WO1996003420A1 - 3-carboxysteroides presentant une chaine laterale fluoree - Google Patents

3-carboxysteroides presentant une chaine laterale fluoree Download PDF

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Publication number
WO1996003420A1
WO1996003420A1 PCT/EP1995/002650 EP9502650W WO9603420A1 WO 1996003420 A1 WO1996003420 A1 WO 1996003420A1 EP 9502650 W EP9502650 W EP 9502650W WO 9603420 A1 WO9603420 A1 WO 9603420A1
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Prior art keywords
carbamoyl
formula
group
compound
carboxylic acid
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PCT/EP1995/002650
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English (en)
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Achille Panzeri
Marcella Nesi
Enrico Di Salle
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Pharmacia S.P.A.
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Priority to EP95925845A priority Critical patent/EP0721460A1/fr
Priority to JP8505394A priority patent/JPH09503228A/ja
Publication of WO1996003420A1 publication Critical patent/WO1996003420A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

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 dihydrotestosterone is catalysed by the enzyme
  • 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. Der atol. III. 1496, 1975; Sandberg A.A. , Urology 12 34, 1981).
  • 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 5 ⁇ -reductase inhibitors.
  • Two 5,10-secosteroids having a 3-keto-4,5-diene system in the expanded ring have been found to be selective inhibitors of rat epididymal 5 ⁇ -reductase (Robaire et al., J. Steroid Biochem. 8., 307-310 (1977)).
  • 5 ⁇ -reductase have been prepared by introducing a 6-methylene moiety into substrates type 3-keto-D 4-progestins and androgens (Petrow et al., Steroids 38, 352-53 (1981); United States Patent 4,396,615) . Later on unsaturated derivatives of 3-carboxy steroids have been reported as uncompetitive 5 ⁇ -reductase inhibitors versus testosterone (Biorg. Chem. 12, 372-376 (1989); Eur. Pat. Appln. No. 0289327; WO 9220700; Eur. Pat. Appln. No. 0465123; Eur. Pat. Appln. No. 0528485; Eur. Pat. Appln. No. 0567271).
  • 4-Aza steroids are by far the most studied steroid 5 ⁇ -reductase inhibitors.
  • the compounds known in the art are reported in a very large number of publications and patents.
  • the 176-acylamides and their metabolites are described in: J. Med. Chem. 27, 1690-1701 (1984); J. Med. Chem. 2£, 2298-2315 (1986); Eur. Pat. Appln. No. 0004949; US patent No. 4,377,584; Eur. Pat. Appln. No. 0155096; US patent No. 4,845,104; Eur. Pat. Appln. No. 200859; Eur. Pat. Appln. No. 0462662; Eur. Pat. Appln. No. 0,484,094 A2; US Patent No. 4,859,681; WO 91/12261; WO 94/03474; WO 94/03475; WO 94/034476.
  • the invention provides compounds of the following formula (I)
  • A is a bond or a straight or branched Ci-C ⁇ alkylene chain
  • W is a group -R 1# -O 2 , -NR 3 R 4 or
  • Y is oxygen or sulphur
  • R l , R 2 and R 4 are: a C 1 -C 10 alkyl group, substituted by one or more fluorine atoms; or a C 6 ⁇ C 15 cycloalkylalkyl group, substituted by one or more fluorine atoms; or an aryl group, substituted by one or more fluorine atoms; or a C 7 -C 15 arylalkyl group, substituted by one or more fluorine atoms;
  • R 3 and each of R 5 , R 6 and R 7 are hydrogen or a Cj-Cio alkyl group, unsubstituted or substituted by one or more fluorine atoms; or a C 6 -Ci 5 cycloalkylalkyl group, unsubstituted or substituted by one or more fluorine atoms; or an aryl group, unsubstituted or substituted by one or more fluorine atoms; or a C- 7 -C 15 arylalkyl group, unsubstituted or substituted by one or more fluorine atoms and, provided that when
  • W is a group ⁇ , at least one of R 5 , R 6 , R 7 is different from hydrogen and contains at least one fluorine atom, and the pharmaceutically acceptable salts thereof.
  • the dotted line ( • ""” ) indicates a substituent in the a-configuration, i.e. below the plane of the ring
  • the wedged line ( - • *** ) indicates a substituent in the ⁇ -configuration, i.e. above the plane of the ring.
  • alkyl groups and the aliphatic portions of the arylalkyl and cycloalkylalkyl groups may be straight or branched chain.
  • a straight or branched Ci-C $ alkylene chain may be, for example, a straight or branched C 1 -C 4 alkylene chain, such as, for example, -CH(CH 3 )-, -CH(CH 3 )CH 2 CH 2 -, -CH 2 -, -CH 2 CH 2 -.
  • An unsubstituted Cj-Cio alkyl group may be, e.g.
  • C 1 -C 5 alkyl such as, for example, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl or neo-pentyl, or a straight Cg-C ⁇ o alkyl such as, for example, n-octyl or n-nonyl.
  • a C 1 -C 10 alkyl group substituted by one or more fluorine atoms may be, for example: -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH(CF 3 ) 2 , -CF 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CF(CF 3 ) 2 , -CF 2 CF 2 CF 2 CF 3 , -CH 2 CH(CH 3 )CF 3 , -CH 2 CH(CF 3 ) 2 , -C(CF 3 ) 3 , -C(CH 3 ) 2 CF 3 , -C(CF 3 ) 2 CH 3 , -C(CH 2 F) 3 , -C(CHF 2 ) 3 , -C(CH 3 ) 2 CH 2 CF 3 , -C(CH 3 ) (CF 3 )CH 2 CF 3 , -CF 2 (CF 2 ) 4 CF 3
