EP0782582A1 - EPIMERES DE (22RS)-N-(1,1,1-TRIFLUORO-2-PHENYLPROP-Y-YL)-3-OXO-4-AZA-5$g(a)-ANDROST-1-ENE-17$g(b)-CARBOXAMIDE - Google Patents

EPIMERES DE (22RS)-N-(1,1,1-TRIFLUORO-2-PHENYLPROP-Y-YL)-3-OXO-4-AZA-5$g(a)-ANDROST-1-ENE-17$g(b)-CARBOXAMIDE

Info

Publication number
EP0782582A1
EP0782582A1 EP96923968A EP96923968A EP0782582A1 EP 0782582 A1 EP0782582 A1 EP 0782582A1 EP 96923968 A EP96923968 A EP 96923968A EP 96923968 A EP96923968 A EP 96923968A EP 0782582 A1 EP0782582 A1 EP 0782582A1
Authority
EP
European Patent Office
Prior art keywords
epimers
formula
oxo
phenylprop
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96923968A
Other languages
German (de)
English (en)
Inventor
Achille Panzeri
Marcella Nesi
Enrico Di Salle
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Italia SRL
Original Assignee
Pharmacia and Upjohn SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia and Upjohn SpA filed Critical Pharmacia and Upjohn SpA
Publication of EP0782582A1 publication Critical patent/EP0782582A1/fr
Withdrawn legal-status Critical Current

Links

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

Landscapes

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

Abstract

L'invention concerne les épimères (22R)-N-(1,1,1-trifluoro-2-phénylprop-2-yl)-3-oxo-4-aza-5α-androst-1-ène-17β-carboxamide et (22S)-N-(1,1,1-trifluoro-2-phénylprop-2-yl)-3-oxo-4-aza-5α-androst-1-ène-17β-carboxamide, servant d'inhibiteurs de la testostérone 5α-réductase. L'invention concerne également un procédé pour leur préparation et les compositions pharmaceutiques les contenant.
EP96923968A 1995-07-21 1996-06-28 EPIMERES DE (22RS)-N-(1,1,1-TRIFLUORO-2-PHENYLPROP-Y-YL)-3-OXO-4-AZA-5$g(a)-ANDROST-1-ENE-17$g(b)-CARBOXAMIDE Withdrawn EP0782582A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ITMI951587 1995-07-21
IT95MI001587A IT1275594B1 (it) 1995-07-21 1995-07-21 Epimeri del (22rs)-n-(1,1,1-trifluoro-2-fenilprop-2-il)-3-osso -4-aza-5alfa-androst-1-ene-17beta-carbossammide
PCT/EP1996/002830 WO1997004002A1 (fr) 1995-07-21 1996-06-28 EPIMERES DE (22RS)-N-(1,1,1-TRIFLUORO-2-PHENYLPROP-Y-YL)-3-OXO-4-AZA-5α-ANDROST-1-ENE-17β-CARBOXAMIDE

Publications (1)

Publication Number Publication Date
EP0782582A1 true EP0782582A1 (fr) 1997-07-09

Family

ID=11372032

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96923968A Withdrawn EP0782582A1 (fr) 1995-07-21 1996-06-28 EPIMERES DE (22RS)-N-(1,1,1-TRIFLUORO-2-PHENYLPROP-Y-YL)-3-OXO-4-AZA-5$g(a)-ANDROST-1-ENE-17$g(b)-CARBOXAMIDE

Country Status (17)

Country Link
EP (1) EP0782582A1 (fr)
JP (1) JPH10506411A (fr)
KR (1) KR970706298A (fr)
CN (1) CN1159195A (fr)
AR (1) AR003967A1 (fr)
AU (1) AU6418396A (fr)
BR (1) BR9606527A (fr)
CA (1) CA2199273A1 (fr)
EA (1) EA199700045A1 (fr)
HU (1) HUP9702465A3 (fr)
IL (1) IL120343A0 (fr)
IT (1) IT1275594B1 (fr)
MX (1) MX9701948A (fr)
NO (1) NO971196D0 (fr)
PL (1) PL319351A1 (fr)
WO (1) WO1997004002A1 (fr)
ZA (1) ZA965678B (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000013509A1 (fr) * 1998-09-09 2000-03-16 Merck & Co., Inc. Procede de determination et de reduction du risque de survenue de problemes urologiques lies a l'adenome prostatique
ES2237408T3 (es) * 1999-01-25 2005-08-01 Smithkline Beecham Corporation Antiandrogenos y procedimientos para tratar una enfermedad.
CN100355772C (zh) * 2005-12-28 2007-12-19 天津大学 具有5α－还原酶抑制活性的甾体化合物及其制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9216284D0 (en) * 1992-07-31 1992-09-16 Erba Carlo Spa Fluorinated 17beta-substituted 4-aza-5alpha-androstane-3-one derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9704002A1 *

Also Published As

Publication number Publication date
HUP9702465A2 (hu) 1998-05-28
HUP9702465A3 (en) 1998-11-30
ITMI951587A1 (it) 1997-01-21
CA2199273A1 (fr) 1997-02-06
ZA965678B (en) 1997-01-24
AU6418396A (en) 1997-02-18
JPH10506411A (ja) 1998-06-23
AR003967A1 (es) 1998-09-30
IL120343A0 (en) 1997-06-10
NO971196L (no) 1997-03-14
ITMI951587A0 (it) 1995-07-21
BR9606527A (pt) 1997-12-23
EA199700045A1 (ru) 1997-12-30
KR970706298A (ko) 1997-11-03
IT1275594B1 (it) 1997-08-06
CN1159195A (zh) 1997-09-10
NO971196D0 (no) 1997-03-14
PL319351A1 (en) 1997-08-04
WO1997004002A1 (fr) 1997-02-06
MX9701948A (es) 1997-06-28

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