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WO1996030391A1 - 6-azacholesten-3-ones substituees - Google Patents

6-azacholesten-3-ones substituees Download PDF

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Publication number
WO1996030391A1
WO1996030391A1 PCT/US1996/004042 US9604042W WO9630391A1 WO 1996030391 A1 WO1996030391 A1 WO 1996030391A1 US 9604042 W US9604042 W US 9604042W WO 9630391 A1 WO9630391 A1 WO 9630391A1
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Prior art keywords
compound
pharmaceutical formulation
safe
formula
mediated disease
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Application number
PCT/US1996/004042
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English (en)
Inventor
Curt Dale Haffner
Stephen Vernon Frye
Original Assignee
Glaxo Wellcome Inc.
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Application filed by Glaxo Wellcome Inc. filed Critical Glaxo Wellcome Inc.
Priority to AU53230/96A priority Critical patent/AU5323096A/en
Publication of WO1996030391A1 publication Critical patent/WO1996030391A1/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

  • the present invention relates to 17 ⁇ -substituted-6-azacholesten-3- ones and their use as 5 ⁇ -testosterone reductase inhibitors.
  • Androgens are responsible for a variety of physiological functions in both males and females. Androgen action is mediated by specific intracellular hormone receptors expressed in androgen responsive cells. Testosterone, the major circulating androgen, is secreted by Leydig cells of the testes under the stimulation of pituitary-derived luteinizing hormone. However, reduction of the 4, 5 double bond of testosterone to dihydrotestosterone (DHT) is required in some target tissues, such as prostate and skin, for androgen action. Steroid 5 ⁇ -reductases in target tissues catalyze conversion of testosterone to DHT in an NADPH dependent fashion as shown below in Scheme A.
  • DHT dihydrotestosterone
  • isozyme specific and dual inhibitors of the two isozymes of 5 ⁇ - reductase will depend upon the type of disease treated (benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness, or hirsutism) as well as the stage of the disease (prevention versus treatment) and the anticipated side-effects in the intended patients (for example treatment of acne vulgaris in pubescent males).
  • testosterone 5 ⁇ - reductase inhibitors (5 ⁇ -reductase inhibitors) have been the subject of active research worldwide. For example, see: Hsia, S. and Voight, W., /. Invest. Derm., 62, 224 (1973); Robaire, B. et al, J. Steroid Biochem., 8, 307 (1977); Petrow, V. et al, Steroids, 38, 121 (1981); Liang, T. et al, J. Steroid Biochem., 19, 385 (1983); Holt, D. et al, J. Med. Chem., 33, 937 (1990); U.S. Patent No. 4,377,584, U.S. Patent No.
  • R1 and R ⁇ independently represent hydrogen or alkyl and the bond between carbons 1 and 2 is a single or a double bond, or R and R ⁇ may be joined together to form a fused cyclopropane ring;
  • R3 represents hydrogen, alkyl or halogen
  • R 4 and R 5 represent independently hydrogen or alkyl
  • R6 represents alkyl; and the pharmaceutically acceptable salts and solvates thereof.
  • R*, R ⁇ , R3 R4 are hydrogen, R ⁇ is hydrogen or methyl, and R 6 is alkyl, more particularly CH3CH(CH2)3CH(CH3)2-
  • safe and therapeutically effective amount means a sufficient amount of a drug , pharmaceutical agent or pharmaceutical formulation to abate or inhibit testosterone-5 ⁇ -reductases without harming the tissues of a mammal, including a human to which the drug is administered.
  • alkyl alone or in combination, as used herein means a linear or branched chain saturated hydrocarbon group from Cl-Cl2.
  • exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-hexyl, and the like.
  • room temperature means from about 20 °C to about 30 °C.
  • other aspects of the invention include: a method of inhibiting testosterone-5 ⁇ -reductases comprising contacting testosterone-5 ⁇ -reductases with a compound of Formula (I); a method of treating androgen responsive or mediated disease comprising administering a safe and therapeutically effective amount of a compound of Formula (I) to a patient in need of such treatment; pharmaceutical formulations containing a compound of Formula (I) as an active ingredient; a method of treating androgen responsive or mediated disease comprising administering a safe and therapeutically effective amount of a compound of Formula (I) to a patient in need of such treatment in combination with an anti-androgen such as flutamide; a method of treating benign prostatic hyperplasia comprising administering a safe and therapeutically effective amount of a compound of Formula (I) to a patient in need of such treatment in combination with an alpha 1 adrenergic receptor blocker (e.g. terazosin); a method of treating benign prostatic hyperplasia comprising administer
  • the protecting groups used in the preparation of compounds of Formula (I) may be used in a conventional manner. See, for example, Protective Groups in Organic Chemistry, Ed. J.F.W. McOmie, Plenum Press, London (1973) or Protective Groups in Organic Synthesis, Theodora Green, John Wiley and Sons, New York (1981).