  • An unsubstituted Cg-C ⁇ cycloalkylalkyl group may be e.g., a Ci-Cirj-cyclopentylalkyl or Ci-Cg-cyclohexylalkyl group; for example:
  • a Ce-Ci 5 cycloalkylalkyl group substituted by one or more fluorine atoms may be, for example:
  • An unsubstituted aryl group may be, for example: phenyl, tolyl, naphthyl.
  • An aryl group substituted by one or more fluorine atoms may be, for example:
  • An unsubstituted C 7 ⁇ C 15 arylalkyl group may be for example an aryl-Cx-Cg alkyl or a bis-aryl-C ⁇ -C 3 -alkyl group; for example:
  • a C 7 -C 15 arylalkyl substituted by one or more fluorine atoms may be, for example:
  • Pharmaceutically acceptable salts of the compounds of the invention are salts with pharmaceutically acceptable bases, either inorganic bases, such as, for example, alkali metal, e.g., sodium or potassium, or alkaline-earth metal, e.g., calcium or magnesium, or zinc or aluminium hydroxides, or organic bases such as, for instance, aliphatic amines as, e.g., methylamine, diethylamine, trimethylamine, ethylamine and heterocyclic amines, e.g., piperidine.
  • inorganic bases such as, for example, alkali metal, e.g., sodium or potassium, or alkaline-earth metal, e.g., calcium or magnesium, or zinc or aluminium hydroxides
  • organic bases such as, for instance, aliphatic amines as, e.g., methylamine, diethylamine, trimethylamine, ethylamine and heterocyclic amines, e.g., piperidine.
  • R 2 , R 3 , R 4 , R 5 , 6 and R 7 are groups containing more than one fluorine atom, preferably, the fluorine atoms are linked to the same carbon atom, forming -CF 2 - (difluoro- methylene) or -CF 3 (trifluoromethyl) groups.
  • preferred compounds are those which contain CF 3
  • a preferred class of compounds according to the invention are the compounds of formula (I) wherein:
  • A is a bond or a -CH-CH 2 -CH 2 - group; W is either a group -Ri which is
  • R 2 is -CF 3 , -CH -CF 3 , -CH(CF ) 2 , -CF 2 -CF 2 -CF 3 , -CH 2 -CH 2 -CF 3 , -CF(CF 3 ) 2 , -CF 2 -CF 2 -CF 2 -CF 3 , -CH 2 -CH(CF 3 ) 2 , -C(CF 3 ) 3 , -C(CH 3 ) 2 CF 3 , -C(CF 3 ) 2 CH 3 , -C(CH 3 ) 2 CH 2 -CF 3 , -C(CH 3 ) (CF 3 )CH 2 CF 3 , -CF 3 - (CF 2 ) 4 -CF 2 -, -CF 2 - (CF 2 ) 7 -CF 3 , -CF 2 - (CF 2 ) 8 -CF 3 ; R3 or a group -N wherein R 3 is -CF 3 , -CH
  • each of R 5 , Rg, and R 7 independently, is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, neo-pentyl, n-octyl, n-nonyl, -CF 3 , CH 2 -CF 3 , -CH(CF 3 ) 2 , -CF 2 -CF 2 -CF 3 , -CH 2 -CH 2 -CF 3 , -CF(CF 3 ) 2 , -CF 2 -CF 2 -CF 2 -CF 3 , -CH 2 -CH(CF 3 ) 2 , -C(CF 3 ) 3 , -C(CH 3 ) 2 CF 3 ,
  • preferred compounds are the compounds of formula (I) , selected from the group consisting of: 1) 21-(1,1, l-trifluoroprop-2-yl)pregna-3,5-dien-20-one-3- carboxylic acid; 2) 21-(1, l,l,3,3,3-hexafluoropropyl)pregna-3,5-dien-20-one-3- carboxylic acid; 3) 21-(l,l,l-trifluoro-3-phenylprop-2-yl)pregna-3,5-dien-20- one-3-carboxylic acid; 4) 21-trifluoromethylpregna-3, 5-dien-20-one-3-carboxylic acid;
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof may be obtained by a process comprising hydrolysing a compound of formula (II)
  • R is a straight or branched C -Cg alkyl group
  • a and W are as defined above, so obtaining a compound of formula (I) , wherein A and W 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) may be carried out, e.g.
  • a suitable solvent such as, for example, methanol, ethanol, tetrahydrofurane, dioxane
  • a suitable solvent such as, for example, methanol, ethanol, tetrahydrofurane, dioxane
  • an alkali metal hydroxide such as, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide
  • a compound of formula (II) wherein R is a straight or branched C ⁇ Cg alkyl group, A and W are as defined above, may be e.g. , obtained by reacting a compound of formula (III) wherein W and A are as defined above, with carbon monoxide (CO) , in the presence of a Ci-Cg alkyl alcohol so obtaining a compound of formula (II) , wherein R, A and W are as defined above.
  • CO carbon monoxide
  • the reaction of a compound of formula (III) , as defined above, with carbon monoxide in the presence of a C -C 6 alkyl alcohol may be carried out, e.g., by treating a solution of the compound of formula (III) in a suitable organic solvent, preferably dimethylformamide (DMF) , with an organic base such as, for example, triethyla ine (TEA) , a palladium complex such as, for example, bis(triphenylphosphine) palladium (II) acetate or bis(triphenylphosphine) palladium (II) chloride, and a C ⁇ cg alkyl alcohol, such as, for example, methanol or ethanol.
  • a suitable organic solvent preferably dimethylformamide (DMF)
  • an organic base such as, for example, triethyla ine (TEA)
  • a palladium complex such as, for example, bis(triphenylphosphine) palladium (II)
  • the palladium complexes can be 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. Then the 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, e.g., from 0°C to 40°C. Analogous procedure is described, e.g., in Tetr. Lett. 26 (8), 1109-12, (1985).
