EP0682672A1 - Steroides pour le traitement d'affections menopausiques - Google Patents

Steroides pour le traitement d'affections menopausiques

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Publication number
EP0682672A1
EP0682672A1 EP94906918A EP94906918A EP0682672A1 EP 0682672 A1 EP0682672 A1 EP 0682672A1 EP 94906918 A EP94906918 A EP 94906918A EP 94906918 A EP94906918 A EP 94906918A EP 0682672 A1 EP0682672 A1 EP 0682672A1
Authority
EP
European Patent Office
Prior art keywords
hydroxy
optionally
alkyl
alkynyl
halogen
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Withdrawn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
EP94906918A
Other languages
German (de)
English (en)
Inventor
Hubert Jan Jozef Loozen
Lodewijk Pieter Cornelis Schot
Jane Margretha Lena Van De Werf-Pieters
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.)
Akzo Nobel NV
Original Assignee
Akzo Nobel NV
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 Akzo Nobel NV filed Critical Akzo Nobel NV
Priority to EP94906918A priority Critical patent/EP0682672A1/fr
Publication of EP0682672A1 publication Critical patent/EP0682672A1/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Withdrawn legal-status Critical Current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
    • A61K31/56—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0096—Alkynyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J11/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J21/005—Ketals
    • C07J21/008—Ketals at position 17
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J33/005—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton spiro-condensed
    • C07J33/007—Cyclic thioketals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0044—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an estrane or gonane skeleton, including 18-substituted derivatives and derivatives where position 17-beta is substituted by a carbon atom not directly bonded to another carbon atom and not being part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

