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WO1996003420A1 - 3-carboxysteroids with a fluorinated side chain - Google Patents

3-carboxysteroids with a fluorinated side chain 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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WO
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Prior art keywords
carbamoyl
formula
group
compound
carboxylic acid
Prior art date
Application number
PCT/EP1995/002650
Other languages
French (fr)
Inventor
Achille Panzeri
Marcella Nesi
Enrico Di Salle
Original Assignee
Pharmacia S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia S.P.A. filed Critical Pharmacia S.P.A.
Priority to JP8505394A priority Critical patent/JPH09503228A/en
Priority to EP95925845A priority patent/EP0721460A1/en
Publication of WO1996003420A1 publication Critical patent/WO1996003420A1/en

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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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Abstract

The present invention provides a compound of formula (I), wherein A is a bond or a straight or branched C1-C6 alkylene chain; W is a group -R1, -OR2, -NR3R4 or (a) wherein: Y is oxygen or sulphur; R1, R2 and R4 are: a C1-C10 alkyl group, substituted by one or more fluorine atoms; or a C6-C15 cycloalkylalkyl group, substituted by one or more fluorine atoms; or an aryl group, substituted by one or more fluorine atoms; or a C7-C15 arylalkyl group, substituted by one or more fluorine atoms; R3 and each of R5, R6, and R7, independently, are hydrogen, or a C1-C10 alkyl group, unsubstituted or substituted by one or more fluorine atoms, or a C6-C15 cycloalkylalkyl group, unsubstituted or substituted by one or more fluorine atoms; or an aryl group, insubstituted or substituted by one or more fluorine atoms; or a C7-C15 arylalkyl group, unsubstituted or substituted by one or more fluorine atoms; provided that when W is a group (b) at least one of R5, R6 and R7 is different from hydrogen and contains at least one fluorine atom, and the pharmaceutically acceptable salts thereof. The compounds of formula (I) and their salts are 5α-reductase inhibitors.

Description

3-CΆRBOXYSTEROIDS WITH A F UORINΆTED SIDE CHAIN
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 5α-reductase inhibition. In certain androgen responsive tissues the action of testosterone is mediated primarily through its 5α-reduced metabolite, dihydrotestosterone (DHT) (Bruchowsky N., Wilson J.D.; J. Biol. Chem. 243. 5953, 1968). The conversion of testosterone to dihydrotestosterone is catalysed by the enzyme
5α-reductase and if 5α-reductase is inhibited, the formation of dihydrotestosterone is reduced and its specific androgenic effect is attenuated or prevented.
The 5α-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). Also breast cancer treatment can take advantage from use of 5α-reductase inhibitors as the said tumour is known to be aggravated by presence of androgens. Androst-4-en-3-one-17β-carboxylic acid and its methyl ester (Voigt and Hsia, Endocrinology, 92., 1216 (1973) ; Canadian Patent No. 970,692) are among the first steroidic compounds described as 5α-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 5α-reductase (Robaire et al., J. Steroid Biochem. 8., 307-310 (1977)).
The (20R)-4-diazo-21-hydroxy-20-methyl-5α-pregnan-3-one and its analogs are reported to be enzyme activated inhibitors of testosterone 5α-reductase (Bloh et al., Biochem. Biophys. Res. Comm. 95, 273-80 (1980); United States Patent 4,317,817). Another series of enzyme-directed irreversible inhibitors of
5α-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 5α-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 5α-reductase inhibitors. The compounds known in the art are reported in a very large number of publications and patents. In particular 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 17β-alkanoyl derivatives are described in J. Med. Chem. 29. 2298-2315 (1986), Eur. Pat. Appln. No. 314119, Eur. Pat. Appln. No. 367502, US Patent 5,061,803, Eur. Pat. Appln. No. 478066.
The invention provides compounds of the following formula (I)
Figure imgf000005_0001
wherein:
A is a bond or a straight or branched Ci-Cβ alkylene chain; W is a group -R1# -O 2, -NR3R4 or
Figure imgf000005_0002
wherein:
Y is oxygen or sulphur;
Rl, R2 and R4 are: a C1-C10 alkyl group, substituted by one or more fluorine atoms; or a C6~C15 cycloalkylalkyl group, substituted by one or more fluorine atoms; or an aryl group, substituted by one or more fluorine atoms; or a C7-C15 arylalkyl group, substituted by one or more fluorine atoms;
R3 and each of R5, R6 and R7, independently, are hydrogen or a Cj-Cio alkyl group, unsubstituted or substituted by one or more fluorine atoms; or a C6-Ci5 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-C15 arylalkyl group, unsubstituted or substituted by one or more fluorine atoms and, provided that when
Figure imgf000006_0001
W is a group γ , at least one of R5, R6, R7 is different from hydrogen and contains at least one fluorine atom, and the pharmaceutically acceptable salts thereof.
In the formulae of this specification the dotted line ( •""" ) indicates a substituent in the a-configuration, i.e. below the plane of the ring, and the wedged line ( -•*** ) indicates a substituent in the β-configuration, i.e. above the plane of the ring.
The configurations of the chiral centers in the side chain is unspecified; the invention is meant to include both the single
"R" and "S" epimers as well as their "RS" mixtures. The invention includes also all the possible isomers of formula (I) and their mixture.
Also the metabolites and the metabolic precursors of the compounds of formula (I) are within the scope of the present invention.
