EP0620823A1 - DERIVES DE LA 6,7$g(a)-DIFLUOROMETHYLENEANDROSTA-1,4-DIEN-3-ONE ET PROCEDES POUR LEUR PREPARATION - Google Patents

DERIVES DE LA 6,7$g(a)-DIFLUOROMETHYLENEANDROSTA-1,4-DIEN-3-ONE ET PROCEDES POUR LEUR PREPARATION

Info

Publication number
EP0620823A1
EP0620823A1 EP93923484A EP93923484A EP0620823A1 EP 0620823 A1 EP0620823 A1 EP 0620823A1 EP 93923484 A EP93923484 A EP 93923484A EP 93923484 A EP93923484 A EP 93923484A EP 0620823 A1 EP0620823 A1 EP 0620823A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
dien
group
difluoromethylenandrosta
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Withdrawn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
EP93923484A
Other languages
German (de)
English (en)
Inventor
Franco Buzzeti
Antonio Longo
Enrico Di Salle
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.)
Pfizer Italia SRL
Original Assignee
Farmitalia Carlo Erba SRL
Pharmacia and Upjohn SpA
Pharmacia SpA
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 SRL, Pharmacia and Upjohn SpA, Pharmacia SpA filed Critical Farmitalia Carlo Erba SRL
Publication of EP0620823A1 publication Critical patent/EP0620823A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • C07J53/004—3 membered carbocyclic rings
    • C07J53/007—3 membered carbocyclic rings in position 6-7
    • 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
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones

Definitions

  • the present invention relates to new 6 , 7 ⁇ -difluoro- methylenandrosta-1 , 4-dien-3-ones , 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, endometrial and ovarian carcinomas.
  • Estrogens are aslo 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, ⁇ 1 -testololactone (U.S.Pat.
  • R is hydrogen or C,-C, alkyl
  • the present invention also provides a compound of formula (I) wherein
  • R is hydrogen or C,-C. alkyl; and A is a group, in which
  • R' is an acyl group; with the exclusion of 17 ⁇ -acetoxy-6 , 7 ⁇ -difluoromethylen- androsta-1 ,4-dien-3-one .
  • the present invention additionally provides a compound of formula (I) with the exclusion of 17 ⁇ -acetoxy-6 , 7 ⁇ - difluoromethylenandrosta-1 , 4-dien-3-one for use in a method of treatment of the human or animal body by therapy.
  • An agent for use as an aromatase inhibitor comprises a compound of formula (I).
  • the compounds of formula ( I ) may be used in a method of treatment of an estrogen-dependent ;ondition which comprises administering to a subject suffering or liable to suffer therefrom an effective dose of the compound of formula (I).
  • A is -OH ⁇ wOH or -CH'v DR j
  • the OH or OR j substituent may be either in the ⁇ - or in the ⁇ -configuration or in both, i.e. a mixture thereof.
  • object of the present invention are also all the possible isomers, e.g. the single 17 ⁇ and 17 ⁇ epimers, as well as the possible mixtures thereof, e.g. 17( ⁇ , ⁇ ).
  • the alkyl radical may be a branched or straight chain.
  • a C.-C. alkyl group is preferably a methyl or ethyl group, more preferably a methyl group.
  • R, as an acyl group may be residue of any physio ⁇ logically tolerable acid.
  • Preferred examples of said acids are the C,-C, alkanoic ones; 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.
  • R is hydrogen
  • Examples of specific compounds of the invention are the following compounds, which, when appropriate, may be also ⁇ , ⁇ -mixtures of the 17 ⁇ -ol and 17 ⁇ -ol epimers: 6 , 7 ⁇ -difluoromethylenandrosta-1 ,4-dien-3,l7-dione ;
  • the compounds of the invention can be obtained by a - 6
  • R and R' are as defined above, with a difluoro- methylene radical generating reagent, so obtaining a compound of formula (I) wherein R is as defined above and A is a -CH- ⁇ OR' group wherein R, is as defined above; and, if desired, b) hydrolyzing a compound of formula (III)
  • the difluoromethylene radical generating reagent may be for example sodium chlorodifluoro acetate.
  • This reaction may be carried out e.g. according to J.H. Fried et al . in J.Med.Chem. 11 , 868 (1968).
  • the difluoromethylene radical can be generated from an alkali or alkaline earth metal salt of trifluoroacetic acid or chlorodifluoroacetic acid.
  • the reaction is performed at temperatures above the decomposition temperature as evidenced by CO, evolution.
  • sodium chlorodifluoroacetate a temperature from about 150° to about 180° is employed.
  • the reaction is preferably effected in an inert non aqueous solvent sufficiently polar to dissolve the salt.
  • Useful solvents are ethylene glycol dimethyl ether, diethyleneglycol dimethylether or triethyleneglycol dimethylether.
  • the hydrolysis of a compound of formula (III), according to the process step b), may be performed by conventional methods, e.g. by treatment with alkali metal hydroxide in anhydrous or aqueous alcoholic solution, preferably with potassium hydroxide in methanol or ethanol at temperatures ranging from about 20°C to reflux temperature.
  • the hydrolysis may be carried out with an alkali metal alkoxide in anhydrous alcohol solution, preferably with sodium methoxide in methanol at room temperature.
  • the oxidation of a compound of formula (IV), according to the process step c), 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 I, 142 (Editor Wiley, 1967).
  • the 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.
  • processes b) and c) can be regarded as optional conversions of a compound of formula (I) into another compound of formula (I).
  • a compound of formula (III) is a compound of formula (I) wherein A is and R and R' are as herein defined.
  • a compound of formula (IV) is a compound of formula ( I ) ' wherein A is _CH ⁇ --OH and R is as herein defined.
  • a compound of formula (II) wherein R and R' are as defined above may be obtained by dehydrobromination of a compound of formula (V)
  • This elimination reaction may be carried out in a polar solvent, e.g. acetonitrile , dimethylformamide , dimethylsulfoxide and similar with inorganic or organic basic agent.
  • An inorganic basic agent may be a mixture of an alkali metal halide with alkali metal carbonate.
  • Preferred examples are mixtures of lithium or sodium chloride or bromide with lithium or sodium carbonate.
  • Preferred examples of organic basic agents are diazabicyclo- undecene ( DBU ) , diazabicyclononene ( DBN ) , pyridine, collidine and the like.
  • the reaction may be performed at temperatures ranging from about 25 °C to about 150 ° C, preferably from about 80 ° C to about 120 ° C.
  • a compound of formula (V) wherein R and R' are as defined above may be obtained by allyl bromination of a compound of formula (VI)
  • the 6 ⁇ - bromination may be carried out according to known procedures, for example, by reaction with a suitable N- bromoacylamide , e.g. N-bromoacetamide or N-bromo- succinimide, in an inert organic solvent, e.g. carbontetrachloride , at a temperature ranging from about room temperature to reflux temperature.
  • a suitable N- bromoacylamide e.g. N-bromoacetamide or N-bromo- succinimide
  • an inert organic solvent e.g. carbontetrachloride
  • the compounds of formula (VI) are known compounds or may be obtained by known methods from known compounds.
  • the compounds of the present invention are inhibitors of the biotransformation of androgens into estrogens, i.e. , they are steroidal aromatase inhibitors.
  • 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.
  • 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 oligo- spermia 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 ( D ) 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. intramuscularly, or by intravenous injection or infusion.
  • 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).
  • 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
  • binding agents e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone
  • 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 pharma ⁇ ceutical 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, 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 togheter 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.
  • Example 1 illustrates but do not limit the invention.
  • Tablets each weighing 0.150 g and containing 25 mg of the active substance, were manufactured as follows: Composition (for 10,000 tablets):
  • 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.
  • composition for 500 capsules each dosed at 0.200 g and containing 20 mg of the active substance were prepared.
  • This formulation was encapsulated in two-piece hard gelatin capsules and dosed at 0.200 g for each capsule.

