WO1995013077A1 - 7β-SUBSTITUES-4-AZA-5α-CHOLESTAN-3-ONES UTILISES COMME INHIBITEURS SELECTIFS DE LA 5α-REDUCTASE 1 - Google Patents

7β-SUBSTITUES-4-AZA-5α-CHOLESTAN-3-ONES UTILISES COMME INHIBITEURS SELECTIFS DE LA 5α-REDUCTASE 1 Download PDF

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WO1995013077A1
WO1995013077A1 PCT/US1994/012817 US9412817W WO9513077A1 WO 1995013077 A1 WO1995013077 A1 WO 1995013077A1 US 9412817 W US9412817 W US 9412817W WO 9513077 A1 WO9513077 A1 WO 9513077A1
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Prior art keywords
aza
alkyl
methyl
compound
cholestan
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PCT/US1994/012817
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English (en)
Inventor
Raman K. Bakshi
Gary H. Rasmusson
Richard L. Tolman
Gool F. Patel
Georgianna Harris
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Merck & Co., Inc.
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Priority to AU81332/94A priority Critical patent/AU8133294A/en
Publication of WO1995013077A1 publication Critical patent/WO1995013077A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin

Definitions

  • the present invention is directed to new 7 ⁇ -substituted-4-aza-5 ⁇ -cholestan-3-ones and related compounds and the use of such compounds as selective 5 ⁇ -reductase 1 inhibitors.
  • testosterone-5 ⁇ -reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation.
  • a number of 4-aza steroid compounds are known in the art .
  • 5 ⁇ -reductase and two distinct isozymes of 5 ⁇ -reductase in humans The isozyme that principally interacts in skin tissues is conventionally designated as 5 ⁇ -reductase 1 (or 5 ⁇ -reductase type 1), while the isozyme that principally interacts within the prostatic tissues is designated as 5 ⁇ -reductase 2 (or 5 ⁇ -reductase type 2). See, e.g., G. Harris, et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-10791 (Nov. 1992).
  • BPH benign prostatic hyperplasia
  • prostatic cancer e.g., benign prostatic hyperplasia (BPH) and/or the prevention and treatment of prostatic cancer
  • one drug entity which is active against both isozymes in the prostate to significantly inhibit dihydrotestosterone production.
  • another drug entity which is selective for inhibiting the isozyme 5 ⁇ -reductase 1 associated with the scalp, for use in treating conditions of the skin and scalp, e.g., acne vulgaris, male pattern baldness and hirsutism in females.
  • a selective 5 ⁇ -reductase 1 inhibitor could be used in combination with a 5 ⁇ -reductase 2 inhibitor such as, e.g., finasteride (PROSCAR®), for therapy in the treatment of conditions such as BPH, prostatitis, and/or the prevention and treatment of prostatic cancer, and for the treatment of skin and scalp-related disorders such as acne vulgaris, seborrhea, female hirsutism, and androgenic alopecia. Therefore it is an object of this invention to provide compounds that have sufficient activity in the inhibition of 5 ⁇ -reductase isozyme 1.
  • a 5 ⁇ -reductase 2 inhibitor such as, e.g., finasteride (PROSCAR®)
  • This invention is concerned with novel 7 ⁇ -substituted-4-aza-5 ⁇ -cholestan-3-one compounds and processes for their preparation.
  • the instant compounds are inhibitors of 5 ⁇ -reductase, and particularly are selective for inhibiting 5 ⁇ -reductase type 1.
  • the invention is also concerned with the use of the novel compounds either alone or in combination with a 5 ⁇ -reductase 2 inhibitor, such as finasteride, or in combination with a dual inhibitor of 5oc-reductase 1 and 2, in the treatment of conditions such as acne vulgaris, androgenic alopecia, seborrhea, and female hirsutism, by topical or internal administration.
  • a 5 ⁇ -reductase 2 inhibitor such as finasteride
  • a dual inhibitor of 5oc-reductase 1 and 2 in the treatment of conditions such as acne vulgaris, androgenic alopecia, seborrhea, and female hirsutism, by topical or internal administration.
  • the invention is further concerned with the use of one of the novel compounds of this invention in combination with an inhibitor of 5 ⁇ -reductase 2, such as finasteride, or in combination with a dual inhibitor of 5 ⁇ -reductase 1 and 2, in the treatment of benign prostatic hypertrophy, prostatitis, and the prevention and treatment of prostatic cancer by internal administration.