  • a phosphine such as triphenylphosphine
  • a palladium salt such as, for example, palladium (II) acetate or palladium (II) chloride.
  • CO carbon monoxide
  • a compound of formula (III) may be obtained, e.g., by reacting a compound of formula (IV)
  • a and W are as defined above with trifluoromethanesulphonic anhydride.
  • the reaction is performed, e.g., by adding to a solution containing the compound of formula (IV) , as defined above, an organic hindered base such as, 2,6-di-tert-butyl-4- methylpyridine, in a suitable organic solvent such as, e.g., methylene chloride, a trifluorosulphonic anhydride, preferably trifluoromethanesulphonic anhydride, accordingly to the procedure reported in Synthesis 438-40 (1979) .
  • an organic hindered base such as, 2,6-di-tert-butyl-4- methylpyridine
  • a suitable organic solvent such as, e.g., methylene chloride, a trifluorosulphonic anhydride, preferably trifluoromethanesulphonic anhydride, accordingly to the procedure reported in Synthesis 438-40 (1979) .
  • a compound of formula (IV) wherein A is as defined above and W
  • reaction (a) a compound of formula (IV) wherein A, Y, R 5 , Rg and R 7 are as defined above, provided that R 5 and Rg are not hydrogens and R 7 is hydrogen, may be obtained reacting a compound of formula (V) , wherein A and Y are as defined above, with a carbodiimide of formula (VI) wherein R 5 and Rg are as defined above.
  • a compound of formula (IV) wherein A, Y, R 5 , Rg, R 7 are as defined above, provided that R 5 is not hydrogen may be obtained from a compound of formula (VII) , wherein A, Y, Rg and R 7 are as defined above, by alkylation with a compound of formula (VIII) wherein R 5 is as defined above, provided that it is not hydrogen, and X is a halogen atom, e.g., iodine.
  • a compound of formula (IV) wherein R 7 is hydrogen and A, Y, R 5 , Rg are as defined above, provided that Rg is not hydrogen may be obtained from a compound of formula (IX) , wherein A and R 5 are as defined above, by reaction with a compound of formula (X) wherein Rg and Y are as defined above, provided that Rg is not hydrogen.
  • the compounds of formula (V) wherein Y is sulfur may be, e.g., obtained from compounds of formula (XI) according to known procedures.
  • One procedure may involve, for example, reacting a compound of formula (XI) wherein Z is chlorine, with gaseous hydrogen sulfide in the presence of di ethylthioformamide, in a solvent such as, for example, CH 2 C1 2 , at room temperature for a time varying from, e.g., ten minutes to some hours under vigorous stirring, according to the method described in Synthesis, 671-2 (1985) .
  • Another procedure may involve, e.g., reacting a compound of
  • reaction may be performed in a solvent such as, for example, methylene chloride, tetrahydrofurane, acetonitrile, at a temperature ranging from, e.g., about 0°C to about 50°C, for a time varying, e.g., from about one hour to about 48 hours.
  • a solvent such as, for example, methylene chloride, tetrahydrofurane, acetonitrile
  • a compound of formula (V) wherein Y is sulphur may also be synthetized according to the general methods described in the literature for the synthesis of thiocarboxylic acids, for example in analogous way as described in Houben Weyl, Bd E 5, pages 832-842, or by Duns F. in Barton and Ollis, Comprehensive Organic Chemistry, Vol. 3 Pergamon Press, Oxford, 1979, pages 420-32.
  • a compound of formula (VII) may be obtained reacting a compound of formula (XI) , as defined above, with an urea or thiourea of formula (XII)
  • a compound of formula (IX) may be obtained, e.g., reacting a compound of formula (XI) , with an a ine of formula (XIII)
  • a compound of formula (XI) may be obtained e.g. from a compound of formula (V) wherein Y is oxygen by well known procedures.
  • the compounds of formula (V) , wherein Y is oxygen, are commercially available compounds or can be prepared by known ' procedures from known compounds.
  • a compound of formula (IV) wherein W is a group NR 3 R or NHR 3 , wherein R 3 and R 4 are as defined above, may be obtained e.g. by the reaction of a compound of formula (XI) , wherein Z is an activating group of the carboxylic function useful in the formation of the a idic and peptidic bond, such as, for example:
  • R and R 4 are as defined above.
  • the reaction may be carried out in a solvent such as, for example, methylene chloride, ethyl acetate, acetonitrile, tetrahydrofurane, dimethylformamide, benzene, toluene at a temperature ranging from about 0°C to the reflux temperature of the reaction mixture, for a time varying from about 1 hour to about 48 hours.
  • a solvent such as, for example, methylene chloride, ethyl acetate, acetonitrile, tetrahydrofurane, dimethylformamide, benzene, toluene
  • a compound of formula (IV), wherein W is a group OR 2 , wherein R 2 is as defined above, may be obtained, e.g., a) by the reaction of a compound of formula (V) , wherein A and Y are as defined above, with a compound of formula (XVI)
