Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/0066—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by a carbon atom forming part of an amide group
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to novel 3-carboxysteroids fluorosubstituted in the side chain, to a process for their preparation, to pharmaceutical compositions containing them and to the use of said compounds as inhibitors of androgen action, by means of testosterone 5 ⁇ -reductase inhibition.
• testosterone 5 ⁇ -reductase inhibition.
• DHT dihydrotestosterone
• the conversion of testosterone to dihydro ⁇ testosterone is catalysed by the enzyme 5 -reductase and if 5 -reductase is inhibited, the formation of dihydro ⁇ testosterone is reduced and its specific androgenic effect is attenuated or prevented.
• the 5 ⁇ -reductase inhibitors may find medical application for the treatment of hyperandrogenic conditions, e.g. certain prostatic diseases, such as benign prostatic hyperplasia and prostatic cancer, and certain skin-hair conditions, such as acne, seborrhoea, female ' hirsutism and male pattern baldness (Siiteri P.K., Wilson J.D., J. Clin. Invest. .49 . , 1737, 1970; Price V.H., Arch. Dermatol, III. 1496, 1975; Sandberg A.A. , Urology 17. 34, 1981) .
• certain prostatic diseases such as benign prostatic hyperplasia and prostatic cancer
• skin-hair conditions such as acne, seborrhoea, female ' hirsutism and male pattern baldness (Siiteri P.K., Wilson J.D., J. Clin. Invest. .49 . , 1737, 1970; Price V.H., Arch. Derma
• breast cancer treatment can take advantage from use of 5 ⁇ -reductase inhibitors as the said tumour is known to be aggravated by presence of androgens.
• Androst-4-en-3-one-17 ⁇ -carboxylic acid and its methyl ester are among the first steroidic compounds described as 5c--reductase inhibitors.
• the invention provides compounds of the following formula (I)
• A is a single bond or a straight or branched C,-C 6 alkylene chain;
• R- is a hydrogen atom or a C,-C 6 alkyl group optionally, substituted by one or more fluorine atoms;
• R 2 is: a) a C,-C 6 alkyl group optionally substituted by one or more substituents chosen among fluoro, Cj-C 4 alkoxycarbonyl, carbamoyl, carboxy, hydroxy, C,-C 4 alkoxy, amino, di-C ⁇ , alkylamino, mercapto and C,- C 4 alkylthio; or b) a C 5 -C 7 cycloalkyl or a C 6 -C 10 cycloalkylalkyl group optionally substituted by one or more fluorine atoms; or c) an aryl or a C 7 -C 10 arylalkyl group, either unsub ⁇ stituted or ring substituted by
• R 3 is hydrogen, a C,-C 4 alkyl group or an aryl or a C 7 -
• C 10 arylalkyl group either unsubstituted or ring substituted by one or more substituents chosen among halogen, C,-C 4 alkyl, C,-C 4 alkoxy, hydroxy and tri- fluoromethyl;
• Z is: a') a C,-C 6 alkyl group optionally substituted by one or more fluorine atoms; b') an -0R 5 group wherein R 5 is a C,-C 6 alkyl group;
• R 6 and R 7 indepen- dently, is hydrogen, C,-C 6 alkyl, C 5 -C 7 cycloalkyl or phenyl, or R 6 and R 7 , taken together with the nitrogen to which they are linked, form a pentatomic or hexatomic saturated heteromono- cyclic ring, optionally containing at least one additional heteroatom selected from oxygen and nitrogen; provided that when Z is a group OR 5 as defined above under b') R 2 is a) a C,-C 6 alkyl group substituted by one or more substituents chosen among fluoro, C,-C 4 alkoxycarbonyl, carbamoyl, carboxy, C,-C 4 alkoxy, a ino, di-C,-C 4 alkylamino, mercapto and C,-C 4 alkylthio or b) a C 5 -C 7 cycloalkyl or a C 6 -C 10 cycloal
• the dotted line (''''') indicates a substituent in the ⁇ -configuration, i.e. below the plane of the ring
• the wedged line (_W ) indicates a substituent in the ⁇ -configuration, i.e. above the plane of the ring.
• R and R 1 are generic substituents.
• ⁇ -fluorinated ketones are meant to include both these forms, i.e. they may exist in the pure ketone form or in the pure hydrate (ge - diol) form or as a mixture of both ketone and hydrate form.
• the invention includes also all the possible isomers of formula (I) and their mixtures. Also the metabolites and the metabolic precursors of the compounds of formula (I) are within the scope of the present invention.
• the alkyl groups and the aliphatic portions of the arylalkyl, cycloalkylalkyl and the heterocyclylalkyl groups may be straight or branched chain.
• a C,-C 4 alkyl group may be, for example, methyl, ethyl, isopropyl, n-butyl or tert-butyl.
• a C,-C 6 straight or branched alkylene chain may be, for example, a straight or branched C,-C 4 alkylene chain,
• a C,-C 6 alkyl group may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl or iso- hexyl.
• the C,-C 6 alkyl group may be unsubstituted or substituted by one or more, preferably 3, 4, 5 or 6, fluorine atoms and may be, in particular, fluoromethyl, difluoromethyl, trifluoromethyl , 2 ,2 , 2-trifluoroethyl, 3 , 3 , 3-trifluoropropyl, 4,4,4-trifluorobutyl, 1-tri- fluoromethylethyl, 2-trifluoromethylprop-1-yl, penta- fluoroethyl, 1, 1, 1-3 , 3 , 3-hexafluoroprop-2-yl . or 4,4,5,5,5-pentafluoropentyl.
• a C,-C 4 alkoxycarbonyl group may be, for example, ethoxy-, ethoxy-, propoxy- or butoxycarbonyl, preferably methoxycarbonyl.
• a C,-C 4 alkoxy group may be, for example, methoxy, ethoxy, propoxy or butoxy, preferably methoxy.
• a di-(C,-C 4 -alkyl) amino may be, for example, dimethylamino.
• a C j -C 4 alkylthio group may be, for example, methylthio, ethylthio, propylthio, or butyl- thio, preferably methylthio or ethylthio.
• a C,-C 6 alkyl group substituted by one or more substituents other than fluorine may be, for example, CH 2 SH, CH 2 SCH 2 CH 3 , CH 2 CH 2 SCH 3 , CH 2 OH, CH 2 OCH 3 , CH(OH)CH 3 , CH(OCH 3 )CH 3 , CH 2 CONH 2 , CH 2 CH 2 CONH 2 , CH 2 COOH, CH 2 CH 2 COOH, CH 2 CH 2 CH 2 CH 2 NH 2 ,
• a C 5 -C 7 cycloalkyl may be, for example, cyclopentyl, cyclohexyl or cycloheptyl.
• a C 6 -C 10 cycloalkylalkyl group may be, for example, a (C 5 -C 7 cycloalkyl) alkyl, preferably (C 5 -C 7 cycloalkyl) methyl or (C 3 -C 7 cycloalkyl) ethyl, in particular, cyclohexylmethyl, cyclohexylethyl, cyclopentylmethyl unsubstituted or substituted by one or more, preferably one, fluorine atoms, in particular, 1-fluoro-1-cyclo- hexylmethyl.
• An aryl group may be, for example, phenyl unsubstituted or substituted by one or more, preferably one, chloro, bromo, fluoro, C ⁇ C,, alkyl, preferably methyl, C,-C 4 alkoxy, preferably methoxy, hydroxy, or trifluoromethyl groups, in particular, 4-methylphenyl, 4-hydroxyphenyl,
• a C 7 -C 10 arylalkyl group may be, for example, phenyl (C t -C 4 alkyl) , preferably benzyl, unsubstituted or ring substituted by one or more, preferably one or two, chloro, bromo, fluoro, C ⁇ C .
• alkoxy preferably methoxy, hydroxy or trifluoromethyl groups, in particular 4-hydroxybenzyl, 4-methoxybenzyl, 4-hydroxy-3-methoxy- benzyl, 3 ,4-dimethoxybenzyl, 4-trifluoromethylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3-fluoro-4-hydroxybenzyl.
