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WO1994015602A1 - METHODE ASSOCIATIVE PERMETTANT DE TRAITER L'ALOPECIE ANDROGENE AU MOYEN DE CARBAMOYLE-Y-AZA-5α-ANDROST-1-EN-3-ONES N-SUBSTITUEES EN POSITION 17β ET DE MINOXIDIL - Google Patents

METHODE ASSOCIATIVE PERMETTANT DE TRAITER L'ALOPECIE ANDROGENE AU MOYEN DE CARBAMOYLE-Y-AZA-5α-ANDROST-1-EN-3-ONES N-SUBSTITUEES EN POSITION 17β ET DE MINOXIDIL Download PDF

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Publication number
WO1994015602A1
WO1994015602A1 PCT/US1994/000176 US9400176W WO9415602A1 WO 1994015602 A1 WO1994015602 A1 WO 1994015602A1 US 9400176 W US9400176 W US 9400176W WO 9415602 A1 WO9415602 A1 WO 9415602A1
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WIPO (PCT)
Prior art keywords
aza
methyl
androst
compound
adamantylcarbamoyl
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PCT/US1994/000176
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English (en)
Inventor
Gary H. Rasmusson
Richard L. Tolman
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Merck and Co Inc
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Merck and Co Inc
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Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to AU60834/94A priority Critical patent/AU6083494A/en
Publication of WO1994015602A1 publication Critical patent/WO1994015602A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof

Definitions

  • the present invention is concerned with the use of 17 ⁇ -N-substituted-carbamoyl-4-aza-5 ⁇ -androst-l-en-3-one compounds as testosterone-5 ⁇ -reductase inhibitors in combination with minoxidil for the treatment of patterned alopecia, i.e., male pattern baldness.
  • Baldness or alopecia in addition to male pattern alopecia, female pattern alopecia, and alopecia senilis, includes alop ⁇ cia areata, and further, diseases accompanied by basic skin lesions such as cicatrix or infectious tumors, or accompanied by systemic disorders, for example, an internal secretion abnormality or nutritional disorder.
  • alopecia areata it is considered that an autoimmune phenomenon participates therein, and therefore, the administration of a substance having an immunosuppressive action can have therapeutical effect on alopecia areata.
  • alopecia also called “androgenic alopecia”
  • alopecia senilis are considered to be: an activation of male hormones at organs such as hair roots and the sebum gland; a lowering in the amount of blood reaching the hair follicles; a scalp abnormality caused by an excessive secretion of sebum, a formation of peroxides, or a propagation of bacteria; genetic causes; and aging.
  • Hair revitalizing materials of the prior art generally comprise compounds having the actions of removing or alleviating the causes mentioned above formulated therein.
  • a compound having the action of inhibiting the activation of male hormones, or a compound having the action of increasing the amount of blood reaching the hair follicles is formulated.
  • the epilation mechanism and the hair generation mechanism are very complicated, and by merely inhibiting an activation of male hormones or increasing the amount of blood reaching the hair follicles, as practiced in the prior art, does not sufficiently treat or prevent baldness or alopecia. Accordingly, there is a long-felt need for a hair revitalizing agent for male pattern alopecia and alopecia senilis, which provides satisfactory results.
  • Patterned baldness is sometimes called androgenic alopecia because male hormones are necessary for its development. It does not occur before adolescence, nor in castrates. Attempts to prevent alopecia by hormonal treatments by using anti-androgens or female hormones have failed. A hereditary component is also recognized since patterned alopecia runs in families. Despite intensive investigation, the mechanism whereby terminal follicles convert to vellus ones is unknown.
  • Minoxidil is a well-known pharmaceutical agent marketed by The Upjohn Company in the form of LONITEN® Tablets for the treatment of hypertension. Numerous investigators have demonstrated that it can stimulate visible hair growth in a majority of balding subjects. The structure and use of this compound is described in U.S. Pat. Nos. 4,139,619 and 4,596,812. This compound has varying degrees of efficacy for moderating androgenic alopecia, depending on the degree of baldness, its duration, the age of the patient and, of course, on the concentration of the drug in an appropriate vehicle.
  • minoxidil (6-amino-l,2-dihydro-l- hydroxy-2-imino-4-piperidinopyrimidine) was approved by the FDA for the treatment of male pattern baldness in August 1988.
  • Minoxidil was recently approved by the FDA for the treatment of female androgenetic alopecia on August 13, 1991.
  • the preparation of minoxidil is described in U.S. Patent Nos. 3.382.247. 3.644.364.
  • Upjohn United States Patents U.S. Patent Nos. 4.139.619 and 4.596.812 *
  • an Upjohn United States Patent (U.S. Patent No. 5.026.691) discloses the use of minoxidil and an anti- inflammatory agent for the treatment of human baldness.
  • Japanese patent Kokai 61-260010 states that topical minoxidil formulations containing other specified agents may be prepared.
  • minoxidil The topical application of minoxidil has met with limited success. What is desired in the art is an improved formulation of minoxidil for treating patterned alopecia.
  • the present invention involves a method for treating patterned alopecia comprising the concomitant administration to a human host in need of such treatment of:
  • Ri and R ⁇ are independently hydrogen, methyl or ethyl
  • R2 is a hydrocarbon radical selected from substituted or unsubstituted:
  • aralkyl of from 7-12 carbons such as e.g. benzyl, -CH2CH2-phenyl, and (e) monocyclic aryl, such as e.g. phenyl, with the proviso that R ⁇ is not t-butyl when R* and R ⁇ are H;
  • R' is hydrogen or methyl;
  • R" is hydrogen or ⁇ -methyl;
  • R' is hydrogen, ⁇ -methyl or ⁇ -methyl; or a pharmaceutically acceptable salt or ester thereof, administered topically or orally; and
  • the compound of formula I applicable in the process of our invention is represented by the formula la:
  • Ri is hydrogen, methyl or ethyl
  • R ⁇ is selected from:
  • Representative compounds of the present invention include the following:
  • alkyl, cycloalkyl, aralkyl, monocyclic aryl, 1- or 2- adamantyl or 1- or 2-norbornanyl moieties can be substituted with one or more substituents of the following: C1-C4 linear or branched alkyl, including methyl, ethyl, isopropyl, n-butyl; nitro; oxo; C7-C9 aralkyl, including benzyl; (CH2)n COOR where n is 0, 1 or 2 and R is H or Cl- C4 linear or branched alkyl including methyl, ethyl; CH2OH; OH; OR a where R a is C1-C4 linear or branched alkyl including methyl, ethyl; halo, including chloro, fluoro, bromo, iodo; COOH; COORb where R D is linear or branched C1-C4 alkyl; -CONH2; CH
  • amino group of the adamantyl or norbornanyl moiety can also be substituted as R* with methyl and ethyl, as well as hydrogen.
  • R* methyl and ethyl
  • norbornanyl and norbornyl as used herein are intended to have the same meaning and may be used interchangeably in this application.
  • compositions or esters where a basic or acidic group is present on the substituted alkyl, cycloalkyl, aralkyl, adamantyl or norbornanyl moiety.
  • 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
  • acidic salts i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like
  • a basic group i.e. amino
  • acidic salts i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like
  • 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.
