US 8,138,185 B2Granted

Urea glucokinase activators

AssigneeNovo Nordisk A/S

InventorsAnthony Murray, Jesper Lau, Per Vedsø

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Abstract

This application relates to novel urea glucokinase activators and use of the compounds of the invention for preparation of a medicament for the treatment of various diseases, e.g. for the treatment of type 2 diabetes. Further encompassed is a pharmaceutical composition comprising a compound according to the invention and a process for preparing such.

Claims11

Dependent claims

A compound selected from the group consisting of:

3-{2-[3-Cyclopentylmethyl-3-(4-fluoro-3-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
3-{2-[3-Cyclopentylmethyl-3-(2,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
3-{2-[3-Cyclopentylmethyl-3-(2,3-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
3-{2-[3-Cyclopentylmethyl-3-(2,3-difluoro-4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-2,5-difluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-tert-Butyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(4-methylsulfanyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-2-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-2-fluoro-5-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2-fluoro-4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(3,4-dichloro-2-fluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(3-Acetylamino-2,4-difluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
(2-{3-Cyclopentylmethyl-3-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-ureido}-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(3-fluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2-fluoro-5-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(2-Fluoro-4-bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2-fluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
[2-(3-Cyclopentylmethyl-3-p-tolyl-ureido)-thiazol-5-ylsulfanyl]-2,2-dimethyl-propionic acid;
{2-[3-(4-Chloro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(4-fluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2-fluoro-4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(3-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
[2-(3-Cyclopentylmethyl-3-tolyl-ureido)-thiazol-5-ylsulfanyl]-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2,4-dichloro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(2-Chloro-4-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Chloro-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(2-Chloro-4-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2-fluoro-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(4-fluoro-2-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(4-isopropyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-3-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
(2-{3-Cyclopentylmethyl-3-[2-fluoro-4-(2-methoxy-ethoxy)-phenyl]-ureido}-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-3-trifluoromethoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-3-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-3-chloro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Chloro-2-trifluoromethyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-3-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(3-oxazol-2-yl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(4-phenylsulfanyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-2,6-difluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(4-methyl-2-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
(2-{3-Cyclopentylmethyl-3-[4-(2-methoxy-ethoxy)-phenyl]-ureido}-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid;
(2-{3-Cyclopentylmethyl-3-[4-(morpholine-4-sulfonyl)-phenyl]-ureido}-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(4-ethoxy-2-fluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(3-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(3-Butylsulfamoyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-3-chloro-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(2-Chloro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
and
{2-[3-(3-Chloro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
or a pharmaceutically acceptable salt thereof.

51 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/522,286Filed 8 Jan 2008 · us provisional application
Priority: EP 071002759 Jan 2007
Published: US 2010/0009989 A114 Jan 2010
Granted: 20 Mar 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 277/48
Acylated amino or imino radicals: by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application60/879,683Us provisional application · filed 10 Jan 2007
US 2010/0009989 A1Pre-grant publication · published 14 Jan 2010
US 8,138,185 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound selected from the group consisting of:

3-{2-[3-Cyclopentylmethyl-3-(4-fluoro-3-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
3-{2-[3-Cyclopentylmethyl-3-(2,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
3-{2-[3-Cyclopentylmethyl-3-(2,3-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
3-{2-[3-Cyclopentylmethyl-3-(2,3-difluoro-4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-2,5-difluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-tert-Butyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(4-methylsulfanyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-2-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-2-fluoro-5-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2-fluoro-4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(3,4-dichloro-2-fluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(3-Acetylamino-2,4-difluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
(2-{3-Cyclopentylmethyl-3-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-ureido}-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(3-fluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2-fluoro-5-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(2-Fluoro-4-bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2-fluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
[2-(3-Cyclopentylmethyl-3-p-tolyl-ureido)-thiazol-5-ylsulfanyl]-2,2-dimethyl-propionic acid;
{2-[3-(4-Chloro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(4-fluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2-fluoro-4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(3-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
[2-(3-Cyclopentylmethyl-3-tolyl-ureido)-thiazol-5-ylsulfanyl]-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2,4-dichloro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(2-Chloro-4-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Chloro-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(2-Chloro-4-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(2-fluoro-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(4-fluoro-2-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(4-isopropyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-3-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
(2-{3-Cyclopentylmethyl-3-[2-fluoro-4-(2-methoxy-ethoxy)-phenyl]-ureido}-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-3-trifluoromethoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-3-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-3-chloro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Chloro-2-trifluoromethyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-3-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(3-oxazol-2-yl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(4-phenylsulfanyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-2,6-difluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(4-methyl-2-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
(2-{3-Cyclopentylmethyl-3-[4-(2-methoxy-ethoxy)-phenyl]-ureido}-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid;
(2-{3-Cyclopentylmethyl-3-[4-(morpholine-4-sulfonyl)-phenyl]-ureido}-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(4-ethoxy-2-fluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-Cyclopentylmethyl-3-(3-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(3-Butylsulfamoyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(4-Bromo-3-chloro-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
{2-[3-(2-Chloro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
and
{2-[3-(3-Chloro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid;
or a pharmaceutically acceptable salt thereof.

51 more elements

Facts

Application

12/522,286Filed 8 Jan 2008 · us provisional application

Priority

EP 071002759 Jan 2007

Published

US 2010/0009989 A114 Jan 2010

Granted

20 Mar 2012

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 277/48
Acylated amino or imino radicals: by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics