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WO1994027989A1 - Derives de carbazole a activite d'inhibition de 17,20-lyase - Google Patents

Derives de carbazole a activite d'inhibition de 17,20-lyase Download PDF

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Publication number
WO1994027989A1
WO1994027989A1 PCT/EP1994/001613 EP9401613W WO9427989A1 WO 1994027989 A1 WO1994027989 A1 WO 1994027989A1 EP 9401613 W EP9401613 W EP 9401613W WO 9427989 A1 WO9427989 A1 WO 9427989A1
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WIPO (PCT)
Prior art keywords
compound
formula
group
carbazole
fluoro
Prior art date
Application number
PCT/EP1994/001613
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English (en)
Inventor
Peter Clive Cherry
John Derek Cocker
Andrew David Searle
Original Assignee
Glaxo Group Limited
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Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to JP7500181A priority Critical patent/JPH08510455A/ja
Priority to EP94917647A priority patent/EP0699196A1/fr
Priority to PL94311702A priority patent/PL311702A1/xx
Priority to CA002162921A priority patent/CA2162921A1/fr
Priority to SK1424-95A priority patent/SK142495A3/sk
Priority to AU69287/94A priority patent/AU6928794A/en
Publication of WO1994027989A1 publication Critical patent/WO1994027989A1/fr
Priority to NO954681A priority patent/NO954681D0/no
Priority to FI955587A priority patent/FI955587A0/fi
Priority to BG100154A priority patent/BG100154A/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to substituted carbazole derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine for the reduction of oestrogen and/or androgen levels.
  • 17,20-Lyase activity is responsible for the conversion of 17 ⁇ - hydroxyprogesterone to androstenedione and of 17 ⁇ -hydroxypregnenolone to dehydroepiandrosterone. This activity is critical for the biosynthesis of androgens and estrogens, and inhibition of 17,20-lyase by ketoconazole (a known antifungal agent) has been shown to reduce testosterone levels in animals (English, H.F. et al.. Cancer Res. 47, 38-42 (1986) and men (Pont, A. et al., Arch. Intern. Med. 142, 2137-2140 (1982).
  • ketoconazole has been used in the treatment of prostate cancer (Trachtenberg, J., J. Urol. 132, 61-63 (1984) and Pont, A., et al., Arch. Intern. Med. 145, 1429-1431 (1985)).
  • doses of ketoconazole that produce inhibition of testosterone production are significantly more toxic than antifungal doses, and more selective 17,20-lyase inhibitors would be expected to have a much better therapeutic index.
  • Inhibition of 17,20-lyase as an approach to inhibition of testosterone biosynthesis, also has the advantage of blocking adrenal as well as testicular derived androgens (English, H.F. et al.. Cancer Res. 46, 38-42 (1986)), and should be a more effective treatment for prostate cancer than that afforded by LHRH agonists.
  • and R each independently represent a hydrogen atom or a C-j ⁇ alkyl group; each R2 may be the same or different and represents an electron-withdrawing group; each R3 may be the same or different and represents an electron-withdrawing group;
  • R 5 is a group of formula
  • R 6 is a halogen atom, a C ⁇ alkyl group or a C ⁇ alkoxy group; m is zero or an integer 1 to 4; n is zero or an integer 1 to 3; and p is zero, 1 or 2 and pharmaceutically acceptable salts and solvates thereof.
  • the substituents R2 may each occupy any available position of the 5, 6, 7 or 8 positions. .
  • the substituents R3 may each occupy any available position of the 1 , 2, 3 or 4 positions, preferably the 1 , 3 or 4 positions.
  • the group — CHR 4 R 5 may occupy any of the 1 , 2, 3 or 4 positions, for example, the 1 , 2 or 3 positions. Preferably the group — CHR 4 R 5 will be in the 2 position.
  • the invention provides compounds of formula (l a )
  • R 1 t R 2 , R3, R4, R5, m and n are as hereinbefore defined.
  • the substituent RQ may be attached to any carbon atom in the pyridyl ring, but preferably is attached in the 3,4 or 5 positions.
  • formula (I) may contain a chiral centre. It is to be understood that formula (I) is intended to encompass all enantiomers and diastereoisomers of the compounds of the invention as well as mixtures thereof, including racemates.
  • Electron-withdrawing groups are well known to those skilled in the art and any such group may be employed.
  • groups include halogen atoms, such as fluorine, chlorine and bromine atoms, nitrile groups, nitro groups, trifluoromethyl groups, aldehydo groups, keto groups and carboxylic acid and ester groups and are preferably selected from fluorine atoms, chlorine atoms and nitrile groups.
  • Particularly preferred as compounds of formula (I) are those wherein each of R2 and R3 represents a fluorine atom.
  • R2 represents a fluorine atom and m is an integer 1 to 4.
  • R2 When m is 1 R2 will preferably be in the 5 or 7 position, especially the 7- position.
  • C- ⁇ ⁇ alkyl and C-,_ 6 alkoxy groups may contain straight or branched chain alkyl groups, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, pentyl or hexyl groups, preferably C ⁇ alkyl groups.
  • and R4 may be a hydrogen atom or a methyl, ethyl, propyl or butyl group.
  • R-l and R4 are each preferably a hydrogen atom or a methyl group.
  • R 5 is a pyridin-3-yl or pyridin-4-yl group.
  • R 6 represents a fluorine atom, a methyl group or a methoxy group.
  • and R4 each represent a hydrogen atom or a methyl group
  • R2 and R3 are fluorine atoms
  • R 6 is a fluorine atom, a methyl group or a methoxy group
  • m is an integer 1 to 4
  • n is zero or an integer 1 to 3
  • p is zero, 1 or 2.
  • R., and R 4 each represent a hydrogen atom
  • R 2 and R 3 are fluorine atoms
  • R 6 is a fluorine atom or a methyl or methoxy group and m
  • n and p each independently represent zero, 1 or 2.
  • Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, citrates, tartrates, maleates, fumarates, succinates, p-toluenesulphonates and methanesulphonates.
  • acid addition salts derived from inorganic and organic acids such as hydrochlorides, hydrobromides, sulphates, phosphates, citrates, tartrates, maleates, fumarates, succinates, p-toluenesulphonates and methanesulphonates.
  • Other suitable salts will be readily apparent to one skilled in the art. Hydrochloride, sulphate and phosphate salts are especially preferred. Salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of formula (I) and these form a further part of the invention.
  • references hereinafter to a compound according to the invention includes both the compounds of formula (I) and their pharmaceutically acceptable salts and solvates.
  • the compounds according to the invention are potent and selective inhibitors of the enzyme steroidal 17,20-lyase, which is a key enzyme involved in the conversion of C21 -steroids (e.g. pregnenolone) into androgens (e.g. testosterone) and oestrogens (e.g. oestradiol).
  • C21 -steroids e.g. pregnenolone
  • androgens e.g. testosterone
  • oestrogens e.g. oestradiol
  • the 17,20-lyase-inhibiting activity of the compounds of formula (I) was demonstrated in vitro by their ability to inhibit the conversion of 17 ⁇ - hydroxypregnenolone into dehydroepiandrosterone by human testicular 17,20- lyase and of 17 ⁇ -hydroxyprogesterone into androstenedione by rat testicular 17,20-lyase.
  • These assays were conducted according to a method based on that of Ayub and Level, J. Steroid Biochem, 1987, 28, 521.
  • the compounds of the invention were tested for their ability to suppress the elevation of testosterone levels produced in male rats when stimulated with human cho onic gonadotrophin (hCG).
  • hCG human cho onic gonadotrophin
  • Inhibitors of 17,20-lyase reduce circulating and local levels of androgens and oestrogens.
  • the compounds of the invention can thus be used in the treatment of androgen- and/or oestrogen-dependant diseases such as malignant and benign diseases of the breast, endometrium, ovary, prostate and pancreas. These diseases include cancer of the prostate, breast and endometrium, prostatic hypertrophy and hyperplasia, fibrocystic breast disease, endomet osis and polycystic ovarian disease.
  • the compounds of formula (I) are also useful in the treatment of Cushing's syndrome, gynecomastia, premature labour, precocious puberty, female hirsutism, premenstrual syndrome, male pattern baldness and acne.
  • the compounds of the invention will be particularly useful in the treatment of prostate cancer.
  • the invention thus further provides compounds of formula (I) and their pharmaceutically acceptable salts and solvates for use as active therapeutic agents in particular for the treatment of conditions whose underlying aetiology is associated with elevated androgen and/or oestrogen levels in animals (especially humans).
  • a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of prostate cancer.
  • a method for the lowering of the levels of androgens and/or oestrogens in a mammal including a human comprising administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a compound of the invention may be administered to a patient as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention accordingly provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof together with one or more pharmaceutically acceptable carriers or excipients and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carriers must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical, implant or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl-g-hydroxybenzoates or sorbic acid).
  • suspending agents e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g. lecithin or acacia
  • non-aqueous vehicles e.g. almond oil, oily esters or ethyl alcohol
  • preservatives e.g
  • the pharmaceutical compositions may take the form of buccal or sub-lingual tablets, drops or lozenges formulated in conventional manner.
  • the compounds of the invention may be formulated as creams, gels, ointments or lotions or as transdermal patches.
  • compositions may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifying, stabilising, dispersing, suspending, and/or colouring agents.
  • the compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example as a sparingly soluble salt.
  • the compounds of the invention may be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi- dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glyceride.
  • the compounds of the invention may be used, for example, as a liquid spray, as a powder or in the form of drops.
  • the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 ,1 ,2-tetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 ,1 ,2-tetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 ,1 ,2-tetrafluoroethane, carbon dioxide or other
  • compositions described above may be presented in a conventional manner associated with controlled release forms.
  • compositions according to the invention are suitable for oral, rectal or topical administration.
  • a convenient unit dose formulation contains the active ingredient in an amount of from 0.1 to 200mg.
  • a suitable dose will be in the range of from about 1 to about 500mg per day, preferably in the range of 20 to 200mg per day, most preferably in the range of 50 to 120mg per day.
