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WO1999058550A1 - 7β-METHYL-16β-((4-METHYLSULFONYL)-PHENOXY)-4-AZA-5α-ANDROST-1-EN-3-ONE UTILISEE COMME INHIBITEUR D'ISO-ENZYME 5α-REDUCTASE 1 - Google Patents

7β-METHYL-16β-((4-METHYLSULFONYL)-PHENOXY)-4-AZA-5α-ANDROST-1-EN-3-ONE UTILISEE COMME INHIBITEUR D'ISO-ENZYME 5α-REDUCTASE 1 Download PDF

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Publication number
WO1999058550A1
WO1999058550A1 PCT/US1999/010159 US9910159W WO9958550A1 WO 1999058550 A1 WO1999058550 A1 WO 1999058550A1 US 9910159 W US9910159 W US 9910159W WO 9958550 A1 WO9958550 A1 WO 9958550A1
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WO
WIPO (PCT)
Prior art keywords
reductase
compound
inhibitor
treatment
effective amount
Prior art date
Application number
PCT/US1999/010159
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English (en)
Inventor
Donald W. Graham
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9812687.3A external-priority patent/GB9812687D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU39779/99A priority Critical patent/AU3977999A/en
Publication of WO1999058550A1 publication Critical patent/WO1999058550A1/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

Definitions

  • Certain undesirable physiological manifestations such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyper-androgenic stimulation caused by an excessive accumulation of testosterone ("T") or similar androgenic hormones in the metabolic system.
  • T testosterone
  • chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own.
  • the estrogens for example, not only counteract the effect of the androgens but have a feminizing effect as well.
  • Non-steroidal antiandrogens have also been developed, for example, 4'-nitro-3'- trifluoromethyl-isobutyranilide. See Neri, et al., Endocrinol. 1972, 91 (2).
  • these products though devoid of hormonal effects, compete with all natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host and/or initiate feed-back effects which would cause hyperstimulation of the testes.
  • the principal mediator of androgenic activity in some target organs is 5 ⁇ -dihydrotestosterone ("DHT"), formed locally in the target organ by the action of testosterone-5 ⁇ -reductase (or simply 5 ⁇ -reductase).
  • DHT 5 ⁇ -dihydrotestosterone
  • Inhibitors of 5 ⁇ -reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. See especially United States Patent Nos. 4,377,584, issued March 22, 1983, and 4,760,071, issued July 26, 1988, both assigned to Merck & Co., Inc.
  • the enzyme 5 ⁇ -reductase catalyzes the reduction of testosterone to the more potent androgen, dihydrotestosterone, as shown below:
  • 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 eg. U.S. 4,760,071. Finasteride is currently prescribed for the treatment of benign prostatic hyperplasia (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 hyperplasia
  • 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.
  • isozymes of 5 ⁇ -reductase there are two isozymes of 5 ⁇ -reductase in humans.
  • One isozyme (type 1 or 5 ⁇ -reductase 1) predominates in sebaceous glands of facial and skin tissue and is relatively insensitive to finasteride (see, e.g., G. Harris, et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787- 10791 (Nov. 1992)); the other (type 2 or 5 -reductase 2) predominates in the prostate and is potently inhibited by finasteride.
  • a genus of 16 ⁇ - substituted-4-azasteroids are described in U.S. Patent 5,719,158.
  • 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 highly selective for inhibiting the isozyme 5 ⁇ -reductase 1 associated with the scalp, for use in treating conditions of the skin and scalp.
  • a selective 5 ⁇ -reductase 1 inhibitor could be used in combination with a selective 5 ⁇ -reductase 2 inhibitor such as, e.g., finasteride (PROSCAR®), for therapy in the treatment of hyperandrogenic conditions such as BPH and/or the prevention and treatment of prostatic cancer, and for the treatment of disorders such as acne vulgaris, seborrhea, female hirsutism, and androgenic alopecia.
  • a single drug entity capable of inhibiting both isozymes could be used for treatment of such hyperandrogenic conditions. Therefore it is an object of this invention to provide compounds that have sufficient activity in the inhibition of 5 ⁇ -reductase isozyme 1.
