# US 11,110,083 B2 · Methods for treating liver disorders using FXR agonists

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- Number: US 11,110,083 B2
- Document ID: US11110083B2
- Status: Granted
- Kind: B2
- Application number: 16/078,431
- Filed: 2017-02-20
- Published: 2019-03-21
- Granted: 2021-09-07
- Earliest claimed: 2016-02-22
- Assignees: Novartis AG
- Applicants: Novartis AG
- Inventors: Bryan Laffitte; Michael Badman; Jin Chen; Sam Lindgren
- Web page: https://patentgrep.com/patent/US11110083B2

## CPC

- A61K 31/46: 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
- A61K 31/4748: forming part of bridged ring systems (strychnine A61K31/475; morphinan derivatives A61K31/485)
- A61K 31/497: containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides methods for modulating the activity of farnesoid X receptors (FXRs) using specific FXR agonists, in particular for treating or preventing liver diseases and disorders.

## Claims

### Claim 1

A method for treating a condition mediated by Farnesoid X receptor (FXR), comprising administering to a subject a compound of Formula (I)
or a stereoisomer, an enantiomer, a pharmaceutically acceptable salt thereof, an amino acid conjugate or acyl glucuronide conjugate thereof, at a dose of about 3 μg to about 100 μg;
wherein said amino acid conjugate or acyl glucuronide conjugate is selected from:
2-({2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclor[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-6-yl}formamido)acetic acid;
2-({2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclor[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-6-yl}formamido)ethane-1-sulfonic acid; and
(2S,3S,4S,5R,6S)-6-((2-((1R,3S,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]thiazole-6-carbonyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; and
wherein said condition mediated by FXR is primary biliary cholangitis (PBC).

### Claim 2 (depends on 1)

The method according to claim 1, comprising administering 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The method according to claim 1, comprising administering 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid in a free form.

### Claim 4 (depends on 1)

The method according to claim 1, comprising administering the amino acid conjugate 2-({2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-6-yl}formamido)acetic acid.

### Claim 5 (depends on 1)

The method according to claim 1, comprising administering the amino acid conjugate 2-({2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-6-yl}formamido)ethane-1-sulfonic acid.

### Claim 6 (depends on 1)

The method according to claim 1, comprising administering the acyl glucuronide conjugate (2S,3S,4S,5R,6S)-6-((2-((1R,3S,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]thiazole-6-carbonyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid.

### Claim 7 (depends on 1)

The method according to claim 1, comprising administering said compound of Formula (I) or a stereoisomer, enantiomer or pharmaceutically acceptable salt, thereof, at a dose of about 10 μg to about 100 μg.

### Claim 8 (depends on 1)

The method according to claim 1, comprising administering about 10 μg, about 30 μg, about 60 μg or about 90 μg of 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof, up to a maximum total dose of about 100 μg per day.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the dose is a daily dose.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the dose is a twice daily dose.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the dose is every two days.

### Claim 12 (depends on 1)

The method according to claim 1, comprising administering about 30 μg to about 60 μg of 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The method according to claim 1, comprising administering about 30 μg to about 90 μg of 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The method according to claim 1, comprising administering about 60 μg of 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

The method according to claim 1, comprising administering about 90 μg of 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

The method according to claim 1, comprising administering once daily about 60 μg of 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid.

### Claim 17 (depends on 1)

The method according to claim 1, comprising administering once daily about 90 μg of 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid.