
  • the outstanding biological properties of the steroids according to the invention can also be benefited from if one were to combine any one of these steroids with another active substance, e.g. a progestagenic or an estrogenic steroid.
  • the present invention further provides for a contraceptive kit in which a single active substance having both progestagenic and estrogenic properties is administered for e.g. 18 to 30, and preferably 21 to 25 days, the remaining days of the cycle being a "pill- free" or placebo interval.
  • a single active substance having both progestagenic and estrogenic properties is administered for e.g. 18 to 30, and preferably 21 to 25 days, the remaining days of the cycle being a "pill- free" or placebo interval.
  • any other number of days is possible, but for practical reasons this is less desired.
  • a pill-free or placebo interval i.e. to provide for the continuous (daily) administration of the aforementioned mixed estrogen/progestagen compound.
  • kits according to the invention provide contraception by "monotherapy” rather than by combination of components having separate activities, but include an estrogenic component so as attain contraceptive efficacy and cycle control comparable to that of combined contraceptives.
  • the pill-free or placebo interval will make for a withdrawal bleeding, which is generally considered desirable, inter alia because thus the natural cycle is mimicked as much as possible, and because it gives the certainty that no pregnancy has occurred.
  • the instant steroids can be administered in various ways.
  • a means for sustained release can be chosen, but it is preferred if the means for administration is in the form of sequential daily dosage units, particularly tablets for oral administration.
  • dosage unit generally refers to physically discrete units suitable as unitary dosages for humans, each containing a predetermined quantity of active material calculated to produce the desired effect, for instance tablets, pills, powders, suppositories, capsules and the like.
  • dosage units e.g. tablets
  • conventional additives e.g. fillers, colourants, polymeric binders and the like
  • any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used in one or more of the compositions.
  • Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like used in suitable amounts. Lactose is a preferred carrier. Mixtures of carriers can also be used.
  • kits may contain any number of daily dosage units, but will generally be adapted to a defined length of the menstrual cycle by having 18-30, and preferably 20-28 daily dosage units.
  • kits are in a form adapted to the normal length of the human menstrual cycle and contain 21-25, most preferably 21 of said daily sequential dosage units and optionally further placebo dosage units to make up a total of 28-32 daily dosage units.
  • Converting the mixture into dosage units generally involves moulding the mixture into a tablet, filling a capsule with a dried mixture, or filling a capsule with a wet mixture.
  • the means for administration of the steroids according to the invention may also be in a form other than that of a daily tablet, e.g an implant or an intravaginal article, such as a vaginal ring, or another type of sustained-release device.
  • sustained-release devices such as implants and vaginal rings
  • EP 303 306 is referred to.
  • Many designs of a vaginal ring releasing two substances are known to the person skilled in the art.
  • the preferably ring-shaped drug delivery system that can be used in the present invention comprises at least one compartment comprising a thermoplastic polymer core containing the mixed-profile steroid compound in an amount which allows a direct release of the compound in physiologically required amounts.
  • the daily dosage of the steroids according to the invention which may be up to 1 mg, generally is in the range of from 50 to 500 ⁇ g, preferably of from 100 to 300 ⁇ g.
  • the amount to be administered preferably is 50-250 ⁇ g per day and more preferably 100-200 ⁇ g per day.
  • the most preferred daily dosage in the case of monotherapy contraception is 140-160 ⁇ g.
  • Org 37678 which is the compound satisfying formula I wherein both of the optional additional bonds are absent, the doses typically are 1,5 to 2 times higher, 200-300 ⁇ g being chosen by preference.
  • the steroids used in the present invention can be prepared in accordance with the general teachings of US 5,710,144 and US 4,292,251.
  • the crude product was dissolved in a mixture of 28 ml of acetone and 0.2 ml of 36% HC1 and the resulting solution was stirred for 24 hours at room temperature (after 3 and 7! 2 hours, 0.7 ml of water was added). Next, another 0.2 ml of 36% HC1 was added and the resulting mixture was once more stirred overnight at room temperature. Finally, the crude mixture was poured into 275 ml of water, which was extracted three times with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous solution of sodium chloride (brine), dried over sodium sulfate, and concentrated under reduced pressure to afford 550 mg of crude product.
  • brine saturated aqueous solution of sodium chloride
  • (l l ⁇ ,17 ⁇ )-l l-Ethenyl-l 7-hydroxy- 19-norpregna-4,20-dien-3-one was prepared from (1 l ⁇ ,17 ⁇ )-l 1 -ethenyl-17-hydroxy- 19-norpregn-4-en-20-yn-3-one as follows: - To a suspension of 175 mg Lindlar catalyst in 15 ml of ethanol, pre-treated with hydrogen gas for 25 minutes, a solution of 500 mg (1 l ⁇ ,17 ⁇ )-l 1 -ethenyl- 17-hydroxy- 19-norpregn-4-en-20-yn-3-one in 5 ml of ethanol was added and the resulting mixture was hydrogenated at atmospheric pressure for 1 hour.
  • compositions are prepared containing a steroid in accordance with the present invention.
  • the compound of Example 6 (Org 4060) is chosen.
  • the compound is mixed with the other ingredients in a standard way, and the mixture is subjected to granulation.
  • the composition is as follows, the same formulation being applicable to other compounds including Org 4325:
  • Org 4060 active 1 - 10 wt.%; Corn Starch (disintegrant) 15 wt.%; Hydroxy Propyl Cellulose (binder) 3 wt.%;
  • progestagenic activity was determined by means of the McPhail test, the estrogenic activity by means of the Allen-Doisy test. Both tests are known in the art, and can be described as follows:
  • test results are indicated in the following table.
  • the compound of Example 6 was employed in monkey studies. Mature female stumptail monkeys (Macaca Arctoides) 5-20 years of age with proven regular menstrual cyclicity were used. The monkeys were housed in a colony of approximately 35 females and one vasectomized male. Experiments were approved by the 'Animal Use Committee' (DEC, AEP nr. E97A0801PV E). To three of these monkeys the compound of Example 6 was administered at a dose of 8 ⁇ g/kg per day. The first day of menstrual bleeding was considered to be day 1 of the cycle and the experiments started with the pre-treatment control cycle (day 1 of the experiment). Treatment (daily) started on day 2 of the treatment cycle until day 22.
  • DEC 'Animal Use Committee'
  • ketamin® dose depending on the monkey, i.m. ⁇ 10 mg/kg.
  • animals were housed individually to regain consciousness and to check for regurgitation. After two hours the animals were allowed to return to the colony.
  • the post-treatment cycle started after the (expected time of) menstrual bleeding of the treatment cycle.

