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Macrocyclic Ghrelin Receptor Antagonists And Inverse Agonists And Methods Of Using The Same

A six-membered ring and five-membered ring technology, applied in the field of macrocyclic compounds, can solve the problems of poor selectivity and limited

Inactive Publication Date: 2012-12-05
OCERA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the use of this particular agent may be limited due to its poor selectivity as it also interacts with neurokinin-1 and bombesin receptors

Method used

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  • Macrocyclic Ghrelin Receptor Antagonists And Inverse Agonists And Methods Of Using The Same
  • Macrocyclic Ghrelin Receptor Antagonists And Inverse Agonists And Methods Of Using The Same
  • Macrocyclic Ghrelin Receptor Antagonists And Inverse Agonists And Methods Of Using The Same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0671] amino acid building block

Embodiment AA1

[0672] Example AA1. Standard Procedure for the Synthesis of H-(3Me)Cpg-OH

[0673]

[0674] Step AA1-1: Cyclopropanation. To a solution of 3-methyl-3-buten-1-ol (AA1-A, 3.52 mL, 34.8 mmol, 1.0 equiv) in DCM (350 mL) was carefully added neat diethyl at -20 °C under argon atmosphere Zinc (17.9 mL, 174 mmol, 5.0 equiv) and diiodomethane (28.1 mL, 348 mmol, 10.0 equiv) were added and the temperature was rapidly raised to 0 °C. (Note: Temperature control is very important. Diiodomethane (melting point: 5-8°C) and diethylzinc (melting point: -28°C) can freeze suddenly and stop stirring, and there is a risk of explosion when melting). The reaction was allowed to warm slowly to room temperature and stirred overnight. Add saturated NH to the mixture 4 Cl (aq), and with Et 2 The aqueous phase was extracted with O (3x). with saturated NaHCO 3 The combined organic phases were washed with aqueous solution (2×), brine (1×), washed over MgSO 4 Dry, filter, and then concentrate the ...

Embodiment AA2

[0681] Example AA2: Standard procedure for the synthesis of H-trans-(3H,4Me)Cpg-OH

[0682]

[0683] Step AA2-1: Cyclopropanation. To a solution of (Z)-pent-3-en-1-ol (AA2-A, 3.34 g, 38.9 mmol, 1.0 equiv) in DCM (390 mL) was carefully added neat diethylzinc (20.0 mL, 194 mmol, 5.0 equiv) and diiodomethane (31.4 mL, 398 mmol, 10.0 equiv), and the temperature was rapidly raised to 0°C. (Note: Temperature control is very important. Diiodomethane (melting point: 5-8°C) and diethylzinc (melting point: -28°C) can freeze suddenly and stop stirring, and there is a risk of explosion when melting). The reaction was allowed to warm slowly to room temperature and stirred overnight. Add saturated NH 4 Cl(aq) with Et 2 The aqueous phase was extracted with O (3x). with saturated NaHCO 3 The combined organic phases were washed with aqueous solution (2×), brine (1×), washed over MgSO 4 Dried, filtered, and concentrated by rotary evaporator at low temperature and low pressure (due to ...

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Abstract

The present invention provides novel conformationalIy- defined macrocyclic compounds of formula (I) that have been demonstrated to be selective modulators of the ghrelin receptor (GRLN, growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and / or variants thereof). Methods of synthesizing the novel compounds are also described herein. These compounds are useful as antagonists or inverse agonists of the ghrelin receptor and as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and / or endocrine disorders, obesity and obesity- associated disorders, appetite or eating disorders, addictive disorders, cardiovascular disorders, gastrointestinal disorders, genetic disorders, hyperproliferative disorders, central nervous system disorders and inflammatory disorders.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application Serial No. 61 / 256,727, filed October 30, 2009, the disclosure of which is hereby incorporated by reference in its entirety. field of invention [0003] The present invention relates to novel conformationally defined macrocyclic compounds which have been shown to act as antagonists or inverse agonists of the ghrelin (growth hormone secretagogue) receptor (GRLN, GHS-R1a) . The invention also relates to intermediates of these compounds, pharmaceutical compositions comprising these compounds and methods of using said compounds. These novel macrocycles are useful as therapeutic agents for a range of indications including metabolic and / or endocrine disorders, obesity and obesity-related disorders, appetite or eating disorders, addictive disorders, cardiovascular disorders, gastric Bowel disorders, genetic disorders, hyperproliferative disorders, central nervous s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/12A61K38/12A61P25/00A61P35/00A61P5/00A61P3/00A61P1/00A61P29/00A61P9/00
CPCC07K5/0812C07K5/0808A61K38/00C07K5/0804A61P1/00A61P1/04A61P1/14A61P1/16A61P25/00A61P25/30A61P25/32A61P25/36A61P29/00A61P3/00A61P3/04A61P35/00A61P3/06A61P43/00A61P5/00A61P9/00A61P3/10
Inventor H.霍维达E.马索尔特H.托马斯G.弗拉泽S.博比恩A.马蒂厄J.贝内特M-A.博宁S.费尼克斯D.德鲁茨M.彼得森S.博歇明M.布拉萨尔M.韦兹纳
Owner OCERA THERAPEUTICS INC
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