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WO1994011386A1 - Acyl-3-carboxy-3,5-dienes a substitution 17-alkyle et 17-beta et utilisation de ces derniers pour inhiber la 5-alpha-reductase - Google Patents

Acyl-3-carboxy-3,5-dienes a substitution 17-alkyle et 17-beta et utilisation de ces derniers pour inhiber la 5-alpha-reductase Download PDF

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Publication number
WO1994011386A1
WO1994011386A1 PCT/US1993/011241 US9311241W WO9411386A1 WO 1994011386 A1 WO1994011386 A1 WO 1994011386A1 US 9311241 W US9311241 W US 9311241W WO 9411386 A1 WO9411386 A1 WO 9411386A1
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Prior art keywords
substituted
alkyl
cycloalkyl
compound
hydrogen
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PCT/US1993/011241
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English (en)
Inventor
Dennis Alan Holt
Mark Alan Levy
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Smithkline Beecham Corporation
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Priority claimed from GB929224213A external-priority patent/GB9224213D0/en
Priority claimed from GB939316954A external-priority patent/GB9316954D0/en
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to AU56717/94A priority Critical patent/AU5671794A/en
Priority to US08/436,240 priority patent/US5641765A/en
Priority to EP94902307A priority patent/EP0669932A4/fr
Publication of WO1994011386A1 publication Critical patent/WO1994011386A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0014—Androstane derivatives substituted in position 17 alfa, not substituted in position 17 beta
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0066—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by a carbon atom forming part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Definitions