  • the present invention provides the novel compound 7 ⁇ - methyl- 16 ⁇ -((4-methylsulfonyl)phenoxy)-4-aza-5 ⁇ -androst-l-en-3-one, novel compositions containing 7 ⁇ -methyl-16 ⁇ -((4- methylsulfonyl)phenoxy)-4-aza-5 ⁇ -androst-l-en-3-one, methods of its use and methods of its manufacture, where such compound is generally pharmacologically useful as an agent in therapies whose mechanism of action rely on the selective inhibition of the isozyme 5 ⁇ - reductase 1.
  • novel compound of this invention has the structural formula (I):
  • this compound has superior pharmacokinetic properties in primates, including humans. It is an object of this invention to provide a compound that alone or in combination with inhibitors of 5 -reductase 2 is useful in the treatment of benign prostatic hyperplasia, prostatitis, and/or the prevention and treatment of prostatic cancer, as well as in the treatment of prostatitis, the treatment of sweat-related conditions such as apocrine gland sweating, hyperhidrosis, and hydradenitis suppurativa, the treatment of polycystic ovary syndrome, the prevention and treatment of bone loss and related diseases, and the prevention and treatment of premature labor, the treatment of acne vulgaris, the treatment of female hirsutism, and the treatment of androgenic alopecia (also known as androgenetic alopecia and human pattern baldness).
  • the compounds of the present invention are useful in the treatment of benign prostatic hyperplasia, prostatitis, and/or the prevention and treatment of prostatic cancer, as well as in the treatment of prost
  • novel compound of the present invention has the general structural formula I:
  • 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, which includes alleviation of the symptoms of the disorder being treated.
  • crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • the present invention has the objective of providing methods of treating the hyperandrogenic conditions of androgenic alopecia including male pattern 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 and/or a potassium channel opener.
  • treating androgenic alopecia is intended to include the arresting and/or reversing of androgenic alopecia, and the promotion of hair growth.
  • the method of the present invention may also be employed in the treatment of sweat- related conditions such as apocrine gland sweating, hyperhidrosis, and hydradenitis suppurativa, in the treatment of polycystic ovary syndrome, in the treatment and prevention of premature labor, in the prevention and treatment of bone loss, and to treat cardiovascular disease by raising HDL cholesterol levels.
  • 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 the novel compounds of formula I either alone or in combination with a 5 ⁇ - reductase 2 inhibitor.
  • 5 ⁇ -reductase inhibitors in the treatment of sweat related conditions is described in U.S. 5,512,555.
  • Hyperhidrosis is defined as an increase above normal in sweat production. This is diagnosed when sweating occurs under contions where it would not normally be expected or is excessive in response to emotional or thermal stimuli.
  • Hydradenitis suppurativa HS
  • the pathogenesis of HS is felt to be similar to acne: poral occlusion, bacterial colonization, androgenic stimulations and inflammation all seem to be important.
  • the use of 5 ⁇ -reductase inhibitors to increase HDL cholesterol levels is described in PCT application US95/07215, which published as WO96/08239.
  • Preventing and treating bone loss and related diseases relates to methods of treating and/or preventing osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • the present invention has the objective of providing methods of treating hyperandrogenic conditions including androgenic alopecia, male pattern 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, preferably selected from finasteride and epristeride, or a potassium channel opener, or a retinoic acid or derivative thereof.
  • a 5 -reductase 2 inhibitor preferably selected from finasteride and epristeride, 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 5 ⁇ -reductase 2 inhibitor, preferably selected from finasteride and epristeride and another active agent such as a potassium channel opener, or a retinoic acid or derivative therof.
  • a 5 ⁇ -reductase 2 inhibitor preferably selected from finasteride and epristeride
  • another active agent such as a potassium channel opener, or a retinoic acid or derivative therof.
  • 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 the novel compounds of formula I either alone or in combination with a 5 -reductase 2 inhibitor, preferably selected from finasteride and epristeride.
  • treatment may encompass administration of a combination of a compound of formula I with a 5 ⁇ -reductase 2 inhibitor and/or another active agent such as an ⁇ l or an ⁇ la adrenergic receptor antagonist ( ⁇ la receptor antagonists were formerly called ⁇ lc receptor antagonists).
