WO1993014105A1 - Derives de difluoromethylenandrostenone et leur procede de preparation - Google Patents

Derives de difluoromethylenandrostenone et leur procede de preparation Download PDF

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Publication number
WO1993014105A1
WO1993014105A1 PCT/EP1993/000105 EP9300105W WO9314105A1 WO 1993014105 A1 WO1993014105 A1 WO 1993014105A1 EP 9300105 W EP9300105 W EP 9300105W WO 9314105 A1 WO9314105 A1 WO 9314105A1
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WIPO (PCT)
Prior art keywords
formula
compound
symbol
group
compounds
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Application number
PCT/EP1993/000105
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English (en)
Inventor
Franco Buzzetti
Antonio Longo
Angelo Crugnola
Enrico Di Salle
Original Assignee
Farmitalia Carlo Erba S.R.L.
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 Farmitalia Carlo Erba S.R.L. filed Critical Farmitalia Carlo Erba S.R.L.
Priority to CA002106457A priority Critical patent/CA2106457A1/fr
Priority to JP5512161A priority patent/JPH06507181A/ja
Publication of WO1993014105A1 publication Critical patent/WO1993014105A1/fr
Priority to FI934093A priority patent/FI934093A/fi

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Classifications

    • 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
    • C07J1/0003—Androstane derivatives
    • C07J1/0014—Androstane derivatives substituted in position 17 alfa, not substituted in position 17 beta
    • 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
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • 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
    • C07J1/0003—Androstane derivatives
    • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • 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
    • C07J1/0003—Androstane derivatives
    • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • C07J1/0025—Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes

Definitions

  • the present invention relates to new 6-difluoromethylen- androstenones, to a process for their preparation, to pharmaceutical compositions containing them, and to their use as therapeutic agents, in particular in the treatment of hormone-dependent diseases in mammals.
  • aromatized metabolites of androgens i.e. the estrogens
  • the hormones involved in the pathogenic cellular changes associated with the growth of some hormone-dependent cancers such as breast, endometrial and ovarian carcinomas.
  • Estrogens are also involved in the pathogenesis of benign prostatic hyperplasia.
  • Endogenous estrogens are ultimately formed from either androstenedione or testosterone as immediate precursors.
  • the reaction of central importance is the aromatization of the steroidic ring A, which is performed by the enzyme aromatase.
  • aromatization is a unique reaction and the last in the series of steps in the biosynthesis of estrogens, it has been envisaged that an effective inhibition of the aromatase, resulting from compounds able to interact with the aromatizing steps, may have useful application for controlling the amount of circulating estrogens, estrogen- dependent processes in reproduction, and estrogen-dipendent tumours.
  • Known steroidal substances which have been reported to be endowed with an aromatase-inhibiting action are, for example, ⁇ 1 -testololactone (U.S. Pat. 2,744,120), 4-hydroxy- androst-4-ene-3, 17-dione and esters thereof (see, for example, U.S.Pat. 4,235,893), 10-(1,2-propadienyl)-estr-4-ene-3, 17- dione (U.S.Pat.4,289,762), 10-(2-propynyl)-estr-4-ene-3,17-dione (J.
  • ⁇ 1 -testololactone U.S. Pat. 2,744,120
  • 4-hydroxy- androst-4-ene-3, 17-dione and esters thereof see, for example, U.S.Pat. 4,235,893
  • 10-(1,2-propadienyl)-estr-4-ene-3, 17- dione U.S.Pat
  • the present invention provides new compounds having the following general formula (I)
  • R is hydrogen or C 1 -C 4 alkyl
  • a substituent is in the ⁇ -configuration, i.e. above the plane of the ring, whereas a dotted line (,,,,,,) indicates that a substituent is in the ⁇ -configuration, and a wavy line indicates that a substituent may be either in the
  • ⁇ -configuration i.e. below the plane of the ring, or in the ⁇ -configuration or in both, i.e. a mixture thereof.
  • the OH or OR substituent may be either in the ⁇ - or in the ⁇ -configuration or in both, i.e. a mixture thereof.
  • the R substituent may be either in the ⁇ - or ⁇ -configuration or in both, i.e. a mixture thereof.
  • the present invention includes all
  • a C 1 -C 4 alkyl group is preferably a methyl or ethyl group, more preferably a methyl group.
  • the alkyl radical may be a branched or straight chain radical.
  • R 1 as an acyl group may be residue of any physiologically tolerable acid.
  • Preferred examples of said acids are
  • C 1 -C 4 alkanoic acids in particular acetic, propionic and butyric acids.
  • the present invention also includes within its scope pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I), i.e. compounds which have a different formula to formula (I) above but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I).
  • pharmaceutically acceptable bio-precursors otherwise known as pro-drugs
  • Preferred compounds of the invention are the compounds of formula (I) wherein
  • R is hydrogen
  • Examples of specific compounds of the invention are the following compounds which, when appropriate, may be either ⁇ - or ⁇ -epimers or ⁇ , ⁇ -mixtures of said epimers:
  • the compounds of the invention can be obtained by a process comprising:
  • R is as defined above, thus obtaining a compound of formula (I) wherein the symbol --- is a single bond and
  • A is a CO group
  • A is a CO group
  • R and the symbol --- are as defined above, thus obtaining a compound of formula (I) wherein R and the symbol --- are as defined above and A is a H OH group; or
  • R 1 is an acyl group
  • the dehydrofluorination of a compound of formula (II) can be carried out by using basic dehydrohalogenation agents such as pyridine or a LiBr-Li 2 CO 3 -DMF mixture.
  • basic dehydrohalogenation agents such as pyridine or a LiBr-Li 2 CO 3 -DMF mixture.
  • the dehydrofluorination is carried out by chromatographing the raw steroid on neutral or basic alumina and using as eluant an inert solvent such as benzene, dichloromethane or ethyl acetate.
  • the dehydrogenation of a compound of formula (III) may be performed according to known methods, e.g. by treatment with DDQ, according to D. Walker and J.D. Hiebert: Chem. Rev. 67, 156 (1967), or by treatment with selenium dioxide, chloranil or benzeneseleninic acid.
  • the reaction is performed by treatment with benzeneseleninic anhydride in an inert organic solvent, such as chlorobenzene or carbon tetrachloride, at a temperature ranging from about 60°C to about 120°C and reaction times varying from about 2 to about 48 hours.
  • the selective reduction of a compound of formula (IV) may be carried out by a well known method, for example as des cribed by C. Djerassi in Steroid Reactions (1963) or by J. Fried in Organic Reactions in Steroid Chemistry Vol. I (1972).
  • the reduction is carried out with a complexed metal hydride, in particular with sodium borohydride in an inert organic solvent, in particular in methanol solution at temperatures ranging from about 0 to about
