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WO1994000121A1 - 17-acyl-4-aza-steroide-3-one a titre d'inhibiteurs de 5-alpha-reductase - Google Patents

17-acyl-4-aza-steroide-3-one a titre d'inhibiteurs de 5-alpha-reductase Download PDF

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Publication number
WO1994000121A1
WO1994000121A1 PCT/US1993/006233 US9306233W WO9400121A1 WO 1994000121 A1 WO1994000121 A1 WO 1994000121A1 US 9306233 W US9306233 W US 9306233W WO 9400121 A1 WO9400121 A1 WO 9400121A1
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compound
compound according
anyone
formula
pharmaceutically acceptable
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Inventor
Dennis Alan Holt
Mark Alan Levy
Hye-Ja Oh
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Priority to JP6502657A priority Critical patent/JPH07508524A/ja
Priority to EP93916878A priority patent/EP0650358A4/en
Publication of WO1994000121A1 publication Critical patent/WO1994000121A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • C07J73/003—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 oxygen as hetero atom
    • 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

Definitions

  • the present invention relates to certain novel 17 ⁇ and 17ß-alkylketone 4-aza steroidal compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds to inhibit steroid 5- ⁇ -reductase isozyme 1 and steroid 5- ⁇ -reductase isozyme 2. Also invented are novel intermediates and processes useful in preparing these compounds.
  • Testosterone is the principal androgen secreted by the testes and is the primary androgenic steroid in the plasma of males. It now is known that 5- ⁇ -reduced androgens are the active hormones in some tissues such as the prostate and sebaceous gland. Circulating
  • testosterone thus serves as a prohormone for dihydrotestosterone (DHT), its 5- ⁇ -reduced analogue, in these tissues but not in others such as muscle and testes.
  • DHT dihydrotestosterone
  • Steroid 5- ⁇ -reductase is a Nicotinamide Adenine dinucleotide Phosphate(NADPH)dependent enzyme that converts testosterone to DHT. The importance of this enzyme in male
  • Imperator-McGinley J., et al., (1979), J. Steroid Biochem. 11:637-648.
  • Metcalf, et al. describes the effect of inhibitors of steroid 5 ⁇ reductase in benign prostatic hyperplasia, male pattern baldness and acne.
  • This invention relates to a compound of the formula I:
  • R is C 1-20 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
  • the invention also is a method for inhibiting 5- ⁇ -reductase isozyme 1 and 5- ⁇ -reductase isozyme 2 activity in mammals, including humans, that comprises administering to a subject an effective amount of a presently invented 5- ⁇ -reductase inhibiting compound.
  • novel processes useful in preparing the presently invented dual inhibitors of 5- ⁇ -reductase are provided.
  • compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention. Also included in the present invention are methods of co-administering the presently invented dual 5- ⁇ -reductase inhibiting compounds with further active ingredients.
  • the compounds of this invention that inhibit 5- ⁇ -reductase isozyme 1 and 5- ⁇ -reductase isozyme 2 have the following Formula (I):
  • R is C 1-20 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
  • such compounds are referred to as dual inhibitors of steroid 5- ⁇ -reductase.
  • R is C 1-20 linear or branched, saturated or unsaturated, alkyl and pharmaceutically acceptable salts, hydrates and solvates thereof.
  • R 2 is C 1-8 linear or branched alkyl
  • Preferred among Formula (III) compounds are those in which R 2 is methyl, ethyl, propyl, 3-methylbutyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, t-butyl, pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, octyl or 3,3-dimethylbutyl.
  • R 2 is 1-methylpropyl, n-butyl, n-pentyl, 3-methylbutyl, isopropyl, 2,2-dimethylpropyl, t-butyl, 1,1-dimethylpropyl, isobutyl, n-octyl, tert-pentyl, n-propyl, methyl or 3,3-dimethylbutyl.
  • Formula (III) compound which is 17ß-(isobutylcarbonyl)-4-aza-5- ⁇ -androst-8(14)-ene-3-one.
  • alkyl C 1-n alkyl and derivatives thereof and in all carbon chains as used herein, unless otherwise defined, is meant a C 1-n linear or branched carbon chain having 1 to n carbons.
  • alkyl and derivatives thereof as used herein include: methyl, ethyl, propyl, 3-methylbutyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, t-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethyl-propyl, n-octyl, tertpentyl and 3,3-dimethylbutyl.
  • treating is meant prophylatic or therapeutic therapy.
  • isobutyl as used herein, is meant -CH 2 CH(CH 3 ) 2 -
  • Compounds of Formula (I) and compounds of formula (IV) are included in the pharmaceutical compositions of the invention and used in the methods of the invention.
  • a pharmaceutically acceptable acetate maleate and the like can be employed for -OH, and those known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • ⁇ -receptor antagonist refers to a known class of alpha-andrenergic receptor antagonist comounds, such as described in Lafferty, et al. U.S. Patent No. 4,963,547, which are utilized in treating vascular disorders such as diabetes, cardiovascular disease, benign prostatic hypertrophy and ocular hypertension.
