Use of R-enantiomer of N-propargyl-1-aminoindan, salts, compositions and uses thereof

Abstract

The subject invention provides methods of treating a subject afflicted with Parkinson's disease, memory disorder, depression, hyperactive syndrome, Attention Deficit Disorder, dementia, brain ischemia, stroke, head trauma injury, spinal trauma injury, neurotrauma, neurodegenerative disease, neurotoxic injury, multiple sclerosis, nerve damage, affective illness, schizophrenia or symptoms of withdrawal from an addictive substance, using the mesylate salt of R(+)-N-propargyl-1-aminoindan.

Description

[0001] Throughout this application, various references are referred to. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. BACKGROUND OF THE INVENTION I. [0002] The subject invention is in the field of selective irreversible inhibitors of the enzyme monoamine oxidase (hereinafter MAO) and provides the R(+) enantiomer of N-propargyl-1-aminoindan (also referred to herein as PAI)which is a selective irreversible inhibitor of the B-form of monoamine oxidase enzyme (hereinafter MAO-B). The subject invention also provides pharmaceutical compositions containing R(+)PAI which are particularly useful for the treatment of Parkinson's disease, a memory disorder, dementia, depression, hyperactive syndrome, an affective illness, a neurodegenerative disease, a neurotoxic injury, stroke, brain ischemia, a head trauma injury, a spinal trauma injury, neurotraum...

AI Technical Summary

Benefits of technology

R(+)-PAI effectively inhibits MAO-B with minimal impact on MAO-A, reducing dopamine breakdown and systemic effects, providing prolonged therapeutic benefits with fewer adverse reactions compared to existing treatments.

Problems solved by technology

Inadequate dopamine release, therefore, leads to the onset of disturbances of voluntary muscle control, which disturbances are symptomatic of Parkinson's disease.

However, L-DOPA treatment has its drawbacks, the main one being that its effectiveness is optimal only during the first few years of treatment.

After this period, the clinical response diminishes and is accompanied by adverse side effects which include dyskinesia, fluctuation in efficacy throughout the day (“on-off effect”) and psychiatric symptoms such as confusional states, paranoia, and hallucinations.

It should be noted, however, that treatments combining L-DOPA with an inhibitor of both MAO-A and MAO-B are undesirable, as they lead to adverse side effects related to an increased level of catecholamines throughout the neuraxis.

Furthermore, complete inhibition of MAO is also undesirable as it potentiates the action of sympathomimetic amines such as tyramine, leading to the so-called “cheese effect” (reviewed by Youdim et al., Handbook of Experimental Pharmacology, ed. by Trendelenburg and Weiner, Springer-Verlag, 90, ch.

Although one enantiomer often shows some stereoselectivity in relative potency towards MAO-A and -B, a given enantiomeric configuration is not always more selective than its mirror image isomer in discriminating between MAO-A and MAO-B.

The lack of data in Table I showing clear structure-activity relationships between isolated (+) or (−)-2-MPAT-makes it impossible to predict the absolute stereochemistry thereof.

Thus, contrary to expectations in the art, 1-MPAI is useless as a pharmaceutical agent.

The structure of the MAO active site is not well enough understood to permit the prediction of the relative potency or selectivity of any given compound or pair of enantiomers thereof.

Survivors often suffer from neurological and motor disabilities.

However, (−)-deprenyl is not without its own adverse sides effects, which include activation of pre-existing gastric ulcers and occasional hypertensive episodes.

Furthermore, (−)-deprenyl is an amphetamine derivative and is metabolized to amphetamine and methamphetamines, which substances may lead to undesirable side effects such as increased heart rate (Simpson, Biochemical Pharmacology, 27, 1951 (1978); Finberg, et al., in “Monoamine Oxidase Inhibitors—The State of the Art,” Youdim and Paykel, eds., Wiley, pp.

Furthermore, racemic PAI.HCl does not potentiate the cardiovascular effects of tyramine (Finberg, et al., in “Enzymes and Neurotransmitters in Mental Disease,” pp.

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