  • an inhibitor of 5 ⁇ -reductase 2 such as finasteride
  • a dual inhibitor of 5 ⁇ -reductase 1 and 2 in the treatment of benign prostatic hypertrophy, prostatitis, and the prevention and treatment of prostatic cancer by internal administration.
  • the invention is still further concerned with pharmaceutical formulations comprising one or more of the novel compounds as active ingredient, either alone or in combination with an inhibitor of 5 ⁇ -reductase 2 such as finasteride or in combination with a dual inhibitor of 5 ⁇ -reductase 1 and 2.
  • R is selected from hydrogen, methyl, ethyl, -OH, -NH 2 , and -SCH 3 ; the dashed lines " - - -" a and b independently represent a single bond or a double bond providing that when b is a double bond, the 5 ⁇ hydrogen, Ha, is absent;
  • R 1 and R 2 independently are selected from:
  • R 1 and R 2 together with the nitrogen atom to which they are attached represent a 5-6 membered saturated heterocycle, optionally containing one other heteratom selected from -O-, -S- and -N(R')- wherein R' is -H or methyl;
  • the 17-substituent cholestane side chain is in the beta configuration. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • C 1 -C 4 alkyl as used herein, is meant to include methyl (Me), ethyl (Et), propyl (Pr), iso-propyl (i-Pr), n-butyl (n-Bu), sec-butyl (s-Bu), iso-butyl (i-Bu) and tert-butyl (t-Bu).
  • C 2 -C 4 alkenyl as used herein is meant to include d e vinyl, allyl, 1-propen-1-yl, 1-propen-2-yl, 1-buten-1-yl, 1 -buten-2-yl, and the like. Included in this invention are all E, Z diastereomers.
  • C 3 -C 6 cycloalkyl as used herein is meant to include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • halo as used herein is meant to include fluoro, chloro, bromo, and iodo.
  • OC 1 -C 4 alkyl or "C 1 -C 4 alkoxy” as used herein is meant to include methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
  • OC 3 -C 6 cycloalkyl or "C 3 -C 6 cycloalkoxy” as used herein is meant to include: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.
  • ⁇ -substituent (dashed lines) is hydrogen and the ⁇ -substituent (wedge) is, e.g., methyl, ethyl, propyl, allyl, carboxy methyl, hydroxy, methoxy, ethoxy,
  • cyclopropyloxy cyclopentyloxy, acetoxy, fluoro, chloro, bromo, trifluoromethyl, fluoromefhyl, chloromefhyl, carboxy, N,N-dimethylcarbamate, hydroxymethyl, and the like.
  • -NR 1 R 2 represent a heterocycle
  • Representative examples wherein -NR 1 R 2 represent a heterocycle include: N-piperidinyl, N-morpholinyl, N-piperazinyl, N-(4-methyl)piperazinyl, N-thiomorpholinyl, N-pyrrolidinyl, N-imidazolidinyl and the like.
  • a basic or acidic group is present on the structure.
  • an acidic substituent i.e. -COOH
  • ammonium, sodium, potassium, calcium salt, and the like for use as the dosage form.
  • a basic group i.e. amino or a basic heteroaryl radical such as, e.g., 4-pyridyl
  • an acidic salt i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like, can be used as the dosage form.
  • esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • Representative salts include the following salts: acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate,
  • glycollylarsanilate sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate,
  • solvates may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • the compounds of the present invention have asymmetric centers and may occur as racemates, racemic mixtures and as individual enanti omens or diastereomers, with all isomeric forms being included in the present invention as well as mixtures thereof. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • terapéuticaally effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the compounds of this invention can be made by procedures outlined in the following Flowsheets. All temperatures are in degrees Celsius. 7-Beta Alkyl Series
  • the compounds of the instant invention comprising Z as a 7 ⁇ alkyl group, e.g., methyl, ethyl, isopropyl, allyl, can be prepared by the procedure outlined in The General Flowsheet.