  • Conventional amino protecting groups may include, for example, arylalkyl groups, such as benzyl and acyl groups, such as N- benzyloxycarbonyl or t-butoxycarbonyl.
  • arylalkyl groups such as benzyl and acyl groups, such as N- benzyloxycarbonyl or t-butoxycarbonyl.
  • R4 represents hydrogen
  • Hydroxy groups may be protected, for example, by benzyl, diphenylmethyl or triphenylmethyl groups, acyl groups, such as acetyl, silicon protecting groups, such as triisopropysilyl or t-butyldimethylsilyl groups, or as tetrahydropyran derivatives.
  • An arylalkyl group such as benzyl may be cleaved by hydrogenolysis in the presence of a catalyst, e.g., palladium on charcoal; an acyl group such as N-benzyloxycarbonyl may be removed by hydrolysis with, for example, hydrogen bromide in acetic acid or by reduction, for example by catalytic hydrogenation; silicon protecting groups may be removed, for example, by treatment with fluoride ion or by hydrolysis under acidic conditions; tetrahydropyran groups may be cleaved by hydrolysis under acidic conditions.
  • a catalyst e.g., palladium on charcoal
  • an acyl group such as N-benzyloxycarbonyl
  • silicon protecting groups may be removed, for example, by treatment with fluoride ion or by hydrolysis under acidic conditions
  • tetrahydropyran groups may be cleaved by hydrolysis under acidic conditions.
  • the present Invention includes all possible stereoisomers and geometric isomers.
  • the compounds contain an asymmetric carbon atom
  • two enantiomeric forms (“ ⁇ " and " ⁇ " configurations) are possible.
  • ⁇ ⁇
  • ⁇ ⁇
  • ⁇ ⁇
  • ⁇ ⁇
  • ⁇ ⁇
  • ⁇ ⁇
  • ⁇ ⁇
  • ⁇ ⁇
  • ⁇ ⁇
  • ⁇ ⁇
  • a black, triangular bond denotes the ⁇ configuration and extends above the plane of the page.
  • a dashed line from an asymmetric carbon indicates an ⁇ bond which extends below the plane of the page.
  • the present Invention is intended to include both enantiomeric forms and any combinations of these forms and where no specific configuration is depicted at the site of an asymmetric carbon, it is to be understood that both enantiomeric forms and mixtures thereof are represented. Additionally, in situations where tautomers of the compounds are possible, the present invention is intended to include all tautomeric forms of the compounds.
  • a compound may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or any convenient intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Carbon Compounds by E. L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen.
  • compounds of the present Invention may exist in a variety of crystalline forms. Compounds of the present Invention are intended to encompass all possible crystalline forms. Also included in the present Invention are other forms of the compounds including: solvates, hydrates, and the like.
  • the compounds of the present Invention can be used in the form of an acid addition salt derived from inorganic or organic acids. Where the salt of compounds of the present Invention is to be used for a human or veterinary medicinal application the salt must be pharmaceutically acceptable. However, non-pharmaceutically acceptable salts of compounds of the present Invention may be useful as intermediates in the preparation of a corresponding pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate salts or salts with an organic acid such as the acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, palmitoate, salicylate and stearate salts.
  • inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate salts or salts with an organic acid such as the acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, palmitoate, salicylate and stearate salts.
  • an organic acid such as the acetate, malate
  • a compound of the invention may be isolated as a salt, this may be achieved by treating the free base of Formula (I) with an appropriate acid, or with creatinine sulfate in a polar, protic solvent, e.g., aqueous ethanol.
  • a polar, protic solvent e.g., aqueous ethanol.
  • step 1 the keto group in the 3 position of compounds of Formula (II), is protected by treatment with ethylene glycol in a protic or nonprotic solvent such as toluene in the presence of an acidic dehydrating agent such as tolulenesulfonic acid, yielding compounds of Formula (III).