  • the acylation of a compound of formula (V) can be performed by reaction with a reactive derivative of a suitable carboxylic acid, such as an anhydride or halide, in the presence of a basic agent, at temperatures ranging from about 0 to about 50°C.
  • a reactive derivative of a suitable carboxylic acid such as an anhydride or halide
  • a basic agent such as a sodium bicarbonate
  • the acylation is carried out by reaction with the respective anhydride in the presence of an organic base, such as pyridine.
  • the separation of a mixture of isomers into the single isomers as well as the conversion of a compound of formula (I) into another compound of formula (I) may be carried out according to known methods.
  • a 17 ⁇ -hydroxy derivative of a compound of formula (I) may be converted into the respective 17 ⁇ -hydroxy derivative by basic catalysis, e.g. with 0.1N sodium hydroxide in an aliphatic alcohol, e.g. ethanol.
  • processes b), c) and d) can be regarded as optional conversions of a compound of formula (I) into an- other compound of formula (I).
  • a compound of for mula (III) is a compound of formula (I) wherein the symbol --- is a single bond, A is CO and R is as herein defined.
  • a compound of formula (IV) is a compound of formula (I) wherein A is CO and the symbol --- and R are as herein
  • a compound of formula (V) is a compound of formula (I) wherein A is CH OH and the symbol --- and
  • R are as herein defined.
  • a compound of formula (II) can be obtained by oxidizing a compound of formula (VI)
  • the oxidation of a compound of formula (VI) can be performed according to known methods, e.g. by treatment with the Jones reagent as described by Fieser and Fieser in Reagents for Organic Synthesis 1, 142 (Wiley 1967).
  • Jones reagent is a solution of chromic acid and sulfuric acid in water.
  • the oxidation may be carried out by titrating a stirred solution of the alcoholic compound in acetone at temperatures ranging from about -20°C to about 30°C with the Jones reagent.
  • a compound of formula (VI) wherein R is as defined above may be obtained by saponification of a compound of formula (VII)
  • R is as defined above and R 1 , being as herein defined, is preferably a lower alkanoyl group, in particular acetyl.
  • the saponification may be performed by a conventional method, e.g. by treatment with an alkali metal hydroxide in alcoholic solution, preferably with potassium hydroxide in methanol or ethanol at temperatures ranging from about 20°C to reflux temperature.
  • a compound of formula (VII), wherein R and R 1 are as defined above, may be obtained from a compound of formula (VIII)
  • R and R 1 are as defined above by applying e.g. the method described in U.S. Pat. 3,504,002. Accordingly, the 6-ketosteroid of formula (VII) is treated with at least equimolar amounts of tributylphosphine and sodium chloro- difluoroacetate, at a temperature in the range of 150 - 200°C, using as solvent disubstituted hydrocarbon amide. It is viewed as involving the in situ production of tri- butylphosphinedifluoromethylene, which reacts with the 6-keto group. Alternatively, the method mentioned in U.S. Pat. 4,567,000 can be used.
  • a solution of the protected 6-ketosteroid in an inert solvent such as THF, dioxane or diglyme is added to a cold solution of (di- ethylphosphinyl )difluoromethyllithium at about -60°C to about -80°C.
  • This reagent may be prepared by treatment of diethyl difluoromethylphosphonate with 1.1 equivalent of lithium diisopropylamide in THF at -78oC.
  • a compound of formula (VIII) wherein R and R 1 are as defined above may be obtained by oxidation of a compound of formula (IX)
  • R and R 1 are as defined above.
  • This conversion may be performed according to a well known oxidation method in steroid chemistry, e.g. according to the method described above.
  • a compound of formula (IX) wherein R and R 1 are as defined above may be obtained by cleavage of the 5 ⁇ , 6 ⁇ -epoxide ring in a compound of formula (X)
  • R and R 1 are as defined above.
  • the cleavage may be carried out, e.g., accordingly to
  • a compound of formula (X), wherein R and R 1 are as defined above, may be obtained from a compound of formula (XI)
  • a compound of formula (XI), wherein R and R 1 are as defined above, may be obtained from a compound of formula (XII)
  • R and R 1 are as defined above;
  • N-bromoamide such as N-bromoacetamide or N-bromosuccinimide
  • perchloric acid in an aqueous solvent mixture such as aqueous dioxan or aqueous 1,2-dimethoxyethane at temperatures ranging from about 0°C to room temperature, e.g. as described in J. Chem. Soc. 1959, 4108.
  • the compounds of formula (XII) are known compounds or may be obtained by known methods from known compounds.
  • they may be protected before the reactions take place and then deprotected at the end of the reaction, according to well known methods in organic chemistry.
  • the compounds of the present invention are inhibitors of the biotransformation of androgens into estrogens, i.e., they are steroidal aromatase inhibitors.
  • the aromatase inhibitory activity of these compounds was demonstrated by employing the in vitro test described by Thompson and Siiteri (E.A. Thompson and P.K. Siiteri, J. Biol. Chem. 249, 5364, 1974) which utilizes the human placental microsomal fraction as enzyme source.
  • the compounds incubated at various concentrations, showed a relevant aromatase inhibitory activity.
