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Spiro[isobenzofuran-1,4'-piperidin]-3-ones and 3H-spiroisobenzofuran-1,4'-piperidines

a technology of spiroisobenzofuran and spiroisobenzofuran, which is applied in the field of substituted spiroisobenzofuran1, 4 ′piperidin3ones and 3hspiroisobenzofuran1, 4 ′piperidines, can solve the problems of poor metabolic stability, low oral bioavailability, and serious shortcomings in therapeutic use, and achieve the effect of inhibiting or enhancing the binding of npy to the npy receptor

Inactive Publication Date: 2006-02-23
BAKTHAVATCHALAM RAJAGOPAL +9
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

These modulators exhibit high affinity binding to NPY5 receptors, effectively modulating NPY binding and providing therapeutic benefits for disorders like obesity, bulimia, diabetes, and cardiovascular diseases, while also serving as probes for receptor detection and localization.

Problems solved by technology

Peptides, however, generally have serious shortcomings for therapeutic use including, poor metabolic stability, low oral bioavailability and poor brain permeability.

Method used

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  • Spiro[isobenzofuran-1,4'-piperidin]-3-ones and 3H-spiroisobenzofuran-1,4'-piperidines
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  • Spiro[isobenzofuran-1,4'-piperidin]-3-ones and 3H-spiroisobenzofuran-1,4'-piperidines

Examples

Experimental program
Comparison scheme
Effect test

example 1

1′-(5-Pyridin-3-Yl-1h-Benzimidazol-2-Yl)-Spiro[Isobenzofuran-1,4′-Piperidin]-3-One

[0132] This Example illustrates the preparation of the representative compound 1′-(5-pyridin-3-yl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one.

[0133] A. 2-chloro-5-iodo-1H-benzimidazole

[0134] Heat a solution of 5-iodo-1,3-dihydro-benzimidazol-2-one (6.50 g, 25.0 mmol; Feitelson et al. (1952) J. Chem. Soc. 2389) and tetramethylammonium chloride (1.37 g, 12.5 mmol) to 100° C. in POCl3 (10 mL) for 18 hours. After cooling, remove the excess POCl3 in vacuo, and triturate the residue in ice-water (200 mL). After stirring for 30 minutes, filter the precipitate to obtain 2-chloro-5-iodo-1H-benzimidazole as a gray solid.

B. 1′-(5-iodo-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one

[0135]

[0136] Heat a solution of 2 chloro-5-iodo-1H-benzimidazole (3.0 g, 10.7 mmol) and spiro[isobenzofuran-1,4′-piperidin]-3-one (2.63 g, 12.9 mmol) in dry NMP (15 mL) at 100° C. for 14 hours. ...

example 2

1′-(5-Oxazol-2-Yl-1h-Benzimidazol-2-Yl)-Spiro[Isobenzofuran-1,4′-Piperidin]-3-One Hydrochloride

[0139] This Example illustrates the preparation of the representative compound 1′-(5-oxazol-2-yl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one.

[0140] Add a solution of oxazole (0.5 mL, 7.24 mmol) in deoxygenated THF (50 mL) at −78° C. to 1.6 M n-butyllithium in hexane (5 mL, 7.96 mmol). After stirring for 30 minutes, add 1M zinc chloride in Et2O (22 mL, 21.7 mmol) and warm the reaction mixture to 0° C. for 2 hours. To the reaction mixture, add first a solution of 1′-(5-iodo-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one (3.2 g, 7.18 mmol), then the palladium catalyst which is prepared by treating a suspension of (Ph3P)2PdCl2 (0.25 g, 0.36 mmol) in deoxygenated THF (50 mL) with 1.6 M n-butyllithium in hexane (0.45 mL, 0.72 mmol). Reflux the reaction mixture for 20 hours. After cooling to ambient temperature, dilute the mixture with EtOAc (50 mL), and wa...

example 3

1′-(5-Cyano-1 h-Benzimidazol-2-Yl)-Spiro[Isobenzofuran-1,4′-Piperidin]-3-One

[0141] This Example illustrates the preparation of the representative compound 1′-(5-cyano-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one.

[0142] Add zinc cyanide (0.016 g, 0.13 mmol) and tetrakistriphenylphosphine palladium(0) (0.018 g, 0.02 mmol) to a solution of 1′-(5-iodo-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one (0.1 g, 0.22 mmol) in NMP (2 mL). Heat the reaction mixture at 130° C. for 19 hours. After cooling to ambient temperature, dilute the mixture with EtOAc (20 mL), and wash with water (20 mL) and saturated aqueous NaCl (20 mL). Dry the organic portion over Na2SO4, filter and concentrate. Purify by preparative TLC (80% EtOAc-hexane) to obtain 1′-(5-cyano-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a white solid.

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Abstract

Substituted spiro[isobenzofuran-1,4′-piperidin]-3-ones and 3H-spiroisobenzofuran-1,4′-piperidines capable of modulating NPY5 receptor activity are provided. Such compounds may be used to modulate ligand binding to NPY5 receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of disorders (e.g., eating disorders such as obesity or bulimia, psychiatric disorders, diabetes and cardiovascular disorders such as hypertension) in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such compounds for detecting NPY5 receptors.

Description

FIELD OF THE INVENTION [0001] This invention relates generally to substituted spiro[isobenzofuran-1,4′-piperidin]-3-ones and 3H-spiroisobenzofuran-1,4′-piperidines that are modulators of mammalian neuropeptide Y5 (NPY5) receptors, and to the use of such compounds for treating a variety of physiological disorders associated with NPY5 receptor activation, such as feeding disorders, psychiatric disorders and cardiovascular diseases. The invention further relates to the use such compounds as probes for the detection and localization of NPY5 receptors. BACKGROUND OF THE INVENTION [0002] Neuropeptide Y (NPY) is a 36 amino acid peptide that mediates a variety of physiological effects in humans and other mammals. This is largely conserved across mammalian species, and belongs to a large family of peptides that includes, among others, peptide YY (PYY) and pancreatic peptide (PP). NPY is the most abundant peptide in the mammalian brain, and is also present in sympathetic neurons. In addition,...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/519A61K31/4747C07D491/10A61K31/438C07D491/107A61K31/444A61K31/4545A61K31/496A61K31/497A61K31/4985A61K31/506A61K31/517A61K51/00A61P3/04A61P3/10A61P9/00A61P25/00A61P25/18A61P25/24A61P43/00C07D487/04C07D487/10C07D519/00
CPCC07D491/10C07D487/04A61P25/00A61P25/18A61P25/24A61P3/04A61P43/00A61P9/00A61P3/10
Inventor BAKTHAVATCHALAM, RAJAGOPALBLUM, CHARLESBRIELMANN, HARRYDARROW, JAMESDE LOMBAERT, STEPHANEHUTCHISON, ALANTRAN, JENNIFERZHENG, XIAOZHANGELLIOTT, RICHARDHAMMOND, MARLYS
Owner BAKTHAVATCHALAM RAJAGOPAL
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