Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1996-08-06
1998-09-22
Kumar, Shailendra
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
514486, 514487, 514476, 514520, 514521, 514522, 514590, 514595, 558391, 560 24, 560 29, 564 36, 564 56, 564142, 564148, A61K 31275, C07C25503
Patent
active
058114564
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/Fr95/0006, filed Jan. 19, 1995.
The subject of the present invention is monoamine oxidase B inhibitors, processes for their preparation and their use in therapy.
Monoamine oxidases (MAO) are enzymes, located mainly in the outer membrane of the mitochondria and responsible for metabolizing a number of monoamines acting as neurotransmitters in mammals.
In the human body, the principal monoamines which are deaminated by MAOs belong either to the indole series: tryptamine and 5-hydroxytryptamine or serotonin, or to the aromatic amino acid series: tyramine and catecholamines such as dopamine, noradrenaline and adrenaline.
Two principal forms of MAO can be currently identified in the body: an A form which is thought to convert more particularly serotonin and noradrenaline, and a B form whose preferred substrates are benzylamine and phenylethylamine, both forms converting, in a roughly equivalent manner, dopamine, tyramine and tryptamine.
Some organs appear to express only one of the two enzymes whereas both forms are simultaneously present in other tissues such as the liver or the brain.
Given that the hypotheses relating to the bio-chemical mechanisms of depression involve certain mono-amines such as serotonin and catecholamines, it was proposed, from 1957, to use MAO inhibitors in the treatment of this pathology.
So far, three generations of MAO inhibitors have appeared in succession:
The major one among them is phenelzine (NARDELZINE.RTM.) and iproniazide (MARSILID.RTM.).
The structure common to these inhibitors is a hydrazine group.
They are termed "mixed" because they inhibit both forms of MAO. They are termed "irreversible" because they form a covalent bond with these enzymes which results in an irreversible inactivation of said enzymes which comes to an end only well after stopping the treatment, when the newly synthesized enzymes have taken over (15 to 21 days). In addition, they are responsible for a modification of blood pressure resulting in undesirable blood pressure disorders: hypotension, vertigo, dizziness, hypothymic and even syncopal tendencies.
This second generation of MAOIs includes three families of compounds which are the arylhydrazines, the propargylics and the cyclopropylamines.
These compounds preferably act on either form of the MAOS. Thus, for example, among the propargylic inhibitors, clorgyline and pargyline inhibit MAO A whereas deprenyl acts on MAO B.
It should however be noted that, although inhibiting the MAOs, some of these compounds, such as pargyline and deprenyl, lack antidepressant effects and have been indicated in the treatment of Parkinson's disease, in combination with L-dopa.
In addition, all these compounds act by first binding noncovalently to the MAOs, and then by forming with them irreversible covalent complexes, limiting their manageability because of the persistence of their action well after stopping the treatment.
Thus, for example, a general anesthetic can only be envisaged in a patient treated with this type of MAOI after a period of about three weeks after stopping the treatment.
These third-generation inhibitors include: and reversible inhibitors of MAO A, with a very short duration of action; which have as principal representative toloxatone (HUMORYL.RTM.) These compounds are described in EP 0,424,243, EP 0,428,421 and EP 0,511,031.
Although the use of these compounds represents a definite advance in therapy because of their rapidly reversible activity (in less than 24 hours), some physiopathological studies relating to senile dementia and Alzheimer's disease appear to show a most special advantage in using the B MAOIs.
Indeed, in these pathologies, a high increase in the MAO B/MAO A ratio is observed which is accompanied by an increase in a destructive activity of the MAOs. The decrease in the number of neurons producing dopamine linked with cellular aging also contributes to this physiological phenomenon. A possible inhibition of MAO B by selective and reversible products should make it possible to reequilibrate the ratio
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Bernard Suzanne
Milcent Rene
Paillat Catherine
Seman Michel
Kumar Shailendra
Laboratoires Mayoly Spindler
Seman Michel
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