Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
  • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
  • C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to two epimers of formula (I) and (ID).
• the epimer mixture proved to be a potent inhibitor of testosterone 5 ⁇ -reductase enzyme both in vitro and in vivo (see data reported in Table (I) , page 33 of WO 94/03475) and therefore useful in those cases in which a reduction of androgenic activity is desired, for example, in treating benign prostatic hyperplasia, breast and prostate cancer and certain skin-hair alterations, for example, in treating acne, seborrhea, female hirsutism and male pattern baldness.
• the two epimers can be obtained, for example, following the method described in WO 94/03475 and subsequent separation of the epimer mixture thereof. Said separation can be carried out, for example, by means of high pressure liquid chromatography (HPLC) .
• HPLC high pressure liquid chromatography
• the single epimers can be obtained, independently from each other, by reacting 3-oxo-4-aza-5 ⁇ - androst-l-ene-17 ⁇ -carboxylic acid with each single enantiomer of 1,1, l-trifluoro-2-phenylprop-2-yl amine previously resolved.
• the single pure epimers can be advantageously obtained by: a) reacting 3-oxo-androst-4-ene-17 ⁇ -carboxylic acid, or a derivative thereof, with ( ⁇ ) -1, 1, l-trifluoro-2- phenylprop-2-yl amine; b) separating the two epimers of the so obtained (22RS) -N- (1,1,l-trifluoro-2-phenylprop-2-yl) -3-oxo-androst-4-ene- 17 ⁇ -carboxamide (e.g. by flash chromatography on silica gel) ; c
• object of the present invention are the two epimers of formula (I) and (II) as reported above, and their use as 5 ⁇ - reductase inhibitors. These epimers are useful in those cases in which a reduction of androgenic activity is desired, for example, in the treatment and/or chemoprevention of benign prostatic hyperplasia and prostatic cancer. Moreover, these epimers can be used in the treatment of breast cancer and certain skin-hair alterations, for example, in the treatment of acne, seborrhea, female hirsutism and male pattern baldness.
• the present invention relates to pharmaceutical compositions comprising one of the epimers of formula (I) or (II) , or a mixture thereof, wherein one of the epimers is present in a prevailing amount with respect to the other epimer, in combination with one or more pharmaceutically acceptable carriers and/or diluents.
• compositions containing the compounds of the invention are usually prepared according to conventional methods and are administered in a suitable pharmaceutical form, such as, for example, one of those described in WO 94/03475.
• the reaction mixture was heated to reflux for 4 h.
• the reaction mixture was poured into a chilled saturated sodium chloride aqueous solution of (200 mL) and extracted with methylene chloride (3 x 100 mL) ; the organic extracts were washed with water, dried over sodium sulfate and the solvent was removed under reduced pressure. 2.150 g of the title compound were obtained.
• the two epimers were separated by flash chromatography on silica gel (eluant: n-hexane/ethyl acetate 70:30) to yield 770 mg of the less retained (R f sup.) epimer and 700 mg of the most retained (R f inf.) epimer.
• FCE 29331 was obtained from (+) - amine
• FCE 29330 was obtained from (-) -amine.
• Inhibition of 5 ⁇ -reductase was evaluated using the particulate fraction from homogenates of hyperplastic human prostates as the enzyme source.
• the particulate fraction was prepared centrifuging prostate homogenates at 140,000 x g. The resulting pellet, washed several times, was resuspended in buffer and stored at -80°C. in aliquots containing « 10 mg protein/ml.
• the assay for 5 ⁇ -reductase was done in a final volume of 0.5 ml, in 40 mM TRIS-HCI buffer pH 5.5, containing 1 mM dithiothreitol, 5 mM NADPH, 1 ⁇ M [ 14 C] testosterone, an aliquot of the enzyme preparation and various concentrations of the inhibitors. After 30 min. incubation at 37°C, the reaction was terminated by addition of 2 ml cold diethyl ether and the organic phase was separated, evaporated under N 2 and resuspended in ethyl acetate. Testosterone metabolites in this extract were separated in TLC on silica gel F 254 plates

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Epidemiology (AREA)
• Steroid Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

Publications (1)

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• 1995
  • 1995-07-21 IT IT95MI001587A patent/IT1275594B1/it active IP Right Grant
• 1996
  • 1996-06-28 BR BR9606527A patent/BR9606527A/pt not_active Application Discontinuation
  • 1996-06-28 CN CN96190785A patent/CN1159195A/zh active Pending
  • 1996-06-28 WO PCT/EP1996/002830 patent/WO1997004002A1/en not_active Application Discontinuation
  • 1996-06-28 PL PL96319351A patent/PL319351A1/xx unknown
  • 1996-06-28 AU AU64183/96A patent/AU6418396A/en not_active Abandoned
  • 1996-06-28 HU HU9702465A patent/HUP9702465A3/hu unknown
  • 1996-06-28 KR KR1019970701797A patent/KR970706298A/ko not_active Application Discontinuation
  • 1996-06-28 CA CA002199273A patent/CA2199273A1/en not_active Abandoned
  • 1996-06-28 EP EP96923968A patent/EP0782582A1/en not_active Withdrawn
  • 1996-06-28 MX MX9701948A patent/MX9701948A/es unknown
  • 1996-06-28 JP JP9506217A patent/JPH10506411A/ja active Pending
  • 1996-06-28 IL IL12034396A patent/IL120343A0/xx unknown
  • 1996-07-04 ZA ZA965678A patent/ZA965678B/xx unknown
  • 1996-07-19 AR ARP960103652A patent/AR003967A1/es unknown
• 1997
  • 1997-03-14 NO NO971196A patent/NO971196D0/no unknown
  • 1997-04-18 EA EA199700045A patent/EA199700045A1/ru unknown

Non-Patent Citations (1)

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