  • reaction between a compound of formula (IV) and a compound of formula (XVI) may be carried out in a solvent such as, for example, methylene chloride, dimethylformamide, acetonitrile, benzene, in the presence of a carbodiimide, such as for example N,N'- dicyclohexylcarbodiimide or N,N'-diisopropylcarbodiimide, and of an acylation catalyst, such as, for example, 4-N,N- dimethylaminopyridine or 4-pyrrolidinopyridine, at a temperature ranging from room temperature to about 50°C, for a time varying from some hours to 2 days.
  • a solvent such as, for example, methylene chloride, dimethylformamide, acetonitrile, benzene
  • a carbodiimide such as for example N,N'- dicyclohexylcarbodiimide or N,N'-diisopropylcarbodiimide
  • the reaction of a compound of formula (XI) with a compound of formula (XVI) , according to the reaction variant b) may be carried out in a solvent such as, for example, methylene chloride, ethyl acetate, acetonitrile, tetrahydrofurane, dimethylformamide, benzene, toluene, chloroform, optionally in the presence of a metal salt, such as, for example, cupric bromide (CuBr ) mercurium (II) trifluoroacetate (Hg(OCOCF ) ) , silver trifluoroacetate (CF 3 COOAg) at a temperature ranging from about 0°C to the reflux temperature of the reaction mixture, for a time varying from 1 hour to about 48 hours.
  • a solvent such as, for example, methylene chloride, ethyl acetate, acetonitrile, tetrahydrofurane, dimethylformamide, benzene
  • a compound of formula (IV), wherein W is a group Ri, wherein R is as defined above, may be obtained by the reaction of a compound of formula (XI) , wherein Z is a group
  • M is a metal atom, in particular an alkali or alkaline- earth metal atom such as, for example, lithium (Li) or magnesium (Mg) , or cadmium (Cd)
  • Hal is a halogen atom, preferably chlorine, bromine or iodine and n is zero, 1 or 2.
  • the reaction may be carried out e.g., treating the compound of formula (XI) with the organo etallic reagent of formula (XVII) , preferably an organomagnesium compound (Grignard reagent) or an organolithium compound, in an anhydrous solvent such as, for example, diethyl ether, tetrahydrofurane, at a temperature ranging from about -78°C to about -30°C, for a time varying from about one hour to four hours, under an inert atmosphere of, for example, nitrogen or argon.
  • organo etallic reagent of formula (XVII) preferably an organomagnesium compound (Grignard reagent) or an organolithium compound
  • an anhydrous solvent such as, for example, diethyl ether, tetrahydrofurane
  • the compounds of formula (XIV), (XV), (XVI), (XVII) are known compounds or they may be synthesized according to known procedures from known compounds.
  • 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.
  • Inhibition of 5 ⁇ -reductase was evaluated using the particulate fraction from ho ogenates 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 Z.10 mg protein/ml.
  • the assay for 5 ⁇ -reductase was done in a final volume of 0.5 ml, in 40 mM TRIS-HC1 buffer pH 5.5, containing 1 mM dithiothreitol, 5 mM NADPH, 1 mM [ 14C]testosterone, an aliquot of the enzyme preparation and various concentrations of the inhibitors. After 30 min 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
  • 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-hair 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 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.
  • 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 about 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
  • the pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g., silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g., starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or 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 pharmacologically inactive substances used in pharmaceutical formulations.
  • diluents e.g., lactose, dextrose, saccha
  • 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, 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, glycol, 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, 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
  • 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 5 ⁇ - reductase inhibitor.
  • the following examples further illustrate, but not limit, the invention.
  • reaction mixture is diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate, with IN hydrochloric acid, with water until neutral and dried over sodium sulphate.
  • Example 5 Scored tablets for oral use, each containing 250 mg of the active substance, were manufactured as follows. Composition (for 10,000 tablets): 17 ⁇ -[N-(1,1,1-trifluoro-2-phenylprop-2- yl)carbamoyl]androsta-3,5-diene-3- carboxylic acid 2500 g
  • 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 into tablets of proper weight.
  • Two-piece hard gelatin capsules for oral use, each containing 250 mg of active substance were manufactured as follows. Composition for 10,000 capsules:
  • the active substance was mixed with the starch-lactose mixture followed by the talc and calcium stearate.