  • the present invention also has a further objective of providing methods of treating acne vulgaris, androgenic alopecia, seborrhea, female hirsutism, benign prostatic hyperplasia, prostatitis and the preventing and/or treating of prostatic cancer, by oral, systemic, parental or topical administration of a combined therapy of 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 present invention further has the objective of treating, preventing, and reducing the risk of premature labor and stopping labor preparatory to Cesarean delivery by oral, rectal, intravaginal, topical or parenteral (including subcutaneous, intramuscular and intravenous administration) administration of a compound of structural formula I either alone or in combination with another 5 ⁇ -reductase inhibitor, either a type 1 inhibitor, a type 2 inhibitor, or a dual inhibitor, other tocolytic agents used in the treatment of preterm labor such as ⁇ - adrenergic agonists (e.g., ritodrine, isoproterenol, terbutaline, albuterol), magnesium sulfate, ethanol, other oxytocin antagonists (e.g., atosiban), calcium transport blockers (e.g., nicardipine, nifedipine), prostaglandin synthesis inhibitors (e.g., indomethacin), nitric oxide donors (e.g.,
  • the compound of structural formula I of the instant invention may also be used in combination with antenatal steroids (e.g., dexamethasone). This particular combination has beneficial effects on the neonate by both decreasing uterine activity to prolong gestation and increasing fetal maturation. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating preterm labor related conditions includes in principle any combination with any pharmaceutical composition useful for treating preterm labor, or stopping labor prior to Cesarean delivery.
  • the present invention further has the objective of treating apocrine gland sweating and hyperhidrosis, by administration of a compound of structural formula I either alone or in combination with a therapeutically effective amount of a topical antiperspirant such as an aluminum salt, e.g. aluminum hydroxide and/or a topical or oral anti-cholinergic agent and optionally including a deodorant.
  • a topical antiperspirant such as an aluminum salt, e.g. aluminum hydroxide and/or a topical or oral anti-cholinergic agent and optionally including
  • Still another objective of the present invention is the treatment of hydradenitis suppurativa by administration of the compounds of structural formula I either alone or in combination with an anticholinergic agent, antibiotics and/or isotretinoin each of which can be administered topically or orally.
  • the active agents can be administered concomitantly, or they each can be administered at separately staggered times.
  • 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 hyperandrogenic 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.
  • intravenous both bolus and infusion
  • intraperitoneal subcutaneous
  • topical with or without occlusion
  • intramuscular form all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • An effective but non-toxic amount of the compound desired can be employed as an antiandrogenic agent.
  • compositions of structural formula I useful in the present invention 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 may be administered systemically, by oral administration or by intravenous or intramuscular injection or topically.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • 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 capsules.
  • 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 incorporated into the mixture.
  • 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.
  • Other dispersing agents which may be employed include glycerin and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • 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 0.1% of the active compound in admixture with a pharmaceutically acceptable carrier.
  • 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, propylene glycol, 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.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • 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 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 the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • 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.
  • 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.
  • doses of the compound of structural formula I useful in the method of the present invention range from 0.01 to 1000 mg per adult human per day. Most preferably, dosages range from 0.1 to 50 mg/day.
  • the compositions are preferably provided in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, particularly 0.01, 0.05, 0.1, 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 1 mg/kg of body weight per day.
  • the active agent 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 of the present invention may be used in the preparation of a medicament useful for the treatment of hyperandrogenic disorders including: acne vulgaris, androgenic alopecia, male pattern baldness, seborrhea, female hirsutism, benign prostatic hyperplasia, prostatitis, prostatic cancer, bone-loss related diseases, polycystic ovary syndrome, and preterm labor.
  • the compounds of the instant invention can be combined with a therapeutically effective amount of another 5 ⁇ -reductase inhibitor, such as finasteride or epristeride, or other 5 ⁇ -reductase inhibitor compounds having type 2 activity, type 1 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 epristeride, or other 5 ⁇ -reductase inhibitor compounds having type 2 activity, type 1 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 or epristeride 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.
  • 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 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.
  • 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 epristeride, or a 5 ⁇ -reductase type 1 inhibitor, 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.
  • a 5 ⁇ -reductase type 2 inhibitor such as finasteride or epristeride
  • a 5 ⁇ -reductase type 1 inhibitor such as a type 1 and type 2 dual inhibitor
  • 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 epristeride, or a 5 ⁇ -reductase type 1 inhibitor, 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.