• a C 6 -C 10 heterocyclylalkyl group may be, for example, heterocyclyl (C,-C 4 alkyl) , for example heterocyclyl- methyl, preferably imidazolyl-methyl or indolylmethyl, unsubstituted or ring substituted by one or more, preferably one, fluorine atoms, in particular, (4- i idazolyl) -methyl, (3-indolyl) -methyl, (5-fluoro- indolyl) -methyl, (6-fluoroindolyl)methyl or (3-imid- azolyl)methyl.
• heterocyclyl C,-C 4 alkyl
• heterocyclyl- methyl preferably imidazolyl-methyl or indolylmethyl, unsubstituted or ring substituted by one or more, preferably one, fluorine atoms, in particular, (4- i idazolyl) -methyl, (3-indolyl
• CH, A is, preferably, a bond or -C IH-.
• R is, preferably, hydrogen or methyl.
• R 2 is, preferably, the side-chain of the most common natural and unnatural uiv- no acids, optionally, substituted by one or more fluorine atoms.
• R 2 is an unsubstituted C,-C 6 alkyl group, it is preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl , sec-butyl , tert-butyl , n-pentyl , iso-pentyl , n-hexyl , iso-hexyl .
• R 2 is a substituted C,-C 6 alkyl group , it is preferably -CH 2 F , -CHF 2 , CF 3 , CF 3 -CH 2 - , CF 3 -CH 2 -CH 2 - , CF 3 CF 3 CF 3
• R 2 is a C 5 -C 7 cycloalkyl, it is preferably cyclo- hexyl.
• R 2 is a C 6 -C 10 cycloalkylalkyl, it is preferably cyclohexylmethyl.
• R 2 is an aryl, it is preferably phenyl.
• R 2 is a C 7 -C lt) arylalkyl, it is preferably benzyl.
• R 2 is a heterocyclyl alkyl, it is preferably (3- imidazolyl) ethyl or (3-indolyl)methyl.
• R 3 is preferably hydrogen, methyl, ethyl, phenyl, benzyl.
• Z is a C,-C 6 alkyl as defined above under a') , preferably it is methyl, ethyl, trifluoromethyl, 2,2,2- trifluoroethyl, pentafluoroethyl, n-propyl, n-butyl, sec-butyl.
• R is preferably methyl, ethyl, t-butyl.
• Z is a group -N as defined above under c') *7 preferably it is -NH 2 , -NHCH 3 , -NHC 2 H 5 , -NHCH(CH 3 ) 2 , - NHC(CH 3 ) 3 , -NHCH 2 C(CH 3 ) 3 , -N(C 2 H 5 ) 2 , -N[CH(CH 3 ) 2 ] 2 , -NH-/ > , NH-Ph, piperidyl, piperazinyl, morpholynyl.
• Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts with inorganic, e.g.
• inorganic bases such as, for example, alkali metal, e.g., sodium or potassium, or alkaline-earth metal
• a preferred class of compounds according to the invention are the compounds of formula (I) wherein: A is a single bond; R, is hydrogen or methyl; R 2 is methyl, iso-propyl, iso-butyl, sec-butyl, tert- butyl, trifluoromethyl, 1-trifluoromethyleth-1-yl, 2- trifluoromethylprop-1-yl, 2-methylthioeth-l-yl, methoxy- methyl, phenyl or benzyl; R 3 is hydrogen or methyl; Z is methyl, n-butyl, trifluoromethyl, pentafluoroethyl; or a group OR 5 wherein R 5 is methyl, ethyl or tert-butyl;
• R 2 is trifluoromethyl, 1-trifluoromethyl- eth-l-yl, 2-trifluoromethylprop-1-yl, 2-methylthioethyl, methoxymethyl.
• R is a straight or branched C,-C 4 alkyl group, A, R,, R 2 , R 3 and Z are as defined above; or 2) oxidizing a compound of formula (III)
• A, R,, R 2 , R 3 and Z are as defined above and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof and/or, if desired, separating a mixture of isomers of formula (I) into the single isomers.
• the hydrolysis of a compound of formula (II) according to the process variant 1) may be carried out, e.g., in a suitable solvent, such as, for example, methanol, ethanol, tetrahydrofurane, dioxane, in the presence of an aqueous concentrated solution of an alkali metal hydroxide such as, for example, potassium hydroxide, sodium hydroxide or, preferably, lithium hydroxide, for a time varying from some hours to some days, at a temperature ranging from about 0°C to the reflux temperature of the solvent, optionally under an inert atmosphere of nitrogen.
