Indole derivatives as 5-HT receptor antagonist

Details Indole derivatives as 5-HT receptor antagonist Indole derivatives as 5-HT receptor antagonist

1999-07-23

2001-05-22

Rotman, Alan L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S256000, C546S277100, C546S277400, C546S280400, C546S283400, C514S337000

Reexamination Certificate

active

06235758

ABSTRACT:

This invention relates to compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders.
WO 94/04533 (Smith Kline Beecham plc) describes indole and indoline derivatives which are described as possessing 5HT
2C
receptor antagonist activity. A structurally distinct class of compounds has now been discovered, which have been found to have 5HT
2C
receptor antagonist activity. Certain compounds of the invention also exhibit 5HT
2B
antagonist activity. 5HT
2C/2B
receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
The present invention therefore provides, in a first aspect, a compound of formula (I) or a salt thereof:
wherein:
P
1
and P
2
are independently phenyl, aromatic or partially saturated monocyclic or bicyclic heterocyclic rings containing up to three heteroatoms selected from nitrogen, oxygen or sulphur;
A is a bond, a chain of 1 to 5 atoms optionally substituted by C
1-6
alkyl or A is an optionally substituted phenyl or an optionally substituted 5- to 7-membered heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur;
R
1
and R
2
groups are each independently hydrogen, C
1-6
alkyl optionally substituted by NR
12
R
13
, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
alkylthio, cyano, nitro, halogen, CF
3
, C
2
F
5
, NR
12
R
13
, CONR
12
R
13
, NR
12
COR
13
, S(O)
p
NR
12
R
13
, CHO, OCF
3
, SCF
3
, COR
14
, CH
2
OR
14
, CO
2
R
14
or OR
14
where p is 1 or 2 and R
12
, R
13
and R
14
are independently hydrogen, C
1-6
alkyl, optionally substituted aryl or optionally substituted arylC
1-6
alkyl;
n and m are independently 0, 1 or 2;
R
3
is hydrogen or C
1-6
alkyl;
R
4
is a group of formula (i):
in which:
X and Y are both nitrogen, one is nitrogen and the other is carbon or a CR
5
group or one is a CR
5
group and the other is carbon or a CR
5
group;
R
5
, R
6
, R
7
and R
8
groups are independently hydrogen, C
1-6
alkyl optionally substituted by one or more fluorine atoms, C
2-6
alkenyl, C
3-6
cycloalkyl, C
3-6
cycloaklylC
1-6
alkoxy, C
2-6
alkynyl, C
3-6
cycloaklyloxy, C
3-6
cycloaklyl-C
1-6
alkyl, C
1-6
alkylthio, C
3-6
cycloaklythio, C
3-6
cycloaklyl-C
1-6
alkythio, C
1-6
alkoxy, hydroxy, halogen, nitro, OCF
3
, SCF
3
, SO
2
CF
3
, SO
2
F, formyl, C
2-6
alkanoyl, cyano, optionally substituted phenyl or thienyl, NR
12
R
13
, CONR
12
R
13
or CO
2
R
14
where where R
12
, R
13
and R
14
are as defined for R
1
; R
6
and R
7
from part of an optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring;
R
9
and R
10
are independently hydrogen or C
1-6
alkyl; or
R
4
is a group of formula (ii):
in which X and Y are both nitrogen, none is nitrogen and the other is a CR
5
group or X and Y are both CR
5
groups, and R
5
, R
6
, R
7
and R
8
are as defined in formula (I); and
R
11
is hydrogen or C
1-6
alkyl, or
R
4
is a group of formula (iii):
in which R
6
, R
7
, X and Y are as defined in formula (i) and Z is O, S, CH
2
or NR
15
where R
15
is hydrogen or C
1-6
alkyl.
C
1-6
Alkyl groups, whether alone or as part of another group, may be straight chain or branched.
Suitably A is a bond or a chain of 1 to 5 atoms optionally substituted by C
1-6
alkyl. Examples of such chains include (CH
2
)
p
X or X(CH
2
)
p
where p is 1 to 4 and X is CO, O, S(O)
x
where x is 0 to 2 or A is NR, CONR, NRCO, NRCONR, CO, CH(OH), C
1-6
alkyl, CH═CH, CH═CF, CF═CF, O, S(O)
x
where x is 1 or 2, NR, or NRSO
2
where R is hydrogen or C
1-6
alkyl. Preferably A is a bond or a group CH
2
