Bicyclic compounds as ligands for 5-HT1 receptors

Details Bicyclic compounds as ligands for 5-HT1 receptors Bicyclic compounds as ligands for 5-HT1 receptors

2000-01-26

2002-05-21

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S316000, C514S323000, C514S329000, C546S187000, C546S193000, C546S201000, C546S202000, C546S205000

Reexamination Certificate

active

06391891

ABSTRACT:

The present invention relates to novel compounds, processes for their preparation, and pharmaceutical compositions containing them.
EPA 0733628 discloses a series of indole derivatives which are said to possess 5HT
1F
agonist activity. These compounds are alleged to be of use in the treatment of migraine and associated disorders. EPA 0533266/7/8 disclose a series of benzanilide derivatives which are said to possess 5-HT
1D
receptor antagonist activity. The 5-HT
1D
receptor was subsequently found to consist of a pair of gene products originally designated 5-HT
1D&agr;
and 5-HT
1D&bgr;
receptors which have more recently been reclassified as 5-HT
1D
and 5-HT
1B
receptors, respectively. (Hartig, P. R. et al., Trends in Pharmacological Sciences 1992, Vol. 13, page 152, Hartig, P. R. et al., Trends in Pharmacological Sciences, 1996, Vol. 17, page 103).
A structurally distinct class of compounds have now been found that are ligands for 5HT
1A
, 5HT
1B
and 5HT
1D
receptors. It is expected that such compounds will be useful for the treatment and prophylaxis of various disorders. In a first aspect, the present invention therefore provides a compound of formula (I) or a salt thereof:
in which R
a
is a group of formula (i)
in which P
1
is phenyl, bicyclic aryl, a 5 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur; R
1
is hydrogen, halogen, C
1-6
alkyl, C
3-6
cycloalkyl, COC
1-6
alkyl, C
1-6
alkoxy, hydroxy, hydroxyC
1-6
alkyl, hydroxyC
1-6
alkoxy, C
1-6
alkoxyC
1-6
alkoxy, nitro, trifluoromethyl, cyano, SR
9
, SOR
9
, SO
2
R
9
, SO
2
NR
10
R
11
, CO
2
R
10
, CONR
10
R
11
, CONR
10
(CH
2
)
c
CO
2
R
11
, (CH
2
)
c
NR
10
R
11
, (CH
2
)
c
CONR
10
R
11
, (CH
2
)
c
NR
10
COR
11
, (CH
2
)
c
CO
2
C
1-6
alkyl, CO
2
(CH
2
)
c
OR
10
, NR
10
R
11
, NR
10
CO
2
R
11
, NR
10
CONR
10
R
11
, CR
10
═NOR
11
where R
9
is C
1-6
alkyl, R
10
and R
11
are independently hydrogen or C
1-6
alkyl and c is 1 to 4;
R
2
is hydrogen, halogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
3-6
cycloalkenyl, C
1-6
alkoxy, COC
1-6
alkyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO
2
R
10
, CONR
10
R
11
, NR
10
R
11
where R
10
and R
11
are as defined in R
1
;
a is 1,2 or 3;
or R
a
is a group of formula (ii)
 wherein
p
2
and p3 are independently phenyl, bicyclic aryl, a 5- to 7- membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;
A is a bond or oxygen, S(O)
m
where m is 0, 1 or 2, carbonyl, or CH
2
or NR
4
where R
4
is hydrogen or C
1-6
alkyl;
R
1
is as defined above for formula (i) or is a 5 to 7-membered heterocyclic ring, containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by C
1-6
alkyl, halogen or C
1-6
alkanoyl;
R
2
and R
3
are as defined for R
2
in formula (i);
and a and b are independently 1, 2 or 3;
L is a group of formula
—Y—C(═V)—DG—
 in which
Y is —NH—, NR
5
where R
5
is C
1-6
alkyl, or Y is —CH
2
— or —O—,
V is oxygen or sulphur;
D is nitrogen, carbon or a CH group, G is hydrogen or C
1-6
alkyl, providing that D is nitrogen or a CH group, or G together with R
b
forms a group W where W is (CR
16
R
17
)
t
where t is 2, 3 or 4 and R
16
and R
17
are independently hydrogen or C
1-6
alkyl or W is (CR
16
R
17
)
u
—J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR
16
═CR
17
, CR
16
═N, ═CR
16
O, ═CR
16
S or ═CR
16
—NR
17
provided that u is not 0 when J is oxygen or sulphur; subject to the proviso that when D is nitrogen, G is hydrogen or C
1-6
