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WO1994013691A1 - Thio- et oxo-azasteroides, leurs procedes de preparation, leur utilisation en tant qu'anti-androgenes, et compositions pharmaceutiques les contenant - Google Patents

Thio- et oxo-azasteroides, leurs procedes de preparation, leur utilisation en tant qu'anti-androgenes, et compositions pharmaceutiques les contenant Download PDF

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Publication number
WO1994013691A1
WO1994013691A1 PCT/EP1993/003400 EP9303400W WO9413691A1 WO 1994013691 A1 WO1994013691 A1 WO 1994013691A1 EP 9303400 W EP9303400 W EP 9303400W WO 9413691 A1 WO9413691 A1 WO 9413691A1
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formula
iii
compounds
hydrogen
compound
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Inventor
Stefano Poli
Germano Coppi
Roberto Girardello
Paride Grisenti
Ambrogio Magni
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Poli Industria Chimica SpA
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Poli Industria Chimica SpA
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Priority claimed from IT002801 external-priority patent/IT1256635B/it
Priority claimed from IT93MI001730A external-priority patent/IT1264535B1/it
Application filed by Poli Industria Chimica SpA filed Critical Poli Industria Chimica SpA
Priority to AU56955/94A priority Critical patent/AU5695594A/en
Publication of WO1994013691A1 publication Critical patent/WO1994013691A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/16—Benz[e]indenes; Hydrogenated benz[e]indenes

Definitions

  • the present invention relates to the new 3-oxo- and 3-thio-4-aza-5 ⁇ (-androstenones and -androstanones substituted at the 17-position, having testosterone 5 ⁇ - reductase inhibiting activity, to the processes for the preparation thereof, to the therapeutic uses thereof and to the pharmaceutical compositions containing them.
  • the present invention relates to compounds of the general formula (A) :
  • the carbon-carbon bond at the 1-2-positions can be simple or double;
  • X is oxygen or sulfur
  • R I is hydrogen or linear or branched C 1 -C 4 alkyl ;
  • R II and R III when X is oxygen, are respectively:
  • R II and R III when X is sulfur, have the same meanings as seen when X is oxygen, and further represent:
  • R II a 17 ⁇ - or 17 ⁇ -hydroxy group, optionally esterified with a linear or branched C 1 -C 6 carboxylic acid, and R III is a hydrogen atom; or R II is an optionally salified carboxy group, an acetyl group, a 17 ⁇ - or 17 ⁇ - CONHR IV , where R IV is a linear or branched C 1 -C 4 alkyl, and R III is hydrogen; or
  • the present invention also relates to the diastereoisomeric and enantiomeric forms, together with the mixtures thereof, of the compounds (A).
  • Preferred compounds of the above general formula are those in which R I is hydrogen, methyl or ethyl.
  • Particularly preferred compounds are those in which R I is hydrogen, X is oxygen and:
  • C(17) are ⁇ - or ⁇ -epoxyde, the carbon-carbon bond at the 1-2 positions being unsaturated (compound 15) or saturated (compound 15 bis); or
  • R II is ⁇ -CH 2 -NH-C(CH 3 ) 3 and R III is hydrogen, the carbon-carbon bond at the 1-2 positions being unsaturated (compound 16) or saturated (compound 16 bis); or
  • R II is ⁇ -CH 2 _NH-CH 3 and R III is hydrogen, the carbon-carbon bond at the 1-2 positions being saturated (compound 19); or
  • R II is ⁇ -CH(CH 3 )-NH-C(CH 3 ) 3 and R III is hydrogen, the carbon-carbon bond at the 1-2 positions being unsaturated (compound 17) or saturated (compound 17 bis); or
  • R II is ⁇ -CH(CH 3 )-NH-CH 3 and R III is hydrogen, the carbon-carbon bond at the 1-2 positions being saturated (compound 20); or
  • R II is ⁇ -CO-NH-NH-C(16), and R III is H, the carbon-carbon bond at the 1-2 positions being unsaturated (compound 18) or saturated (compound 18 bis).
  • R II is ⁇ - or ⁇ -OH and R III is hydrogen, (compounds 2 and 4); or
  • R II is ⁇ - or ⁇ -CO-NH-R IV
  • R III is H (compounds 13 and 14).
  • R II is ⁇ - or ⁇ -acetyl, and R III is hydrogen (compound 11); or
  • R II is ⁇ - or ⁇ -COOH and R III is hydrogen (compound 12).
  • drugs capable of specifically inhibiting the process of testosterone 5 ⁇ -reduction can be important for the therapy of pathologies associated with 5 ⁇ -reductase hyperactivity, such as for example prostatic hypertrophy, prostatic carcinoma, acne and seborrhea, hirsutism, hair loss, [R.E. Gloyna, J.D. Wilson J. Clin. Endocr. 29, 970 (1969); G.H. Jacobi, J.D. Wilson J. Clin. Endocr. Metab. 44, 107 (1977); F.K. Habib, A.L. Tesdale, G.D. Chisholm, A. Busuttil J. Endocrinol. 91, 23 (1981)].
  • pathologies associated with 5 ⁇ -reductase hyperactivity such as for example prostatic hypertrophy, prostatic carcinoma, acne and seborrhea, hirsutism, hair loss, [R.E. Gloyna, J.D. Wilson J. Clin. Endocr. 29, 970
  • step b) the compounds obtained in step a) are treated with a peroxyacid to give compounds of formula (A), wherein R II and R III are respectively:
  • 3-thioxo-4- azaandrostanes (1, 2, 6, 7) are obtained starting from 3-oxo-4-azaandrostan-17-one (I), which is firstly thionated at the 3-position to give the compound (1), of which, subsequently, the keto group at the 17- position is reduced, to give the hydroxy-derivative (2).
  • the starting compound (I) is transformed into the compound of the invention (5) by means of the Wittig reaction on the carbonyl group at the 17-position.
  • (5) is thionated to give (6), which, through the transformation of the double bond at the 17-position, leads to the epoxy-derivative (7).
  • the corresponding ⁇ unsaturated compounds (3, 4,
  • R II is an optionally salified carboxy group, an acetyl group, a 17 ⁇ - or 17 ⁇ -CONHR IV , where R IV is a linear or branched C 1 -C 4 alkyl, and R III is hydrogen; are prepared by a process comprising that a compound of formula (III)
  • the compounds (11), (12), (13), and (14) are prepared starting from the well known azasteroid (III) (J. Med. Chem., 29, 2298 (1986)); and in an alternative way, according to Scheme 2, the compounds (13) and (14) may also be prepared from the well known azasteroids (IV) and (V), which are disclosed in EP 0 155 096.