  • a suitable daily dose for use in prophylaxis will generally be in the range of 0.1 mg to 50mg.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the compound is conveniently administered in unit dosage form.
  • the compounds of the present invention may also be used in combination with other therapeutic agents, for example, other androgen and/or oestrogen lowering agents, or anticancer agents.
  • other therapeutic agents for example, other androgen and/or oestrogen lowering agents, or anticancer agents.
  • the compounds of the invention may be employed together with known anticancer agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) as defined herein together with another therapeutically active agent, in particular an anticancer agent.
  • Another therapeutically active agent in particular an anticancer agent.
  • the combination referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier therefor comprise a further aspect of the invention.
  • the compounds When compounds of formula (I) are used in combination with a second therapeutic agent, the compounds may be administered either sequentially or simultaneously by any of the routes described above.
  • Suitable therapeutic agents for use in the combinations defined above include, for example cyproterone acetate, flutamide and anandron.
  • each compound When compounds of formula (I) are used in combination with a second therapeutic agent effective to reduce levels of androgens and/or oestrogens in a mammal including a human the dose of each compound may vary from that when the compound is used alone. Thus when compounds of formula (I) are used together with a second therapeutic agent the dose of each compound may be the same or different to that employed when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • the compounds according to the invention may be prepared by any process known in the art for the preparation of compounds of analogous structure.
  • , R2, R3, R4, R5, R 6 , m, n and p are as defined for general formula (I) unless otherwise specified.
  • represents a hydrogen atom may be prepared from an intermediate of formula
  • reaction is conveniently effected in the presence of a suitable solvent, such as a hydrocarbon solvent, for example dodecane, or a halogenated solvent, such as dichlorobenzene, preferably at elevated temperature, for example 100 to 300°C, preferably 150 to 220°C.
  • a suitable solvent such as a hydrocarbon solvent, for example dodecane, or a halogenated solvent, such as dichlorobenzene, preferably at elevated temperature, for example 100 to 300°C, preferably 150 to 220°C.
  • a suitable solvent such as a hydrocarbon solvent, for example dodecane
  • a halogenated solvent such as dichlorobenzene
  • reaction by treatment with sodium nitrite in the presence of a mineral acid, e.g. sulphuric acid, followed by sodium azide.
  • a mineral acid e.g. sulphuric acid
  • the reaction is conveniently effected in aqueous solution.
  • a hydrogen-donor e.g. ammonium formate
  • a catalyst such as a noble metal catalyst, e.g. platinum, palladium, platinum oxide or rhodium, which may be supported, e.g. on charcoal.
  • the reduction may be carried out in a solvent such as an alcohol e.g. methanol or ethanol (which may be aqueous), acetic acid, aqueous acetic acid, an ether e.g. dioxan, an ester e.g. ethyl acetate or an amide e.g. dimethylformamide, and conveniently at a temperature of from '10 to +5 ⁇ OC, preferably 20 to 30°C.
  • Compounds of formula (IV) may be prepared from compounds of formula (V)
  • reaction by treatment with a compound of formula HR 5 or the sodium salt thereof.
  • the reaction is conveniently effected in a suitable solvent, e.g dimethylformamide.
  • reaction is conveniently effected in a non-polar solvent, such as a halogenated solvent, e.g. chloroform or tetrachloromethane, at a temperature of 20 to ⁇ O ⁇ C.
  • a non-polar solvent such as a halogenated solvent, e.g. chloroform or tetrachloromethane, at a temperature of 20 to ⁇ O ⁇ C.
  • Suitable palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base, e.g. sodium carbonate
  • a suitable aqueous solvent such as an alcohol, e.g. ethanol, an aromatic hydrocarbon, e.g. benzene, or an ether, e.g. dimethoxyethane, or an aqueous mixture of solvents.
  • Suitable atoms or groups represented by L include halogen atoms, e.g. bromine or iodine atoms, or a triflate group.
  • a compound of formula (I) may be prepared from a compound of formula (IX)
  • the deoxygenation reaction is effected using a suitable reducing agent such as hydrogen in the presence of a catalyst, such as a noble metal catalyst, e.g. platinum, palladium, platinum oxide or rhodium, which may be supported, e.g. on charcoal.
  • a catalyst such as a noble metal catalyst, e.g. platinum, palladium, platinum oxide or rhodium, which may be supported, e.g. on charcoal.
  • the reaction may conveniently be carried out in a solvent such as an alcohol, e.g. methanol or ethanol, which may be aqueous, in the presence of an acid, e.g. hydrochloric acid, preferably at elevated temperature, e.g. at the reflux temperature of the solvent or at elevated pressure.
  • General process (B) is particularly useful for the preparation of compounds of formula (I) wherein R 5 is a pyridyl group.
  • Hal - R 5 (XI) in the presence of a suitable base such as an alkyllithium, e.g. n-butyllithium.
  • a suitable base such as an alkyllithium, e.g. n-butyllithium.
  • the reaction is conveniently effected in the presence of a suitable solvent such as an ether, e.g. diethyl ether, dimethoxyethane or tetrahydrofuran, or a mixture of solvents, suitably at low temperature, e.g. -90 to - 50 ⁇ , preferably about -70°C.
