Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-09-18
2001-06-26
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S214020, C514S249000, C514S299000, C514S306000, C540S579000, C540S593000, C544S349000, C546S112000, C546S138000, C546S183000
Reexamination Certificate
active
06251893
ABSTRACT:
This invention relates to indole compounds having affinity for the serotonin 5-HT
6
receptor, to pharmaceutical and diagnostic compositions containing them and to their medical use, particularly in the diagnosis and treatment of CNS conditions.
According to one aspect of the invention, there are provided compounds of Formula I and a salt, solvate of hydrate thereof:
wherein:
R
1
, R
2
, R
3
and R
4
are independently selected from the group consisting of H, halo, OH, C
1-6
alkyl, C
1-6
alkoxy, C
2-6
alkenyl, C
2-6
alkynyl, C
3-7
cycloalkyl, C
4-7
cycloalkenyl, C
3-7
cycloalkoxy, C
3-7
cycloalkylthio, halo-substituted-C
1-6
alkyl, C
1-6
alkylthio, C
2-7
alkanoyl, C
2-7
alkanoyloxy, nitro, cyano, optionally substituted phenyl, optionally substituted furanyl, optionally substituted thienyl, optionally substituted phenyloxy, NR
8
R
9
, C(O)NR
8
R
9
, SO
2
NR
8
R
9
, CH
2
SO
2
NR
8
R
9
, CO
2
R
10
, NHC(O)R
11
, NHC(NR
12
)R
11
, C(NR
13
)NR
14
R
15
, C(O)R
16
, OC(O)R
16
, SCF
3
, SO
2
CF
3
, formyl, CF
3
and CF
3
O;
R
5
is selected from the group consisting of SO
2
Ar, C(O)Ar, CH
2
Ar and Ar;
R
6
is independently selected from the group consisting of H, C
1-6
alkyl, optionally substituted phenyl and optionally substituted benzyl
R
7
is independently selected from the group consisting of H, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, optionally substituted phenyl, optionally substituted benzyl, optionally substituted phenoxy and optionally substituted benzyloxy;
————— represents a single or double bond, provided that there is only one double bond in the ring at a time;
n is selected from an integer of from 1-3;
X is selected from the group consisting of CR
17
and N;
Z is selected from the group consisting of C, CH and N, provided that when ————— is a double bond, Z is C and when ————— is a single bond, Z is selected from CH and N;
Ar is an optionally substituted aromatic group selected from the group consisting of phenyl, pyridyl, thienyl, furanyl, naphthyl, quinolyl and isoquinolyl wherein the optional substituents are independently selected from 1-4 members of the group consisting of halo, OH, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, CF
3
and CF
3
O;
R
8
, R
9
and R
10
are independently selected from the group consisting of H, C
1-6
alkyl and phenyl or R
8
and R
9
may form an alkylene chain, —(CH
2
)
m
—, where m=3-6, to form, together with the nitrogen to which they are attached a 4- to 7- membered ring;
R
11
is selected from the group consisting of C
1-6
alkyl, C
1-6
alkoxy, phenyl, phenoxy, NH
2
, alkylamino, dialkylamino, benzyl and benzyloxy;
R
12
is selected from the group consisting of H and C
1-6
alkyl;
R
13
is selected from the group consisting of H and C
1-6
alkyl;
R
14
and R
15
are independently selected from the group consisting of H and C
1-6
alkyl or one of R
14
and R
15
, together with R
3
, forms an alkylene chain, —(CH
2
)
p
—, where p=2 or 3, bridging the nitrogen atoms to which they are attached;
R
16
is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl, optionally substituted furanyl and optionally substituted naphthyl; and
R
17
is selected from the group consisting of H, C
1-6
alkyl and benzyl.
It is an aspect of the invention to provide compounds which bind to the 5-HT
6
receptor.
According to another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of Formula I in an amount effective to antagonize the 5-HT
6
receptor, and a pharmaceutically acceptable carrier.
