Isoquinoline derivatives

Details Isoquinoline derivatives Isoquinoline derivatives

2003-04-16

2004-11-16

Seaman, D. Margaret (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S142000, C546S143000, C546S147000, C546S141000, C514S307000, C514S309000, C514S310000

Reexamination Certificate

active

06818774

ABSTRACT:

SUMMARY OF THE INVENTION
This invention relates to novel isoquinolino derivatives that are selective monoamine oxidase B inhibitors. These compounds are useful in the treatment or control of Alzheimer's disease and dementia. This invention also relates to pharmaceutical compositions containing these compounds and to methods of treating Alzheimer's disease and dementia using these compounds.
BACKGROUND OF THE INVENTION
Monoamine oxidase (MAO, EC 1.4.3.4) is a flavin-containing enzyme responsible for the oxidative deamination of endogenous monoamine neurotransmitters such as dopamine, serotonin, adrenaline, or noradrenaline, and trace amines, e.g. phenylethyl-amine, as well as a number of amine xenobiotics. The enzyme exists in two forms, MAO-A and MAO-B, encoded by different genes (A. W. Bach et al.,
Proc. Natl. Acad. Sci. USA
1988, 85, 4934-4938) and differing in tissue distribution, structure and substrate specificity. MAO-A has higher affinity for serotonin, octopamine, adrenaline, and noradrenaline; whereas the natural substrates for MAO-B are phenylethylamine and tyramine. Dopamine is thought to be oxidised by both isoforms. MAO-B is widely distributed in several organs including brain (A. M. Cesura and A. Pletscher, Prog. Drug Research 1992, 38, 171-297). Brain MAO-B activity appears to increase with age. This increase has been attributed to the gliosis associated with aging (C. J. Fowler et al.,
J. Neural. Transm.
1980, 49, 1-20). Additionally, MAO-B activity is significantly higher in the brains of patients with Alzheimer's disease (P. Dostert et al.,
Biochem. Pharmacol.
1989, 38, 555-561) and it has been found to be highly expressed in astrocytes around senile plaques (Saura et al.,
Neuroscience
1994, 70, 755-774). In this context, since oxidative deamination of primary monoamines by MAO produces NH
3
, aldehydes and H
2
O
2
, agents with established or potential toxicity, it is believed that selective MAO-B inhibitors are useful for the treatment of dementia and Parkinson's disease. Inhibition of MAO-B causes a reduction in the enzymatic inactivation of dopamine and thus prolongation of the availability of the neurotransmitter in dopaminergic neurons. The degeneration processes associated with age and Alzheimer's and Parkinson's diseases may also be attributed to oxidative stress due to increased MAO activity and consequent increased formation of H
2
O
2
by MAO-B. Therefore, MAO-B inhibitors may act by both reducing the formation of oxygen radicals and elevating the levels of monoamines in the brain.
Given the implication of MAO-B in the neurological disorders mentioned above, there is considerable interest to obtain potent and selective inhibitors that would permit control over this enzymatic activity. The pharmacology of some known MAO-B inhibitors is for example discussed by D. Bentué-Ferrer et al. in
CNS Drugs
1996, 6, 217-236. Whereas a major limitation of irreversible and non-selective MAO inhibitor activity is the need to observe dietary precautions due to the risk of inducing a hypertensive crisis when dietary tyramine is ingested, as well as the potential for interactions with other medications (D. M. Gardner et al.,
J. Clin. Psychiatry
1996, 57, 99-104), these adverse events are of less concern with reversible and selective MAO inhibitors, in particular of MAO-B. Thus, there is a need for MAO-B inhibitors with a high selectivity and without the adverse side-effects typical of irreversible MAO inhibitors with low selectivity for the enzyme.


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