Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-09
2004-08-31
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S202000, C546S197000, C546S201000, C546S198000, C546S199000, C546S153000, C546S079000, C514S324000, C514S321000, C514S322000, C514S323000, C514S290000, C514S312000, C544S350000
Reexamination Certificate
active
06784180
ABSTRACT:
Pharmaceutical researchers have discovered that the neurons of the brain which contain monoamines are of extreme importance in a great many physiological processes which 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 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 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.
The present invention provides compounds which have highly selective activity as antagonists and partial agonists of the serotonin 1
A
receptor and a second activity as inhibitors of reuptake of serotonin. 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 well documented and publicized. 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.
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. Compounds of the present invention are potent serotonin reuptake inhibitors and antagonists of the 5-HT
1A
receptor.
The present invention provides compounds of formula I:
wherein
A is hydrogen, OH or (C
1
-C
6
) alkoxy:
B is selected from the group consisting of:
represents a single or a double bond;
X is hydrogen, OH or C
1
-C
6
alkoxy when
represents a single bond in the piperidine ring, and X is nothing when
represents a double bond in the piperidine ring;
Y is S or CH
2
;
R
1
is hydrogen, F, C
1
-C
20
alkyl, —C(═O)NR
8
R
9
, or CN;
R
2
is hydrogen, F, Cl, Br, I, OH, C
1
-C
6
alkyl or C
1
-C
6
alkoxy;
R
3
and R
4
are each independently hydrogen or C
1
-C
4
alkyl;
R
5
and R
6
are each independently hydrogen, F, Cl, Br, I, OH, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo(C
1
-C
6
)alkyl, phenyl, —C(═O)NR
8
R
9
, NO
2
, NH
2
, 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, NO
2
, NH
2
, CN, and phenyl;
R
7
is hydrogen, F, Cl, Br, I, OH, C
1
-C
6
alkyl or (C
1
-C
6
alkyl)NR
8
R
9
;
R
8
and R
9
are each independently hydrogen or C
1
-C
10
alkyl;
m is 0, 1, or 2;
n is 0, 1, or 2;
p is 0, 1, 2, 3 or 4; and
q is 0, 1, 2 or 3; 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 patient 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, Alzheimer's disease, 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 patient 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 patient an effective amount of a compound of formula I in combination with an effective amount of 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, or a pharmaceutically acceptable salt thereof as defined hereinabove for the manufacture of a medicament for inhibiting the reuptake of serotonin and antagonizing the 5-HT
1A
receptor.
According to yet another aspect, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof as defined hereinabove for inhibiting the reuptake of serotonin and antagonizing the 5-HT
1A
receptor.
It is understood that the compounds of formula Ia:
are included within the scope of the definition of formula I wherein the substituents are defined as hereinabove.
It is further understood that the compounds of the formula Iaa:
are included within the scope of the definition of formula I wherein the substituents are defined as hereinabove.
As used herein, the terms “Me”, “Et”, “Pr”, “iPr”, “Bu” and “t-Bu” refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, respectively.
As used herein, the terms “Halo”, “Halide” or “Hal” refer to a chlorine, bromine, iodine or fluorine atom, unless otherwise specified herein.
As used herein the term “C
1
-C
4
alkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
As used herein the term “C
1
-C
6
alkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.
As used herein the term “C
1
-C
10
alkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 10 carbon atoms and includes, but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like.
As used herein the term “C
1
-C
20
alkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-nonadecyl, n-eicosyl and the like.
As used herein the term “halo(C
1
-C
6
)alkyl” refers to a straight or branched alkyl chain having from one to six carbon atoms with 1, 2 or 3 halogen atoms attached to it. Typical halo(C
1
-C
6
)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like. The term “halo(C
1
-C
6
)alkyl” includes within its definition the term “halo(C
1
-C
4
)alkyl”.
As used herein the term “C
1
-C
6
alkoxy” refers to a straight or branched alkyl chain having from one to six carbon atoms attach
He John Xiaoqiang
Honigschmidt Nicholas Allan
Kohn Todd Jonathan
Rocco Vincent Patrick
Spinazze Patrick Gianpietro
Eli Lilly and Company
Liu Hong
Raymond Richard L.
Sayles Michael J.
LandOfFree
Piperidines derivatives and their use as serotonin receptor... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Piperidines derivatives and their use as serotonin receptor..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Piperidines derivatives and their use as serotonin receptor... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3354277