  • the starting 3-acetoxy-cholest-5-ene I (see Example 1 for synthesis) is oxidized to the corresponding 5-en-7-one II by treatment with hydrogen t-butyl peroxide and chromium hexacarbonyl in, e.g., acetonitrile at reflux.
  • the C 1 -C 4 alkyl group, designated Alk, e.g., methyl can be introduced at this point by a Grignard reaction using, e.g., alkyl magnesium chloride in, e.g., anhydrous tetrahydrofuran (THF) at 0-23°C to produce the 7-alkyl-7-hydroxy adduct III.
  • the delta-5 double bond is isomerized to the 4-ene by use of DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene) in, e.g., refluxing THF to produce the 7-beta-alkyl 4-en-3-one, VI.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • the A Ring is next cleaved by treatment with, e.g., potassium permanganate, sodium periodate in t-butyl alcohol at 80°C to produce the corresponding seco-acid VII.
  • the seco-acid VII can be similarly treated with
  • R can also be -OH, -NH 2 or SCH 3 in the Formula.
  • the 7-ethyl substituent is introduced into the cholestane series as illustrated in Flowsheets C and D by the same analogous procedure as described in the General Flowsheets.
  • the starting cholesteryl acetate CA is available commercially (Aldrich). This is treated using the analogous chromium hexacarbonyl/-hydrogen t-butylperoxide/acetonitrile oxidation procedure (described in JCS Perkin Trans. 1985, p. 267 by A. J. Pearson) to yield the 3-acetoxy-cholest-5-en-7-one 1. This can be reacted with an alkyl Grignard reagent, e.g., ethyl magnesium chloride to form the adduct 2. This is oxidized under Oppenauer conditions to yield the dienone 3, which then can undergo metal-ammonia reduction to yield the 7 ⁇ -ethyl-5-en-3-one, 4.
  • an alkyl Grignard reagent e.g., ethyl magnesium chloride
  • the 7-carboxy substituent is formed through the corresponding 7-allyl group.
  • 7-oxo-cholesteryl acetate 1 is reacted with allyl Grignard reagent to form the adduct 11 which is oxidized to the dienone 12 by Oppenauer conditions.
  • Metal-ammonia reduction affords the 5-ene analog 13, followed by DBU-catalyzed double bond isomerization to 14.
  • This in turn can be oxidized in a key step to form the 7-carboxymethyl seco-acid 15.
  • Treatment with amines, e.g., ammonia forms the 4-aza derivative, 16 which is then reduced to the cholestane 17.
  • Use of methylamine in place of ammonia can yield the corresponding 4-methyl analogs of 16 and 17.
  • the 7-propyl analogs are made starting with the 7-allyl-4-en-3-one 14, which is reduced by hydrogenation using Wilkinson's catalyst to the propyl derivative 18, oxidized to the seco-acid 19, then condensed with amines, e.g., methylamine, to form the 4-methyl analog 20 and then reduced to the cholestane 21.
  • Corresponding treatment with ammonia is shown in Flowsheet E shows the corresponding unsubstituted 4-aza 22 and cholestane 23 analogs.
  • the 7-beta methyl cholestane series is prepared by the analogously same route as described in Flowsheets A and B for the ethyl derivatives.
  • the methyl Grignard reagent is used to form the adduct 24, followed by Oppenauer oxidation to form 25, metal-ammonia reduction to form 26, double bond isomerization to form 27, seco-acid oxidation to form 28, and treatment by an ammonium salt to form 29, and reduction to form 30.
  • Corresponding treatment with methylamine produces the corresponding 4-methyl-4-aza compounds, 31 and by reduction, 32.
  • the 7-beta acetoxy series is prepared by the oxidation of starting 33 to the 5-en-7-one 34 by the chromium hexacarbonyl procedure described for 1, or by pyridine-dichromate/t-butyl hydroperoxide oxidation as described in the Examples. Subsequent noble metal, e.g., platinum, ruthenium, catalyzed reduction of 34 yields two products, the reduced 7-oxo compound 35, and 7-beta hydroxy compound 36.
  • noble metal e.g., platinum, ruthenium
  • the 7-beta ethers in the cholestane series are prepared from the 7-beta-ol (7-beta hydroxy derivative).
  • the 4-N-methyl-7-beta ol 36 can be reacted with, e.g., methyl iodide and sodium hydride in, e.g., dimethylformamide, to produce the
  • the C 3 -C 6 cycloalkyl ethers can be prepared according to the analogous procedure of Steroids, 1972, vol. 19, pp. 639-647 by R. Gardi, et al.