  • a protic or nonprotic solvent such as toluene
  • an acidic dehydrating agent such as tolulenesulfonic acid
  • Compounds of Formula (III), in step 2 are treated with ozone in a polar solvent or mixture of polar solvents, such as methylene chloride and methanol, at dry ice /acetone temperatures of about -78°C, and purged with an inert or low reactive gas, such as nitrogen and reduced with a moderately strong organic acid, such as acetic acid and zinc.
  • the mixture is filtered and is then treated with an oxidizing agent such as sodium chlorite and an acid buffer such as sodium hydrogen phosphate monobasic in an alcoholic solvent system such as i-butanol followed by 2-methyl-2- butene. Then using column chromatography the mixture yields the corresponding compound of Formula (rV).
  • the carboxylic acid of the compounds of Formula (IV), in step 3, are converted to the corresponding acid halide intermediate by treatment with a halogenating agent such as oxalyl chloride, in an aprotic solvent such as methylene chloride.
  • a halogenating agent such as oxalyl chloride
  • an aprotic solvent such as methylene chloride.
  • the acid halide intermediate is then treated with a metal azide, such as an alkaline metal azide in a polar solvent or mixture of polar solvents such as acetone and water, to yield the corresponding azide compounds of Formula (IVa).
  • step 4 compounds of Formula (V) corresponding to the desired compounds of Formula (I) are heated in an aprotic solvent such as toluene, generating the compounds of Formula (Va).
  • the compounds of Formula (Va) are then converted to the corresponding compounds of Formula (I) with isolation, by standard methods used in the art.
  • the solvent may be removed by in vacuo distillation, the residue acidified then heated in a polar solvent such as tetrahydrofuran, at reflux and purified by chromatography.
  • Incorporation of other than a hydrogen at position R ⁇ in compounds of Formula (I), (e.g. lower alkyl groups) requires modification of Scheme C. This modification, producing compounds of Formula (I) with a 7 position lower alkyl group is depicted below in Scheme D.
  • Compounds contained in brackets and labeled with a lower case "a" are compounds which progress during the synthesis to the next primary compound.
  • Step 3 compounds of Formula (Vm) are reduced to the compounds of Formula (IX) by treatment with a metal catalyst such as tristriphenylphosphine rhodium(I) chloride under an atmosphere of hydrogen in a polar aprotic solvent like ethyl acetate yielding the corresponding compounds of Formula (IX).
  • a metal catalyst such as tristriphenylphosphine rhodium(I) chloride
  • a polar aprotic solvent like ethyl acetate
  • R ⁇ is halogen some Steps in the procedures shown in Schemes C and D are incompatible with survival of the halogen functional group.
  • the R ⁇ halogen is either introduced subsequent to the incompatible Step or is present in a protected form.
  • An example is where the R3 halogen is introduced by reacting a compound of Formula (I) with a halogenated succinimide, such as N-bromosuccinimide.
  • a double bond may be inserted between the carbon in the 1 position and the carbon in the 2 position by conventional means such as dehydrogenation with 2,3-dichloro-5, 6-dicyano-l,4-benzoquinone by refluxing in an aprotic solvent to produce a compound of Formula (I) that is unsarurated in the 1, 2 position.
  • a compound of Formula (I) with a double bond in the 1, 2 position may then be treated with the anion of trimetylsulfoxonium iodide, prepared by deprotonation with a base such as sodium hydride, in an aprotic solvent to give a compound of Formula (I) herein Rl and R ⁇ taken together form a cyclopropane ring.
  • the compound of Formula (I) and the intermediate compounds, shown in Schemes I and II may be purified by any convenient means known in the art, e.g., chromatography or crystallization.
  • Enzyme activities may be determined using microsomes derived from: 1) prostate tissue from benign prostatic hyperplasia (BPH) patients; 2) recombinant baculovirus infected SF9 cells that express human type 1 5 ⁇ - reductase; 3) prostate tissue from the rat; or 4) recombinant baculovirus infected SF9 cells that express human type 2 5 ⁇ -reductase.
  • Microsomes were prepared by homogenization of the tissue or cells, followed by differential centrifugation of the homogenate.