alkyl, Q is selected such that together with the phenyl ring to which it is attached it forms an indole ring and further that when:
(a) Y is —NH— or —NR
5
— and V is oxygen or sulphur; or
(b) both Y and V are oxygen; or
(c) Y is CH
2
and V is oxygen
then p
1
is not phenyl within the definition of R
a
formula (i) and
R
a
is not an unsubstituted biphenyl within the definition of formula (ii)
Q is an optionally substituted 5- to 7-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;
R
Y
is a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur;
R
b
is hydrogen, halogen, hydroxy, C
1-6
alkyl, trifluoromethyl, C
1-6
alkoxy or aryl; or R
b
together with G forms a group W as defined above;
C
1-6
alkyl groups whether alone or as part of another group may be straight chain or branched. The term ‘acyloxy’ is used herein to describe a group —OC(O)C
1-6
alkyl. The term ‘aryl’ is used herein to describe, unless otherwise stated, a group such as phenyl. The term ‘aralkyl’ is used herein to describe, unless otherwise stated, a group such as benzyl.
The bicyclic aryl group represented by p
1
, p
2
and/or p
3
, which may be partially saturated, is preferably naphthyl.
Examples of bicyclic heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur include quinoline, isoquinoline, indole, benzofuran and benzothiophene rings. The heterocyclic groups can be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom.
Examples of 5 to 7 membered heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur represented by p
1
, p
2
and/or p
3
, include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrimidyl and pyrazinyl, preferably pyridyl.
R
1
is preferably a halogen atom for example, fluorine, chlorine or bromine, and R
2
and/or R
3
are each preferably hydrogen, halogen for example a chloro group or a C
1-6
alkyl group for example a methyl group.
a and b are each preferably 1 or 2.
Within the definition of R
a
formula (ii), A is preferably a bond.
In the group L, as defined above:
Y is preferably —NH—.
V is preferably oxygen.
D is preferably nitrogen and G is preferably a hydrogen atom or together with R
b
forms group W, preferably —(CH
2
)
2
—.
R
b
is preferably hydrogen or R
b
together with G forms group W referred to above.
Suitably Q is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur. Preferably Q is a 5- or 6-membered ring containing one or two heteroatoms. Preferably Q, together with the phenyl group to which it attached, forms an indole, indoline, benzoxazole, benzopyran, benzothiophene or benzoxazine ring. Suitable optional substituents for the ring Q include groups R
1
and R
2
as defined above, preferably C
1-6
alkyl, most preferably methyl.
The group R
Y
can be fully or partially saturated and can be linked to the group Q via a carbon atom or, when present, a suitable nitrogen atom. Preferably R
Y
is 5 or 6 membered heterocyclic containing 1 or 2 nitrogen atoms. Most preferably R
Y
is a piperidinyl group.
Particularly preferred compounds according to the invention include:
N-[3-(1-Methylpiperidin-4-yl)indol-5-yl]-N-[4-(pyridin-4-yl)naphth-1-yl]-urea,
N-[3-(1-Methylpiperidin-4-yl)indol-5-yl]-N′-[3-methyl-4-(pyridin-4-yl)phenyl]-urea,
N-[2,3-Dichloro-4-(pyridin-4-yl)phenyl]-N′-[3-(-methylpiperidin-4-yl)indol-5-yl]-urea,
N-[2-Chloro-4-(pyridin-4-yl)phenyl]-N′-[3-(1-methylpiperidin-4-yl)indol-5-yl]-urea
N-[3-(1-Methylpiperidin-4-yl)indol-5-yl]-4-(pyridin-4-yl)naphth-1-ylacetamide,
N-[2,3-Dichlorophenyl]-N′-[7-(1-methylpiperidin-4-yl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indol-1-yl]-urea,
N-[7-(1-Methylpiperidin-4-yl)-1,2,3,5-tetrahydropyrrolo[2,3f]indol-1-yl]-N′-[4-(pyridin-4-yl)naphth-1-yl]-urea,
N-[3-Chloro-4-(pyridin-4-yl)phenyl]-N′-[3-(1-methylpiperidin-4-yl)i

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