• the oxidation of a compound of formula (III) according to the process variant 2) may be carried out according to the Swern methodology, as described, e.g., in Synthesis 1981, 165.
• the oxidation may be carried out treating the compound dissolved in a solvent such as, for example, methylene chloride with dimethylsulphoxide and oxalyl chloride, at a temperature ranging from about -78°C to room temperature for a time varying from about 15 minutes to about 2 hours.
• a solvent such as, for example, methylene chloride with dimethylsulphoxide and oxalyl chloride
• Z is a fluorinated alkyl group, particularly a CF 3 group
• the oxidation may be fruitfully performed also with the Dess-Martin reagent, as reported, e.g., in Tetr.Lett. 1987, 2 . 8, 4259.
• Standard procedures may be used for converting a compound of formula (I) into a pharmaceutically acceptable salt thereof as well as for obtaining a free compound from the corresponding salt and for separating a mixture of isomers of formula (I) into the single isomers .
• a compound of formula (II) may be obtained by carbalkoxylation of a compound of formula (IV)
• Tf is a trifluoromethansulphonyl group (CF 3 -S0 2 -)
• W is a carbonyl group or a -CH- group wherein P is hydrogen or a suitable protecting group of the hydroxy function, R,, R 2 , R 3 and Z are as defined above, so obtaining, when W is a carbonyl group, a compound of formula (II) or, when W is a -CH- group, a compound of
• a compound of formula (V) may then be transformed into a compound of formula (II) by removing the protecting group P of the hydroxy function, if it is present, and oxidizing.
• the carboxylation may be carried out, e.g., by treating a solution of the compound of formula (IV) in a suitable organic solvent, preferably dimethylformamide (DMF) , with an organic base such as, for example, triethylamine (TEA) , a palladium complex such as, for example, bis (triphenylphosphine) palladium (II) acetate or bis (triphenylphosphine) palladium (II) chloride, and a C,-C 4 alkyl alcohol.
• a suitable organic solvent preferably dimethylformamide (DMF)
• an organic base such as, for example, triethylamine (TEA)
• a palladium complex such as, for example, bis (triphenylphosphine) palladium (II) acetate or bis (triphenylphosphine) palladium (II) chloride
• a C,-C 4 alkyl alcohol e.g., by treating a
• the palladium complexes can ha formed in situ, by adding, separately, a phosphine, such as triphenylphosphine, and a palladium salt, such as, for example, palladium (II) acetate or palladium (II) chloride.
• a phosphine such as triphenylphosphine
• a palladium salt such as, for example, palladium (II) acetate or palladium (II) chloride.
• reaction mixture is purged with carbon monoxide (CO) for some minutes and then stirred under a CO balloon for a time varying from one hour to 48 hours, at a temperature ranging from 0°C to 40°C.
• CO carbon monoxide
• a suitable protecting group of the hydroxy function may be, for example, a tetrahydropyranyl group or a silyl group, preferably trimethylsilyl or di ethyltertbutyl- ⁇ ilyl.
• the removal of the protecting group of the hydroxy function in a compound of formula (V) may be achieved by the usual methods known in the art.
• the oxidation of a compound of formula (V) wherein P is hydrogen may be performed as described above for the oxidation of a compound of formula (III) according to the process variant 2) .
• a compound of formula (IV) may be obtained by reacting a compound of formula (VI)
• R 3 wherein R,, R 2 , R 3 , W and Z are as defined above.
• a reaction between a compound of formula (VI) and a compound of formula (VII) may be carried out, e.g., in an inert solvent such as, for example, CH 2 C1 2 , THF, AcOEt, DMF, benzene, at a temperature ranging from about 0°C to about 100°C, optionally in the presence of an organic base such as, for example, pyridine, p-dimethyl- aminopyridine or triethylamine, for a time varying from about one hour to about 5 days.
• an inert solvent such as, for example, CH 2 C1 2 , THF, AcOEt, DMF, benzene
• an organic base such as, for example, pyridine, p-dimethyl- aminopyridine or triethylamine
• the compounds of formula (VII) are often used as N-salt- derivatives, preferably hydrochlorides or trifluoro- acetates, and the free amino group is formed in situ in the presence of an organic base such as, for example, pyridine, or a tri-C,-C 6 -alkylamine, preferably triethyl ⁇ amine.