In another aspect of the invention there are provided compositions containing a compound of Formula I in amounts for pharmaceutical use to treat CNS conditions where a 5-HT
6
antagonist is indicated, for example, for the treatment or prevention of central nervous system disturbances such as psychosis, schizophrenia, manic depression, depression, neurological disturbances, memory disturbances, Parkinsonism, amylotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease.
In another aspect of the invention, there are provided compounds useful as intermediates in the preparation of compound of Formula I and having a general structure according to Formula II:
wherein:
R
5
is H and R
1
-R
4
, R
6
-R
17
, X, Z, n and ————— are as defined in Formula I and a salt, solvate or hydrate thereof.
These and other aspects of the present invention are described in greater detail hereinbelow.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
The term “C
1-6
alkyl” as used herein means straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
The term “C
1-6
alkoxy” as used herein means straight and branched chain alkoxy radicals containing from one to six carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
The term “C
2-4
alkenyl” as used herein means straight and branched chain alkenyl radicals containing from two to six carbon atoms and includes ethenyl, 1-propenyl, 1-butenyl and the like.
The term “C
2-6
alkynyl” as used herein means straight and branched chain alkynyl radicals containing from two to six carbon atoms and includes 1-propynyl (propargyl), 1-butynyl and the like.
The term “C
3-7
cycloalkyl” as used herein means saturated carbocyclic radicals containing from 3-7 carbon atoms and includes cyclopropyl, cyclohexyl and the like.
The term “C
3-7
cycloalkyloxy” as used herein means saturated carbocyclo-oxy radicals containing from 3-7 carbon atoms and includes cyclopropyloxy, cyclohexyloxy and the like.
The term “C
3-7
cycloalkylthio” as used herein means saturated carbocycloalkylthio radicals containing from 3-7 carbon atoms and includes cyclopropylthio, cyclohexylthio and the like.
The term “C
2-7
alkanoyl” as used herein means straight and branched chain alkanoyl radicals (—C(O)C
1-6
alkyl) containing from 2-7 atoms and includes acetyl, propionyl, butyryl and the like.
The term “C
2-7
alkanoyloxy” as used herein means straight and branched chain alkanoyloxy radicals (—OC(O)C
1-6
alkyl) containing from 2-7 carbon atoms and includes acetoxy, propionyloxy, butyryloxy and the like.
The term “C
4-7
cycloalkenyl” as used herein means carbocyclic radicals containing from 4-7 carbon atoms and 1 unit of unsaturation and includes cyclopent-1-enyl, cyclohex-1-enyl and the like.
The term “optionally substituted phenyl” as used herein means an unsubstituted phenyl radical or a phenyl radical substituted with 1-3 substituents independently selected from halo, OH, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, CF
3
and CF
3
O.
The term “optionally substituted pyridyl” as used herein means an unsubstituted pyridyl radical or a pyridyl radical substituted with 1-3 substituents independently selected from halo, OH, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, CF
3
and CF
3
O.
The term “optionally substituted naphthyl” as used herein means an unsubstituted naphthyl radical or a naphthyl radical substituted with 1-4 substituents independently selected from halo, OH, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, CF
3
and CF
3
O.
The term “optionally substituted phenoxy” as used herein means an unsubstituted phenoxy radical or a phenoxy radical substituted with 1-3 substituents independently selected from halo, OH, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, CF
3
and CF
3
O.
The term “optionally substituted thienyl” as used herein means an unsubstituted thienyl radical or a thienyl radical substituted with 1-2 substituents independently selected from halo, OH, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, CF
3
and CF
3
O.
The term “optionally substituted furanyl” as used herein means an unsubstituted furanyl radical or a furanyl radical substituted with 1-2 substituents independently selected from halo, OH, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, CF
3
and CF
3
O.
The term “optionally substituted benzyl” as used herein means an unsubstituted benzyl radical or a benzyl radical substituted on the phenyl ring
Maddaford Shawn
Qiao Qi
Slassi Abdelmalik
Tehim Ashok
Xin Tao
Arent Fox Kintner Plotkin & Kahn
Coleman Brenda
NPS Allelix Corp.
Shah Mukund J.
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