  • the compounds of the invention are useful in mammals, including humans, in the treatment and prevention of various estrogen-dependent diseases, i.e. breast, endometrial, ovarian and pancreatic cancers, gynecomastia, benign breast disease, endometriosis, polycystic ovarian disease and precocious puberty.
  • various estrogen-dependent diseases i.e. breast, endometrial, ovarian and pancreatic cancers, gynecomastia, benign breast disease, endometriosis, polycystic ovarian disease and precocious puberty.
  • Another application of the compounds of the invention is in the therapeutic and/or prophylactic treatment of prostatic hyperplasia, a disease of the estrogen-dependent stromal tissue.
  • the compounds of the invention can find also use for the treatment of male infertility associated with oligospermia and for female fertility control, by virtue of their ability to inhibit ovulation and egg nidation.
  • the compounds of the invention can be used safely in medicine.
  • the approximate acute toxicity (LD 50 ) of the compounds of the invention in the mouse determined by single adminis tration of increasing doses and measured on the seventh day after the treatment was found to be negligible.
  • the compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous injection or infusion.
  • the dosage depends on the age, weight, conditions of the patient and admininistration route; for example, the dosage adopted for oral administration to adult humans may range from about 10 to about 150-200 mg pro dose, from 1 to 5 times daily.
  • compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent).
  • a pharmaceutically acceptable excipient which can be a carrier or diluent.
  • compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • diluents e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch
  • lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
  • binding agents e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrol
  • a starch alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs, sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
  • the liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
  • the syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • a pharmaceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • the solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
  • the suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g.
  • cocoa-butter polyethylene glycol, a polyoxyethylene
  • the present invention also provides a compound of formula (I) for use in a method of treatment of the human or animal body by therapy, especially for use as an aromatase
  • the present invention additionally provides the use of a compound of formula (I) in the manufacture of a medicament for use as an aromatase inhibitor.
  • the present invention further provides a method of
  • the present invention still further provides an aromatase inhibiting agent comprising a compound of formula (I).
  • First Jones reagent is prepared by dissolving 2.672 g of chromic trioxide in 2.3 ml of cone. sulfuric acid and diluting with water to a volume of 10 ml. Then to a stirred solution of 6-difluoromethylene-5 ⁇ (-fluoroandrostan-3,17- diol (358 mg, 1 mmol) in acetone (30 ml) is added portionwise under cooling 2 ml Jones reagent. After stirring for 1 ⁇ 2 h at 10-15°C and another1 ⁇ 2 h at 20-25°C, methanol ( 1 ml ) is added to destroy excess reagent.
  • the resultant green solution is filtered to remove the chromium salts and then carefully diluted with water in order to precipitate raw 6-difluoromethylene-5 ⁇ -fluoroandrostan-3,17-dione.
  • the precipitate is filtered off, desiccated, dissolved in
  • Tablets each weighing 0.150 g and containing 25 mg of the active substance, were manufactured as follows:
  • Composition for 10,000 tablets:
  • Magnesium stearate 5 g The 6-difluoromethylenandrost-4-ene-3,17-dione, the lactose and half the corn starch were mixed; the mixture was then forced through a sieve of 0.5 mm mesh size. Corn starch (10 g) was suspended in warm water (90 ml) and the resulting paste was used to granulate the powder.
  • the granulate was dried, comminuted on a sieve of 1.4 mm mesh size, then the remaining quantity of starch, talc and magnesium stearate was added, carefully mixed and processed into tablets.
  • Capsules each dosed at 0.200 g and containing 20 mg of the active substance were prepared.
  • composition for 500 capsules is Composition for 500 capsules:
  • This formulation was encapsulated in two-piece hard gelatin capsules and dosed at 0.200 g for each capsule.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouvelles 6-difluorométhylènandrosténones répondant à la formule (I), dans laquelle le symbole -^_-^_-^_ représente une liaison simple ou double; R représente hydrogène ou alkyle C1-4; et A représente un groupe =C=O, =CH$(1,3)$OH ou =CH$(1,3)$OR1 dans lequel R1 représente un groupe acyle. Ces dérivés peuvent être utilisés comme inhibiteurs de l'aromatase stéroïdienne.
PCT/EP1993/000105 1992-01-21 1993-01-18 Derives de difluoromethylenandrostenone et leur procede de preparation WO1993014105A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002106457A CA2106457A1 (fr) 1992-01-21 1993-01-18 Derives de la difluoromethylenandrosterone et procede pour leur preparation
JP5512161A JPH06507181A (ja) 1992-01-21 1993-01-18 ジフルオロメチレンアンドロステノン誘導体およびその調製方法
FI934093A FI934093A (fi) 1992-01-21 1993-09-17 Difluormetylenandrostenonderivat och foerfarande foer deras framstaellning

