WO1997010217A1 - 4-azasteroides utilises pour le traitement d'etats hyperandrogeniques - Google Patents

4-azasteroides utilises pour le traitement d'etats hyperandrogeniques Download PDF

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Publication number
WO1997010217A1
WO1997010217A1 PCT/US1996/014564 US9614564W WO9710217A1 WO 1997010217 A1 WO1997010217 A1 WO 1997010217A1 US 9614564 W US9614564 W US 9614564W WO 9710217 A1 WO9710217 A1 WO 9710217A1
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WIPO (PCT)
Prior art keywords
methyl
ene
aza
oxo
androst
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PCT/US1996/014564
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English (en)
Inventor
Raman K. Bakshi
Soumya P. Sahoo
Richard L. Tolman
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Merck & Co., Inc.
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Priority claimed from GBGB9603487.1A external-priority patent/GB9603487D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to US09/029,926 priority Critical patent/US6001844A/en
Priority to JP9512068A priority patent/JPH11512434A/ja
Priority to EP96930822A priority patent/EP0859761A4/fr
Priority to AU69737/96A priority patent/AU707324B2/en
Priority to CA002231041A priority patent/CA2231041A1/fr
Priority to US10/020,740 priority patent/USRE39056E1/en
Publication of WO1997010217A1 publication Critical patent/WO1997010217A1/fr

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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
    • C07J73/005—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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Definitions

