Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1993-12-23
1996-04-16
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514672, 564509, 564510, A61K 3113
Patent
active
055083110
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to a series of aliphatic propargylamines, their salts and to pharmaceutical compositions containing such compounds. The compounds are useful as selective monoamine oxidase B inhibitors and have demonstrated neuroprotective properties in human and veterinary medicine.
BACKGROUND OF THE INVENTION
Monoamine oxidase (MAO) is an enzyme that oxidizes monoamine neurotransmitters and neuromodulators, as well as exogenous bioactive monoamines. It was first characterized by Hare in 1928 and was later called MAO by Zeller in 1938. Following the characterization of this enzyme, it was later discovered that its inhibition could have positive effects on psychiatric disorders such as depression.
Iproniazid, described in the late 1950's and used as a treatment for tuberculosis, was found to have mood-elevating properties. It was later shown to be a suitable MAO inhibitor and was used thereafter as an effective antidepressant. However, the drug had to be withdrawn from the U.S. market in the early 1960's because of the reports of hepatic toxicity and occasional hypertensive crises associated with its use. Still, the success of Iproniazid as an antidepressant stimulated pharmaceutical companies to search for new MAO inhibitors having antidepressant properties without adverse side effects. Since then, a large number of MAO inhibitors have been synthesized and administered.
Until 1972, when it was discovered for the first time that MAO existed in two forms, namely MAO-A and MAO-B, the first generation of MAO inhibitors had no selective inhibitory activity towards MAO-A and/or MAO-B. Examples of these compounds are the drugs phenelzine and tranylcypromine, respectively patented in 1959 (U.S. Pat. No. 3,000,903) and 1961 (U.S. Pat. No. 2,997,422). Apart from inhibiting the activity of both MAO-A and MAO-B, these non-selective irreversible MAO inhibitor antidepressants also exhibit other important drawbacks. Hence, these drugs have been categorized as "dirty" drugs. In other words, they also block other enzymes and most importantly, they can, similarly to Iproniazid, cause severe hepatotoxicity and hypertension resulting from the ingestion of tyraminerich food and drinks. This is caused by the fact that dietary amines are not broken down after ingestion and thus release circulating catecholamines which may lead to hypertensive crises and sometimes death. Thus, non-selective MAO inhibitors of this type have acquired a bad reputation and although they are very effective antidepressants, they have been avoided by most psychiatrists in favour of the relatively safer tricyclic antidepressants.
In the mid 1960's, a French group headed by Jacques R. Boissier published data on the synthesis of three series of new aliphatic and cycloaliphatic derivatives of hydrazine, propargylamine and cyclopropylamine, suspected to be useful as monoamine oxidase inhibitors (Chimie Therapeutique (1966), 320-326). Boissier et al. suggested that these non-selective total MAO inhibitors might possess therapeutic properties for the treatment of depression or angina pain. In French Patent 1,453,844, N-propynylalkylamines having a linear or branched alkyl group of 6 to 9 carbon atoms on the amino moiety are described.
In a further 1967 publication (Therapie, XXII, 1967, 367-373), Boissier et al. reported the results of tests conducted with these compounds to evaluate their antidepressant activity. Based on the results obtained, Boissier et al. concluded that the aliphatic compounds of the propargylamine series were practically inactive in vivo, regardless of whether the amine was secondary or tertiary, and only moderately active in vitro. From these results, it seemed that a promising future could not be foreseen for aliphatic propargylamines as effective MAO inhibitors. Hence, research involving compounds of this type was completely abandoned after the 1965, '66 and '67 publications by Boissier et al. It turned out that most of the research done later on MAO inhibitors concentrated on aromatic compounds.
In th
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Boulton Alan A.
Davis Bruce A.
Yu Peter H.
Raymond Richard L.
University of Saskatchewan
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