USRE39056E1 - 4-Azasteroids for treatment of hyperandrogenic conditions - Google Patents
4-Azasteroids for treatment of hyperandrogenic conditions Download PDFInfo
- Publication number
- USRE39056E1 USRE39056E1 US10/020,740 US2074096A USRE39056E US RE39056 E1 USRE39056 E1 US RE39056E1 US 2074096 A US2074096 A US 2074096A US RE39056 E USRE39056 E US RE39056E
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- Prior art keywords
- methyl
- aza
- androst
- ene
- oxo
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Classifications
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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
- A61P5/28—Antiandrogens
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 hyperplasia.
- hyperandrogenic diseases such as acne vulgaris, seborrhea, female hirsutism, also called androgenic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia.
- 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-1-ene-3-one) as shown below, is a potent inhibitor of the human prostate enzyme.
- PROSCAR® finasteride is known to be useful in the treatment of hyperandrogenic conditions; see e.g. U.S. Pat. No. 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 Oct. 5, 1988; EP 0 285,383, published Oct. 5, 1988; Canadian Patent no. 1,302,277; and Canadian Patent no. 1,302,276.
- Finasteride is a 5 ⁇ -reductase inhibitor
- the enzyme 5 ⁇ -reductase catalyzes the reduction of testosterone to the more potent androgen, dihydrotestosterone, as shown below:
- DHT 5 ⁇ -dihydrotestosterone
- isozymes of 5 ⁇ -reductase there are two isozymes of 5 ⁇ -reductase in humans.
- One isozyme (type 1) predominates in sebacious glands of facial and skin tissue and is relatively insensitive to finasterides, the other (type 2) predominates in the prostate and is potently inhibited by finasteride.
- European patent publication EP 0 547 691 discloses 17-substituted 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) and a pharmaceutically acceptable salts and esters thereof which are potent antiandrogens. These compounds inhibit 5 ⁇ -reductase type 1 and 2.
- 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 hyperplasia, acne vulgaris, seborrhea, androgenic alopecia (also called androgenic alopecia) which includes male- and female-pattern baldness, female hirsutism, and prostatitis.
- Another object of this invention is to provide compounds of formula I in combination with other active agents, for example a 5 ⁇ -reductase type 2 inhibitor, such as finasteride, or a potassium channel operator, such as minioxidil, or a retionic acid or a derivative thereof, or an ⁇ 1- or ⁇ 1 ⁇ -adrenergic receptor antagonist, or combinations of such other 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 operator, such as minioxidil, or a retionic acid or a derivative thereof, or an ⁇ 1- or ⁇ 1 ⁇ -adrenergic receptor antagonist, or combinations of such other 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.
- novel compounds of the present invention have structural Formula I: or a pharmaceutically acceptable salt or ester thereof, wherein:
- R 3 is diarylmethyl, either unsubstituted or substituted on an aryl moiety with one to three substituents independently selected from
- Examples of compounds of this subclass exhibiting both 5 ⁇ -reductase type 1 and type 2 inhibitory and androgen receptor antagonistic activity are:
- R 1 is methyl
- R 3 is heteroaryl, either unsubstituted or substituted with one to three substituents independently selected from:
- heteroaryl is pyridyl pyrazinyl pyrazolyl, or thiazolyl.
- R 3 is naphthyl, either unsubstituted or substituted with one to three substituents independently selected from:
- R 3 is unsubstituted naphthyl.
- Examples of compounds of this class include:
- alkyd 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), propyls, butyl, pentyl, hexyls, heptyl, octyls, 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, isopropxy, 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 and 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, and acidic salt, i.e., hydrochloride, 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 polymorphs 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 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, 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 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 hyperplasia, prostatis, 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 ⁇ 1 or an ⁇ 1 ⁇ adrenergic receptor antagonist.
- the present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formations 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.
- 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.
- the daily dosage of the products may be varied over a range from 0.01 to 1,000 mg per adult human/per day.
- the compositions are preferably provided in the form of tablets containing 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 mgas/g mg/kg of body weight per day.
- the range is more particularly from about 0.001 msg/kg 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 the 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 orals, systemics, or parental 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, ran 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. Pat. Nos. 4,596,812, 4,139,619 and WO 92/02225, published Feb. 20, 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-1 ⁇ 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 ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as “carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
- 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.
- suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
- 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-celluose and the like.
- suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-celluose 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 preparations containing the active drug component can be admixed with a variety of carrier materials well known in the art such as, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, PPG2 myristyl propionate, and the like, to form, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotionss, 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 unilamellare vesicles and multilamellar vesicles.
- Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
- the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, 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 3 4-methyl-3-oxo-4-aza-5 ⁇ -androst-1-ene-17 ⁇ -(2-thiopyridine) carboxylate
- 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 1,500 ⁇ G 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 mM [7- 3 H]-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- 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 established 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 655 ⁇ 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.
