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3-substituted 1,2,3-triazin-4-one's and 3-substituted 1,3-pyrimidinone's for enhancing glutamatergic synaptic responses

A CH2, C-H technology, applied in the field of compounds for the treatment of these pathological conditions, and the field of synaptic receptors, can solve the problems of uncertain mechanism of effect and low activity

Inactive Publication Date: 2010-08-11
CORTEX PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The metabolite anisoyl-GABA has been found to be less active than aniracetam
In addition to these, aniracetam is speculated to affect numerous other neurotransmitter and enzyme sites in the brain, making the mechanism of any purported therapeutic drug effect uncertain

Method used

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  • 3-substituted 1,2,3-triazin-4-one's and 3-substituted 1,3-pyrimidinone's for enhancing glutamatergic synaptic responses
  • 3-substituted 1,2,3-triazin-4-one's and 3-substituted 1,3-pyrimidinone's for enhancing glutamatergic synaptic responses
  • 3-substituted 1,2,3-triazin-4-one's and 3-substituted 1,3-pyrimidinone's for enhancing glutamatergic synaptic responses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0447] 3-Cyclopropyl-8-[(1R)-1-methyl-2-(2H-tetrazol-2-yl)ethyl]-3,8-dihydro[1,2,3]triazine [4,5-g][1,2,3]benzotriazine-4,9-dione

[0448]

[0449] Intermediates 7 and 8 (2.70 g, 9.8 mmol) were dissolved in THF (100 ml) and methanol (75 ml). A solution of potassium hydroxide (6.0 g) in water (60 ml) was added and the mixture was stirred (20°C) for 45 minutes. Hydrochloric acid was added to the mixture (to pH 2) and the solvent was evaporated. The mixture was dissolved in DMF (100ml) and the solvent was evaporated to remove water. (2R)-1-(2H-tetrazol-2-yl)propan-2-amine hydrochloride (2.0 g, 10 mmol) and DMF (100 ml) were added and the solvent was evaporated. Add DMF (80ml), dimethylaminopiperidine (DMAP) (1.22g, 10mmol), hydroxybenzotriazole (HOBT) (1.35g, 10mmol), NEt 3 (2ml) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI) (5.5g, 28.5mmol) and the mixture was stirred at 45°C under nitrogen for 4 hours. Evaporate the solvent, add water (100ml), use 2N H 2...

Embodiment 2

[0451] 3-cyclopropyl-8-[(2R)-1-(5-methyl-2H-tetrazol2-yl)prop-2-yl]-3,8-dihydro[1,2-d:4 ,5-d'] Bis[1,2,3]triazine-4,9-dione

[0452]

[0453] The title compound was prepared from Intermediate 3 following the procedure of Example 1. The obtained white solid has the following characteristics: mp=157-160°C; 1 H NMR (300MHz, CDCl 3 )δ9.15(1H, s), 9.05(1H, s), 5.90-5.75(1H, m), 5.26(1H, dd, J=8.4 and 14.4Hz), 5.05(1H, dd, J=4.8 and 14.4 Hz), 4.12-4.02 (1H, m), 2.44 (3H, s), 1.79 (3H, d, J = 6.9 Hz) and 1.48-1.24 ppm (4H, m).

Embodiment 3

[0455] 3-cyclopropyl-8-[(2R)-1-(5-methyl-1H-tetrazol-1-yl)prop-2-yl]-3,8-dihydrobenzo [1,2-d:4,5-d']bis[1,2,3]triazine-4,9-dione

[0456]

[0457] Intermediate 4 was used to prepare the title compound following the procedure of Example 1. The obtained white solid has the following characteristics: mp=208-211°C; 1 H NMR (300MHz, CDCl 3 )δ9.14(1H, s), 9.02(1H, s), 5.90-5.79(1H, m), 5.03(1H, dd, J=9.6 and 14.4Hz), 4.69(1H, dd, J=5.1 and 14.4Hz), 4.11-4.03 (1H, m), 2.62 (3H, s), 1.80 (3H, d, J = 6.9Hz) and 1.45-1.25ppm (4H, m).

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Abstract

This invention relates to compounds, pharmaceutical compositions and methods for use in the prevention and treatment of cerebral insufficiency, including enhancement of receptor functioning in synapses in brain networks responsible for basic and higher order behaviors. These brain networks, which are involved in regulation of breathing, and cognitive abilities related to memory impairment, such as is observed in a variety of dementias, in imbalances in neuronal activity between different brain regions, as is suggested in disorders such as Parkinson's disease, schizophrenia, respiratory depression, sleep apneas, attention deficit hyperactivity disorder and affective or mood disorders, and in disorders wherein a deficiency in neurotrophic factors is implicated, as well as in disorders of respiration such as overdose of an alcohol, an opiate, an opioid, a barbiturate, an anesthetic, or a nerve toxin, or where the respiratory depression results form a medical condition such as central sleep apnea, stroke- induced central sleep apnea, obstructive sleep apnea, congenital hypoventilation syndrome, obesity hypoventilation syndrome, sudden infant death syndrome, Rett syndrome, spinal cord injury, traumatic brain injury, Cheney-Stokes respiration, Ondines curse, Prader-Willi's syndrome and drowning. In a particular aspect, the invention relates to compounds useful for treatment of such conditions, and methods of using these compounds for such treatment.

Description

technical field [0001] The present invention relates to compounds, pharmaceutical compositions and methods for the prevention and treatment of cerebral insufficiency, including the enhancement of receptors acting on synapses in brain networks responsible for various behaviors. These brain networks are involved in basic functions such as breathing, to more complex functions such as memory and cognition. Imbalances in neural activity between different brain regions can lead to many diseases, including psychiatric and neurological disorders, including memory deficits, Parkinson's disease, schizophrenia, attention deficits and affective or mood disorders, respiratory depression and neurological deficits involving Diseases of nutritional factors. In particular, the invention relates to compounds useful in the treatment of these conditions, and methods of treatment using such compounds. [0002] related application [0003] This application claims priority to US Provisional Appli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D255/04C07D239/88
CPCC07D487/04A61P9/10A61P11/00A61P25/00A61P25/04A61P25/14A61P25/16A61P25/18A61P25/20A61P25/24A61P25/28A61P43/00
Inventor R·米勒L·J·斯特里特S·拉赫瓦尔K·阿利萨拉
Owner CORTEX PHARMA
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