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Benzofurazan compounds which enhance AMPA receptor activity

The technology of a compound, benzofurazan, is applied in the field of prevention and treatment of cerebral insufficiency, which can solve the problem of low activity

Inactive Publication Date: 2000-03-15
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Its metabolite methoxybenzoyl-GABA is less active than aniracetam

Method used

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  • Benzofurazan compounds which enhance AMPA receptor activity
  • Benzofurazan compounds which enhance AMPA receptor activity
  • Benzofurazan compounds which enhance AMPA receptor activity

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preparation example Construction

[0042] III. Preparation of Compounds of the Invention

[0043] The compounds of the present invention can be synthesized by various methods using conventional synthetic chemistry techniques. The preparation method of the compound of the present invention includes as follows.

[0044] where R 4 and R 8 Compounds of the invention which do not form a linking moiety may be obtained according to figure 1 Preparation as shown: the carboxyl group of suitably substituted benzoic acid or nicotinic acid, pyrazinic acid, pyridizine (pyridizine) carboxylic acid or pyrimidine carboxylic acid is treated with carbonyldiimidazole or other reactive groups such as thionyl chloride in anhydrous solvent such as Activate in dichloromethane, chloroform, tetrahydrofuran or ethyl acetate. The cyclic amine is then reacted with the activated carboxyl group. According to the above preferred structures, the cyclic amine preferably comprises an optionally substituted piperidine derivative. Rings may...

Embodiment 1

[0099] Example 1: 1-(Benzo-2.1.3-thiadiazol-5-ylcarbonyl)piperidine (1)

[0100] Trimethylaluminum (2M in toluene; 3.0ml, 6.0mmol) was diluted with 30ml of dichloromethane and piperidine (0.55g, 6.5mmol) and benzo-2,1,3-thiadiazole- 5-Methyl carboxylate (1.16 g, 6.00 mmol). The reaction was stirred at room temperature for 2 hours, then concentrated to half its original volume by rotary evaporation. Dry toluene (25ml) was added and the reaction was heated at 80°C for 1 hour. Additional piperidine (ca. 0.2 g) was added and the temperature was raised to 100° C. for 1 hour. The solution was cooled to room temperature and stirred overnight, then quenched with 10% citric acid and hydrochloric acid. The solution was diluted with ethyl acetate, washed successively with 10% citric acid, saturated sodium hydrogenphosphate solution and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solution was concentrated on silica gel and the product was elut...

Embodiment 2

[0101] Example 2: 1-(benzofurazan-5-ylcarbonyl)piperidine (2)

[0102] Method A:

[0103] Benzofurazan-5-carboxylic acid (2.0 g, 12.2 mmol) was suspended in 10 ml of dichloromethane. Carbonyldiimidazole (2.0 g, 12.3 mmol) was added and the suspension began to dissolve with gas evolution. The resulting yellow solution was stirred at room temperature for 40 minutes, then piperidine (1.2 g, 14.1 mmol) was added. The solution was stirred overnight, then concentrated onto silica gel. The product was eluted with hexane / ethyl acetate (2:1) and purified by distillation in a kugelrohr at 155-170° C. and 0.5 mmHg to give 1-(benzofurazan-5-ylcarbonyl)piperidine, 2 (2.78 g, 99%), the product was initially a light yellow oil which crystallized on cooling.

[0104] IR: 2938, 2857, 1630, 1519, 1439, 1266, 1223, 996, 881, 816, and 740cm -1 . 1 H NMR (500MHz): δ7.90 (1H, d, J = 9.7Hz); 7.84 (1H, s); 7.44 (1H, dd, J = 9.4 and 1.4Hz); 3.74 (2H, br s); 3.39 ...

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Abstract

Compounds of general structural formula (I) are shown to have AMPA receptor enhancing properties. The compounds are useful for such therapeutic purposes as facilitating the learning of behaviors dependent upon AMPA receptors, and in treating conditions, such as memory impairment, in which AMPA receptors, or synapses utilizing these receptors, are reduced in numbers or efficiency. They may also be used to enhance excitatory synaptic activity in order to restore an imbalance between brain subregions, as in treatment of schizophrenia or schizophreniform behavior.

Description

field of invention [0001] The present invention relates to the prevention and treatment of cerebral insufficiency, including enhancing the function of receptors in synapses responsible for higher behaviors in brain networks. These brain networks are associated with cognitive abilities involving memory impairment (such as observed in various dementias) and also imbalances in neuronal activity between different brain regions (such as postulated in schizophrenia) . In particular, the invention relates to compounds useful in the treatment of said diseases and methods of using these compounds for said treatment. Background of the invention [0002] Glutamate released by synapses in many parts of the mammalian forebrain stimulates two classes of postsynaptic receptors. These types are commonly referred to as AMPA / quisquitinate and N-methyl-D-aspartate (NMDA) receptors. AMPA / quistinate receptors mediate voltage-independent, fast excitatory postsynaptic currents (fast EPSCs), whe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4245A61K31/4439A61K31/445A61K31/454A61K31/519A61K31/53A61K31/535A61K31/5377A61K31/54A61P5/00A61P25/00A61P25/18A61P25/28C07D271/12C07D285/14C07D413/06C07D417/06C07D498/10
CPCC07D271/12A61K31/519A61K31/53C07D285/14C07D413/06A61P25/00A61P25/18A61P25/24A61P25/28A61P43/00A61P5/00
Inventor 加里·A·罗杰斯克里斯托弗·A·马尔斯
Owner RGT UNIV OF CALIFORNIA
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