Serotonin-like 9-substituted hypoxanthine and methods of use

Details Serotonin-like 9-substituted hypoxanthine and methods of use Serotonin-like 9-substituted hypoxanthine and methods of use

1999-05-04

2001-10-16

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S276000

Reexamination Certificate

active

06303617

ABSTRACT:

FIELD OF THE INVENTION
The present invention is broadly directed to purine based compounds. More particularly, the present invention is directed to a novel purine analog having activity involving the serotonin neurotransmitter system in addition to other physiological activities and to associated methods of use.
BACKGROUND OF THE INVENTION
The efficacy of many contemporary pharmaceutical compounds intended to treat neurological and physiological conditions is limited by their inability to cross the blood-brain barrier. As a result, large molecules that may have neurological activity cannot be administered orally or through injection into the bloodstream because the blood-brain barrier serves as a filter to keep these molecules from leaving the bloodstream and entering the brain and spinal cord. Currently there are three alternative approaches to achieving blood-brain barrier access. The first is to introduce pharmaceutical compounds by direct injection into the brain through the skull. While such treatments have demonstrated some success the possibility of infection coupled with the complexity and expense of such procedures have limited their practical usefulness. Additionally, there is resistance among many patients to the administration of such injections directly into the skull. The second approach involves the utilization of chemical agents which temporarily break down the blood-brain barrier in order to allow molecules to enter the central nervous system. At present, this approach is in the very early stages of development and carries with it the potential for allowing molecules of all sizes (including undesirable compounds) to cross the blood-brain barrier. This approach, unless and until it can be refined to allow for greater selectivity in crossing the blood-brain barrier, carries with it serious risks. The third approach, pioneered by the present inventor, involves developing small molecules which can mimic the activities of bioactive molecules yet can pass through the blood-brain barrier following oral administration or administration through injection into the bloodstream.
Therefore, there is a need for the development of small molecules that can mimic physiological activities of bioactive molecules and can cross the blood-brain barrier efficiently without requiring complete degradation of the blood-brain barrier.
It is accordingly an object of the present invention to provide such compounds which can either mimic the actions of molecules normally unable to cross the blood-brain barrier or which can stimulate other, unexpected physiological activities.
It is an additional object of the present invention to produce pharmaceutical medicaments configured from such compounds and to provide methods for using these pharmaceutical compositions to treat a variety of physiological, neurological, and psychological disorders and disease conditions.
SUMMARY
I have found that novel 9-substituted hypoxanthine derivatives have unexpected properties and have monoamine oxidase inhibitor activity.
One embodiment of the present invention is a 9-substituted hypoxanthine derivative of formula (I)
where n is an integer from 1 to 6, R
1
is selected from the group consisting of H, COOH, and COOW
1
, where W
1
selected from the group consisting of lower alkyl, amino, and lower alkylamino, and R
2
is selected from the group consisting of H and OH.
Preferably, n is 2. When n is 2, one particularly preferred 9-substituted hypoxanthine derivative is N-(2-(5-hydroxyindol-3-yl)ethyl)-3-(6-oxohydropurin-9-yl)propanamide, where n is 2, R
1
is H, and R
2
is OH; this compound is designated AIT-202. Another particularly preferred 9-substituted hypoxanthine derivative is N-(2-(indol-3-yl)ethyl)-3-(6-oxohydropurin-9-yl)propanamide, where n is 2, R
1
is H, and R
2
is H; this compound is designated AIT-072. Still another particularly preferred 9-substituted hypoxanthine derivative is N-(1-carboxyl)-(2-(5-hydroxyindol-3-yl)ethyl-3-(6-oxohydropurin-9-yl)propanamide, where n is 2, R
1
is COOH, and R
2
is OH; this compound is designated AIT-111.
Another aspect of the present invention is a pharmaceutical composition comprising:
(1) an effective amount of a 9-substituted hypoxanthine derivative according to the present invention as described above; and
(2) a pharmaceutically acceptable carrier.
Yet another aspect of the present invention is a method of treating a disease or condition in a mammal treatable by inhibiting the activity of a monoamine oxidase comprising the step of administering an effective amount of a 9-substituted hypoxanthine derivative according to the present invention to the mammal.
Still another aspect of the present invention is a method of treating obesity in a mammal comprising the step of administering an effective amount of a 9-substituted hypoxanthine derivative according to the present invention to the mammal.
An additional aspect of the present invention is a method of lowering the level of serum cholesterol in a mammal comprising the step of administering an effective amount of a 9-substituted hypoxanthine derivative according to the present invention to the mammal.
Yet another aspect of the present invention is a method for increasing the level of HDL cholesterol in the blood serum of a mammal comprising the step of administering an effective amount of a 9-substituted hypoxanthine according to the present invention to the mammal.


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