  • a 5 ⁇ -reductase type 2 inhibitor such as e.g., finasteride
  • an alpha- 1 adrenergic receptor antagonist such as e.g., terazosin, doxazosin, prazosin, bunazosin, indoramin or alfuzosin
  • 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 (formerly called an alpha- lc adrenergic receptor antagonist).
  • a 5 -reductase type 2 inhibitor such as e.g., finasteride
  • an alpha- la adrenergic receptor antagonist previously called an alpha- lc adrenergic receptor antagonist.
  • Compounds which are useful as alpha- la adrenergic receptor antagonists can be identified according to procedures known to those of ordinary skill in the art, for example, as described in PCT/US93/09187 (WO94/08040, published April 14, 1994); PCT/US94/03852 (WO 94/22829, published October 13, 1994); PCT/US94/10162 (WO 95/07075, published March 16, 1995), and U.S. Patent 5,403,847.
  • 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 concurrently, or they each can be administered at separately staggered times.
  • the compound of the present invention can be prepared readily according to the following reaction 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.
  • Ph is phenyl
  • Ac is an acyl group
  • t-Bu is tert-butyl
  • Et is ethyl
  • Me is methyl
  • i-Am is iso-amyl
  • EtOAc is ethyl acetate.
  • the starting material for the process is produced according to the procedures in Miller et al., Tetrahedron Letters 37(20) 3429-3432 (1996) and those in PCT publication WO 95/32215, and is generally known and available in the art.
  • Oxidation of the triol (2) to the dienedione (3) was carried out under Oppenauer conditions with 2-butanone, aluminum isopropoxide, and triethylamine. Concurrent hydrolysis of the aluminum salts and elimination of the 7-OH occurred upon aging with concentrated HC1. Butanone dimers can be removed from the reaction mixture by a water distillation before carrying on to the next step, or the dienedione (3) may be isolated.
  • a chemo- and stereoselective reduction of the dienone (3) to the 7- ⁇ methyl enone (4) was achieved under transfer hydrogenation conditions using 10% Pd/C and cyclohexene as the hydrogen donor.
  • the oxidative cleavage of the enone (4) to the seco acid (5) was carried using sodium periodate and catalytic potassium permangante with sodium carbonate. Introduction of the nitrogen atom into the A ring occurs in refluxing acetic acid with ammonium acetate. BHT was added as a radical inhibitor to prevent decomposition of enelactam ketone (6). Chemo- and stereoselective reduction of the crude enelactam ketone (6) was carried out with L-Selectride (tri-sec-butvl- borohydride) at -5°C.
  • the enelactam alcohol (7) is crystallized from acetonitrile. Running this reaction under more dilute conditions and reducing the level of toluene improves yield. Hydrogenation of the enelactam alcohol (7) is critical because enelactam left behind does not crystallize away from the NH lactam ⁇ -alcohol (8) and impacts on the purity of the final product. Conversion of the lactam ⁇ -alcohol (8) to the lactam ⁇ - alcohol (10) proceeds through the 4-nitrophenyl ester (9) which is not purified.
  • delta- 1 double bond to form the 7 ⁇ - methyl-16 ⁇ -hydroxy-4-aza-5 ⁇ -androst-l-en-3-one (11) proceeds through the process described in U.S. 5,084,574 by reacting with a silylating agent in the present of a quinone.
  • a silylating agent in the present of a quinone.
  • other known processes for insertion of the delta- 1-double bond may be employed, see e.g., U.S. 5,091,534; U.S. 5,120,847; and U.S. 5,021,575.
  • Formation of the 16 ⁇ - mesylate (12) is optionally carried out in a non-polar aprotic solvent such as methylene chloride in the presence of an organic base such as pyridine by reaction with methane sulfonyl chloride.
  • a non-polar aprotic solvent such as methylene chloride
  • an organic base such as pyridine
  • DMAP dimethylaminopyridine
  • the 16 ⁇ -mesylate is converted into the desired 16 ⁇ -(4- (methylsulfonyl)phenoxy) product (13) by reaction with 4- (methylsulfonyl)phenol and cesium carbonate in a polar aprotic solvent such as DMSO.
  • ACN is acetonitrile
  • BHT is 2,6-t- butyl-4-methylphenol
  • ca circa
  • DBU is (1,8- diazabicyclo[5.4.0]undec-7-ene
  • IPA is isopropyl alcohol
  • L- Selectride® is lithium tri-sec-butylborohydride
  • MEK is methyl ethyl ketone
  • NMP is l-methyl-2-pyrrolidinone
  • PDA photodiode array
  • THF is tetrahydrofuran
  • TMEDA is N,N,N',N-
  • TMSC1 is chlorotrimethylsilane.