In this specification the 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 C1-C4 alkylene chain, such as, for example, -CH(CH3)-, -CH(CH3)CH2CH2-, -CH2-, -CH2CH2-. An unsubstituted Cj-Cio alkyl group may be, e.g. straight or branched C1-C5 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 C1-C10 alkyl group substituted by one or more fluorine atoms may be, for example: -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, -CF2CF2CF3, -CH2CH2CF3, -CF(CF3)2, -CF2CF2CF2CF3, -CH2CH(CH3)CF3, -CH2CH(CF3)2, -C(CF3)3, -C(CH3)2CF3, -C(CF3)2CH3, -C(CH2F)3, -C(CHF2)3, -C(CH3)2CH2CF3, -C(CH3) (CF3)CH2CF3, -CF2(CF2)4CF3, -CF2(CF2)7CF3, -CF2(CF2)8CF3.
An unsubstituted Cg-C^ cycloalkylalkyl group may be e.g., a Ci-Cirj-cyclopentylalkyl or Ci-Cg-cyclohexylalkyl group; for example:
Figure imgf000008_0001
A Ce-Ci5 cycloalkylalkyl group substituted by one or more fluorine atoms may be, for example:
Figure imgf000008_0002
CH2CF3 CF- CF,
CF,
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:
Figure imgf000008_0003
An unsubstituted C7~C15 arylalkyl group may be for example an aryl-Cx-Cg alkyl or a bis-aryl-Cι-C3-alkyl group; for example:
-CH, •
Figure imgf000008_0004
A C7-C15 arylalkyl substituted by one or more fluorine atoms may be, for example:
Figure imgf000009_0001
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. When Ri, R2, R3, R4, R5, 6 and R7 are groups containing more than one fluorine atom, preferably, the fluorine atoms are linked to the same carbon atom, forming -CF2- (difluoro- methylene) or -CF3 (trifluoromethyl) groups. In particular, preferred compounds are those which contain CF3
(trifluoromethyl) groups.
A preferred class of compounds according to the invention, are the compounds of formula (I) wherein:
A is a bond or a -CH-CH2-CH2- group;
Figure imgf000010_0001
W is either a group -Ri which is
-CF3, -CH2-CF3, -CH(CF3)2, -CF2CF2-CF3, -CH2-CH2-CF3, -CF(CF3)2, -CF2-CF2-CF2-CF3, -CH2-CH(CH3)CF3, -CH2-CH(CF3)2, *"C(CF3)3, -C(CH3)2CF3, -C(CF3)2CH3, -C(CH3)2CH2-CF3, -C(CH3) (CF3)CH2CF3, -CF3-(CF2)4-CF2-, -CF2-(CF2)7-CF3, -CF2-(CF2)8-CF3,
Figure imgf000010_0002
or a group -OR2, wherein R2 is -CF3, -CH -CF3, -CH(CF )2, -CF2-CF2-CF3, -CH2-CH2-CF3, -CF(CF3)2, -CF2-CF2-CF2-CF3, -CH2-CH(CF3)2, -C(CF3)3, -C(CH3)2CF3, -C(CF3)2CH3, -C(CH3)2CH2-CF3, -C(CH3) (CF3)CH2CF3, -CF3- (CF2) 4-CF2-, -CF2- (CF2) 7-CF3 , -CF2- (CF2 ) 8-CF3 ; R3 or a group -N wherein R3 is hydrogen, -CF f -CH2-CF3,
R4
-CH(CF3)2, -CF2-CF2-CF3, -CH2-CH2-CF3 , -CF(CF3)2, -CF2-CF2-CF2-CF3, -CH2-CH(CF3)2, -C(CF3)3, -C(CH3)2CF3, -C(CF3)2CH3, -C(CH3)2CH2-CF3, -C(CH3) (CF3) CH2CF3; -CF2-(CF2)4-CF3, -CF2-(CF2)7-CF3, -CF2- (CF2) 8-CF3; and R is -CF3, CH2-CF3, -CH(CF3)2, -CF2-CF2-CF3/ -CH2-CH2-CF3, -CF(CF3)2, -CF2-CF2-CF2-CF3, -CH2-CH (CF3) 2, -C(CF3)3, -C(CH3)2CF3, -C(CF3)2CH3, -C(CH3) 2CH2-CF3 , -C(CH3) (CF3) CH2CF3, -CF2-(CF2)4-CF3, -CF2-(CF2)7-CF3, -CF2- (CF2) 8-CF3,
Figure imgf000011_0001
Figure imgf000012_0001
or a group γ wherein each of R5, Rg, and R7, independently, is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, neo-pentyl, n-octyl, n-nonyl, -CF3, CH2-CF3, -CH(CF3)2, -CF2-CF2-CF3, -CH2-CH2-CF3, -CF(CF3)2, -CF2-CF2-CF2-CF3, -CH2-CH(CF3)2, -C(CF3)3, -C(CH3)2CF3,
-C(CF3)2CH3, -C(CH3)2CH2-CF3, C(CH3) (CF3)CH2CF3 , -CF3-(CF2)4-CF2, -CF2-(CF2)7-CF3, -CF2-(CF2)8-CF3 phenyl, tolyl, naphthyl,
Figure imgf000012_0002
provided that, when W is γ at least one of R5, Rg and R7 is different from hydrogen and contains at least one fluorine atom and the pharmaceutically acceptable salts thereof.