  • Preferred alpha-andrenergic receptor antagonists for use in combination with the compounds of Formula I include amsulosin, terazosin, doxazosin, alfuzosin, indoramin, prazosin and 7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno[4,3,2-ef][3]-benzapine.
  • amsulosin as used herein is meant a compound of the formula
  • amsulosin is designated as (-)-(R)-5-[2-[[2-(O-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide.
  • Amsulosin is disclosed in U.S. Patent Number 4,703,063 and claimed in U.S. Patent Number 4,987,125 as being useful in treating lower urinary tract dysfunction.
  • terazosin as used herein is meant a compound of the formula
  • terazosin is designated as 1-(4-amino-6,7-dimethoxy-2 quinazolinyl)-4-[(tetrahydro-2-furoyl)carbonyl]piperazine.
  • Terazosin is disclosed in U.S. Patent Number 4,251,532.
  • doxazosin as used herein is meant a compound of the formula
  • doxazosin is designated as 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxin-2-yl)carbonyl]-piperazine.
  • alfuzosin as used herein is meant a compound of the formula
  • Chemically alfuzosin is designated as N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide.
  • indoramin as used herein is meant a compound of the formula
  • prazosin as used herein is meant a compound of the formula
  • Chemically prazosin is designated as 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine.
  • Prazosin is disclosed in U.S. Patent Number 3,511,836.
  • alpha-andrenergic receptor antagonist a compound other than one specifically referred to herein is a alpha-andrenergic receptor antagonist by utilizing the assay described in Lafferty I. Thus, all such compounds are included within the scope of the term "alphaandrenergic receptor antagonist" as used herein.
  • minoxidil as used herein is meant the compound of the formula:
  • Minoxidil is the active ingredient in Rogaine ® which is sold as topical solution for stimulating hair growth by the Upjohn Compnay, Kalamazoo, Michigan.
  • aromatase inhibitor refers to a known class of compounds, steroidal and non- steroidal, which prevent the conversion of androgens to estrogens, such as described in Gormley et al. International Publication Number WO 92/18132. Aromatase inhibitors are disclosed in Gormley et al. as having utility in treating benign prostatic hyperplasia when used in combination with a 5- ⁇ -reductase inhibitor.
  • a preferred aromatase inhibitor for use in the compositions and methods of the invention 4-(5,6,7,8-tetrahydroimidazo-[1,5- ⁇ ]pyridin-5-yl)benzonitrile (fadrazole). Fadrazole is disclosed in U.S. Patent No. 4,728,645. Additionally, all compounds disclosed in Gormley, et al.
  • said 5- ⁇ -reductase inhibitor can be co-administered with said further active ingredient or ingredients.
  • co-administering and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a 5- ⁇ -reductase inhibiting compound, as described herein, and a further active ingredient or ingredients, such as other compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy or prostatic adenocarcinoma or compounds known to have utility when used in combination with 5- ⁇ -reductase inhibitors.
  • the administration is not simultaneous, the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
  • novel compounds of Formula (II) of the present invention can be prepared by methods outlined in Schemes 1 and 2 below and in the examples from known and readily available methyl androst-4-en-3-one 17ß-carboxylate which has the formula:
  • compound (a) is dissolved in a suitable organic solvent such as C 1 -C 4 alkanol, preferably t-butanol, and treated with Na 2 CO 3 in water.
  • a suitable organic solvent such as C 1 -C 4 alkanol, preferably t-butanol
  • the resulting solution is brought to reflux and treated with ruthenium dioxide/sodium periodate, potassium permanganate, ozone, or, preferably sodium periodiate/potassium permanganate in water followed by acidification to yield a compound of formula (b) (Step A).
  • a compound of formula (d) in a suitable organic solvent, such as toluene, is reacted with a benzylamine, preferably a substituted benzylamine, most preferably 2, 4-dimethoxybenzylamine, at a temperature of approximately 65°C to 125°C, preferably 95°C to form an intermediate which upon heating, preferably to reflux temperature, in a suitable organic solvent, preferably toluene, in the presence of P- toluenesulfonic acid monohydrate with constant water removal yields a compound of formula (e) (Step D).
  • a benzylamine preferably a substituted benzylamine, most preferably 2, 4-dimethoxybenzylamine
  • a compound of formula (f) is prepared from a compound of formula (e) by standard hydrogenation of a compound of formula (e) using hydrogenation agents such as palladium on carbon, Raney nickel, or, preferably platinum dioxide and hydrogenation solvents, such as ethyl acetate, preferably in the presence of an acid, such as acetic acid.
  • hydrogenation agents such as palladium on carbon, Raney nickel, or, preferably platinum dioxide and hydrogenation solvents, such as ethyl acetate, preferably in the presence of an acid, such as acetic acid.