Abstract

Cette invention concerne l'utilisation de composés de la formule (I) dans laquelle R représente hydrogène ou C1-C4alkyle; et A représente un groupe (a), (b) ou (c) dans lequel R' représente un groupe acyle; pour la fabrication d'un médicament destiné à être utilisé comme inhibiteur d'aromatase; et descomposés de la formule (I) à l'exclusion de la 7alpha-acétoxy-6,7alpha-difluorométhylèneandrosta-1,4-dièn-one.
EP93923484A 1992-10-28 1993-10-18 DERIVES DE LA 6,7$g(a)-DIFLUOROMETHYLENEANDROSTA-1,4-DIEN-3-ONE ET PROCEDES POUR LEUR PREPARATION Withdrawn EP0620823A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9222669 1992-10-28
GB929222669A GB9222669D0 (en) 1992-10-28 1992-10-28 6,7 alpha-difluoromethylenandrosta-1,4-dien-3-one derivatives and process for their preparation
PCT/EP1993/002864 WO1994010190A1 (fr) 1992-10-28 1993-10-18 DERIVES DE LA 6,7α-DIFLUOROMETHYLENEANDROSTA-1,4-DIEN-3-ONE ET PROCEDES POUR LEUR PREPARATION

Publications (1)

Publication Number Publication Date
EP0620823A1 true EP0620823A1 (fr) 1994-10-26

Family

ID=10724212

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93923484A Withdrawn EP0620823A1 (fr) 1992-10-28 1993-10-18 DERIVES DE LA 6,7$g(a)-DIFLUOROMETHYLENEANDROSTA-1,4-DIEN-3-ONE ET PROCEDES POUR LEUR PREPARATION

Country Status (4)

Country Link
EP (1) EP0620823A1 (fr)
JP (1) JPH07502759A (fr)
GB (1) GB9222669D0 (fr)
WO (1) WO1994010190A1 (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3322285A1 (de) * 1983-06-18 1984-12-20 Schering AG, 1000 Berlin und 4709 Bergkamen 1-alkyl-androsta-1,4-dien-3,17-dione, verfahren zu deren herstellung und diese enthaltende pharmazeutische praeparate
JP2860821B2 (ja) * 1990-05-30 1999-02-24 帝国臓器製薬株式会社 ６，７―メチレンステロイド誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9410190A1 *

Also Published As

Publication number Publication date
GB9222669D0 (en) 1992-12-09
JPH07502759A (ja) 1995-03-23
WO1994010190A1 (fr) 1994-05-11

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