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Fused pyrazole derivatives and uses of methods of treatment of metabolic-related disorders thereof

A technology of compounds and hydrates, applied in the field of treatment of metabolic-related disorders including the following disorders, can solve the problems of inability to identify nicotinic acid receptors, obstacles and the like

Inactive Publication Date: 2007-12-12
ARENA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Rational development of novel nicotinic acid receptor agonists with fewer side effects is valuable but has so far been hampered by the inability to identify nicotinic acid receptors at the molecular level

Method used

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  • Fused pyrazole derivatives and uses of methods of treatment of metabolic-related disorders thereof
  • Fused pyrazole derivatives and uses of methods of treatment of metabolic-related disorders thereof
  • Fused pyrazole derivatives and uses of methods of treatment of metabolic-related disorders thereof

Examples

Experimental program
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preparation example Construction

[0471] Will 125 Synthetic methods for incorporating activity levels of I into target molecules include:

[0472] A. Sandmeyer and its analogs - This procedure converts an aryl or heteroaryl amine to a diazonium salt such as tetrafluoroborate, and then uses Na 125 I convert it into 125 I labeled compound. A representative procedure is reported by Zhu, D.-G. and co-workers in J. Org. Chem. 2002, 67, 943-948.

[0473] B. o 125 Phenol I - This procedure allows incorporation at the ortho position of the phenol 125 I, as reported by Collier, T.L. and coworkers in J. Labeled Compd Radiopharm. 1999, 42, S264-S266.

[0474] C. Aryl and heteroaryl bromides with 125 I Exchange - This method is usually a two-step process. The first step is to use (for example) Pd to catalyze the reaction [ie Pd(Ph 3 P) 4 ] or via an aryl or heteroaryl lithium in a trialkyltin halide or hexaalkylditin [e.g., (CH 3 ) 3 SnSn(CH 3 ) 3 ], the aryl or heteroaryl bromide is converted to the correspo...

example

[0480] The following examples are provided for illustrative purposes and not by way of limitation. Based on the disclosure herein, one of ordinary skill in the art will be able to devise equivalent assays and methods, all of which form a part of the present invention.

example 1

[0482] Rodent Diabetic Models

[0483] Rodent models of type 2 diabetes associated with obesity and insulin resistance have been developed. To understand the pathophysiology of disease and to test candidate therapeutic compounds, genetic models such as db / db and ob / ob in mice [see Diabetes (1982) 31:1-6] and fa / fa in zucker rats have been developed [ Diabetes (1983) 32:830-838; Annu Rep Sankyo Res Lab (1994) 46:1-57]. The homozygous animal C57BL / KsJ-db / db mouse developed by Jackson Laboratory (Jackson Laboratory) is a mouse with obesity, hyperglycemia, insulin hypersecretion and insulin resistance [J Clin Invest (1990) 85: 962-967 ], while heterozygotes are lean and normoglycemic. In the db / db model, mice progressively develop insulin deficiency with age, a feature commonly observed in advanced stages of human type 2 diabetes when glucose levels are not adequately controlled. Since this model is similar to the human type 2 diabetes model, the compounds of the invention were...

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Abstract

The present invention relates to certain fused pyrazole derivatives of Formula (Ia), and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists for the RUP25 receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of metabolic-related disorders, including dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, type 2 diabetes, Syndrome-X and the like. In addition, the present invention also provides for the use of the compounds of the invention in combination with other active agents such as those belonging to the class of alpha-glucosidase inhibitors, aldose reductase inhibitors, biguanides, HMG-CoA reductase inhibitors, squalene synthesis inhibitors, fibrates, LDL catabolism enhancers, angiotensin converting enzyme (ACE) inhibitors, insulin secretion enhancers, DP receptor antagonists, and the like.

Description

technical field [0001] The present invention relates to certain fused pyrazole derivatives and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, eg, as agonists of the nicotinic acid receptor (RUP25). The present invention also provides pharmaceutical compositions containing one or more compounds of the present invention, and methods of using the compounds and compositions of the present invention to treat metabolic-related disorders including: dyslipidemia, atherosclerosis, coronary heart disease , insulin resistance, type 2 diabetes, syndrome X and similar conditions. Furthermore, the invention also provides the use of the compounds of the invention in combination with other active agents such as those belonging to the following classes: alpha-glucosidase inhibitors, aldose reductase inhibitors, biguanides, HMG-CoA reductase inhibitors agents, squalene synthesis inhibitors, fibrates, LDL catabolism enhancers, angiotensin converting ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/54C07D403/04A61K31/416A61K31/4155A61P9/10
Inventor 道格拉斯·P·博特曼托马斯·O·施拉德尔格雷姆·森普尔菲利普·J·斯金纳郑载奎
Owner ARENA PHARMA