Modified bile acids process for their preparation and their use

• US 5,641,767 A
• Filed: 09/12/1995
• Issued: 06/24/1997
• Est. Priority Date: 09/14/1994
• Status: Expired due to Fees

• Current Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Original Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Inventors: Bock, Klaus, Wess, Gunther, Ehnsen, Alfons, Kramer, Werner
• Primary Examiner(s): PRIOR, KIMBERLY
• Application Number:
  US08/525,231
• Time in Patent Office: 651 Days
• Field of Search: 552/505, 552/554, 552/555, 552/553, 514/172, 514/182, 540/4, 540/114
• US Class Current: 514/172
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: C07J 17/00 Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton cardanolide, bufanolide C07J19/00
• CPC Class Codes: C07J 41/0055 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
• CPC Class Codes: C07J 41/0061 one of the carbon atoms being part of an amide group
• CPC Class Codes: C07J 51/00 Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
• CPC Class Codes: C07J 9/005 containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Abstract

The invention relates to linker-modified bile acid derivatives of the formula I: ##STR1## wherein the radicals X¹, X², X³ and Y and n are as defined in the claims, and to a process for their preparation. The compounds according to the invention are therapeutically active and are thus suitable as drugs, especially as hypolipldemics. The invention further relates to the use of the bile acid derivatives according to the invention as drugs.

Claims

1. A linker-modified bile acid derivative of the formula I:

##STR34## wherein

space="preserve" listing-type="tabular">______________________________________ X.sup.1 is CH.sub.2 OH, where Sil is a silyl protecting group CH.sub.2 NH.sub.2, of the formula CH.sub.2 OSil, SiMe.sub.3, SiMe.sub.2 t-Bu or SiPh.sub.2 t-Bu, CH.sub.2 OTHP, where phenyl can be substituted by CH.sub.2 OCH.sub.2 Ph, p-methoxy, CH.sub.2 O-trityl, where acyl is a linear or branched CH.sub.2 O-acyl, radical having 2 to 8 carbon atoms, CH.sub.2 O-benzoyl, where the aromatic ring can also be monosubstituted to trisubstituted by a linear or branched C.sub.1 -C.sub.4 -alkyl radical, OCH.sub.3, F or Cl, CH.sub.2 OCHO, where acyl is a linear or branched CH.sub.2 OC(O)OCH.sub.2 Ph, radical having 2 to 8 carbon atoms, CH.sub.2 NH-acyl, CH.sub.2 NH-benzoyl, where the aromatic ring can also be monosubstituted to trisubstituted by a linear or branched C.sub.1 -C.sub.4 -alkyl radical, OCH.sub.3, F or Cl, CH.sub.2 N(CH.sub.2 Ph).sub.2, where the aromatic rings can also be monosubstituted to trisubstituted by a linear or branched C.sub.1 -C.sub.4 -alkyl radical, OCH.sub.3, F or Cl, CH.sub.2 O--CH.sub.2 --CH═

CH.sub.2, where M is an CO.sub.2 H, CO.sub.2 M, alkali metal or alkaline earth metal, CO.sub.2 N(X.sup.4).sub.4, where X.sup.4 is identical or different and is an H atom or a linear or branched alkyl radical having 1 to 8 carbon atoms, or CO.sub.2 X.sup.5, where X.sup.5 is methyl, ethyl, alkyl or benzyl;

X.sup.2 and X.sup.3 are identical or different radicals selected from the group consisting of H, OH, OTHP, OAc, where the phenyl group can also be SiMe.sub.3, OSiMe.sub.2 t-Bu, monosubstituted to trisubstituted by a SiPh.sub.2 t-Bu, OCH.sub.2 Ph, linear or branched C.sub.1 -C.sub.4 -alkyl radical, OCH.sub.3, F or Cl, O--CH.sub.2 CH═

CH.sub.2, where the phenyl group can also be OC(O)CH.sub.2 Ph, monosubstituted to trisubstituted by a linear or branched C.sub.1 -C.sub.4 -alkyl radical, OCH.sub.3, F or Cl, OC(O)Ph, where the phenyl group can also be monosubstituted to trisubstituted by a linear or branched C.sub.1 -C.sub.4 -alkyl radical, OCH.sub.3, F or Cl, and OC(O)O-alkyl, the radical X.sup.2 being located in the α

- or β

-position and the radical X.sup.3 only in the α

-position;

Y is OH, a linear or branched alkoxy radical having 1 to 8 carbon atoms, O--CH.sub.2 Ph, where the phenyl group can also be monosubstituted to trisubstituted by a linear or branched C.sub.1 -C.sub.4 -alkyl radical, OCH.sub.3, F or Cl, O-Ph, where the phenyl group can also be monosubstituted to trisubstituted by a linear or branched C.sub.1 -C.sub.4 -alkyl radical, OCH.sub.3, F or Cl, OM.sup.1, where M.sup.1 is an alkali metal, ONX.sub.4.sup.6, where X.sup.6 is an H atom or a C.sub.1 -C.sub.8 -alkyl group, OTHP, OCH.sub.2 --CH═

CH.sub.2, NH.sub.2, NH(CH.sub.2).sub.2 SO.sub.3 H, N(CH.sub.3)(CH.sub.2).sub.2 SO.sub.3 H, NHCH.sub.2 CO.sub.2 H or N(CH.sub.3)CH.sub.2 CO.sub.2 N;

______________________________________

the hydroxyl group in ring position C-3 can be located in either the α

- or β

-position and n is equal to 0 to 47.

2. A bile acid derivative of the formula I as claimed in claim 1, wherein

X¹ is

CH₂ OH,

CH₂ NH₂,

CH₂ OSiMe₂ t-Bu,

CH₂ OTHP,

CO₂ H or

CO₂ CH₃ ;

X² and X³ are identical or different radicals selected from the group consisting of

H,

OH,

OAc and

OTHP,

the radical X² being located in the α

- or β

-position and the radical X³ only in the α

-position;

Y is

OH,

OCH₃ or

Ot-Bu;

the hydroxyl group in ring position C-3 is located in the α

-position and n is equal to 0 to 47.

3. A process for the preparation of bile acid derivatives of the formula I as claimed in claim 1, which comprises reacting a bile acid ketone of the formula II:

##STR35## with a compound of the formula III;

space="preserve" listing-type="equation">HC.tbd.C--(CH.sub.2).sub.n --X.sup.1 (III)

after conversion to the acetylide with a strong base, to give an addition product of the formula IV;

##STR36## which is then converted by Pd/C-catalyzed hydrogenation to a compound of the formula I;

##STR37## wherein, in the formulae, the radicals X¹, X², X³ and Y and n are as defined in claim 1.

4. A pharmaceutical composition containing at least one bile acid derivative of the formula I as claimed in claim 1, and a pharmaceutically acceptable carrier.

5. A hypolipidemic containing a bile acid derivative of the formula I as claimed in claim 1.

6. A method of treating a host in need of a hypolipidemic agent comprising:

administering to said host a bile acid derivative of the formula I as claimed in claim 1.