• the compound of formula (VI) are known compounds (European Patent Application 0465123 A2) .
• a compound of formula (VII) may be obtained by known methods as, for example, deprotecting a compound of formula (VIII)
• R,, R 2 , R 3 and Z are as defined above and Y is an amino protecting group commonly used in the synthesis of ⁇ -aminoacids and peptides, such as, for example, N-benzoyl, N-benzyloxycarbonyl (Cbz) , N-tert-butoxy- carbonyl (BOC) , 2, 2 , 2-trichloroethoxycarbonyl (TClOC) , 2, 2 , 2-tribromoethoxycarbonyl (Tbcoc) , trifluoroacetyl (Tfac) .
• the reaction conditions for the deprotection depend on the amino protecting group used.
• the reaction may be carried out in a solvent such as, for example, methylene chloride, chloroform or ethyl acetate, in the presence of a strong acid, e.g. hydrochloric acid or trifluoro- acetic acid, optionally in the presence of a tert-butyl cation scavenger such as thioanisole, at a temperature from about 0°C to about 40°C, for a time varying from half an hour to 24 hours.
• a strong acid e.g. hydrochloric acid or trifluoro- acetic acid
• a tert-butyl cation scavenger such as thioanisole
• R,, R 2 , R 3 , Y are as defined above and X is an activating group of the carboxy function with a compound of formula (X) .
• X may be for example one of the following groups:
• the reaction when X is the reaction may be carried out in a solvent such as methylene chloride, ethyl acetate or dimethylformamide, for a time varying from about half an hour to 24 hours, at a temperature ranging from about 0°C to the reflux temperature of the solvent.
• a solvent such as methylene chloride, ethyl acetate or dimethylformamide
• the compounds of formula (VIII) wherein R,, R 2 , R 3 and Y are as defined above and Z is a C,-C 6 alkyl group are known compounds; for example, they can be prepared starting from ⁇ -amino acids, according to the procedure reported in J.O.C. 4_8, 2260-2266 (1983) or to the Dakin- West reaction (J. Biol. Chem. 78 . , 91, 1928) .
• the compounds of formula (VIII) wherein R,, R 2 , R 3 are as defined above and Z is a OR, group are known.
• W is a -CH- group, wherein P is a protecting
• the reaction may be carried out treating a solution of a compound of formula (XI) and an organic hindered base such as, for example, 2,6-ditertbutyl-4-methylpyridine, in a solvent such as, for example, methylene, chloride, with trifluoromethansulphonic anhydride, at a tempera ⁇ ture ranging for example from 0°C to about 50°C, for a time ranging from some minutes to about 3 hours, under an inert atmosphere of, for example, nitrogen.
• a compound of formula (XI) wherein W is a group -CH-,
• OP wherein P is a protecting group of the hydroxy group, and A, R-, R 2 , R 3 and Z are as defined above, may be obtained by protection of a compound of formula (XI) , wherein W is a -CH- group and A, R,, R 2 , R 3 and Z are as
• Preferred protecting group for the hydroxy group of a compound of formula (XI) are, for example, tetrahydro- pyranyl or trimethylsilyl, and the protection is carried out in the usual conditions known in the art.
• a compound of formula (III) may be obtained hydrolyzing a compound of formula (V) wherein R is a straight or branched C,-C 4 alkyl group, P is hydrogen and R,, R 2 , R 3 and Z are as defined above.
• the hydrolysis of a compound of formula (V) may be carried out as reported for the hydrolysis of a compound of formula (II) according to the process variant 1) .
• the compounds of formula (I) of the present invention inhibit specifically the testosterone 5 ⁇ -reductase enzyme and, therefore, are potent antiandrogens.
• the inhibitory effect of the compounds of the invention on 5 -reductase was determined in vitro according to the procedure reported herebelow. In vitro assay of 5 ⁇ -reductase inhibition. Inhibition of 5 ⁇ .-reductase was evaluated using the particulate fraction from homogenates of hyperplastic human prostates as the enzyme source. The particulate fraction was prepared centrifuging prostate homogenate at 140,000 x g. The resulting pellet, washed several times, was resuspended in buffer and stored at -80°C in aliquots containing _____ 10 mg protein/ml.
