Piperidine derivatives as serotonine reuptake inhibitors

Details Piperidine derivatives as serotonine reuptake inhibitors Piperidine derivatives as serotonine reuptake inhibitors

2002-07-16

2003-12-16

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S256000, C546S281100, C546S284100, C514S337000

Reexamination Certificate

active

06664274

ABSTRACT:

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. For example, many of the tricyclic antidepressant drugs are now known to be active as inhibitors of serotonin and norepinephrine reuptake, and also to have anticholinergic, antihistaminic or anti-&agr;-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.
The present invention provides compounds which have selective activity as antagonists and partial agonists of the serotonin-1
A
receptor and the serotonin-2
A
receptor, and activity as inhibitors of serotonin reuptake. The best-known pharmaceutical with the latter efficacy is fluoxetine, and the importance of its use in the treatment of depression and other conditions is extremely well documented and publicized. Recent scientific articles, for example, Artigas,
TIPS
, 14, 262 (1993), have suggested that the efficacy of a reuptake inhibitor may be decreased by the activation of serotonin-1
A
receptors with the resultant reduction in the firing rate of serotonin neurons. Accordingly, present research in the central nervous system is focusing on the effect of combining reuptake inhibitors with compounds which affect the 5-HT
1A
receptor. In addition, it has been suggested that a 5-HT
2A
receptor antagonist would provide treatment of depression with fewer side effects than a typical serotonin reuptake inhibitor.
Compounds exhibiting both serotonin reuptake inhibition activity and 5-HT
1A
antagonist activity have been described, for example in U.S. Pat. No. 5,576,321, issued Nov. 19, 1996. It has been found that the compounds of the present invention are potent serotonin reuptake inhibitors, antagonists of the 5-HT1 A receptor and antagonists of the 5-HT
2A
receptor.
The present invention provides compounds of formula I:
wherein:
X represents O or S;
Y represents —C(═O)—, —CH(OH)—, —CH
2
—, S, SO, or SO
2
;
represents a single or a double bond;
n is 1, 2, 3 or 4;
R
1a
, R
1b
, R
1c
, and R
2
are each independently H, F, Cl, Br, I, OH, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo(C
1
-C
6
)alkyl, phenyl, NO
2
, —NR
7
R
8
, CN or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo(C
1
-C
6
)alkyl, phenyl, NO
2
, NH
2
, or CN;
R
3
represents H, OH, hydroxy(C
1
-C
6
)alkyl, C
1
-C
6
alkyl, or C
1
-C
6
alkoxy;
R
4
represents aryl, heterocycle, C
3
-C
8
cycloalkyl, aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo(C
1
-C
6
)alkyl, phenyl, NO
2
, NH
2
, or CN; or heterocycle substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo(C
1
-C
6
)alkyl, phenyl, NO
2
, NH
2
, or CN;
R
5
represents aryl, heterocycle, C
3
-C
8
cycloalkyl, aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkyl, phenyl, NO
2
, NH
2
, or CN; heterocycle substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C
1
-C
6
alkyl,C
1
-C
6
alkoxy, hydroxy(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkyl, phenyl, NO
2
, NH
2
, or CN; or C
3
-C
8
cycloalkyl substituted with C
1
-C
4
alkyl;
R
6a
and R
6b
are each independently H or C
1
-C
3
alkyl;
R
7
and R
8
are each independently H, C
1
-C
6
alkyl, aryl or aryl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo(C
1
-C
6
)alkyl, phenyl, NO
2
, NH
2
, or CN;
or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of inhibiting the reuptake of serotonin and antagonizing the 5-HT
1A
receptor which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I.
In addition, the present invention provides a method of inhibiting the reuptake of serotonin, antagonizing the 5-HT
1A
receptor, and antagonizing the 5-HT
2
A receptor, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I.
More particularly, the present invention provides a method for 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, sexual dysfunction, brain trauma, memory loss, eating 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.
In addition, the present invention provides a method of potentiating the action of a serotonin reuptake inhibitor comprising administering to a subject in need of such treatment a compound of formula I in combination with a serotonin reuptake inhibitor.
In addition, the invention provides pharmaceutical compositions of compounds of formula I, including the hydrates thereof, comprising, as an active ingredient, a compound of formula I in combination with a pharmaceutically acceptable carrier, diluent or excipient. This invention also encompasses novel intermediates, and processes for the synthesis of the compounds of formula I.
According to another aspect, the present invention provides the use of a compound of formula I for the manufacture of a medicament for inhibiting the reuptake of serotonin, antagonizing the 5-HT
1A
receptor, and antagonizing the 5-HT
2A
receptor.
In addition, the present invention provides the use of a compound of formula I for inhibiting the reuptake of serotonin, antagonizing the 5-HT
1A
receptor, and antagonizing the 5-HT
2A
receptor.
As used herein, an acyclic or cyclic acetal or ketal is represented by the following:
and corresponds for example, to the following groups:
As used herein the term “Pg” refers to a protecting group on the amine which are commonly employed to block or protect the amine while reacting other functional groups on the compound. Examples of protecting groups (Pg) used to protect the amino group and their preparation are disclosed by T. W. Greene, “Protective Groups in Organic Synthesis,” John Wiley & Sons, 1981, pages 218-287. Choice of the protecting group used will depend upon the substituent to be protected and the conditions that will be employed in subsequent reaction steps wherein protection is required, and is well within the knowledge of one of ordinary skill in the art. Preferred protecting groups are t-butoxycarbonyl also known as a BOC protecting group, and benzyloxycarbonyl.
As used herein, the terms “Halo”, “Halide” or “Hal” refers to a chlorine, bromine, iodine or fluorine atom, unless otherwise specified herein.
As used herein, the term “Me” refers to a methyl group,

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