6.alpha.-alkyl-3,7-dione steroids as intermediates for the production of steroidal FXR modulators

• US 10,538,550 B2
• Filed: 11/19/2015
• Issued: 01/21/2020
• Est. Priority Date: 11/19/2014
• Status: Active Grant

• Current Assignee: NZP UK Ltd,
• Original Assignee: NZP UK Ltd,
• Inventors: Weymouth-Wilson, Alexander, Komsta, Zofia, Boydell, James, Wallis, Laura, Batchelor, Rhys, Otter, Carl, Davies, Ieuan
• Primary Examiner(s): Zucker, Paul A
• Application Number:
  US15/528,331
• Publication Number:
  US 20180340006A1
• Time in Patent Office: 1,524 Days
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: C07J 71/001 Oxiranes
• 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 compounds of formula (I) wherein R¹, R², Y¹, R⁴ and R⁵ are as defined herein. The compounds are intermediates in the synthesis of synthetic bile acid derivatives with pharmacological activity. The invention further provides methods related to the synthesizing of these intermediates, and methods of preparing obeticholic acid and obeticholic acid analogues from the compounds of the invention.

Claims

1. A compound of general formula (I):

2. A compound according to claim 1 wherein R¹ is ethyl.

3. A compound according to claim 1 wherein Y¹ is an alkylene linker group having from 1 to 8 carbon atoms and optionally substituted with one or more groups R³, wherein R³ is as defined in claim 1.

4. A compound according to claim 1 wherein, independently or in any combination:

Y¹ is a bond or an alkylene group having 1 to 3 carbon atoms and is optionally substituted with one or two R³ groups;

R⁴ is C(O)OR¹⁰, SO₃R¹⁰, or OSO₃R¹⁰, where R¹⁰ is H, C_1-6 alkyl or benzyl;

R⁵ is H or OH.

5. A compound according to claim 4 wherein, independently or in any combination:

R¹ is ethyl; and

/or

R² is H; and

/or

Y¹ is a bond, —

CH₂—

or —

CH₂CH₂—

; and

/or

R⁴ is C(O)OR¹⁰, where R¹⁰ is H, C_1-6 alkyl or benzyl; and

/or

R⁵ is H.

6. A compound according to claim 1 which is (6β

, 5β

)-3,7-dioxo-6-ethyl-cholan-24-oic acid or a C_1-6 alkyl or benzyl ester thereof or salt thereof.

9. A process according to claim 7 for the preparation of a compound of general formula (I) in which R⁴ is C(O)OR¹⁰, wherein R¹⁰ is as defined in claim 1 from a compound of general formula (II) where R⁴ is also C(O)OR¹⁰.

18. A compound according to claim 1 which is (6β

, 5β

)-3,7-dioxo-6-ethyl-cholan-24-oic acid or the methyl or ethyl ester thereof.

7. A process for the preparation of a compound of general formula (I):

8. A process according to claim 7 wherein the oxidation is carried out using:

a Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol) oxidation;

or

sodium hypochlorite under acidic conditions;

or

a Jones reaction using sodium dichromate or chromic trioxide in dilute sulfuric acid.

10. A process for the preparation of a compound of general formula (XX):

11. A process according to claim 10 wherein, in the epimerization reaction of step (i), the compound of general formula (I) is dissolved in an alcoholic solvent, optionally mixed with water and contacted with a base.

12. A process according to claim 11 wherein the base is sodium or potassium hydroxide or a sodium or potassium alkoxide.

13. A process according to claim 12 wherein, in the compound of general formula (I), R⁴ is C(O)OR¹⁰, where R¹⁰ is C_1-6 alkyl or benzyl and wherein the base is sodium or potassium hydroxide, such that the epimerization reaction is accompanied by hydrolysis to give a compound of general formula (XXI) in which R⁴ is C(O)OH.

14. A process according to claim 10 wherein, in the compound of general formula (I), R² and/or R⁵ is a group OC(O)OR¹⁴, where R¹⁴ is C_1-6 alkyl or benzyl;

and wherein the epimerisation step yields a compound of general formula (XXI) in which R² and/or R^5b is OH.

15. A process according to claim 10 wherein, in the compound of general formula (I), R² and/or R⁵ is a protected OH which is stable under basic conditions and the process further comprises the step of removing the protecting group before or after step (ii).

16. A process according to claim 10 wherein, in step (ii), the reducing agent is a hydride.

17. A process according to claim 10 for the preparation of a compound of general formula (XX) in which R¹ is ethyl, R² and R^5a are both H, Y¹ is —

CH₂CH₂—

, and R⁴ is C(O)OH.