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US 10,538,550 B2Granted
6.alpha.-alkyl-3,7-dione steroids as intermediates for the production of steroidal FXR modulators
AssigneeNZP UK Limited
InventorsAlexander Weymouth-Wilson, Zofia Komsta, James Boydell, Laura Wallis, Rhys Batchelor, Carl Otter, Ieuan Davies
Life of this patent
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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.
Claims18
A compound of general formula (I):
- wherein:
- R1 is C1-4 alkyl optionally substituted with one or more substituents selected from halo, OR6 and NR6R7;
- where each of R6 and R7 is independently selected from H and C1-4 alkyl;
- R2 is H, halo or OH or a protected OH;
- Y1 is a bond or an alkylene linker group having from 1 to 20 carbon atoms and optionally substituted with one or more groups R3;
- each R3 is independently halo, OR8 or NR8R9;
- where each of R8 and R9 is independently selected from H and C1-4 alkyl;
- and
- R4 is C(O)OR10, OC(O)R10, C(O)NR10R11, OR10, OSi(R13)3, S(O)R10, SO2R10, OSO2R10, SO3R10, or OSO3R10;
- where each R10 and R11 is independently:
- a. hydrogen or
- b. C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, —O—C1-20 alkyl, —O—C2-20 alkenyl or —O—C2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 and N(R19)2, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2;
- or
- c. a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 and N(R19)2;
- d. a polyethylene glycol residue;
- each R19 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with halo, C1-6 alkyl or C1-6 haloalkyl;
- each R13 is independently
- a. C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl optionally substituted with one or more substituents selected from halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 and N(R19)2, a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SO2R19, SO3R19 or N(R19)2;
- or
- b. a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 and N(R19)2;
- each R19 is independently selected from H, C1-6 alkyl and C1-6 haloalkyl;
- R5 is H or OH or a protected OH;
- or a salt thereof.
20 more elements
A process for the preparation of a compound of general formula (I):
- wherein:
- R1 is C1-4 alkyl optionally substituted with one or more substituents selected from halo, OR6 or NR6R7;
- where each of R6 and R7 is independently selected from H or C1-4 alkyl;
- R2 is H, halo or OH or a protected OH;
- Y1 is a bond or an alkylene linker group having from 1 to 20 carbon atoms and optionally substituted with one or more groups R3;
- each R3 is independently halo, OR8 or NR8R9;
- where each of R8 and R9 is independently selected from H or C1-4 alkyl;
- and
- R4 is C(O)OR10, OC(O)R10, C(O)N—R10R11, OR10, OSi(R13)3, S(O)R10, SO2R10, OSO2R10, SO3R10, or OSO3R10;
- where each R10 and R11 is independently:
- a. hydrogen or
- b. C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, —O—C1-20 alkyl, —O—C2-20 alkenyl or —O—C2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2;
- or
- c. a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2;
- d. a polyethylene glycol residue;
- each R19 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with halo, C1-6 alkyl or C1-6 haloalkyl;
- each R13 is independently
- a. C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl optionally substituted with one or more substituents selected from halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2, a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SO2R19, SO3R19 or N(R19)2;
- or
- b. a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2;
- each R19 is independently selected from H, C1-6 alkyl or C1-6 haloalkyl;
- R5 is H or OH or a protected OH;
- said process comprising either:
- A oxidation of a compound of general formula (II):
- or
- B conversion of a compound of general formula (I) to another compound of general formula (I).
23 more elements
A process for the preparation of a compound of general formula (XX):
- wherein
- R1 is C1-4 alkyl optionally substituted with one or more substituents selected from halo, OR6 or NR6R7;
- where each of R6 and R7 is independently selected from H or C1-4 alkyl;
- R2 is H, halo or OH;
- Y1 is a bond or an alkylene linker group having from 1 to 20 carbon atoms and optionally substituted with one or more groups R3;
- each R3 is independently halo, OR8 or NR8R9;
- where each of R8 and R9 is independently selected from H or C1-4 alkyl;
- and
- R4 is C(O)OR10, OC(O)R10, C(O)NR10R11, OR10, OSi(R13)3, S(O)R10, SO2R10, OSO2R10, SO3R10, or OSO3R10;
- where each R10 and R11 is independently:
- a. hydrogen or
- b. C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, —O—C1-20 alkyl, —O—C2-20 alkenyl or —O—C2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2;
- or
- c. a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2;
- d. a polyethylene glycol residue;
- each R19 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with halo, C1-6 alkyl or C1-6 haloalkyl;
- each R13 is independently
- a. C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl optionally substituted with one or more substituents selected from halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2, a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SO2R19, SO3R19 or N(R19)2;
- or
- b. a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2;
- each R19 is independently selected from H, C1-6 alkyl or C1-6 haloalkyl;
- R5a is H or OH;
- R5a is H or OH;
- the process comprising:
- i. epimerisation of a compound of general formula (I):
- wherein R2 is H, halo or a protected OH;
- and R5 is H or OH or a protected OH;
- to give a compound of general formula (XXI):
- wherein
- R2 is H, halo or OH or a protected OH group which is stable under basic conditions;
- and
- R5b is H or OH or a protected OH group which is stable under basic conditions;
- and
- ii reduction of the compound of general formula (XXI) using a reducing agent and, where R2 and/or R5b is a protected OH, removal of the protecting group(s), to give a compound of general formula (XX) as defined above, wherein removal of the protecting group can take place before or after the reduction;
- and optionally
- iii conversion of a compound of general formula (XX) to another compound of general formula (XX).
33 more elements
Dependencies are inferred from the claim text.