Substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors

Patent metadata

Field	Value
Publication number	US-10174007-B2
Application number	US-201715729885-A
Country	US
Kind code	B2
Filing date	Oct 11, 2017
Priority date	Dec 29, 2015
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

Abstract

Provided herein are substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors, processes to make said compounds, and methods comprising administering said compounds to a mammal in need thereof.

First claim

It is claimed:

1. A method of treating a disease for which an inhibitor of KHK is indicated, the method comprising the administration to a mammal in need thereof a therapeutically effective amount of a compound, wherein the compound is [(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid, or pharmaceutically acceptable salt thereof; and
wherein the disease is selected from any one or combination of T1D, T2D, insulin resistance, hypertriglyceridemia, NAFLD, steatosis, and NASH.

2. The method of claim 1 , wherein the compound is

or pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein the compound is [(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.

4. The method of claim 1 , wherein the compound is a sodium salt form of [(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.

5. The method of claim 4 , wherein the compound is a crystalline sodium salt form of [(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.

6. The method of claim 5 , wherein the crystalline form of the compound is characterized substantially by the following principal powder x-ray diffraction pattern peaks expressed in terms of 2θ as measured with a copper radiation chosen from 5.9, 11.5, 11.8, 13.3, and 21.5+/−0.2°.

7. The method of claim 1 , wherein the disease is T2D.

8. The method of claim 1 , wherein the disease is insulin resistance.

9. The method of claim 1 , wherein the disease is hypertriglyceridemia.

10. The method of claim 1 , wherein the disease is NAFLD.

11. The method of claim 1 , wherein the disease is steatosis.

12. The method of claim 1 , wherein the disease is NASH.

Assignees

• Pfizer

Inventors

• Dowling Matthew
• Fernando Dilinie
• Futatsugi Kentaro
• Huard Kim
• Magee Thomas Victor
• Raymer Brian
• Shavnya Andre
• Smith Aaron
• Thuma Benjamin
• Tsai Andy
• Tu Meihua

Classifications

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title