Definitions

  • the invention relates to the use of steroids for the manufacture of a medicament for treating or preventing menopausal complaints, especially for treating or preventing osteoporosis.
  • ll ⁇ -alkyl steroid are known from USP 3,983,144. These steroids are described to have
  • R-L represents 0, (H,OH), or two hydrogens atoms;
  • R 2 is hydroxy, optionally etherified or esterified;
  • R 3 is (2-6 C) alkynyl, optionally substituted with hydroxy;
  • R is CN or one of the hydrocarbon groups selected from (1-6 C) alkyl, (1-6 C) alkoxy, (2-6 C) alkenyl, (2-6 C) alkynyl, and (2-6 C) alkylidene, each of said hydro ⁇ carbon groups may optionally be substituted with halogen, hydroxy or (1-6 C) alkoxy; and
  • R 5 is hydrogen or (1-6 C) alkyl, can be used for treating or preventing postmenopausal complaints, and especially osteoporosis.
  • the aim of this invention is to provide a medicament which is able to prevent bone loss, and possibly to increase bone mass, and further to treat climacteric complaints.
  • the active ingre ⁇ pros of these medicaments have strong estrogen and weak or non-existing androgenic activity.
  • Preferred medicaments further have favourable bleeding properties , do not induce endometrium proliferation, and have a favourable HDL/LDL (high/low density lipid) ratio.
  • the compounds have the general formula I wherein R-L represents 0 or two hydrogens atoms; R is hydroxy; R 3 is ethynyl; R 4 is selected from the group consisting of methyl, (2-6 C) alkynyl, (2-6 C) alkylidene, and one of (2-6 C) alkyl, (2-7 C) alkoxy- alkyl, (1-6 C) alkoxy, or (2-6 C) alkenyl, which may optionally be substituted with halogen; and R 5 is hydro- gen or (1-6 C) alkyl.
  • R ⁇ is 0; R 2 is hydroxy; R 3 is ethyn- yl; R 4 is ethyl, 2-fluoroethyl, ethynyl, (2-6 C) alkenyl optionally substituted with fluorine, or (2-6 C) alkyli ⁇ dene optionally substituted with fluorine; and R 5 is hydrogen or methyl. In the preferred embodiment R 5 is hydrogen.
  • steroids having the general formula I wherein: R- ⁇ is O; R 2 is hydroxy; R 3 is ethynyl; R 4 is ethyl or ethynyl; and R 5 is hydrogen.
  • the invention further relates to new steroids having the general formula I wherein:
  • R ⁇ represents 0
  • R 2 is hydroxy, optionally etherified or esterified;
  • R 3 is (2-6 C) alkynyl, optionally substituted with hydroxy;
  • R 4 is CN, (2-6 C) alkyl optionally substituted with halogen, or (2-6 C) alkenyl substituted with halogen; and R 5 is hydrogen or (1-6 C) alkyl; or wherein
  • R- L represents two hydrogens atoms
  • R 2 is hydroxy, optionally etherified or esterified;
  • R 3 is (2-6 C) alkynyl, optionally substituted with hydroxy;
  • R 4 is CN or one of the hydrocarbon groups selected from (2-6 C) alkyl, (1-6 C) alkoxy, (2-6 C) alkenyl, (2-6 C) alkynyl, and (2-6 C) alkylidene, each of said hydro ⁇ carbon groups may optionally be substituted with halogen, hydroxy or (1-6 C) alkoxy; and R 5 is (1-6 C) alkyl.
  • steroids of general formula I wherein R ⁇ is O; R 2 is hydroxy; R 3 is ethynyl; R 4 is 2-fluoroethyl or 2-fluoro- ethenyl; and R 5 is hydrogen are preferred steroids.
  • Other preferred steroids are steroids of general formula I wherein R j represents two hydrogens atoms; R 2 is hydroxy; R 3 is ethynyl; R 4 is (2-6 C) alkyl, (2-6 C) alkylidene or (2-6 C) alkenyl, each of which groups may be substituted with fluorine; and R 5 is methyl.
  • the OH group may be etherified or esterified.
  • etherified means that the hydroxy group is etherified with a lower alkyl group, preferably having 1-6 carbon atoms, such as methyl, ethyl, propyl, sec-butyl and the like.
  • esterified means that the hydroxy group is esterified with a lower alkanoyl group, preferably having 2-6 carbon atoms, like acetyl, propionyl, and the like. In principle any ester suffices as long as the ester group cleaves when the compound is administered in vivo .
  • the (1-6 C) alkyl group in the definition of formula I is a branched or unbranched alkyl group having 1-6 carbon atoms, such as methyl, ethyl, propyl, butyl, tert-butyl, pentyl and hexyl.
  • the alkyl group is methyl (especially for R 5 ) and ethyl (especially for R 4 ).
  • the term (2-6 C) alkyl has the same meaning with the exception of methyl.
  • the (2-6 C) alkenyl group is a branched or unbranched alkenyl group having 2-6 carbon atoms, like vinyl, 2- propenyl, and 1,3-butadienyl.