- IC 50 values represent the concentration of inhibitor required to decrease enzyme conversion of testosterone to dihydrotestosterone by 50% of the control. IC 50 values were determined using a 6 point titration where the concentration of the inhibitor was varied from 0.1 to 1000 nM. 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 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 Dernmal Papilla Cells From Human Hair Follicles,” Br. J. Deimatol., 110:685-689 (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 with phosphate-buffered saline, scraped from dishes by rubber policemen, and collected into a centrifuge tube.
- the cell suspensions are centrifuged at 1,500 rpm 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 MgCl 2 , and 2 mM CaCl 2 , 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 ⁇ g for 10 min. to yield a crude nuclear pellet.
- the resultant supernatant is centrifuged at 10,000 ⁇ g for 15 min. to produce a crude mitochondrial pellet.
- the supernatant is centrifuged at 100,000 ⁇ 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 [ 3 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 the 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- 3 H]-osterone (55.2 Ci/mmol) is obtainable from New England Nuclear Corporation (Boston, Mass.) and unlabeled steroids can be purchased from Sigma Chemical Company (St. Louis, Mo.). Fetal calf serum is obtainable from Hazleton (Lenaza, Kans.). All other chemicals are of reagent grade.
- 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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Abstract
and pharmacologically acceptable salts and esters thereof possess 5α-reductase inhibitory activity. These compounds inhibit 5α-reductase type 1 and type 2. 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 hyperplasia, acne vulgaris, seborrhea, androgenic alopecia (also called androgenetic alopecia) which includes male- and female-pattern baldness, female hirsutism, and prostatitis. A class of compounds of the present invention are also potent antiandrogens. The present invention also relates to novel compositions containing such compounds, methods of their use and methods of their manufacture.
Description
Under the trade name PROSCAR®, finasteride is known to be useful in the treatment of hyperandrogenic conditions; see e.g. U.S. Pat. No. 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 Oct. 5, 1988; EP 0 285,383, published Oct. 5, 1988; Canadian Patent no. 1,302,277; and Canadian Patent no. 1,302,276.
and a pharmaceutically acceptable salts and esters thereof which are potent antiandrogens. These compounds inhibit 5α-reductase type 1 and 2. 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 hyperplasia, acne vulgaris, seborrhea, androgenic alopecia (also called androgenic alopecia) which includes male- and female-pattern baldness, female hirsutism, and prostatitis.
or a pharmaceutically acceptable salt or ester thereof, wherein:
-
- R1 is selected from methyl and ethyl;
- R2 is selected from
- (a) H, and
- (b) C3-6 alkyl;
- R3 is selected from:
- (a) diarylmethyl, either unsubstituted or substituted on one or both of the aryl ringses with one to three substituents independently selected from:
- (1) halo (F, Cl, Br, I),
- (2) C1-2 alkyl;
- (3) trifluoromethyl,
- (4) nitro,
- (5) hydroxy,
- (6) cyano,
- (7) phenyl,
- (8) C1-2 alkyloxy,
- (9) heteroaryl,
- (10) S(O)nR4, wherein n is selected from 0, 1, and 2, and
- (11) alkyoxy;
- (b) phenyl substituted with one to three substituents independently selected from:
- (1) halo (F, Cl, Br, I),
- (2) C1-2 alkyl;
- (3) trifluoromethyl,
- (4) nitro,
- (5) hydroxy,
- (6) cyano,
- (7) phenyl,
- (8) C1-2 alkyloxy,
- (9) heteroaryl,
- (10) S(O)nR4, wherein n is selected from 0, 1, and 2, and
- (11) alkyoxy;
- (c) heteroaryl, either unsubstituted or substituted with one to three substituents independently selected from:
- (1) halo (F, Cl, Br, I),
- (2) C1-2 alkyl;
- (3) trifluoromethyl,
- (4) nitro,
- (5) hydroxy,
- (6) cyano,
- (7) amino,
- (8) C1-2 alkyloxy,
- (9) phenyls, and
- (10) heteroaryl;
- (d) naphthyl, either unsubstituted or substituted with one to three substituents independently selected from:
- (1) halo (F, Cl, Br, I),
- (2) C1-2 alkyl;
- (3) trifluoromethyl,
- (4) nitro,
- (5) hydroxy,
- (6) cyano,
- (7) amino,
- (8) C1-2 alkyloxy, and
- (9) S(O)nR4, wherein n is selected from 0, 1, and 2; and
- (a) diarylmethyl, either unsubstituted or substituted on one or both of the aryl ringses with one to three substituents independently selected from:
- R4 is selected from:
- (a) C1-4 alkyl,
- (b) phenyl, and
- (c) heteroaryl.