  • Microsome extracts were incubated with varying concentrations of [l,2,6,7-3H]-testosterone, lmM NADPH, and varying amounts of the compounds of Formula I, i.e. a test compound, in buffer containing a NADPH regenerating system capable of maintaining NADPH concentrations for a period of time within the range 0.5-240 minutes. Corresponding incubations were carried out with no test compound as a control study. For type 1 IC5 0 measurements, assay components except testosterone were preincubated for 10 minutes at pH 7.0, and following the addition of lOOnM testosterone the assays were allowed to proceed for 10-120 minutes.
  • the in vivo activity of steroid 5 ⁇ -reductase inhibitors may be determined in both acute and chronic rat models.
  • the acute model utilizes castrated male rats that receive testosterone (1 mg) subcutaneously and test compound (10 mg/kg) p.o., at 0.5 hr. and 4.5 hr. prior to sacrifice, respectively.
  • Levels of DHT in the serum and prostate indicate the ability of the test compound to inhibit steroid 5 ⁇ -reductase in an acute rat model.
  • Known steroid 5 ⁇ -reductase inhibitors were tested in parallel to ensure consistency of the assay method.
  • the chronic model also utilizes castrated male rats that are dosed daily with testosterone (20 ⁇ g/rat) subcutaneously and with test compound (0.01-10 mg/kg) p.o. for 7 days. The animals are then sacrificed and their prostates weighed. Reduction in the size of testosterone- stimulated prostate weight demonstrated activity of the test compound.
  • Known steroid 5 ⁇ -reductase inhibitors were tested in parallel to ensure consistency of the assay method. UTILITY
  • the steroid 5 ⁇ -reductase inhibitors of the present invention are useful in the treatment of androgen responsive diseases, e.g., benign and malignant diseases of the prostate, especially benign prostatic hyperplasia.
  • the amount of compound of Formula (I) required to be a safe and therapeutically effective amount as an 5 ⁇ -reductase inhibitor will, of course, vary with the individual mammal being treated and is ultimately at the discretion of the medical or veterinary practitioner. The factors to be considered include the condition being treated, the route of administration, the nature of the Formulation, the mammal's body weight, surface area, age and general condition, and the particular compound to be administered. However, a suitable safe and therapeutically effective 5 ⁇ -reductase inhibitory dose is in the range of about 0.01 to about 5 mg/kg body weight per day, preferably in the range of about 0.05 to about 2 mg/kg per day.
  • the total daily dose may be given as a single dose, multiple doses, e.g., two to six times per day, or by intravenous infusion for a selected duration. Dosages above or below the range cited above are within the scope of the present invention and may be administered to the individual patient if desired and necessary. For example, for a 75 kg mammal, a dose range would be about 5 to about 150 mg per day, and a typical dose would be about 20 mg per day. If discrete multiple doses are indicated, treatment might typically be 5 mg of a compound of Formula (I) given 4 times per day.
  • the compounds of Formula (I) may also be administered in a topical Formulation, e.g., ointment, cream, gel, or lotion, in cases of dermatological disorders such as acne vulgaris.
  • a safe and therapeutically effective topical Formulation contains from about 0.25% to about 10% by weight, of a compound of Formula (I) which is applied at the rate of about 0.1 g to about 1.0 g per square centimeter of infected skin area.
  • a dose is about 1 gram of a 1% ointment, cream, gel, or lotion of a compound of Formula (I) gently rubbed onto the square centimeter of skin in need of treatment.
  • Formulations of the present invention for medical use comprise an active compound, i.e., a compound of Formula (I), together with an acceptable carrier thereof and optionally other therapeutically active ingredients.
  • the carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the Formulation and not deleterious to the recipient thereof.
  • the present invention therefore, further provides a pharmaceutical formulation comprising a compound of Formula (I) together with a pharmaceutically acceptable carrier thereof.
  • the formulations include those suitable for oral, rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration. Preferred are those suitable for oral or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier and then, if necessary, shaping the product into desired unit dosage form.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension or solution in an aqueous liquid or non-aqueous liquid, e.g., a syrup, an elixir, an emulsion or a draught.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, inert diluents, surface active or dispersing agents.
  • Molded tablets may be made by molding in a suitable machine, a mixture of the powdered active compound with any suitable carrier.
  • a syrup or suspension may be made by adding the active compound to a concentrated, aqueous solution of a sugar, e.g., sucrose, to which may also be added any accessory ingredients.
  • a sugar e.g., sucrose
  • Such accessory ingredient(s) may include flavoring, a preservative, an agent to retard crystallization of the sugar or an agent to increase the solubility of any other ingredient, e.g., as a polyhydric alcohol, for example, glycerol or sorbitol.