Specific examples of preferred compounds, according to the invention, 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;
5) 17β-(2,2,2-trifluoroethoxycarbonyl)androsta-3, 5-diene-3- carboxylic acid;
6) 17β-[N-(2,2,2-trifluoroethyl)carbamoyl]androsta-3,5-diene- 3-carboxylic acid;
7) 17β-[N,N-di-(2,2,2-trifluoroethyl)carbamoyl]androsta-3,5- diene-3-carboxylic acid;
8) 17β-[N-(2,2,2-trifluoroethyl) -N-(2,2,3,3, 3-penta- fluoropropyl)carbamoyl]androsta-3,5-diene-3-carboxylic acid;
9) 17β-[N-(2,2,2-trifluoro-1-phenylethyl)carbamoyl]androsta- 3,5-diene-3-carboxylic acid;
10) 17β-[N-(l, 1,1-trifluoro-2-phenylprop-2-yl)carbamoyl] androsta-3,5-diene-3-carboxylic acid; 11) 17β-[N-(l, 1, 1,3,3,3-hexafluoro-2-phenylpropyl)carbamoyl] androsta-3,5-diene-3-carboxylic acid
12) 17β-[N-(l,1,1-trifluoro-2-methylprop-2-yl)carbamoyl] androsta-3,5-diene-3-carboxylic acid;
13) 17β-[N-(l,1,1,3,3,3-hexafluoro-2-methylpropyl)carbamoyl] androsta-3,5-diene-3-carboxylic acid;
14) 17β-{N-(2,2,2-trifluoroethyl) -N-[N-(2,2,2-trifluoroethyl) carbamoyl]carbamoyl}androsta-3,5-diene-3-carboxylic acid;
15) 17β-{N-(2,2,2-trifluoroethyl) -N-[N,N-diethylcarbamoyl] carbamoyl}androsta-3 , 5-diene-3-carboxylic acid; and 16) 17β-{N-(4-trifluoromethylphenyl)-N-[N-(4-trifluoromethyl- phenyl)carbamoyl]carbamoyl}androsta-3,5-diene-3-carboxylic acid; and the pharmaceutically acceptable salts thereof.
The above reported preferred compounds are tabulated herein below, with reference to the substituents as defined for formula (I) .
Figure imgf000014_0001
A compound of formula (I) or a pharmaceutically acceptable salt thereof may be obtained by a process comprising hydrolysing a compound of formula (II)
Figure imgf000015_0001
wherein 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. , in a suitable solvent, such as, for example, methanol, ethanol, tetrahydrofurane, dioxane, in the presence of an aqueous solution of an alkali metal hydroxide such as, for example, potassium hydroxide, sodium hydroxide, 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 reaction mixture, optionally under an inert atmosphere of nitrogen.
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)
Figure imgf000016_0001
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.
The reaction of a compound of formula (III) , as defined above, with carbon monoxide in the presence of a C -C6 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 Cι~cg alkyl alcohol, such as, for example, methanol or ethanol.
Optionally 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 compound of formula (III), may be obtained, e.g., by reacting a compound of formula (IV)
Figure imgf000017_0001
wherein 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) . A compound of formula (IV) , wherein A is as defined above and W
Figure imgf000017_0002
is a group ° , wherein R5, Rg, R7 are as defined above, may be obtained according to the pathways of synthesis depicted in the following scheme I. According to reaction (a) a compound of formula (IV) wherein A, Y, R5, Rg and R7 are as defined above, provided that R5 and Rg are not hydrogens and R7 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 R5 and Rg are as defined above.
According to reaction (b) , a compound of formula (IV) wherein A, Y, R5, Rg, R7 are as defined above, provided that R5 is not hydrogen, may be obtained from a compound of formula (VII) , wherein A, Y, Rg and R7 are as defined above, by alkylation with a compound of formula (VIII) wherein R5 is as defined above, provided that it is not hydrogen, and X is a halogen atom, e.g., iodine.
According to reaction (c) , a compound of formula (IV) wherein R7 is hydrogen and A, Y, R5, Rg are as defined above, provided that Rg is not hydrogen, may be obtained from a compound of formula (IX) , wherein A and R5 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.
Figure imgf000019_0001
Compounds of formula (V) wherein Y=S, compounds of formula (VII) and compounds of formula (IX) , may be obtained from a compound of formula (XI) wherein Z may be any suitable activating group of the carboxylic function. It may be, for instance, one of the following groups:
Figure imgf000020_0001
In particular, 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, CH2C12, 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
formula (XI) wherein Z is
Figure imgf000020_0002
that is the S-2- pyridylthioate derivative, with an excess of sodium hydrogen sulphide monohydrate. The 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 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) , as defined above, may be obtained reacting a compound of formula (XI) , as defined above, with an urea or thiourea of formula (XII)
Re / H2N-C-N (XII)
II \
O R7 wherein Rg and R7 are as defined above.
A compound of formula (IX), may be obtained, e.g., reacting a compound of formula (XI) , with an a ine of formula (XIII)
R5-NH2 (XIII) wherein R5 is as defined above. 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 NR3R or NHR3, wherein R3 and R4 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:
Figure imgf000022_0001
with a compound of formula (XIV) or (XV)
NH (XI ) R4NH2 (XV)
/
wherein R and R4 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 compound of formula (IV), wherein W is a group OR2, wherein R2 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)
R20H (XVI) wherein R2 is as defined above, or b) by the reaction of a compound of formula (XI) , wherein Z is an activating function of the carboxylic group which is useful for the formation of the ester bond, such as, for example,
Figure imgf000023_0001
with a compound of formula (XVI) , wherein R2 is as defined above.
The reaction between a compound of formula (IV) and a compound of formula (XVI) , according to the reaction variant a) 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.
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 (CF3COOAg) 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 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
Figure imgf000024_0001
with a compound of formula (XVII) R!-M(Hal)n (XVII) wherein 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.
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 5α-reductase enzyme and, therefore, are potent antiandrogens.
For example, the inhibitory effect of the compounds of the invention on 5α-reductase was determined in vitro according to the procedure reported herebelow.
In vitro assay of Sα-reductase inhibition
Inhibition of 5α-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 5α-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 N2 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 5α-reduction of testosterone was calculated by
relating the 14C-radi.oacti.vi.ty i.n the 5α-reduced metabolites
(5α-dihydrotestosterone, 3α- and 3β- androstanediols) regions
to the total radioactivity in the testosterone and 5 -reduced metabolites regions.
The concentration of each compound required to reduce control
5α-reductase activity by 50% (IC5Q) was determined by plotting
% inhibition versus log for inhibitor concentration.