  • the batch was sampled and reaction completion confirmed by HPLC: ⁇ 0.1A% (1) detected.
  • the Grignard reaction mixture was slowly added to a quenching solution formed by the addition of toluene (70 kg) to a solution of water (146L) and solid citric acid (43.9 kg). Care was made to maintain the temperature at ⁇ 20°C.
  • the reaction vessel and transfer lines were rinsed with THF (10 kg).
  • the mixture was stirred for 15 minutes then settled for 30 minutes. Both phases were cut to drums and the aqueous layer returned to was back extracted with 39 kg of ethyl acetate (agitated for 10 mins, settled for 30 mins). The aqueous layer was cut to waste drums and the THF batch layer was combined with the ethyl acetate layer. 20% sodium carbonate solution (49.2 kg) was added to the stirred solution over 15 minutes then the mixture settled for 30 minutes and the aqueous phase cut to waste. The batch layer was washed with 51.5 kg of 20% sodium chloride solution (agitated for 10 mins, settled for 30 minutes) and the aqueous phase cut to waste.
  • Triethylamine (4.8 kg) was added and the solution concentrated in vacuo to ca 100L. Toluene was added and distillation continued, until the level of THF/ethyl acetate had dropped to ⁇ 0.5vol% by GC. The final volume was made up to 275L, with toluene and the slurry held was used in Example 2.
  • Diene-dione (3) (12.9 kg) was converted to enone (4) (11.69 assay kg, 90.0% yield) in one batch.
  • the enone was not isolated but carried through for use in Example 4 as a solution in t-butanol.
  • To the reaction vessel was added 10% Pd/C (5.32kg, 51.5% water wet), followed by the toluene solution of diene-dione obtained as a product of Example 2, (12.9 kg in 70L), ethanol (38.1L), and cyclohexene (64.9L).
  • the mixture was agitated and DBU (1.28 kg) was added.
  • the batch was filtered through a 45cm plate filter set with a polypropylene cloth, card, and Solka Floe diatomaceous earth (1.5 kg).
  • the filter became blocked after about 50% of the slurry had passed through and had to be dismantled and reset.
  • Enone (4) (11.69 assay kg) was converted to seco acid (10.3 assay kg) in 83% yield in two batches. The product was not isolated but held as a solution in ethyl acetate for Example 5. The oxidizing solution was made up first. Water (150L), sodium periodate (25.54 kg) and potassium permanganate (0.47 kg) were added to the reaction vessel and the mixture warmed to 65°C until all the solids had dissolved (ca 30 minutes).
  • the batch was aged at 60°C for 30 mins then sampled and assayed for starting material (0.07 mg/ml, 99% complete), and then heated at 80°C for 30 mins to decompose excess oxidant.
  • the resulting brown slurry was cooled to 12-15°C, aged for 15 mins then filtered through a 65 cm filter fitted with a polypropylene cloth.
  • the vessel and filter pad were rinsed with aqueous t-butanol (water 70L, t-butanol 35L). The filter removed the bulk of the inorganic solids but some fine brown material passed through.
  • the liquors were returned to the reaction vessel via a 0.5 ⁇ cotton cartridge filter, then the pH of the solution was measured at 9.
  • the cartridge filter became blocked with the fine brown inorganic solid and required changing several times during the transfer. If the pH had been ⁇ 9, it would have been adjusted by addition of sodium carbonate solution.
  • Seco-acid (9.8 kg) was converted to ene lactam ketone (9.07 kg) in a single batch.
  • the product was not isolated, but instead carried through to Example 6 as a toluene solution.
  • a solution of seco-acid (10.3 kg) in ethyl acetate (282 kg) was added to a reaction vessel and concentrated in vacuo to a minimum stirred volume of ca 35L.
  • the solvent was then switched to acetic acid in ⁇ acuo.
  • a total of 80kg of acetic acid was added, and 60L distilled to achieve an ethyl acetate concentration of ⁇ lmg/ml in a final volume of 76L (seco-acid concentration: 124.9 g/L).
  • a portion of this solution (4L, containing 500g of seco-acid) was removed for other studies.
