WO1997004002A1 - EPIMERS OF (22RS)-N-(1,1,1-TRIFLUORO-2-PHENYLPROP-2-YL)-3-OXO-4-AZA-5α-ANDROST-1-ENE-17β-CARBOXAMIDE - Google Patents

EPIMERS OF (22RS)-N-(1,1,1-TRIFLUORO-2-PHENYLPROP-2-YL)-3-OXO-4-AZA-5α-ANDROST-1-ENE-17β-CARBOXAMIDE Download PDF

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Publication number
WO1997004002A1
WO1997004002A1 PCT/EP1996/002830 EP9602830W WO9704002A1 WO 1997004002 A1 WO1997004002 A1 WO 1997004002A1 EP 9602830 W EP9602830 W EP 9602830W WO 9704002 A1 WO9704002 A1 WO 9704002A1
Authority
WO
WIPO (PCT)
Prior art keywords
epimers
formula
oxo
phenylprop
compound
Prior art date
Application number
PCT/EP1996/002830
Other languages
English (en)
French (fr)
Inventor
Achille Panzeri
Marcella Nesi
Enrico Di Salle
Original Assignee
Pharmacia & Upjohn S.P.A.
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 & Upjohn S.P.A. filed Critical Pharmacia & Upjohn S.P.A.
Priority to AU64183/96A priority Critical patent/AU6418396A/en
Priority to PL96319351A priority patent/PL319351A1/xx
Priority to EP96923968A priority patent/EP0782582A1/en
Priority to KR1019970701797A priority patent/KR970706298A/ko
Priority to IL12034396A priority patent/IL120343A0/xx
Priority to BR9606527A priority patent/BR9606527A/pt
Priority to JP9506217A priority patent/JPH10506411A/ja
Priority to MX9701948A priority patent/MX9701948A/es
Publication of WO1997004002A1 publication Critical patent/WO1997004002A1/en
Priority to NO971196A priority patent/NO971196L/no
Priority to EA199700045A priority patent/EA199700045A1/ru

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
PCT/EP1996/002830 1995-07-21 1996-06-28 EPIMERS OF (22RS)-N-(1,1,1-TRIFLUORO-2-PHENYLPROP-2-YL)-3-OXO-4-AZA-5α-ANDROST-1-ENE-17β-CARBOXAMIDE WO1997004002A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
AU64183/96A AU6418396A (en) 1995-07-21 1996-06-28 Epimers of (22RS)-N-(1,1,1-trifluoro-2-phenylprop-2-yl)-3-ox-4-aza-5alp ha-androst-1-ene-17beta-carboxamide
PL96319351A PL319351A1 (en) 1995-07-21 1996-06-28 Epimers of (22rs)-n-(1,1,1-trifluoro-2-phenyprop-2-y)-3-oxo-4-aza-5a-androst-1-ene-17b carboxylamide
EP96923968A EP0782582A1 (en) 1995-07-21 1996-06-28 EPIMERS OF (22RS)-N-(1,1,1-TRIFLUORO-2-PHENYLPROP-2-YL)-3-OXO-4-AZA-5$g(a)-ANDROST-1-ENE-17$g(b)-CARBOXAMIDE
KR1019970701797A KR970706298A (ko) 1995-07-21 1996-06-28 (22RS)-N-(1,1,1-트리플루오로-2-페닐프로프-2-일)-3-옥소-4-아자-5α-안드로스트-1-엔-17β-카복스아미드의 에피머(Epimers of(22RS)-N-(1,1,1,-Trifluoro-2-phenylprop-2-yl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide)
IL12034396A IL120343A0 (en) 1995-07-21 1996-06-28 Epimers of (22RS)-N-(1,1,1-trifluoro-2-phenylprop-2-YL)-3-oxo-4-aza-5alpha-androst-1-ene-17beta-carboxamide
BR9606527A BR9606527A (pt) 1995-07-21 1996-06-28 Epímeros processo para a preparação de um epimero composição farmacêutica que compreende um epímero e composto
JP9506217A JPH10506411A (ja) 1995-07-21 1996-06-28 （２２ＲＳ）−Ｎ−（１，１，１−トリフルオロ−２−フェニルプロプ−２−イル）−３−オキソ−４−アザ−５α−アンドロスト−１−エン−１７β−カルボキサミド
MX9701948A MX9701948A (es) 1995-07-21 1996-06-28 Epimeros de (22rs-n-(1,1,1-trifluoro-2-fenilprop-2-il)-3-oxo-4-aza-5alfa-androst-1-e n-17beta-carboxamida.
NO971196A NO971196L (no) 1995-07-21 1997-03-14 Epimerer av (22RS)-N-(1,1,1-trifluor-2-fenylprop-2-yl)-3-okso-4-aza-5<alfa>-androst-1-en-17<beta>-karboksamid
EA199700045A EA199700045A1 (ru) 1995-07-21 1997-04-18 ЭПИМЕРЫ (22RS)-N-(1,1,1-ТРИФТОР-2-ФЕНИЛПРОП-2-ИЛ)-3-ОКСО-4-АЗА-5α-АНДРОСТ-1-ЕН-17β-КАРБОКСАМИДА