In view of the activity shown in the above test the compounds of the invention can be therapeutically useful in the situations in which a decrease in androgen action, by means of 5α-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.
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. As already said, 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) . The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form. For example, 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. 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.
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.
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 5α-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 5α- reductase inhibitor. The following examples further illustrate, but not limit, the invention.
The reported NMR data are determined in CDC13.
Example 1
(22RS)-17β-[N-(1,1,1-trifluoro-2-phenylprop-2-yl) carbamoyl]androsta-3,5-diene-3-carboxylie acid
[Compound (I): A=bond, W=NR3R4, wherein R3=H, R4=-C(CH3) (CF3)Ph]
A mixture of methyl (22RS)-17β-[N-(1, 1,1-trifluoro-2- phenylprop-2-y1)carbamoyl]androsta-3,5-diene-3-carboxylate (531 mg) , methanol (20 ml) and aqueous lithium hydroxide (200 mg in 5 ml of water) is stirred at room temperature for 5 days. The methanol is evaporated under vacuum and water is added; the mixture is acidified with IN hydrochloric acid and extracted with methylene chloride; the organic layers are washed with brine, with water until neutral, dried over sodium sulphate and the solvent is removed under vacuum. The yellowish solid so obtained is purified by flash chromatography on silica gel (eluant: methylene chloride/acetone 9:1), so obtaining 380 mg of the title compound.
NMR (CDC13) δ: 0.68 and 0.72 (2s, 3H, CH3(18)), 0.88 (s, 3H, CH3(19)), 2.05 and 2.10 (2s, 3H, C(CH3)CF3Ph) , 5.82 (m, 1H, H(6)), 7.13 (m, 1H, H(4)), 7.25-7.6 (m, 5H, Ph) . Following and analogous procedure the compounds listed below are prepared:
(21RS)-21-(1,1,1-trifluoroprop-2-yl)pregna-3,5-dien-20-one-3- carboxylic acid NMR (CDC13) δ: 0.70 (2s, 3H, CH3(18)), 0.90 (s, 3H, CH3(19)),
0.92 (d, 3H, CH(CH3)CF3), 2.3 (m, 2H, C0CH2-) , 2.4 (m, IH,
CH(CH3)CF3 ), 2.5 (t, IH, H(17α)), 5.82 (m, IH, H(6)), 7.13 (m,
IH, H(4)).
21-(1,1,1,3,3,3-hexafluoropropyl)pregna-3,5-dien-20-one-3- carboxylic acid;
21-(1,1,1-trifluoro-3-phenylprop-2-y1)pregna-3,5-dien-20-one-3- carboxylic acid;
21-trifluoromethylpregna-3,5-dien-20-one-3-carboxylic acid; 17β-(2,2,2-trifluoroethoxycarbonyl)androsta-3,5-diene-3- carboxylic acid;
17β-[N-(2,2,2-trifluoroethyl)carbamoyl]androsta-3,5-diene-3- carboxylic acid;
17β-[N,N-di-(2,2,2-trifluoroethyl)carbamoyl]androsta-3,5-diene- 3-carboxylic acid;
17β-[N-(2,2,2-trifluoroethyl)-N-(2,2,3,3,3-pentafluoropropyl) carbamoyl]androsta-3,5-diene-3-carboxylic acid;
17β-[N-(l,l,l,3,3,3-hexafluoro-2-phenylpropyl)carbamoyl] androsta-3,5-diene-3-carboxylic acid NMR (CDC13) δ: 0.74 (s, 3H, CH3(18)), 0.98 (s, 3H, CH3(19)), 5.70 (s, IH, NH) , 5.8 (id, IH, H(6)), 7.1 ( , IH, H(4)), 7.2-7.4 (m, 5H, Ph) .
17β-[N-(l,1,1-trifluoro-2-methylprop-2-yl)carbamoyl]androsta- 3,5-diene-3-carboxylic acid;
17β-[N-(1,1,1,3,3,3-hexafluoro-2-methylpropy1)carbamoyl] androsta-3,5-diene-3-carboxylic acid;
17β-[N-(2,2,2-trifluoro-1-phenylethyl)carbamoyl]androsta-3,5- diene-3-carboxylic acid;
17β-[N-(1,1,1-trifluoro-2-methylprop-2-y1)carbamoyl]androsta- 3,5-diene-3-carboxylic acid;
17β-{N-(2,2,2-trifluoroethyl)-N-[N-(2,2,2-trifluoroethyl) carbamoyl]carbamoyl}androsta-3,5-diene-3-carboxylic acid
NMR (CDC13) δ: 0.75 (s, 3H, CH3(18)), 0.90 (s, 3H, CH3(19)), 3.98 (m, 2H, NHCH2CF3) , 4.3 and 5.1 (2m, 2H, CON(CH2CF3)CO) , 5.82 (m, IH, H(6)), 7.13 (m, IH, H(4)), 9.6 (bs, IH, NH) ;
17β-{N-(2,2,2-trifluoroethyl)-N-(N,N-diethylcarbamoyl) carbamoyl}androsta-3,5-diene-3-carboxylic acid
NMR (CDC13) δ: 0.72 (s, 3H, CH3(18)), 0.85 (s, 3H, CH3(19)), 1.2 (t, 6H, N(CH2CH3)2), 3.42 (q, 4H, N(CH2CH3)2), 4.15 and 4.45 (2m, 2H, NCH2CF3) , 5.80 (m, IH, H(6)), 7.1 (m, IH, H(4)); and 17β-{N-(4-trifluoromethylphenyl)-N-[N-(4-trifluoromethylphenyl) carbamoyl]carbamoyl}androsta-3,5-diene-3-carboxylic acid. Example 2
Methyl (22RS)-17β-[N-(1,1,1-trifluoro-2-phenylprop-2-yl) carbamoyl]androsta-3,5-diene-3-carboxylate [Compound (II) : A=bond, W=NR3R wherein R3=H and R4=-C(CH3) (CF3)Ph, R=CH3].