  • the present invention relates to certain novel 17 ⁇ and 17B substituted acyl-3-carboxy 3,5-diene steroidal compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds to inhibit steroid 5- ⁇ -reductase. Also invented are novel intermediates and processes useful in preparing these compounds.
  • 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 hypertropy 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 analogue, 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.
  • 5- ⁇ -reductase inhibitors are known in the art. For example,
  • _ i a linear or branched, saturated or unsaturated hydrocarbon chain containing irom 1-12 carbon atoms
  • R is substituted alkyl, cycloalkyl or aryl where a) substituted alkyl is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbon atoms substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano, oxo, halogen, -C(O)OR 6 and -S(O) n R 5 , where
  • Ro is hydrogen or alkyl, n is 0-2 and
  • R5 is hydrogen, cycloalkyl, CQ-Ci2 . ⁇ yl, substituted cycloalkyl, substitut e si CQ-C- -aryl, alkyl or alkyl substituted with one or more substituents sele, - from the group consisting of: alkoxy, acyloxy, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, aryloxy, -C(0)0R6, -S(O) n R'-* ⁇ nitro, cyano, halogen, CQ-C ⁇ aryi, substituted Cg-Ci2 ar yl and protected -OH, where ⁇ ⁇ is hydrogen or alkyl, n is 0-2 and R 7 is hydrogen or alkyl; b) cycloalkyl is nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-Ci2 » optionally containing one or more heteroatoms
  • R6 is hydrogen or alkyl, n is 0-2,
  • R 7 is hydrogen or alkyl
  • R5 is hydrogen, cycloalkyl, C6-Ci2 ar yl. substituted cycloalkyl, substituted C6-Ci2 ar yl > alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)OR 6 , -S(O) n R 7 , nitro, cyano, halogen, C,3-Ci2ar l, substituted CQ-CI2 ⁇ ⁇ and protected -OH, where R ⁇ is hydrogen or alkyl, n is 0-2 and R 7 is hydrogen or alkyl; and c) aryl is cyclic or polycyclic aromatic C3-C12' optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms,
  • ⁇ is hydrogen or alkyl
  • n is 0-2
  • R 7 is hydrogen or alkyl and R5 is hydrogen, cycloalkyl, C6-Ci2 ryl, substituted cycloalkyl, substituted Cg-C ⁇ ryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)OR6, -S(O) n R 7 , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C6-Ci2 a:r yl > substituted C6-Ci2 a ryl and protected -OH, where R ⁇ is hydrogen or alkyl, n is 0-2 and R 7 is hydrogen or alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
  • the invention also is a method for inhibiting 5- ⁇ -reductase activity in mammals, including humans, that comprises administering to a subject an effective amount of a presently invented 5- ⁇ -reductase inhibiting compound.
  • novel intermediates and novel processes useful in preparing the presently invented 5- ⁇ -reductase inhibiting compounds include pharmaceutical compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention. Also included in the present invention are methods of co- administering the presently invented 5- ⁇ -reductase inhibiting compounds with further active ingredients.
  • A is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbon atoms
  • R is substituted alkyl, cycloalkyl or aryl where a) substituted alkyl is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbon atoms substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano, oxo, halogen, -C(O)OR6 and -S(O) n R 5 , where
  • R6 is hydrogen or alkyl, n is 0-2 and
  • ⁇ is hydrogen, cycloalkyl, C3-Ci2 ar yl» substituted cycloalkyl, substituted alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, aryloxy, -C(O)OR6, -S(O) n R 7 , nitro, cyano, halogen, Cg-Ci2 ar yl > substituted CQ-C ⁇ a ryl and protected -OH, where R ⁇ is hydrogen or alkyl, n is 0-2 and R 7 is hydrogen or alkyl; b) cycloalkyl is nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C12, optionally containing one or more heteroatoms, and optionally substituted with one or more substituents selected from the group consisting of:
  • R6 is hydrogen or alkyl, n is 0-2,
  • R 7 is hydrogen or alkyl and R5 is hydrogen, cycloalkyl, C6-Ci2 a ryl» substituted cycloalkyl, substituted Ce-Ci 2 ar yl» alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)OR6, -S(O) n R 7 , nitro, cyano, halogen, Cg-G ⁇ aryl, substituted C ⁇ -C ⁇ aryl and protected -OH, where R ⁇ is hydrogen or alkyl, n is 0-2 and R 7 is hydrogen or alkyl; and c) aryl is cyclic or polycyclic aromatic C3-C12, optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms
  • R6 is hydrogen or alkyl, n is 0-2,
  • R 7 is hydrogen or alkyl
  • Rp is hydrogen, cycloalkyl, C f 3-Ci2 ar yl» substituted cycloalkyl, substituted C6-Ci2 ar yl > alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)OR ⁇ , -S(O) n R 7 , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C ⁇ -C-j ⁇ aryl, substituted Cg-C- ⁇ aryl and protected -OH, where " R ⁇ is hydrogen or alkyl, n is 0-2 and R 7 is hydrogen or alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
  • Formula (I) compounds are those in which A is a linear or branched, saturated or unsatur ⁇ ri hydrocarbon chain containing from 2-12 carbon atoms.
  • A is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbon atoms
  • R is substituted alkyl, cycloalkyl or aryl where a) substituted alkyl is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbon atoms substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano, oxo, halogen, -C(O)OR 6 and -S(O) n R 5 , where
  • R ⁇ is hydrogen or alkyl
  • n is 0-2 and R5 is hydrogen, cycloalkyl, C ⁇ -C- ⁇ aryl, substituted cycloalkyl, substituted Cg-C- ⁇ aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, aryloxy, -C(O)OR6, -S(O) n R 7 , nitro, cyano, halogen, C6-Ci2aryl, substituted Cg-C- ⁇ aryl and protected -OH, where R ⁇ is hydrogen or alkyl, n is 0-2 and R 7 is hydrogen or alkyl; b) cycloalkyl is nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C12- " optionally containing one or more hetero
  • R ⁇ is hydrogen or alkyl, n is 0-2,
  • R 7 is hydrogen or alkyl
  • R5 is hydrogen, cycloalkyl, Cg-Ci2aryl, substituted cycloalkyl, substituted Cg-Ci ⁇ aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)OR 6 , -S(O) n R 7 , nitro, cyano, halogen, Cg-C ⁇ aryl, substituted Cg-C-j ⁇ aryl and protected -OH, where R is hydrogen or alkyl, n is 0-2 and R 7 is hydrogen or alkyl; and c) aryl is cyclic or polycyclic aromatic C3-Ci2 > optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms, and when C is 4 the aromatic
  • R 7 is hydrogen or alkyl
  • R5 is hydrogen, cycloalkyl, Cg-C- ⁇ aryl, substituted cycloalkyl, substituted C -Ci2 ryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)OR6, -S(O) n R 7 , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, Cg-Ci2aryl, substituted C -C ⁇ 2aryl and protected -OH, where is hydrogen or alkyl, n is 0-2 and R 7 is hydrogen or alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
  • Preferred among the presently invented Formula II compounds are those in which A is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 2-12 carbon atoms.
