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Compounds of estrogen-related receptor modulators and the uses thereof

a receptor modulator and estrogen technology, applied in the field of small molecules, can solve the problems of increasing the cost of treatment, putting a major burden on the healthcare system of developed and developing countries, increasing bone loss leading to osteoporosis, and reducing bone nodule formation, so as to improve glucose homeostasis in diabetic patients, and reduce the extent of insulin resistance.

Inactive Publication Date: 2015-01-08
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention proposes that compounds that activate the functions of a protein called ERRα and its partner PGC-1α can improve insulin resistance, glucose homeostasis, and restore insulin sensitivity in diabetic patients. These compounds may also reduce blood glucose levels and the level of a marker called hemoglobin A1c. Additionally, they may enhance the effects of current and future insulin sensitizers and insulin secretagogues drugs when used together.

Problems solved by technology

The healthcare cost associated with treatment is putting major burdens on the healthcare systems of developed as well as developing countries.
In addition, reduction of estrogen levels in post-menopausal results in an increase of bone loss leading to osteoporosis.
Over-expression of ERRα in osteoblasts increases bone nodule formation, while reducing the expression by anti-sense results in a decrease of bone nodule formation.
However, no definitive ERRα agonist has been identified so far that would improve insulin resistance through enhancing the function of PGC1.

Method used

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  • Compounds of estrogen-related receptor modulators and the uses thereof
  • Compounds of estrogen-related receptor modulators and the uses thereof
  • Compounds of estrogen-related receptor modulators and the uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

8-methoxy-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0114]

[0115]The solution of compound A and 5% mol sodium bromide in thionyl chloride was refluxed for 24 h, then the residual thionyl chloride was removed in vacuo to get compound B, compound B was added dropwisely mathanol at 0° C. the mixture was refluxed for 24 h, then the solvent was removed in vacuo. The residue was transferred into ethyl acetate and washed with saturated aqueous sodium bicarbonate, and brine. The solution was then dried over sodium sulfate, filtered, concentrated and purified by column chromatography to provide the desired compound C. Compound C in methanol was added hydrazine (1.5 eqiv), the mixture was refluxed for 4 h and then cooled to room temperature, filtrated to get compound D.

[0116]To an ice-bath solution of compound D in dry tetrahydrofuran was added dropwise trifluoroacetic acid (1.0 eqiv), followed by t-Butyl nitrite (3.0 eqiv), the mixture was continued to stirred for additional 30 min at the same ...

example 2

8-methoxy-3-methyl-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0121]

[0122]Synthetic route is the same as shown in Example 1.

[0123]MS(ESI), m / z: 267 (M+H)+.

example 3

8-hydroxy-2-phenyl-4H-pyrido[1,2a]pyrimidin-4-one

[0124]

[0125]Synthetic route is the same as shown in Example 1.

[0126]1HNMR (400 MHz, DMSO-d6), δ 9.02 (d, J=7.6 Hz, 1H), 8.15˜8.16 (d, J=6.0 Hz, 2H), 7.67˜7.69 (m, 3H), 7.14˜7.17 (m, 2H), 6.80 (s, 1H);

[0127]MS(ESI), m / z: 239 (M+H)+.

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PUM

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Abstract

The compounds according to formula (VIII), their pharmaceutically acceptable acid or base addition salts, and the uses thereof. These compounds and their pharmaceutically acceptable acid or base addition salts can be used for preparing medicaments for modulating estrogen related receptors (ERR), and treating metabolic diseases, such as high blood fat, fatty liver, hyperglycemia, diabetes, obesity. The substituents of the formula are defined in the description.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 13 / 054,664, filed on May 20, 2011, issuing, which is the U.S. National Phase of International application No. PCT / CN2009 / 000243, filed Mar. 6, 2009, which claims priority to Chinese Patent Application No. CN 200810029586.9, filed Jul. 18, 2008. The entire contents of all of the aforementioned patent applications are hereby expressly incorporated herein by reference.FIELD OF THE INVENTION [0002]This invention relates to small molecules which function as modulators of estrogen-related receptors.BACKGROUND OF THE INVENTION[0003]In recent years, the increasing incidences of metabolic diseases including obesity, diabetes, dyslipidemia, hypertension, and atherosclerosis, have led to higher risks of heart 10 diseases, a leading cause of mortality worldwide. The healthcare cost associated with treatment is putting major burdens on the healthcare systems of developed as well as developing countries. The...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D471/04
CPCC07D471/04A61P1/16A61P3/00A61P3/04A61P3/06A61P3/08A61P43/00A61P5/50A61P9/00A61P9/10A61P3/10
Inventor DING, KEWONG, CHIWAIPENG, LIJIEKANG, ZHANFANGZHOU, XI
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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