To a solution of (22RS)-3-{[ (trifluoromethyl)sulphonyl]oxy}- 17β-[N-(1,1,1-trifluoro-2-phenylprop-2-y1)carbamoyl]androsta- 3,5-diene (497 mg) in anhydrous dimethylformamide (2 ml), methanol (2 ml) and triethylamine (0.223 ml) bis(triphenyl- phosphine) palladium (II) acetate (18 mg) is added; 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) . Ethyl acetate is added and the organic solution is washed with water until neutral, dried over sodium sulphate and the solvent is removed under vacuum. The crude oil so obtained is purified by flash chromatography on silica gel (eluant: n-hexane/ethyl acetate 75:25) to yield 370 mg of the title compound NMR (CDC13) δ: 0.68 and 0.72 (2s, 3H, CH3(18)), 0.88 (s, 3H,
CH3(19)), 2.05 and 2.10 (2s, 3H, C(CH3)CF3Ph) , 3.75 (s, 3H, C00CH3) , 5.80 (m, IH, H(6)), 7.05 ( , IH, H(4)), 7.25-7.60 (m, 5H, Ph) .
Following an analogous procedure the compounds listed below are prepared: Methyl 21-(1,1,1-trifluoroprop-2-yl)pregna-3,5-dien-20-one-3- carboxylate;
Methyl 21-(1,1,1,3,3,3-hexafluoropropyl)pregna-3,5-dien-20-one-
3-carboxylate; Methyl 21-(1,1,1-trifluoro-3-phenylprop-2-yl)pregna-3,5-dien-
20-one-3-carboxylate;
Methyl 21-trifluoromethylpregna-3,5-dien-20-one-3-carboxylate;
Methyl 17β-(2,2,2-trifluoroethoxycarbonyl)androsta-3,5-diene-3- carboxylate; Methyl 17β-[N-(2,2,2-trifluoroethyl)carbamoyl]androsta-3,5- diene-3-carboxylate;
Methyl 17β-[N,N-di-(2,2,2-trifluoroethyl)carbamoyl]androsta-
3,5-diene-3-carboxylate;
Methyl 17β-[N-(2,2,2-trifluoroethyl)-N-(2,2,3,3,3- pentafluoropropyl)carbamoyl]androsta-3,5-diene-3-carboxylate;
Methyl 17β-[N-(2,2,2-trifluoro-1-phenylethy1)carbamoyl] androsta-3,5-diene-3-carboxylate;
Methyl 17β-[N-(l,1,1-trifluoro-2-methylprop-2-yl)carbamoyl] androsta-3,5-diene-3-carboxylate; Methyl 17β-{N-(2,2,2-trifluoroethyl)-N-[N-(2,2,2-trifluoro- ethyl)carbamoyl]carbamoyl}androsta-3,5-diene-3-carboxylate;
Methyl 17β-{N-(2,2,2-trifluoroethyl)-N-[N,N-diethylcarbamoyl] carbamoyl}androsta-3,5-diene-3-carboxylate;
Methyl 17β-{N-(4-trifluoromethylphenyl)-N-[N-(4-trifluoro- methylphenyl)carbamoyl]carbamoyl}androsta-3,5-diene-3- carboxylate; Methyl 17β-[N-(1,1,1,3,3,3-hexafluoro-2-phenylpropyl)carbamoyl] androsta-3,5-diene-3-carboxylate; and
Methyl 17β-[N-(1,1,1,3,3,3-hexafluoro-2-methylpropyl)carbamoyl] androsta-3,5-diene-3-carboxylate.
Example 3
(22RS)-3-{[ (trifluoromethyl)sulphonyl]oxy}-17β-[N-(1,1,1- trifluoro-2-phenylprop-2-yl)carbamoyl]androsta-3,5-diene [Compound (III) : A=bond, W=NR R4 wherein R =H and R=-C(CH3) (CF3)Ph] .
To a stirred solution of (22RS)-N-(1,1,1-trifluoro-2- phenylprop-2-yl)3-oxo-androst-4-ene-17β-carboxamide (670 mg) and 2,6-ditertbutyl-4-methylpyridine (363 mg) in methylene chloride (6 ml) maintained under inert atmosphere of nitrogen at room temperature, trifluoromethanesulphonic anhydride (0.254 ml) is added dropwise during 10 minutes.
After stirring for 30 minutes, the 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.
Evaporation of the solvent at reduced pressure affords a foam which is purified by flash chromatography on silica gel (eluant: n-hexane/ethyl acetate 75:25) to yield 500 mg of the title compound. NMR (CDC13) δ: 0.68 and 0.72 (2s, 3H, CH3(18)), 1.16 (s, 3H, CH3(19)), 2.05 and 2.10 (2s, 3H, C(CH3)CF3Ph) , 5.45 (m, IH, H(6)), 5.80 ( , IH, H(4)), 7.25-7.60 (m, 5H, Ph) .