  • the present invention relates to novel compounds, novel compositions, methods of their use and methods of their manufacture where such compounds are generally pharmacologically useful as agents in therapies for diseases relating to hyperandrogenic stimulation, particularly caused by excessive accumulation of testosterone (“T”) dihydrotestosterone (“DHT”) and similar androgenic hormones in the metabolic system.
  • T testosterone
  • DHT dihydrotestosterone
  • novel compounds of the present invention are especially useful in the prevention and treatment of prostatic carcinoma, and they may also be useful in the treatment and prevention of other hyperandrogenic diseases such as acne vulgaris, seborrhea, female hirsutism, also called androgenic alopecia which includes female and male pattern baldness, and benign prostatic hype ⁇ lasia.
  • hyperandrogenic diseases such as acne vulgaris, seborrhea, female hirsutism, also called androgenic alopecia which includes female and male pattern baldness, and benign prostatic hype ⁇ lasia.
  • the compounds of the present invention are 3-oxo-4- azasteroids, particularly 17-substituted, 4-aza-5 ⁇ -androstan-3-one derivatives.
  • Finasteride ( 17 ⁇ -(N-tert-butylcarbamoyl)-3-oxo-4-aza-5 ⁇ - androst-l -ene-3-one) as shown below, is a potent inhibitor of the human prostate enzyme.
  • finasteride is known to be useful in the treatment of hyperandrogenic conditions; see e.g. U.S. 4.760,071. Finasteride is currently prescribed for the treatment of benign prostatic hype ⁇ lasia (BPH), a condition afflicting to some degree the majority of men over age 55. Finasteride's utility in the treatment of androgenic alopecia and prostatic carcinoma is also disclosed in the following documents: EP 0 285,382, published 5 October 1988; EP 0 285,383, published 5 October 1988; Canadian Patent no. 1 ,302,277; and Canadian Patent no. 1 ,302,276.
  • BPH benign prostatic hype ⁇ lasia
  • Finasteride is a 5 ⁇ -reductase inhibitor.
  • the enzyme 5 ⁇ - reductase catalyzes the reduction of testosterone to the more potent androgen, dihydrotestosterone, as shown below:
  • the principal mediator of androgenic activity in some target organs e.g. the prostate, is 5oc-dihydrotestosterone ("DHT"), foimed locally in the target organ by the action of testosterone-5 ⁇ -reductase.
  • DHT 5oc-dihydrotestosterone
  • Inhibitors of testosterone-5 ⁇ -reductase prevent or lessen symptoms of hyperandrogenic stimulation in these organs.
  • One isozyme (type 1 ) predominates in sebacious glands of facial and skin tissue and is relatively insensitive to finasteride; the other (type 2) predominates in the prostate and is potently inhibited by finasteride.
  • European patent publication EP 0 547 691 discloses 17-subst ⁇ tuted 4-aza- 5 -androstan-3-one derivatives useful in the treatment of prostatic carcinoma.
  • European Patent Publication 0 484 094 discloses 4- azasteroid compounds with 17-aryl carboxamide substitutions.
  • hydroxy-flutamide the active form of flutamide
  • CasodexTM the trademark for ICI 176,334 from Imperial Chemical Industries PLC.
  • novel compounds of the present invention are those of structural Formula (I)
  • the compounds of structural Formula I are useful in the systemic, including oral, and parenteral, including topical, treatment and prevention of hyperandrogenic conditions including prostatic carcinoma, benign prostatic hype ⁇ lasia, acne vulgaris, seborrhea, androgenic alopecia (also called androgenetic alopecia) which includes male- and female-pattern baldness, female hirsutism, and prostatitis.
  • Another object of this invention is to provide compounds ot formula I in combination with other active agents, for example a 5 ⁇ - reductase type 2 inhibitor, such as finasteride. or a potassium channel opener, such as minoxidil, or a retinoic acid or a derivative thereot. or an ⁇ l - or ⁇ l -adrenergic receptor antagonist, or combinations ot such othei active agents with a compound of Formula I, wherein such combinations would be useful in one or more of the above-mentioned methods of treatment or pharmaceutical compositions.
  • active agents for example a 5 ⁇ - reductase type 2 inhibitor, such as finasteride. or a potassium channel opener, such as minoxidil, or a retinoic acid or a derivative thereot. or an ⁇ l - or ⁇ l -adrenergic receptor antagonist, or combinations ot such othei active agents with a compound of Formula I, wherein such combinations would be useful in one or more of the above-ment
  • novel compounds of the present invention have structural Formula I:
  • R 1 is selected from methyl and ethyl
  • R2 is selected from (a) H, and
  • R is selected from:
  • heteroaryl either unsubstituted or substituted with one to three substituents independently selected from: ( 1 ) halo (F, Cl, Br, I), (2) Cl-2 alkyl;
  • (I I ) alkyoxy In one class of this embodiment are compounds wherein R is unsubstituted dipheny Imethyl.
  • R3 is phenyl substituted with one to three substituents independently selected from ( 1 ) halo (F, Cl, Br, I),
  • R ' is methyl
  • Examples of compounds exhibiting both 5 ⁇ -reductase type 1 and type 2 inhibitory and androgen receptor antagonistic activin of this class are: N-(2-methylphenyl)-3-oxo-4-aza-4-methyl-5 ⁇ -androst- 1 - ene- 17 ⁇ -carboxamide;
  • N-(2-methoxyphenyl)-3-oxo-4-aza-4-methyl-5 ⁇ -androst- 1 - ene- 17 ⁇ -carboxamide N-(2-chlorophenyl)-3-oxo-4-aza-4-methyl-5 ⁇ -androst -1 - ene- 17 ⁇ -carboxamide;
  • R3 is heteroaryl, either unsubstituted or substituted with one to three substituents independently selected from:
  • heteroaryl is pyridyl, pyrazinyl. pyrazolyl, or thiazolyl. Examples of compounds of this class are:
  • R is naphthyl, either unsubstituted or substituted with one to three substituents independently selected from: (1 ) halo (F, Cl, Br, I),
  • Examples of compounds of this class include:
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g.. methyl (Me), ethyl (Et ). propyl. butyl, pentyl. hexyl. heptyl. octyl. nonanyl. decyl, undecyl. dodecyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), secbutyl (s-Bu), tertbutyl (t-Bu). isopentane, isohexane, etc.
  • Alkyloxy (or “alkoxy”) represents an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, e.g.. methoxy. ethoxy, propyloxy, iso-propoxy. n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and the like.
  • aryl is intended to include: phenyl and naphthyl; and “heteroaryl” is intended to include: pyridyl, furyl, pyrryl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl, and benzoxazolyl.
  • heteroaryl represents pyridyl, pyrazinyl, pyrazolyl, and thiazolyl.