  • 36 can be reacted with 1 ,1-dimethoxycyclohexane to produce the enol ether 38, which can be reduced to the corresponding saturated compound by the use of palladium catalyzed hydrogenation.
  • the 7-haloalkyl series is made by the procedure illustrated in Flowsheet K.
  • the haloethyl compounds can be made by starting with the 7-carboxymethyl analog 17 which can be reacted with a reducing agent, e.g. borane, to produce the primary alcohol 41. This in turn can be reacted with triphenylphosphine and carbon tetrabromide to produce the bromoethyl derivative 42.
  • a reducing agent e.g. borane
  • the halomethyl compounds can be produced starting with the carboxymethyl derivative 17. This is treated with lead tetraacetate under oxidative decarboxylation/halogenation conditions, with a chloride, bromide or iodide salt to yield, e.g. the 7-chloromethyl analog 43.
  • the carboxymethyl compound 17 can be treated with a fluorinating agent (XeF 2 ) to yield the 7-fluoromethyl analog 44.
  • the 7-trifluoromethyl derivative can be made from the 7-carboxy derivative 45, by conventional Dast halogenation conditions using SF 4 to yield the 7-trifluoromethyl analog 46.
  • Flowsheet N illustrates the 7-methylene series.
  • the Wittig reaction using e.g. Ph 3 PCH(CH 2 CH 3 ), carried out on the 7-oxo compound 35, leads to the 7-(ethyl)methylene compound 47.
  • Flowsheet O illustrates the synthesis of the 1-ene 7-substituted analogs.
  • compound 30 is stirred with DDQ, BSTFA (bis-trimethylsilyltrifluoroacetamide) and trifluoromethyl sulfonic acid in toluene at room temperature for 24 hours, methyl acetoacetate is added and the mixture reluxed for 24 hours and purified by preparative thin layer chromatography on silica gel using 3:1 chloroform/acetone to yield 49.
  • BSTFA bis-trimethylsilyltrifluoroacetamide
  • Another embodiment of this invention is the use of one of the novel compounds of this invention in a method of prevention and/or treatment of hyperandrogenicity through the activity of the 5oc-reductase 1 isozyme.
  • the activity of the novel compounds as selective 5 ⁇ -reductase 1 inhibitors is determined by the following Biological assays: Biological Assays
  • Samples of human tissue were pulverized using a freezer mill and homogenized in 40 mM potassium phosphate, pH 6.5, 5 mM magnesium sulfate, 25 mM potassium chloride, 1 mM
  • phenylmethylsulfonyl fluoride 1 mM dithiothreitol (DTT) containing 0.25 M sucrose using a Potter-Elvehjem homogenizer.
  • DTT dithiothreitol
  • a crude nuclear pellet was prepared by centrifugation of the homogenate at 1 ,500xg for 15 min. The crude nuclear pellet was washed two times and resuspended in two volumes of buffer. Glycerol was added to the resuspended pellet to a final concentration of 20%. The enzyme suspension was frozen in aliquots at -80°C. The prostatic and scalp reductases were stable for at least 4 months when stored under these conditions.
  • the reaction mixture for the type 1 5oc-reductase contained 40 mM potassium phosphate, pH 6.5, 5 ⁇ M [7-3H]-testosterone, 1 mM dithiothreitol and 500 ⁇ M NADPH in a final volume of 100 ⁇ l.
  • the reaction mixture for the type 2 5 ⁇ -reductase contained 40 mM sodium citrate, pH 5.5, 0.3 ⁇ M [7-3H]-testosterone, 1 mM dithiothreitol and 500 ⁇ M NADPH in a final volume of 100 ⁇ l.
  • the assay was initiated by the addition of 50-100 ⁇ g prostatic homogenate or 75-200 ⁇ g scalp homogenate and incubated at 37°C. After 10-50 min the reaction was quenched by extraction with 250 ⁇ l of a mixture of 70%
  • the HPLC system consisted of a Waters Model 680 Gradient System equipped with a Hitachi Model 655A autosampler, Applied Biosystems Model 757 variable UV detector, and a Radiomatic Model A 120 radioactivity analyzer. The conversion of T to DHT was monitored using the radioactivity flow detector by mixing the HPLC effluent with one volume of Flo Scint 1 (Radiomatic). Under the conditions described, the production of DHT was linear for at least 25 min. The only steroids observed with the human prostate and scalp preparations were T, DHT and androstanediol.