Following an analogous procedure the compounds listed below are prepared:
3-{[ (trifluoromethyl)sulphonyl]oxy}-21-(1,1,1-trifluoroprop-2- yl)pregna-3,5-dien-20-one;
3-{ [ (trifluoromethyl)sulphonyl]oxy}-21-(l,l,1,3,3,3- hexafluoropropyl)-3,5-dien-20-one;
3-{[ (trifluoro ethyl)sulphonyl]oxy}-21-(l,1,1-trifluoro- phenylprop-2-yl)-3,5-dien-20-one;
3-{[ (trifluoromethyl)sulphonyl]oxy}-21-trifluoromethyl-pregna-
3,5-dien-20-one; 3-{[(trifluoromethyl)sulphonyl]oxy}-17β-(2,2,2-trifluoro- ethoxycarbonyl)androsta-3,5-diene;
3-{[ (trifluoromethyl)sulphonyl]oxy}-17β-[N-(2,2,2-trifluoro¬ ethyl)carbamoyl]androsta-3,5-diene;
3-{[(trifluoromethyl)sulphonyl]oxy}-17β-[N,N-di-(2,2,2- trifluoroethyl)carbamoyl]androsta-3,5-diene;
3-{[ (trifluoromethyl)sulphonyl]oxy}-17β-[N-(2,2,2-trifluoro¬ ethyl)-N-(2,2,3,3,3-pentafluoropropyl)carbamoyl]androsta-3,5- diene;
3-{[ (trifluoromethyl)sulphonyl]oxy}-17β-[N-(2,2,2-trifluoro-1- phenylethyl)carbamoyl]androsta-3,5-diene;
3-{[(trifluoromethyl)sulphonyl]oxy}-17β-[N-(l,1,1-trifluoro-2- methylprop-2-yl)carbamoyl]androsta-3,5-diene; 3-{[ (trifluoromethyl)sulphonyl]oxy}-17β-{N-(2,2,2- trifluoroethyl)-N-[N-(2,2 ,2-trifluoroethyl)carbamoyl] carbamoyl}androsta-3,5-diene;
3-{[ (trifluoromethyl)sulphonyl]oxy}-17β-{N-(2,2,2-trifluoro- ethyl)-N-(N,N-diethylcarbamoy1)carbamoyl}androsta-3,5-diene; 3-{[(trifluoromethyl)sulphonyl]oxy}-17β-{N-(4-trifluoromethyl¬ phenyl)-N-[N-(4-trifluoromethylphenyl)carbamoyl]carbamoyl} androsta-3,5-diene;
3-{[ (trifluoromethyl)sulphonyl]oxy}-17β-[N-(1,1,1,3,3,3- hexafluoro-2-phenylpropyl)carbamoyl]androsta-3,5-diene; and 3-{[ (trifluoromethyl)sulphonyl]oxy}-17β-[N-(1,1,1,3,3,3- hexafluoro-2-methylpropy1)carbamoyl]androsta-3,5-diene.
Example 4 (22RS)-N-(1,1,1-trifluoro-2-phenylprop-2-yl)-3-oxo-androst-4- ene-17β-carboxamide
[Compound (IV) : A=bond, W=NR3R4 wherein R3=H and R=-C(CH3) (CF3)Ph].
To a stirred suspension of 3-oxo-androst-4-ene-17β-carboxylic acid (500 mg) in anhydrous toluene (7.0 ml) and pyridine (0.16 ml) , under a nitrogen atmosphere, at about 10°C, a solution of oxalyl chloride (0.17 ml) in anhydrous toluene (1 ml) is added dropwise. Then the mixture is stirred at room temperature for 1.5 h: during this time the carboxylic acid dissolves completely. The solvent is removed under vacuum at room temperature. The white solid 3-oxoandrosta-4-ene-17β-carboxyl chloride so obtained is dissolved in chloroform (25 ml) , cooled to about 0°C under nitrogen atmosphere. Triethylamine (0.219 ml) is added followed by dropwise addition of a solution of 1,1,1-trifluoro-2-phenylprop-2-yl-amine (593 mg) in chloroform (1 ml) ; the reaction mixture is heated to reflux for 4 hrs.
After cooling to room temperature the reaction mixture is poured into brine (50 ml) and extracted with methylene chloride (2 x30 ml) : the combined organic extracts are washed with IN HCl, with water until neutral and dried over sodium sulphate. The solvent is removed under vacuum and the crude solid material is purified by flash chromatography on silica gel (eluant: n-hexane/ethyl acetate 65:35) to yield 600 mg of the title compound.
NMR (CDC13) δ: 0.71 and 0.74 (2s, 3H, CH3(18)), 1.2 (s, 3H, CH3(19)), 2.03 and 2.07 (2s, 3H, C(CH3)CF3Ph) , 5.74 (s, IH, H(4)), 5.86 and 5.90 (2bs, IH, NH) , 7.25-7.60 ( , 5H, Ph) .
A small amount of epimeric mixture was further purified by flash chromatography (n-hexane/ethyl acetate 70:30) in order to separate the (22S) and (22R) epimers. There are obtained:
1) compound with Rf sup. (m.p. 186-188°C)
NMR (CDC13) δ: 0.74 (s, 3H, CH3(18)), 1.2 (s, 3H, CH3(19)), 2.07 (s, 3H, C(CH3)CF3Ph) , 5.74 (s, IH, H(4)), 5.86 (bs, IH, NH) , 7.25-7.60 (m, 5H, Ph) .
2) compound with Rf inf. (m.p. 158-160°C) NMR (CDC13) δ: 0.71 (s, 3H, CH3(18)) , 1.2 (s, 3H, CH3(19)), 2.03 (s, 3H, C(CH3)CF3Ph) , 5.74 (s, IH, H(4)), 5.90 (bs, IH, NH) , 7.25-7.60 (m, 5H, Ph) .
Following an analogous procedure the compounds listed below are prepared:
N-(1,1,1,3,3,3-hexafluoro-2-phenylpropyl)-3-oxo-androst-4-ene- 17β-carboxamide
NMR (CDC13) δ: 0.74 (s, 3H, CH3(18)), 1.20 (s, 3H, CH3(19)), 5.42 (s, IH, NH) , 5.74 (ε, IH, H(4)), 7.35-7.54 (m, 5H, Ph) .
