Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-22
2002-04-23
Rotman, Alan L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S017000
Reexamination Certificate
active
06376505
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 the serotonin 1
A
and 1
D&agr;
receptors.
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.
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
1A
and 5-HT
1D&agr;
receptor mediated diseases.
We have now discovered a class of compounds which have activity both at the 5-HT
1A
and 5-HT
1D&agr;
receptor.
This invention provides a compound of formula I
wherein:
R is —(C
3
-C
10
)cycloalkyl or —S(C
1
-C
10
)alkyl;
X is
and
n is an integer from 1 to 3 both inclusive;
or a pharmaceutically acceptable salt, racemate, optical isomer 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 5-HT
1A
receptor comprising administering to a mammal in need of such treatment a therapeutically effective amount of a direct acting 5-HT
1A
antagonist 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 of such treatment 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 5-HT
1A
and 5-HT
1D&agr;
receptors comprising administering to a mammal in need of such treatment a therapeutically effective amount of a direct acting 5-HT
1A
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 5-HT
1A
receptor which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a direct acting 5-HT
1A
antagonist 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 of such treatment 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 5-HT
1A
and 5-HT
1D&agr;
receptors which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a direct acting 5-HT
1A
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 any condition mediated by inhibiting the 5HT
1A
receptor of the type represented by withdrawal or partial withdrawal from the use of tobacco or of nicotine; a method of alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine, a method of treating anxiety; and a method of treating a condition chosen from the group consisting of depression, hypertension, cognitive disorders, psychosis, sleep disorders, gastric motility disorders and obesity, substance abuse, obsessive-compulsive disease, panic disorder and migraine; which methods comprise administering to a subject in need of such treatment an 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 any condition mediated by inhibiting the 5HT
1D&agr;
receptor of the type represented by depression, 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.
Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.
Definitions
As used herein, the term, “(C
1
-C
10
)alkyl” by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl, decyl and the like. The term “(C
1
-C
10
)alkyl” encompasses “(C
1
-C
6
)alkyl” and “(C
1
-C
4
)alkyl”.
The term “(C
3
-C
10
) cycloalkyl” refers to a hydrocarbon ring having the stated number of carbon atoms. Typical (C
3
-C
10
) cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. The term “(C
3
-C
10
) cycloalkyl” includes “(C
4
-C
6
) cycloalkyl”.
The term “protecting group” is used herein as it is frequently used in synthetic organic chemistry, to refer to a group which will prevent a functional group from participating in a reaction carried out on some other functional group of the molecule, but which can be removed when it is desired to do so. Such group
Eli Lilly and Company
Joyner Charles T.
Lentz Nelson L.
Rotman Alan L.
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