  • Lawesson's reagent is an effective thionating reagent for carboxamides, ketones, lactones, lactams and 3-keto-carboxyl derivatives [Reviews: R.A. Cherkasov, G.A. Kutyrev, A.N. Pudvik, Tetrahedron (1985), 41 (13), 2567-2624; 41 (22), 5061-5087].
  • Lawesson's reagent which is [2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiaphosphetan- 2,4-disulfide], in a ratio ranging from 1 to 2 equivalents per mol of substrate, is added to a solution of the lactam, in a concentration ranging from 0.2 to 1 M, in an anhydrous apolar solvent, under stirring at a temperature ranging from 0° to 60°C.
  • reaction mixture is left under stirring for a time interval ranging from 1 to 12 hours.
  • the reaction mixture is then under vacuum concentrated and the residue is purified through silica chromatography (ratio 1:60, elution in dichloromethane/methanol gradient); the so obtained product (with yields ranging from 30 to 80%) may further be purified by crystallization from methanol/water or acetonitrile.
  • Compounds of formula (A), wherein X is sulfur, R II and R III are a hydroxyl group and a hydrogen atom respectively, are obtained by reducing compounds (1) and (3) with NaBH 4 .
  • NaBH 4 solid or in 1M NaOH solution, in a ratio ranging from 1 to 3 equivalents per mol of substrate, is added to a solution of the substrate in a concentration ranging from 0.1 to 1 M, in an alcoholic solvent, preferably methanol, under stirring at a temperature ranging from 5 to 25°C.
  • the reaction mixture is maintained under stirring for a time interval ranging from 0.5 to 2 hours, then pH is adjusted to 4 with 1N HCl and the organic solvent is evaporated off.
  • aqueous phase is extracted three times with an equal amount of dichloromethane, dried over Na 2 SO 4 , filtered and evaporated to dryness to give the desired product, with yields higher than 90%. These products may subsequently be crystallized from acetonitrile.
  • Compounds of formula (A), wherein X is oxygen, R II and R III form an epoxy group, may directly be prepared from compound (I) according to the following procedure: NaH (from 2 to 10 mol per mol of compound (I)) is added to anhydrous dimethyl sulfoxide (DMSO) (final concentration ranging from 0.5 to 5 M). The obtained suspension is warmed up to 75°C until complete dissolution (about 45 minutes). A 0.54 M trimethylsulfoxonium iodide solution (0.72 mol per mol of NaH) in DMSO is added to the so obtained solution and subsequently a 0.5 M solution of compound (I) is added.
  • DMSO dimethyl sulfoxide
  • the reaction mixture is maintained under stirring at a temperature ranging from -5 to 20°C for a time interval ranging from 1 to 5 hours.
  • the reaction mixture is worked up by diluting with water (1:6) and extracting with dichloromethane.
  • the organic phase is evaporated under vacuum to dryne ⁇ s to give a crude which is subsequently purified by silica gel chromatography (1:80 ratio, elution with dichloromethane/methanol 95/5) to give the desired product with yields ranging from 60 to 95%.
  • reaction mixture may be prepared starting from compounds (5) and (8) by epoxidation with meta-chloroperbenzoic acid (from 1 to 5 mol per mol of substrate) in a dichloromethane solution under stirring at a temperature ranging from -5 to 25°C for a time interval ranging from 1 to 7 hours.
  • the reaction mixture is worked up by subsequent 5% NH 3 and aqueous sodium thiosulfate washings until negative reaction for oxidants.
  • the organic phase is dried over Na 2 SO 4 , evaporated to dryness to give a crude which is subsequently crystallized from diethyl ether thus obtaining the desired product with yields ranging from 50 to 77%.
  • the passage from the androstanic nucleus to the androst-1-enic nucleus is generally carried out by well known methods of ⁇ 1-dehydrogenation of steroids.
  • ⁇ 1-dehydrogenation of compounds (5) and (13) may be carried out, for example, by treating the substrate solution, in concentration ranging from 0.02 to 0.1 M in an anhydrous aprotic solvent, such as toluene, diglyme or, preferably, chlorobenzene, with phenylselenic anhydride (from 1 to 1.5 equivalents per mol of substrate).
  • anhydrous aprotic solvent such as toluene, diglyme or, preferably, chlorobenzene
  • the reaction mixture is then warmed to 110°C for a time interval ranging from 6 to 18 hours, then the solvent is removed under vacuum.
  • the so obtained crude is purified by silica gel chromatography (1:60 ratio, elution with dichloromethane/acetone gradient) to give the desired product with yields from 50 to 85%.
