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Novel muscarinic receptor antagonist and application thereof

A technology of enantiomers and optical isomers, applied in the field of new muscarinic receptor antagonists and their uses

Inactive Publication Date: 2009-12-09
HEBEI RUISHENG MEDICINE TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] But there is no report about the ether compounds of 3-azabicyclo (3,3,1) nonanol and its optical isomers and quaternary ammonium salts

Method used

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  • Novel muscarinic receptor antagonist and application thereof
  • Novel muscarinic receptor antagonist and application thereof
  • Novel muscarinic receptor antagonist and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Example 1Rac-9-(2'-phenyl-2'-cyclohexyl-2'-hydroxy-ethoxy)-N-methyl-3-azabicyclo(3.3.1)nonane (Rac-1 ) preparation

[0092] Under the protection of nitrogen, put 0.6g (15mmol) NaH in a dry three-necked flask, add 10mL of anhydrous DMSO, after stirring for 5min, dropwise add N-methyl-3-azabicyclo(3.3.1) nonanol ( 2.0g (14.2mmol) in 10mL DMSO solution, stirred at 60°C for 1h. After cooling to room temperature, slowly add α-phenyl-α-cyclohexyl-1,2-oxirane 2.61g (14mmol) in 10mL DMSO solution. Stir the reaction at 50°C for 3 hours, cool, and carefully add 20 mL of water dropwise. Extract with ether, wash with water, wash the ether layer with 10% hydrochloric acid solution, and combine the water phase; Drying over sodium, distilling off the solvent to give 9-(2'-phenyl-2'-cyclohexyl-2'-hydroxy-ethoxy)-N-methyl-3-azabicyclo(3.3.1)nonane Alkane colorless liquid, 3.02g, yield 67%. 1 H-NMR: δ (ppm, CD 3 Cl), 7.44(m, 2H), 7.25(m, 3H), 5.02(s, 1H), 3.71-3.85(m, 2H), 2.91-3.05(...

Embodiment 2

[0093] Example 2Rac-9-(2'-phenyl-2'-cyclohexyl-2'-hydroxy-ethoxy)-N-methyl-3-azabicyclo(3.3.1)nonane hydrochloride ( Preparation of Rac-1·HCl)

[0094]Dissolve 2.0 g of 9-(2'-phenyl-2'-cyclohexyl-2'-hydroxy-ethoxy)-N-methyl-3-azabicyclo(3.3.1)nonane in 5 mL of ether , the ether layer was cooled, 5ml of 2N hydrochloric acid solution was added, and the solid was precipitated by stirring. The solid was collected by filtration, washed with ice water, and recrystallized from 95% ethanol to obtain 1.8 g of the title compound as a white solid, yield 81%, melting point: 189-191°C.

[0095] H-NMR: δ (ppm, CD 3 Cl), 10.87(s, 1H), 7.61(m, 2H), 7.25(m, 3H), 5.08(s, 1H), 3.63-3.80(m, 2H), 2.92-3.05(m, 4H), 2.82 (s, 3H), 2.21 (s, 1H), 2.03 (s, 1H), 2.01 (m, 2H), 1.31-1.75 (m, 12H).

Embodiment 3

[0096] Example 3Rac-9-(2'-phenyl-2'-cyclohexyl-2'-hydroxy-ethoxy)-N,N-dimethyl-3-azabicyclo(3.3.1)nonane quaternary Amiodonium salt (Rac-1-CH 3 l) Preparation

[0097] Dissolve 1.0 g of 9-(2'-phenyl-2'-cyclohexyl-2'-hydroxy-ethoxy)-N-methyl-3-azabicyclo(3.3.1)nonane and excess iodomethane In 20mL of acetonitrile, stirred and refluxed for 5 days, TLC detected that the reaction reached equilibrium, cooled to room temperature, evaporated the solvent, the residue was washed 3 times with ethyl acetate, and recrystallized from ethanol to obtain the target compound as a yellow solid 0.86g, Yield: 61%, melting point: 161-163°C. H-NMR: δ (ppm, DMSO), 11.27 (s, 1H), 7.58 (m, 2H), 7.37 (m, 3H), 4.98 (s, 1H), 3.43-3.70 (m, 2H), 2.82- 3.10(m, 4H), 2.88(s, 3H), 2.76(s, 3H), 2.25(s, 1H), 2.06(s, 1H), 2.04(m, 2H), 1.37-1.81(m, 12H) .

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Abstract

The invention relates to a novel muscarinic receptor antagonist and application thereof, relating to the preparation of novel ether compound of 3-azabicyclo(3, 3,1) nonanol and an optical isomer and quaternary ammonium salt thereof, and application of the compounds as medicament. The compounds show high affinity; and can be used for treating diseases or disease symptoms concerning the cholinergic systems of the central nervous system (CNS), and the peripheral nervous system (PNS), smooth muscle contraction, internal secretion, neurodegeneration, inflammation, aches, withdrawal caused by the termination of abuse of chemicals, and the like.

Description

technical field [0001] The present invention relates to the preparation of new ether compounds of 3-azabicyclo (3,3,1) nonanol, optical isomers and quaternary ammonium salts thereof, their medicinal compositions, and the use of these compounds as medicines. The compounds of the present invention show high affinity for muscarinic receptors, and due to their pharmaceutical properties, the compounds of the present invention can be used for the treatment of cholinergic systems associated with the central nervous system (CNS), peripheral nervous system (PNS) Diseases or conditions related to smooth muscle contraction, endocrine diseases or conditions, diseases or conditions related to neurodegeneration, diseases or conditions related to inflammation, pain, and withdrawal symptoms caused by cessation of chemical substance abuse or illness. Background technique [0002] Muscarinic acetylcholine receptors (mAChR) are G protein-coupled receptors. M receptors are involved in many im...

Claims

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Application Information

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IPC IPC(8): C07D221/22A61K31/439A61P11/00A61P1/00A61P13/00A61P25/00
Inventor 李静马宏志
Owner HEBEI RUISHENG MEDICINE TECH
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