Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-31
2002-01-29
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S364000
Reexamination Certificate
active
06342498
ABSTRACT:
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 increasing the level of serotonin in the brain and inhibiting the serotonin 1
D&agr;
receptor.
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 generation of serotonin-affecting drugs tended to have a variety of different physiological functions, considered from both the mechanistic and therapeutic points of view. For example, many of the tricyclic antidepressant drugs are now known to be active as inhibitors of serotonin reuptake, and also to have anticholinergic, antihistamine or anti-alpha-adrenergic activity. 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 free of extraneous mechanisms of action are advantageous to the patient. Accordingly, the objective of research now is to discover agents which affect only functions of serotonin, for example, at specific identifiable receptors.
Perhaps the most dramatic discovery in medicinal chemistry in the recent past is fluoxetine, a serotonin reuptake inhibitor, which is extremely effective in the treatment of depression. As a reuptake inhibitor, it increases the availability of serotonin in the synapse by reducing the uptake of serotonin by the serotonin uptake carrier. Dysfunction of the serotonin neurons resulting from excessive uptake results in depression, as well as other pathologies of the central nervous system. Not only is fluoxetine spectacularly effective in depression, it is also effective in treating numerous other conditions.
Over the last several years it has become apparent that serotonin is associated directly or indirectly with a number of physiological phenomena, including appetite, memory, thermo-regulation, sleep, sexual behavior, anxiety, depression, and hallucinogenic behavior [Glennon, R. A., J. Med. Chem., 30, 1 (1987)].
5-HT receptors have been identified in the central nervous system (CNS; brain and spinal cord) and in peripheral tissues including the gastrointestinal tract, lung, heart, blood vessels, and various other smooth muscle tissues.
It has been recognized that there are multiple types of 5-HT receptors. These receptors have been classified as 5-HT
1
, 5-HT
2
and 5-HT
3
receptors, with the former being further divided into the sub-classes 5-HT
1A
, 5-HT
1B
, 5-HT
1C
, 5-HT
1D
, 5-HT
1E
and 5-HT
1F
.
Few ligands have selectivity for 5-HT
1D
receptors. Sumatriptan possesses limited 5-HT
1D
selectivity. GR 127935 has also been identified as a potent and selective 5-HT
1D
receptor antagonist. Hayer, et al.,
Pharmacological Reviews
, Vol. 46, No. 2, pp. 157-203 (1994).
Molecular cloning has demonstrated that pharmacologically defined 5-HT
1D
receptors are encoded by two separate but closely related genes, designated 5-HT
1D&agr;
and 5-HT
1D&bgr;
, which are members of the GPRC superfamily. These receptors display highly conserved transmembrane homology (75%) and similar binding properties and second messenger coupling (inhibition of adenylate cyclase). Leonhardt, S., et al.,
J. Neurochem
, 53:465-471 (1989).
It is desirable to develop new compounds and treatments for 5-HT
1D&agr;
receptor mediated diseases and diseases mediated by inhibiting the reuptake of serotonin.
We have now discovered a class of compounds which have activity at the 5-HT
1D&agr;
receptor and which inhibit the reuptake of serotonin.
This invention provides a compound of formula I
wherein
R
1
and R
2
are each independently hydrogen, halo, —(C
1
-C
6
)alkyl or —(C
1
-C
6
)alkoxy;
R
3
is hydrogen or —(C
1
-C
6
)alkyl;
Y is —CO— or —CH
2
-;
Z is —NH—, —N(COR)— or —CH
2
—, where R is —(C
1
-C
6
)alkyl or —(C
3
-C
8
)cycloalkyl;
represents a double or single bond; and
n and m are each independently an integer from 1 to 3, both inclusive; or a pharmaceutically acceptable salt or solvate thereof.
This invention also provides a pharmaceutical formulation comprising a compound of formula I in association with one or more pharmaceutically acceptable diluents, carriers and excipients.
This invention further provides a method of inhibiting the reuptake of serotonin comprising administering to a mammal in need thereof, a therapeutically effective amount of a serotonin reuptake inhibitor of formula I.
This invention provides in addition a method of inhibiting the 5-HT
1D&agr;
receptor comprising administering to a mammal in need thereof a therapeutically effective amount of a direct acting 5-HT
1D&agr;
antagonist of formula I.
This invention further provides a method of inhibiting the reuptake of serotonin and inhibiting the 5-HT
1D&agr;
receptor comprising administering to a mammal in need thereof a therapeutically effective amount of a serotonin reuptake inhibitor and 5-HT
1D
antagonist of formula I.
This invention also provides a method of alleviating the pathological effects of diseases mediated by inhibiting the reuptake of serotonin which comprises administering to a mammal in need thereof a therapeutically effective amount of a serotonin reuptake inhibitor of formula I.
Still further, this invention also provides a method of alleviating the pathological effects of diseases mediated by inhibiting the 5-HT
1D&agr;
receptor which comprises administering to a mammal in need thereof a therapeutically effective amount of a direct acting 5-HT
1D&agr;
antagonist of formula I.
This invention also provides a method of alleviating the pathological effects of diseases mediated by inhibiting the reuptake of serotonin and inhibiting the 5-HT
1D&agr;
receptor which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a serotonin reuptake inhibitor and 5-HT
1D&agr;
antagonist of formula I.
Another aspect of the invention is a method of treating a mammal suffering from or susceptible to depression or anxiety; which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula I.
Yet another aspect of the invention is a method of treating a condition chosen from the group consisting of obsessive-compulsive disease, obesity, migraine, pain, particularly neuropathic pain, bulimia, premenstrual syndrome or late luteal syndrome, alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic syndrome, memory loss, dementia of aging, social phobia, attention-deficit hyperactivity disorder, disruptive behavior disorders, impulsive control disorders, borderline personality disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism and trichotilomania, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula I.
A still further aspect of the invention is a method of treating a mammal suffering from or susceptible to dementia, Parkinson's disease, anxiety, appetite modulation, sexual dysfunction, seasonal affective disorder, hyperprolactinemia, cerebral vascular disease, antisocial behavior, obsessive/compulsive disorder, amnesia, tardive dyskensia, hypertension and gastric motility disorder, which comprises administering to a subject in need of such treatment, a therapeutically effective amount of a compoun
Walker Clint Duane
Wong David Taiwai
Xu Yao-Chang
Bernhardt Emily
Eli Lilly and Company
Joyner Charles T.
Lentz Nelsen L.
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