  • a suspension of the substrate in anhydrous dioxane in a concentration ranging from 0.1 to 0.4 M, is added with DDQ (2,3-dichloro-5,6-dicyano- 1 ,4-benzoquinone) (from 1 to 1.5 mol per mol of substrate), then is treated with N,O- bis (trimethylsilyl) trifluoroacetamide (from 4 to 6 mol per mol of substrate).
  • the reaction mixture is maintained to stand for 4 hours under stirring at room temperature, then at 110°C for a time interval ranging from 8 to 24 hours.
  • the reaction is worked up by diluting it in a 1:2 ratio with dichlorometane and washing it with 1% sodium hydrosulfite.
  • the precipitate is filtered off and the organic phase is washed with 2N HCl, dried over Na 2 SO 4 and evaporated to dryness.
  • the so obtained crude may be purified by crystallization from acetonitrile or methanol/water to give the desired product with yields ranging from 60 to 85%.
  • the so obtained complex is dissolved into a 10% KOH 1/1 methanol/water solution at a concentration ranging from 5 to 20% and maintained under stirring for a time interval ranging from 10 minutes to 1 hour.
  • the organic solvent is then evaporated under vacuum and the residue is taken up with water to a concentration ranging from 10 to 20% and acidified with 6N HCl.
  • the so formed precipitate is recovered by filtration and dried at 80°C (12 mmHg) for 12 hours to give the desired product (12) with yields ranging from 65 to 78%.
  • compound (12) On its turn compound (12) may be used to obtain the compounds of the present invention wherein X is sulfur and R II and R III are a carbamoyl group and a hydrogen atom, respectively.
  • pyridine from 1.2 to 1.6 mol per mol of substrate
  • a solution of substrate (12) in a concentration ranging from 0.1 to 0.3 M in a anhydrous aprotic solvent such as THF, ether, preferably toluene.
  • oxalyl chloride from 1.1 to 1.3 mol per mol of substrate
  • the reaction temperature is maintained for a time interval ranging from 0.5 to 2 hours, then an amine of formula R IV NH2, wherein R IV is as above defined, (in a ratio from 2 to 7 mol per mol of substrate).
  • the reaction mixture is then warmed to a temperature ranging from 40 to 70°C for 30 minutes.
  • the reaction mixture is worked up by diluting it in a 1:2 ratio with water and adjusting pH to neutrality.
  • the organic phase is separated and the aqueous phase is extracted twice with an equal volume of dichloromethane.
  • the gathered organic phases are then dried on Na 2 SO 4 , filtered and evaporated to dryness to give a crude which is purified by silica gel chromatography (1:60 ratio, elution with dichloromethane/methanol gradient) to give the desired product with yields ranging from 30 to 70%.
  • compounds (13) and (14) are obtained by thionating compounds (IV) and (V), disclosed in EP 0 155 096, with Lawesson's reagent.
  • Ra and R III is hydrogen may be obtained from compound
  • reaction mixture is then neutralized with aqueous NaHCO 3 and extracted with ether.
  • organic layer is dried onNa 2 SO 4 and evaporated to dryness to give the desired product (VII) with yields ranging from 75 to 92%.
  • This last is transformed into the final compound by reaction in alcoholic solution, under stirring at room temperature for a time interval ranging from 1 to 3 hours, with the desired amine R a -NH 2 (from 1 to 3 mol per mol of aldehyde).
  • the intermediate Schiff base (VIII) is reduced with a 2.4 M NaBH 4 alcoholic solution (from 2 to 6 equivalents) and maintained under stirring at room temperature for a time interval ranging from 2 to 8 hours.
  • reaction mixture is neutralized with IN HCl, the organic phase is evaporated under vacuum and extracted with dichloromethane. The organic phase is dried over Na 2 SO 4 , evaporated to dryness and the crude is purified through silica chromatography to give the desired compound with yields ranging from 40 to 70%.
  • the subsequent transformation of this product into the corresponding ⁇ 1-unsaturated compound is carried out by conventional processes of ⁇ 1-dehydrogenation already described for compounds (5) and (13) to give the desired compounds with yields ranging from 60 to 78%.
  • reaction mixture may be prepared by reacting the intermediate aldehyde (VII) with titanium (IV) isopropylate (from 1 to 2 mol per mol of aldehyde) and the proper amine (from 2 to 4 mol per mol of aldehyde) under stirring at room temperature for a time interval ranging from 1 to 2 hours. Then the reaction mixture is diluted 1:10 with ethanol and reduced with NaBH 3 CN (from 1 to 3 equivalents) at room temperature for a time interval ranging from 10 and 18 hours. The reaction mixture is acidified with 1N HCl and extracted with dichloromethane. After the usual purification, compounds (19 and 16 bis) are obtained with yields ranging from 60 and 80%.
