Therapeutically useful 2-aminotetralin derivatives

Details Therapeutically useful 2-aminotetralin derivatives Therapeutically useful 2-aminotetralin derivatives

1992-03-12

2001-12-18

Chang, Ceila (Department: 1203)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S247000, C548S560000, C548S562000, C564S428000

Reexamination Certificate

active

06331636

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to new 1,2,3,4tetrahydro-2-naphthylamines, to processes for preparing such compounds, pharmaceutical preparation of such compounds and the use of such compounds in manufacture of a pharmaceutical preparation.
BACKGROUND OF THE INVENTION
Psychiatric diseases are thought to be due to dysfunctions in monoaminergic neuronal systems, particularly those involving serotonin (5-HT) and dopamine (DA).
Anxiety is associated with increased activity in 5-HT systems. In animals where 5-HT has been depleted, benzodiazepine anxiolytics are not active in anti-anxiety assays that they. otherwise are effective in. Seronotin neurons have autoreceptors that, when activated by agonists, depress firing rates of 5-HT cells. These receptors are of the 5-HT
1A
subtype. 5-HT
1A
agonists are anxiolytic. Buspirone is a marketed 5-HT
1A
agonist that is an anxiolytic. Gepirone is another 5-HT
1A
agonist with clinically demonstrated anti-anxiety activities.
Depression is a psychiatric condition thought to be associated with decreased 5-HT release. Many anti-depressants potentiate the effects of 5-HT by blocking the termination of activity through reuptake into nerve terminals. 5-HT
1A
agonists can activate postsynaptically; they thus may also be anti-depressants. Gepirone has already been demonstrated to have ameliorative effects on some depressive endpoints in some patients.
Serotonin is also involved in the regulation of feeding and sexual behavior and in cardiovascular regulation. Thus, 5-HT
1A
agonists may be useful in treating overeating and sexual dysfunction. These compounds have been shown to alter feeding and sexual behavior in animals. They may also be useful in the treatment of obsessive/compulsive disorders, alcohol abuse and violent behavior. 5-HT
1A
agonists are also known to depress sympathetic nerve discharge and thus lower blood pressure. Thus, they may be useful in treating hypertension, congestive heart failure (by reducing cardiovascular afterload) and heart attack (be removing sympathetic drive to the heart).
Schizophrenia is thought to be due to hyperactivity in DA systems. Thus, currently available anti-psychotics are DA antagonists. Dopamine autoreceptors depress DA neuron firing rates, DA synthesis and release. Thus DA autoreceptor agonists can also be expected to be anti-psychotics. DA agonists are also useful for treating Parkinsonism, a disease caused by degeneration of DA neurons, and hyperprolactinemia, since DA agonists depress prolactin release.
Dopamine autoreceptor antagonists are a new class of drugs that increase release of DA by releasing the DA neuron from autoreceptor control. Thus, these drugs can be expected to be useful in conditions treatable with amphetamine and other similar stimulants which directly release DA. However, DA autoreceptor agonists will be much milder stimulants because, rather than directly releasing DA, they simply increase the release associated with the normal DA activity by releasing the cell from autoreceptor control. Thus, DA autoreceptor antagonists can be expected to be useful in treating overeating, attention deficit disorders, psychiatric, cognitive and motor retardation in demented and elderly patients, and in treating nausea and dizziness with space travel.
The compounds of the present invention have a variety of effects at 5-HT
1A
and DA receptors, and offer a variety of utilities associated with those activities.
Clinically, 5-HT
1A
agonists have also demonstrated anxiolytic properties. The drug, Buspirone, is the only currently available marketed 5-HT
1A
agonist having anxiolytic activity. This compound antagonizes dopamine receptors at the same dose it stimulates 5-HT
1A
receptors. A similar drug, Gepirone, also has dopamine antagonist properties. These dopamine antagonist properties reduce the clinical utility of these compounds however because long term treatment with dopamine antagonists can produce tardive dyskinesia.
The search for new CNS active compounds is focused on finding compounds with selective 5-HT
