14,15-cyclopropano steroids of the 19-norandrostane series, method for the production thereof and pharmaceutical preparations containing said compounds

• US 6,388,109 B1
• Filed: 12/20/2000
• Issued: 05/14/2002
• Est. Priority Date: 06/22/1998
• Status: Expired due to Fees

• Current Assignee: Bayer Schering Pharma AG (Bayer AG)
• Original Assignee: Jenapharm GmbH & Co. KG (Bayer AG)
• Inventors: Ring, Sven, Schwarz, Sigfrid, Elger, Walter, Schneider, Birgitt, Schubert, Gerd, Sobek, Lothar, Kaufmann, Günter
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US09/719,910
• Time in Patent Office: 510 Days
• Field of Search: 552/508, 552/523, 552/525, 552/623, 552/500, 514/172, 514/173, 514/174, 514/182
• US Class Current: 552/525
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07J 53/004 3 membered carbocyclic rings

Abstract

Described are new 14,15-cyclopropano steroids of the 19-norandrostane series of general formula (I) and their pharmaceutically acceptable salts, a process for their production and pharmaceutical preparations that contain these compounds. The compounds are distinguished by hormonal (gestagenic and/or androgenic) activity.

Claims

1. A compound of formula I

in which

R₁ is a hydrogen atom or an alkyl radical with 1-9 carbon atoms,

R₂ is a hydrogen atom or a methyl group,

R₃ and R₄, independently of one another, stand for a

a hydrogen atom,

for a hydroxy group,

for an acyloxy group —

O—

CO—

R₅,

with R₅ standing for an alkyl of 1-10 carbon atoms,

for a carbamoyloxy group —

O—

CO—

NHR₆,

with R₆ standing for a hydrogen atom or an alkyl or aryl radical,

for a sulfamoyloxy group —

O—

SO₂—

NR₇R₈,

with R₇ and R₈, independently of one another, in each case standing for a hydrogen atom, an alkyl group with 1 to 5 carbon atoms or together with the nitrogen atom for a pyrrolidino, piperidono or morpholino group,

for a grouping —

CH₂R₉ with R₉ standing for a hydroxy group,

an alkyloxy group with 1-5 carbon atoms, a chlorine or bromine atom, an azido, nitrilo or thiocyano group or for a grouping —

