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WO1995028384A1 - COMPOSES DE DIAZO-PHENANTHRENONE INHIBANT LA REDUCTASE 5-$g(a) - Google Patents

COMPOSES DE DIAZO-PHENANTHRENONE INHIBANT LA REDUCTASE 5-$g(a) Download PDF

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Publication number
WO1995028384A1
WO1995028384A1 PCT/US1995/004599 US9504599W WO9528384A1 WO 1995028384 A1 WO1995028384 A1 WO 1995028384A1 US 9504599 W US9504599 W US 9504599W WO 9528384 A1 WO9528384 A1 WO 9528384A1
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Prior art keywords
compound
alkyl
halogen
trifluoromethyl
composition according
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Inventor
Dennis Alan Holt
Andrew David Abell
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Priority to AU22900/95A priority Critical patent/AU2290095A/en
Priority to EP95916384A priority patent/EP0755378A4/fr
Priority to JP7527102A priority patent/JPH09512017A/ja
Publication of WO1995028384A1 publication Critical patent/WO1995028384A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/12—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

Definitions

  • the present invention relates to certain novel diazo-phenanthrenone compounds, pharmaceutical compositions containing these compounds, methods for making these compounds, and methods for using these compounds to inhibit steroid 5- ⁇ -reductase.
  • the class of steroidal hormones known as androgens is responsible for the physical characteristics that differentiate males from females. Of the several organs that produce androgens, the testes produce these hormones in the greatest amounts. Centers in the brain exert primary control over the level of androgen production. Numerous physical manifestations and disease states result when ineffective control results in excessive androgen hormone production. For example, acne vulgaris, seborrhea, female hirsutism, male pattern baldness and prostate diseases such as benign prostatic hypertrophy are correlated with elevated androgen levels. Additionally, the reduction of androgen levels has been shown to have a therapeutic effect on prostate cancer.
  • Testosterone is the principal androgen secreted by the testes and is the primary androgenic steroid in the plasma of males. It now is known that 5- ⁇ - reduced androgens are the active hormones in some tissues such as the prostate and sebaceous gland. Circulating testosterone thus serves as a prohormone for dihydrotestosterone (DHT), its 5- ⁇ -reduced analog, in these tissues but not in others such as muscle and testes.
  • DHT dihydrotestosterone
  • Steroid 5- ⁇ -reductase is a nicotinamide adenine dinucleotide phosphate (NADPH) dependent enzyme that converts testosterone to DHT.
  • NADPH nicotinamide adenine dinucleotide phosphate
  • the present invention resides in the discovery that steroid 5- ⁇ -reductase is inhibited by certain diazo-phenanthrenone compounds.
  • Presently preferred compounds of the invention, and compounds used in the invented pharmaceutical compositions and the invented methods, have the formula:
  • R! is hydrogen or Ci -Cg alkyl
  • a presently preferred compound of the invention and a compound used in the invented pharmaceutical compositions and invented methods, has the name: (+/-) ⁇ ⁇ trans- 1 -diazo-8-methoxy-4a-methyl- 1 ,2,3 ,4,4a,9, 10, 1 Oa- octahydrophenanthren-2-one.
  • Another aspect of the invention is a pharmaceutical composition comprising a compound represented by the Formula (I), as defined previously, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • alkyl refers to a monovalent hydrocarbon radical having a straight or branched chain of carbon atoms, where the number of carbon atoms is selected from within a stated range.
  • exemplary alkyl radicals include methyl (-CH3), ethyl (-CH2CH3), «-propyl (-CH2CH2CH3), isopropyl (-CH(CH 3 ) ), ⁇ -butyl (-CH2CH2CH2CH3), isobutyl (-CH 2 CH(CH 3 ) 2 ), .yec-butyl (-CH(CH3)CH2CH3), t-butyl (-C(CH3)3) and, where indicated, higher homologs and isomers such as w-pentyl (-CH2CH2CH2CH2CH3), H-hexyl (-CH2CH2CH2CH2CH3), 2-methylpentyl (-CH 2 CH(CH 3 )CH
  • alkoxy refers to an alkyl, alkenyl or alkynyl radical having a number of carbon atoms selected from within a stated range, where the alkyl, alkenyl or alkynyl radical is bonded through an oxygen atom to the residue of a compound of Formula (I).