1A
receptor agonist effects without detrimentally influencing central dopamine receptors.
Drugs acting on central dopamine transmission are clinically effective in treating a variety of central nervous system disorders such as parkinsonism, schizophrenia, and manic-depressive illness. In parkinsonism, for example, the nigro-neostriatal hypofunction can be restored by an increase in postsynaptic dopamine receptor stimulation. In schizophrenia, the condition can be normalized by achieving a decrease in postsynaptic dopamine receptor stimulation. Classical anti-psychotic agents directly block the postsynaptic dopamine receptor. The same effect can be achieved by inhibition of intraneuronal presynaptic events essential for the maintenance of adequate neurotransmission, transport mechanism and transmitter synthesis.
In recent years a large body of pharmacological, biochemical and electrophysical evidence has provided considerable support in favor of the existence of a specific population of central autoregulatory dopamine receptors located in the dopaminergic neuron itself These receptors are part of a homeostatic mechanism that modulates nerve impulse flow and transmitter synthesis and regulates the amount of dopamine released from the nerve endings.
Direct dopamine redeptor agonists, like apomorphine, are able to activate the dopamine autoreceptors as well as the post synaptic dopamine receptors. The effects of autoreceptor stimulation appear to predominate when apomorphine is administered at low doses, whereas at higher doses the attenuation of dopamine transmission is outweighed by the enhancement of postsynaptic receptor stimulation. The anti-psychotic and anti-dyskinetic effects in man of low doses of apomorphine are likely due to the autoreceptor-stimulator properties of this dopamine receptor agonist. This body of knowledge indicates dopamine receptor stimulants with a high selectivity for central nervous dopamine autoreceptors would be valuable in treating psychiatric disorders.
INFORMATION DISCLOSURE STATEMENT
The following documents could be important in the examination of this application.
Arvidsson, L.-E., et al., J. Med. Chem., 24, 921 (1981), describes hydroxy-2-aminotetralins where the amine is substituted with one n-propyl, one benzyl or two n-propyl substituents. The 5-, 6-, and 7-hydroxy compounds are described as active central dopamine-receptor agonists and the 8-hydroxy compound is described as a central 5-HT receptor agonist devoid of dopamine receptor stimulating activity.
Arvidsson, L.-E., et al., J. Med. Chem., 27, 45 (1984), describes 2-aminotetralins where the amine is substituted with one or two methyl, ethyl, n-propyl, i-propyl, n-butyl, or benzyl substituents. The 2-piperidinyltetralin is also described. Several of these compounds were found to be potent 5-HT agonists devoid of dopamine-mimetic effects.
Arvidsson, L.-E., et al., J. Med. Chem., 30, 2105 (1987), describes 8-hydroxy-1-methyl-2-(di-n-propylamino)tetralins. These compounds were 5-HT receptor agonists.
The Arvidsson, L.-E. et al 8-hydroxy and 8-methoxy tetralin compounds are also disclosed in Derwent documents 00389J/47, 94981D/51 and 045535J.48.
McDermed, et al., J. Med. Chem., 18, 362 (1975) describes 5,6 dihydroxy-2-aminotetralins. In addition, the 5,8 and 7,8 disubstituted compounds are also disclosed. The amine can be a mono or di substituted with simple alkyl groups, benzyl groups alkylalkoxy groups or the amine can be a 5 or 6 membered hydrocarbon or heterocyclic amine. These compounds are indicated to have dopaminergic properties although certain compounds are reported to be inactive.
McDermed, et al., J. Med. Chem., 19, 547 (1976) describes 5-, 6-, or 7-hydroxy-2-dipropylaminotetralins. These compounds are described as dopaminergic compounds.
Rusterholz, et al., J. Med. Chem., 19, 99 (1976) describes 5,8 disubstituted-2-aminotetralins with the amine being substituted with hydrogen, methyl, or cyanopropyl groups. Some of these compounds are potent prolactin inhib

Affiliated with

Also associated with

Rating

Therapeutically useful 2-aminotetralin derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Therapeutically useful 2-aminotetralin derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Therapeutically useful 2-aminotetralin derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2559300