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

Abstract

L'invention concerne un kit de contraception qui comprend un système destiné à l'administration quotidienne d'un agent contraceptif, caractérisé en ce que l'agent contraceptif unique se présente comme un composé stéroïde possédant un profil d'activité combinant de façon inhérente les activités progestagénique et oestrogénique. A l'intérieur d'une classe générale de composés stéroïdaux connus, on a découvert des stéroïdes qui possèdent un profil combiné remarquable, constitué de propriétés biologiques pouvant être utilisés pour la contraception, surtout par le biais de monothérapie. Ces stéroïdes sont sélectionnés dans le groupe constitué de stéroïdes qui correspondent à la formule structurelle (I) et de leurs promédicaments, dans laquelle les pointillés indiquent de façon indépendante une liaison optionnelle.
PCT/EP1999/001404 1998-03-09 1999-03-03 Nouveau kit de contraception WO1999045886A2 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
AU31437/99A AU756882B2 (en) 1998-03-09 1999-03-03 New contraceptive kit
BR9908605-0A BR9908605A (pt) 1998-03-09 1999-03-03 Kit anticoncepcional, uso de um composto esteróide, e, processo de contracepção
JP2000535302A JP2002506014A (ja) 1998-03-09 1999-03-03 新規な避妊用キット
IL13754199A IL137541A0 (en) 1998-03-09 1999-03-03 New contraceptive kit
HU0101007A HUP0101007A3 (en) 1998-03-09 1999-03-03 Contraceptive kit for monotherapy
PL99343428A PL343428A1 (en) 1998-03-09 1999-03-03 New contraceptive kit
NZ506115A NZ506115A (en) 1998-03-09 1999-03-03 Contraceptive kit containing a compound with both estrogenic and progestagenic activity
CA002319765A CA2319765A1 (fr) 1998-03-09 1999-03-03 Nouveau kit de contraception
KR1020007009917A KR20010041698A (ko) 1998-03-09 1999-03-03 신규 피임 키트
EP99939157A EP1061928A2 (fr) 1998-03-09 1999-03-03 Nouveau kit de contraception
NO20004492A NO20004492D0 (no) 1998-03-09 2000-09-08 Nytt kontraseptivt sett for monoterapi

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP98200744 1998-03-09
EP98200744.5 1998-03-09

Publications (2)

Publication Number Publication Date
WO1999045886A2 true WO1999045886A2 (fr) 1999-09-16
WO1999045886A3 WO1999045886A3 (fr) 1999-12-02

Family

ID=8233452

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/001404 WO1999045886A2 (fr) 1998-03-09 1999-03-03 Nouveau kit de contraception

Country Status (20)