  • Formulations for rectal administration may be presented as a suppository with a conventional carrier, e.g., cocoa butter or Witepsol S55 (trademark of Dynamite Nobel Chemical, Germany), for a suppository base.
  • a conventional carrier e.g., cocoa butter or Witepsol S55 (trademark of Dynamite Nobel Chemical, Germany)
  • Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient.
  • Such formulations suitably comprise a solution or suspension of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of Formula (I) that is isotonic with the blood of the recipient.
  • Such formulations may conveniently contain distilled water, 5% dextrose in distilled water or saline and a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the Formula (I) that has an appropriate solubility in these solvents, for example the hydrochloride, isothionate and methanesulfonate salts, preferably the latter.
  • Useful Formulations also comprise concentrated solutions or solids containing the compound of Formula (I) which upon dilution with an appropriate solvent give a solution suitable for parental administration.
  • Parenteral formulations of the present Invention must be in a sterile form. Any of the various methods known to persons skilled in the art employed to prepare sterile parenteral preparations that will not degrade components of the present Invention are suitable for use in the sterile preparation of the formulations
  • Topical Formulations include ointments, creams, gels and lotions which may be prepared by conventional methods known in the art of pharmacy.
  • topical formulation my also contain preservatives, perfumes, and additional active pharmaceutical agents.
  • Formulations of the present Invention may be packaged as articles of manufacture comprising a safe and therapeutically effective amount of a compound of Formula (I) and its physiologically acceptable salts and solvates and one or more optional accessory ingredient(s) utilized in the art of pharmaceutical formulations.
  • the packaging material may also have labeling and information relating to the pharmaceutical composition printed thereon.
  • an article of manufacture may also have a brochure, report, notice, pamphlet, or leaflet containing product information. This form of pharmaceutical product information is sometimes, in the pharmaceutical industry, called the "package insert.”
  • a package insert may be attached to or included with a an article of manufacture.
  • the package insert and any article of manufacture labeling provides information relating to the pharmaceutical formulation contained therein. This information and labeling provides various forms of information utilized by health care professionals and patients that describes the formulation, its dosage and various other parameters required by regulatory agencies, such as the United States Food and Drug Administration.
  • the formulations of this invention may further include one or more optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, e.g., diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.
  • optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, e.g., diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.
  • Ozone is bubbled through a CH2Cl2/MeOH solution (140 mL/40 mL) containing cholest-5-en-3-one ethylene ketal (4.65 g, 10.8 mmoL), the starting material prepared as in /. Org. Chem. 1952, 17, 1341, cholest-5-ene- 3-one-3-ethylene-ketal, is cooled to -78 °C until the characteristic blue color persisted ( ⁇ 5 minutes). Nitrogen is then bubbled through the solution to dissipate any excess ozone. The reaction mixture is transferred to an ice-water bath and activated zinc dust (3.55 g, 54.3 mmoL) is added.
  • Glacial acetic acid (4 mL) is added dropwise and upon stirring an additional 45 minutes the zinc metal is removed via vacuum filtration. The bulk of the solvent is removed in vacuo , dissolved in CH2CI2 and washed with H2O. Drying over MgS ⁇ 4 and concentration afforded the crude ketoaldehyde which is taken directly on into the next step.
  • the crude ketoaldehyde is dissolved in 100 mL of t-butanol and then 2-methyl- 2-butene (6.82 g, 97.2 mmoL) is added.
  • CH2CI2 solution (6 mL) containing oxalyl chloride (295 mg, 2.33 mmoL) cooled to 0 °C is added CH2CI2 solution (5 mL) containing 7- carboxy-secocholest-3,5-dione-3-ethylene ketal (616 mg, 1.30 mmoL), prepared as in example 1 and pyridine (205 mg, 2.59 mmoL) added to it. After 5h the solvent is removed in vacuo and the residue pumped on under high vacuum overnight. The resulting solid is dissolved in 8 mL of acetone, cooled to 0 °C and 3 mL of an aqueous solution of sodium azide (505 mg, 7.77 mmoL) added.
  • Ozone is bubbled through a CH2Cl2/MeOH solution (60 mL/20 mL) containing 7 ⁇ , ⁇ -methyl-cholest-5-en-3-one ethylene ketal, prepared as in example 5, (1.89 g, 4.28 mmoL) at -78 °C for 8 minutes. Nitrogen is then bubbled through the solution to dissipate any excess ozone. The flask is transferred to an ice-water bath and activated zinc dust (1.4 g, 21.4 mmoL) added. Glacial acetic acid (2 mL) is added dropwise and 30 minutes later the mixture filtered to remove the zinc metal.
