Piperazine derivatives as 5-HT1B antagonists

Details Piperazine derivatives as 5-HT1B antagonists Piperazine derivatives as 5-HT1B antagonists

2002-03-25

2004-06-08

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S253090, C514S254090, C514S252110, C514S254020, C514S254050, C544S367000, C544S364000, C544S373000, C544S357000, C544S369000, C544S366000, C544S371000

Reexamination Certificate

active

06747030

ABSTRACT:

The present invention relates to novel piperazine derivatives, processes for their preparation, pharmaceutical compositions containing the same and to their use in the treatment of CNS and other disorders.
WO 95/06637 discloses a series of piperazine derivatives which are said to possess 5-HT
1D
receptor antagonist activity. These compounds are alleged to be of use in the treatment of various CNS disorders such as depression. The human 5-HT
1D
receptor is now known to be encoded by two distinct genes initially designated 5-HT
1D&agr;
and 5-HT
1D&bgr;
and subsequently redesignated as 5-HT
1D
and 5-HT
1B
respectively (P. R. Hartig et al, Trends in Pharmacological Science, 1996, 17, 103-105). WO 98/50538 and WO 98/47885 disclose a series of piperazine derivatives that are said to exhibit combined 5-HT
1A
, 5-HT
1B
and 5-HT
1D
receptor antagonist activity. WO 98/27058 discloses a series of carboxamide derivatives that are claimed to be 5-HT
6
receptor antagonists.
A structurally novel class of compounds has now been found which also exhibit 5-HT
1B
receptor activity. In a first aspect, the present invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
in which R
a
is a group of formula (i)
wherein P
1
is phenyl, naphthyl or heteroaryl;
R
1
is halogen, C
1-6
alkyl, C
3-6
cycloalkyl, COC
1-6
alkyl, C
1-6
alkoxy, hydroxy, hydroxyC
1-6
alkyl, nitro, CF
3
, cyano, SR
6
, SOR
6
, SO
2
R
6
, SO
2
R
6
, SO
2
NR
6
R
7
, CO
2
R
6
, CONR
6
R
7
, OCONR
6
R
7
, NR
6
R
7
, NR
6
CO
2
R
7
, NR
6
CONR
7
R
8
, CR
6
═NOR
7
where R
6
, R
7
and R
8
are independently hydrogen or C
1-6
alkyl;
a is 0, 1, 2 or 3;
or R
a
is a group of formula (ii)
 wherein
P
2
is phenyl, naphthyl, heteroaryl or a 5 to 7 membered heterocyclic ring;
P
3
is phenyl, naphthyl or heteroaryl;
A is a bond or oxygen, carbonyl, CH
2
or NR
4
where R
4
is hydrogen or C
1-6
alkyl;
R
2
is as defined above for R
1
in formula (i) or R
2
is heteroaryl optionally substituted by C
1-6
alkyl, halogen or COC
1-6
alkyl or is a 5-7 membered heterocyclic ring optionally substituted by oxo;
R
3
is halogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
1-6
alkoxy, COC
1-6
alkyl, hydroxy, nitro, CF
3
, cyano, CO
2
R
6
, CONR
6
R
7
, NR
6
R
7
where R
6
and R
7
are as defined above;
b and c are independently 0, 1, 2 or 3;
Y is a single bond, CH
2
, O or NR
5
where R
5
is hydrogen or C
1-6
alkyl;
W is —(CR
9
R
10
)
t
— where t is 2, 3 or 4 and R
9
and R
10
are independently hydrogen or C
1-6
alkyl or W is a group CH═CH;
R
b
is hydrogen, halogen, hydroxy, C
1-6
alkyl, CF
3
, COC
1-6
alkyl, cyano or C
1-6
alkoxy;
R
c
is hydrogen or C
1-6
alkyl;
R
d
and R
e
are independently C
1-4
alkyl.
Alkyl groups, whether alone or as part of another group, may be straight chain or branched. The term ‘halogen’ is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.
Where used herein the term naphthyl is intended, unless otherwise stated, to denote both naphth-1-yl and naphth-2-yl groups.
The term “heteroaryl” is intended to mean an aromatic or a benzofused aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur. Suitable examples of such aromatic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl and pyridyl. Suitable examples of such benzofused aromatic rings include quinolinyl, isoquinolinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl and the like.
