Selective serotonin receptor antagonists and therapeutic...

Details Selective serotonin receptor antagonists and therapeutic... Selective serotonin receptor antagonists and therapeutic...

2003-05-06

2004-10-19

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S437000, C514S454000, C548S411000, C549S026000, C549S344000

Reexamination Certificate

active

06806283

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention generally relates to selective serotonin receptor antagonists and methods of their use as antidepressant and antianxiety agents. In particular, the invention provides spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine (SPAN) and derivatives thereof as selective high affinity antagonists of 5-HT receptors.
2. Background of the Invention
Serotonin (5-hydroxytryptamine, or 5-HT; see Formula 1) is a product of tryptophan metabolism that mediates many diverse physiological activities. Most fundamentally, this well-characterized tryptamine derivative functions as a potent neurotransmitter by regulating G-protein coupled and ligand gated ion channel receptors at the surface of nerve and muscle cells. This activity is mediated by the binding of serotonin to several classes of cell-surface 5-HT receptors. Numerous 5-HT receptors are known and have been categorized into several families (5-HT
1
-5-HT
7
) and some are further divided into subfamilies (e.g. 5-HT
2A
and 5-HT
2C
). Many of the 5-HT receptors have been cloned and their specific functions elucidated.
Imbalances in serotonin activity are believed to be responsible for a variety of clinically recognized disorders. For example, many brain disorders in humans are associated with fluctuations in serotonin levels and are effectively treated with drugs that interact specifically with 5-HT receptors or that block the reuptake of serotonin into the presynaptic axon terminals, suggesting that serotonin dysregulation may be involved in these disorders. For example, serotonin receptor ligands are clinically approved as drugs for the treatment of depression, psychosis, anxiety, and certain sexual aberrations, as well as for other conditions such as migraine headaches, chemotherapy-induced nausea, high blood pressure, certain abnormal cardiovascular activities and abnormal thermoregulation.
However, most of these existing agents are relatively nonselective in that they exhibit affinities for several 5-HT receptor classes, as well as for central dopaminergic, noradrenergic, histaminergic, and/or cholinergic receptors, as well as blocking serotonin and dopamine reuptake into the nerve terminus. As a consequence of activity at nonserotonergic sites, the use of these agents may result in undesirable side effects such as tardive dyskinesia, tardive dystonia, excessive weight gain, etc. These side effects can be debilitating and may require clinical treatment in and of themselves. The possibility of the occurrence of side effects is a cause of distress to patients, and is a likely contributor to patient non-compliance with suggested drug therapy regimens.
Ligands which bind with varying degrees or selectivity to some families of 5-HT receptors are known. For example, U.S. Pat. Nos. 5,496,957 and 5,504,101 to Glennon (Mar. 5, 1996 and Apr. 2, 1996, respectively, the complete contents of which are hereby incorporated by reference) describe agents which bind to the 5-HT
1D&bgr;
receptor. And U.S. Pat. No. 5,942,536 to Fritz et al. (Aug. 24, 1999, the complete contents of which is hereby incorporated by reference) describes agents which bind to the 5-HT
1f
receptor. Roth et al. (1994) describe the binding affinities of 36 typical and atypical antipsychotic agents to 5-HT
6
and 5-HT
7
receptors, and Glennon et al. (1989) describe classes of agents which bind to 5-HT
1A
receptors. Finally, Glennon et al. (1994) describe the effect of different amine substitutions on phenylalkylamine and indolylalkylamine derivatives which bind to 5-HT
2A
and 5-HT
2C
serotonin receptors. There is an ongoing need for the development of alternative agents that selectively bind to specific families of 5-HT receptors with high affinity.
SUMMARY OF THE INVENTION
It is an object of this invention to provide compounds having the formula
In the compounds, R1 and R2 may be —H, —OH, —OCH
3
, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C
1
-C
10
alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; or —SO
2
—. In some embodiments, R1 may be —H, —CH
2
CH
2
CH
2
Ph, —OCH
3
, —CH
2
(CH
2
)
4
CH
3
, phenyl, or —OH. In some embodiments, R2 may be —H, —CH
3
or CH
2
Ph. In some embodiments, X may be —CH
2
—, —C(CH
3
)
2
—, —O— or —S—.
Specific embodiments include compounds with the following formulas:
The invention further provides a pharmaceutical composition comprising, a compound of formula
in which R1 and R2 may be —H, —OH, —OCH
3
, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C
1
-C
10
alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; or —SO
2
—. In some embodiments, R1 may be —H, —CH
2
CH
2
CH
2
Ph, —OCH
3
, —CH
2
(CH
2
)
4
CH
3
, phenyl, or —OH. In some embodiments, R2 may be —H, —CH
3
or CH
2
Ph. In some embodiments, X may be —CH
2
—, —C(CH
3
)
2
—, —O— or —S—, and a pharmaceutically acceptable carrier.
The present invention also provides a method of treating a condition caused by abnormal serotonin activity in a patient in need thereof. The method includes the step of administering a compound of formula
in which R1 and R2 may be —H, —OH, —OCH
3
, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C
1
-C
10
alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; or —SO
2
—. In some embodiments, R1 may be —H, —CH
2
CH
2
CH
2
Ph, —OCH
3
, —CH
2
(CH
2
)
4
CH
3
, phenyl, or —OH. In some embodiments, R2 may be —H, —CH
3
or CH
2
Ph. In some embodiments, X may be —CH
2
—, —C(CH
3
)
2
—, —O— or —S—. The compound is administered in a quantity sufficient to ameliorate symptoms of said condition in said patient. The condition may be for example, clinical depression or anxiety, schizophrenia, schizoaffective disorder, and various eating and sleeping disorders. The compound may be an antagonist of 5HT2 receptors, an antagonist of H1 receptors, or an antagonist of both 5HT2 receptors and H1 receptors.
The invention further provides a method of blocking a 5HT2 receptor in a patient in need thereof. The method includes the step of administering to the patient of a compound of formula
in which R1 and R2 may be —H, —OH, —OCH
3
, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C
1
-C
10
alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; or —SO
2
—. In some embodiments, R1 may be —H, —CH
2
CH
2
CH
2
Ph, —OCH
3
, —CH
2
(CH
2
)
4
CH
3
, phenyl, or —OH. In some embodiments, R2 may be —H, —CH
3
or CH
2
Ph. In some embodiments, X may be —CH
2
—, —C(CH
3
)
2
—, —O— or —S—. The compound is administered in a quantity sufficient to block the 5HT2 receptor.
The invention further provides a method of blocking an H1 receptor in a patient in need thereof The method includes the step of administering to the patient a compound of formula
in which R1 and R2 may be —H, —OH, —OCH
3
, halogen, aryl, alkylaryl, or substituted or unsubstituted branched or unbranched C
1
-C
10
alkyl or alkylaryl, and may be the same or different, and X may be a) carbon with two —H substituents, b) carbon with one or two lower alkyl substituents, or c) a heteroatom or heteroatomic group selected from the group consisting of —O—; —S—; or —SO
2
—. In some embodiments, R1 may be —H, —CH
2
CH
2
CH
2
Ph, —OCH
3
, —CH
2
(CH
2
)
4
CH
3
, phenyl, or —OH. In

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