  • the bulk of the solvent is removed in vacuo, the residual material dissolved in CH2CI2 and then washed with H2O. Drying over MgS ⁇ 4 and concentration yielded the crude ketoaldehyde. This material is then taken directly into the next reaction.
  • the aldehyde is dissolved in 40 mL of t-butanol and to this solution is added 2-methyl-2-butene (2.7 g, 38.5 mmoL). Then 10 mL of an aqueous solution containing sodium chlorite (1.5 g, 17.1 mmoL) and sodium hydrogen phosphate monobasic (1.3 g, 10.7 mmoL) added. After 30 minutes the bulk of the t-butanol is removed in vacuo.
  • acyl azide (ER showed the characteristic azide stretch at 2130 cm ⁇ l).
  • the crude acyl azide is dissolved in 6 mL of toluene and heated to 80 °C for 1.5h. The toluene is removed in vacuo and the product pumped on under high vacuum overnight. The residual oil is dissolved in 7 mL of THF followed by addition 1.8 mL of a aqueous 4.0M HC1 solution. After being heated to 65 °C for lh 45 minutes the bulk of the THF is removed in vacuo.
  • the silicon fluid and active compound are mixed together and the colloidal silicon dioxide is added to increase viscosity.
  • the material is then dosed into a subsequently heat sealed polymeric laminate comprised of the following: polyester release liner, skin contact adhesive composed of silicone or acrylic polymers, a control membrane which is a polyolefin (e.g. polyethylene, polyvinyl acetate or polyurethane), and an impermeable backing membrane made of a polyester multilaminate.
  • the resulting laminated sheet is then cut into 10 sq. cm patches.
  • the active compound and the starch are granulated with water and dried. Magnesium stearate is added to the dried granules and the mixture is thoroughly blended. The blended mixture is compressed into tablets.
  • the active compound and buffering agents are dissolved in the propylene glycol at about 50°C.
  • the water for injection is then added with stirring and the resulting solution is filtered, filled into ampules, sealed and sterilized by autoclaving.
  • the finely ground active compound is mixed with the lactose and stearate and packed into gelatin capsules.

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Abstract

La présente invention concerne des 6-azacholesten-3-ones 17β-substituées de formule suivante (I) où R1 et R2 représentent indépendamment hydrogène ou alkyle et où la liaison entre les carbones 1 et 2 est une liaison simple ou double, ou où R1 et R2 peuvent être joints pour former un noyau cyclopropane condensé; R3 représente hydrogène, alkyle ou halogène; R4 et R5 représentent indépendamment hydrogène ou alkyle; R6 représente alkyle; ainsi que leurs sels et solvates pharmaceutiquement acceptables et leur utilisation en tant qu'inhibiteurs de la 5α-testostérone réductase.
PCT/US1996/004042 1995-03-31 1996-03-25 6-azacholesten-3-ones substituees WO1996030391A1 (fr)

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AU53230/96A AU5323096A (en) 1995-03-31 1996-03-25 Substituted 6-azacholesten-3-ones

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GBGB9506678.3A GB9506678D0 (en) 1995-03-31 1995-03-31 Substituted 6-azacholesten-3-ones
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5741795A (en) * 1995-10-19 1998-04-21 Merck & Co., Inc. 16-substituted-6-aza-androsten-4-ene-3-ones as 5-α-reductase inhibitors
US6461596B1 (en) * 1997-02-18 2002-10-08 Andrea Taylor Composition and method for promoting hair growth

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991000731A1 (fr) * 1989-07-07 1991-01-24 Endorecherche Inc. Therapie combinee pour la prophylaxie et/ou le traitement de l'hyperplasie prostatique benigne
WO1992016213A1 (fr) * 1991-03-20 1992-10-01 Merck & Co., Inc. Combinaison pharmaceutique pour le traitement de l'hyperplasie de la prostate renfermant un inhibiteur de 5 alpha-reductase et un antiandrogene
WO1993023053A1 (fr) * 1992-05-21 1993-11-25 Endorecherche Inc. INHIBITEURS D'ACTIVITE DE LA TESTOSTERONE 5α-REDUCTASE
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