  • Suitable oxidising agents will be readily apparent to one skilled in the art and include pyridinium chlorochromate, potassium dichromate in sulphuric acid and barium manganate.
  • the reaction may conveniently be effected in the presence of a solvent, e.g. a halogenated solvent such as dichloromethane.
  • reaction is conveniently effected in the presence of a suitable solvent, such as a hydrocarbon solvent, e.g. dodecane, or a halogenated solvent, e.g. dichloromethane, preferably at elevated temperature, e.g. 100 to 300°C, preferably 150 to 22 ⁇ OC.
  • a suitable solvent such as a hydrocarbon solvent, e.g. dodecane, or a halogenated solvent, e.g. dichloromethane, preferably at elevated temperature, e.g. 100 to 300°C, preferably 150 to 22 ⁇ OC.
  • reaction by treatment with sodium nitrite in the presence of a mineral acid, e.g. sulphuric acid, followed by sodium azide.
  • a mineral acid e.g. sulphuric acid
  • the reaction is conveniently effected in aqueous solution.
  • G represents a hydroxy protecting group
  • a hydrogen-donor e.g. ammonium formate
  • a catalyst such as a noble metal catalyst, e.g. platinum, palladium, platinum oxide or rhodium, which may be supported, e.g. on charcoal and subsequent removal of the protecting group G.
  • the reduction may conveniently be carried out in a solvent such as an alcohol, e.g. methanol or ethanol, which may be aqueous, optionally in the presence of an acid, e.g. hydrochloric acid.
  • Suitable hydroxy protecting groups are described hereinafter.
  • Suitable palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base, e.g. sodium carbonate
  • a suitable aqueous solvent such as an alcohol, e.g. ethanol, an aromatic hydrocarbon, e.g. benzene, or an ether, e.g. dimethoxyethane, or an aqueous mixture of solvents preferably at elevated temperature.
  • Suitable atoms or groups represented by L include a halogen atom, e.g. a bromine or iodine atom, and a triflate group.
  • a compound of formula (I) wherein R- represents a hydrogen atom may be alkylated using conventional techniques.
  • the reaction may be effected using a suitable al ylating agent such as an alkyl halide, alkyl tosylate or dialkylsulphate.
  • the reaction may conveniently be carried out in an inert organic solvent such as an amide, e.g. dimethylformamide, or an ether, e.g. tetrahydrofuran, preferably in the presence of a base.
  • Suitable bases include, for example, alkali metal hydrides, e.g. sodium hydride, alkali metal carbonates, e.g.
  • alkali metal alkoxides e.g. sodium or potassium, methoxide, ethoxide or t-butoxide.
  • the alkylation reaction is conveniently effected at a temperature of 25 to lOO ⁇ C.
  • a compound of formula (I) according to the invention, or a salt thereof may be prepared by subjecting a protected derivative of formula (I) or a salt thereof to reaction to remove the protecting group or groups.
  • a protected derivative of formula (I) or a salt thereof it may have been necessary and/or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions.
  • Such protection may be effected in conventional manner, for example as described in 'Protective Groups in Organic Chemistry' Ed.J.F.W. McOmie (Plenum Press 1973) or 'Protective Groups in Organic Synthesis' by T W Greene (John Wiley and Sons 1981 ).
  • represents hydrogen
  • may be protected for example with a conventional amino protecting group.
  • groups may include for example aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups such as tosyl, N- benzyloxycarbonyl or t-butoxycarbonyl.
  • an aralkyl group such as benzyl
  • a catalyst e.g. palladium on charcoal
  • an acyl group such as t-butoxycarbonyl may be removed by cleavage with, for example, hydrogen chloride in dioxan or sodium methoxide in methanol.
  • a compound of the invention for example as an acid addition salt
  • this may be achieved by treating the free base of general formula (I) with an appropriate acid, preferably with an equivalent amount.
  • Solvates of the compounds of the invention may be prepared by crystallisation from or evaporation of an appropriate solvent solution of the compounds of formula (I). Separation of enantiomers of formula (I) may be carried out in conventional manner, for example by resolution of racemic mixtures e.g. using chiral HPLC techniques or by stereospecific synthesis from isome cally pure starting material or any convenient intermediate, for example as described in Stereochemistry of Carbon Compounds by E.L. Eliel (McGraw Hill, 1962) and Tables of Resolving Agents by S.H. Wilen.
  • the following reactions may, if necessary and/or desired be carried out in any appropriate sequence subsequent to any of the processes (A) to (C):
  • the general methods indicated above for the preparation of the compounds of the invention may also be used for the introduction of the desired groups at an intermediate stage in the preparation of the required compound. It should therefore be appreciated that in such multi-stage processes, the sequence of reactions should be chosen in order that the reaction conditions do not affect groups present in the molecule which are desired in the final product.
  • Biological activity in vitro was determined by measuring the inhibition of 17,20- lyase activity in a microsomal preparation from human testes. A range of concentrations of each compound was incubated with the microsomal preparation and 17-oc-hydroxy (21- 1 C) pregnenolone as substrate for 60 mins at 37 C C. Radioactive product was assayed and enzyme inhibition determined by comparison with uninhibited control samples.
