US 12,419,897 B2Granted

Synthetic derivatives of cholic acid 7-sulfate and uses thereof

AssigneesPresident and Fellows of Harvard College, The Brigham and Women's Hospital, Inc.

InventorsAbigail Sloan Devlin, Snehal N. Chaudhari, Eric Garland Sheu, David A. Harris, Jinbo Lee

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Abstract

The compositions and methods provided herein are related, in part, to the discovery of cholic acid 7-sulfate as a treatment for diabetes. Provided herein is a method for treating a metabolic disorder (e.g., diabetes, obesity), or an inflammatory disease (e.g., Crohn's disease, inflammatory bowel disease, ulcerative colitis, pancreatitis, hepatitis, appendicitis, gastritis, diverticulitis, celiac disease, food intolerance, enteritis, ulcer, gastroesophageal reflux disease (GERD), psoriatic arthritis, psoriasis, and rheumatoid arthritis) in a subject in need thereof comprising administering to a subject a compound of Formulae (I)-(XVII).

Claims19

Dependent claims

A method for treating diabetes, obesity, or an inflammatory disease in a subject, the method comprising administering to a subject in need thereof a compound of Formula (I):

wherein:
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
m is 1;
Z is —C(O)—, —C(O)O—, —C(O)NR18- or —CH2-;
X is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR18, —N(R18)2, —SR18, halogen, CN, —CHO, —CO2H, —CO2R18, —NO2, —ONO2, —SO2Cl, —SO3, —OSO3, —NR18SO3, —PO32−, —OPO32−, —OSO2R18, —OSO2N(R18)2, —NR18SO2R18, —SO2N(R18)2, -NHNH2, —ONH2, -NHC(O)NHNH2, or a polar amino acid;
each R1, R2, R4, R11, R15, R16, and R17 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR18, —N(R18)2, —SR18, halogen, CN, —CHO, —CO2H, —CO2R18, —NO2, —ONO2, —SO2Cl, —SO3−, —OSO3−, —NR18SO3, —PO32−, —OPO32−, —OSO2R18, —OSO2N(R18)2, —NR18SO2R18, —SO2N(R18)2, -NHNH2, —ONH2, or -NHC(O)NHNH2;
each R3, R6, and R12 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR18, —N(R18)2, —SR18, halogen, —CN, —CHO, —CO2H, —CO2R18, —NO2, —ONO2, —SO2Cl, —SO3, —OSO3, —NR18SO3, —PO32−, —OPO32−, —OSO2R18, —OSO2N(R18)2, —NR18SO2R18, —SO2N(R18)2, -NHNH2, —ONH2, or -NHC(O)NHNH2;
R7 is —C(R18)2SO3H, —C(R18)2SO3, —SO2N(R18)2, —OSO2N(R18)2, —NR18SO3H, or —NR18SO3;
each R18 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
or a pharmaceutically acceptable salt thereof.

7 more elements

A compound of Formula (I):

wherein:
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
m is 1;
Z is —C(O)—, —C(O)O—, —C(O)NR18-, or —CH2-;
X is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR18, —N(R18)2, —SR18, halogen, —CN, —CHO, —CO2H, —CO2R18, —NO2, —ONO2, —SO2Cl, —SO3, —OSO3, —NR18SO3, —PO32−, —OPO32−, —OSO2R18, —OSO2N(R18)2, —NR18SO2R18, —SO2N(R18)2, -NHNH2, —ONH2, -NHC(O)NHNH2, or a polar amino acid;
each R1, R2, R4, R11, R15, R16, and R17 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR18, —N(R18)2, —SR18, halogen, —CN, —CHO, —CO2H, —CO2R18, —NO2, —ONO2, —SO2Cl, —SO3−, —OSO3, —NR18SO3, —PO32−, —OPO32−, —OSO2R18, —OSO2N(R18)2, —NR18SO2R18, —SO2N(R18)2, -NHNH2, —ONH2, or -NHC(O)NHNH2;
each R3, R6, and R12 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR18, —N(R18)2, —SR18, halogen, —CN, —CHO, —CO2H, —CO2R18, —NO2, —ONO2, —SO2CI, —SO3, —OSO3, —NR18SO3, —PO32−, —OPO32−, —OSO2R18, —OSO2N(R18)2, —NR18SO2R18, —SO2N(R18)2, -NHNH2, —ONH2, or -NHC(O)NHNH2;
R7 is —C(R18)2SO3H, —C(R18)2SO3, —SO2N(R18)2, —OSO2N(R18)2, —NR18SO3H, or —NR18SO3;
each R18 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
or a pharmaceutically acceptable salt thereof.

7 more elements

A pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier or excipient, wherein compound of Formula (I) has the structure:

wherein:
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
m is 1;
Z is —C(O)—, —C(O)O—, —C(O)NR18-, or —CH2-;
X is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR18, —N(R18)2, —SR18, halogen, —CN, —CHO, —CO2H, —CO2R18, —NO2, —ONO2, —SO2CI, —SO3, —OSO3, —NR18SO3, —PO32−, —OPO32−, —OSO2R18, —OSO2N(R18)2, —NR18SO2R18, —SO2N(R18)2, -NHNH2, —ONH2, -NHC(O)NHNH2, or a polar amino acid;
each R1, R2, R3, R4, R11, R15, R16, and R17 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR18, —N(R18)2, —SR18, halogen, —CN, —CHO, —CO2H, —CO2R18, —NO2, —ONO2, —SO2CI, —SO3−, —OSO3−, —NR18SO3−, —PO32−, —OPO32−, —OSO2R18, —OSO2N(R18)2, —NR18SO2R18, —SO2N(R18)2, -NHNH2, —ONH2, or -NHC(O)NHNH2,
each R3, R6, and R12 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR18, —N(R18)2, —SR18, halogen, —CN, —CHO, —CO2H, —CO2R18, —NO2, —ONO2, —SO2Cl, —SO3, —OSO3, —NR18SO3, —PO32−, —OPO32−, —OSO2R18, —OSO2N(R18)2, —NR18SO2R18, —SO2N(R18)2, -NHNH2, —ONH2, or -NHC(O)NHNH2;
R7 is —C(R18)2SO3H, —C(R18)2SO3, —SO2N(R18)2, —OSO2N(R18)2, —NR18SO3H, or —NR18SO3;
each R18 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
or a pharmaceutically acceptable salt thereof.

7 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/309,520Filed 4 Dec 2019 · us provisional application
Priority: 4 Dec 2018
Published: US 2022/0016138 A120 Jan 2022
Granted: 23 Sep 2025
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

A61K 31/664
Phosphorus compounds: amides of phosphorus acids
C07J 51/00
Normal steroids with unmodified cyclopentahydrophenanthrene skeleton not provided for in groups c07j1/00
A61K 31/575
Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids: substituted in position 17 beta by a chain…
C07J 31/003
Normal steroids containing one or more sulfur atoms not belonging to a hetero ring: the S atom directly linked to a ring carbon atom of the…