-
- (1) halo (F, Cl, Br, I),
- (2) C1-2 alkyl;
- (3) trifluoromethyl,
- (4) nitro,
- (5) hydroxy
- (6) cyano,
- (7) phenyl,
- (8) C1-2 alkyloxy,
- (9) heteroaryl,
- (10) S(O)nR4, wherein n is selected from 0, 1, and 2, and
- (11) alkyoxy.
-
- N-(diphenylmethyl)-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide;
- N-(diphenylmethyl)-N-methyls-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide.
-
- (1) halo, (F, Cl, Br, I),
- (2) C1-2 alkyl;
- (3) trifluoromethyl,
- (4) nitro,
- (5) hydroxy,
- (6) cyano,
- (7) phenyl,
- (8) C1-2 alkyloxy,
- (9) heteroaryl,
- (10) S(O)nR4, wherein n is selected from 0, 1, and 2, and
- (11) alkyoxy;
-
- N-(2-methylphenyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide;
- N-(2-methoxyphenyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide;
- N-(2-chlorophenyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide;
- N-(4-chlorophenyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide;
- N-(2-fluorophenyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide;
- N-(2-trifluoromethyl-phenyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide;
- N-(2,5-bistrifluoromethyl-phenyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide;
- N-(2-biphenyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide;
- N-(4-biphenyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide;
-
- (1) halo (F, Cl, Br, I),
- (2) C1-2 alkyl;
- (3) trifluoromethyl,
- (4) nitro,
- (5) hydroxy,
- (6) cyano,
- (7) amino,
- (8) C1-2 alkyloxy,
- (9) phenyl, and
- (10) heteroaryl;
-
- N-(4-pyridyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
- N-(3-pyridyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
- N-(pyrazinyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
- N-(3-pyrazoyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide, and
- N-(2-thiazolyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide.
-
- (1) halo (F, Cl, Br, I),
- (2) C1-2 alkyl;
- (3) trifluoromethyl,
- (4) nitro,
- (5) hydroxy,
- (6) cyano,
- (7) amino,
- (8) C1-2 alkyloxy, and
- (9) S(O)nR4, wherein n is selected from 0, 1, and 2.
-
- N-(2-naphthyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide, and
- N-(1-naphthyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide,
|
400 MHZ, 1H-NMR (δ ppm) CDCl3 |
Ex. | Mass | |||||||
No. | R | C18 | C19 | C5 | NCH3 | Δ2 | other | spec |
2 | 2- | 0.74s | 0.92s | 3.34m | 2.94s | 5.84d | 3.87s | 437 |
OMe | 6.68d | (OMe) | (M + 1) | |||||
3 | 2-F | 0.74s | 0.90s | 3.34m | 2.93s | 5.50d | 425 | |
6.67d | (M + 1) | |||||||
4 | 2- | 0.77s | 0.91s | 3.35m | 2.94s | 5.84d | 475 | |
CF3 | 6.77d | (M + 1) | ||||||
5 | 2-Me | 0.79s | 0.91s | 3.35m | 2.94s | 5.85d | 2.24s | 421 |
6.67d | (2-Me) | (M + 1) | ||||||
6 | 2-Cl | 0.75s | 0.91s | 3.34m | 2.94s | 5.84d | 441 | |
6.68d | (M + 1) | |||||||
7 | 2,5- | 0.77s | 0.91s | 3.34m | 2.94s | 5.84d | 543 | |
bis | 6.67d | (M + 1) | ||||||
CF3 | ||||||||
8 | 2- | 0.62s | 0.87s | 3.30m | 2.92s | 5.86d | 483 | |
phen- | 6.65d | (M + 1) | ||||||
yl | ||||||||
9 | 4- | 0.78s | 0.91s | 3.35m | 2.94s | 5.86d | 483 | |
phen- | 6.67d | (M + 1) | ||||||
yl | ||||||||
|
400 MHZ, 1H-NMR (δ ppm) CDCl3 |
Ex. | Mass | |||||||
No. | R3 | C18 | C19 | C5 | NCH3 | Δ2 | other | spec |
12 | 4-pyri- | 0.75s | 0.90s | 3.33m | 2.94s | 5.85d | 2408 | |
dyl | 6.66d | (M + 1) | ||||||
13 | 3-pyri- | 0.76s | 0.91s | 3.34m | 2.94s | 5.85d | 408 | |
dyl | 6.67d | (M + 1) | ||||||
14 | pyra- | 0.76s | 0.91s | 3.34m | 2.94s | 5.85d | 409 | |
zine | 6.66d | (M + 1) | ||||||
15 | 3-pyra- | 0.76s | 0.89s | 3.33m | 2.94s | 5.83d | 397 | |
zole | 6.65d | (M + 1) | ||||||
16 | 2-thia- | 0.73s | 0.90s | 3.34m | 2.93s | 5.84d | 414 | |
zole | 6.65d | (M + 1) | ||||||
17 | 2-naph- | 0.80s | 0.91s | 3.36m | 2.95s | 5.89d | 457 | |
thyl | 6.69d | (M + 1) | ||||||
18 | 1-naph- | 0.85s | 0.94s | 3.35m | 2.96s | 5.85d | 457 | |
thyl | 6.69d | (M + 1) | ||||||