  • alkoxy radicals include methoxy (-OCH3), ethoxy (-OCH2CH3), n-propoxy (-OCH2CH2CH3), isopropoxy (-OCH(CH3)2), propynyloxy (-OC ⁇ C ⁇ CH) and the like.
  • alkylamino refers to an alkyl, alkenyl or alkynyl radical having a number of carbon atoms selected from within a stated range, where the alkyl, alkenyl or alkynyl radical is bonded through an amine diradical (-NH-) to the residue of a compound of Formula (I).
  • alkylene refers to a divalent hydrocarbon radical having a branched or straight chain of carbon atoms, where the number of carbon atoms is selected from within a stated range.
  • alkylene radicals include methylene (-CH2-), 1,2-ethanediyl (-CH2CH2-), 3-methyl-l,5-pentanediyl (-CH2CH2CH(CH3)CH 2 CH 2 -) 1,6-hexanediyl (-CH2CH2CH2CH2CH2CH2-) and the like.
  • alkylsulfinyl refers to an alkyl, alkenyl or alkynyl radical having a number of carbon atoms selected from within a stated range, and bonded to a sulfur atom of a sulfinyl group (-S(O)-), where the sulfur atom of the sulfmyl group is also bonded to the residue of a compound of Formula (I).
  • exemplary alkylsulfinyl radicals include -S(O)CH 3 , -S(O)CH 2 CH 3 , -S(O)CH(CH 3 ) 2 and the like.
  • alkylthio refers to an alkyl, alkenyl or alkynyl radical having a number of carbon atoms selected from within a stated range,where the alkyl, alkenyl or alkynyl radical is bonded through a sulfur (S) atom to the residue of a compound of Formula (I).
  • exemplary alkylthio radicals include methylthio (-SCH3), ethylthio (-SCH2CH3), /.-propylthio (-SCH2CH2CH3), isopropylthio (-SCH(CH 3 )2) and the like.
  • alkynylene refers to a divalent hydrocarbon radical having a branched or straight chain of carbon atoms, and a single carbon-carbon triple bond (C ⁇ C), where the number of carbon atoms is selected from within a stated range.
  • exemplary alkynylene radicals include 1,2-acetylenediyl (-C ⁇ C-), l-propyne-1,3- diyl (-C ⁇ C-CH2-), 2-butyne-l,4-diyl (-CH2-C ⁇ C-CH 2 -) and the like.
  • amino refers to the -NH2 radical.
  • cyano also known as "nitrile”, refers to the -C ⁇ N radical.
  • co-administering or “co-administered” or “co-administer” etc. refer to either the simultaneous administration, or any manner of separate sequential administration, of a 5- ⁇ -reductase inhibiting compound, as described herein, and a further active ingredient or ingredients.
  • Such further active ingredient or ingredients include compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy, prostatic adenocarcinoma, or any other compound known to have utility when used in combination with 5- ⁇ -reductase inhibitors.
  • the compounds being co-administered are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g., one compound may be admimstered topically and another compound may be administered orally.
  • dialkylamino refers to a radical having two groups bonded to a single nitrogen atom (N), where the nitrogen atom is also bonded to the residue of a compound of Formula (I), where the two groups bonded to the nitrogen atom are selected from alkyl, alkenyl or alkynyl radicals, wherein each alkyl, alkenyl or alkynyl radical has a number of carbon atoms selected from within a stated range and selected independently from the other alkyl, alkenyl or alkynyl radical.
  • dialkylamio radicals include dimethylamino (-N(CH3)2), ethylmethylamino (-N(CH3)(CH2CH3)), isobutenylisopropylamino (-N(CH2C(CH 3 )CH2)(CH(CH 3 )2)) and the like.
  • diazo-phenanthrenone refers to compound having the basic structure
  • halogen refers to any of fluoro, chloro, bromo or iodo.
  • hydroxy or "hydroxyl” refers to the -OH radical.
  • mercapto also known as “thio” refers to the -SH radical.
  • alpha-receptor antagonist or " ⁇ -receptor antagonist” refers to a known class of alpha-andrenergic receptor antagonist compounds, such as described in Lafferty, et al. U.S. Patent No. 4,963,547, which are utilized in treating vascular disorders such as diabetes, cardiovascular disease, benign prostatic hypertrophy and ocular hypertension.
