Novel 2,5-diazabicyclo [2.2.1] heptane derivatives

A technology of diazabicycles and derivatives, which is applied in the field of novel 2, and can solve problems such as the unreported role of monoamine receptors or corresponding transporters

Inactive Publication Date: 2007-08-15
NEUROSEARCH AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Their effects on monoamine receptors or corresponding transporters have not been reported

Method used

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  • Novel 2,5-diazabicyclo [2.2.1] heptane derivatives
  • Novel 2,5-diazabicyclo [2.2.1] heptane derivatives
  • Novel 2,5-diazabicyclo [2.2.1] heptane derivatives

Examples

Experimental program
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Effect test

Embodiment 1

[0139] General overview: All reactions involving air-sensitive reagents or intermediates were performed under nitrogen and anhydrous solvents. Magnesium sulfate was used as a drying agent in the working procedure and the solvent was evaporated under reduced pressure.

[0140] 2-(2-Quinolinyl)-(1S,4S)-2,5-diazabicyclo-[2.2.1]-heptane fumarate (Compound 1)

[0141]Sodium (0.87g; 37.9mmol), methanol (70ml) and (1S,4S)-(+)-2,5-diazabicyclo-[2.2.1]-heptane dihydrobromide (3.94 g; 15.2 mmol) the mixture was stirred at reflux for 1 hour. The mixture was evaporated to dryness. To this mixture were added 2-chloroquinoline (2.48 g; 15.2 mmol) and dioxane (70 ml). The mixture was stirred at 100°C for 2.5 hours. The solvent was evaporated. Aqueous sodium hydroxide solution (1M; 50ml) was added followed by extraction with diethyl ether (3 x 50ml). Silica gel chromatography using dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound as the free base. Yield 0.8...

Embodiment 2

[0161] biological activity

[0162] In this example, the biological activity of the compounds of the invention was determined using the serotonin transporter / uptake assay. It is postulated that the serotonin transporter / uptake site on nerve terminals functions to terminate neuronal signaling by removing serotonin from the synaptic cleft. Uptake by synaptosomes in vitro 3 H-serotonin was used to measure the activity of the serotonin transporter membrane-intrinsic protein.

[0163] tissue preparation

[0164] The preparation was carried out at 0-4°C. Cerebral cortex from male Wistar rats (150-200 g) was homogenized in 100 volumes of ice-cold 0.32 M sucrose containing 1 mM parjiline and using a motor-driven Teflon pestle in a glass homogenization vessel for 5- 10 seconds.

[0165] Monoamine oxidase activity is inhibited by pagyline.

[0166] The homogenate was centrifuged at 1000xg for 10 minutes. The resulting supernatant was centrifuged at 27,000 xg for 50 minutes and ...

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Abstract

The present invention relates to novel 2,5-diazabicyclo[2.2.1]heptane derivatives, which are found to be potent modulators of the monoamine receptors and transporters. Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

Description

technical field [0001] The present invention relates to novel 2,5-diazabicyclo[2.2.1]heptane derivatives which have been found to be potent modulators of monoamine receptors and transporters. [0002] Due to their pharmacological properties, the compounds of the present invention can be used in the treatment of various diseases or disorders involving the cholinergic system of the central nervous system (CNS), peripheral nervous system (PNS), diseases or disorders involving smooth muscle contraction, endocrine diseases or Disorders, diseases or disorders involving neurodegeneration, diseases or disorders involving inflammation, pain, and withdrawal symptoms resulting from cessation of chemical substances of abuse. Background technique [0003] Several CNS disorders can actually be attributed to cholinergic, dopaminergic, adrenergic or serotonergic deficits. [0004] 2,5-Diazabicyclo[2.2.1]heptane derivatives N-substituted by monocyclic heterocyclic aryl groups are disclosed ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/08A61K31/495A61P25/00C07D471/06A61K31/5025A61K31/407A61K31/4995A61P3/04A61P15/00A61P25/02A61P25/08A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28C07D487/08
CPCA61K31/4995C07D487/08A61P15/00A61P25/00A61P25/02A61P25/08A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P3/04
Inventor D·皮特斯G·M·奥森E·O·尼尔森P·K·阿灵T·D·约恩森
Owner NEUROSEARCH AS
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