  • compounds of formula (A), wherein R II is ⁇ -CH(CH 3 )NH-Ra and R III is hydrogen, and particularly compound (17), may be obtained from compound (XI) in the same way as compound (VII) (the same weight ratios and reaction conditions) to give the intermediates (XIII) with yields ranging from 50 to 82%.
  • the intermediates are then oxidized according to the classical Oppenauer reaction to give, after crystallization from hexane, the intermediates (XIV) with yields ranging from 50 to 65%.
  • Secosteroids are obtained through a process which comprises their heath oxidation (80°C) with a 26% NaIO 4 and 2% KMnO 4 water solution (5.8 ml per mmol of substrate (XIV)) which is slowly added to a 0.17 M solution of compound (XIV) in 7.5:1 t-butanol/water containing 2.5% Na 2 CO 3 .
  • the reaction mixture is refluxed for a time interval ranging from 1 to 2.5 hours, then is cooled to 30°C and after 1 hour is filtered under vacuum.
  • the filtrate is then concentrated under vacuum to about 1/3 of the starting volume and acidified with 6M HCl (pH 3), the precipitate so obtained is recovered by filtration to give the intermediates (XV) with yields ranging from 40 to 75%.
  • Compounds (XV) are transformed into the intermediates (XVI) by heating a 0.36 M solution of the secosteroid in ethylene glycol saturated with an excess of liquid ammonia or the proper amine R I NH 2 (about 26 mol per mol of secosteroid). The reaction is heated to 180°C within 45 minutes then is maintained at this temperature for 15 minutes. Then, the reaction mixture is cooled to room temperature, diluted with water and acidified to pH 3 with concentrated HCl.
  • Compounds (XVI) wherein R I is hydrogen are recovered by filtration; those wherein R I is alkyl are extracted with chloroform with yields ranging from 50 to 75%.
  • Compound (17 bis) is obtained from compound (XVI) by catalytic hydrogenation (10% Pd/C or 5% Pt/C w/w) from 0.07 M methanol or acetic acid solutions bubbling hydrogen at atmospheric pressure or at 3 atm at the temperature of 60°C. After a time interval ranging from 30 minutes to 2 hours the reaction mixtures is worked up, degassing hydrogen under vacuum and filtrating off the catalyst.
  • Compound (17 bis) is isolated by evaporating under vacuum the filtrate and subsequent crystallization from acetonitrile with yields ranging from 80 to 93%.
  • R II and R III are respectively: ⁇ -CH(CH,)-NH-R a , where R a is a linear or branched C 1 -C 4 alkyl, and R III is ⁇ -hydrogen;
  • a) is reacted with an amine of formula R a NH 2 , wherein R a is a linear or branched C 1 -C 4 alkyl, and finally treated with NaBH 4 , or alternatively, the intermediate compound is treated with Ti (IV) isopropoxide, reacted with an amine of formula R a NH 2 , and finally treated with NaBH 3 CN,
  • step b) the compound from step a) is reacted with aluminum isopropoxide
  • step b) the compound from step b) is treated with an oxidant to give secosteroid
  • azasteroid (III) may be prepared from the known azasteroid (III) according to the same method for the preparation of compound (16 bis). Using the already described technique, which uses titanium (IV) isopropoxide as dehydrating agent and NaBH 3 CN as reducing agent. The desired product is obtained after purification by silica gel chromatography (1:10 ratio, elution with dichloromethane/methanol gradient) with yields ranging from 30 to 77%.
  • step b) the intermediate of step b) is treated with an oxidant to convert the 17-formyl group into 17-carboxyl group;
  • step d) said derivative of step d) is ozonized and the intermediate acylhydrazone is then treated with NaBH 4 , to give a compound of formula (A) wherein R II and R III are as above defined;
  • the compounds (A) of the present invention are testosterone 5 ⁇ -reductase inhibiting agents therefore they are useful as therapeutic agents.
  • a further object of the present invention is the use of compounds of formula (A) for the manufacturing of a medicament useful for the treatment of hyperandrogenic conditions, particularly, prostatic hypertrophy, prostatic carcinoma, acne vulgaris, seborrhea, female hirsutism, male hair loss.
  • Vials not containing proteins are used for the blank determination.