  • the (2-6 C) alkynyl group is a branched or unbranched alkynyl group having 2-6 carbon atoms, like ethynyl, propynyl, butynyl, and the like.
  • the (2-6 C) alkylidene group is a branched or unbranched alkylidene group having 2-6 ' carbon atoms, like ethylidene, propylidene, 2-methylpropylidene, and the like.
  • halogen used in the definition of formula I means fluorine, chlorine, bromine or iodine. Fluorine is the preferred halogen.
  • (1-6 C) alkoxy means an alkoxy group, the alkyl moiety of which is a (1-6 C) alkyl group as previously defined.
  • (2-7 C) alkoxyalkyl means a (1-6 C) alkyl group as previously defined substituted by a (1-6 C) alkoxy group as previously defined, the total number of carbon atoms being between 2 and 7.
  • the new compounds of this invention can be prepared by condensation of 11-keto steroids of the general formula:
  • R- L represents 0
  • R 2 is hydroxy, optionally etherified or esterified
  • R 3 is (2-6 C) alkynyl, optionally substituted with hydroxy
  • R 5 is hydrogen or (1-6 C) alkyl; or wherein
  • R- L represents two hydrogens atoms
  • R 2 is hydroxy, optionally etherified or esterified
  • R 3 is (2-6 C) alkynyl, optionally substituted with hydroxy
  • R 5 is (1-6 C) alkyl; the active groups of which are optionally protected, is condensed with a Wittig(-like) compound of the formula
  • R 'R 4 "CH-W wherein R 4 R 4 // C forms the group R 4 which is the optionally halogen, hydroxy, or (1-6 C) alkoxy substituted (2-6 C) alkylidene group as previously defined, or R 4 "'Li, wherein R 4 '" is (2-6 C) alkyl or (2-6 C) alkenyl optionally substituted with halogen, hydroxy, or (1-6 C) alkoxy, in which reactive groups can be protected by protective groups which are known in the art (see for example T.W.
  • W is a Wittig, Wittig-Horner or Peterson-like moiety, optionally followed by halogenation and dehydration or by hydration, after which the compound obtained is converted into a nitrile or condensed with a Wittig(*- like) compound of the formula R g W, wherein W has the previously given meaning and R 6 is independently hydrogen, halogen or (1-6 C) alkyl, followed by hydroboration, optionally followed by alkylation, halogenation, or halogenation and dehydrohalogenation, or (partial) hydrogenation, after which optionally present protective groups are removed.
  • Suitable reagents are triphenylphosphoranes such as R 4 R 4 / CH-P(Hal)Ph 3 and the like, and suitable Peterson reagents are, for example, trimethylsilane reagents like R 4 'R ' , C(MgHal)Si(CH 3 ) 3 , wherein Hal denotes a halogen like chlorine or bromine.
  • the steroids of the invention can be used to prevent and treat estrogen deficiency induced disorders such as menopausal complaints, as is demonstrated in the estrogen-induced bone loss assay.
  • young mature female Wistar rats are ovariectomized and treated with the test compound for 1 month.
  • blood is collected and in the lithium-heparin plasma the bone turnover parameter (osteocalcin) is determined according to the method of Verhaeghe et al., J. Endrocrinol. , 120 , 143-151.
  • the right femur is dissected and the bone density of the distal part of the metaphyse is measured using an X-ray densitometric method.
  • the bone density, in mm aluminum equivalent is expressed in a percentage relative to the intact control group which is 100 % by definition, and to the ovariectomized control group which is 0 % by definition.
  • osteocalcin is defined as 100 % for the ovariectomized group and 0 % for the intact group. Active compounds inhibit the bone turnover, and thus have an osteocalcin value lower than 100 %. Table I gives the results of this assay.
  • the compounds of the invention may be administered enterally or parenterally, and for humans preferably in a daily dosage of 0,001-10 mg per kg body weight.
  • pharmaceutically suitable auxiliaries e.g. as described in the standard reference, Gennaro et al.. Remington's Pharmaceutical Sciences, (18th ed. , Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture
  • the compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
  • the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.
  • a spray e.g. a nasal spray.
  • dosage units e.g. tablets
  • conventional additives such as fillers, colorants, poly ⁇ meric binders and the like is contemplated.