  • Preferred alpha-andrenergic receptor antagonists for use in the compositions and methods of the invention include amsulosin, terazosin, doxazosin, alfuzosin, indoramin, prazosin, 7-chloro-2-ethyl-3,4,5,6-tetrahydro-4- methylthieno[4,3,2-ef][3]-benzazepine and 8- ⁇ 3-[4-(2-methoxyphenyl)-l- piperazinyl]-propylcarbamoyl ⁇ -3-methyl-4-oxo-2-phenyl-4H-l-benzopyran.
  • amsulosin refers to a compound of the structure
  • amsulosin is designated as (-)- (i?)-5-(2-((2-(O-ethoxyphenoxy)ethyl)amino)propyl)-2- methoxybenzenesulfonamide.
  • Amsulosin is disclosed in U.S. Patent Number 4,703,063, and claimed in U.S. Patent Number 4,987,125 as being useful in treating lower urinary tract dysfunction.
  • terazosin refers to a compound of the structure cH 3 o .N
  • terazosin is designated as 1- (4-amino-6,7-dimethoxy-2 quinazolinyl)-4-((tetrahydro-2- furoyl)carbonyl)piperazine.
  • Terazosin is disclosed in U.S. Patent Number 4,251,532.
  • doxazosin refers to a compound of the structure
  • doxazosin is designated as 1- (4-a ⁇ -ino-6,7-dimethoxy-2-quinazolinyl)-4-((2,3-dihydro-l,4-benzodioxin-2- yl)carbonyl)piperazine.
  • Doxazosin is disclosed in U.S. Patent Number 4,188,390.
  • alfuzosin refers to a compound of the structure
  • alfuzosin is designated as N- (3-((4-ammo-6,7-dime oxy-2-quinazolinyl)memylamino)propyl)tetrahydro-2- furancarboxamide.
  • Alfuzosin is disclosed in U.S. Patent Number 4,315,007.
  • the term "indoramin” refers to a compound of the structure
  • prazosin is designated as l-(4- - nino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine. Prazosin is disclosed in U.S. Patent Number 3,511,836.
  • EPO Publn. No. 0558245 Al 8- ⁇ 3-[4-(2-methoxyphenyl)-l-piperazinyl]- propylcarbamoyl ⁇ -3-methyl-4-oxo-2-phenyl-4H-l-benzopyran is disclosed in EPO Publn. No. 0558245 Al, to Leonardi, et al., (Recordata S.A.). Additionally, all compounds disclosed in EPO Publn. No. 0558245 Al, as alpha-adrenergic receptor antagonists are preferred alpha-adrenergic receptor antagonists as used herein.
  • aromatase inhibitor refers to a known class of compounds, steroidal and non-steroidal, which prevent the conversion of androgens to estrogens, such as described in Gormley et al., International Publication Number WO
  • Aromatase inhibitors are disclosed in Gormley et al. as having utility in treating benign prostatic hyperplasia when used in combination with a 5- ⁇ - reductase inhibitor. All compounds disclosed in Gormley et al. as having aromatase inhibiting activity are preferred aromatase inhibitors as used herein.
  • Another preferred aromatase inhibitor for use in the compositions and methods of the present invention is 4-(5,6,7,8-tetrahydroimidazo-[l,5- ⁇ ]pyridin-5-yl)benzonitrile, which is also known as fadrazole. Fadrazole is disclosed in U.S. Patent Number 4,728,645.
  • minoxidil refers to a compound of the structure
  • minoxidil is designated as 2,4-pyrimidineadiamine-6-(l-piperidinyl)-3- oxide.
  • Minoxidil is the active ingredient in Rogaine® which is sold as a topical solution for stimulating hair growth by the Upjohn Company, Kalamazoo, Michigan.
  • R 1 is hydrogen or Ci -Cg alkyl
  • R is independently hydrogen; halogen; NO2; cyano; trifluoromethyl
  • R! is hydrogen or methyl
  • novel compounds of Formula (I) of the present invention can be prepared by the method outlined in SCHEME I below, and in the Example, from the starting material described in SCHEME I. Analogous compounds of the invention can be prepared according to similar methods from the same or alternative starting materials.
  • SCHEME I shows a synthesis of a diazo-phenanthrenone compound of
  • a compound comprising an ⁇ , ⁇ -unsaturated ketone is a convenient starting material for the preparation of the dizao-phenanthrenone compounds of the invention, and a representative ⁇ , ⁇ -unsaturated ketone compound can be prepared according to the method of Comforth, J.W.; Robinson, R. J. Chem. Soc. 1949, 1855.
  • An ⁇ , ⁇ - unsaturated ketone compound can be converted to a compound readily susceptible to functionalization at the ⁇ -carbon, as shown by reaction 'b' in SCHEME I, which shows the conversion of an ⁇ , ⁇ -unsaturated ketone to a silyl enol ether
  • a silyl enol ether containing compound including the trimethylsilyl enol ether compound shown in SCHEME I, can be reacted with an acylating agent to provide a 1,3-diketone which serves as a convenient precursor to the diazo- phenanthrenone compounds of Formula (I).