The term “5-7 membered heterocyclic ring” is used herein to mean a non aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur. Suitable examples of such non aromatic rings include piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl.
The heteroaryl and 5-7 membered heterocyclic rings, as described above, may be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom.
Within the Definition of R
a
Formula (i)
When P
1
is heteroaryl a preferred example is pyridyl. Preferably P
1
is phenyl or naphthyl, most preferably phenyl.
When a is other than 0, preferred R
1
groups include halogen (particularly fluoro or chloro), C
1-6
alkyl group (particularly methyl), CF
3
and cyano. When a is 2 or 3 the groups R
1
can be the same or different.
Preferably a is 1 or 2, most preferably 2.
Within the Definition of R
a
Formula (ii)
Preferably A is a bond.
When P
3
is heteroaryl preferred examples include quinolinyl and pyrazolyl. P
3
is preferably phenyl or naphthyl. A preferred substitution arrangement for such naphthyl groups is 1,4 or 1,5, that is to say, a naphth-1-yl group in which the group A is attached at the 4 or 5 position respectively.
P
2
is preferably phenyl, a heteroaryl group such as pyridyl, pyrazinyl, oxadiazolyl or oxazolyl or P
2
is a 5-7 membered heterocycle such as piperidinyl.
When b is other than 0, preferred R
2
groups include halogen (particularly chloro), C
1-6
alkyl group (particularly methyl), heteroaryl (particularly oxadiazolyl optionally substituted by C
1-6
alkyl) or a 5-7 membered heterocyclic ring (particularly 2-oxo pyrrolidinyl). When b is 2 or 3 the groups R
2
may be the same or different. Preferably b is 0, 1 or 2.
When c is other than 0, preferred R
3
groups are halogen (particularly chloro) and C
1-6
alkyl group (particularly methyl). When c is 2 or 3 the groups R
3
may be the same or different. Preferably c is 0 or 1.
A preferred group of formula (ii) is that in which A is a single bond, P
2
is pyridyl (particularly 2-pyridyl) and P
3
is naphthyl particularly naphth-1-yl). A further preferred group of formula (ii) is that in which A is a single bond, P
2
is pyridyl and P
3
is phenyl. Such groups may be optionally substituted by the preferred R
2
and R
3
groups as described above.
Y is preferably a single bond, CH
2
or a NH group.
It will be appreciated that when W is a group —CH═CH— an indole ring is formed. Within the definition of the group W, the groups R
9
and R
10
are each preferably hydrogen and t is preferably 2 or 3, most preferably 2.
R
b
is preferably hydrogen, C
1-6
alkoxy group (particularly methoxy) or C
1-6
alkyl group (particularly methyl).
R
c
is preferably hydrogen or methyl.
Preferably both R
d
and R
e
are methyl.
Preferred compounds of this invention are examples E1-E73 (as described below) or a pharmaceutically acceptable salt thereof. Particularly preferred compounds according to this invention are:
cis-1-[(2-chloro-3-trifluoromethylphenyl)acetyl]-6-(3,4,5-trimethylpiperazin-1-yl)indole,
cis-1-[(2-fluoro-3-trifluoromethylphenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline,
cis-1-[(2,3dichlorophenyl)acetyl]-6-(3,5-dimethylpiperazin-1-yl)-5-methoxyindoline
cis-6-(3,5-dimethylpiperazin-1-yl)-5-methoxy-1-[4-(2-methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)benzoyl]indoline,
cis-1-[(3-chloro-2-fluorophenyl)acetyl]-6-(3,5-dimethylpiperazin-1-yl)-5-methoxyindole,
cis-1-[(2-fluoro-3-trifluoromethylphenyl)acetyl]-5-fluoro-6-(3,4,5-trimethylpiperazin-1-yl)indole,
cis-1-[2-chloro-3-(trifluoromethyl)phenyl)aminocarbonyl]-5-methyl-6-(3,4,5-trimethylpiperazin-1-yl)indoline
or a pharmaceutically acceptable salts thereof.
The compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
The compounds of formula (I) may be prepared in crys

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