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  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

La présente invention concerne un composé de la formule (I), dans laquelle A représente une liaison ou une chaîne droite ou ramifiée alkylène C1-C6, W représente un groupe -R1, -OR2, -NR3R4 ou (a), dans lequel: Y représente oxygène ou soufre; R1, R2 et R4 représentent un groupe alkyle C1-C10, substitué par un ou plusieurs atomes de fluor, ou bien un groupe cycloalkylaklyle C6-C15, substitué par un ou plusieurs atomes de fluor, ou bien un groupe aryle substitué par un ou plusieurs atomes de fluor, ou bien un groupe arylalkyle C7-C15, substitué par un ou plusieurs atomes de fluor; R3 et chacun des groupes R5, R6 et R7 représentent, indépendamment, hydrogène, ou bien groupe alkyle C1-C10, non substitué ou substitué par un ou plusieurs atomes de fluor, ou bien un groupe cycloalkylalkyle C6-C15, non substitué ou substitué par un ou plusieurs atomes de fluor, ou bien un groupe aryle, non substitué ou substitué par un ou plusieurs atomes de fluor, ou bien un groupe arylalkyle C7-C15, non substitué ou substitué par un ou plusieurs atomes de fluor, à condition que lorsque W est un groupe (b), au moins un des groupes R5, R6 et R7 ne soit pas un groupe hydrogène et contienne au moins un atome de fluor. La présente invention concerne également les sels pharmaceutiquement acceptables d'un tel composé. Des composés de la formule (I) et leurs sels constituent des inhibiteurs de la 5α-réductase.
PCT/EP1995/002650 1994-07-28 1995-07-07 3-carboxysteroides presentant une chaine laterale fluoree WO1996003420A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP95925845A EP0721460A1 (fr) 1994-07-28 1995-07-07 3-carboxysteroides presentant une chaine laterale fluoree
JP8505394A JPH09503228A (ja) 1994-07-28 1995-07-07 フッ素化側鎖を有する３−カルボキシステロイド