  • R ⁇ as substituted norbornanyl moieties are (where NB is norbornanyl): 2-NB; l,7,7-trimethyl-4-phenyl-2-NB; 3-carboxy-2-NB; 3-phenyl-2- carboxy-2-NB; 2-cyano-3-phenyl-2-NB; 3-hydroxy-4,7,7-trimethyl-2- NB; 6-hydroxymethyl-2-NB; 5-cyano-2-NB; 3-allyl-2-NB; 1-NB; 7,7- dimethyl-l-hydroxymethyl-2-NB; 3-methoxy-4,7,7-trimethyl-2-NB; 3- aminocarbonyl-2-NB; 3-ethoxycarbonyl-2-NB; 3,3-dimethyl-2-NB; 7- oxo-l-NB; 3-phenyl-2-NB; l-carboxy-methyl-7,7-dimethyl-2-NB; 1- ethyl-2-NB; l-methyl-2-NB; 2,2,3,3,5,5,6,6,7 ,7-decafluoro-
  • novel compounds of formula I of the present invention can be prepared by a method starting with the known steroid ester (H) of the formula:
  • 17 ⁇ -(carbomethoxy)-4-aza-5- ⁇ -androstan-3-ones which includes the stages of optionally 1) dehydrogenating said starting material to produce the corresponding compound containing a double-bond in the Im ⁇ position of the A-ring, 2) converting the 17-carbomethoxy substituent into an N-substituted alkyl, cycloalkyl, aralkyl, monocyclid acyl, or adamantylcarbamoyl substituent and, if desired, 3) alkylating the A-ring nitrogen to introduce a N-methyl or N-ethyl substituent into the A ring 4-position.
  • the 4-aza nitrogen be unsubstituted.
  • the alternate pathways can consist of one or more discrete chemical steps and if desired can take place before step (1) or following step (1) or step (3).
  • the products of our invention are formed by optionally: (1) heating a 17 ⁇ -alkoxycarbonyl-4-aza-5 ⁇ -androstan-3-ones, compound III, (prepared in the literature as described in the reference US Patent 4,377,584) with a dehydrogenating agent such as benzeneseleninic anhydride in a refluxing inert solvent, e.g.
  • silica gel and (6) said pyridyl- thio ester can be then reacted with 1 -adamantyl-, 2-adamantylamine or norbornanylamine in an inert solvent e.g. tetrahydrofuran, to form the desired product 17 ⁇ -N-adamantylcarbamoyl-4-alkyl-4-aza-5 ⁇ -androst- l-en-3-one VIII which can be isolated by chromatography e.g. on silica gel.
  • an inert solvent e.g. tetrahydrofuran
  • the corresponding N-unsubstituted-17 ⁇ (N-adamantyl-carbamoyl)-4-aza-5 - androst-l-en-3-one XIV is readily prepared from the 17 ⁇ (alkoxy- carbonyl)-4-aza-5 ⁇ -androstane-3-one IV by repeating the above series of reaction steps but omitting the alkylation Step 2 herein above, i.e. treatment of the 4-aza-5 ⁇ -androst-l-en-3-one with e.g. sodium amide followed by methyl or ethyl iodide via intermediates XQ and XIII.
  • the 16-methyl derivative wherein R'" is methyl are prepared from known 16-methyl-17-acyl-4-methyl-4-aza-5 ⁇ -androstan- 3-ones, e.g. 4,16 ⁇ -dimethyl-17 ⁇ -acetyl-4-aza-5 ⁇ -androstan-3-one by known dehydrogenation procedures for 4-methyl-4-aza compounds to produce the corresponding 4,16 ⁇ -dimethyl-17 ⁇ -acetyl-4-aza-5 ⁇ - androst- 1 -en-3-one.
  • X is 2-pyridylthio or 1-benzotriazoloxy.
  • R ⁇ is 1- or 2-adamantyl or norbornanyl.
  • the compounds of the present invention prepared in accordance with the method described above, are, as already described, potent and selective antiandrogens in the treatment of patterned alopecia by virtue of their ability to specifically inhibit testosterone-5 ⁇ - reductase.
  • the compounds of Formula I may be employed in a pharmaceutical composition additionally comprising a potassium channel opener, such as one selected from the group consisting of minoxidil, cromakalim, pinacidil, a compound selected from the classes of s-triazine, thiane-1 -oxide, benzopyran, or pyridinopyran derivatives, or a pharmaceutically acceptable salt thereof.
  • a potassium channel opener such as one selected from the group consisting of minoxidil, cromakalim, pinacidil, a compound selected from the classes of s-triazine, thiane-1 -oxide, benzopyran, or pyridinopyran derivatives, or a pharmaceutically acceptable salt thereof.
  • a potassium channel opener such as one selected from the group consisting of minoxidil, cromakalim, pinacidil, a compound selected from the classes of s-triazine, thiane-1 -oxide, benzopyran, or pyridinopyran derivatives
  • compositions are useful in hair revitalizing, such as in the treatment of male pattern alopecia, female pattern alopecia, alopecia senilis or alopecia areata, by providing epilation prevention, hair germination, and/or a promotion of hair generation and hair growth.
  • the compound of formula I may be administered topically, parenterally or systemically, including orally, while the potassium channel opener, e.g., minoxidil, is administered topically, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • the potassium channel opener e.g., minoxidil
  • parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • modes of administration include topical administration of minoxidil in combination with oral or topical administration of a compound of Formula I.
  • the present invention is thus also concerned with providing suitable topical and systemic pharmaceutical formulations for use in the novel methods of treatment of the present invention.
  • the active agents can be administered in a single topical pharmaceutical formulation, or each active agent can be administered in a separate pharmaceutical formulation, e.g., in separate topical pharmaceutical formulations, or e.g., an oral pharmaceutical formulation of a compound of formula I in combination with a topical pharmaceutical 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 potassium channel openers.
  • the active agents can be administered concomitantly, or they each can be administered at separately staggered times.
  • a compound of Formula I may be administered prior to, concurrent with, or subsequent to the topical administration of minoxidil.
  • compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds of the present invention as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for oral, external, enteral or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non- toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
  • Topical pharmaceutical compositions may be, e.g., in the form of a solution, cream, ointment, gel, lotion, shampoo or a formulation suitable for spraying onto the skin such as an aerosol formulation.
  • the compounds of Formula I and minoxidil may be utilized with hydroxypropyl methyl-cellulose essentially as described in U.S Patent No. 4.916.138. issued April 10, 1990, or with a surfactant essentially as described in EPO Publication 0.428.169.
  • Dosage forms for external application may be prepared essentially as described in EPO Publication 0.423.714 or in U.S. Patent No. 4.938.953.