  • any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used.
  • Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
  • Rf 0.77 (toluene-ethyl acetate 9/1) .
  • a mixture of 6.1 g of (7 ⁇ )-3,3-ethanedithio-17,17- ethylenedioxy-7-methyl-ll-methylene-estr-4-en, 90 ml of acetone, 50 ml of tetrahydrofuran and 3 ml of 6 N hydrochloric acid was stirred at ambient temperature. After 1 h the mixture was diluted by addition of 700 ml of 5% sodium carbonate and stirred for h. The precipitate was filtered and dried to provide 5.4 g of (7 ⁇ )-3,3-ethanedithio-7-methyl-ll-methylene-estr-4-en- 17-one.
  • R f 0.74 (toluene-ethyl acetate 9/1).
  • Acetylene gas was passed through a solution of 50 g of potassium tert-butoxide in 500 ml of dry tetrahydro ⁇ furan. After 2 h a solution of 30 g of (7 ⁇ )-3,3- ethanedithio-7-methyl-ll-methylene-estr-4-en-17-one in 400 ml of tetrahydrofuran was introduced dropwise at 0 °C. After stirring for an additional 1 h the mixture was poured into 7 1 of water and stirred for an additional h.
  • Dehydration of the oxime was effected by reacting 0.8 g of (7 ⁇ ,ll ⁇ ,17 ⁇ )-3,3-ethanedithio-17-tetrahydropyranyl- oxy-7-methylestr-4-en-ll-carboxaldehyde oxime in 8 ml of acetic anhydride during 45 min. Concomitant replacement of the 17-tetrahydropyran ether by an acetate group was observed. The reaction mixture was poured into 50 ml of ice water and stirred for 30 min.
  • Acetylene gas was passed through a solution of 10.5 g of potassium tert-butoxide in 60 ml of dry tetrahydrofuran for 1 h at 0 °C. Then a solution of 9.3 g of (7 ⁇ ,ll ⁇ )- 3,3-ethanedithio-17-oxo-7-methylestr-4-en-ll-carbo- nitrile in 100 ml of tetrahydrofuran were added drop- wise. After stirring for 1 h at 0-5 °C the mixture was poured into 500 ml of saturated ammonium chloride solution and the product was extracted with ethyl acetate.
  • lithium diisopropylamide prepared from 250 mg of dii ⁇ opropylamine and 1.6 ml of a 1.6M butyl lithium-hexane ⁇ olution
  • 3 ml of tetrahydrofuran wa ⁇ added a solution of 600 mg of difluoromethyldiphenyl- pho ⁇ phinoxide in 2 ml of tetrahydrofuran at -50 °C.
  • Acetylene gas was bubbled into a solution of 0.48 g of potassium tert-butoxide in a mixture of 5 ml of tetrahydrofuran and 0.5 ml of t-butanol. After 15 min a solution of 250 mg of ll ⁇ -(2,2-difluoroethylene)-estr-4- en-3,17-dione in 3 ml of tetrahydrofuran was added and 15 min later the mixture was quenched with water and the product extracted with ethyl acetate.
  • the organic material wa ⁇ purified by chromatography to provide 1.9 g of (ll ⁇ ,E,17 ⁇ )-ll-(2-chloroethenyl-17-hydroxy-19-norpregn- 4-en-20-yn-3-one; M.p. 180 °C.
  • Ba ⁇ e granule ⁇ were prepared by mixing the lactose with a portion of starch. The remainder of the starch wa ⁇ mixed to a slurry with water and added to the mixture. The whole was granulated and dried. The ⁇ e ba ⁇ e granule ⁇ were mixed with ascorbyl palmitate and the active ingredient, sieved, finely mixed with magnesium ⁇ tearate and then tabletted.
  • Example 9 The components were mixed with one another in the manner described in Example 9, granulated and filled into gelatin cap ⁇ ule ⁇ .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Reproductive Health (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Toxicology (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un stéroïde représenté par la formule générale (I), dans laquelle R1 représente O, (H, OH) ou deux atomes d'hydrogène; R2 représente hydroxy éventuellement éthérifié ou estérifié; R3 représente (2-6 C) alkynyle éventuellement à substituion hydroxy; R4 représente CN ou un des groupes hydrocarbure choisi parmi (1-6 C) alkyle, (1-6 C) alcoxy, (2-6 C) alcényle, (2-6 C) alkynyle, et (2-6 C) alkylidène, chaque groupe hydrocarbure pouvant éventuellement présenter une substitution halogène, hydroxy ou (1-6 C) alcoxy; et R5 représente hydrogène ou (1-6 C) alkyle. Le stéroïde selon l'invention est utilisé pour la fabrication d'un médicament destiné au traitement ou à la prévention d'affections ménopausiques et plus particulièrement l'ostéoporose.
EP94906918A 1993-02-08 1994-02-04 Steroides pour le traitement d'affections menopausiques Withdrawn EP0682672A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP94906918A EP0682672A1 (fr) 1993-02-08 1994-02-04 Steroides pour le traitement d'affections menopausiques