Country Link
EP (1) EP1061928A2 (fr)
JP (1) JP2002506014A (fr)
KR (1) KR20010041698A (fr)
CN (1) CN1292702A (fr)
AR (1) AR018313A1 (fr)
AU (1) AU756882B2 (fr)
BR (1) BR9908605A (fr)
CA (1) CA2319765A1 (fr)
CO (1) CO5070598A1 (fr)
HU (1) HUP0101007A3 (fr)
ID (1) ID25621A (fr)
IL (1) IL137541A0 (fr)
NO (1) NO20004492D0 (fr)
NZ (1) NZ506115A (fr)
PE (1) PE20000330A1 (fr)
PL (1) PL343428A1 (fr)
RU (1) RU2225714C2 (fr)
TR (1) TR200002593T2 (fr)
WO (1) WO1999045886A2 (fr)
ZA (1) ZA991851B (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999051214A2 (fr) * 1998-04-07 1999-10-14 Akzo Nobel N.V. Kit contraceptif base uniquement sur la progestogene
WO2001018027A1 (fr) * 1999-09-06 2001-03-15 Akzo Nobel N.V. Steroides oestrogeniques non aromatiques possedant un substituant hydrocarbure en position 11
JP2005519962A (ja) * 2002-03-11 2005-07-07 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ スルファターゼを阻害する継続的プロゲストゲン避妊レジメン
JP2005519964A (ja) * 2002-03-11 2005-07-07 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ スルファターゼ阻害プロゲストゲンのみの避妊レジメン
US7696190B2 (en) 2000-07-28 2010-04-13 N.V. Organon 16Alpha-methyl or ethyl substituted estrogens
US7838516B2 (en) 2004-09-08 2010-11-23 N.V. Organon 15 β-substituted steroids having selective estrogenic activity

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4292251A (en) * 1977-02-10 1981-09-29 Akzona Incorporated 11β-Substituted steroids
WO1994004157A1 (fr) * 1992-08-21 1994-03-03 Schering Aktiengesellschaft Agent d'application transdermique contenant du 3-ceto-desogestrel
WO1994018224A1 (fr) * 1993-02-08 1994-08-18 Akzo Nobel N.V. Steroides pour le traitement d'affections menopausiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4292251A (en) * 1977-02-10 1981-09-29 Akzona Incorporated 11β-Substituted steroids
WO1994004157A1 (fr) * 1992-08-21 1994-03-03 Schering Aktiengesellschaft Agent d'application transdermique contenant du 3-ceto-desogestrel
WO1994018224A1 (fr) * 1993-02-08 1994-08-18 Akzo Nobel N.V. Steroides pour le traitement d'affections menopausiques

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999051214A2 (fr) * 1998-04-07 1999-10-14 Akzo Nobel N.V. Kit contraceptif base uniquement sur la progestogene
WO1999051214A3 (fr) * 1998-04-07 2000-05-11 Akzo Nobel Nv Kit contraceptif base uniquement sur la progestogene
WO2001018027A1 (fr) * 1999-09-06 2001-03-15 Akzo Nobel N.V. Steroides oestrogeniques non aromatiques possedant un substituant hydrocarbure en position 11
US6677329B1 (en) 1999-09-06 2004-01-13 Akzo Nobel N V. Non-aromatic estrogenic steroids with a hydrocarbon substituent in position 11
US7696190B2 (en) 2000-07-28 2010-04-13 N.V. Organon 16Alpha-methyl or ethyl substituted estrogens
JP2005519962A (ja) * 2002-03-11 2005-07-07 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ スルファターゼを阻害する継続的プロゲストゲン避妊レジメン
JP2005519964A (ja) * 2002-03-11 2005-07-07 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ スルファターゼ阻害プロゲストゲンのみの避妊レジメン
US7838516B2 (en) 2004-09-08 2010-11-23 N.V. Organon 15 β-substituted steroids having selective estrogenic activity

Also Published As

Publication number Publication date
RU2225714C2 (ru) 2004-03-20
NO20004492L (no) 2000-09-08
ID25621A (id) 2000-10-19
HUP0101007A3 (en) 2002-02-28
JP2002506014A (ja) 2002-02-26
CO5070598A1 (es) 2001-08-28
HUP0101007A2 (hu) 2001-12-28
NO20004492D0 (no) 2000-09-08
KR20010041698A (ko) 2001-05-25
BR9908605A (pt) 2001-04-24
WO1999045886A3 (fr) 1999-12-02
ZA991851B (en) 1999-09-22
NZ506115A (en) 2003-07-25
AU756882B2 (en) 2003-01-23
EP1061928A2 (fr) 2000-12-27
TR200002593T2 (tr) 2000-12-21
AU3143799A (en) 1999-09-27
CN1292702A (zh) 2001-04-25
IL137541A0 (en) 2001-07-24
PE20000330A1 (es) 2000-05-16
AR018313A1 (es) 2001-11-14
CA2319765A1 (fr) 1999-09-16
PL343428A1 (en) 2001-08-13

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