  • the heteroaryl ring may be substituted, or attached within structural formula I, at any heteroatom (N, O or S) or carbon atom in the ring which results in the creation of a stable, uncharged structure.
  • compositions of formula I where a basic or acidic group is present on the structure.
  • a basic group such as amino
  • an acidic salt i.e., hydro ⁇ chloride, hydrobromide, acetate, pamoate, and the like, can be used as the dosage form.
  • 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, sul
  • the compounds of the present invention may have chiral centers other than those centers whose stereochemistry is depicted in Formula I, and therefore may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. with all such isomeric forms being included in the present invention as well as mixtures thereof.
  • some of the crystalline forms for compounds of the present invention may exist as polymo ⁇ hs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • terapéuticaally effective amount means 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, which includes alleviation of the symptoms of the disorder being treated.
  • the novel methods of treatment of this invention are for disorders known to those skilled in the art.
  • the term “mammal” includes humans.
  • the present invention has the objective of providing methods of treating hyperandrogenic conditions including androgenic alopecia, male pattem baldness, acne vulgaris, seborrhea, and female hirsutism by oral, systemic, parenteral or topical administration of the novel compounds of formula I either alone or in combination with a 5 ⁇ -reductase 2 inhibitor, or a potassium channel opener, or a retinoic acid or derivative thereof.
  • treatment may encompass administration of a combination of a compound of Formula I with a 5oc-reductase 2 inhibitor and another active agent such as a potassium channel opener, or a retinoic acid or derivative thereof.
  • 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 hype ⁇ lasia, prostatitis. and treating and/or preventing prostatic carcinoma by oral, systemic or parenteral administration of the novel compounds of formula I either alone or in combination with a 5 ⁇ -reductase 2 inhibitor.
  • treatment may encompass administration of a combination of a compound of formula I with a 5 ⁇ -reductase 2 inhibitor and another active agent such as an ⁇ l or an ⁇ l a adrenergic receptor antagonist.
  • the present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention.
  • the compositions containing the present compounds as the active ingredient for use in the treatment of the above-noted conditions can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration.
  • the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection.
  • compositions are preferably provided in the form of tablets containing 0.01 , 0.05, 0J , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, and 50.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • an effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg kg to about 50 mg/kg of body weight per day. The range is more particularly from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • 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.
  • 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 compounds of the present invention may be administered in a pharmaceutical composition comprising the active compound in combination with a pharmaceutically acceptable carrier adapted for topical administration.
  • 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.
  • These topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle.
  • the compounds of the instant invention can be combined with a therapeutically effective amount of another 5 ⁇ - reductase inhibitor, such as finasteride, or other 5 ⁇ -reductase inhibitor compounds having type 2 activity or dual activity for both isozymes, in a single oral, systemic, or parenteral pharmaceutical dosage formulation.
  • another 5 ⁇ - reductase inhibitor such as finasteride, or other 5 ⁇ -reductase inhibitor compounds having type 2 activity or dual activity for both isozymes
  • a combined therapy can be employed wherein the compound of formula I and the other 5 ⁇ -reductase inhibitor are administered in separate oral, systemic, or parenteral dosage formulations.
  • the compounds of the instant invention and another 5 ⁇ -reductase inhibitor such as finasteride 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.
  • a compound of the present invention in combination with a therapeutically effective amount of a potassium channel opener, such as minoxidil, cromakalin, pinacidil, a compound selected from the classes of S-triazine, thiane- 1 -oxide, benzopyran, and pyridinopyran derivatives or a pharmaceutically acceptable salt thereof, may be used for the treatment of androgenic alopecia including male pattern baldness.
  • Therapy may further comprise the administration of a 5 ⁇ -reductase type 2 inhibitor such as finasteride, or a type 1 and type 2 dual inhibitor, in combination with a compound of the present invention and a potassium channel opener such as minoxidil.
  • the active agents can be administered in a single topical dosage formulation, or each active agent can be administered in a separate dosage formulation, e.g., in separate topical dosage formulations, or an oral dosage formulation of a compound of formula I in combination with a topical dosage formulation of, e.g., minoxidil, or a single oral dosage formulation of a compound of formula I and another 5 ⁇ -reductase inhibitor, in combination with a topical dosage formulation of, e.g., minoxidil. See, e.g., U.S. Patent No.'s 4,596,812, 4, 139,619 and WO 92/02225, published 20 February 1992, for dosages and formulations of calcium channel openers.
  • a combined therapy can be used by administering a therapeutically effective amount of a compound of formula I in combination with a therapeutically effective amount of retinoic acid or a derivative thereof, e.g., an ester or amide derivative thereof, such as e.g., tretinoin or isotretinoin.
  • this combined therapy for acne vulgaris may further include a 5 ⁇ -reductase type 2 inhibitor such as finasteride, or a dual type 1 and type 2 inhibitory compound.
  • a combined therapy comprising a administration of a compound of formula I with a 5 ⁇ -reductase type 2 inhibitor, such as e.g., finasteride, and an alpha- 1 adrenergic receptor antagonist, such as e.g., terazosin, doxazosin, prazosin, bunazosin, indoramin or alfuzosin, may be employed.
  • the combined therapy can comprise administering a compound of formula I with a 5 ⁇ -reductase type 2 inhibitor, such as e.g., finasteride, and an alpha- la adrenergic receptor antagonist.