  • benzoyl chloride is a suitable acylating agent, which will react with a trimethylsilyl enol ether to provide a 1,3-diketone compound.
  • the 1,3-diketone compound prepared according to reaction 'c' can be converted to a diazoketone compound of Formula (I) by reaction with an azide compound such as tosylazide, as shown as reaction 'd' in SCHEME I.
  • the pharmaceutically active compounds of the invention inhibit steroid 5- ⁇ -reductase activity, they have therapeutic utility in treating diseases and conditions wherein decreases in DHT activity produce the desired therapeutic effect.
  • diseases and conditions include acne vulgaris, seborrhea, female hirsutism, male pattern baldness, prostate diseases such as benign prostatic hypertrophy, and prostatic adenocarcinoma.
  • Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5- ⁇ -reductase isoenzyme 1 (Andersson, S., Berman, D.M., Jenkins, E.P., and Russell, D.W. (1991) Nature 354:159-161) were homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, 1 mM dithiothreitol, and 50 ⁇ M NADPH (buffer A) using a Dounce glass-to-glass hand homogenizer (Kontes Glass Co., Vineland, N.J.).
  • Membrane particulates were isolated by centrifugation (100,000 x g at 4°C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6.5, containing 20% glycerol, 1 mM dithiothreitol, and 50 ⁇ M NADPH (buffer B). The suspended particulate solution was stored at -80°C.
  • CHO cells containing expressed, recombinant human steroid 5- ⁇ -reductase isozyme 2 were homogenized in buffer A using a Dounce hand homogenizer.
  • Membrane particulates containing the recombinant human enzyme were isolated by centrifugation (100,000 x g at 4°C for 60 minutes) and resuspended in buffer B. The suspended particulate solution was stored at -80°C until used.
  • Assay for enzvmes activities and inhibitors potency A constant amount of [ 14 C]testosterone (50 to 55 mCi/mmol) in ethanol, and varying amounts of potential inhibitor in ethanol, were deposited in test tubes and concentrated to dryness in vacuo. To each tube was added buffer, 10 ⁇ L (recombinant isoenzyme 1 or isoenzyme 2) or 20 ⁇ L (isoenzyme 2 from human prostate tissue) of 10 mM NADPH and an aliquot of a steroid 5- ⁇ -reductase preparation to a final volume of 0.5 mL.
  • Assays for human steroid 5- ⁇ -reductase isoenzyme 1 were conducted with a sample of the recombinant protein expressed in CHO cells in 50 mM phosphate buffer, pH 7.5 while assays of isoenzyme 2 were conducted with a suspension of human prostatic particulates and/or recombinant protein expressed in CHO cells in 50 mM citrate buffer at pH 5.0. After incubating the solution at 37°C for 20 or 30 minutes, the reaction was quenched by the addition of 4 mL ethyl acetate and 0.25 ⁇ mol each of testosterone, 5 ⁇ -dihydrotestosterone, androstanediol, and androstanedione as carriers.
  • the organic layer was removed to a second test tube and evaporated to dryness in a Speed Vac.
  • the residue was dissolved in 40 ⁇ L chloroform, spotted on an individual lane of a 20 x 20 cm prechannelled silica gel TLC plate (Si 250F-PA, Baker Chemical) and developed twice with acetone: chloroform (1 :9).
  • the radiochemical content in the bands of the substrate and the products was determined with a BIOSCAN Imaging Scanner (Bioscan Inc., Washington, D.C.). The percent of recovered radiolabel converted to product was calculated and used to determine enzyme activity. All incubations were conducted such that no more than 20% of the substrate (testosterone) was consumed.
  • the experimentally obtained data was computer fit to a linear function by plotting the reciprocal of the enzyme activity (1 /velocity) against the variable inhibitor concentration.
  • the value for the inhibition constant (Ki) was calculated according to Levy, M. (1989) Biochemistry 29:2815-2824.
  • Compounds within the scope of this invention have been tested and have shown an activity of from 0.5 Ki(nM) to 120 Ki(nM) against isozyme 1 and an activity of >2000 Ki(nM) against isozyme 2.
  • Particularly preferred among the compounds of the invention and the compounds used in the invented pharmaceutical compositions and invented methods is (+/-)-tr ⁇ «5-l-diazo-8- methoxy-4a-methyl- 1 ,2,3 ,4,4a,9, 10,1 Oa-octahydrophenanthren-2-one.