  • IC 50 values represent the concentration of inhibitor required to decrease enzyme activity to 50% of the control. IC 50 values were determined using a 6 point titration where the concentration of the inhibitor was varied from 0.1 to 1000 nM.
  • a compound referrred to herein as a 5 ⁇ -reductase 2 inhibitor is a compound that shows inhibition of the 5oc-reductase 2 isozyme in the above-described assay, having an IC 50 value of about or under 100nM.
  • a compound referrred to herein as a dual 5 ⁇ -reductase 1 and 2 inhibitor is a compound that shows inhibition of both the 5 ⁇ -reductase 1 and 2 isozymes in the above-described assay, having an IC 50 value for each of type 1 and type 2 of about or under 100nM.
  • the present invention has the objective of providing methods of treating the hyperandrogenic conditions of androgenic alopecia including female and male pattern baldness, acne vulgaris, seborrhea, and female hirsutism by oral, systemic, parenteral or topical administration of a therapeutically effective amount of one or more novel compounds of formula I optionally in combination with a 5 ⁇ -reductase 2 inhibitor or with a dual inhibitor of both 5 ⁇ -reductase 1 and 2.
  • the term "treating androgenic alopecia" is intended to include the arresting and/or reversing of androgenic alopecia, and the promotion of hair growth.
  • the present invention has the further objective of providing methods of treating benign prostatic hyperplasia, prostatitis, and treating and/or preventing prostatic carcinoma by oral, systemic or parenteral administration of a therapeutically effective amount of one or more novel compounds of formula I optionally in combination with a 5 ⁇ -reductase 2 inhibitor or in combination with a dual inhibitor of both 5 ⁇ -reductase 1 and 2.
  • the daily dosage of the compounds of formula I may be varied over a wide range from 0.1 mg to 1 ,000 mg per adult human/per day.
  • An effective amount of one of the novel compounds of this invention is ordinarily from about 0.002 mgs/kg to 50 mgs./kg. of body weight per day, and more particularly the range is from about 0.01 mgs/kg to 7 mgs/kg of body weight per day.
  • the daily dosage of the 5 ⁇ -reductase 2 inhibitor, e.g., finasteride is from about 0.01 mg to 50 mg per adult human/per day, and more particularly from about 0.2 mg to 5 mg per adult human/per day.
  • an effective amount of the 5 ⁇ -reductase 2 inhibitor e.g., finasteride
  • an effective amount of the 5 ⁇ -reductase 2 inhibitor is ordinarily from about 0.00015 mgs/kg to about 0.7 mgs/kg of body weight per day, and more particularly the range is from about 0.002 mgs/kg to 0.07 mgs/kg of body weight per day.
  • Effective amounts of a dual 5 ⁇ -reductase 1 and 2 inhibitor would be in the same ranges as the described above for the compounds of formula I.
  • the present invention also has the objective of providing suitable systemic, oral, parenteral and topical pharmaceutical
  • compositions containing the active ingredient, for use in the treatment of the above-noted hyperandrogenic conditions can be administered in a wide variety of therapeutic dosage forms in
  • the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release
  • pills pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions.
  • they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the
  • compositions can be provided in the form of scored or unscored tablets containing 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, and 50.0 milligrams of the active ingredients for the symptomatic adjustment of the dosage to the patient to be treated.
  • Topical pharmaceutical compositions may be, e.g., in the form of a solution, cream, ointment, gel, lotion, shampoo or aerosol formulation adapted for application to the skin.
  • Topical pharmaceutical compositions useful in the method of treatment of the present invention may include about 0.001% to 15% by weight of the active compound in admixture with a pharmaceutically acceptable carrier.
  • the compounds of the instant invention can be combined with a therapeutically effective amount of a 5 ⁇ -reductase 2 inhibitor, such as finasteride, or a dual 5 ⁇ -reductase 1 and 2 inhibitor, in a single oral, systemic, or parenteral pharmaceutical dosage formulation.