  • the active agents can be administered concurrently, or they each can be administered at separately staggered times.
  • 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 or arrest the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • the compounds herein described in detail can form the active ineredient, 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 administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • suitable pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders include, without limitation, 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, without limitation, 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 an. 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 foimed 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, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the compounds of the present invention can be prepared readily according to the following Schemes and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
  • Step 2 4-methyl-3-oxo-4-aza-5 ⁇ -androst- l -ene- 17 ⁇ -carboxylic acid
  • Step 3 4-methyl-3-oxo-4-aza-5 ⁇ -androst-l -ene-17 ⁇ -(2- thiopyridine carboxylate
  • Step 4 N-(4-chlorophenyl)-3-oxo-4-methyl-4-aza-5 ⁇ -androst- l - ene- 17 ⁇ -carboxamide
  • the reaction mixture for the type 1 5 ⁇ -reductase contained 40 mM potassium phosphate, pH 6.5, 5 mM [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 mM [7- ⁇ H]-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 C. After 10-50 min. the reaction was quenched by extraction with 250 ⁇ L of a mixture of 70% cyclohexane: 30% ethyl acetate containing 10 ⁇ g each DHT and T. The aqueous and organic layers were separated by centrifugation at 14,000 ⁇ m in an Eppendorf microfuge. The organic layer was subjected to normal phase HPLC ( 10 cm Whatman partisil 5 silica column equilibrated in 1 ml/min 70% cyclohexane: 30% ethyl acetate; retention times: DHT.
  • HPLC 10 cm Whatman partisil 5 silica column equilibrated in 1 ml/min 70% cyclohexane: 30% ethyl acetate; retention times: DHT.
  • the HPLC system consisted of a Waters Model 680 Gradient System equipped with a Hitachi Model 655 ⁇ 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.
  • IC50 values represent the concentration of inhibitor required to decrease enzyme conversion of testosterone to dihydrotestosterone by 50% of the control. IC50 values were determined using a 6 point titration where the concentration of the inhibitor was varied from 0J to 1000 nM. Representative compounds of this invention were tested in the above described assay for 5 ⁇ -reductase type 1 and type 2 inhibition.
  • the dermal papilla is a small group of cells at the base of each hair follicle, and it is presently thought that these cells are stem cells that form the basis for hair growth. These cells have been shown to have 5 ⁇ reductase activity, and it is therefore possible to test inhibitors of 5 ⁇ reductase in these cell culture systems.
  • Isolated and cultured dermal papilla cells are prepared according to the methods of Messenger, A.G., "The Culture of Dermal Papilla Cells From Human Hair Follicles," Br. J. Dermatol., 1 10:685- 689 ( 1984) and Itami, S. et al, "5 ⁇ -Reductase Activity In Cultured Human Dermal Papilla Cells From Beard Compared With Reticular Dermal Fibroblasts," J. Invest. Dermatol.. 94: 150- 152 ( 1990). Beard dermal papilla cells and occipital scalp hair of two different individuals are used throughout the study. All experiments are performed at confluency after the fourth to sixth subculture.
  • Confluent monolayers are rinsed twice with phosphate-buffered saline, scraped from dishes by rubber policemen, and collected into a centrifuge tube.
  • the cell suspensions are centrifuged at 1 ,500 ⁇ m for 10 min. at 4°C.
  • the pellets are resuspended in 20 mM Tris-HCl buffer, pH 7.5, at 4°C, containing 250 mM sucrose, 1 mM MgCl2, and 2 mM CaCl2, by vortexing and 10 passes through a 25-gauge needle.
  • the crude homogenate is further homogenized by a teflon-glass homogenizer, and is used as the cell homogenate.
  • the cell homogenate is centrifuged at 800 x g for 10 min. to yield a crude nuclear pellet.
  • the resultant supematant is centrifuged at 10,000 x g for 15 min. to produce a crude mitochondrial pellet.
  • the supematant is centrifuged at 100,000 x g for 60 min. to yield a microsomal pellet and cytosol. Each particulate fraction is washed twice and resuspended in the buffer.
  • a standard incubation mixture will consist of 50 nM f ⁇ H] -testosterone, 1 mM NADPH, 100 mM sodium citrate, pH 5.5 or 100 mM Tris-HCl, pH 7.5, and 50 ml of the cell homogenate, in a final volume of 100 ml. Each tube contains 50-100 mg of cellular protein. Incubation is carried out at 37°C for 30 min. During this incubation, the reaction is proportional to the time. For the study of optimum pH, citrate buffer is used at pH 4.5-6.5, and the Tris HCl buffer at pH 7.0-9.0. The protein content is determined by the method of Lowry, et al., "Protein Measurement With The Folin Phenol Reagent.” J. Biol. Chem., 193:265-275 ( 1951 ).
  • [ 1 ,2-3H]- testosterone (55.2 Ci/mmol) is obtainable from New England Nuclear Co ⁇ oration (Boston, MA) and unlabeled steroids can be purchased from Sigma Chemical Company (St. Louis, MO). Fetal calf serum is obtainable from Hazleton (Lenaxa, Kansas). All other chemicals are of reagent grade.
  • 5 ⁇ -Reductase (5aR) Activities and Anti-Androgen Activity (hAR) of compounds of the present invention are illustrated in the table below:
  • Haircount target area Equipment Film: Kodak-T-max 24 exposure each of same emulsion lot number
  • the haircount area on the patient is prepared as follows:
  • a small ( ⁇ lmm) dot tattoo is placed at the beginning of the study at the leading edge of the bald area directly anterior to the center of the vertex bald spot, using a commercial tattooing machine or manually (needle and ink).
  • Each lens supplied has a fixed reproduction ratio of 1 : 1.2.
  • Aperture Every photograph is taken at f/22. Film: T-Max 100 (24 exposure) is used. 3. Patient's haircount target area. Three exposures (-2/3, 0, and +2/3 f-stop).
  • a trained technician places a transparency over the photographic print and, using a felt tip pen, places a black dot over each visible hair.
  • the dot map transparency is then counted using image analysis with computer assistance.
  • Photographs are coded with a random number corresponding to study site, visit number and patient allocation number to insure blinding to time. At Month 6, baseline and Month 6 photographs are counted and data analyzed for interim analysis. At Month 12, baseline, Month 6 and Month 12 photographs are counted and data analyzed for the primary endpoint.