  • Preferred among the presently invented Formula II compounds are those in which A is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-6 carbon atoms and R is a) a linear or branched, saturated or unsaturated hydrocarbon chain containing 1-12 carbon atoms substituted with one or more substituents selected from the group consisting of: -OCg-Ci2 a ryl, carboxy,
  • n 0-2 and R 7 is hydrogen or C 1.4 alkyl
  • heteroatom and optionally substituted with one or more substituents selected from the group consisting of: -OCg-Ci2aryl, -(CH2) m OH, C -Ci2 ar yl > C ⁇ -C4alkyl,-OC ⁇ -C4alkyl, trifluoromethyl, halogen, -(CH2) p COOH, -S(O) n R 7 and protected -OH, where m is 0-4, p is 0-3, n is 0-2 and R 7 is hydrogen or C ⁇ alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
  • substituents selected from the group consisting of: -OCg-Ci2aryl, -(CH2) m OH, C -Ci2 ar yl > C ⁇ -C4alkyl,-OC ⁇ -C4alkyl, trifluoromethyl, halogen, -(CH2) p COOH, -S(O) n R 7 and
  • Preferred among said Formula II compounds are those in which A is a linear or branched, saturated or unsaturated hydrocarbon chain containing from-2-6 carbon atoms.
  • Formula II compounds are those in which A is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-4 carbon atoms and R is a) a linear or branched hydrocarbon chain containing 1-6 carbon atoms substituted with one or more halogens, b) C3-C8 nonaromatic, unsaturated or saturated cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, thio, methylsulfonyl, methylsulfoxyl, methylthio, carboxy, hydroxy, trifluoromethyl, phenoxy and methoxy or c) C4-Ci2aryl, optionally containing one more heteroatoms, provided that when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: halogen, thio, methylsulfonyl, methylsulfoxyl, methylthio
  • Preferred among said Formula II compounds are those in which A is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 2-4 carbon atoms.
  • Formula II compounds are those in which A is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-4 carbon atoms and R is a) CF3 b) C5-C7 cycloalkyl or c) 4-C12 aryl, optionally containing one or more heteroatoms, provided that when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: halogen, thio, methylsulfonyl, methylsulfoxyl, methylthio, carboxy, hydroxy, trifluoromethyl, phenoxy and methoxy and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
  • Preferred among said Formula II compounds are those in which A is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 2-4 carbon atoms.
  • formula II compounds are: 17 ⁇ -(phenylpropylcarbonyl)-androsta-3,5-diene-3-carboxylic acid, 17 ⁇ -(benzylcarbonyl)-androsta-3,5-diene-3-carboxylic acid,
  • ⁇ as used herein, follows standard chemical terminology and means up or that the corresponding substituent is attached above the plane of the paper.
  • protected hydroxy or “protected -OH” as used herein, is meant the alcoholic or carboxylic-OH groups which can be protected by conventional blocking groups in the art as described in “Protective Groups In Organic Synthesis” by Theodora W. Greene, Wiley- Interscience, 1981, New York. Preferred are the triorganosilyl groups, e.g. t-butyldimethylsilyl, phenyldimethylsilyl, diphenylmethylsilyl, and the like.
  • C x -C v is meant a moiety having from x to y carbons.
  • aryl as used herein, unless otherwise defined, is meant cyclic or polycyclic aromatic C3-C12, optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, Cg-Ci2 aryl, substituted cycloalkyl, substituted Cg-Cj ⁇ aryl, aryloxy, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, -C(O)OR 6 , -S(O) n R 5 , protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C -Ci2 a ryl, substituted C -Ci2aryl, amino,
  • aryl and substituted aryl substituents as used herein include: phenyl, naphthyl, furanyl, biphenyl, hydroxyphenyl, pyridyl, fluorophenyl, dihydroxyphenyl, methylenedioxyphenyl, dimethylhydroxyphenyl, methoxyphenyl, trifluoromethylphenyl carboxymethylphenyl, phenoxyphenyl, methylsulfonylphenyl, methylthiophenyl, difluorophenyl, carboxyphenyl, methylsulfoxylphenyl and thiophenyl.
  • aryl and substituted aryl substituents as used herein include: phenyl, 4-fluorophenyl, 2,6-difluorophenyl, 1- naphthyl, 4-biphenyl, 4-methoxyphenyl, 4-phenoxyphenyl, 4- trilluoromethylphenyl, 4-methylsulfonylphenyl, 4-methylthiophenyl, 3,5-difluorophenyl, 4-hydroxyphenyl, 4-carboxyphenyl, 2-furanyl, 4- methylsulfoxylphenyl, 3-thiophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and 3,4-methylenedioxyphenyl.
  • C6 ⁇ 12 aryl
  • substituted as used herein, unless otherwise defined, is meant that the subject chemical moiety has one or more substituents selected from the group consisting of: hydroxyalkyl, alkoxy, acyloxy, alkyl, amino, N-acylamino, hydroxy, -(CH2)gC(O)OR 6 , -S(O) n R 7 , nitro, cyano, halogen, trifluoromethyl and protected -OH, where g is 0-6, R ⁇ is hydrogen or alkyl, n is 0-2, and R 7 is hydrogen or alkyl.
  • alkoxy as used herein is meant -Oalkyl where alkyl is as described herein including -OCH3 and -OC(CH3)2CH3.
  • cycloalkyl as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C12.
  • cycloalkyl and substituted cycloalkyl substituents as used herein include: cyclohexyl, 4-hydroxy-cyclohexyl, 2- ethylcyclohexyl, propyl 4-methoxycyclohexyl, 4-methoxycyclohexyl, 4- carboxycyclohexyl and cyclopentyl.
  • acyloxy as used herein is meant -OC(O)alkyl where alkyl is as described herein.
  • Examples of acyloxy substituents as used herein include: -OC(O)CH 3 , -OC(O)CH(CH 3 ) 2 and -OC(O)(CH 2 )3CH 3 .
  • N-acylamino as used herein is meant -N(H)C(O)alkyl, where alkyl is as described herein.
  • Examples of N- acylamino substituents as used herein include: -N(H)C(O)CH3, -N(H)C(O)CH(CH 3 ) 2 and -N(H)C(O)(CH 2 )3CH 3 .
  • aryloxy as used herein is meant -OCg-Ci2 a ryl where C -Ci2 a ryl is phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl or biphenyl optionally substituted with one or more substituents selected from the group consisting of: alkyl, hydroxyalkyl, alkoxy, trifuloromethyl, acyloxy, amino, N-acylamino, hydroxy,
  • aryloxy substituents as used herein include: phenoxy, 4-fluorophenyloxy and biphenyloxy.
  • heteroatom as used herein is meant oxygen, nitrogen or sulfur.
  • halogen as used herein is meant a substituent selected from bromide, iodide, chloride and fluoride.
  • alkyl and derivatives thereof and in all carbon chains as used herein is meant a linear or branched, saturated or unsaturated hydrocarbon chain having C1-C12 carbon atoms.
  • alkyl substituents as used herein include: -CH3, -CH2-CH3,
  • treating prophylatic or therapeutic therapy.
  • metal-catalyzed coupling reaction as used herein is meant that the prepared 3-trifluoromethyl sulfonylate or 3- fluorosulfonylate compound is reacted in a suitable organic solvent; preferably dimethylsulfoxide, toluene, dichloroethane, dimethylformamide or THF; with a base, preferably a tertiaryamine base such as triethylamine, pyridine or tributylamine; a Cj-Cg alcohol (when an ester is desired) or a Cj-Cg carboxylic acid salt, preferably KOAc (when an acid is desired) and a phosphine, such as bis(diphenylphosphino)alkane, preferably 1,3 bis(diphenylphosphino)propane, tri-o-tolyphosphine or 1,1- bis(
  • Coupled reagent as used herein is meant a compound which is capable of reacting with said metalated complex to form an ester or a carboxylic acid substituent.