  • the active object compounds are included in the pharmaceutical composition in a therapeutically effective amount, that is, an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the compound of Formula I may be formulated within the range of, for example, 0.0001% to 60% by weight, preferably from 0.001% to 10% by weight, and most preferably from about 0.005% to 0.8% by weight.
  • the dose of the compound of Formula I for a human being is preferably 1 to 2000 mg, more preferably 1 to 20 mg, per day per person,
  • minoxidil may be formulated in the composition within the range of, for example, 0.1% to 10.0% by weight, and preferably from 1% to 5% by weight.
  • compositions of the present invention may be administered on an intermittent basis; i.e. at semidaily, daily, semiweekly, weekly, semi-monthly or monthly intervals.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • a lotion comprising the composition shown below may be prepared.
  • An emulsion is prepared from A phase and B phase having the following compositions.
  • the A phase and the B phase are respectively heated and melted and maintained at 80°C, both phases are mixed to be emulsified, and are cooled under stirring to normal temperature to obtain an emulsion.
  • a cream is prepared from A phase and B phase having the following compositions.
  • the A phase is heated and melted, and maintained at 70°C, the B phase is added to the A phase followed by stirring, and the obtained emulsion is cooled to obtain a cream.
  • a hair liquid comprising the composition shown below may
  • polyoxypropylene butyl ether Into ethanol is added polyoxypropylene butyl ether, propylene glycol, polyoxyethylene hardened castor oil, a compound of Formula I, minoxidil, and perfume, which are mixed under stirring, and to the mixture is added purified water, to obtain a hair liquid.
  • a hair shampoo comprising the composition shown below may be prepared.
  • the present invention is also particularly concerned with providing a method of treating patterned baldness in human males and females by topical, systemic or oral administration by concomitant therapy of the compounds of the present invention.
  • the present invention is thus also concerned with providing suitable topical and systemic pharmaceutical formulations for use in the novel methods of treatment of the present invention.
  • the compositions containing the compounds of the present invention as the active ingredient for use in the treatment of patterned baldness can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration, as, for example, by oral administration in the form of tablets, capsules, solutions, or suspensions, of by intravenous injection.
  • the compositions are preferably provided in the form of scored tablets containing 0.1, 1, 5, 10, 25, 50, 100, 150, 250, and 500 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 0.01 mg.
  • 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, com starch or magnesium stearate.
  • the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methylcellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methylcellulose 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 preservative are employed when intravenous administration is desired.
  • the compound of formula I is administered orally and the minoxidil administered topically as a cream or lotion.
  • a suspension of 25 g of the product of Example 2 in 125 ml of methanol was treated with a solution of KOH (*12.5 g) in 12.5 ml of water. After refluxing for 4 hours, the solution was acidified with 6 NHCl and then was diluted with water. The crude acid (23.32 g) was separated, dried and had m.p. 300°C.
  • Example 3A In a similar fashion the product of Example 1 was converted into S-(2-pyridyl) 3-oxo-4-aza-5 ⁇ -androst-l-ene-17 ⁇ - thiocarboxylate, m.p. 230-232°C.
  • a suspension of 64.7 g of the dioic acid of Step 5 in 350 ml of ethylene glycol was treated with 80 ml of liquid ammonia.
  • the resulting solution was heated at a rate of 3°/min. up to 180°C and was held at that temperature for 15 minutes.
  • 1 liter of water was added and the mixture was acidified with 10% hydrochloric acid to a pH of 1.5.
  • the product was removed and washed with water, then air dried to leave 57.5 g of the product, m.p. 310°C.
  • This material is also obtained by saponification of methyl 3-oxo-4-aza-5 ⁇ -androstane-17 ⁇ -carboxylate (methyl 3-oxo-4-aza-5 ⁇ - etien-17 ⁇ -oate) in 7% methanolic potassium hydroxide followed by an acidic work-up.
  • Example 5D is repeated using t-butylamine in place of 2,2,4-trimethyl-2-pentylamine to obtain N-t-butyl 3-oxo-4-,aza-5cx- androstane-17 ⁇ -carboxamide, m.p. 274-276°C.
  • Example 1 The 17 ⁇ -androstane carboxylate starting material of Example 1 was hydrolyzed with 7% KOH in isopropanol or aqueous methanol, followed by an acidic work-up to give the corresponding 17 ⁇ carboxylic acid which was utilized in Example 11.
  • the acid was readily converted into benzotriazyl-l-yl-3- oxo-4 methyl-4-aza-5 ⁇ -androstane-17 ⁇ -carboxylate as described in Example 13.
  • the activated ester (the benzotriazoyl derivative) was purified on TLC (4 plates, 20 cm x 20 cm x 20 cm x lOOO ⁇ m silica gel) eluted with 4:96 (MeOH-CHCl3).
  • the isolated product was washed with ether to give the active ester m.pt. 198-200°C with decomposition.
  • the title compound is made by reacting 17 ⁇ - carbomethoxy-androst-3,5-diene-3-protected carboxylic acid in e.g., THF, with phenyl magnesium bromide under standard Grignard conditions. Standard workup procedure yields the title compound, m.p.222-225°C.
  • Oxalyl chloride (2 ml) was dropped to a solution of the carboxylic acid prepared in reference example 2 (325 mg) in methylene chloride (2 ml). The solution was stirred for 1 hr and evaporated. To an ice-cooled mixture of ethyl 4-(2-aminophenoxy)butanoate (232 mg), pyridine (1 ml) and methylene chloride (15 ml), the above solution was dropped. The mixture was stirred for 30 mins at the same temperature and for 1 hr at room temperature. The reaction solution was washed with water, dried and evaporated.
  • the following components are admixed in conventional method and punched out to obtain 100 tablets each containing 50 mg of active ingredient.
  • Compounds of formula I may also be used in combination with the compounds 4-[2-[4-(4-isobutylbenzyloxy)-2,3-dimethylbenzoyl- amino]phenoxy]butanoic acid and 4-[2-(4-[l-(4-isobutylphenyl)-ethoxy]- 2,3-dimethylbenzoylamino-phenoxy]butanoic acid and the therapeutically active stereoisomers thereof as well as the pharmaceutically acceptable salts and esters thereof for the treatment of human patterned alopecia.