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929201224A GB9201224D0 (en) 1992-01-21 1992-01-21 Difluoromethylenandrostenone derivatives and process for their preparation
GB9201224.4 1992-01-21

Publications (1)

Publication Number Publication Date
WO1993014105A1 true WO1993014105A1 (fr) 1993-07-22

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PCT/EP1993/000105 WO1993014105A1 (fr) 1992-01-21 1993-01-18 Derives de difluoromethylenandrostenone et leur procede de preparation

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JP (1) JPH06507181A (fr)
AU (1) AU3351593A (fr)
CA (1) CA2106457A1 (fr)
FI (1) FI934093A (fr)
GB (1) GB9201224D0 (fr)
HU (1) HUT64968A (fr)
IL (1) IL104204A0 (fr)
MX (1) MX9300244A (fr)
WO (1) WO1993014105A1 (fr)
ZA (1) ZA9335B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001366A1 (fr) * 1993-06-29 1995-01-12 Pharmacia S.P.A. Derives de 6-methylenandrosta-1,4-dien-3-one fluores et procedes de preparation
US5914324A (en) * 1996-08-19 1999-06-22 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. 6-Hydroxy and 6-oxo-androstane derivatives active on the cardiovascular system and pharmaceutical compositions containing same

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2177700A (en) * 1985-07-09 1987-01-28 Erba Farmitalia Substituted androsta-1, 4-diene-3,17-diones useful as aromatase inhibitors
EP0260975A1 (fr) * 1986-09-17 1988-03-23 FARMITALIA CARLO ERBA S.r.l. Dérivés de 6-alkylidène-androstène-3,17-dione substitués en 4 et procédé de préparation
EP0307135A1 (fr) * 1987-09-11 1989-03-15 FARMITALIA CARLO ERBA S.r.l. Dérivés d'androsta-1,4-diène 3-one substituées en 17
EP0307134A1 (fr) * 1987-09-11 1989-03-15 FARMITALIA CARLO ERBA S.r.l. Procédé de préparation de dérivés d'androsta-1,4-diène 3,17-dions substitués par un méthylène
EP0326340A2 (fr) * 1988-01-26 1989-08-02 FARMITALIA CARLO ERBA S.r.l. Synthèse de dérivés de 6-méthylène-androsta-1,4-diène-3,17-diones

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2177700A (en) * 1985-07-09 1987-01-28 Erba Farmitalia Substituted androsta-1, 4-diene-3,17-diones useful as aromatase inhibitors
EP0260975A1 (fr) * 1986-09-17 1988-03-23 FARMITALIA CARLO ERBA S.r.l. Dérivés de 6-alkylidène-androstène-3,17-dione substitués en 4 et procédé de préparation
EP0307135A1 (fr) * 1987-09-11 1989-03-15 FARMITALIA CARLO ERBA S.r.l. Dérivés d'androsta-1,4-diène 3-one substituées en 17
EP0307134A1 (fr) * 1987-09-11 1989-03-15 FARMITALIA CARLO ERBA S.r.l. Procédé de préparation de dérivés d'androsta-1,4-diène 3,17-dions substitués par un méthylène
EP0326340A2 (fr) * 1988-01-26 1989-08-02 FARMITALIA CARLO ERBA S.r.l. Synthèse de dérivés de 6-méthylène-androsta-1,4-diène-3,17-diones

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANTI-CANCER DRUG DESIGN vol. 5, no. 2, 1990, pages 221 - 235 D. D. MICKEY ET AL 'Growth Modulation Effects of Synthetic Steroids on Rat Prostatic Adenocarcinoma and Human Breast Adenocarcinoma' *
JOURNAL OF STEROID BIOCHEMISTRY vol. 6, no. 3-4, 1975, pages 317 - 322 P. K. SIITERI ET AL 'Human Placental Aromatase' *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001366A1 (fr) * 1993-06-29 1995-01-12 Pharmacia S.P.A. Derives de 6-methylenandrosta-1,4-dien-3-one fluores et procedes de preparation
US5914324A (en) * 1996-08-19 1999-06-22 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. 6-Hydroxy and 6-oxo-androstane derivatives active on the cardiovascular system and pharmaceutical compositions containing same

Also Published As

Publication number Publication date
FI934093A0 (fi) 1993-09-17
HUT64968A (en) 1994-03-28
IL104204A0 (en) 1993-05-13
AU3351593A (en) 1993-08-03
GB9201224D0 (en) 1992-03-11
MX9300244A (es) 1993-07-01
HU9302649D0 (en) 1993-12-28
ZA9335B (en) 1993-08-05
CA2106457A1 (fr) 1993-07-22
JPH06507181A (ja) 1994-08-11
FI934093A (fi) 1993-09-17

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