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WO1995001366A1 - Derives de 6-methylenandrosta-1,4-dien-3-one fluores et procedes de preparation - Google Patents

Derives de 6-methylenandrosta-1,4-dien-3-one fluores et procedes de preparation Download PDF

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Publication number
WO1995001366A1
WO1995001366A1 PCT/EP1994/001993 EP9401993W WO9501366A1 WO 1995001366 A1 WO1995001366 A1 WO 1995001366A1 EP 9401993 W EP9401993 W EP 9401993W WO 9501366 A1 WO9501366 A1 WO 9501366A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
dien
fluorine
methylenandrosta
Prior art date
Application number
PCT/EP1994/001993
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English (en)
Inventor
Franco Buzzetti
Antonio Longo
Enrico Di Salle
Original Assignee
Pharmacia S.P.A.
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 Pharmacia S.P.A. filed Critical Pharmacia S.P.A.
Priority to JP6521435A priority Critical patent/JPH08500609A/ja
Priority to EP94919642A priority patent/EP0656901A1/fr
Publication of WO1995001366A1 publication Critical patent/WO1995001366A1/fr

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Classifications

    • 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
    • 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

Definitions

  • the present invention relates to new fluorinated 6- methylenandrosta-l ,4-dien-3-one derivatives, 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.
  • Basic and clinical data indicate that aromatized metabolites of androgens, i.e. the estrogens, are the hormones involved in the pathogenic cellular changes associated with the growth of some hormone-dependent cancers, such as breast, emdometrial 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-dependent tumours.
  • Known steroidal substances which have been reported to be endowed with an aromatase-inhibiting action are, for example, ⁇ '-testololactone (U.S.Pat. 2,744,120), 4- hydroxyandrost-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.Amer.Chem.Soc. , 103. 3221 (1981) and U.S.Pat.
  • Non fluorinated 6-methylenandrosta-l ,4-diene-3-one derivatives are disclosed in U.S.Pat. 4,822,528; whilst otherwise halogen substituted 6-methylenandrosta-l ,4- diene-3-one derivatives are disclosed in U.S.Pat. 4,808,616, U.S.Pat. 4,824,830, U.S.Pat. 4,873,233 and our co ⁇ >eiic.ng U.K.Pat.Appl . 9201224.4.
  • the present invention provides new compounds having the following general formula (I) wherein
  • R 3 is also fluorine.
  • the invention includes within its scope all the possible isomers, stereoisomers and their mixtures, and the metabolites and the metabolic precursors or bioprecursors of the compound of formula (I) .
  • the heavy solid lines ( - ⁇ ) indicate that 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, i.e. beneath the plane of the ring, and a wavy line ( ⁇ V) indicates that a substituent may be either in the ⁇ - configuration or in the ⁇ -configuration or both, i.e. a mixture thereof.
  • A is
  • the ⁇ H and OR 4 substituent respectively may be either in the ⁇ - or in the ⁇ - configuration or both, i.e. a mixture thereof.
  • R is a fluorine substituent the fluorine may be either in the E- or in the Z- configuration or both, i.e. a mixture thereof.
  • An acyl group may be a residue of any physiologically tolerable acid.
  • Preferred examples of said acids are the C.-C. alkanoic ones; in particular acetic, propionic and butyric acids.
  • the acyl group is therefore preferably a C j -C j alkanoyl group, more preferably a C,-C j alkanoyl group, such as acetyl , propionyl or butyryl.
  • 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 also fluorine.
  • the compounds of the invention can be obtained by a process comprising:
  • R , R and R are as defined above, thus obtaining a compound of formula ( I ) in which R , R and R are as defined above and A is a >CH--w ⁇ ⁇ R group wherein R is an acyl group; or
  • the epoxide cleavage with hydrogen fluoride of a compound of formulae (II), (IV), (V) or (VI) according, respectively, to the process steps (a), (c) (d) and (e) in order to obtain an unstable fluorohydrin intermediate, which dehydrates under acidic conditions to give the desired 2-fluoro- ⁇ -or 4-fluoro- ⁇ -compound respectively, may be performed according to known procedures. Preferably it is carried out by reaction with anhydrous hydrofluoric acid in an inert organic solvent such as tetrahydrofuran, chloroform or mixtures thereof at temperatures ranging from about -78 * C to room temperature. In the case there is no simultaneous dehydration it can be induced e.g. by catalysis with cone, hydrochloric acid in hot ethanol solution.
  • the dehydrogenation of a compound of formula (III) according to the process step (b) may be performed according to known methods, e.g. by treatment with DDQ as described by Walker and Hiebert in Chem. Rev. 6 . , 156 (1967). Alternatively it can be performed by treatment with enzene seleninic anhydride as described by Barton et al. in Chem. Commun. 1978, 130. In the latter case the reaction is carried out in an inert organic solvent, such as chlorobenzene or carbon tetrachloride , at a temperature ranging from about 60' to 120 * C.
  • an inert organic solvent such as chlorobenzene or carbon tetrachloride
  • the selective reduction of a compound of formula (IA) according to process (f) may be carried out by well known methods, for example as described by Djerassi in Steroid Reactions (Holden-Day Inc. 1963) or by Fried in Organic Reactions in Steroid Chemistry (1972).
  • the reduction is carried out with complexed metal hydrides, in particular with sodium borohydride in an inert organic solvent, preferably in methanol solution at temperatures ranging from about 0 * C to 50 * C.
  • the acylation of a compound of formula (I) according to process step (g) can be performed, e.g., 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"C to about 50 * C.
  • a reactive derivative of a suitable carboxylic acid such as an anhydride or halide
  • a basic agent at temperatures ranging from about 0"C to about 50 * C.
  • the acylation is carried out by reaction with the respective anhydride in the presence of an organic base such as pyridine.
  • the oxidation of a compound of formula (I) according to process step (h) can be performed according to known methods, e.g. by treatment with Jones reagent as described by Fieser and Fieser in Reagents for Organic Synthesis i,142 (Ed. 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 a temperature ranging from about -20 * C to about 30"C, with the Jones reagent.
  • the conversion of a compound of formula (I) into another compound of formula (I) includes for example the conversion of a 17 ⁇ -hydroxy derivative of a compound of formula (I) into the corresponding 17 ⁇ -hydroxy derivative which may be carried out by basic catalysis, e.g. with 0.1N sodium hydroxide in an aliphatic alcohol, e.g. ethanol.
  • a compound of formula (II) can be obtained by epoxidation of a compound of formula (VII)
  • the epoxidation may be carried out by treatment with a suitable oxidizing agent, e.g. 36% H-O, in hydroalcoholic alkali hydroxide solution, preferably KOH or NaOH in methanol, at a temperature ranging from about 0 * to 30 * C for reaction times lasting from 2h to several days.
  • a suitable oxidizing agent e.g. 36% H-O
  • hydroalcoholic alkali hydroxide solution preferably KOH or NaOH in methanol
  • a compound of formula (III) can be obtained by fluorination of a compound of formula (VIII)
  • reaction of the aldehyde with DAST is carried out without or with a solvent such as dichloromethane or trichlorofluoro- methane or mixtures thereof at temperatures ranging from about 0' to about 80 * C.
  • the compounds of formula (VIII) are known or may be obtained by known methods from known compounds (see e.g. D. Burn et al . in Tetrahedron 1964. 20. 597-609).
  • a compound of formula (IV) can be obtained by dehydrogenation of a compound of formula (IX) wherein A is as defined above.
  • the dehydrogenation may be performed according to known methods, e.g. as described at process step (b).
  • a compound of formula (IX) can be obtained by alkaline epoxidation of a compound of formula (III) wherein A is as defined above. The same method can be applied as that described above for the epoxidation of compound (VII).
  • a compound of formula (V) can be obtained by alkaline epoxidation of a compound of formula (X)
  • the compounds of formula (X) are known or may be obtained by known methods from a known compound. E.g. they may be obtained according to U.S. Pat. 4,808,816 and U.S. Pat 4,873,233.
  • a compound of formula (VI) can be obtained by alkaline epoxidation of a compound of formula (IC)
  • alkaline epoxidation may be carried out as described above.
  • the compounds of formula ( IC) can be prepared as described in process step (b).
  • 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 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 estro n-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 (LDJ Q ) of the compounds of the invention in the mouse determined by single administration 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.
  • the dosage depends on the age, weight, conditions of the patient and administration 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.
  • the invention includes pharmaceutical 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.
  • the pharmaceutical 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 dispersion 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.
  • 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 sorbitan fatty acid ester surfactant or lecithin.
  • a pharmaceutically acceptable carrier e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • the hydrogen fluoride solution was immersed in an acetone-dry ice bath while the steroid was added.
  • IR cm '1 3050, 1735, 1655, 1610.
  • 6-methylenandrosta-l ,4-diene-3 , 17-dione ( 2.964 , 10 mmol ) was dissolved in methanol (200 ml) and the resulting solution cooled to O'C. Thereupon ice cold 36% hydrogen peroxide (20 ml) and 2% sodium hydroxide (10 ml) were added. The mixture was stirred for about 24 h at O'C and then poured into ice water. The product was filtered off, washed with water and then dried to give almost pure title compound in about 50% yield (1.560 g).
  • Diethylaminosulfur trifluoride (DAST, 6.45 g, 40 mmol) was added at room temperature to a stirred solution of 6- formyl-3-methoxyandrosta-3, 5-dien-17-one (3.285 g, 10 mmol) in dry dichloromethane (50 ml). The solution was stirred for 44 h, diluted with dichloromethane, poured onto crushed ice, and the organic layer was collected. The aqueous layer was further extracted twice with dichloromethane. The combined organic phases were washed with 5% NaHCO, solution and water, dried over Na.SO. and evaporated to dryness.
  • DAST Diethylaminosulfur trifluoride
  • 6-fluoromethylenandros -4-ene-3, 17-dione (3.164 g, 10 mmol) was dissolved in methanol (200 ml) and the resulting solution cooled to O'C. Thereupon ice cold 36% hydrogen peroxide (10 ml) were added. The mixture was stirred for about 24 h at O'C and then poured into ice water. The product was filtered off, washed with water and then dried to give 4 ,5-epoxy-6-fluoromethylen- androstane-3,17-dione in about 50% yield (1.662 g).
  • 6-fluoromethylenandrost-4-ene-3, 17-dione (3.144 g, 10 mmol) was dissolved in methanol (20 ml) and the resulting solution cooled to O'C. Thereupon ice cold 36% H j O j (20 ml) and 2% NaOH (10 ml) was added. The mixture was stirred for about 24 h at O'C and then poured into ice water. The product was filtered off, washed with water and then dried to give almost pure title compound in about 50% yield.
  • Tablets each weighing 0.150 g and containing 25 mg of the active substance, can be manufactured as follows: composition (for 10,000 tablets):
  • Capsules each dosed at 0.200 g and containing 20 mg of the active substance can be prepared.
  • composition for 500 capsules is Composition for 500 capsules:
  • This formulation is 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à des composés de la formule (I) dans laquelle A représente un groupe ⊃C=O, ⊃CHvvvOH ou ⊃CHvvvOR4, R4 représentant un groupe acyle; un ou deux éléments parmi R?1, R2 et R3¿ représente fluor, et les autres représentent des hydrogènes; à condition que, lorsque R2 représente fluor, R1 ou R3 représente également fluor. Les composés de cette invention sont aptes à être utilisés comme inhibiteurs d'aromatase.
PCT/EP1994/001993 1993-06-29 1994-06-06 Derives de 6-methylenandrosta-1,4-dien-3-one fluores et procedes de preparation WO1995001366A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP6521435A JPH08500609A (ja) 1993-06-29 1994-06-06 フッ素化６−メチレンアンドロスタ−１，４−ジエン−３−オン誘導体及び該誘導体の製造方法
EP94919642A EP0656901A1 (fr) 1993-06-29 1994-06-06 Derives de 6-methylenandrosta-1,4-dien-3-one fluores et procedes de preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9313420.3 1993-06-29
GB939313420A GB9313420D0 (en) 1993-06-29 1993-06-29 Fluorinated 6-methylenandrosta-1,4-dien-3-one-derivatives and process for their preparations