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  • Steroid Compounds (AREA)

Abstract

L'invention porte sur des composés représentés par la formule développée (I), et sur leurs sels et leurs esters pharmaceutiquement acceptables, possédant une activité inhibitrice de 5α-réductase. Ces composés inhibent la 5α-réductase des types 1 et 2. Les composés de formule développée (I) servent au traitement curatif et préventif systémique - y compris oral, et parentéral - y compris local, d'états hyperandrogéniques, y compris de carcinomes prostatiques, de l'hyperplasie prostatique, de l'acné vulgaire, de la séborrhée, de l'alopécie androgénique (également appelée alopécie androgénétique), qui comprend la calvitie masculine et féminime, l'hirsutisme féminin et la prostatite. Des composés de la présente invention sont également de puissants anti-androgènes. L'invention porte également sur des compositions contenant de tels composés, sur leurs procédés d'utilisation et leurs procédés de fabrication.
PCT/US1996/014564 1995-09-15 1996-09-11 4-azasteroides utilises pour le traitement d'etats hyperandrogeniques WO1997010217A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US09/029,926 US6001844A (en) 1995-09-15 1996-09-11 4-Azasteroids for treatment of hyperandrogenic conditions
JP9512068A JPH11512434A (ja) 1995-09-15 1996-09-11 アンドロゲン過剰状態治療用の４−アザステロイド
EP96930822A EP0859761A4 (fr) 1995-09-15 1996-09-11 4-azasteroides utilises pour le traitement d'etats hyperandrogeniques
AU69737/96A AU707324B2 (en) 1995-09-15 1996-09-11 4-azasteroids for treatment of hyperandrogenic conditions
CA002231041A CA2231041A1 (fr) 1995-09-15 1996-09-11 4-azasteroides utilises pour le traitement d'etats hyperandrogeniques
US10/020,740 USRE39056E1 (en) 1995-09-15 1996-09-11 4-Azasteroids for treatment of hyperandrogenic conditions