  • the incubation is carried out in a 37°C thermostated stirring bath for two hours under a 98/2 O 2 /CO 2 flow. At the end of incubation, the reaction is stopped placing the samples in ice.
  • tritium labelled DHT and 3 ⁇ -diol (about 5000 dpm) are added to each sample before the extraction with the scope to evaluate the recovery.
  • the formed metabolites are twice extracted with 5.5 ml of diethyl ether.
  • the extracts after dissolution into 200 ul of ethanol, containing non labelled DHT and 3 ⁇ -diol, as reference standards, are separated by thin layer chromatography on silica gel plates (Merck 60 F 254, DC), eluted three times with a 11:1 dichloromethane/diethyl ether mixture at a temperature of 4°C.
  • DHT and 3 ⁇ -diol spots are detected with iodine vapours, whereas those of testosterone by UV light exposition (UV absorption of the 4-5 double bond conjugated with the 3-keto group).
  • the silica gel areas where DHT and 3 ⁇ (-diol respectively have been evidenced are scratched and put into tubes for count.
  • compounds of formula (A) inhibit testosterone induced increase of prostate and seminal vesicles in the castrated rat (Di Salle E. et Al., J. Steroid Biochem. Biol. Molec. Biol., 41,765,1992).
  • the prostates and seminal vesicles were removed and weighted. The results are expressed as the percent decrease of the two organs with respect to the group treated with testosterone only.
  • Compounds of formula (A) show percent decrease of the prostate ranging from 40 to 60% compared with the 50% decrease of finasteride; moreover, the former showed seminal vesicle percent decrease ranging from 50 to 70% compared with 60% of finasteride.
  • the present invention relates also to oral, parenteral and topical pharmaceutical compositions containing a compound of the invention in admixture with conventional excipients and vehicles.
  • oral pharmaceutical compositions are tablets, capsules, sachets and suspensions
  • parenteral pharmaceutical compositions are liophilized vials or sterile suspensions
  • topical pharmaceutical compositions are creams, ointments, gels, aerosol or foam formulation.
  • compositions according to the invention are prepared by conventional methods, such as for example those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. XVII ed. N.Y. U.S.A.
  • the daily oral dosage ranges from 5 to 50 mg; the unit doses may contain from 2.5 to 25 mg of active ingredient.
  • the concentration of the active ingredient ranges from 0.1 to 10%, preferably 5%, the daily applications may be one or two.
  • reaction mixture was then cooled down to 10°C and 537 mg (4.23 mmol) of oxalyl chloride into 3 ml of toluene were slowly added.
  • the reaction mixture was maintained under stirring for 1 hours at 10°C then a solution of 1.78 ml of t-butylamine in toluene was added.
  • the reaction temperature was raised to 40°C and kept for 30 minutes. Thereafter the reaction mixture was poured into 16 g of ice and neutralized. The organic phase was separated and the aqueous phase was extracted with dichloromethane (2x15 ml).
  • compounds (13) and (14) may be directly obtained from the well known compounds (IV) and (V), using the method described for compound (1) with yields, after purification by silica chromatography and crystallization from acetonitrile, of 80 and 65%, respectively.
  • Acid (XXI) was used in the next step without further purification 13.75 g (33.8 mmol) of compound (XXI) were dissolved into 170 ml of anhydrous toluene and 3.75 ml of pyridine. The reaction mixture was then cooled down to 10°C and 5.37 g (42.35 mmol) of oxalyl chloride into 10 ml of toluene were slowly added. The reaction temperature was kept 1 hour at 10°C, then 16 ml of a toluene solution containing 5.37 g (168 mmol) of hydrazine were added.
  • reaction mixture was maintained under stirring at 40°C for 30 minutes, then the reaction mixture was added with 160 g of ice and neutralized with IN HCl and the organic phase was separated.
  • the aqueous phase was extracted with dichloromethane (150 ml) and the organic phases were collected, dried over Na 2 SO 4 and evaporated under vacuum to give a crude which was subsequently purified by silica gel chromatography (1:40) eluting with a 9/1 dichloromethane/methanol mixture, thus obtaining 14.11 g (29.4 mmol; 87% yield) of 16-benzylydene-17 ⁇ -N- hydrazinylcarbamoyl-3-oxo-4-aza-5 ⁇ -androstane (XXII).
  • compound (17) was prepared starting from 20 g (63.19 mmol) of 5- pregnen-3 ⁇ -ol-20-one. 19.32 mg (51.8 mmol; 82% yield) of compound (XIII) were obtained after chromatographic purification.