Ex | IC50 (nM, human) |
No. | R3 | R2 | Type 1 5aR | Type 2 5aR | hAR |
1 | 4-chlorophenyl | H | 40 | 100 | 10 |
2 | 2-methoxyphenyl | H | 20 | 100 | 40 |
3 | 2-fluorophenyl | H | 20 | 60 | 9 |
4 | 2-CF3-phenyl | H | 2 | 7 | 30 |
5 | 2-methylphenyl | H | 20 | 20 | 30 |
6 | 2-chlorophenyl | H | 6 | 10 | 8 |
7 | 2.5-bisCF3- | H | 4 | 20 | 20 |
phenyl | |||||
10 | diphenylmethyl | H | 20 | 2 | 40 |
11 | diphenylmethyl | CH3 | 3 | 0.3 | 850 |
Location: | ID card |
Haircount target area | |
Equipment: | Film: Kodak-T-max 24 exposure each of same emulsion lot |
number | |
Camera: | Nikon N-6000 |
Lens: | Nikkor 60 mm f2.8 |
Flashes: | Nikon SB-21B Macroflash |
Device: | registration device |
Photographic Procedure:
-
- 1. The haircount area on the patient is prepared as follows:
- A small (˜1 mm) dot tatoo 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). An area approximately one square inch in size, centered at the tattoo at the leading edge of the balding area, is clipped short (˜2 mm). Cut hairs are removed from the area to be photographeds, using tape. Compressed air and/or ethanol wipes may also be used to facilitate removal of cut hairs.
- 2. Magnification: 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).
- 1. The haircount area on the patient is prepared as follows:
Locations: | Color card/patient Id |
Global photograph | |
Equipment: | Film: Kodachrome KR-64 24 exposure each of same |
emulsion lot number | |
Camera: | Nikon N-6000 |
Lens: | Nikkor 60 mm f2.8 |
Flashes: | Nikon SB-23 |
Photographic Procedure
-
- Aperture: Every photograph will be taken at f11.
- Film: Kodachrome (24 exposure) is used.
Claims (15)
Applications Claiming Priority (3)
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US382695P | 1995-09-15 | 1995-09-15 | |
US09/029,926 US6001844A (en) | 1995-09-15 | 1996-09-11 | 4-Azasteroids for treatment of hyperandrogenic conditions |
PCT/US1996/014564 WO1997010217A1 (en) | 1995-09-15 | 1996-09-11 | 4-azasteroids for treatment of hyperandrogenic conditions |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US09/029,926 Reissue US6001844A (en) | 1995-09-15 | 1996-09-11 | 4-Azasteroids for treatment of hyperandrogenic conditions |
Publications (1)
Publication Number | Publication Date |
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USRE39056E1 true USRE39056E1 (en) | 2006-04-04 |
Family
ID=26672243
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US09/029,926 Ceased US6001844A (en) | 1995-09-15 | 1996-09-11 | 4-Azasteroids for treatment of hyperandrogenic conditions |
US10/020,740 Expired - Fee Related USRE39056E1 (en) | 1995-09-15 | 1996-09-11 | 4-Azasteroids for treatment of hyperandrogenic conditions |
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US09/029,926 Ceased US6001844A (en) | 1995-09-15 | 1996-09-11 | 4-Azasteroids for treatment of hyperandrogenic conditions |
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US (2) | US6001844A (en) |
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US6645974B2 (en) * | 2001-07-31 | 2003-11-11 | Merck & Co., Inc. | Androgen receptor modulators and methods for use thereof |
EP1622567B1 (en) * | 2003-05-07 | 2013-07-24 | Merck Sharp & Dohme Corp. | Androgen receptor modulators and methods of use thereof |
US20080125403A1 (en) * | 2004-04-02 | 2008-05-29 | Merck & Co., Inc. | Method of Treating Men with Metabolic and Anthropometric Disorders |
US20090123571A1 (en) | 2005-03-25 | 2009-05-14 | Alan Meehan | Method of treating men with testosterone supplement and 5alpha-reductase inhibitor |
US20110092470A1 (en) * | 2006-03-21 | 2011-04-21 | Alan Meehan | Method of treating men with erectile dysfunction |
CN103554213A (en) * | 2012-01-05 | 2014-02-05 | 中国药科大学 | 4-oxa-androstane-3-ketone-17beta-amides derivatives, as well as preparation method and medical applications thereof |
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