  • a combined therapy can be employed wherein the compound of formula I and the 5 ⁇ -reductase 2 inhibitor or the dual inhibitor are administered in separate oral, systemic, or parenteral dosage formulations.
  • the compounds of the instant invention and a 5 ⁇ -reductase 2 inhibitor or a dual inhibitor can be formulated for topical administration.
  • a compound of formula I and finasteride can be administered in a single oral or topical dosage formulation, or each active agent can be administered in a separate dosage formulation, e.g., in separate oral dosage formulations, or an oral dosage formulation of finasteride in combination with a topical dosage formulation of a compound of formula I. See, e.g., U.S. Patent No.'s 4,377,584 and 4,760,071 which describe dosages and formulations for 5 ⁇ -reductase inhibitors.
  • a combined therapy can be used by administering a therapeutically effective amount of a compound of formula I in
  • retinoic acid or a derivative thereof e.g., an ester or amide derivative thereof, such as, e.g., tretinoin or isotretinoin.
  • a combined therapy can be used by administering a therapeutically effective amount of a compound of formula I with a therapeutically effective amount of an anti-androgen, such as, e.g., flutamide, spironolactone or casodex.
  • an anti-androgen such as, e.g., flutamide, spironolactone or casodex.
  • the active agents can be administered concomitantly, or they each can be
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition.
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Capsules containing the product of this invention can be prepared by mixing an active compound of the present invention with lactose and magnesium stearate, calcium stearate, starch, talc, or other carriers, and placing the mixture in gelatin capsule. Tablets may be prepared by mixing the active ingredient with conventional tableting ingredients such as calcium phosphate, lactose, corn starch or magnesium stearate.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • Other dispersing agents which may be employed include glycerin and the like.
  • glycerin for parenteral administration, sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • Topical preparations containing the active drug component can be admixed with a variety of carrier materials well known in the art, such as, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, PPG2 myristyl propionate, and the like, to form, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations. See, e.g., EP 0 285 382.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone,
  • polyhydroxy butyric acid polyorthoesters, polyacetals,
  • polydihydropyrans polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the fast atom bombardment (FAB) mass spectral values are reported as (M+1 ) molecular ion peaks, being the molecular weight plus one atomic mass unit.
  • the electron impact (El) mass spectrum values are reported as molecular ion peaks and are indicated in parentheses, either being (M) or (M+2), the molecular weight, MW, or the MW plus two atomic units.
  • the nuclear magnetic resonance data was taken at 400 MHz in CDCl 3 and is tabulated for unique proton values of each compound at the end of the Examples.
  • the coupling constant J is given in Hertz, Hz.
  • CA Cholesteryl acetate
  • the seco acid 6, 0.5 g. and ammonium acetate, 0.5 g., in 3.5 ml acetic acid were refluxed for 3 hours.
  • the reaction mixture was cooled, water added and then extracted with ethyl acetate.
  • the organic layer was dried over sodium sulfate and concentrated to yield a residue which was eluted on a silica gel column with 10% EtOAc/hexane to give pure title compound 9, mp. 147-149°C.
  • triphenylphosphine rhodium chloride (Wilkinson's catalyst) were allowed to stir two hours (under H 2 atmosphere). The reaction products were filtered through 25 ml. silica gel, and evaporated to dryness to yield fairly pure title product, 18, as confirmed by proton NMR.
  • Mass Spec. 430 (M+1 ) calc'd MW 429.40.
  • the seco acid 28 was treated analogously as in Example 7 to give pure title compound 31.
  • Compound 34 is hydrogenated by the analogous procedure of Example 8 to produce the 7-H analog 35, and the 7 ⁇ -ol, 36.

