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2-aza-bicyclo[2.2.1]heptane compounds and uses thereof

A compound, the technology of heterocycloalkyl, applied in the field of 2-aza-bicyclo[2.2.1]heptane compounds, can solve problems such as neurotoxicity

Inactive Publication Date: 2012-04-04
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In principle, this could be achieved by treatment with direct NMDA agonists; however, such compounds are known to cause neurotoxicity

Method used

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  • 2-aza-bicyclo[2.2.1]heptane compounds and uses thereof
  • 2-aza-bicyclo[2.2.1]heptane compounds and uses thereof
  • 2-aza-bicyclo[2.2.1]heptane compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0271] Example 1. (R * ) -N-(7-Azabicyclo[2.2.1]heptan-1-yl(phenyl)methyl)-2,6-dimethylbenzamide.

[0272]

[0273] Step A. Preparation of 7-azabicyclo[2.2.1]heptane-1,7- from (1s, 4s)-7-azabicyclo[2.2.1]heptane-1-carboxylic acid hydrochloride Dicarboxylic acid·7-tert-butyl ester·1-methyl ester.

[0274]

[0275] Acetyl chloride (3.90 mL, 54.89 mmol) was slowly added to methanol (80 mL) at 0°C. After 10 minutes, the solution was added to (1s, 4s)-7-azabicyclo[2.2.1]heptane-1-carboxylic acid (3.25 g, 1830 mmol; according to A. Avenoza et al. Tetrahedron 2001, 57, 545-548) to obtain a beige mixture. The mixture was warmed to 60°C and maintained under these conditions for 16 hours. The mixture was concentrated to a minimum volume, concentrated again from methanol, and dried under vacuum to give crude (1s, 4s)-7-azabicyclo[2.2.1]heptane-1-carboxylic acid methyl ester (3.46g) , It is hydrochloride and light gray solid. To crude 7-azabicyclo[2.2.1]heptane-1-carboxylic acid methyl es...

Embodiment 2

[0300] Example 2. Preparation (R * )-N-((7-Methyl-7-azabicyclo[2.2.1]heptan-1-yl)(phenyl)methyl)-2-(methylthio)nicotinamide

[0301]

[0302] Step A. From (R * )-1-(Amino(phenyl)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylic acid tert-butyl ester preparation (R * )-1-((Benzyloxycarbonylamino)(phenyl)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylic acid tert-butyl ester

[0303]

[0304] To (R * )-1-(Amino(phenyl)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylic acid tert-butyl ester (0.133g, 0.44mmol; according to step AF of Example 1 Operational preparation) and DIPEA (0.230 mL, 1.32 mmol) in dichloromethane (4.09 mL) was added benzyl chloroformate (0.073 mL, 0.48 mmol). The resulting light yellow solution was stirred for 20 minutes and another 35 uL of benzyl chloroformate was added. The reaction was stirred for another 45 minutes, then quenched with methanol (1 mL) and concentrated to a minimum volume. The resulting solution was passed through flash column chromatography (SiO 2 ...

Embodiment 32

[0317] Example 3.2 Preparation of 6-Dimethyl-N-((7-methyl-7-azabicyclo[2.2.1]heptan-1-yl)(phenyl)methyl)benzamide

[0318]

[0319] Step A. Preparation of 7-formyl-7-azabicyclo[2.2.1] from (1s, 4s)-7-azabicyclo[2.2.1]heptane-1-carboxylic acid methyl ester hydrochloride Methyl heptane-1-carboxylate

[0320]

[0321] At 0°C, to acetic anhydride (1.596 mL, 16.92 mmol) was added formic acid (0.757 mL, 17.63 mmol). After 5 minutes, the clear, colorless solution was warmed to 60°C. After 1 hour, the solution was cooled, and 0.5 mL was added to triethylamine (9.83 mL, 70.50 mmol) and (1s, 4s)-7-azabicyclo[2.2.1]heptane-1 at 0°C -A mixture of methyl carboxylate hydrochloride (2.70 g, 14.1 mmol; prepared according to the procedure of A. Avenoza et al. Tetrahedron 2001, 57, 545-548) in dichloromethane (70 mL). After 10 minutes, the white mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (x3). The combined organic layer was dried over sodium su...

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Abstract

This invention relates to 2-aza-bicyclo [2.2.1] heptane compounds (and salts thereof), the process for making such a compound and pharmaceutical compositions comprising such a compound. The invention also relates to the use of the compounds for modulating the glycine transporter 1 (GIyTl) and for the treatment of psychosis, cognitive disorders, bipolar disorders, depression disorders, anxiety disorders, post-traumatic stress disorders and pain.

Description

[0001] Cross reference to related patent applications [0002] The present invention claims priority rights in U.S. Provisional Patent Application 61 / 148,024 (filed on January 28, 2009). The full text of the above-mentioned patent application is incorporated into the present invention by reference. Technical field [0003] The present invention relates to 2-aza-bicyclo[2.2.1]heptane compounds. The present invention also relates to a pharmaceutical composition containing the compound, the use of the compound (including, for example, treatment methods and pharmaceutical preparation), and a method of preparing the compound. Background technique [0004] Due to the discovery of the unique behavioral effects of PCP, several studies have been conducted to evaluate the similarity between the symptoms and neurocognitive deficits induced by NMDA antagonists and those endogenously observed in schizophrenia. The study was first conducted using PCP itself until the drug was withdrawn from the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/08A61K31/407A61K31/416A61K31/4184A61K31/4427A61K31/506A61P25/04A61P25/18A61P25/22A61P25/24
CPCA61K31/4427A61K31/416A61K31/506C07D487/08A61K31/407A61K31/4184A61P25/00A61P25/04A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P29/00A61P43/00
Inventor J.S.阿尔伯特C.阿尔哈姆布拉T.A.布鲁格尔G.E.厄恩斯特W.弗雷特兹L.欣克利J.G.瓦尼斯王霞熊辉D·安迪希克
Owner ASTRAZENECA AB