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9415183A GB9415183D0 (en) 1994-07-28 1994-07-28 3-carboxysteroids with a fluorinated side-chain
GB9415183.4 1994-07-28

Publications (1)

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WO1996003420A1 true WO1996003420A1 (fr) 1996-02-08

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EP (1) EP0721460A1 (fr)
JP (1) JPH09503228A (fr)
GB (1) GB9415183D0 (fr)
WO (1) WO1996003420A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0465142A1 (fr) * 1990-06-28 1992-01-08 Merck & Co. Inc. 17-Bêta-acyl-3-carboxy-androsta-3,5-diènes comme inhibiteurs de testostérone 5-alpha réductase
EP0517047A1 (fr) * 1991-05-24 1992-12-09 FARMITALIA CARLO ERBA S.r.l. 3-Carboxy steroides insaturés, et substitués en position 17-béta
EP0567271A2 (fr) * 1992-04-20 1993-10-27 Sankyo Company Limited Stéroides pour le traitement de l'hypertrophie prostatique, leur préparation et utilisation
WO1994003474A1 (fr) * 1992-07-31 1994-02-17 Pharmacia/Farmitalia Carlo Erba Srl Steroides a chaine laterale de type acylureidique fluore
WO1994011004A1 (fr) * 1992-11-18 1994-05-26 Smithkline Beecham Corporation Steroides 17 substitutes acyle-3-carboxy 3,5-diene en tant qu'inhibiteurs de 5-alpha-reductase
WO1995014709A1 (fr) * 1993-11-26 1995-06-01 Pharmacia S.P.A. 3-carboxysteroides a substitution fluoro dans la chaine laterale

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0465142A1 (fr) * 1990-06-28 1992-01-08 Merck & Co. Inc. 17-Bêta-acyl-3-carboxy-androsta-3,5-diènes comme inhibiteurs de testostérone 5-alpha réductase
EP0517047A1 (fr) * 1991-05-24 1992-12-09 FARMITALIA CARLO ERBA S.r.l. 3-Carboxy steroides insaturés, et substitués en position 17-béta
EP0567271A2 (fr) * 1992-04-20 1993-10-27 Sankyo Company Limited Stéroides pour le traitement de l'hypertrophie prostatique, leur préparation et utilisation
WO1994003474A1 (fr) * 1992-07-31 1994-02-17 Pharmacia/Farmitalia Carlo Erba Srl Steroides a chaine laterale de type acylureidique fluore
WO1994011004A1 (fr) * 1992-11-18 1994-05-26 Smithkline Beecham Corporation Steroides 17 substitutes acyle-3-carboxy 3,5-diene en tant qu'inhibiteurs de 5-alpha-reductase
WO1994011386A1 (fr) * 1992-11-18 1994-05-26 Smithkline Beecham Corporation Acyl-3-carboxy-3,5-dienes a substitution 17-alkyle et 17-beta et utilisation de ces derniers pour inhiber la 5-alpha-reductase
WO1995014709A1 (fr) * 1993-11-26 1995-06-01 Pharmacia S.P.A. 3-carboxysteroides a substitution fluoro dans la chaine laterale

Also Published As

Publication number Publication date
EP0721460A1 (fr) 1996-07-17
JPH09503228A (ja) 1997-03-31
GB9415183D0 (en) 1994-09-21

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