O, OCH
2
, or O.
Suitably A is an optionally substituted phenyl group or an optionally substituted 5- or 6-membered heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur. Preferably A is thiazolyl, isothiazoly, oxazoly, isoxazolyl, thoadiazoly, triazoly, pyridyl, pyrimidyl or pyrazinyl. Most preferably A is thiazolyl. Optional substitutents when A is a phenyl or a heterocyclic group include those groups R
1
and R
2
listed above.
The urea moiety can be attached to a carbon or any available nitrogen atom of the ring P
2
, preferably it is attached to a carbon atom. Suitable moieties when the rings P
1
and P
2
are 5-membered aromatic heterocyclic rings include isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl and triazolyl. Suitable moieties when the rings P
1
and R
2
are 6-membered aromatic heterocyclic rings include, for example, pyridyl, pyrimidyl or pyrazinyl. Optional substituents for P
1
or P
2
groups include those groups R
1
and R
2
listed above.
When A is a bond, P
1
is preferably phenyl, pyridyl, pyrimidyl, pyraxinyl or pyridazinyl, preferably phenyl or pyridyl, in particular 3-pyridyl.
When A is a chain of 1 to 5 atoms, P
1
is preferably phenyl or pyridyl and P
2
is preferably phenyl or pyridyl, in particular 3-pyridyl.
When A is an optionally substituted phenyl group or an optionally substituted 5- or 6-membered aromatic heterocyclic ring, P
1
is preferably phenyl or pyridyl and P
2
is preferably phenyl or pyridyl, in particular 3-pyridyl.
Preferably R
1
is hydrogen or methyl.
Preferably R
2
is hydrogen, halogen, methyl, CF
3
or OCF
3
.
Preferably R
3
is hydrogen.
Preferably R
4
is a group of formula (i). Preferably X and Y form part of a phenyl ring, that is to say one of X or Y is carbon and the other is a CH group or both of X and Y are CH groups. Most preferably R
4
is a group of formula (A):
in which R
6
and R
7
are defined in formula (i).
Suitably R
6
and R
7
groups are independently hydrogen, C
1-6
alkyl optionally substituted by one or more fluorine atoms for example CF
3
or C
2
F
5
, C
2-6
alkenyl, C
3-6
cycloalkyl, C
3-6
cycloalkyl C
1-6
alkoxy, C
2-6
alkynyl, C
3-6
cycloalkyloxy, C
3-6
cycloalkyl-C
1-6
alkyl, C
1-6
alkylthio, C
3-6
cycloalkylthio, C
3-6
cycloalkyl-C
1-6
alkythio, C
1-6
alkoxy, hydroxy, halogen, nitro, CF
3
, C
2
F
5
, OCF
3
, SCF
3
, SO
2
CF
3
, SO
2
F, formyl, C
2-6
alkanoyl, cyano, optionally substituted phenyl or thienyl, NR
12
R
13
, CONR
12
R
13
or CO
2
R
14
where R
12
, R
13
and R
14
are as defined for R
1
; or R
6
ad R
7
form part of an optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring. Examples of such rings include cyclopentane and dihydrofuran rings.
Preferably R
6
is trifluoromethyl or halogen and R
7
is C
1-6
alkoxy, in particular methoxy, C
1-6
alkylthio, in particular methylthio or C
1-6
alkyl in particular methyl.
Suitably n and m are independently 0, 1 or 2. Preferably n and m are both 1.
Particular compounds of the invention include:
1-[(3-Pyridyl)-3-phenyl carbamoyl]-5-methoxy-6-trifluromethyl indoline,
1-[(4-Pyridyl)-3-phenyl carbamoyl]-5-methylthio-6-trifluoromethyl indoline,
1-[(3-Pyridyl)-3-phenyl carbamoyl]-5-methylthio-6-trifluoromethyl indoline,
1-[(3-Pyridyl)-4-phenyl carbamoyl]-5-methoxy-6-trifluoromethylindoline,
1-[(4-Pyridyl)-4-phenyl carbamoyl]-5-methoxy-6-trifluoromethyl indoline,
1-[(2-Pyridyl)-3-phenyl carbamoyl]-5-methoxy-6-trifluoromethyl indoline,
1-[(4-Methyl-3-(3-Pyridyl)-phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline,
1-[3-Fluoro-5-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline,
1-[2-Fluoro-5-(3-pyridyl)phenyl carbamoyl]-5-methoxy-6-trifluoromethyl indoline,
1-(5-Phenyl pyrid-3-yl carbamoyl)-5-methoxy-6-trifluoromethyl indoline,
1-(5-Phenyl pyr

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