  • the activated ester (i) is produced (Step H) by treating (h) with 2,2'-dipyridyl disulfide and triphenylphosphine in an appropriate organic solvent solution, such as tetrahydrofuran/toluene, or, preferably dichloromethane, preferably at ambient temperature.
  • an appropriate organic solvent solution such as tetrahydrofuran/toluene, or, preferably dichloromethane, preferably at ambient temperature.
  • the 17-alkylketone derivative (j) is produced (Step I) by treating (i) with a Grignard reagent, described hereinbelow, in a tetrahydrofuran or diethyl ether solvent, at a temperature of -50 to -100°C, preferably
  • Scheme II outlines formation of formula (II) compounds in which the C 7 - C 8 bond is unsaturated.
  • the starting material for Scheme II is compound (e) from Scheme I.
  • a compound of formula (k) is prepared (Step J) by hydrogenation of a compound of formula (e) compound using Raney nickel and close monitoring of the reaction to minimize or prevent formation of a C 8 -C 14 double bond.
  • the activated ester (n) is produced (Step M) by treating compound (m) with 2,2'-dipyridyl disulfide and triphenyl phosphine in an appropriate organic solvent solution, such as tetrahydrofuran/toluene, or, preferably dichloromethane, preferably at ambient temperature.
  • an appropriate organic solvent solution such as tetrahydrofuran/toluene, or, preferably dichloromethane, preferably at ambient temperature.
  • the 17-alkylketone derivative (o) is produced (Step N) by reacting (n) with a Grignard reagent, described hereinbelow, in a solvent, preferably tetrahydrofuran or diethyl ether, at a temperature of -50°C to -100°C preferably -78°C.
  • Grid reagents as used herein is meant compounds of the formula R-Li or RMgX where R and X are as used herein.
  • Grignard reagents of the type, RMgX, (where R is C 1-20 linear or branched, saturated or unsaturated alkyl) for use in preparing all of the species included within the scope of this invention, are available or can be made readily by one skilled in the art.
  • a base such as a hydroxide or alkoxide base, preferably sodium hydroxide, potassium hydroxide or sodium methoxide, at a temperature over 100°C preferably at reflux temperatures to yield the corresponding ⁇ epimer, after isolation and work up.
  • dimethyl sulfoxide or other non-reactive high boihng solvents are preferred when the starting 17ß dual 5 ⁇ -reductase inhibiting steroidal compound contains reactive substituents or reactive unsaturated bonds that are, for example, subject to nucleophilic attack and ethylene glycol, or other reactive high boiling solvents can be used when the reactivity of the substituents or any unsaturated bonds of the starting 17ß dual 5 ⁇ -reductase inhibiting steroidal compound is not a consideration.
  • Y is ⁇ or ß
  • R is C 1-20 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
  • Preferred among the presently invented ketone reduction products described above are the secondary alcohols wherein the substituent is in the ß position. These compounds can be made by conventional sodium
  • the borohydride reduction can be carried out in e.g. water or aqueous methanol, at a temperature of room temperature to 50°C and the product then isolated and purified by conventional means.
  • the compounds are also active as dual inhibitors of 5-alpha reductase.
  • solvent or "appropriate solvent” as used herein and the in the claims is meant a solvent such as methylene chloride, ethylene chloride, chloroform, ethylene glycol, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, hexane, dimethylsulfoxide (DMSO), N,N'-dimethyl-N,N'-propylene urea, Nmethyl-2-pyrrolidinone, methanol, isopropylalcohol, dimethylformamide (DMF), water, pyridine, quinoline or ethanol.
  • solvent such as methylene chloride, ethylene chloride, chloroform, ethylene glycol, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, hexane, dimethylsulfoxide (DMSO), N
  • R is C 1-20 linear or branched alkyl and pharmaceutically acceptable salts, hydrates and solvates thereof comprises reacting a compound of the formula
  • the presently invented pharmaceutically active compounds are potent dual inhibitors of steroid 5- ⁇ -reductase activity, they have therapeutic utility in treating diseases and conditions wherein decreases in DHT activity produces the desired therapeutic effect.
  • diseases and conditions include acne vulgaris, seborrhea, female hirsutism, male pattern baldness, prostate diseases such as benign prostatic hypertrophy, and prostatic adenocarcinoma.
  • Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5 ⁇ -reductase isoenzyme 1 were homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, 1 mM dithiothreitol, and 50 ⁇ M
  • NADPH buffer A
  • Dounce glass-to-glass hand homogenizer Kontes Glass Co., Vineland, N.J.
  • Membrane particulates were isolated by centrifugation (100,000 ⁇ g at 4°C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6.5, containing 20% glycerol, 1 mM dithiothreitol, and 50 ⁇ M NADPH (buffer B).
  • the suspended particulate solution was stored at -80°C. Preparation of prostatic membrane particulates used as source for steroid 5 ⁇ -reductase isozyme 2.
