Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-30
2003-12-23
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S217030, C514S217080, C514S217090, C514S217100, C514S218000, C540S575000, C540S596000, C540S602000, C540S603000
Reexamination Certificate
active
06667303
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to aryl substituted 1,4-diazepanes having affinity at the serotonin 5-hydroxytryptamine 2C (5HT2C) receptor and functioning as agonists at that receptor. Compounds having this activity are useful for the treatment of disorders such as obsessive-compulsive disorder, depression, anxiety, schizophrenia, migraine, sleep disorders, eating disorders, sexual dysfunction, obesity, and epilepsy.
BACKGROUND TO THE INVENTION
Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, feeding behavior, sexual activity, and neuroendocrine regulation among others. 5-HT2C receptor ligands are believed to be of potential use in the treatment of certain central nervous system (CNS) disorders such as anxiety disorders such as generalized anxiety, obsessive-compulsive disorder, social phobias, and panic disorder; affective (i.e., mood) disorders such as depression, atypical depression and bipolar disorders; psychoses involving gross impairment of reality such as schizophrenia and related disorders; sleep disorders; eating disorders (e.g., anorexia, and bulimia); obesity; epilepsy; diabetes; and migraine. EP556889A1 reports the synthesis of arylpiperazines and arylhomopiperazines. WO99/32461 presents a scenario similar to EP556889A1 with the homopiperazine attached to the 1-position of the 1,2,3,4-tetrahydronaphthyl ring.
SUMMARY OF THE INVENTION
This invention relates to novel aryl substituted 1,4-diazepanes, such as derivatives of 6-(1,4-diazepan-1-yl)benzo[cd]indol-2(1H)-one, 6-(1,4-diazepan-1-yl)acenaphthylen-1 (2H)-one and 5-(1,4-diazepan-1-yl)-2H-naphtho[1,8-cd]isothiazole-1,1-dioxide; to processes for their preparation; to pharmaceutical compositions containing them and to their use in therapy. These compounds are believed to have affinity at the serotonin 5-hydroxytrptamine 2C (5HT2C) receptor and are believed to function as agonists at that receptor. Compounds having this activity are useful for the treatment of disorders such as anxiety disorders such as generalized anxiety, obsessive-compulsive disorder, social phobias, and panic disorder; affective (i.e., mood) disorders such as depression, atypical depression and bipolar disorders; psychoses involving gross impairment of reality such as schizophrenia; sleep disorders; eating disorders (e.g., anorexia and bulimia); obesity; epilepsy; diabetes; and migraine.
Compounds of this invention include those of Formula (1) or a non-toxic, pharmaceutically acceptable salt thereof
where:
X is C or N;
Y is CH
2
, C═O, S═O, or SO
2
;
Z is N or C;
R
1
, R
1a
and R
11
are each independently selected from hydrogen, or an alkyl, cycloalkyl, arylalkyl, alkenyl, or heteroarylalkyl group;
R
2
, R
3
, R
4
, R
5
and R
6
are each independently selected from hydrogen, halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, alkanoyl, CN, CHO, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, OCOOalkyl, OCOOaryl, OCONR
18
, COOH, COOalkyl, COOaryl, CONR
18
R
19
, CONHOH, NR
18
R
19
, SO
2
NR
18
R
19
, NO
2
, NH
2
, or OH group, where R
18
and R
19
are each independently selected from hydrogen, or an alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, perfluoroalkyl, COalkyl, COaryl, COheteroaryl, COOalkyl, COOaryl, COOheteroaryl, CONHalkyl, CON(alkyl)
2
, CONHaryl, CONHheteroaryl, cycloalkyl, cycloheteroalkyl, S(O)
m
-alkyl or S(O)
m
-aryl group, where m is 0, 1 or 2;
R
7
, R
8
, R
9
, R
10
, R
12
, R
13
, R
14
, R
15
, R
16
, and R
17
are each independently selected from hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl or heteroaryl group; and
where p is 1 when X is carbon and p is zero when X is nitrogen.