  • the reaction was quenched by addition of 20% aqueous sodium hydroxide solution (37.4 kg), maintaining the temperature at ⁇ 20°C, followed by 27% hydrogen peroxide (19.8 kg) at ⁇ 30°C.
  • the mixture was stirred at 15-20 °C for 1 hr then excess peroxide confirmed using a Merckoquant test strip (E. Merck).
  • the nitrogen purge rate was increased to 15L/min during the hydrogen peroxide addition.
  • 10% aqueous sodium sulfite solution (129 kg) was added, and the batch aged for 15 mins. The absence of peroxide was confirmed, and then the batch was settled for 15 mins and the aqueous phase cut to waste.
  • 10% aqueous sodium chloride solution (58 kg) was added, the mixture agitated for 5 mins, settled for 15 mins and the aqueous phase cut to waste. The brine wash was repeated.
  • the organic phase (128.3 kg) was transferred to another reaction vessel via a 0.5m cotton cartridge filter.
  • the batch was concentrated to ca 40L at atmospheric pressure then the solvent was switched to acetonitrile.
  • a total of 200 kg of acetonitrile was charged and the mixture distilled to a final volume of 65L.
  • a sample was taken and toluene level (spec-200 mg/ml, measured-0.7 mg/ml) and KF(spec-400 mg/L, measured-73 mg/L) measured.
  • Ene-lactam alcohol (750 g) was dissolved in a mixture of
  • IPA IPA (10L) and water (1.6L) by warming to 30-40°C in a 20L flask.
  • BHT (3 g) and 50% wet 10%Pd/C (375 g) was added and the mixture charged using vacuum via the dip-leg to a 20L autoclave, and then rinsed in with IPA (1L).
  • the slurry was stirred under an atmosphere of hydrogen (60psig) at 50°C for 6 hours then at 68°C for 16 hrs.
  • the batch was sampled via the dip-leg and checked for completion by HPLC (spec ⁇ 0.05A% starting material). If the end point had not been reached, stirring under hydrogen was continued.
  • the batch was cooled to 30-40°C, flushed with nitrogen several times, then transferred from the autoclave and filtered through Solka Floe (1 kg).
  • the autoclave and filter pad were washed with 1:10 water/IPA (2L), and the combined filtrates stored.
  • the procedure above was repeated 10 times and the 10 batches of filtrate were combined and concentrated at atmospheric pressure to a volume of ca 25L.
  • water (42L) was added over 45 minutes and the batch cooled to 5°C and aged for 1 hr.
  • the solid was collected on a 33cm filter fitted with a polypropylene cloth and then washed with 4:1 water/IPA (10L).
  • the damp solid was transferred to trays and dried in vacuo at 35°C overnight to give the lactam alcohol (8).
  • the impure 4-nitrophenyl ester was suspended in EtOH (6.8 L) and 0.5 N NaOH (1.3 L, 0.65 moles) was added. The mixture was stirred mechanically at room temperature for 1.5 hr in a N atmosphere. Most of the EtOH was removed in ⁇ acuo. The residue was diluted with HO and extracted three times with CH 2 Cl2. The combined CH2CI2 extracts were washed once with IN HC1 and saturated brine. The aqueous washes were extracted twice with CH 2 C1 2 . The combined CH 2 Cl2 extracts were dried (MgSO) and concentrated in ⁇ acuo.
  • the organic phase was washed once with saturatedNaHCO andsaturated NaCl solutions.
  • the combined aqueous phases were extracted twice withCH ⁇ C ⁇ .
  • the combined organic phases were evaporated in ⁇ acuo without drying. The residue was dissolved in
  • the material was purified by column chromatography on silica gel (1.6 Kg).
  • the steroid was dissolved in a small amount of MeOH-CH 2 Cl2 for loading on the column; then elution with 5-40% acetone-C ⁇ C ⁇ and 5-
  • TLC (30% acetone-C ⁇ C ⁇ ) indicated a little 11 was still present; small quantities (10% of initial amounts) of pyridine, DMAP, and MsCl were added. After 2.5 hr at room temperature no 11 was detectable by TLC.
  • the reaction mixture was washed with water (2 L), and the aqueous wash back extracted with CH 2 C1 2 .