• the assay for 5 ⁇ -reductase was done in a final volume of 0.5 ml, in 40 itiM TRIS-HC1 buffer pH 5.5, containing 1 mM dithiothreitol , 5 mM NADPH, 1 ⁇ M [ 14 C]testosterone, an aliquot of the enzyme preparation and various concentrations of the inhibitors. After 30 in incubation at 37°C the reaction was terminated by addition of 2 ml cold diethyl ether and the organic phase was separated, evaporated under N 2 and resuspended in ethyl acetate.
• Testosterone metabolites in this extract were separated in TLC on silica gel F 254 plates (Merck) , using chloroform, acetone and n-hexane (2:1:2) as developing solvent system.
• Radioactivity on the plate was scanned and analysed from quantitative plots printed by a TLC-analyzer (Berthold) .
• the fractional 5 ⁇ -reduction of testosterone was calculated by relating the 14 C-radioactivity in the 5 ⁇ - reduced metabolites (5 ⁇ -dihydrotestosterone, 3 ⁇ - and 3 ⁇ - androstanediols) regions to the total radioactivity in the testosterone and Sen-reduced metabolites regions.
• the concentration of each compound required to reduce control 5 -reductase activity by 50% was determined by plotting % inhibition versus log of inhibitor concentration.
• the compounds of the invention can be therapeutically useful in the situations in which a decrease in androgen action, by means of 5 ⁇ -reductase inhibition, is desirable such as, for example, benign prostatic hyperplasia, prostatic and breast cancers and certain skin-air conditions such as, e.g., acne, seborrhoea, female hirsutism and male pattern baldness.
• a mammal e.g., a human or animal, may thus be treated by a method which comprises administering thereto a pharmaceutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof as defined above.
• the toxicity of the compounds of the invention is quite negligible so that they can be safely used in therapy.
• 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., intra-muscularly, or by intravenous injection or infusion; or topically, e.g., in the form of creams.
• 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 1 to 200 mg pro dose, from 1 to 3 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
• compositions containing the compounds of the invention are usually prepared following con ⁇ ventional methods and are administered in a pharma ⁇ ceutically 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 polyvinylpyrrolidone; disaggregating agents, e.g., a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dye-stuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general non-toxic and
• 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; in particular a syrup to be administered to diabetic patients can contain as carriers only products not metabolizable to glucose, or metabolizable in very small amount to glucose, for example sorbitol.
• the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethyl ⁇ cellulose, 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, glycol, 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.
• Conventional carriers may be used for topical formulations.
• the present invention further provides a compound of formula (I) , or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy in particular for use as a testosterone ⁇ -reductase inhibitor.
• the present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as a testosterone 5o:-reductase inhibitor.
• the methanol is evaporated under vacuum and water is added; the mixture is acidified with IN HC1 and extracted with methylene chloride; the organic layers are washed with brine, with water until neutrality, anhydrified over sodium sulphate and the solvent removed under vacuum.
• the yellowish solid obtained is purified by flash chro atography on silica gel (eluant: ethyl acetate/n- hexane 50:50 to 70:50) so obtaining 118.0 mg of the title compound as a white solid (mp: 210-220°C dec.) as a mixture of the ketone and hydrate form (ratio 1:2) .
• the crude is purified by flash chromatography (eluant ethyl acetate/n-hexane 70:50) so obtaining 80 mg of the title compound.
• the mixture is purged with carbon monoxide for 5 minutes and then is stirred overnight at room temperature under a carbon monoxide atmosphere (maintained by means of a balloon) .
• Example 12 Scored tablets for oral use, each containing 250 mg of the active substance, were manufactured as follows. Composition (for 10,000 tablets)
• the active substance was granulated with a 4% w/v aqueous solution of methyl cellulose. To the dried granules a mixture of the remainder of the ingredients is added and the final mixture compressed ir ' : ⁇ tablets of proper weight.
• Two-piece hard gelatin capsules for oral use, each containing 250 mg of active substance were manufactured as follows.

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