Preferred compounds of the present invention are represented by the general Formula (II) or a pharmaceutically acceptable salt thereof.
where:
X is either C or N;
Y is either CH
2
, C(O) or SO
2
;
R
1
, R
1a
, and R
11
are each independently selected from hydrogen, or an alkyl, cycloalkyl, arylalkyl, or alkenyl group; and
R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
12
, R
13
, R
14
, R
15
, R
16
, and R
17
are dedined as before.
A second preferred class of compounds of the present invention is represented by Formulas (III) or (IV), or a pharmaceutically acceptable salt thereof:
where
R
1
and R
11
are each independently selected from hydrogen, or an alkyl, cycloalkyl, arylalkyl, alkenyl, or heteroarylalkyl group; and
R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
12
, R
13
, R
14
, R
15
, R
16
, and R
17
are defined as before.
A third preferred class of compounds of the present invention is represenited by Formulas (V) or (VI), or a pharmaceutically acceptable salt thereof:
where:
R
1
, R
1a
and R
11
are each independently selected from hydrogen, or an alkyl, cycloalkyl, arylalkyl, alkenyl, or heteroarylalkyl group; and
R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
12
, R
13
, R
14
, R
15
, R
16
, and R
17
are defined as before.
A fourth preferred class of compounds of the present invention is represented by Formulas (VII) or (VIII), or a pharmaceutically acceptable salt thereof:
where:
R
1
, R
1a
and R
11
are each independently selected from hydrogen, or an alkyl, cycloalkyl, arylalkyl, alkenyl, or heteroarylalkyl group; and
R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
12
, R
13
, R
14
, R
15
, R
16
, and R
17
are defined as before.
A fifth preferred class of compounds of the present invention is represented by Formulas (IX) or (X), or a pharmaceutically acceptable salt thereof
where:
R
1
and R
11
are each independently selected from hydrogen, or an alkyl, cycloalkyl, arylalkyl, alkenyl, or heteroarylalkyl group; and
R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
12
, R
13
, R
14
, R
15
, R
16
, and R
17
are defined as before.
Within each of the classes of compounds of Formulas (I) through (X), it is preferred that the moiety:
where R
21
, R
22
, and R
23
are each independently selected from hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl or heteroaryl group, and R
11
is defined as before for each formula.
In another embodiment of Formulas (I) through (X), the variables R
7
, R
8
, R
9
, R
10
R
12
, R
13
, R
14
, R
15
, R
16
and R
17
are preferably hydrogen and R
11
is defined as before for each formula.
In another embodiment of Formulas (I) through (X), the variables R
2
, R
3
, R
4
, R
5
and R
6
are each hydrogen and R
1
and R
7
through R
17
are as defined before for each formula.
DETAILED DESCRIPTION OF THE INVENTION
Compounds of the invention include those of Formula (I) or a non-toxic, pharmaceutically acceptable acid addition salt thereof
where:
X is C or N;
Y is CH
2
, C═O, S═O, or SO
2
;
Z is Cor N;
R
1
, R
1a
, and R
11
are each independently selected from hydrogen, or an alkyl, cycloalkyl, arylalkyl, alkenyl, or heteroarylalkyl group;
R
2
, R
3
, R
4
, R
5
and R
6
are each independently selected from hydrogen, halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, alkanoyl, CN, CHO, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, OCOOalkyl, OCOOaryl, OCONR
18
, COOH, COOalkyl, COOaryl, CONR
18
R
19
, CONHOH, NR
18
R
19
, SO
2
NR
18
R
19
, NO
2
, NH
2
, or OH group, where R
18
and R
19
are each independently selected from hydrogen, or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, perfluoroalkyl, COalkyl, COaryl, COheteroaryl, COOalkyl, COOaryl, COOheteroaryl, CONHalkyl, CON(alkyl)
2
, CONHaryl, CONHheteroaryl, cycloalkyl, cycloheteroalkyl, S(O)
m
-alkyl or S(O)
m
-aryl group, where m is 0, 1 or 2;
R
7
, R
8
, R
9
, R
10
, R
12
, R
13
, R
14
, R
15
, R
16
, and R
17
are each independently selected from hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl or heteroaryl group; and where p is 1 when X is carbon and p is zero when X is nitrogen.
As used
Gu Yansong
Pelletier Jeffrey Claude
Hild Kimberly R.
Kifle Bruck
Wyeth
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