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Abstract

Les 7β-substitués-4-aza-5α-cholestan-3-ones et les composés apparentés sont des inhibiteurs sélectifs de la 5α-réductase 1 qui sont utiles dans le traitement des pathologies hyperandrogéniques.
PCT/US1994/012817 1993-11-12 1994-11-07 7β-SUBSTITUES-4-AZA-5α-CHOLESTAN-3-ONES UTILISES COMME INHIBITEURS SELECTIFS DE LA 5α-REDUCTASE 1 WO1995013077A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU81332/94A AU8133294A (en) 1993-11-12 1994-11-07 7beta -substituted-4-aza-5alpha-cholestan-3-ones as selective 5alpha-reductase 1 inhibitors

Applications Claiming Priority (2)

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US15300693A 1993-11-12 1993-11-12
US153,006 1993-11-12

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WO1995013077A1 true WO1995013077A1 (fr) 1995-05-18

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AU (1) AU8133294A (fr)
IL (1) IL111467A0 (fr)
WO (1) WO1995013077A1 (fr)
ZA (1) ZA948909B (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0786999A1 (fr) * 1994-10-21 1997-08-06 Merck & Co., Inc. Procede combine de traitement de l'acne
EP0792371A1 (fr) * 1994-10-21 1997-09-03 Merck & Co., Inc. Procede combine de traitement de l'acne
WO1998050419A2 (fr) * 1997-05-07 1998-11-12 Novopharm Limited 4-azasteroides
US6369247B1 (en) 1994-05-19 2002-04-09 Merck & Co., Inc. Process for oxidation of steroidal compounds having allylic groups
EP1734963A2 (fr) * 2004-04-02 2006-12-27 Merck & Co., Inc. Methode destinee a traiter des hommes presentant des troubles metaboliques et anthropometriques
WO2012110768A1 (fr) 2011-02-18 2012-08-23 The University Of Birmingham Utilisations thérapeutiques des diarylalcanes tels que le mitotane

Citations (5)

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WO1991013550A1 (fr) * 1990-03-16 1991-09-19 Smithkline Beecham Corporation Compositions synergiques
WO1992007586A1 (fr) * 1990-10-31 1992-05-14 Beecham Group Plc Composition topique comprenant un stimulateur de penetration retinoide
WO1992016233A1 (fr) * 1991-03-20 1992-10-01 Merck & Co., Inc. Combinaison pharmaceutique d'un inhibiteur de la 5 alpha reductase et d'un antiandrogene pour le traitement du cancer de la prostate
US5237064A (en) * 1992-05-20 1993-08-17 Merck & Co., Inc. Process for producing 7β-substituted-aza-5αandrostan-3-ones
WO1993023419A1 (fr) * 1992-05-20 1993-11-25 Merck & Co., Inc. NOUVELLES 4-AZA-5α-CHOLESTAN-ONES SUBSTITUEES EN POSITION 7β ET UTILISEES COMME INHIBITEURS DE 5α-REDUCTASE

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
WO1991013550A1 (fr) * 1990-03-16 1991-09-19 Smithkline Beecham Corporation Compositions synergiques
WO1992007586A1 (fr) * 1990-10-31 1992-05-14 Beecham Group Plc Composition topique comprenant un stimulateur de penetration retinoide
WO1992016233A1 (fr) * 1991-03-20 1992-10-01 Merck & Co., Inc. Combinaison pharmaceutique d'un inhibiteur de la 5 alpha reductase et d'un antiandrogene pour le traitement du cancer de la prostate
US5237064A (en) * 1992-05-20 1993-08-17 Merck & Co., Inc. Process for producing 7β-substituted-aza-5αandrostan-3-ones
WO1993023419A1 (fr) * 1992-05-20 1993-11-25 Merck & Co., Inc. NOUVELLES 4-AZA-5α-CHOLESTAN-ONES SUBSTITUEES EN POSITION 7β ET UTILISEES COMME INHIBITEURS DE 5α-REDUCTASE

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PCT/US 93/04615 *
S.L. SUDDUTH: "Finasteride: the first 5alpha-reductase inhibitor", PHARMACOTHERAPY, vol. 13, no. 4, August 1993 (1993-08-01), pages 309 - 329 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6369247B1 (en) 1994-05-19 2002-04-09 Merck & Co., Inc. Process for oxidation of steroidal compounds having allylic groups
EP0786999A1 (fr) * 1994-10-21 1997-08-06 Merck & Co., Inc. Procede combine de traitement de l'acne
EP0792371A1 (fr) * 1994-10-21 1997-09-03 Merck & Co., Inc. Procede combine de traitement de l'acne
EP0792371A4 (fr) * 1994-10-21 1998-12-30 Merck & Co Inc Procede combine de traitement de l'acne
EP0786999A4 (fr) * 1994-10-21 1999-01-20 Merck & Co Inc Procede combine de traitement de l'acne
WO1998050419A2 (fr) * 1997-05-07 1998-11-12 Novopharm Limited 4-azasteroides
WO1998050419A3 (fr) * 1997-05-07 1999-02-04 Novopharm Ltd 4-azasteroides
EP1734963A2 (fr) * 2004-04-02 2006-12-27 Merck & Co., Inc. Methode destinee a traiter des hommes presentant des troubles metaboliques et anthropometriques
EP1734963A4 (fr) * 2004-04-02 2008-06-18 Merck & Co Inc Methode destinee a traiter des hommes presentant des troubles metaboliques et anthropometriques
WO2012110768A1 (fr) 2011-02-18 2012-08-23 The University Of Birmingham Utilisations thérapeutiques des diarylalcanes tels que le mitotane

Also Published As

Publication number Publication date
IL111467A0 (en) 1994-12-29
ZA948909B (en) 1995-10-10
AU8133294A (en) 1995-05-29

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