N-(2,2,2-trifluoroethyl)-3-oxo-androst-4-ene-17β-carboxamide;
N,N-di-(2,2,2-trifluoroethyl)-3-oxo-androst-4-ene-17β- carboxamide; N-(2,2,2-trifluoroethyl) -N-(2,2,3,3,3,-pentafluoropropyl)-3- oxo-androst-4-ene-17β-carboxamide;
N-(2,2,2-trifluoro-1-phenylethyl)-3-oxo-androst-4-ene-17β- carboxamide;
N-(l,1,1-trifluoro-2-methylprop-2-yl)-3-oxo-androst-4-ene-17β- carboxamide;
N-(1,1,1,3,3,3-hexafluoro-2-methylpropyl)-3-oxo-androst-4-ene-
17β-carboxamide.
Example 5 Scored tablets for oral use, each containing 250 mg of the active substance, were manufactured as follows. Composition (for 10,000 tablets): 17β-[N-(1,1,1-trifluoro-2-phenylprop-2- yl)carbamoyl]androsta-3,5-diene-3- carboxylic acid 2500 g
Corn starch 275 g Talc powder 187 g
Calcium stearate 38 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.
Example 6
Two-piece hard gelatin capsules for oral use, each containing 250 mg of active substance were manufactured as follows. Composition for 10,000 capsules:
17β-[N-(1,1,1-trifluoro-2-phenylpropyl]-3-oxo-
4-aza-5α-androst-l-ene-17β-carboxamide 2500 g
Lactose 1000 g
Corn starch 300 g Talc powder 65 g
Calcium stearate 35 g
The active substance was mixed with the starch-lactose mixture followed by the talc and calcium stearate.

Claims

1. A compound of formula (I)
Figure imgf000041_0001
wherein:
A is a bond or a straight or branched Cι~C alkylene chain;
W is a group -Rj., -OR2, -NR3R4 or
Figure imgf000041_0002
wherein:
Y is oxygen or sulphur;
Rl, R2 and R4 are: a CI-CIO alkyl group, substituted by one or more fluorine atoms; or a C -Cis cycloalkylalkyl group, substituted by one or more fluorine atoms; or an aryl group, substituted by one or more fluorine atoms; or a C7-C15 arylalkyl group, substituted by one or more fluorine atoms; R3 and each of R5, Rg and R7, independently, are hydrogen, or a CI-CIO alkyl group, unsubstituted or substituted by one or more fluorine atoms; or a Cg-Cis 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 C7-C 5 arylalkyl group, unsubstituted or substituted by one or more fluorine atoms;
Figure imgf000042_0001
provided that when W is a Y group at least one of R5, Rg and R7 is different from hydrogen and contains at least one fluorine atom, or a pharmaceutically acceptable salt thereof.
A compound of formula (I), according to claim 1, wherein: A is a bond or a -CH-CH2-CH2- group;
Figure imgf000042_0002
W is either a group -Ri which is -CF3, CH2-CF3, -CH(CF3)2, -CF2CF2-CF3, -CH2-CH2-CF3, -CF(CF3)2, -CF2-CF2-CF2-CF3, -CH2CH(CF3)CH3, -CH2-CH(CF3)2, -C(CF3)3, -C(CH3)2CF3, -C(CF3)2CH3, -C(CH3)2CH2-CF3, -C(CH3) (CF3)CH2CF3, -CF3-(CF2)4-CF2-, -CF2-(CF2)7-CF3, -CF2-(CF2)8-CF3,
Figure imgf000043_0001
or a group -0R2, wherein R2 is -CF3, CH2-CF3, -CH(CF3)2, -CF2-CF2-CF3, -CH2-CH2-CF3, -CF(CF3)2, -CF2-CF2-CF2-CF3, -CH2-CH(CF3)2, -C(CF3)3, -C(CH3)2CF3, -C(CF3)2CH3,
-C(CH3)2CH2-CF3, -C(CH3) (CF3)CH2CF3, -CF3- (CF2) 4-CF2-, -CF2-(CF2)7-CF3, -CF2-(CF2)8-CF3;
R3 / or a group -N wherein R3 is hydrogen, -CF3, -CH -CF /
\ R4
-CH(CF3)2, -CF2-CF2-CF3, -CH2-CH2-CF3, -CF(CF3)2,
-CF2-CF2-CF2-CF3, -CH2-CH(CF3)2, -C(CF3)3, -C(CH3)2CF3, -C(CF3)2CH3, -C(CH3)2CH2-CF3, -C(CH3) (CF3) CH2CF3,
-CF2-(CF2)4-CF3, -CF2-(CF2)7-CF3, -CF2- (CF2) 8-CF3 and R4 is -CF3, CH2-CF3, -CH(CF3)2, -CF2-CF2-CF3, -CH2-CH2-CF3, -CF(CF3)2, -CF2-CF2-CF2-CF3, -CH2-CH (CF3) 2, -C(CF3)3, -C(CH3)2CF3, -C(CF3)2CH3, -C(CH3) 2CH2-CF3, -C(CH3) (CF3) CH2CF3, -CF2-(CF2)4-CF3, -CF2- (CF2) 7-CF3, -CF2- (CF2) 8-CF3,
Figure imgf000044_0001
or a group wherein each of R5, Rg and R7, independently is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, neo-pentyl, n- octyl, n-nonyl, -CF3, CH2-CF3, -CH(CF3)2, -CF2-CF2-CF3, -CH2-CH2-CF3, -CF(CF3)2, -CF2-CF2-CF2-CF3, -CH2-CH(CF3)2, -C(CF3)3, -C(CH3)2CF3, -C(CF3)2CH3, -C(CH3)2CH2-CF3, -C(CH3) (CF3)CH2CF3, -CF3-CF2)4-CF2, -CF2-(CF2)7-CF3, -CF2-(CF2)8-CF3, phenyl, tolyl, naphthyl.
Figure imgf000044_0002
Figure imgf000045_0001
provided that, when W is γ at least one of R5, Rg and R7 is different from hydrogen and contains at least one fluorine atom, or a pharmaceutically acceptable salt thereof.