  • All of the compounds within the scope of this invention are useful in inhibiting steroid 5- ⁇ -reductase in a mammal, including humans, in need thereof.
  • a 5- ⁇ -reductase inhibitor as described herein, and a further active ingredient or ingredients are utilized together, said 5- ⁇ -reductase inhibitor can be co- administered with said further active ingredient or ingredients.
  • the pharmaceutically active compounds of the present invention are preferably incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations.
  • Solid or liquid pharmaceutical carriers may be employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra-alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
  • the preparation will preferably be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as maintained in an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
  • Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.01 - 1000 mg/kg of active compound, preferably 0.1 - 100 mg/kg.
  • the selected dose is administered preferably from 1-6 times daily, orally or parenterally.
  • Preferred forms of parenteral administration include topically, rectally, transdermally, by injection, and continuously by infusion.
  • Oral dosage units for human administration preferably contain from 1 to 500 mg of active compound.
  • Oral administration which uses lower dosages, is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.
  • the method of this invention of inhibiting steroid 5- ⁇ -reductase activity in mammals, including humans, comprises administering to a subject in need of such inhibition an effective steroid 5- ⁇ -reductase inhibiting amount of a pharmaceutically active compound of the present invention.
  • the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in the inhibition of steroid 5- ⁇ -reductase.
  • the invention also provides for a pharmaceutical composition for use in the treatment of benign prostate hypertrophy which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the invention also provides for a pharmaceutical composition for use in the treatment of prostatic adenocarcinoma which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the invention also provides for a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and a compound of Formula (I) which comprises bringing the compound of Formula (I) into association with the pharmaceutically acceptable carrier or diluent.
  • the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy or prostatic adenocarcinoma or compounds known to have utility when used in combination with 5- ⁇ -reductase inhibitors.
  • further active ingredients such as other compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy or prostatic adenocarcinoma or compounds known to have utility when used in combination with 5- ⁇ -reductase inhibitors.
  • Particularly preferred is the co-administration of a 5- ⁇ -reductase inhibitor, as disclosed herein, and minoxidil for use in the treatment of male pattern baldness.
  • Particularly preferred is the co-aclministration of a 5- ⁇ -reductase inhibitor, as disclosed herein, and a ⁇ -receptor antagonist for use in the treatment of benign prostatic hypertrophy.
  • a 5- ⁇ -reductase inhibitor as disclosed herein
  • an aromatase inhibitor for use in the treatment of benign prostatic hypertrophy.
  • a 5- ⁇ -reductase inhibitor as disclosed herein, an alpha-receptor antagonist and an aromatase inhibitor for use in the treatment of benign prostatic hypertrophy.
  • the invention also provides a compound of Formula (I) for use in therapy and for use in the manufacture of a medicament for use as a steroid 5- ⁇ -reductase inhibitor.
  • the invention further provides a compound of Formula (I) for use in the manufacture of a medicament for use in treatment to reduce prostate size or the treatment of prostatic adenocarcinoma.
  • the invention also provides for a composition comprising a compound represented by Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient, for use in therapy or for use in the manufacture of a medicament for use as a steroid 5- ⁇ -reductase inhibitor.