  • Carbon monoxide is a preferred coupling reagent which when added to the metal-catalyzed coupling reaction, as described herein, yields the desired ester or carboxylic acid group.
  • esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • ⁇ -receptor antagonist refers to a known class of alpha-andrenergic receptor antagonist comounds, such as described in Lafferty, et al. U.S. Patent No. 4,963,547, which are utihzed 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- 1-benzopyran.
  • amsulosin as used herein is meant a compound of the structure
  • amsulosin is designated as (-)-(R)-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 4,987,152 as being useful in treating lower urinary tract dysfunction.
  • terazosin as used herein is meant a compound of the structure and salts, hydrates and solvates thereof.
  • terazosin is designated as l-(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 as used herein is meant a compound of the formula
  • doxazosin is designated as l-(4-amino-6,7- dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-l,4-benzodioxin-2- yl)carbonyl]-piperazine.
  • alfuzosin as used herein is meant a compound of the formula
  • Chemically alfuzosin is designated as N-[3-[(4-amino-6,7- dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2- furancarboxamide.
  • indoramin as used herein is meant a compound fo the formula and salts, hydrates and solvates thereof.
  • prazosin as used herein is meant a compound of the formula
  • Chemically prazosin is designated as l-(4-amino-6,7-dimethoxy-2- quinazolinyl)-4-(2-furanylcarbonyl)piperazine.
  • Prazosin is disclosed in U.S. Patent Number 3,511,836.
  • alpha-adrenergic receptor antagonists are preferred alpha- adrenergic receptor antagonists as used herein.
  • alpha-andrenergic receptor antagonist a compound other than one specifically referred to herein is a alpha-andrenergic receptor antagonist by utilizing the assay described in Lafferty I. Thus, all such compounds are included within the scope of the term "alpha- andrenergic receptor antagonist" as used herein.
  • minoxidir as used herein is meant the compound of the formula:
  • Minoxidil is the active ingredient in Rogaine® which is sold as topical solution for stimulating hair growth by the Upjohn Company, Kalamazoo, Michigan.
  • 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 92/18132.
  • 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.
  • a preferred aromatase inhibitor for use in the compositions and methods of the invention 4-(5,6,7,8-tetrahydroimidazo-[l,5- ⁇ ]pyridin-5- yDbenzonitrile (fadrazole). Fadrazole is disclosed in U.S.
  • co-administering and derivatives thereof as used herein is meant either 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 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.
  • the administration is not simultaneous, the compounds 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 administered topically and another compound may be administered orally.
  • Formula (II) compounds are prepared as shown in Schemes I, II and III wherein A is as described in Formula (II).
  • R8 is R or moieties which can be converted to those of R by chemical reactions readily is known to those of skill in the art, such as described in Arthur Barton and U.D. Ollis, Comprehensive Organic Chemistry: The Synthesis and Reactions of Organic Compounds. Pub: Pergamon Press (1979), provided that R8 does not include any such moieties that render inoperative the Schemes I, II or III processes.
  • reactions to convert R to R are performed on products of the synthetic pathways of Schemes I, II or III or where appropriate or preferable, on certain intermediates in these synthetic pathways.
  • methylthio substituents can be converted to the methylsulfonyl by oxidation.
  • Methoxy substituents can be converted to the hydroxy by treatment with boron tribromide.
  • Hydroxy substituents can be converted to the carboxy by reaction with a trihaloalkylsulfonic anhydride, such as trifluoromethanesulfonic anhydride, followed by a metal catalyzed coupling reaction.
  • novel compounds of Formula (II) of the present invention can be prepared by methods outlined in schemes 1-3 below and in the examples from the known and readily available steroid acid of the structure (X):
  • Scheme I outlines formation of Formula II compounds.
  • compound (b) is prepared from compound (a) by treating (a) with halogen- Vilsmeier reagent, described hereinbelow, in an appropriate solvent, preferably methylene chloride followed by quenching with excess Grignard reagent, described hereinbelow.
  • the 3- cyano derivative (c) is produced by treating (b) with a cyanating reagent, described hereinbelow, in an appropriate solvent, preferably dimethylformamide.
  • the 17-acyl derivative (c) is saponified, described hereinbelow, to yield compounds (d).
  • Scheme II outlines formation of Formula II compounds.
  • Rl is CF3O2SO- or FO2SO-.
  • the enone acid (a) is converted to the 3- trifluoromethylsulfonylate or 3-fluorosulfonylate derivative (e) (step A) by treating (a) with trifluoromethylsulfonyl anhydride or fluorosulfonic anhydride and an amine base, such as pyridine, preferably 2,5 di-t-butyl- 3-methyl-pyridine, in an appropriate organic solvent, preferably dichloromethane at about -20°C to 20°C, preferably 0°.
  • an amine base such as pyridine, preferably 2,5 di-t-butyl- 3-methyl-pyridine
  • the activated ester (f) is produced (step B) by treating (e) with 2,2- dithiopyridyl and triphenylphosphine in an appropriate organic solvent solution preferably, tetrahydrofuran/toluene at room temperature for about 8-14 hours.
  • the 17-acyl derivative (g) is produced (step C) by treating (f) with a Grignard reagent, described hereinbelow, in tetrahydrofuran or diethyl ether solvent, at a temperature of about -50 to -70°, for 1-16 hours.
  • the 3-alkyl ester (j) is produced (step D) by treating (g) under carbonylation conditions, preferably by bubbling carbon monoxide gas through a solution of (g) in an appropriate organic solvent, preferably methanol, containing palladium acetate catalyst, triphenylphosphine, and a tertiary organic amine preferably triethylamine at about room temperature for 1-16 hours.
  • Compound (j) next is reacted with a suitable base, preferably potassium carbonate and acidified (step F) to yield compounds (d).
  • a suitable base preferably potassium carbonate and acidified (step F)
  • Compounds (d) can also be produced (step H) by treating (g) under carboxylation conditions, preferably by bubbling carbon monoxide gas through a solution of (g) in appropriate non-alcoholic solvent, preferably DMF, containing a palladium catalyst, preferably bis(triphenylphoshine)palladium II diacetate, and a carboxylate salt, preferably potassium acetate, preferably at increased temperatures.
  • a palladium catalyst preferably bis(triphenylphoshine)palladium II diacetate
  • carboxylate salt preferably potassium acetate
  • $ is aroyl, which also contains a protected hydroxy group, e.g. with dimethyl-t-butyl-silyl
  • this may be removed by treating with tetrabutylammonium floride in an appropriate, organic solvent, preferably tetrahydrofuran with a small amount of added acetic acid, from 0°C to reflux for 1-4 hours prior to carrying out step F.
  • Route 2 involves converting the starting steroidal acid (a) to the 3- trifluoromethylsulfonylate or the 3-fluorosulfonylate derivative (e) by the above-described step A; carbonylating (e) to (h) by step D; forming the activated 2-pyridylthio ester (i) by step B; forming the 17-acyl compound (j) by step C; and hydrolyzing the 3-ester to the 3 acid final product (d) by step F.
  • Route 3 involves converting the starting steroid acid (a) to the 3- trifluoromethylsulfonylate or the 3-fluorosulfonylate derivative (e) by the above-described step A.
  • the 3-cyano derivative (k) is produced (step E) by treating (e) with a cyanating agent (as described hereinbelow) in an appropriate solvent, preferably dimethylformamide.
  • the activated 2- pyridylthio derivative (1) is prepared from (k) by step B.
  • Forming the 17- acyl compound (c) involves reacting 0) by step C.
  • the 17-acyl derivative (c) is saponified (step G) (as described herein) to yield compounds (d).
  • compound (1) is prepared from compound (k) by treatment with phosphorusoxychloride in toluene followed by treatment with methanol.
  • Formula (1) compounds are reacted with a reducing agent, preferably diisobutylaluminum hydride, to yield formula (m) compounds.
  • a reducing agent preferably diisobutylaluminum hydride
  • Formula (n) compounds are produced by treating formula (m) compounds with a G ⁇ gnard Reagent (as described in Scheme II) in tetrahydrofuran or diethylether solvent, at a temperature of about -50°C to -70°C, for 1-16 hours.
  • Formula (o) compounds are prepared by oxidation of formula (n) compounds. Preferably said oxidation will utilize tetrapropylammonium peruthenate or a Jone's reagent.
  • Formula (d) compounds are prepared by oxidation of formula (o) compounds.
  • oxidation will utilize sodium chlorite.
  • Grignard reagents of the type, XMgAR ⁇ , for all of the species included within the scope of this invention, are available or can be made readily by one skilled in the art.
  • a AR8 is hydroxyphenyl
  • this can be derived by starting with an appropriate bromophenol, e.g. p-bromophenol, protecting the phenolic-OH with a conventional blocking group, e.g. triorganosilyl, i.e. t-butyldimethylsilyl, carrying out the Grignard reaction and then deblocking the silyl group by the use of, e.g. refluxing aqueous tetrabutylammonium fluoride.
  • a AR ⁇ being hydroxyethylphenyl
  • the same blocking procedure can be analogously conducted starting with the appropriate hydroxyalkyl bromophenol, e.g. p-hydroxymethylbromobenzene, or p- hydroxymethylbromobenzene, or p-hydroxyethylbromobenzene.
  • AR8 is carboxyphenyl
  • this can be obtained by the chromic acid oxidation of the appropriate hydroxymethylbenzene, e.g. p- bromo-hydroxymethylbenzene, formed as described above.
  • Formula I compounds in which Z is in the ⁇ position are prepared from compounds which contain the corresponding ⁇ substituent by the General Method below.
  • a base such as a Iiydroxide or alkoxide base, preferably sodium hydroxide, potassium hydroxide or sodium methoxide, at a temperature over 100 °C preferably at reflux temperatures to yield the corresponding ⁇ epimer, after isolation and work up.
  • dimethyl sulfoxide or other non-reactive high boihng solvents are preferred when the starting 17 ⁇ 5 ⁇ -reductase inhibiting steroidal compound contains reactive substituents or reactive unsaturated bonds that are, for example, subject to nucleophilic attack and ethylene glycol, or other reactive high boiling solvents can be used when the reactivity of the substituents or any unsaturated bonds of the starting 17 ⁇ 5 ⁇ -reductase inhibiting steroidal compound is not a consideration.
  • I -C-A-R a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbon atoms;
  • R is substituted alkyl, cycloalkyl or aryl, where a) substituted alkyl is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbon atoms substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano, oxo, halogen, -C(O)OR 6 and -S(O) n R 5 , where
  • R- is hydrogen or alkyl, n is 0-2 and
  • R5 is hydrogen, cycloalkyl, Cg-C ⁇ aryl, substituted cycloalkyl, substituted C -Ci2 a ryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, aryloxy, -C(O)OR 6 , -S(O) n R 7 , nitro, cyano, halogen, Cg-Ci2aryl, substituted Cg-Ci2aryl and protected -OH, where R 6 is hydrogen or alkyl, n is 0-2 and R 7 is hydrogen or alkyl; b) cycloalkyl is nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-Ci2 > optionally containing one or more heteroatoms, and optionally substituted with one or more substituent
  • R6 is hydrogen or alkyl, n is 0-2,
  • R 7 is hydrogen or alkyl and R5 is hydrogen, cycloalkyl, C -Ci2aryl, substituted cycloalkyl, substituted Cg-Ci2 a ryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)OR6, -S(O) n R 7 , nitro, cyano, halogen, C -Ci2 a ryl, substituted Cg-Ci2 a ryl and protected -OH, where R& is hydrogen or alkyl, n is 0-2 and R 7 is hydrogen or alkyl; and c) aryl is cyclic or polycyclic aromatic C3-C12:- optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains
  • R ⁇ is hydrogen or alkyl
  • n is 0-2
  • R 7 is hydrogen or alkyl
  • R5 is hydrogen, cycloalkyl, Cg-Ci2 a ryl, substituted cycloalkyl, substituted C -Ci2 a ryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)OR ⁇ , -S(O) n R 7 , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C -Ci2 a ⁇ yl, substituted Cg-C ⁇ aryl and protected -OH, where R*-** is hydrogen or alkyl, n is 0-2 and R 7 is hydrogen or alkyl; and pharmaceutically acceptable salts, hydrates solvates and esters thereof.
  • ketone reduction products described above are those in which A is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 2-12 carbon atoms.
  • These compounds can be made by conventional sodium borohydride reduction of the carbonyl attached to A without epimerization or reducing the carboxyl in Ring A or the 3,5-double bonds.
  • the R substituent contains a carbonyl function, it can be selectively blocked and then regenerated after the borohydride reduction by conventional methods.
  • the borohydride reduction can be carried out in e.g. water or aqueous methanol, at a temperature of room temperature to 50°C and the product then isolated and purified by conventional means.
  • the compounds are also active as 5-alpha reductase inhibitors.
  • halogen- Vilsmeier reagent as used herein is meant a halogenated disubstituted formamide reagent of the structure:
  • R ⁇ and R ⁇ - are independently selected from an alkyl, aryl or arylalkyl group; and X is Br or I; and y is a counter ion, which is prepared by a) reacting, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro- Vilsmeier reagent, said chloro- Vilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodine source, preferably hydrogen bromide gas or b) reacting, preferably at reduced temperatures, a bromide source or an iodide source, preferably oxalyl bromide, with a disubstituted formamide reagent,
  • reduced temperature as used herein is meant below 25°C, preferably between -15 and 15°C, most preferably between 0 and 10°C.
