Oxadiazole and thiadiazole compounds and their use as nicotinic acetylcholine receptor modulators

A technology of compounds and mixtures, applied in the field of oxadiazolyl and thiadiazolyl derivatives, can solve problems such as not describing the activity of nicotinic receptor modulators

Inactive Publication Date: 2009-10-07
NEUROSEARCH AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the oxadiazolyl and thiadiazolyl derivatives of the present invention are not described or certainly never suggested their activity as modulators of nicotinic receptors

Method used

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  • Oxadiazole and thiadiazole compounds and their use as nicotinic acetylcholine receptor modulators
  • Oxadiazole and thiadiazole compounds and their use as nicotinic acetylcholine receptor modulators
  • Oxadiazole and thiadiazole compounds and their use as nicotinic acetylcholine receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0240] 5-furan-2-yl-[1,3,4]oxadiazole-2-thiol (intermediate compound)

[0241]

[0242] Dissolve 6.7g (0.12mole) of potassium hydroxide in 125ml of methanol, add 13.7g (0.11mole) of 2-furanoic hydrazide (2-furanoic hydrazide) and keep the temperature at 25°C for half an hour, then add 16.5g ( 0.22mole) of carbon disulfide. The reaction mixture was heated to reflux and stirred for 8 hours, then evaporated to an oil. Water was added to the residue, and concentrated hydrochloric acid was added until pH=4. The precipitate was isolated by filtration and dried. Yield 12.9 g (77 mmol, 70%).

[0243] In the same way, the following intermediate compound was similarly prepared: 5-pyridin-3-yl-[1,3,4]oxadiazole-2-thiol.

Embodiment 2

[0245] 2-(5-furan-2-yl-[1,3,4]oxadiazol-2-ylsulfanyl)-pyrazine (compound 2.1)

[0246]

[0247] 5-furan-2-yl-[1,3,4]oxadiazole-2-thiol (1.8 g, 11 mmole) was dissolved in 50 ml of dry dioxane, and 1.3 g (11 mmole) was added to the solution of chlorpyrazine and 1.4 g (11 mmole) of ethyldiisopropylamine. The reaction mixture was heated at reflux for 3 days and evaporated to an oil. 1 N (aq.) sodium hydroxide was added to the oil and the product was isolated by filtration and purified by column chromatography. Yield 1.1 g (4.5 mmole, 41%); Mp. 92-93°C.

[0248] With this, the following intermediate compounds are obtained similarly:

[0249] 3-(5-Benzylsulfanyl-[1,3,4]oxadiazol-2-yl)-pyridine (Compound 2.2) Mp.209-210°C; and

[0250] 3-Chloro-6-(5-furan-2-yl-[1.3.4]oxadiazol-2-ylsulfanyl)-pyridazine (Compound 2.3) Mp. 132-133°C.

Embodiment 3

[0252] N-(5-phenylmethanesulfonyl-[1,3,4]oxadiazol-2-yl)-acetamide (compound 3.1)

[0253]

[0254] To 2-acetylamino-5-benzylthio-[1,3,4]thiadiazole (3 g, 11 mmole) in dichloromethane was added 8.6 g (50 mmole) of 3-chloroperoxybenzoic acid. The reaction mixture was stirred at room temperature for 90 minutes and filtered. The filtrate was evaporated to an oil. The oil was titrated with water and a white precipitate formed which was isolated by filtration, washed with water and dried. Yield 2.6 g (8.7 mmole, 79%); Mp. 245-248°C.

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Abstract

This invention relates to oxadiazolyl and thiadiazolyl derivatives, which are found to be modulators of the nicotinic acetylcholine receptors. 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 oxadiazolyl and thiadiazolyl derivatives which have been found to be modulators of nicotinic acetylcholine receptors. Due to their pharmacological characteristics, the compounds of the present invention are useful 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 involving neurodegeneration, diseases or disorders involving inflammation, pain, and withdrawal symptoms resulting from cessation of chemical substance abuse. Background technique [0002] The endogenous cholinergic neurotransmitter, acetylcholine, exerts its biological effects via two types of cholinergic receptors, muscarinic acetylcholine receptors (mAChR) and nicotinic acetylcholine receptors (nAChR). [0003] Nicotinic acetylcholine receptors (nAChRs) are pentameri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04C07D413/14C07D417/14C07D285/135A61K31/4245A61K31/433A61P25/00
CPCA61K31/4245C07D285/12C07D285/135C07D413/04C07D413/14C07D417/04
Inventor B·H·达尔D·彼得斯G·M·奥尔森D·B·蒂默曼S·哲根森
Owner NEUROSEARCH AS
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