  • ACTIVITY in vivo Biological activity in vivo was determined in a rat model of testosterone biosynthesis. Compounds were administered p.o. at a dose of 3mg/kg. One hour later the rats were given human chorionic gonadotrophin (hCG) s.c. to stimulate testosterone synthesis and two hours after hCG administration, blood was taken and serum testosterone concentrations measured. Inhibitory activity was determined by comparison to values from rats receiving vehicle only. The results of the in vitro and in vivo assays for the compounds of the following examples are shown in Table 1. The results for the known 17,20-lyase inhibitor ketoconazole are included for comparison.
  • hCG human chorionic gonadotrophin
  • ketoconazole * The dose of ketoconazole was 30mg/kg.
  • R 2 is in the 7-position of formula (I)
  • Example 8 R 2 is in the 5 and 7 positions
  • Example 7 R 3 is in the 1 -position
  • Example 9 R 3 is in the 1 and 4 positions of formula (I).
  • Individual compound names are in accordance with IUPAC nomenclature.
  • Kiii 1-(4'-Fluoro-2'-nitro-biphenyl-4-ylmethyl)-1 H-f1.
  • 41triazole A solution of 1 ,2,4-triazole (0.613g) in DMF (5ml) was treated with sodium hydride (0.266g of an 80% dispersion, in oil). After 5 minutes when all effervescence had ceased, mixture was treated with a solution of 1 ii) (3.1g) in DMF(3ml). Resulting pale brown solution was stirred at room temperature for 20h.
  • Reaction mixture was diluted with ethyl acetate (600ml) and washed with water (2 x 100ml), brine (100ml), dried (MgS0 4 ) and evaporated to give a brown oil. Chromatography on silica gel (750g), eluting with cyclohexane -> cyclohexane/ethyl acetate (15:1 ) gave the title compound as a yellow oil.
  • the aqueous phase was further extracted with ethyl acetate (2000ml), then the combined ethyl acetate layers were washed with brine (1500ml), dried (MgS0 4 ) and evaporated to give a pale cream solid, (228.12g). The solid was crystallized from boiling water (1100ml) to give the title compound (152.18g).
  • Toluene has also been found to be a suitable solvent for this reaction.
  • Neat triethylphosphite has also been found to be a suitable solvent for this reaction.
  • This oil was dissolved in methanol (500ml) and treated with sodium methoxide (37g of a 25% solution in methanol). After stirring for 24 hours, the reaction was concentrated to 50ml, then water (250ml) was added and the mixture was extracted with ethyl acetate (3 x 250ml). The combined organic layers were extracted with HCI (20% aqueous solution, 3 x 250ml). The combined HCI layers were washed with ethyl acetate (250ml). The aqueous layer was then neutralized to pH10 with NaOH pellets, then was extracted with methylene chloride (2 x 500ml).
  • Tablets of other strengths may be prepared by altering the ratio of active ingredient e.g. to lactose or altering the compression weight.
  • the tablets may be film-coated with suitable film-forming materials such as hydroxypropyl methylcellulose using standard techniques.
  • suitable film-forming materials such as hydroxypropyl methylcellulose using standard techniques.
  • the tablets may be sugar coated or enteric coated.
  • the sodium carboxymethylcellulose and magnesium aluminium silicate is hydrated in a solution of sodium lauryl sulphate in water for 24 hours. Active ingredient is suspended in the vehicle with the aid of a mixer. The preservatives are dissolved in the remaining water by heating and after cooling to room temperature, the sorbitol solution is added. The solution is added to the suspension, flavour mixed in and the pH adjusted as needed. The final suspension is mixed in a homogenizer.
  • glycols are blended with warming until homogeneous. Active ingredient is added and the mixture homogenised and filled into an appropriate gelatin mass to give soft gelatin capsules containing the appropriate fill weight.
  • Active ingredient micronized 2 Witepsol W32, hard fat 98
  • a slurry of the active ingredient in a portion of molten Witepsol (approximately 36°C) is prepared using a high speed mixer and is then evenly dispersed in the remaining molten hard fat.
  • the suspension is filled, using suitable machinery, into 1 or 2g size suppository moulds and allowed to cool.
  • the silicone fluid and active ingredient are mixed together and the colloidal silicon dioxide is added to increase viscosity.
  • the material is then dosed into a subsequently heat sealed polymeric laminate comprised of the following: polyester release liner, skin contact adhesive composed of silicone or acrylic polymers, a control membrane which is a polyolefin (e.g. polyethylene or polyvinyl acetate) or polyurethane, and an impermeable backing membrane made of a polyester multilaminate.
  • the laminated sheet is then cut into patches.
  • Phosphate buffer (monobasic 7.0 and dibasic potassium phosphate)
  • Phosphate buffer (monobasic 7.0 and dibasic potassium phosphate)
  • Active ingredient is dissolved in the water with the remaining components and sterile filtered (0.22 ⁇ m filter).
  • the solution is filled into glass vials, stoppered and lyophilised before sealing.
