Arylpiperazines having activity at the serotonin 1A receptor

Details Arylpiperazines having activity at the serotonin 1A receptor Arylpiperazines having activity at the serotonin 1A receptor

2001-12-18

2003-11-11

Jarvis, William R. A. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S253010, C514S649000

Reexamination Certificate

active

06645967

ABSTRACT:

FIELD OF THE INVENTION
The present invention belongs to the fields of pharmacology and medicinal chemistry, and provides new pharmaceuticals which are useful for the treatment of diseases which are caused or affected by disorders of the serotonin-affected neurological systems, particularly those relating to the 1
A
receptor.
BACKGROUND OF THE INVENTION
Pharmaceutical researchers have discovered in recent years that the neurons of the brain which contain monoamines are of extreme importance in a great many physiological processes which very strongly affect many psychological and personality-affecting processes as well. In particular, serotonin (5-hydroxytryptamine; 5-HT) has been found to be a key to a very large number of processes which affect both physiological and psychological functions. Drugs which influence the function of serotonin in the brain are accordingly of great importance and are now used for a surprisingly large number of different therapies.
The early generations of serotonin-affecting drugs tended to have a variety of different physiological functions, considered from both the mechanistic and therapeutic points of view. More recently, it has become possible to study the function of drugs at individual receptors in vitro or ex vivo, and it has also been realized that therapeutic agents with a single mechanism of action are often advantageous to the patient. Accordingly, the objective of research now is to discover not only agents which affect only functions of serotonin, but agents which affect only a single function of serotonin, at a single identifiable receptor.
The present invention provides compounds which have highly selective activity as antagonists of the serotonin 1
A
receptor.
SUMMARY OF THE INVENTION
The present invention provides a series of new aryl piperazine compounds, methods of using them for pharmaceutical purposes, and pharmaceutical compositions whereby the compounds may be conveniently administered.
The invention also provides methods of antagonizing, the 5HT-1
A
receptor, and therapeutic methods which are related to their effect on the 5HT-1
A
receptor. Such methods of treatment include, particularly, methods of alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine, comprising the administration to a patient in need of such treatment of a compound of Formula I
wherein
Ar′ is a mono- or bi-cyclic aryl or heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylthio, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
1
-C
6
)alkylhalo, (C
3
-C
8
)cycloalkyl, (C
3
-C
8
)cycloalkenyl or halo;
R
1
is hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylthio;
R
2
is phenyl, naphthyl or (C
3
-C
12
)cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylthio, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
1
-C
6
)alkylhalo, (C
3
-C
8
)cycloalkyl, (C
3
-C
8
)cycloalkenyl or halo;
R
3
is selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylthio, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
1
-C
6
)alkylhalo, (C
3
-C
8
)cycloalkyl, (C
3
-C
8
)cycloalkenyl or halo;
X is —C(═O)—, —CHOH— or —CH
2
—;
or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof.
Further, such therapeutic methods include methods of treatment of anxiety, depression, hypertension, cognitive disorders, psychosis, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, eating disorders and obesity, substance abuse, obsessive-compulsive disease, panic disorder and migraine.
A further treatment method provided by the present invention is a method for potentiating the action of a serotonin reuptake inhibitor, comprising administering to a patient an effective amount of a compound of Formula I in combination with the serotonin reuptake inhibitor.
More specifically, the present invention provides compounds of formula Ia;
or the pharmaceutically acceptable salts thereof.
The compounds of formula Ia are enclosed within the scope of the compounds of Formula I and are therefore useful for the methods described herein for Formula I. For example, the present invention provides methods of antagonizing, the 5HT-1
A
receptor, and therapeutic methods which are related to their effect on the 5HT-1
A
receptor. Such methods of treatment include, particularly, methods of alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine, comprising the administration to a patient in need of such treatment, an effective amount of a compound of formula Ia. Further, such therapeutic methods include methods of treatment of anxiety, depression, hypertension, cognitive disorders, psychosis, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, eating disorders and obesity, substance abuse, obsessive-compulsive disease, panic disorder and migraine.
In addition, the present invention provides a method for potentiating the action of a serotonin reuptake inhibitor, comprising administering to a patient an effective amount of a compound of formula Ia in combination with the serotonin reuptake inhibitor.
The invention further provides a method of assisting a patient in ceasing or reducing their use of tobacco or nicotine comprising administering to a patient an effective amount of a compound of the Formula I or formula Ia.
This invention also encompasses novel processes for the synthesis of the compounds of formula I and formula Ia, the synthesis of novel intermediates thereof, and further encompasses novel intermediates per se.
DESCRIPTION OF PREFERRED EMBODIMENTS
In the present document, all descriptions of concentrations, amounts, ratios and the like will be expressed in weight units unless otherwise stated. All temperatures are in degrees Celsius.
The Compounds
It is believed that the general description of the compounds above is sufficient to explain their nature to the skilled reader; attention to the Examples which follow is also encouraged. Some additional description will be provided to assure that no misunderstanding occurs.
In the general description, the general chemical terms are all used in their normal and customary meanings. For example, the small alkyl and alkoxy groups, such as (C
1
-C
6
)alkyl and (C
1
-C
6
)alkoxy groups include, depending on the size of the groups, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, pentyl, 3-methylbutyl, hexyl, and branched hexyl groups, and the corresponding alkoxy groups, as may be allowed by the individually named groups. Where a number of possible substituent groups are permitted on a group, such as the one to three alkyl, alkoxy or halo groups permitted on an Ar group, it will be understood by the reader that only substitution which is electronically and sterically feasible is intended.
The term “alkenyl” as used herein represents an unsaturated branched or linear group having at least one double bond. Examples of such groups include radicals such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl as well as dienes and trienes of straight and branched chains.
The term “alkynyl” denotes such radicals as ethynyl, propynyl, butynyl, pentynyl, hexynyl as well as di- and tri-ynes.
The term “(C
1
-C
6
)alkylthio” defines a straight or branched alkyl chain having one to six carbon atoms attached to the remainder of the molecule by a sulfur atom. Typical (C
1
-C
6
)alkylthio groups include methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like.
The term “(C
1
-C
6
)alkylhalo” refers to alkyl substituents having one or more independently selected halo atoms attached at one or more available carbon atoms. These terms include chloromethyl, bromoethyl, trifluoroethyl, trifluoromethyl, 3-bromopropyl, 2-bromopropyl, 3

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