Aryl carbonyl derivatives as therapeutic agents

• US 7,541,373 B2
• Filed: 03/01/2006
• Issued: 06/02/2009
• Est. Priority Date: 06/27/2002
• Status: Expired

• Current Assignee: vTv Therapeutics LLC (vTv Therapeutics, Inc.)
• Original Assignee: Novo Nordisk A/S
• Inventors: Subramanian, Govindan, Kodra, Janos Tibor, Vedso, Per, Lau, Jesper, Polisetti, Dharma Rao, Andrews, Robert Carl, Santhosh, Kalpathy Chidambareswaran, Guzel, Mustafa, Mjalli, Adnan M. M., Jeppesen, Lone, Ankersen, Michael, Murray, Anthony, Bloch, Paw
• Primary Examiner(s): Saeed; Kamal
• Assistant Examiner(s): Coppins; Janet L
• Application Number:
  US11/365,534
• Publication Number:
  US 20060183783A1
• Time in Patent Office: 1,189 Days
• Field of Search: 548/189, 514/370
• US Class Current: 514/370
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 277/48 by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
• CPC Class Codes: C07D 277/52 to sulfur atoms, e.g. sulfonamides
• CPC Class Codes: C07D 277/54 Nitrogen and either oxygen or sulfur atoms
• CPC Class Codes: C07D 277/56 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 285/135 Nitrogen atoms
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 473/38 attached in position 6

Abstract

This invention relates to aryl carbonyl derivatives which are activators of glucokinase which may be useful for the management, treatment, control, or adjunct treatment of diseases, where increasing glucokinase activity is beneficial.

Claims

1. A compound of Formula (Ib)

2. The compound, pharmaceutically acceptable salt or solvate thereof of claim 1, wherein G¹ is cyclopentyl.

3. The compound, pharmaceutically acceptable salt or solvate thereof of claim 1, wherein R²⁴ is methyl.

4. The compound, pharmaceutically acceptable salt or solvate thereof of claim 2, wherein R²⁴ is methyl.

5. The compound, pharmaceutically acceptable salt or solvate thereof of claim 1, wherein R⁵⁴ is hydrogen.

6. The compound, pharmaceutically acceptable salt or solvate thereof of claim 2, wherein R⁵⁴ is hydrogen.

7. The compound, pharmaceutically acceptable salt or solvate thereof of claim 3, wherein R⁵⁴ is hydrogen.

8. The compound, pharmaceutically acceptable salt or solvate thereof of claim 4, wherein R⁵⁴ is hydrogen.

9. The compound, pharmaceutically acceptable salt or solvate thereof of claim 1, wherein R⁴³ is —

CH₂—

C(O)OR⁵⁴.

10. The compound of claim 1, wherein the compound is selected from the group consisting of;

{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester;

{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl} acetic acid;

2-[3-(2-Cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazole-4-carboxylic acid ethyl ester;

2-[3-(2-Cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazole-4-carboxylic acid;

{2-[3-(4-Methyl-2-[2-methylpropoxy] phenyl)-ureido]-thiazol-4-yl}-acetic acid;

{2-[3-(4-Bromo-2-cyclopentanecarbonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester;

{2-[3-(4-Bromo-2-cyclopentanecarbonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid;

3- {2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-propionic acid ethyl ester;

3- {2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-propionic acid;

{2-[3-(2-Cyclohexanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester;

{2-[3-(2-Cyclohexanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic;

{2-[3-(4-Chloro-2-cyclopentanecarbonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester;

{2-[3-(4-Chloro-2-cyclopentanecarbonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid;

{2-[3-(2-Cyclopentanecarbonyl-4-fluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester; and

{2-[3-(2-Cyclopentanecarbonyl-4-fluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid or a pharmaceutically acceptable salt or solvate thereof.

11. The compound {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl} acetic acid or a pharmaceutically acceptable salt or solvate thereof.

12. A pharmaceutical composition comprising the compound of Formula (Ib)

13. The pharmaceutical composition of claim 12, wherein G¹ is cyclopentyl.

14. The pharmaceutical composition of claim 12, wherein R²⁴ is methyl.

15. The pharmaceutical composition of claim 13, wherein R²⁴ is methyl.

16. The pharmaceutical composition of claim 12, wherein R⁵⁴ is hydrogen.

17. The pharmaceutical composition of claim 13, wherein R⁵⁴ is hydrogen.

18. The pharmaceutical composition of claim 14, wherein R⁵⁴ is hydrogen.

19. The pharmaceutical composition of claim 15, wherein R⁵⁴ is hydrogen.

20. The pharmaceutical composition of claim 12, wherein R⁴³ is —

CH₂—

C(O)OR⁵⁴.

21. The pharmaceutical composition of claim 12, wherein the compound is selected from the group consisting of {2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester;

{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl} acetic acid;

2-[3-(2-Cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazole-4-carboxylic acid ethyl ester;

²-[3-(2-Cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazole-4-carboxylic acid;

{2-[3-(4-Methyl-2-[²-methylpropoxy] phenyl)-ureido]-thiazol-4-yl}-acetic acid;

{2-[3-(⁴-Bromo-2-cyclopentanecarbonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester;

{2-[3-(4-Bromo-2-cyclopentanecarbonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid;

3-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-propionic acid ethyl ester;

3-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-propionic acid;

{2-[3-(2-Cyclohexanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester;

{2-[3-(2-Cyclohexanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic;

{2-[3-(4-Chloro-2-cyclopentanecarbonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester;

{2-[3-(4-Chloro-2-cyclopentanecarbonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid;

{2-[3-(2-Cyclopentanecarbonyl-4-fluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester; and

{2-[3-(2-Cyclopentanecarbonyl-4-fluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, or a pharmaceutically acceptable salt or solvate thereof.

22. A pharmaceutical composition comprising the compound {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl} acetic acid or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier, diluent, excipient, or mixture thereof.