Chroman derivatives as 5-hydroxytryptamine-6 ligands

Details Chroman derivatives as 5-hydroxytryptamine-6 ligands Chroman derivatives as 5-hydroxytryptamine-6 ligands

2002-10-02

2004-03-16

Lambkin, Deborah C (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S457000, C514S458000, C514S337000, C514S314000, C549S398000, C549S404000, C549S408000, C549S060000, C549S058000, C546S283100, C548S126000, C548S146000, C544S062000

Reexamination Certificate

active

06706757

ABSTRACT:

Various central nervous system disorders such as anxiety, depression, motor disorders, etc., are believed to involve a disturbance of the neurotransmitter 5-hydroxytryptamine (5-HT) or serotonin. Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among others. The effects of serotonin are regulated by the various 5-HT receptor subtypes. Known 5-HT receptors include the 5-HT1 family (e.g. 5-HT1A), the 5-HT2 family (e.g. 5-HT2A), 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 subtypes.
The recently identified human 5-hydroxytryptamine-6 (5-HT6) receptor subtype has been cloned, and the extensive distribution of its mRNA has been reported. Highest levels of 5-HT6 receptor mRNA have been observed in the olfactory tubercle, the striatum, nucleus accumbens, dentate gyrus and CA1, CA2 and CA3 regions of the hippocampus. Lower levels of 5-HT6 receptor mRNA are seen in the granular layer of the cerebellum, several diencephalic nuclei, amygdala and in the cortex.
Northern blots have revealed that 5-HT6 receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues. The high affinity of a number of antipsychotic agents for the 5-HT6 receptor, in addition to its mRNA localization in striatum, olfactory tubercle and nucleus accumbens suggests that some of the clinical actions of these compounds may be mediated through this receptor. Therefore, 5-HT6 receptor ligands are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, attention deficit disorder, migraine, cognitive memory enhancement (e.g. for the treatment of Alzheimer's disease), sleep disorders, feeding disorders (e.g. anorexia and bulimia), panic attacks, withdrawal from drug abuse (e.g. cocaine, ethanol, nicotine and benzodiazepines), schizophrenia, or the like; or in the treatment of certain gastrointestinal disorders such as irritable bowel syndrome.
Therefore, it is an object of this invention to provide compounds which are useful as therapeutic agents in the treatment of a variety of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is a feature of this invention that the compounds provided may also be used to further study and elucidate the 5-HT6 receptor.
These and other objects and features of the invention will become more apparent by the detailed description set forth hereinbelow.
SUMMARY OF THE INVENTION
The present invention provides a chroman compound of formula I
wherein
Y is SO
2
NR
9
R
10
or NR
11
ZR
12
;
Z is SO
2
, CONH or CSNH;
R is halogen, CN, OR
13
, CO
2
R
14
, CONR
15
R
16
, SO
x
R
17
or a C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
3
-C
6
cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;
R
1
, R
2
, R
5
, R
6
, R
7
, R
8
and R
11
are each independently H or an optionally substituted C
1
-C
6
alkyl group;
R
3
and R
4
are each independently H or a C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl or heterocyclylalkyl group each optionally substituted or R
3
and R
4
may be taken together with the atom to which they are attached to represent a 3- to 10-membered optionally substituted mono- or bicyclic ring system optionally containing one or two additional heteroatoms selected from N, O or S with the proviso that when R
12
is an optionally substituted C
1
-C
6
alky or aryl group then R
3
and R
4
must be other than an optionally substituted C
3
-C
6
cycloalkyl or cycloheteroalkyl group;
m is 0 or an integer of 1, 2 or 3;
n is an integer of 1, 2, 3 or 4;
x is 0 or an integer of 1 or 2;
R
9
and R
10
are each independently H or a C
1
-C
6
alkyl, aryl or heteroaryl group each optionally substituted;
R
12
and R
17
are each independently a C
1
-C
6
alkyl, aryl or heteroaryl group each optionally substituted;
R
13
is H, CO
2
R
18
or a C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, aryl or heteroaryl group each optionally substituted;
R
14
and R
18
are each independently H or a C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
3
-C
6
cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; and
R
15
and R
16
are each independently H or an optionally substituted C
1
-C
6
alkyl group; or
the stereoisomers thereof or a pharmaceutically acceptable salt thereof.
The present invention also provides methods and compositions useful for the therapeutic treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.
DETAILED DESCRIPTION OF THE INVENTION
The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the most recent receptors to be identified by molecular cloning. Its ability to bind a wide range of therapeutic compounds used in psychiatry, coupled with its intriguing distribution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor. Significant efforts are being made to understand the possible role of the 5-HT6 receptor in psychiatry, cognitive dysfunction, motor function and control, memory, mood and the like. To that end, compounds which demonstrate a binding affinity for the 5-HT6 receptor are earnestly sought both as an aid in the study of the 5-HT6 receptor and as potential therapeutic agents in the treatment of central nervous system disorders, for example see C. Reavill and D. C. Rogers, Current Opinion in Investigational Drugs, 2001, 2(1):104-109, Pharma Press Ltd.
Surprisingly, it has now been found that chroman derivatives of formula I demonstrate 5-HT6 affinity. Advantageously, said chroman derivatives may be used as effective therapeutic agents for the treatment of central nervous system (CNS) disorders associated with or affected by the 5-HT6 receptor. Accordingly, the present invention provides chroman derivatives of formula I
wherein
Y is SO
2
NR
9
R
10
or NR
11
ZR
12
;
Z is SO
2
, CONH or CSNH;
R is halogen, CN, OR
13
, CO
2
R
14
, CONR
15
R
16
, SO
x
R
17
or a C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
3
-C
6
cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;
R
1
, R
2
, R
5
, R
6
, R
7
, R
8
and R
11
are each independently H or an optionally substituted C
1
-C
6
alkyl group;
R
3
and R
4
are each independently H or a C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl or heterocyclylalkyl group each optionally substituted or R
3
and R
4
may be taken together with the atom to which they are attached to represent a 3- to 10-membered optionally substituted mono- or bicyclic ring system optionally containing one or two additional heteroatoms selected from N, O or S with the proviso that when R
12
is an optionally substituted C
1
-C
6
alky or aryl group then R
3
and R
4
must be other than an optionally substituted C
3
-C
6
cycloalkyl or cycloheteroalkyl group;
m is 0 or an integer of 1, 2 or 3;
n is an integer of 1, 2, 3 or 4;
x is 0 or an integer of 1 or 2;
R
9
and R
10
are each independently H or a C
1
-C
6
alkyl, aryl or heteroaryl group each optionally substituted;
R
12
and R
17
are each independently a C
1
-C
6
alkyl, aryl or heteroaryl group each optionally substituted;
R
13
is H, CO
2
R
18
or a C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, aryl or heteroaryl group each optionally substituted;
R
14
and R
18
are each independently H or a C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
3
-C
6
cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; and
R
15
and R
16
are each independently H or an optionally substituted C
1
-C
6
alkyl group; or
the stereoisomers thereof or a pharmaceutically acceptable salt thereof.
The present invention also provides methods and composit

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