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Heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders

A heteroaryl and substituent technology, applied in the field of heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders, can solve the problems of elevated, undiscovered PDE cell type selectivity, etc.

Active Publication Date: 2009-12-30
CYMABAY THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The second component is the failure to respond to a hyperglycemic challenge to increase insulin release above an already elevated basal output
Inhibitors of cAMP phosphodiesterases have been shown to increase insulin secretion in vitro and in vivo, including PDE1C, PDE3B, PDE10 (Han P et al., J Biol Chem. 6 Aug 1999; 274(32):22337-44; Harndahl L et al., J Biol Chem. 2002 Oct 4; 277(40):37446-55; Walz HA et al People, J Endocrinol. 2006 Jun;189(3):629-41; ChoiYH et al., J Clin Invest. 2006 Dec;116(12): 3240-51; and Cantin LD et al., Bioorg Med Chem Lett. 2007 May 15; 17(10):2869-73), but so far, no PDE classes have the cell-type selectivity necessary to avoid undesired effects

Method used

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  • Heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders
  • Heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders
  • Heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders

Examples

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preparation example Construction

[0237] Preparation of the compounds of the invention

[0238] The compounds of the present invention can be prepared by many methods well known to those skilled in the art of organic synthesis. The synthetic route of the compounds of the present invention is not limited to the methods provided in the summary or examples below. Individual compounds may need to manipulate conditions to suit various functional groups and may require the proper use of protecting groups. If necessary, it can be eluted on a silica gel column with an appropriate organic solvent system to achieve purification. Reverse phase HPLC or recrystallization can also be used.

[0239] One aspect of the present invention provides a method for increasing the content of intracellular cyclic AMP (cAMP) in cells expressing GPR119. The method comprises exposing cells expressing GPR119 to a compound as described herein. The cyclic AMP content was determined by the method disclosed herein. Preferred cells expressing GPR11...

example 1

[0376] 4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

[0377]

[0378] Heat 4-(4-chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 1,463mg, 1.46mmol), 4-methanesulfonyl-phenol (252mg, 1.46mmol) and K 2 CO 3 A mixture of (404 mg, 2.92 mmol) in acetone (25 mL) overnight. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexane, 1:1) to give the desired product. 1 H NMR(CDCl 3 ): δ 7.88 (2H, d, J = 8.8 Hz), 7.23 (1H, s), 7.12 (2H, d, J = 8.8 Hz), 5.24 (2H, s), 4.21 (2H, br), 3.17 (1H, m), 3.04 (3H, s), 2.88 (2H, m), 2.11 (2H, m), 1.73 (2H, m), 1.47 (9H, s).

example 2

[0381] 4-[4-(4-imidazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester

[0382]

[0383] 1 H NMR(DMSO-d 6 ): δ 8.12 (1H, s), 7.63 (2H, m), 7.54 (2H, d, J = 9.2 Hz), 7.15 (2H, d, J = 9.2 Hz), 7.05 (1H, s), 5.15 (2H, s), 3.98 (2H, m), 3.21 (1H, m), 2.87 (2H, m), 2.01 (2H, m), 1.52 (2H, m), 1.39 (9H, s).

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Abstract

Compounds and methods are provided for the treatment of, inter alia, Type II diabetes and other diseases associated with poor glycemic control. The compounds of the invention are orally active.

Description

[0001] Cross references to related applications [0002] This application claims the priority of 60 / 877,903 filed on December 28, 2006. [0003] Declaration of rights to inventions obtained under federally sponsored research and development [0004] Not applicable [0005] Reference to "Sequence List", form or appendix of computer program list submitted on CD [0006] Not applicable Technical field [0007] The present invention provides compounds and methods that are particularly useful in the treatment of type II diabetes and other diseases associated with poor blood glucose control. The compounds of the present invention have oral activity. Background technique [0008] Diabetes can be divided into two clinical syndromes: type I diabetes and type II diabetes. Type I diabetes or insulin-dependent diabetes is a chronic autoimmune disease characterized by insulin-producing β-cells (hereinafter referred to as "islets of Langerhans" or "islets of Langerhans" in the pancreas. )...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/40A61K31/445A61K31/497
Inventor 陈新程鹏L·爱德华·克莱门斯杰弗里·D·约翰逊马靖原艾莉森·墨菲伊马德·纳沙希比克里斯多夫·J·拉巴特宋建高玛利亚·E·威尔逊朱严赵祖春
Owner CYMABAY THERAPEUTICS
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