  • cyanating reagent as used herein and in the claims is meant a compound or reagents which are capable of reacting with a halogenated moiety to form a cyanated moiety under appropriate conditions.
  • cyanated moiety is prepared by reacting the corresponding halogenated moiety with a cyanating agent in an appropriate solvent, such as N,N-dimethyl-N,N-propylene urea (DMPU), N,N-dimethylformamide (DMF) or N-methyl-2-pyrrolidinone (NMP), preferably DMF, at increased temperatures.
  • a cyanating agent such as N,N-dimethyl-N,N-propylene urea (DMPU), N,N-dimethylformamide (DMF) or N-methyl-2-pyrrolidinone (NMP), preferably DMF
  • said carboxylic acid substituted moiety is prepared by reacting the corresponding cyanated moiety with a hydroxide base, preferably aqueous sodium hydroxide, in an appropriate solvent, such as; ethylene glycol, isopropyl alcohol or ethanol, preferably ethanol, at increased temperatures with subsequent acidification.
  • a hydroxide base preferably aqueous sodium hydroxide
  • an appropriate solvent such as; ethylene glycol, isopropyl alcohol or ethanol, preferably ethanol
  • cyanating reagents for use in the presently disclosed processes utilize cyanide complexes such as described in Richard C. Larock, Comphrehensive Organic Transformations: A Grid? to Functional Group Preparations. Pub: VCH Publishers, Inc. (1989) P. 861.
  • An example of a cyanide complex as used herein is the in ⁇ ai co- mixture of KCN, NiBr2(PPh3)2, Zn, PPI13.
  • Other examples include: Co(CN) 3 4 ; K4Ni 2 (CH)g, KCN; KCN, cat Pd(PPh 3 ) 4 ; Co(CN) 3 5 ; CuCN and
  • NaCu(CN)2 refers to the reagent formed by co-mixing CuCN and NaCN in sun.
  • NaCu(CN) 2 Preferably said NaCu(CN)2 complex is prepared by adding 1 molar equivalent of sodium cyanide to cuprous cyanide in situ.
  • solvent or "appropriate solvent” as used herein and the in the claims is meant a solvent such as methylene chloride, ethylene chloride, chloroform, ethylene glycol, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, hexane, dimethylsulfoxide (DMSO), N,N'-dimethyl-N,N'-propylene urea, N- methyl-2-pyrrolidinone, methanol, isopropylalcohol, diinethylformamide (DMF), water, pyridine, quinoline or ethanol.
  • DMSO dimethylsulfoxide
  • DMSO dimethylsulfoxide
  • N,N'-dimethyl-N,N'-propylene urea N- methyl-2-pyrrolidinone
  • methanol isopropylalcohol
  • diinethylformamide (DMF)
  • R 2 is 2-thiopyridylcarbonyl and R 3 is fluorosulfonyloxy or cyano.
  • A is as defined in Formula (II) and R- is R as defined in Formula ( ⁇ ) or moieties which can be converted to those of R by known reactions such as desired in Arthur Barton and U.S. Ollis,
  • R ⁇ is fluorosulfonyloxy, halogen, cyano, or -CHO.
  • A is a linear or branched, saturated or unsaturated hydrocarbon containing from 1-12 carbon atoms
  • R is as defined in Formula (II) above and pharmaceutically acceptable salts, hydrates, solvates and esters thereof comprises reacting a compound of the formula
  • a and R8 are as defined in Formula (IV) with fluorosulfonic anhydride and a base, preferably, 2,5-t-butyl-3-methyl-pyridine, in a solvent, preferably dichloromethane, to form a compound of the formula in which A and R-- are as described above and subsequently reacting said compound in a metal-catalyzed coupling reaction in the presence of an approrpirate coupling reagent, preferably, carbon monoxide followed by an optional, if applicable, hydrolysis reaction and optionally, if applicable converting R& to R, to form a compound of Formula II, and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • an approrpirate coupling reagent preferably, carbon monoxide followed by an optional, if applicable, hydrolysis reaction and optionally, if applicable converting R& to R, to form a compound of Formula II, and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • the above formula (VIII) compounds are prepared by first activating the 17-position carboxyic acid substituent of compounds of structure (X), as described herein, preferably with an acid chloride, such as thionylchloride or by forming a thiopyridylester by reaction with 2,2- dithiopyridyl, and then treating with a Grignard reagent as described herein.
  • an acid chloride such as thionylchloride
  • a thiopyridylester by reaction with 2,2- dithiopyridyl
  • a and R are a defined above and pharmaceutically acceptable salts, hydrates, solvates and esters thereof comprises reacting, at a reduced temperature, a compound of the formula
  • a and R * ⁇ are as defined above and subsequently saponifying said compound and optionally, if applicable, converting R& to R, to form a compound of Formula II and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate.
  • a and R are as defined in Formula (II); and pharmaceutically acceptable salts, hydrates, solvates and esters thereof which comprises either
  • the presently invented pharmaceutically active compounds inhibit steroid 5- ⁇ -reductase activity, they have therapeutic utility in treating diseases and conditions wherein decreases in DHT activity produces 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., Be ⁇ nan, 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.
  • Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5- ⁇ -reductase isozyme 2 were homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, ImM dithiothreitol, and 50 ⁇ M NADPH (buffer A) using a Douce 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 20 mM potassium phosphate, pH 6.5 containing 20% glycerol, ImM dithiothreitol, and 50 ⁇ M NADPH (buffer B). The suspended particulate solution was stored at -80°C until used.
  • Assay for enzvmes activities and inhibitors potency A constant amount of [ 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.
  • 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, from which enzyme activity was determined. All incubations were conducted such that no more than 20% of the substrate (testosterone) was consumed.
  • the pharmaceutically active compounds within the scope of this invention are useful in inhibiting steroid 5- ⁇ -reductase in a mammal, including humans, in need thereof.
  • Solid or liquid pharmaceutical carriers are 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 be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as 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 ingreidents, 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 0.1 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) or a compound of Formula (V) 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 or a compound of Formula (V) 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 or a compound of Formula (V) 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 or a compound of Formula (V) which comprises bringing the compound of Formula I or the compound of Formula (V) 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.
  • a 5- ⁇ -reductase inhibitor as disclosed herein
  • minoxidil for use in the treatment of male pattern baldness
  • a 5 ⁇ -reductase inhibitor as disclosed herein
  • a ⁇ -receptor antagonist for use in the treatment of benign prostatic hypertrophy.
  • the solution is cooled to 0-5°C, and treated with 6.9 mL (2.5 molar equivalents) of oxalyl chloride while maintaining the temperature between 0-10°C. A white precipitate formed.
  • 50.1 grams (19.6 molar equivalents) of hydrogen bromide gas is bubbled through the solution while maintaining the temperature between 0- 10°C.
  • the suspension becomes a clear colorless solution.
  • the solution is degassed by reducing the solution volume by about one-half by vacuum distillation and restoring to its original volume with methylene chloride. This concentration refill procedure is repeated.
  • Androst-4-en-3-one-17b-carboxylic acid 10.0 grams (1 molar equivalent), is added to the resulting white suspension and the mixture is warmed to room temperature and stirred for 2 hours.
  • the reaction mixture is quenched into a vessel containing 100 mL of methylene chloride and 1 molar equivalent of phenethylmagnesium bromide while maintaining the temperature between 0-10°C.
  • the mixture is stirred for 30 minutes.
  • About 100 mL of water is added and the biphase mixture is filtered through a pad of Celite.
  • the organic phase is separated and reduced to about half its volume by vacuum distillation.
  • the solution is restored to its original volume with acetone. This concentration/fill procedure is repeated twice more.
  • the resulting acetone solution (about 300 mL) is warmed to about 50°C and was treated with about 100 mL of water to precipitate the product.
  • the suspension is cooled, and the product, 17 ⁇ -(phenethylcarbonyl)-androsta-3-bromo-3,5-diene, is isolated by filtration and dried.
  • a stirred mixture of 17 ⁇ -(phenethylcarbonyl)-androsta-3-bromo-3,5-diene (50 grams, 1 molar equivalent), cuprous cyanide (11.0 grams, 1 molar equivalents), and dimethylformamide (200 mL) is heated to reflux for 3.5 hours.
  • the reaction is cooled to 90-100°C and quenched with stirring into a solution of 100 mL of cone, aqueous ammonia and 200 mL of water.
  • the reaction flask is rinsed out with 25 mL of dimethylformamide, which is also added to the quench solution.
  • the resulting suspension is extracted twice with 200 mL portions of methylene chloride, and the organic extracts is filtered through a pad of celite.
  • the organic phase is washed with three 200 mL portions of 50/50 v/v cone, aqueous ammonia/water, followed by two 200 mL portions of water.
  • the organic phase is concentrated under vacuum to 150 mL and 250 mL of ethanol is added.
  • the solution is again concentrated under vacuum to 150 mL, and 250 mL of ethanol is added.
  • the solution is concentrated under vacuum to 300 mL, and 30 m-L of water is added to induce crystallization.
  • the resulting suspension is chilled for 2 hours at 0-5°C.
  • the solid product is collected by filtration and is dried at 65°C under vacuum to afford 17 ⁇ -(phenethylcarbonyl)-androsta-3-cyano-3,5- diene.
  • a mixture of 17 ⁇ -(phenethylcarbonyl)-androsta-3-cyano-3,5-diene (20.0 grams, 1 molar equivalent), 50% aqueous sodium hydroxide (80 mL, 30 molar equivalents), and ethanol (200 mL) is heated to reflux for 18 hours.
  • the reaction suspension is cooled to 50°C and is added to a stirred mixture of 6N hydrochloric acid (300 mL) and methylene chloride (200 mL).
  • the final pH of the aqueous phase is 1.5-2.0.
  • the organic phase is separated and the aqueous phase is reextracted with 250 mL of methylene chloride.
  • the combined organic phases are stirred with 2 grams of decolorizing charcoal for one hour and are filtered through a pad of celite.
  • the organic phase was concentrated under vacuum to 120 mL and 200 mL of ethyl acetate is added.
  • the suspension is again concentrated under vacuum to 120 mL and 200 mL of ehtyl acetate is added.
  • the resulting suspension is concentrated under vacuum to a final volume of 120 mL and is heated at reflux for 2 hours.
  • the suspension is chilled at 0-5°C for two hours and filtered.
  • the solid product is dried under vacuum at 65°C to afford 17 ⁇ - (phenethylcarbonyl)-androsta-3,5-diene-3-carboxylic acid.
  • a solution of 3-(fluorosulfonyloxy)-androsta-3,5-diene-17 ⁇ - carboxylic acid in dimethylformaide is treated with an excess of cuprous cyanide at reflux.
  • the reaction solution is quenched into aqueous ammonia and is filtered.
  • the filtered solids are dissolved in methylene chloride aqueous hydrochloric acid. Conventional workup and isolation by column chromatography yields the title compound.
  • Example 2(iii) The title compound is prepared according to Example 2(iii) by substituting S-(2-pyridyl)-3-cyano-androsta-3 ,5-diene- 17B- thiocarboxylate, as prepared in Example 9(iii), for S-(2-pyridyl)-3- (tiifluoromethanesulfonyloxy )-androsta-3 ,5-diene- 17 ⁇ -thiocarboxylate .
  • Phosophorus oxychloride (40ml, 429 mmol) was added to a solution of (17 ⁇ )-17-N-t-butyl carboxamidyl androsta-3,5-diene-3- carboxylic acid (15.5 g, 39 mmol) in benzene (500 ml) and was heated to reflux. After 12 h the reaction was treated with MeOH (10 ml), then aqueous NaHCO3, extracted with CH2CI2, dried (MgSO4), filtered, concentrated, chromatographed (silica gel, 20% EtOAc hexanes), and recrystallized (EtOAc hexanes) to yield the title compound as a yellow solid.
  • Tetrapropyl ammonium perruthenate (10 mg, 0.028 mmol) was added to a solution of (17 ⁇ )-17-(5,5,5-trifluoro-l-hydroxypentyl)- androsta-3,5-diene-3-methanol (65 mg, 0.15 mmol) and 4- methylmorpholine N-oxide (80 mg, 0.68 mmol) in CH2CI2 (2.0 ml) at RT.
  • EXAMP E 18 An oral dosage form for administering Formula I comounds is produced by screening, mixing, and filling into hard gelatin capsules the ingredients in the proportions shown in Table 1, below.
  • 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.
  • 17 ⁇ -(phenethylcarbonyl)-androsta-3,5-diene-3-carboxylic acid 75 mg, is dispursed in 25 ml of normal saline to prepare an injectable preparation.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cette invention concerne des analogues d'acyl-3-carboxy-3,5-diène à substitution 17α et 17β de composés stéroïdiens synthétiques, des compositions pharmaceutiques renfermant ces composés, des procédés d'utilisation de ces composés permettant d'inhiber la 5-α-réductase stéroïdienne; ainsi que de nouveaux intermédiaires et des procédés de préparation desdits composés.
PCT/US1993/011241 1992-11-18 1993-11-18 Acyl-3-carboxy-3,5-dienes a substitution 17-alkyle et 17-beta et utilisation de ces derniers pour inhiber la 5-alpha-reductase WO1994011386A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU56717/94A AU5671794A (en) 1992-11-18 1993-11-18 17-alpha and 17-beta substituted acyl-3-carboxy-3,5-dienes and use in inhibiting 5-alpha-reductase
US08/436,240 US5641765A (en) 1992-11-18 1993-11-18 17-αand 17-βsubstituted acyl-3-carboxy-3,5-dienes and use in inhibiting 5-α-reductase
EP94902307A EP0669932A4 (fr) 1992-11-18 1993-11-18 Acyl-3-carboxy-3,5-dienes a substitution 17-alkyle et 17-beta et utilisation de ces derniers pour inhiber la 5-alpha-reductase.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9224213.0 1992-11-18
GB929224213A GB9224213D0 (en) 1992-11-18 1992-11-18 Compounds
GB939316954A GB9316954D0 (en) 1993-08-14 1993-08-14 Compounds
GB9316954.8 1993-08-14

Publications (1)

Publication Number Publication Date
WO1994011386A1 true WO1994011386A1 (fr) 1994-05-26

Family

ID=26302003

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US1993/011241 WO1994011386A1 (fr) 1992-11-18 1993-11-18 Acyl-3-carboxy-3,5-dienes a substitution 17-alkyle et 17-beta et utilisation de ces derniers pour inhiber la 5-alpha-reductase
PCT/US1993/011225 WO1994011004A1 (fr) 1992-11-18 1993-11-18 Steroides 17 substitutes acyle-3-carboxy 3,5-diene en tant qu'inhibiteurs de 5-alpha-reductase

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US1993/011225 WO1994011004A1 (fr) 1992-11-18 1993-11-18 Steroides 17 substitutes acyle-3-carboxy 3,5-diene en tant qu'inhibiteurs de 5-alpha-reductase

Country Status (12)

Country Link
EP (2) EP0669932A4 (fr)
JP (1) JPH08503471A (fr)
CN (2) CN1101916A (fr)
AP (1) AP9300589A0 (fr)
AU (2) AU5671794A (fr)
CA (1) CA2149427A1 (fr)
IL (1) IL107611A0 (fr)
MA (1) MA23036A1 (fr)
MX (1) MX9307203A (fr)
NZ (1) NZ258723A (fr)
SI (1) SI9300601A (fr)
WO (2) WO1994011386A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996003422A1 (fr) * 1994-07-28 1996-02-08 Pharmacia S.P.A. 4-azasteroides ayant des fluorocetones comme chaines laterales
WO1996003420A1 (fr) * 1994-07-28 1996-02-08 Pharmacia S.P.A. 3-carboxysteroides presentant une chaine laterale fluoree
US5541322A (en) * 1994-10-14 1996-07-30 Glaxo Wellcome Inc. Synthesis of 6-azaandrostenones
US5543417A (en) * 1994-10-21 1996-08-06 Merck & Co., Inc. Combination method of treating acne using 4-AZA-5α-cholestan-ones and 4-AZA-5α-androstan-ones as selective 5α-reductase inhibitors with anti-bacterial, keratolytic, or anti-inflammatory agents
US5565467A (en) * 1993-09-17 1996-10-15 Glaxo Wellcome Inc. Androstenone derivative
EP0784627A4 (fr) * 1994-10-05 1998-05-06 Smithkline Beecham Corp Procede de preparation d'acides androsta-3,5-diene-3-carboxyliques a substitution en 17 beta
US7388031B2 (en) 2000-11-30 2008-06-17 Sanofi-Aventis Cyclohexyl(alkyl)-propanolamines, preparation method and pharmaceutical compositions containing same

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1043324B1 (fr) 1997-11-12 2004-06-16 Mitsubishi Chemical Corporation Derives de purine et medicament les renfermant en tant qu'ingredient actif
ATE254616T1 (de) 1999-05-11 2003-12-15 Mitsubishi Chem Corp Dihydrat eines purinderivates, medikamente die dieses als aktiven wirkstoff enthalten und zwischenprodukte zu dessen herstellung
GB201102913D0 (en) 2011-02-18 2011-04-06 Univ Birmingham Novel therapeutic

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US5032586A (en) * 1989-08-24 1991-07-16 Smithkline Beecham Corporation 7-keto or hydroxy 3,5-diene steroids as inhibitors of steroid 5-alpha reductase
US5041433A (en) * 1987-04-29 1991-08-20 Smithkline Beecham Corporation 11-keto or hydroxy 3,5-diene steroids as inhibitors of steriod 5-α-reductase
US5137882A (en) * 1990-06-11 1992-08-11 Holt Dennis A Steroidal 3-acetic acid derivatives as 5-alpha-reductase inhibitors
US5196411A (en) * 1991-08-16 1993-03-23 Merck & Co., Inc. 17β-acyl-3-carboxy-androsta-3,5-dienes as testosterone 5α-reductase inhibitors

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US4910226A (en) * 1987-04-29 1990-03-20 Smithkline Beckman Corporation Steroid 5-alpha-reductase inhibitors
US4954446A (en) * 1988-05-25 1990-09-04 Smithkline Beecham Corporation Aromatic steroid 5-α-reductase inhibitors
US5091380A (en) * 1990-06-28 1992-02-25 Merck & Co., Inc. N-monosubstituted adamantyl/norbornanyl 17β-carbamides of 3-carboxy-androst-3,5-dienes as testosterone 5α-reductase inhibitors
CA2045866A1 (fr) * 1990-06-28 1991-12-29 Gary H. Rasmusson 17-beta-acyl-3-carboxyandrosta-3,5-dienes comme inhibiteurs de la testosterone-5-alpha-reductase
EP0465123A3 (en) * 1990-06-28 1992-05-06 Merck & Co. Inc. New intermediates in the synthesis of 17beta-acyl-3-carboxy-androsta-3,5-dienes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5041433A (en) * 1987-04-29 1991-08-20 Smithkline Beecham Corporation 11-keto or hydroxy 3,5-diene steroids as inhibitors of steriod 5-α-reductase
US5032586A (en) * 1989-08-24 1991-07-16 Smithkline Beecham Corporation 7-keto or hydroxy 3,5-diene steroids as inhibitors of steroid 5-alpha reductase
US5137882A (en) * 1990-06-11 1992-08-11 Holt Dennis A Steroidal 3-acetic acid derivatives as 5-alpha-reductase inhibitors
US5196411A (en) * 1991-08-16 1993-03-23 Merck & Co., Inc. 17β-acyl-3-carboxy-androsta-3,5-dienes as testosterone 5α-reductase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0669932A4 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5565467A (en) * 1993-09-17 1996-10-15 Glaxo Wellcome Inc. Androstenone derivative
US5846976A (en) * 1993-09-17 1998-12-08 Glaxo Wellcome Inc. Androstenone derivative
WO1996003422A1 (fr) * 1994-07-28 1996-02-08 Pharmacia S.P.A. 4-azasteroides ayant des fluorocetones comme chaines laterales
WO1996003420A1 (fr) * 1994-07-28 1996-02-08 Pharmacia S.P.A. 3-carboxysteroides presentant une chaine laterale fluoree
EP0784627A4 (fr) * 1994-10-05 1998-05-06 Smithkline Beecham Corp Procede de preparation d'acides androsta-3,5-diene-3-carboxyliques a substitution en 17 beta
US5541322A (en) * 1994-10-14 1996-07-30 Glaxo Wellcome Inc. Synthesis of 6-azaandrostenones
US5543417A (en) * 1994-10-21 1996-08-06 Merck & Co., Inc. Combination method of treating acne using 4-AZA-5α-cholestan-ones and 4-AZA-5α-androstan-ones as selective 5α-reductase inhibitors with anti-bacterial, keratolytic, or anti-inflammatory agents
US7388031B2 (en) 2000-11-30 2008-06-17 Sanofi-Aventis Cyclohexyl(alkyl)-propanolamines, preparation method and pharmaceutical compositions containing same
US7419974B2 (en) 2000-11-30 2008-09-02 Sanofi-Aventis Cyclohexyl(alkyl)propanolamines, preparation method and pharmaceutical compositions containing same
US7718646B2 (en) 2000-11-30 2010-05-18 Sanofi-Aventis Cyclohexyl(alkyl)propanolamines, preparation method and pharmaceutical compositions containing same

Also Published As

Publication number Publication date
AP9300589A0 (en) 1994-01-31
MA23036A1 (fr) 1994-07-01
SI9300601A (en) 1994-06-30
EP0669932A1 (fr) 1995-09-06
AU5671794A (en) 1994-06-08
CN1101914A (zh) 1995-04-26
MX9307203A (es) 1994-07-29
EP0669932A4 (fr) 1995-10-25
AU5613394A (en) 1994-06-08
EP0673251A4 (fr) 1995-10-25
EP0673251A1 (fr) 1995-09-27
IL107611A0 (en) 1994-02-27
CA2149427A1 (fr) 1994-05-26
CN1101916A (zh) 1995-04-26
JPH08503471A (ja) 1996-04-16
NZ258723A (en) 1996-12-20
WO1994011004A1 (fr) 1994-05-26

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