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Abstract

L'invention concerne des composés représentés par la formule générale (A), dans laquelle : la liaison carbone-carbone en postion 1-2 peut être simple ou double; X représente oxygène ou soufre; RI représente hydrogène ou alkyle C¿1?-C4 en chaîne droite ou ramifiée; R?II et RIII¿, lorsque X représente hydrogène, représentent respectivement: le groupe -CH¿2?- et un atome d'oxygène qui, conjointement avec l'atome de carbone en position 17, forment un α ou β-époxyde; ou R?II¿ représente β-CH¿2?-NH-Ra ou β-CH(CH3)-NH-Ra, Ra représant un alkyle C1-C4 en chaîne droite ou ramifiée, et R?III¿ représente α-hydrogène; ou RII représente β-CO-NH-NH-C(16), C(16) étant l'atome de carbone en position 16, et RIII représente α-hydrogène, ou R?II et RIII¿ forment conjointement un groupe -CH¿2?; et R?II et RIII¿, lorsque X représente soufre, ont la même signification que lorsque X représente hydrogène, et représentent également: RII un groupe 17α- ou 17β-hydroxy, éventuellement estérifié avec un acide carboxylique C¿1?-C6 en chaîne droite ou ramifiée, et R?III¿ un atome d'hydrogène; ou RIII un groupe carboxy salifié, un groupe acétyle, un 17α- ou 17β-CONHRIV, RIV représentant un alkyle C¿1?-C4 en chaîne droite ou ramifiée, et R?III¿ oxygène; ou R?II et RIII¿, conjointement avec l'atome de carbone en position 17, forment un groupe céto. Lesdits composés présentent une activité inhibant la 5-α-réductase de la testostérone.
PCT/EP1993/003400 1992-12-10 1993-12-03 Thio- et oxo-azasteroides, leurs procedes de preparation, leur utilisation en tant qu'anti-androgenes, et compositions pharmaceutiques les contenant Ceased WO1994013691A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56955/94A AU5695594A (en) 1992-12-10 1993-12-03 Thio- and oxo-azasteroids, processes for the preparation thereof, use thereof as antiandrogens and pharmaceutical compositions containing them

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
ITMI92A002801 1992-12-10
IT002801 IT1256635B (it) 1992-12-10 1992-12-10 Antiandrogeni per la terapia dell'ipertrofia prostatica, dell'irsutismo, dell'acne e della seborrea e relativi procedimenti di preparazione
IT93MI001730A IT1264535B1 (it) 1993-07-30 1993-07-30 Tioazasteroidi,loro uso come antiandrogeni e composizioni farmaceutiche che li contengono
ITMI93A001730 1993-07-30

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WO1994013691A1 true WO1994013691A1 (fr) 1994-06-23

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JPH07508034A (ja) * 1992-05-20 1995-09-07 メルク　エンド　カンパニー　インコーポレーテッド １７−アミノ置換４−アザステロイド５α−レダクターゼ阻害剤

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0004949A1 (fr) * 1978-04-13 1979-10-31 Merck & Co. Inc. 4-Aza-5-alpha-androstanes 3-one substitués en position 17, leurs A- et D-homo analogues, procédé pour leur préparation et compositions pharmaceutiques les contenant

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0004949A1 (fr) * 1978-04-13 1979-10-31 Merck & Co. Inc. 4-Aza-5-alpha-androstanes 3-one substitués en position 17, leurs A- et D-homo analogues, procédé pour leur préparation et compositions pharmaceutiques les contenant

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
G. H. RASMUSSON ET AL: "Azasteroids as inhibitors of rat prostatic 5-alpha-reductase", JOURNAL OF MEDICINAL CHEMISTRY, vol. 27, no. 12, December 1984 (1984-12-01), WASHINGTON, US, pages 1690 - 1701, XP002009302, DOI: doi:10.1021/jm00378a028 *
J. R. BROOKS ET AL: "5-alpha-reductase inhibitory and anti-androgenic activities of some 4-azasteroids in the rat", STEROIDS, vol. 47, no. 1, January 1986 (1986-01-01), STONEHAM, US, pages 1 - 19, XP002014015 *

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IL107903A0 (en) 1994-04-12
MX9307794A (es) 1994-07-29

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