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP93200332 1993-02-08
EP93200332 1993-02-08
PCT/EP1994/000348 WO1994018224A1 (fr) 1993-02-08 1994-02-04 Steroides pour le traitement d'affections menopausiques
EP94906918A EP0682672A1 (fr) 1993-02-08 1994-02-04 Steroides pour le traitement d'affections menopausiques

Publications (1)

Publication Number Publication Date
EP0682672A1 true EP0682672A1 (fr) 1995-11-22

Family

ID=8213615

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94906918A Withdrawn EP0682672A1 (fr) 1993-02-08 1994-02-04 Steroides pour le traitement d'affections menopausiques

Country Status (15)

Country Link
EP (1) EP0682672A1 (fr)
JP (1) JPH08506116A (fr)
KR (1) KR100364113B1 (fr)
CN (1) CN1046735C (fr)
AU (1) AU4675897A (fr)
BR (1) BR9405825A (fr)
CA (1) CA2155532A1 (fr)
FI (1) FI114101B (fr)
HU (2) HU220615B1 (fr)
NO (1) NO308583B1 (fr)
NZ (1) NZ261581A (fr)
PL (1) PL182901B1 (fr)
RU (1) RU2172740C2 (fr)
WO (1) WO1994018224A1 (fr)
ZA (1) ZA94715B (fr)

Families Citing this family (6)

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Publication number Priority date Publication date Assignee Title
TW403736B (en) * 1997-02-21 2000-09-01 Akzo Nobel Nv Steroid compounds having contraceptive and anti-osteoporosis activity
ID25621A (id) * 1998-03-09 2000-10-19 Akzo Nobel Nv Perlengkapan kontrasepsi baru
MXPA02001831A (es) 1999-09-06 2002-10-23 Akzo Nobel Nv Esteroides estrogenicos no aromaticos con un sustituyente de hidrocarburo en posicion 11.
AU8201601A (en) 2000-07-28 2002-02-13 Akzo Nobel Nv 16alpha-methyl or ethyl substituted estrogens
UA89964C2 (ru) 2004-09-08 2010-03-25 Н.В. Органон 15β-ЗАМЕЩЕННЫЕ СТЕРОИДЫ, КОТОРЫЕ ИМЕЮТ СЕЛЕКТИВНУЮ ЭСТРОГЕННУЮ АКТИВНОСТЬ
ES2881336T3 (es) * 2016-03-03 2021-11-29 Crystal Pharma Sau Procedimiento y nuevos productos intermedios para la preparación de 11-metilen-esteroides

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US3465010A (en) * 1966-11-22 1969-09-02 Searle & Co 17 - (unsaturated hydrocarbon - substituted) 11,13beta - dialkylgon -4 - ene - 3,17beta-diols and esters thereof
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Also Published As

Publication number Publication date
HU0102320D0 (en) 2001-08-28
NO953089L (no) 1995-10-06
RU2172740C2 (ru) 2001-08-27
WO1994018224A1 (fr) 1994-08-18
HUT72971A (en) 1996-06-28
HU220615B1 (hu) 2002-03-28
BR9405825A (pt) 1995-12-05
NZ261581A (en) 1997-06-24
HU9501940D0 (en) 1995-09-28
FI953747A (fi) 1995-09-12
FI114101B (fi) 2004-08-13
PL310125A1 (en) 1995-11-27
FI953747A0 (fi) 1995-08-07
CN1046735C (zh) 1999-11-24
PL182901B1 (pl) 2002-03-29
NO953089D0 (no) 1995-08-07
NO308583B1 (no) 2000-10-02
ZA94715B (en) 1994-10-24
AU4675897A (en) 1998-02-19
JPH08506116A (ja) 1996-07-02
CN1117735A (zh) 1996-02-28
AU682170B2 (en) 1997-09-25
CA2155532A1 (fr) 1994-08-18
AU6039494A (en) 1994-08-29
KR100364113B1 (ko) 2003-04-08

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