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US382695P 1995-09-15 1995-09-15
US60/003,826 1995-09-15
GBGB9603487.1A GB9603487D0 (en) 1996-02-20 1996-02-20 4-azasteroids for the treatment of hyperandrogenic conditions
GB9603487.1 1996-02-20

Publications (1)

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WO1997010217A1 true WO1997010217A1 (fr) 1997-03-20

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PCT/US1996/014564 WO1997010217A1 (fr) 1995-09-15 1996-09-11 4-azasteroides utilises pour le traitement d'etats hyperandrogeniques

Country Status (5)

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EP (1) EP0859761A4 (fr)
JP (1) JPH11512434A (fr)
AU (1) AU707324B2 (fr)
CA (1) CA2231041A1 (fr)
WO (1) WO1997010217A1 (fr)

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WO2000013509A1 (fr) * 1998-09-09 2000-03-16 Merck & Co., Inc. Procede de determination et de reduction du risque de survenue de problemes urologiques lies a l'adenome prostatique
US6645974B2 (en) 2001-07-31 2003-11-11 Merck & Co., Inc. Androgen receptor modulators and methods for use thereof
EP1434786A1 (fr) * 2001-10-03 2004-07-07 Merck & Co., Inc. Androstane 17-beta-carboxamides en tant que modulateurs de recepteurs d'androgenes
WO2006104762A3 (fr) * 2005-03-25 2006-11-30 Merck & Co Inc Traitement d'humains de sexe masculin par supplementation en testosterone associee a un inhibiteur de 5alpha-reductase
US7323490B2 (en) 2003-05-16 2008-01-29 Ambit Biosciences Corporation Pyrrole compounds and uses thereof
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques

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CN1652786A (zh) * 2002-03-13 2005-08-10 麦克公司 作为雄激素受体调节剂的氟代4－氮杂甾体衍生物

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000013509A1 (fr) * 1998-09-09 2000-03-16 Merck & Co., Inc. Procede de determination et de reduction du risque de survenue de problemes urologiques lies a l'adenome prostatique
US6645974B2 (en) 2001-07-31 2003-11-11 Merck & Co., Inc. Androgen receptor modulators and methods for use thereof
EP1434786A1 (fr) * 2001-10-03 2004-07-07 Merck & Co., Inc. Androstane 17-beta-carboxamides en tant que modulateurs de recepteurs d'androgenes
EP1434786A4 (fr) * 2001-10-03 2009-03-25 Merck & Co Inc Androstane 17-beta-carboxamides en tant que modulateurs de recepteurs d'androgenes
US7323490B2 (en) 2003-05-16 2008-01-29 Ambit Biosciences Corporation Pyrrole compounds and uses thereof
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
WO2006104762A3 (fr) * 2005-03-25 2006-11-30 Merck & Co Inc Traitement d'humains de sexe masculin par supplementation en testosterone associee a un inhibiteur de 5alpha-reductase
EP2371367A1 (fr) 2005-03-25 2011-10-05 Merck Sharp & Dohme (I.A.) Corp. Traitement d'humains de sexe masculin par supplémentation en testostérone associée a un inhibiteur de 5alpha-reductase

Also Published As

Publication number Publication date
AU707324B2 (en) 1999-07-08
AU6973796A (en) 1997-04-01
JPH11512434A (ja) 1999-10-26
CA2231041A1 (fr) 1997-03-20
EP0859761A1 (fr) 1998-08-26
EP0859761A4 (fr) 2000-01-26

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