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WO1995001366A1 true WO1995001366A1 (fr) 1995-01-12

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PCT/EP1994/001993 WO1995001366A1 (fr) 1993-06-29 1994-06-06 Derives de 6-methylenandrosta-1,4-dien-3-one fluores et procedes de preparation

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EP (1) EP0656901A1 (fr)
JP (1) JPH08500609A (fr)
GB (1) GB9313420D0 (fr)
WO (1) WO1995001366A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072106A3 (fr) * 2001-01-26 2003-10-30 Pharmacia Italia Spa Procede combine de traitement de troubles hormonodependants
WO2011127232A2 (fr) 2010-04-08 2011-10-13 Emory University Androst-4-ène diones substituées

Citations (3)

* 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
EP0253591A1 (fr) * 1986-07-14 1988-01-20 FARMITALIA CARLO ERBA S.r.l. Dérivés de 6- ou 7-méthylène-androsta-1,4-diène-3,17-dione et procédé de préparation
WO1993014105A1 (fr) * 1992-01-21 1993-07-22 Farmitalia Carlo Erba S.R.L. Derives de difluoromethylenandrostenone et leur procede de preparation

Patent Citations (3)

* 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
EP0253591A1 (fr) * 1986-07-14 1988-01-20 FARMITALIA CARLO ERBA S.r.l. Dérivés de 6- ou 7-méthylène-androsta-1,4-diène-3,17-dione et procédé de préparation
WO1993014105A1 (fr) * 1992-01-21 1993-07-22 Farmitalia Carlo Erba S.R.L. Derives de difluoromethylenandrostenone et leur procede de preparation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072106A3 (fr) * 2001-01-26 2003-10-30 Pharmacia Italia Spa Procede combine de traitement de troubles hormonodependants
WO2011127232A2 (fr) 2010-04-08 2011-10-13 Emory University Androst-4-ène diones substituées
US8969327B2 (en) 2010-04-08 2015-03-03 Emory University Substituted androst-4-ene diones

Also Published As

Publication number Publication date
JPH08500609A (ja) 1996-01-23
GB9313420D0 (en) 1993-08-11
EP0656901A1 (fr) 1995-06-14

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