  • the invention further provides for a composition comprising a compound represented by Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient, for use in treatment to reduce prostatic size, or for use in treatment of prostatic adenocarcinoma.
  • the invention also provides a process for the preparation of
  • component (b) an effective amount of a compound of the Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or ester thereof, which process comprises bringing component (a) into association with component (b).
  • the invention further provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in inhibiting steroid 5- ⁇ -reductase.
  • the invention also provides for a method of inhibiting steroid 5- ⁇ -reductase in mammals which comprises the administration to a mammal in need of such inhibition, an effective amount of a compound of Formula (I).
  • the invention further provides for the use of a compound of Formula (I) and an alpha-receptor antagonist compound as an active therapeutic substance, which use comprises co-administration of a compound of Formula (I) and an alpha-receptor antagonist compound.
  • the invention also provides for the use of a compound of Formula (I) and an alpha-receptor antagonist compound, in the manufacture of medicament for use in the treatment of benign prostatic hypertrophy which use comprises co-administration of a compound of Formula (I) and an alpha-receptor antagonist compound.
  • the invention also provides for the use of a compound of Formula (I) and minoxidil as an active therapeutic substance which use comprises co-administration of a compound of Formula (I) and minoxidil.
  • the invention further provides for the use of a compound of Formula (I) and minoxidil, in the manufacture of a medicament for use in the treatment of male pattern baldness which use comprises co-administration of a compound of Formula (I) and minoxidil.
  • the invention also provides for the use of a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient, in the manufacture of a medicament for use in inhibiting steroid 5- ⁇ -reductase.
  • the invention further provides for a method of inhibiting steroid 5- ⁇ -reductase in mammals which comprises the administration to a mammal in need of such inhibition, an effective amount of a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient, and an alpha-receptor antagonist compound as an active therapeutic substance which use consist of co- administration of a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient, and an alpha-receptor antagonist compound.
  • composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient, and an alpha- receptor antagonist compound in the manufacture of medicament for use in the treatment of benign prostatic hypertrophy
  • a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient, and an alpha-receptor antagonist compound.
  • composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient, and minoxidil as an active therapeutic substance which use comprises co-administration of a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient and minoxidil.
  • the invention also provides for the use of a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient and minoxidil in the manufacture of a medicament for use in the treatment of male pattern baldness which use comprises co-administration of a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient, and minoxidil.
  • (+l-)-trans- 1 -Benzoyl-8-methoxy-4a-methyl- 1 ,2,3 ,4,4a-9, 10,1 Oa-octahydro- phenanthren-2-one (270 mg, 0.76 mmol) in tetrahydrofuran (2 mL) was added dropwise to a stirred suspension of sodium hydride (60 % dispersion in oil, 65 mg, 1.63 mmol) in tetrahydrofuran (3 mL).
  • the mixture was cooled in a water bath and tosylazide (250 mg, 1.27 mmol) was added dropwise under argon. After 45 min stirring at room temperature, the mixture was filtered and concentrated in vacuo.
  • EXAMPLE 2 An oral dosage form for administering Formula (I) compounds is produced by screening, mixing, and filling into hard gelatin capsules the ingredients in the proportions shown in Table 1 , below. able I Ingredients. Amounts
  • sucrose, calcium sulfate dihydrate and Formula (I) compound shown in Table II below are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.