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Abstract

Carbamoyle-4-aza-5α-androst-1-en-3-ones N-substituées en position 17β, répondant à la formule (I), dans laquelle la ligne pointillée représente une liaison double lorsqu'elle est présente, et R' et R3 sont indépendamment choisis parmi hydrogène, méthyle et éthyle, et R2 représente un alkyle ramifié ou non ramifié, substitué ou non substitué, cycloalkyle, aralkyle contenant 1 à 12 atomes de carbone, ou aryle monocyclique contenant éventuellement un ou plusieurs substituants alkyle inférieur contenant 1 ou 2 atomes de carbone et/ou au moins 1 halogène, et R', R'', R''' représentent hydrogène ou méthyle, à condition que R2 ne représente pas t-butyle lorsque R' et R3 représentent H. Ces composés peuvent être utilisés en thérapie associative avec du minoxidil afin de traiter l'alopécie androgène, l'alopécie régionale masculine, l'alopécie régionale féminine, l'alopécie sénile ou l'alopécie circonscrite.
PCT/US1994/000176 1993-01-07 1994-01-05 METHODE ASSOCIATIVE PERMETTANT DE TRAITER L'ALOPECIE ANDROGENE AU MOYEN DE CARBAMOYLE-Y-AZA-5α-ANDROST-1-EN-3-ONES N-SUBSTITUEES EN POSITION 17β ET DE MINOXIDIL Ceased WO1994015602A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU60834/94A AU6083494A (en) 1993-01-07 1994-01-05 Combination method for treating patterned alopecia with 17beta -n-substituted-carbamoyl-4-aza-5alpha-androst-1-en-3- ones and minoxidil

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US137393A 1993-01-07 1993-01-07
US001,373 1993-01-07

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6645974B2 (en) 2001-07-31 2003-11-11 Merck & Co., Inc. Androgen receptor modulators and methods for use thereof
USRE39056E1 (en) 1995-09-15 2006-04-04 Merck & Co, Inc. 4-Azasteroids for treatment of hyperandrogenic conditions

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4377584A (en) * 1978-04-13 1983-03-22 Merck & Co., Inc. 4-Aza-17β-substituted-5α-androstan-3-one-reductase inhibitors
US4596812A (en) * 1976-05-24 1986-06-24 The Upjohn Company Methods and solutions for treating male pattern alopecia
US4760071A (en) * 1984-02-27 1988-07-26 Merck & Co., Inc. 17β-N-monosubstituted carbamoyl-4-aza-5α-androst-1-en-3-ones which are active as testosterone 5α-reductase inhibitors
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