  • the combined CH 2 C1 2 phases were washed with IN HC1 (1 L), and the acid wash was back extracted with CH 2 C1 2 .
  • the combined CH 2 C1 2 phases were washed once with water, saturated NaHCO, and saturated NaCl and dried (MgSO). Evaporation in ⁇ acuo gave crude 12.
  • the material was purified by column chromatography on silica gel (1.6 Kg). Elution with 10-30% acetone-CH 2 Cl 2 and evaporation in ⁇ acuo gave the pure material which was recrystallized from CH2CI2 -hexane to give the title compound as a
  • a magnetically stirred suspension of 7 ⁇ -methyl-16 ⁇ - methanesulfonyloxy-4-aza-5 -androst-l-en-3-one (12) (1.14 g, 3 mmoles), 4-(methylsulfonyl)phenol (Acros) (0.542 g, 3.15 mmoles), and cesium carbonate (1.47 g, 4.5 mmoles) in DMSO (6 ml) was heated at 65° for 6 hours in a N2 atmosphere.
  • the cooled suspension was diluted with water (60 ml), and the suspension stirred at room temperature for 30 min.
  • the cream colored solid was filtered, slurry-washed three times with water, and dried (house vacuum, 45°, 16 hrs) to give crude 13.
  • EXAMPLE 12 ORAL COMPOSITION
  • 5 mg of 7 ⁇ -methyl-16 ⁇ -(4- methylsulfonyl)phenoxy)-4-aza-5 ⁇ -androst-l-en-3-one is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • 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 phenylmethyl- sulfonyl fluoride, 1 mM dithiothreitol (DTT) containing 0.25 M sucrose using a Potter-Elvehjem homogenizer.
  • a crude nuclear pellet was prepared by centrifugation of the homogenate at l,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 5 ⁇ -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- 3 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. 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 rpm 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, 6.8-7.2 min; androstanediol, 7.6-8.0 min; T, 9.1-9.7 min).
  • 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 A120 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 activity to 50% of the control. IC50 values were determined using a 6 point titration where the concentration of the inhibitor was varied from 0.1 to 1000 nM.
  • Representative compounds of this invention were tested in the above desribed assay for 5 ⁇ -reductase type 1 and type 2 inhibition.
  • the compounds For the inhibition of 5 ⁇ -reductase type 1, the compounds have IC50 values lower than 600 nM, with the majority of compounds having IC50 values ranging from about 0.3 nM to about 200 nM.
  • the same compounds For the inhibition of 5 ⁇ -reductase type 2, the same compounds have IC50 values greater than about 155 nM, with the majority of compounds having IC50 values greater than 1000 nM.
  • a compound referrred to herein as a 5 ⁇ -reductase 2 inhibitor is a compound that shows inhibition of the 5 -reductase 2 isozyme in the above-described assay.
  • 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 alpha reductase activity, and it is therefore possible to test inhibitors of 5 alpha 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. 110:685- 689, 1984 and Itami, S. et.
  • the pellets are resuspended in 20 mM Tris-HCl buffer, pH 7.5, at 4°C, containing 250 mM sucrose, ImM MgCl2, and 2mM 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 supernatant is centrifuged at 10,000 x g for 15 min to produce a crude mitochondrial pellet.
  • the supernatant 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
  • Each tube contains 50-100 ⁇ g of cellular protein.
  • Incubation is carried out at 37°C for 30 min. During this incubation, the reaction is proportional to the time.
  • citrate buffer is used at pH 4.5-6.5
  • the Tris HC1 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.
  • [l,2- 3 H]-testosterone (55.2 Ci/mmol) is obtainable from New England Nuclear Corporation (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.
  • Rats are a variety of rat that has stunted hair growth, brown colored seborrhea covering their entire back skin and abnormally increased sebum production after puberty that has been demonstrataed to be due to circulating androgens.
  • 0.1, 0.05 and 0.025% solutions of a selected 5 ⁇ -reductase inhibitor of interest are prepared in a vehicle of propylene glycol, isopropanol, isopropyl myristate and water (50/30/2/18%), and is topically applied onto the backs of adult male fuzzy rats, 0.2 ml per animal daily for 4 weeks. Controls receive the vehicle alone and 5 of them are castrated.
  • bromodeoxyuridine (BrdU, 200 mg/kg) is intraperitoneally injected 2 hours before sacrifice.