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI95A001587 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

Publications (1)

Publication Number Publication Date
WO1997004002A1 true WO1997004002A1 (en) 1997-02-06

Family

ID=11372032

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/002830 WO1997004002A1 (en) 1995-07-21 1996-06-28 EPIMERS OF (22RS)-N-(1,1,1-TRIFLUORO-2-PHENYLPROP-2-YL)-3-OXO-4-AZA-5α-ANDROST-1-ENE-17β-CARBOXAMIDE

Country Status (17)

Country Link
EP (1) EP0782582A1 (no)
JP (1) JPH10506411A (no)
KR (1) KR970706298A (no)
CN (1) CN1159195A (no)
AR (1) AR003967A1 (no)
AU (1) AU6418396A (no)
BR (1) BR9606527A (no)
CA (1) CA2199273A1 (no)
EA (1) EA199700045A1 (no)
HU (1) HUP9702465A3 (no)
IL (1) IL120343A0 (no)
IT (1) IT1275594B1 (no)
MX (1) MX9701948A (no)
NO (1) NO971196L (no)
PL (1) PL319351A1 (no)
WO (1) WO1997004002A1 (no)
ZA (1) ZA965678B (no)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000013509A1 (en) * 1998-09-09 2000-03-16 Merck & Co., Inc. Method of determining and reducing the risk of bph-related urologic events
EP1146873A1 (en) * 1999-01-25 2001-10-24 Smithkline Beecham Corporation Anti-androgens and methods for treating disease

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994003475A1 (en) * 1992-07-31 1994-02-17 Farmitalia Carlo Erba S.R.L. FLUORINATED 17β-SUBSTITUTED 4-AZA-5α-ANDROSTAN-3-ONE DERIVATIVES

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994003475A1 (en) * 1992-07-31 1994-02-17 Farmitalia Carlo Erba S.R.L. FLUORINATED 17β-SUBSTITUTED 4-AZA-5α-ANDROSTAN-3-ONE DERIVATIVES

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
E. DI SALLE ET AL: "Novel Aromatase and 5.alpha.-Reductase Inhibitors", JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, vol. 49, no. 4-6, 1994, pages 289 - 294, XP002016863 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000013509A1 (en) * 1998-09-09 2000-03-16 Merck & Co., Inc. Method of determining and reducing the risk of bph-related urologic events
EP1146873A1 (en) * 1999-01-25 2001-10-24 Smithkline Beecham Corporation Anti-androgens and methods for treating disease
EP1146873A4 (en) * 1999-01-25 2003-03-26 Smithkline Beecham Corp ANTI-ANDROGENS AND TREATMENT METHODS

Also Published As

Publication number Publication date
NO971196D0 (no) 1997-03-14
AU6418396A (en) 1997-02-18
CA2199273A1 (en) 1997-02-06
PL319351A1 (en) 1997-08-04
ITMI951587A0 (it) 1995-07-21
ITMI951587A1 (it) 1997-01-21
HUP9702465A3 (en) 1998-11-30
NO971196L (no) 1997-03-14
HUP9702465A2 (hu) 1998-05-28
AR003967A1 (es) 1998-09-30
EA199700045A1 (ru) 1997-12-30
BR9606527A (pt) 1997-12-23
EP0782582A1 (en) 1997-07-09
MX9701948A (es) 1997-06-28
JPH10506411A (ja) 1998-06-23
CN1159195A (zh) 1997-09-10
IT1275594B1 (it) 1997-08-06
KR970706298A (ko) 1997-11-03
ZA965678B (en) 1997-01-24
IL120343A0 (en) 1997-06-10

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