  • Frozen human prostates were thawed and minced into small pieces ( Brinkmann Polytron (Sybron Corp., Westbury, New York). The solution was sonicated for 3 to 5 minutes with a Sonifier (Branson Sonic Power Co.) followed by hand homogenization in a Dounce hand homogenizer. Prostatic particles were obtained by differential
  • the pellet obtained from the 140,000 ⁇ g centrifugation was washed with 5 to 10 tissue volumes of the buffer described above and centrifuged at 140,000 ⁇ g. The resulting pellet was suspended in buffer B and the particulate suspension was stored at -80°C.
  • Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5- ⁇ -reductase isozyme 2 were homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, ImM dithiothreitol, and 50 ⁇ M NADPH (buffer A) using a Douce hand homogenizer.
  • Membrane particulates containing the recombinant human enzyme were isolated by centrifugation (100,000 ⁇ g at 4°C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6.5 containing 20% glycerol, ImM dithiothreitol, and 50 ⁇ M NADPH (buffer B). The suspended particulate solution was stored at -80°C until used.
  • Assays for human steroid 5 ⁇ -reductase isoenzyme 1 were conducted with a sample of the recombinant protein expressed in CHO cells in 50 mM phosphate buffer, pH 7.5 while assays of isoenzyme 2 were conducted with a suspension of human prostatic particulates and/or recombinant protein expressed in CHO cells in 50 mM citrate buffer at pH 5.0.
  • the radiochemical content in the bands of the substrate and the products was determined with a BIOSCAN Imaging Scanner (Bioscan Inc., Washington, D.C.). The percent of recovered radiolabel converted to product was calculated, from which enzyme activity was determined. All incubations were conducted such that no more than 20% of the substrate (testosterone) was consumed.
  • a compound within the scope of this invention has been tested and has shown an activity of 5 Ri(nM) against isozyme 1 and an activity of 100 Ki(nM) against isozyme 2.
  • Particularly preferred among the compounds of the invention and the compounds used in the invented pharmaceutical compositions and invented methods is 17ß-(isobutylcarbonyl)-4-aza-5- ⁇ -androst 8(14)-en-3-one.
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl
  • the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
  • a liquid carrier is used, the
  • preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical preparations are made following
  • Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.1 - 1000 mg/kg of active compound, preferably 1 - 100 mg/kg.
  • the selected dose is administered preferably from 1-6 times daily, orally or parenterally.
  • Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion.
  • Oral dosage units for humaniadministration preferably contain from 1 to 500 mg of active compound.
  • Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.
  • the method of this invention of inhibiting steroid 5- ⁇ -reductase isozyme 1 and steroid 5- ⁇ -reductase isozyme 2 activity in mammals, including humans, comprises administering to a subject in need of such inhibition an effective dual inhibiting amount of a compound of the present invention.
  • the invention also provides for the use of a compound of Formula (I) or a compound of Formula (IN) in the manufacture of a medicament for use in the dual inhibition of steroid 5- ⁇ -reductase.
  • the invention also provides for a pharmaceutical composition for use in the treatment of benign prostate hypertrophy which comprises a compound of Formula I or a compound of Formula (IV) and a
  • the invention also provides for a pharmaceutical composition for use in the treatment of prostatic adenocarcinoma which comprises a compound of Formula I or a compound of Formula (IV) and a
  • the invention also provides for a process for preparing a
  • composition containing a pharmaceutically acceptable carrier or diluent and a compound of Formula I or a compound of
  • the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy or prostatic adenocarcinoma or compounds known to have utility when used in combination with 5- ⁇ -reductase inhibitors.
  • further active ingredients such as other compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy or prostatic adenocarcinoma or compounds known to have utility when used in combination with 5- ⁇ -reductase inhibitors.
  • Particularly preferred is the co-administration of a dual 5- ⁇ -reductase inhibitor, as disclosed herein, and minoxidil for use in the treatment of male pattern baldness.
  • a dual 5 ⁇ -reductase inhibitor as disclosed herein
  • a ⁇ -receptor antagonist for use in the treatment of benign prostatic hypertrophy.
  • a dual 5- ⁇ -reductase inhibitor as disclosed herein
  • an aromatase inhibitor for use in the treatment of benign prostatic hypertrophy.
  • a dual 5- ⁇ -reductase inhibitor as disclosed herein, a ⁇ -receptor
  • triphenylphosphine (0.35 g, 1.34 mmol) and dichloromethane (50 mL) was stirred at ambient temperature under argon overnight. The resulting solution was concentrated and the residue was
  • sucrose, calcium sulfate dihydrate and Formula (I) compound shown in Table II below are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Steroid Compounds (AREA)