  • the lyophilised product is reconstituted with saline prior to administration.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention se rapporte à des dérivés de carbazole substitués, à des procédés destinés à leur préparation, à des compositions pharmaceutiques les contenant ainsi qu'à leur utilisation à des fins médicales pour la réduction des niveaux d'÷strogènes et/ou d'androgènes. L'invention concerne particulièrement des composés de la formule (I), dans laquelle R1 et R4 représentent chacun indépendamment un atome d'hydrogène ou un groupe C1-6 alkyle; tous les R2 peuvent être identiques ou différents et représentent un groupe d'enlèvement d'électrons; tous les R3 peuvent être identiques ou différents et représentent un groupe d'enlèvement d'électrons; R5 représente un groupe de la formule (a), (b) ou (c); R6 représente un atome d'halogène, un groupe C1-6 alkyle ou un groupe C1-6 alcoxy; m vaut zéro ou un entier de 1 à 4; n vaut zéro ou un entier de 1 à 3; et p vaut zéro, 1 ou 2. Des solvants et sels pharmaceutiquement acceptables de ces composés sont également décrits.
PCT/EP1994/001613 1993-05-21 1994-05-19 Derives de carbazole a activite d'inhibition de 17,20-lyase WO1994027989A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP7500181A JPH08510455A (ja) 1993-05-21 1994-05-19 １７，２０―リアーゼ阻害活性を有するカルバゾール誘導体
EP94917647A EP0699196A1 (fr) 1993-05-21 1994-05-19 Derives de carbazole a activite d'inhibition de 17,20-lyase
PL94311702A PL311702A1 (en) 1993-05-21 1994-05-19 Chemical compounds
CA002162921A CA2162921A1 (fr) 1993-05-21 1994-05-19 Derives du carbazole avec activite inhibitrice de la 17,20-lyase
SK1424-95A SK142495A3 (en) 1993-05-21 1994-05-19 Carbazole derivatives, process for preparing the same, pharmaceutical compositions containing the same and their use
AU69287/94A AU6928794A (en) 1993-05-21 1994-05-19 Carbazole derivatives with 17,20-lyase-inhibiting activity
NO954681A NO954681D0 (no) 1993-05-21 1995-11-20 Kjemiske forbindelser
FI955587A FI955587A0 (fi) 1993-05-21 1995-11-20 Kemialliset yhdisteet
BG100154A BG100154A (en) 1993-05-21 1995-11-21 Carbazole derivatibes having inhibiting effect to 17,20-lyase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939310635A GB9310635D0 (en) 1993-05-21 1993-05-21 Chemical compounds
GB9310635.9 1993-05-21

Publications (1)

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WO1994027989A1 true WO1994027989A1 (fr) 1994-12-08

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EP (1) EP0699196A1 (fr)
JP (1) JPH08510455A (fr)
CN (1) CN1126473A (fr)
AU (1) AU6928794A (fr)
BG (1) BG100154A (fr)
CA (1) CA2162921A1 (fr)
CZ (1) CZ305195A3 (fr)
FI (1) FI955587A0 (fr)
GB (1) GB9310635D0 (fr)
HU (1) HUT73790A (fr)
IL (1) IL109703A0 (fr)
NO (1) NO954681D0 (fr)
OA (1) OA10195A (fr)
PE (1) PE31195A1 (fr)
PL (1) PL311702A1 (fr)
SK (1) SK142495A3 (fr)
TW (1) TW279866B (fr)
WO (1) WO1994027989A1 (fr)
ZA (1) ZA943494B (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996014090A1 (fr) * 1994-11-07 1996-05-17 Janssen Pharmaceutica N.V. Compositions comprenant des carbazoles et des cyclodextrines
EP0721943A4 (fr) * 1993-09-30 1996-09-04 Yamanouchi Pharma Co Ltd Derive d'azole et composition pharmaceutique le contenant
EP0820989A4 (fr) * 1995-03-01 1998-05-06 Yamanouchi Pharma Co Ltd Derives d'imidazole et composition medicinale a base desdits derives
EP0974584A4 (fr) * 1997-02-21 2000-05-17 Takeda Chemical Industries Ltd Composes a anneaux condenses, leur procede de production et leur utilisation
WO2002046186A1 (fr) 2000-12-08 2002-06-13 Takeda Chemical Industries, Ltd. Dérivés thiazole substitués porteurs de groupes 3-pyridyl, procédé d'élaboration et leur utilisation
US6960586B2 (en) 2000-11-20 2005-11-01 Takeda Pharmaceutical Company Limited Imidazole derivatives, process for their preparation and their use
EP1681290A2 (fr) 2000-11-17 2006-07-19 Takeda Pharmaceutical Company Limited Dérivés d'imidazole, leur procédé de préparation et leur application pharmaceutique
WO2007002181A3 (fr) * 2005-06-24 2007-03-01 Lilly Co Eli Derives tetrahydrocarbazole convenant comme modulateurs du recepteur d'angrogene