  • the skin tissues are incubated with EDTA (20 mM) in phosphate buffer, 1.5 hours at 37°C.
  • the pilo-sebaceous unit attached to the epidermis is striped from the dermis and fixed with formalin for immuno-staining of BrdU.
  • DNA synthesis cells showing a BrdU-positive nucleus are located in the outer glandular border. The number of S-phase cells per lobe is determined with a micro-image apparatus.
  • Haircount target area Equipment Film: Kodak-T-max 24 exposure each of same emulsion lot number
  • Photographic Procedure In these clinical photographs, the only variable allowed is the haircount. Film emulsion, lighting, framing, exposure, and reproduction ratios are held constant.
  • 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 interior to the center of the vertex bald spot, using a commercial tattooing machine or manually (needle and ink). An area approximately one square inch in size, centered at the tattoo at the leading edge of the balding area, is clipped short ( ⁇ 2mm). Cut hairs are removed from the area to be photographed, using tape. Compressed air and/or ethanol wipes may also be used to facilitate removal of cut hairs.
  • a trained technician places a transparency over the photograph 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.
  • baseline and Month 6 photographs are counted and data analyzed for interim analysis.
  • Month 12 photographs are counted and data analyzed for the primary endpoint.
  • Methodology for detection of hair growth is also described in Olsen, E.A. and Delong, E., J. American Academy of Dermatology. Vol. 23, p. 470 (1990).

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Abstract

L'invention se rapporte à un composé 7β-méthyl-16β-((4-méthylsulfonyl)-phénoxy)-4-aza-5α-androst-1-en-3-one qui est utilisé comme inhibiteur de l'iso-enzyme 5α-réductase 1 et qui s'avère utile, seul ou en combinaison avec un inhibiteur de 5α-réductase 2, pour le traitement des troubles associés à une hyperandrogénie tels que l'acné simple, la séborrhée, l'hirsutisme féminin, la calvitie de type masculin et l'hyperplasie prostatique bénigne. L'invention se rapporte également à des compositions pharmaceutiques contenant ce composé.
PCT/US1999/010159 1998-05-14 1999-05-10 7β-METHYL-16β-((4-METHYLSULFONYL)-PHENOXY)-4-AZA-5α-ANDROST-1-EN-3-ONE UTILISEE COMME INHIBITEUR D'ISO-ENZYME 5α-REDUCTASE 1 WO1999058550A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU39779/99A AU3977999A (en) 1998-05-14 1999-05-10 7beta-methyl-16beta-((4-methylsulfonyl)-phenoxy)-4-aza-5alph a-androst-1-en-3-oneas a 5-alpha-reductase isozyme inhibitor

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US8545098P 1998-05-14 1998-05-14
US60/085,450 1998-05-14
GB9812687.3 1998-06-12
GBGB9812687.3A GB9812687D0 (en) 1998-06-12 1998-06-12 16-substituted-4-aza-androstane 5-alpha-reductase isozyme 1 inhibitor

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WO1999058550A1 true WO1999058550A1 (fr) 1999-11-18

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011254A1 (fr) * 1993-10-21 1995-04-27 Merck & Co., Inc. INHIBITEURS DE L'ISOZYME 5α-REDUCTASE 1 DE 4-AZA-ANDROSTANE-5 A SUBSTITUTION EN POSITION 16

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011254A1 (fr) * 1993-10-21 1995-04-27 Merck & Co., Inc. INHIBITEURS DE L'ISOZYME 5α-REDUCTASE 1 DE 4-AZA-ANDROSTANE-5 A SUBSTITUTION EN POSITION 16

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LI X ET AL: "SYNTHESIS AND IN VITRO ACTIVITY OF 17BETA-(N-ALKYL/ARYLFORMAMIDO)- AND 17BETA- (N-ALKYL/ARYL)ALKYL/ARYLAMIDO-4-METHYL-AZA-3-OXO -5ALPHA- ANDROSTAN-3-ONES AS INHIBITORS OF HUMAN 5ALPHA-REDUCTASES AND ANTAGONISTS OF THE ANDROGEN RECEPTOR", JOURNAL OF MEDICINAL CHEMISTRY, vol. 38, no. 7, 31 March 1995 (1995-03-31), pages 1158 - 1173, XP002030536, ISSN: 0022-2623 *

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