Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-03-27
2001-01-09
Raymond, Richard L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S234500, C514S322000, C514S338000, C544S124000, C544S129000, C546S016000, C546S187000, C546S199000, C546S273400
Reexamination Certificate
active
06172073
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 serotonin 1
A
receptor and those relating to the reuptake of serotonin.
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. 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. Accordingly, the objective of research now is to discover agents which affect only functions of serotonin, for example, at a single identifiable receptor.
The present invention provides an extensive series of pharmaceuticals, some of which have highly selective activity as antagonists and partial agonists of the serotonin 1
A
receptor.
Some of the present pharmaceuticals have a second activity as inhibitors of reuptake of serotonin. The best-known pharmaceutical with that 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,
mTIPS,
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 5HT-1
A
receptor.
It has very surprisingly been found that a defined portion of the present pharmaceuticals are potent serotonin reuptake inhibitors, as well as having effects at the 5HT-1
A
receptor. Such compounds are not believed to have been known before.
SUMMARY OF THE INVENTION
The present invention provides a series of new compounds, methods of using them for pharmaceutical purposes, and pharmaceutical compositions whereby the compounds may be conveniently administered. The scope of the compounds useful in the methods is somewhat more broad than the scope of the novel compounds.
The invention provides the following compounds of formula I:
wherein
r is 0-4;
s is 0-1;
D is a residue which combines with the carbon atoms to which it is attached to complete a pyrrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl group; wherein X is hydrogen, phenyl, hydroxy or methoxy; provided that X is hydrogen or phenyl when r is 0;
R is
the dotted line is an optional double bond;
R
1
is piperidinyl, piperazino, morpholino or pyrrolyl, substituted with 0-1 phenyl or benzyl group or 0-4 C
1
-C
3
alkyl, C
1
-C
3
alkoxy or halo groups; which phenyl or benzyl group is substituted with 0-2 C
1
-C
3
alkyl, halo, trifluoromethyl or C
1
-C
3
alkoxy groups;
or R
1
is
n and m are independently 4-5, and the group of Formula VI may be substituted with 0-1 oxo group and 0-2 C
1
-C
3
alkyl, C
1
-C
3
alkoxy or halo groups;
or R
1
is C
1
-C
4
alkyl,
substituted with pyrrolyl, furyl, thienyl, pyridinyl, morpholinyl, piperidinyl, tetrahydropyrrolyl, piperazinyl, tetrahydrofuryl, benzazepinyl, dibenzazepinyl or quinolinyl,
substituted with 0-4 C
1
-C
3
alkyl, C
1
-C
3
alkoxy or halo groups;
R
2
is hydroxy, hydrogen, cyano, C
1
-C
4
alkyl, or (phenyl or benzyl substituted with 0-2 C
1
-C
3
alkyl, C
1
-C
3
alkoxy or halo groups);
or R
2
is amino substituted with phenyl or benzyl, substituted with 0-2 C
1
-C
3
alkyl, C
1
-C
3
alkoxy, halo or trifluoromethyl groups;
or R
2
is absent when the dotted line is a double bond;
R
3
is C
1
-C
4
alkyl,
substituted with 0-2 phenyl groups,
substituted with 0-2 C
1
-C
3
alkyl, C
1
-C
3
alkoxy or halo groups;
or R
3
is C
1
-C
4
alkyl substituted with hydroxyimino or hydroxy;
or R
3
is phenoxy,
substituted with 0-1 methylenedioxy or substituted with 0-2 C
1
-C
3
alkyl, C
1
-C
3
alkoxy, trifluoromethyl or halo groups;
or R
3
is dibenzocycloheptenyl, benzodioxolyl, benzodioxinyl,
or dibenzocyclohexenyl;
or R
3
is phenyl, naphthyl, tetralinyl, tetrazolyl, benzimidazolyl, indolyl, benzofuryl, benzothienyl, piperidino
or morpholino,
substituted with 0-2 C
1
-C
3
alkyl, C
1
-C
3
alkoxy, C
4
-C
8
cycloalkylalkoxy, halo, nitro, trifluoromethyl, difluoromethyl, hydroxy or trifluoromethoxy groups; or substituted with 0-1 phenyl, piperidinonyl, hexahydropyridazinonyl or piperazinonyl group,
substituted with 0-2 C
1
-C
3
alkyl, oxo, C
1
-C
3
alkoxy, halo or trifluoromethyl groups;
provided that R
3
is not halo- or trifluoromethyl-substituted phenyl when R
2
is hydroxy;
or R
2
and R
3
combine to form C
1
-C
4
alkylidene,
substituted with 0-2 phenyl groups,
substituted with 0-2 C
1
-C
3
alkyl, C
1
-C
3
alkoxy, phalo or trifluoromethyl groups;
R
5
is C
1
-C
6
alkyl;
or R
5
is C
1
-C
3
alkyl substituted with benzodioxinyl or benzodioxolyl,
substituted on the phenyl ring with 0-2 C
1
-C
3
alkyl, C
1
-C
3
alkoxy or halo groups;
or R
5
is pyridinyl, pyrimidinyl, indolyl, benzofuryl, benzothienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyridazinyl or quinazolinyl,
substituted with 0-2 C
1
-C
3
alkyl, trifluoromethyl, C
1
-C
3
alkoxy or halo groups;
or R
5
is
B is oxygen or sulfur;
Y is a residue which combines with the atoms to which it is attached to complete a triazolyl, imidazolyl, thiazolyl or pyrrolyl ring;
A is a residue which combines with the nitrogen atom to-which it is attached to complete
a) an azabicyclo(octyl, nonyl or decyl) group;
M is a residue which combines with the carbon atom to which it is attached to complete an indanyl, indenyl, pyrrolidinyl, tetralinyl, benzopyranyl, dihydroindolyl, naphthodihydrofuranyl, benzodihydrothienyl, benzodihydrofuranyl, benzodihydropyranyl, naphthodihydrothienyl, or naphthodihydropyrrolyl group
wherein the spiro junction is not to an aromatic ring, substituted with 0-2 C
1
-C
3
alkyl, oxo, C
1
-C
3
alkoxy, pyrrolidinyl- or piperidinyl-C
1
-C3 alkoxy, C
1
-C
2
alkylenedioxy, phenoxy, benzyloxy, phenyl or halo groups;
p represents 0-2;
R
6
and R
7
independently represent phenyl groups, substituted with 0-2 C
1
-C
3
alkyl, C
1
-C
3
alkoxy or halo groups;
or R
6
and R
7
combine with the atom to which they are attached to complete a fluorenyl or dihydroanthracenyl group;
or R
6
and R
7
represent hydrogen, provided that p must not be 1;
q represents 0-2;
Q represents a residue which combines with the atoms to which it is attached to complete a phenyl or naphthyl group, substituted with 0-2 C
1
-C
3
alkyl, C
1
-C
3
alkoxy or halo groups;
R
8
is hydrogen or C
1
-C
3
alkyl;
or a pharmaceutically acceptable salt thereof.
The following genus of compounds, which is enclosed within the compounds of formula I, have efficacy as serotonin reuptake inhibitors, as well as activity at the 5HT-1
A
receptor.
wherein
r is 0-3;
X is hydrogen or hydroxy;
R is
the dotted line is an optional double bond;
R
2
is hydroxy or h
Audia James E.
Hibschman David J.
Krushinski, Jr. Joseph H.
Mabry Thomas E.
Nissen Jeffrey S.
Eli Lilly and Company
Lentz Nelsen L.
Raymond Richard L.
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