Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-12
2002-11-05
Chang, Ceila (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S323000, C514S338000, C546S198000, C546S201000, C546S270100
Reexamination Certificate
active
06476051
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention pertains to cyclic amino derivatives having psychotropic and bio-affecting properties and to their preparation and use in treating patients suffering from or susceptible to psychosis, acute mania, mild anxiety states, or depression in combination with psychotic episodes by the administration of these cyclic amino derivatives. More specifically, the invention is concerned with the medicinal use of compounds having benzene or benzothiazole rings linked by sidechains to the nitrogen atom of 4-substituted-1,2,5,6-tetrahydropyridine and -piperidine moieties. These compounds possess unique dopaminergic and serotonergic profiles that make them useful in the treatment of psychosis and other mental illnesses caused by disorders of the dopaminergic and serotonergic systems.
The combination of a serotonin reuptake inhibitor, such as fluoxetine, with a dopaminergic antipsychotic agent, such as olanzapine, has been described as an improved treatment for psychosis, (European Patent Application 830864, published Sep. 22, 1997).
The preparation and use of tetrahydropyridinyl- and piperidinylindoles, 1, and related compounds as serotonin 5-HT
1F
agonists for the treatment of migraine, allergic rhinitis, and associated diseases has been described. Cf: U.S. Pat. No. 5,521,197 (May 28, 1996), WO Patent Publication No. 9811895 (Mar. 26, 1998) and WO 9806402 (Feb. 19, 1998), and European Patent Application 714894 (Jun. 5, 1996).
In 1, Y=O, S, or a bond, and R
1
is naphthyl, phenyl, substituted phenyl, halo, alkyl, alkylthio, alkoxy, benzyloxy, OH, CONH
2
.
A series of aryloxy propanolamines, including compound 2, was disclosed by Obase, et al., in
Chem. Pharm. Bull.,
30(2), 474-83, 1982, as antihypertensive agents.
The synthesis and adrenergic &bgr;-blocking activity of some non-cyclic amine derivatives; e.g., 3, has been described by Obase, et al.,
Chem. Pharm. Bull.,
26(5), 1443-52, 1978, and by Franke, et al.,
Arzneim.
-
Forsch.,
30(11), 1831-8, 1980.
Some derivatives of 4-(1H-indol-3-yl)-1 piperidine-ethanol derivatives, 4, having antiarrhythmic activity were described by Clemence, et al., in U.S. Pat. No. 4,530,932 (Jul. 23, 1985).
In 4, Ar is aryl or a selected group of heteroaryl moieties not including benzothiazole.
The preparation and use of indane and dihydroindole derivatives of indolylpiperidine compounds, 5, as dopamine D
4
receptor, 5-HT receptor, and 5-HT transporter ligands was described in WO Patent Publication No. 9828293 (Jul. 2, 1998).
In sum, none of these references suggest the novel compounds of the present invention.
A series of nitrogen-containing heterocycles linked by oxygen to alkanamines comprising, inter alia, compounds of formula 6, were disclosed and claimed for the treatment of conditions related to the reuptake of serotonin and by the 5-HT
1a
receptor (U.S. Pat. No. 5,741,789, Apr. 21, 1998, and U.S. Pat. No. 5,627,196, May 6, 1997). In formula 6, D represents a nitrogen-containing residue that completes
fused pyrrolo, imidazolo, pyrido, pyrazino, pyridazino, or pyrimido moieties.
Z can be
with R
2
being absent when a double bond is intended or being hydrogen or a substituent, including a benzyl group. R
3
is a non-hydrogen substituent that can be indole.
SUMMARY OF THE INVENTION
In its broadest aspect, the invention is concerned with the use of certain benzene or benzothiazole compounds linked by sidechains to indolyl-1,2,5,6-tetrahydropyridines and -piperidines or substituted 4-benzylpiperidines. These compounds possess a unique dopaminergic and serotonergic profile useful for treating CNS disorders such as psychosis and depression and they conform to Formula I:
In Formula I:
Ar is selected from
Z is II or III;
Y is sulfur or oxygen;
R
1
and R
4
are independently selected from H and lower alkyl;
R
2
, R
3
, R
6
and R
7
are independently selected from H, halogen, and lower alkoxy;
R
5
is selected from H, halogen, lower alkoxy and cyano;
m is an integer from 2-6;
n is zero or the integer 1 or 2; and
a dotted line represents an optional double bond.
“Halo” or “halogen” refers to fluoride, chloride, bromide or iodide substituents with fluoride, chloride and bromide preferred.
“Lower” refers to an alkyl or alkoxy group having from one to four carbon atoms.
Additionally, compounds of Formula I also encompass all pharmaceutically acceptable acid addition salts and/or solvates thereof. The present invention is also considered to include stereoisomers including geometric as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diasteromers, which arise as a consequence or structural asymmetry in certain compounds of the instant series. Separation of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.
Several classes of Formula I compounds are intended and result from selection among benzene, benzothiazole, and II and III structural moieties. The benzothiazole classes of compounds are novel.
Preferred compounds are those wherein m is 3, n is 1 and Y is oxygen.
Preferred compound examples where Z is Formula II are shown below.
A. Benzothiazole Derivatives
5-{3-[4-(5-fluoroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{3-[4-(5-cyanoindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{3-[4-(5-fluoroindol-3-yl)piperidinyl]propoxy}-2-methylbenzothiazole;
5-{3-[4-(5-cyanoindol-3-yl)piperidinyl]propoxy}-2-methylbenzothiazole;
5-{4-[4-(5-cyanoindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{4-[4-(5-cyanoindol-3-yl)piperidinyl]butoxy}-2-methylbenzothiazole;
5-{3-[4-(5-bromoindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{3-[4-(4-fluoroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{4-[4-(4-fluoroindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{5-[4-(4-fluoroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole;
5-{4-[4-(5-fluoroindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{5-[4-(5-fluoroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole;
5-{3-[4-(7-fluoroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{4-[4-(7-fluoroindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{5-[4-(7-fluoroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole;
5-{4-[4-(5-chloroindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{5-[4-(5-chloroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole;
5-{3-[4-(6-chloroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{4-[4-(6-chloroindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{5-[4-(6-chloroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole;
5-{3-[4-(6-bromoindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{4-[4-(6-bromoindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{5-[4-(6-bromoindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole;
5-{3-[4-(7-bromoindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{4-[4-(7-bromoindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{5-[4-(7-bromoindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole;
5-{3-[4-(5-methoxyindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5
Denhart Derek
Eison Arlene S.
Mattson Ronald J.
Yevich Joseph P.
Yuan Jun
Bristol--Myers Squibb Company
Chang Ceila
Ryan Richard P.
Wright Sonya
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