WO2007068905A1 (fr) * 2005-12-13 2007-06-21 Sterix Limited Derives de 1,2,4-triazol-l-yl bisphenyle utilises pour le traitement de tumeurs a dependance endocrinienne
WO2010149755A1 (fr) 2009-06-26 2010-12-29 Novartis Ag Dérivés d'imidazolidin-2-one 1,3-disubstitués en tant qu'inhibiteurs de cyp 17
WO2011097496A1 (fr) * 2010-02-04 2011-08-11 Radius Health, Inc. Modulateurs sélectifs du récepteur des androgènes
US8093279B2 (en) 2005-12-13 2012-01-10 Gillian Reed, legal representative Compound
WO2012035078A1 (fr) 2010-09-16 2012-03-22 Novartis Ag Inhibiteurs de la 17α-hydroxylase/c17,20-lyase
WO2012149413A1 (fr) 2011-04-28 2012-11-01 Novartis Ag Inhibiteurs de 17α-hydroxylase/c17,20-lyase
WO2014158875A1 (fr) 2013-03-14 2014-10-02 Pellficure Pharmaceuticals Inc. Nouvelle thérapie pour le carcinome de la prostate
US9133182B2 (en) 2010-09-28 2015-09-15 Radius Health, Inc. Selective androgen receptor modulators
US9555014B2 (en) 2010-05-12 2017-01-31 Radius Health, Inc. Therapeutic regimens
US9655868B2 (en) 2010-08-04 2017-05-23 Pellficure Pharmaceuticals, Inc. Treatment of prostate carcinoma
WO2018080933A1 (fr) 2016-10-24 2018-05-03 Pellficure Pharmaceuticals Inc. Compositions pharmaceutiques de 5-hydroxy-2-méthylnaphtalène-1, 4-dione
US10071066B2 (en) 2014-03-28 2018-09-11 Duke University Method of treating cancer using selective estrogen receptor modulators
US10093620B2 (en) 2014-09-12 2018-10-09 Pellficure Pharmaceuticals, Inc. Compositions and methods for treatment of prostate carcinoma
US10385008B2 (en) 2017-01-05 2019-08-20 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US10420734B2 (en) 2014-03-28 2019-09-24 Duke University Method of treating cancer using selective estrogen receptor modulators
US11771682B2 (en) 2016-06-22 2023-10-03 Ellipses Pharma Ltd. AR+ breast cancer treatment methods

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100586932C (zh) * 2007-01-26 2010-02-03 中国医学科学院医药生物技术研究所 抗肿瘤化合物及其制备方法
US9492460B2 (en) * 2013-02-27 2016-11-15 Bristol-Myers Squibb Company Carbazole compounds useful as bromodomain inhibitors

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EP0069513A2 (fr) * 1981-07-07 1983-01-12 Pfizer Limited Inhibiteurs d'indiole de synthétase de thromboxane, procédés pour leur préparation et compositions pharmaceutiques les contenant
EP0219193A1 (fr) * 1985-07-24 1987-04-22 Glaxo Group Limited Dérivés de tétrahydrocarbazolone, procédés pour leur préparation et compositions pharmaceutiques les contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0069513A2 (fr) * 1981-07-07 1983-01-12 Pfizer Limited Inhibiteurs d'indiole de synthétase de thromboxane, procédés pour leur préparation et compositions pharmaceutiques les contenant
EP0219193A1 (fr) * 1985-07-24 1987-04-22 Glaxo Group Limited Dérivés de tétrahydrocarbazolone, procédés pour leur préparation et compositions pharmaceutiques les contenant

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0721943A4 (fr) * 1993-09-30 1996-09-04 Yamanouchi Pharma Co Ltd Derive d'azole et composition pharmaceutique le contenant
US5807880A (en) * 1993-09-30 1998-09-15 Yamanouchi Pharmaceutical Co., Ltd. Azole derivative and pharmaceutical composition thereof
WO1996014090A1 (fr) * 1994-11-07 1996-05-17 Janssen Pharmaceutica N.V. Compositions comprenant des carbazoles et des cyclodextrines
EP0820989A4 (fr) * 1995-03-01 1998-05-06 Yamanouchi Pharma Co Ltd Derives d'imidazole et composition medicinale a base desdits derives
EP0974584A4 (fr) * 1997-02-21 2000-05-17 Takeda Chemical Industries Ltd Composes a anneaux condenses, leur procede de production et leur utilisation
EP1681290A2 (fr) 2000-11-17 2006-07-19 Takeda Pharmaceutical Company Limited Dérivés d'imidazole, leur procédé de préparation et leur application pharmaceutique
US7141598B2 (en) 2000-11-17 2006-11-28 Takeda Pharmaceutical Company, Ltd. Imidazole derivatives, production method thereof and use thereof
US6960586B2 (en) 2000-11-20 2005-11-01 Takeda Pharmaceutical Company Limited Imidazole derivatives, process for their preparation and their use
WO2002046186A1 (fr) 2000-12-08 2002-06-13 Takeda Chemical Industries, Ltd. Dérivés thiazole substitués porteurs de groupes 3-pyridyl, procédé d'élaboration et leur utilisation