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Abstract

Composés de diazo-phénanthrénone et préparations pharmaceutiques les contenant, inhibant la réductase stéroïde 5-α. L'invention porte également sur leurs méthodes de préparation et d'utilisation.
PCT/US1995/004599 1994-04-15 1995-04-13 COMPOSES DE DIAZO-PHENANTHRENONE INHIBANT LA REDUCTASE 5-$g(a) Ceased WO1995028384A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU22900/95A AU2290095A (en) 1994-04-15 1995-04-13 Diazo-phenanthrenone compounds useful for inhibiting 5-alpha-reductase
EP95916384A EP0755378A4 (fr) 1994-04-15 1995-04-13 Composes de diazo-phenanthrenone inhibant la reductase 5-alpha
JP7527102A JPH09512017A (ja) 1994-04-15 1995-04-13 ５−α−レダクターゼ阻害に有用なジアゾ−フェナンスレノン化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9407511.6 1994-04-15
GB9407511A GB9407511D0 (en) 1994-04-15 1994-04-15 Compounds

Publications (1)

Publication Number Publication Date
WO1995028384A1 true WO1995028384A1 (fr) 1995-10-26

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Application Number Title Priority Date Filing Date
PCT/US1995/004599 Ceased WO1995028384A1 (fr) 1994-04-15 1995-04-13 COMPOSES DE DIAZO-PHENANTHRENONE INHIBANT LA REDUCTASE 5-$g(a)

Country Status (6)

Country Link
EP (1) EP0755378A4 (fr)
JP (1) JPH09512017A (fr)
AU (1) AU2290095A (fr)
GB (1) GB9407511D0 (fr)
WO (1) WO1995028384A1 (fr)
ZA (1) ZA953053B (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3046113A (en) * 1951-06-30 1962-07-24 Azoplate Corp Light sensitive material
US4317817A (en) * 1979-08-27 1982-03-02 Richardson-Merrell Inc. Novel steroid 5α-reductase inhibitors
US4556513A (en) * 1982-12-03 1985-12-03 Meiji Seika Kaisha, Ltd. Process for the production of antibiotic 1-oxadethiacephalosporins, and intermediate
US4624908A (en) * 1985-04-15 1986-11-25 J. T. Baker Chemical Company Deep ultra-violet lithographic resist composition and process of using
US4996301A (en) * 1989-01-12 1991-02-26 Hoechst Aktiengesellschaft Polyfunctional α-diazo-β-keto esters and their use in light-sensitive compositions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3046113A (en) * 1951-06-30 1962-07-24 Azoplate Corp Light sensitive material
US4317817A (en) * 1979-08-27 1982-03-02 Richardson-Merrell Inc. Novel steroid 5α-reductase inhibitors
US4556513A (en) * 1982-12-03 1985-12-03 Meiji Seika Kaisha, Ltd. Process for the production of antibiotic 1-oxadethiacephalosporins, and intermediate
US4624908A (en) * 1985-04-15 1986-11-25 J. T. Baker Chemical Company Deep ultra-violet lithographic resist composition and process of using
US4996301A (en) * 1989-01-12 1991-02-26 Hoechst Aktiengesellschaft Polyfunctional α-diazo-β-keto esters and their use in light-sensitive compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0755378A4 *

Also Published As

Publication number Publication date
EP0755378A4 (fr) 1997-06-11
GB9407511D0 (en) 1994-06-08
JPH09512017A (ja) 1997-12-02
EP0755378A1 (fr) 1997-01-29
AU2290095A (en) 1995-11-10
ZA953053B (en) 1995-12-18

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