Abstract

L'invention concerne des analogues de 17α et 17β-alkylecétone-4-aza de composés stéroïdiens synthétiques, des compositions pharmaceutiques contenant ces composés, ainsi que des procédés d'utilisation de ceux-ci pour inhiber l'isozyme 1 5-α-réductase stéroïdienne ainsi que l'isozye 2 5-β-réductase stéroïdienne. L'invention concerne également des procédés utilisés dans la préparation de ces composés.
PCT/US1993/006233 1992-06-30 1993-06-30 17-acyl-4-aza-steroide-3-one a titre d'inhibiteurs de 5-alpha-reductase Ceased WO1994000121A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP6502657A JPH07508524A (ja) 1992-06-30 1993-06-30 ５−アルファ−レダクターゼ阻害剤としての１７−アシル−４−アザ−ステロイド−３−オン
EP93916878A EP0650358A4 (en) 1992-06-30 1993-06-30 17-acyl-4-aza-steroid-3-one as 5-alpha-reductase inhibitors.

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GB9213901.3 1992-06-30
GB929213901A GB9213901D0 (en) 1992-06-30 1992-06-30 Compounds

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US5543417A (en) * 1994-10-21 1996-08-06 Merck & Co., Inc. Combination method of treating acne using 4-AZA-5α-cholestan-ones and 4-AZA-5α-androstan-ones as selective 5α-reductase inhibitors with anti-bacterial, keratolytic, or anti-inflammatory agents
US5843953A (en) * 1994-10-25 1998-12-01 Merck & Co., Inc. 7-substituted 4-aza cholanic acid derivatives and their use
WO2012110768A1 (fr) 2011-02-18 2012-08-23 The University Of Birmingham Utilisations thérapeutiques des diarylalcanes tels que le mitotane

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EP0650358A1 (fr) 1995-05-03
JPH07508524A (ja) 1995-09-21
EP0650358A4 (en) 1995-06-07

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