3. A compound of formula (I), according to claim 1, selected from the group consisting of:
21-(1,1, 1-trifluoroprop-2-yl)pregna-3, -dien-20-one-3- carboxylic acid; 21-(1, 1,1,3,3,3-hexafluoropropyl)pregna-3, 5-dien-20-one-3- carboxylic acid;
21-(1,1,1-trifluoro-3-phenylprop-2-yl)pregna-3,5-dien-20- one-3-carboxylic acid;
21-trifluoromethylpregna-3, 5-dien-20-one-3-carboxylic acid; 17β-(2,2,2-trifluoroethoxycarbonyl)androsta-3,5-diene-3- carboxylic acid;
17β-[N-(2,2,2-trifluoroethyl)carbamoyl]androsta-3,5-diene-3- carboxylic acid;
17β-[N,N-di-(2,2,2-trifluoroethyl)carbamoyl]androsta-3,5- diene-3-carboxylic acid;
17β-[N-(2,2,2-trifluoroethyl) -N-(2,2,3,3,3- pentafluoropropyl)carbamoyl]androsta-3,5-diene-3-carboxylic acid;
17β-[N-(2,2,2-trifluoro-1-phenylethyl)carbamoyl]androsta- 3,5-diene-3-carboxylic acid; 17β-[N-(1,1,1-trifluoro-2-phenylprop-2-y1)carbamoyl] androsta-3,5-diene-3-carboxylic acid;
17β-[N-(1,1,1,3,3,3-hexafluoro-2-phenylpropyl)carbamoyl] androsta-3,5-diene-3-carboxylic acid 17β-[N-(1,1,1-trifluoro-2-methylprop-2-y1)carbamoyl] androsta-3,5-diene-3-carboxylie acid;
17β-[N-(l,1,1,3,3,3-hexafluoro-2-methylpropyl)carbamoyl] androsta-3,5-diene-3-carboxylic acid; 17β-{N-(2,2,2-trifluoroethyl)-N-[N-(2,2,2-trifluoroethyl) carbamoyl]carbamoyl}androsta-3,5-diene-3-carboxylic acid; 17β-{N-(2,2,2-trifluoroethyl)-N-(N,N-diethylcarbamoyl) carbamoyl}androsta-3,5-diene-3-carboxylic acid; 17β-{N-(4-trifluoromethylphenyl)-N-[N-(4-trifluoro¬ methylphenyl)carbamoyl]carbamoyl}androsta-3,5-diene-3- carboxylic acid; and the pharmaceutically acceptable salts thereof.
4. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, comprising hydrolysing a compound of formula (II)
°γw
Figure imgf000046_0001
wherein R is a straight or branched Cι~Cg alkyl group, A and W are as defined in claim 1, so obtaining a compound of formula (I) , wherein A and W are as defined in claim 1 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.
5. A pharmaceutical composition comprising a pharmaceutical acceptable diluent and/or carrier and, as active principle, a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.
6. A compound of formula (I) , as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.
7. A compound or salt according to claim 6 for use as a testosterone 5α-reductase inhibitor.
8. Use of a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as a testosterone 5α- reductase inhibitor.
PCT/EP1995/002650 1994-07-28 1995-07-07 3-carboxysteroids with a fluorinated side chain WO1996003420A1 (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0465142A1 (en) * 1990-06-28 1992-01-08 Merck & Co. Inc. 17Beta-acyl-3-carboxy-androsta-3, 5-dienes as testosterone 5alpha-reductase inhibitors
EP0517047A1 (en) * 1991-05-24 1992-12-09 FARMITALIA CARLO ERBA S.r.l. Unsaturated 17beta-substituted 3-carboxy steroids
EP0567271A2 (en) * 1992-04-20 1993-10-27 Sankyo Company Limited Steroid derivatives for the treatment of prostatic hypertrophy, their preparation and uses
WO1994003474A1 (en) * 1992-07-31 1994-02-17 Pharmacia/Farmitalia Carlo Erba Srl Steroids with a fluorinated acylureidic type side chain
WO1994011004A1 (en) * 1992-11-18 1994-05-26 Smithkline Beecham Corporation 17 substituted acyl-3-carboxy 3,5-diene steroidals as 5-alpha-reductase inhibitors
WO1995014709A1 (en) * 1993-11-26 1995-06-01 Pharmacia S.P.A. Side chain fluoro substituted 3-carboxysteroids

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0465142A1 (en) * 1990-06-28 1992-01-08 Merck & Co. Inc. 17Beta-acyl-3-carboxy-androsta-3, 5-dienes as testosterone 5alpha-reductase inhibitors
EP0517047A1 (en) * 1991-05-24 1992-12-09 FARMITALIA CARLO ERBA S.r.l. Unsaturated 17beta-substituted 3-carboxy steroids
EP0567271A2 (en) * 1992-04-20 1993-10-27 Sankyo Company Limited Steroid derivatives for the treatment of prostatic hypertrophy, their preparation and uses
WO1994003474A1 (en) * 1992-07-31 1994-02-17 Pharmacia/Farmitalia Carlo Erba Srl Steroids with a fluorinated acylureidic type side chain
WO1994011004A1 (en) * 1992-11-18 1994-05-26 Smithkline Beecham Corporation 17 substituted acyl-3-carboxy 3,5-diene steroidals as 5-alpha-reductase inhibitors
WO1994011386A1 (en) * 1992-11-18 1994-05-26 Smithkline Beecham Corporation 17-alpha and 17-beta substituted acyl-3-carboxy-3,5-dienes and use in inhibiting 5-alpha-reductase
WO1995014709A1 (en) * 1993-11-26 1995-06-01 Pharmacia S.P.A. Side chain fluoro substituted 3-carboxysteroids

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