US7067537B2 (en) 2000-12-08 2006-06-27 Takeda Pharmaceutical Company Limited Substituted thiazole derivatives bearing 3-pyridyl groups, process for preparing the same and use thereof
WO2007002181A3 (fr) * 2005-06-24 2007-03-01 Lilly Co Eli Derives tetrahydrocarbazole convenant comme modulateurs du recepteur d'angrogene
US7935722B2 (en) 2005-06-24 2011-05-03 Eli Lilly And Company Tetrahydrocarbazole derivatives useful as androgen receptor modulators
US8022224B2 (en) 2005-12-13 2011-09-20 Sterix Limited 1,2,4-triazol-1-yl bisphenyl derivatives for use in the treatment of endocrine-dependent tumors
WO2007068905A1 (fr) * 2005-12-13 2007-06-21 Sterix Limited Derives de 1,2,4-triazol-l-yl bisphenyle utilises pour le traitement de tumeurs a dependance endocrinienne
US8093279B2 (en) 2005-12-13 2012-01-10 Gillian Reed, legal representative Compound
WO2010149755A1 (fr) 2009-06-26 2010-12-29 Novartis Ag Dérivés d'imidazolidin-2-one 1,3-disubstitués en tant qu'inhibiteurs de cyp 17
WO2011097496A1 (fr) * 2010-02-04 2011-08-11 Radius Health, Inc. Modulateurs sélectifs du récepteur des androgènes
US8987319B2 (en) 2010-02-04 2015-03-24 Radius Health, Inc. Selective androgen receptor modulators
US9555014B2 (en) 2010-05-12 2017-01-31 Radius Health, Inc. Therapeutic regimens
US10245240B2 (en) 2010-08-04 2019-04-02 Pellficure Pharmaceuticals, Inc. Treatment of prostate carcinoma
US9655868B2 (en) 2010-08-04 2017-05-23 Pellficure Pharmaceuticals, Inc. Treatment of prostate carcinoma
US9877932B2 (en) 2010-08-04 2018-01-30 Pellficure Pharmaceuticals, Inc. Treatment of prostate carcinoma
WO2012035078A1 (fr) 2010-09-16 2012-03-22 Novartis Ag Inhibiteurs de la 17α-hydroxylase/c17,20-lyase
US9920044B2 (en) 2010-09-28 2018-03-20 Radius Pharmaceuticals, Inc. Selective androgen receptor modulators
US9133182B2 (en) 2010-09-28 2015-09-15 Radius Health, Inc. Selective androgen receptor modulators
WO2012149413A1 (fr) 2011-04-28 2012-11-01 Novartis Ag Inhibiteurs de 17α-hydroxylase/c17,20-lyase
WO2014158875A1 (fr) 2013-03-14 2014-10-02 Pellficure Pharmaceuticals Inc. Nouvelle thérapie pour le carcinome de la prostate
US10071066B2 (en) 2014-03-28 2018-09-11 Duke University Method of treating cancer using selective estrogen receptor modulators
US10420734B2 (en) 2014-03-28 2019-09-24 Duke University Method of treating cancer using selective estrogen receptor modulators
US11779552B2 (en) 2014-03-28 2023-10-10 Duke University Method of treating cancer using selective estrogen receptor modulators
US11951080B2 (en) 2014-03-28 2024-04-09 Duke University Method of treating cancer using selective estrogen receptor modulators
US12263142B2 (en) 2014-03-28 2025-04-01 Duke University Method of treating cancer using selective estrogen receptor modulators
US10093620B2 (en) 2014-09-12 2018-10-09 Pellficure Pharmaceuticals, Inc. Compositions and methods for treatment of prostate carcinoma
US10577315B2 (en) 2014-09-12 2020-03-03 Pellficure Pharmaceuticals, Inc. Compositions and methods for treatment of prostate carcinoma
US11771682B2 (en) 2016-06-22 2023-10-03 Ellipses Pharma Ltd. AR+ breast cancer treatment methods
US12329746B2 (en) 2016-06-22 2025-06-17 Ellipses Pharma Ltd AR+breast cancer treatment methods
WO2018080933A1 (fr) 2016-10-24 2018-05-03 Pellficure Pharmaceuticals Inc. Compositions pharmaceutiques de 5-hydroxy-2-méthylnaphtalène-1, 4-dione
US10385008B2 (en) 2017-01-05 2019-08-20 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL

Also Published As

Publication number Publication date
OA10195A (en) 1996-12-18
EP0699196A1 (fr) 1996-03-06
AU6928794A (en) 1994-12-20
IL109703A0 (en) 1994-08-26
GB9310635D0 (en) 1993-07-07
CN1126473A (zh) 1996-07-10
NO954681L (no) 1995-11-20
TW279866B (fr) 1996-07-01
SK142495A3 (en) 1996-06-05
CZ305195A3 (en) 1996-06-12
HUT73790A (en) 1996-09-30
BG100154A (en) 1996-07-31
ZA943494B (en) 1995-01-23
FI955587A7 (fi) 1995-11-20
CA2162921A1 (fr) 1994-12-08
PE31195A1 (es) 1995-10-18
HU9503321D0 (en) 1996-01-29
NO954681D0 (no) 1995-11-20
PL311702A1 (en) 1996-03-04
JPH08510455A (ja) 1996-11-05
FI955587A0 (fi) 1995-11-20

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