SR₁₀

with R₁₀ standing for an alkyl group with 1-5 carbon atoms,

R₃ and R₄ together stand for an oxo group, or

R₃ and R₄, with C-17, form a spirooxirane or a 2,2-dimethyl-1,3-dioxolane group,

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1,

17β -hydroxy-14α

,15α

-methylenstr-4-en-3-one or a pharmaceutically acceptable salt thereof,

17α

-hydroxy-14α

,15α

-methylenestr-4-en-3-one or a pharmaceutically acceptable salt thereof,

17β

-hydroxy-15β

-methyl-14α

,15α

-methylenstr-4-en-3-one or a pharmaceutically acceptable salt thereof,

17β

-hydroxy-15α

-methyl-14β

,15β

-methylenestr-4-en-3-one or a pharmaceutically acceptable salt thereof,

17β

-hydroxy-17α

-hydroxymethyl-14α

,15α

-methylenestr-4-en-3-one or a pharmaceutically acceptable salt thereof,

17α

-methoxy-17β

-methoxymethyl-14α

,15α

-methylenestr-4-en-3-one or a pharmaceutically acceptable salt thereof,

17β

-hydroxy-7α

-methyl-14α

,15α

-methylenestr-4-en-3-one or a pharmaceutically acceptable salt thereof,

17,20-isopropylidenedioxy-14α

,15α

-methylene-19,21-bis-nor-17α

-pregn-4-en-3-one or a pharmaceutically acceptable salt thereof,

3-oxo-14α

,15α

-methylenstr-4-en-17β

-yl-sulfamate or a pharmaceutically acceptable salt thereof,

3-oxo-14α

,15α

-methylenestr-4-en-17β

-yl-n-butanoate or a pharmaceutically acceptable salt thereof,

17β

-hydroxy-17α

-methyloxymethyl-14β

-,15β

-methylenestr-4-en-3-one or a pharmaceutically acceptable salt thereof,

17α

-ethylthiomethyl-17β

-hydroxy-14β

,15β

-methylenestr-4-ene-3-one or a pharmaceutically acceptable salt thereof,

17α

-chloromethyl-17β

-hydroxy-14β

,15β

-methylenestr-4-en-3-one or a pharmaceutically acceptable salt thereof,

17α

-azidomethyl-17β

-hydroxy-14β

,15β

-methylenestr-4-en-3-one or a pharmaceutically acceptable salt thereof,

17α

-bromomethyl-17β

-hydroxy-14β

,15β

-ethylenestr-4-en-3-one or a pharmaceutically acceptable salt thereof,

17β

-hydroxy-17α

-rhodanomethyl-14β

,15β

-methylenestr-4-en-3-one or a pharmaceutically acceptable salt thereof or,

17α

-cyanomethyl-17β

-hydroxy-14β

,15β

-methylenestr-4-en-3-one or a pharmaceutically acceptable salt thereof.

3. A process for the production of a compound according to claim 1 and its pharmaceutically acceptable salt comprising enol-ether cleaving a corresponding 14,15-cyclopropano-enol ether of the general formula II,

in which

R₁ is a hydrogen atom or an alkyl radical with 1-9 carbon atoms,

R₂ is a hydrogen atom or a methyl group,

R₃ and R₄, independently of one another, stand for a hydrogen atom

for a hydroxy group,

for a acyloxy group —

O—

CO—

R₅

with R₅ standing for an alkyl of 1-10 carbon atoms,

for a carbamoyloxyl group —

O—

CO—

NHR₆,

with R₆ standing for a hydrogen atom, or an alkyl or aryl radical,

for a sulfamoyloxy group —

O—

SO₂—

NR₇R₈,

with R₇ and R₈, independently of one another, in each case standing for a hydrogen atom, an alkyl group with 1-5 carbon atoms or together with the nitrogen atom for a pyrrolidino, piperidono or morphilino group,

for a grouping —

CH₂R₉ with R₉ standing for a hydroxy group, an alkyloxy group with 1-5 carbon atoms, a chlorine or bromine atom, an azido, nitrilo or thiocyano group or for a grouping —

SR₁₀ with R₁₀ standing for an alkyl group with 1-5 carbon atoms,

R₃ and R₄ together stand for an oxo group, or

R₃ and R₄, with C-17, form a spirooxirane or a 2,2-dimethyl-1,3-dioxolane group.

4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

5. A compound of formula I

in which

R₁ is a hydrogen atom or an alkyl radical with 1-9 carbon atoms,

R₂ is a hydrogen atom or a methyl group,

R₃ and R₄, independently of one another, stand for a

a hydrogen atom,

for a hydroxy group,

for an acyloxy group —

O—

CO—

R₅,

with R₅ standing for an alkyl of 1-10 carbon atoms,

for a carbamoyloxy group —

O—

CO—

NHR₆,

with R₆ standing for a hydrogen atom or an alkyl radical,

for a sulfamoyloxy group —

O—

SO₂—

NR₇R₈,

with R₇ and R₈, independently of one another, in each case standing for a hydrogen atom, an alkyl group with 1 to 5 carbon atoms or together with the nitrogen atom for a pyrrolidino, piperidono or morpholino group,

for a grouping —

CH₂R₉ with R₉ standing for a hydroxy group,

an alkyloxy group with 1-5 carbon atoms, a chlorine or bromine atom, an azido, nitrilo or thiocyano group or for a grouping —

SR₁₀

with R₁₀ standing for an alkyl group with 1-5 carbon atoms,

R₃ and R₄ together stand for an oxo group, or

R₃ and R₄, with C-17, form a spirooxirane or a 2,2-dimethyl-1,3-dioxolane group,

or a pharmaceutically acceptable salt thereof.