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Non-sedating barbituric acid derivatives

a barbituric acid and derivative technology, applied in the field of new drugs, can solve the problems of irreversible damage to neurons and brain infarction, no adequate therapies are yet in practice, and phenobarbital has sedative and hypnotic effects, and achieves long-acting neurological activity, without significant hypnotic and sedative effects

Inactive Publication Date: 2006-02-16
TARO PHARMA INDS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides novel non-sedating barbituric acid derivatives with a long acting neurological activity and devoid of significant hypnotic and sedative effects. These compounds have various structures and can be used in the treatment of neurological disorders such as neuroprotective, anti-stress and anti-strain, anti-convulsant, anti-seizure, muscle relaxant, anti-nervous strain, and anti-anxiety. The compounds have good solubility, low toxicity, and can be easily synthesized.

Problems solved by technology

However, like other barbituric acid derivatives, phenobarbital has sedative and hypnotic effects, which are a disadvantage in the treatment of epilepsy.
When blood supply to the brain is reduced below a critical threshold, a cascade of biochemical events leads to irreversible damage to neurons and brain infarction.
Research on treatment and prevention of ischemia is extensive but unfortunately it remains at a basic stage and no adequate therapies are yet in practice (Stroke Therapy: Basic clinical and pre-clinical directions, Leonard P. Miller, ed.
The literature regarding the neuroprotective effects of anesthetic barbiturates is over two decades old, but the clinical use of barbiturates has been severely limited because of toxicity.
The dosages and blood and brain levels necessary to confer neuroprotection are toxic and cause lethargy, stupor, and coma.
These toxic side effects establish a “functional ceiling” on dosage for barbiturates, and have discouraged further research into the use of anesthetic / sedative barbiturates to protect from ischemia.
Thus, the prior art teaches away from using sedative barbiturates for neuroprotection because of their toxicity, and also teaches away from using non-sedative barbiturates as neuroprotectants because they lack sedating or anesthetic properties.

Method used

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Examples

Experimental program
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example 1

[0101] The anticonvulsant activity of the barbituric acid derivatives of the invention may be demonstrated or tested by evaluating the protection against a maximal electro shock seizure (MES) in treated rats. MES tests are widely used for the assessment of anticonvulsant properties of chemical compounds, mainly due to the good correlation between the test results and the clinical finding of efficacy in patients suffering from epilepsy. In a typical MES test carried out to evaluate the anticonvulsant properties of barbituric acid derivatives of the invention, corneal electrodes are employed, a current of about 150 milliamperes is used and a 60 hertz stimulus applied for about 200 milliseconds. Rats are tested on the day prior to drug administration so as to eliminate from the study any animals failing to respond with a complete tonic convulsion including tonic hind-limb extension (THE), which serves as the basis for the assessment of the efficacy of the active material employed. Anim...

example 2

[0103] The non-toxicity of barbituric acid derivatives of the invention can be tested by repeated administration of a high dosage, as follows:

[0104] The test compound suspended in warm polyethylene glycol 400 or other suitable solvent is administered in an initial dose of about 1500 mg / kg by gastric tube to, for example, Sprague Dawley rats. A similar dose is administered to same rats after 24 hours and again 48 hours after the first administration. Animals are examined for several hours after administration, again prior to the next dosing, and through an additional 3 days after the last administration. The toxic effects of administration are monitored as well as behavioral effects such as, for example, locomotion, escape behavior, feeding or any other observable effect.

example 3

[0105] The tranquilizing and muscle relaxant properties of the barbituric acid derivatives of the invention can be demonstrated by monitoring the behavioral and motor effects observed with treated mice.

[0106] For example, the test composition in alkalinized saline may be administered intraperitoneally to, for example, Swiss Webster mice. The time required for animals receiving various doses to exhibit particular motor and behavioral effects is noted. Effects monitored may include, for example, muscle hypotonia, motor activity, quietness and escape behavior. Toxic effects are also noted.

[0107] The efficacy of the composition can be evaluated relative to known centrally acting skeletal muscle relaxants and / or tranquilizing drugs. The combination of the tranquilizing effect without impairing the capacity of the animal to react to its environment is highly desirable in agents used for the treatment of anxiety. Hypnotic activity or depression of the central nervous system is preferably...

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Abstract

The present invention relates to novel non-sedating barbituric acid derivatives, pharmaceutical compositions containing them and methods of neuroprotection in cases of cerebral ischemia, head trauma and other acute neurologic injuries, and prevention of resulting neuronal damage. The invention also relates to the use of non-sedating barbituric acid derivatives given in a manner and dosage effective to produce blood levels and brain levels of these drugs and / or their active metabolites sufficient to provide a therapeutic effect.

Description

BACKGROUND OF THE INVENTION [0001] The present invention relates to novel non-sedating barbituric acid derivatives, pharmaceutical compositions containing them and methods of neuroprotection in cases of cerebral ischemia, head trauma and other acute neurologic injuries, and prevention of resulting neuronal damage. The invention also relates to the use of non-sedating barbituric acid derivatives given in a manner and dosage effective to produce blood levels and brain levels of these drugs and / or their active metabolites sufficient to provide a therapeutic effect. [0002] Barbituric acid and its derivatives have been known since the turn of the century to possess pharmacological properties and some of them serve as active ingredients in widely used drugs. Barbituric acid derivatives are known to act mainly as sedatives, hypnotics and anaesthetics. Certain derivatives also have an anticonvulsive effect and are therefore employed in the treatment of epilepsy. Thus, pharmaceutical composi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/515A61K31/675
CPCA61K31/675A61K31/515
Inventor GUTMAN, DANIELLAMOROS, DANIEL A.
Owner TARO PHARMA INDS
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