Azaindole derivatives and their use as therapeutic agents

Details Azaindole derivatives and their use as therapeutic agents Azaindole derivatives and their use as therapeutic agents

2001-07-11

2002-11-05

Rao, Deepak R. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S303000, C514S322000, C514S323000, C514S256000, C514S278000, C546S113000, C546S118000, C546S121000, C546S199000, C546S200000, C546S016000, C546S017000, C544S231000

Reexamination Certificate

active

06476045

ABSTRACT:

This invention relates to indole and azaindole derivatives and their use as tachykinin antagonists, and in particular as neurokinin-1 receptor antagonists.
We have now found a class of indole and azaindole derivatives which are potent receptor antagonists of tachykinins, especially of the neurokinin-1 (substance P) receptor.
The present invention accordingly provides the compounds of the formula (I):
wherein:
Het represents a heterocyclic residue selected from:
where the dotted line in (b) represents an optional double bond;
A completes a fused pyridine ring;
B completes a fused benzene or pyridine ring;
X represents an oxygen atom, a sulfur atom, two hydrogen atoms, ═NH or ═N(C
1-6
alkyl);
Y is a straight or branched C
1-4
alkylene chain optionally substituted by halogen, oxo or hydroxy; or Y represents a straight or branched C
2-4
alkenylene or C
2-4
alkynylene chain;
Z represents CR
5
R
6
or NR
7
so as to complete a piperidine or piperazine ring;
R
1a
and R
1b
each independently represent hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
1-6
alkoxy, fluoroC
1-6
alkyl, fluoroC
1-6
alkoxy, halogen, cyano, NR
a
R
b
, SR
a
, SOR
a
, SO
2
R
a
, OSO
2
R
a
, NR
a
COR
b
, COR
a
, CO
2
R
a
or CONR
a
R
b
;
R
2
represents hydrogen, C
1-6
alkyl, fluoroC
1-6
alkyl, (CH
2
)
m
COR
a
, (CH
2
)
p
CO
2
R
a
, (CH
2
)
p
OH, (CH
2
)
m
CONR
a
R
b
, (CH
2
)
m
phenyl or SO
2
C
1-6
alkyl;
R
3
represents phenyl, biphenyl, naphthyl or heteroaryl, wherein said phenyl, biphenyl, naphthyl or heteroaryl group may be optionally substituted by one, two or three groups independently selected from halogen, C
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkyl, fluoroC
1-6
alkoxy, NO
2
, cyano, SR
a
, SOR
a
, SO
2
R
a
, COR
a
, CO
2
R
a
, CONR
a
R
b
, C
2-6
alkenyl, C
2-6
alkynyl, C
1-4
alkoxyC
1-4
alkyl or —O(CH
2
)
1-2
O—;
R
4
represents hydrogen, C
1-6
alkyl, carbonyl (═O), (Ch
2
)
p
phenyl or a C
1-2
alkylene bridge across the piperidine or piperazine ring;
R
5
and R
6
each independently represent hydrogen, halogen, C
1-6
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, C
2-6
alkenyl, cyano, naphthyl, fluorenyl, (CH
2
)
m
phenyl, (CH
2
)
m
heteroaryl, CH(phenyl)
2
, CH(C
1-6
alkyl)(phenyl), C(C
1-6
alkyl)(phenyl)
2
, CO(phenyl), C(OH)(phenyl)
2
, C
2-4
alkenyl(phenyl), (CH
2
)
m
NR
c
R
d
, (CH
2
)
p
CONR
c
R
d
, (CH
2
)
p
NR
a
COR
b
, (CH
2
)
m
COR
c
, (CH
2
)
m
CO
2
R
c
or (CH
2
)
m
OH wherein said phenyl, naphthyl, fluorenyl or heteroaryl groups may be optionally substituted by one, two or three groups independently selected from halogen, C
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkyl, fluoroC
1-6
alkoxy, NO
2
, cyano, SR
a
, SOR
a
, SO
2
R
a
, COR
a
, CO
2
R
a
, CONR
a
R
b
, C
2-6
alkenyl, C
2-6
alkynyl, C
1-4
alkoxyC
1-4
alkyl or —O(CH
2
)
1-2
O—; or R
5
and R
6
together are linked so as to form a 5- or 6-membered ring optionally substituted by ═O, ═S or a C
1-4
alkyl or hydroxy group, and optionally containing a double bond, which ring may optionally contain in the ring one or two heteroatoms selected from O and S, or groups selected from NR
c
, SO or SO
2
, and to which ring there is either fused or attached a benzene or thiophene ring, which benzene or thiophene ring is optionally substituted by 1, 2 or 3 substituents selected from C
1-6
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, phenylC
1-4
alkyl, trifluoromethyl, cyano, OR
a
, SR
a
, SOR
a
, SO
2
R
a
, NR
a
R
b
, NR
a
COR
b
, NR
a
CO
2
R
b
, NR
a
SO
2
R
b
, COR
a
, CO
2
R
a
or CONR
a
R
b
, wherein the phenyl moiety of a phenylC
1-4
alkyl group may be substituted by C
1-6
alkyl, C
1-6
alkoxy, halogen or trifluoromethyl;
R
7
represents C
1-6
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, C
2-6
alkenyl, (CH
2
)
m
phenyl, naphthyl, fluorenyl, (CH
2
)
m
heteroaryl, CH(phenyl)
2
, CH(C
1-6
alkyl)(phenyl), C
2-4
alkenyl(phenyl), (CH
2
)
p
NR
c
R
d
, (CH
2
)
m
CONR
c
R
d
, (CH
2
)
m
COR
c
, (CH
2
)
m
CO
2
R
c
or (CH
2
)
p
OH, where said phenyl, naphthyl, fluorenyl or heteroaryl groups may be optionally substituted by one, two or three groups independently selected from halogen, C
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkyl, fluoroC
1-6
alkoxy, NO
2
, cyano, SR
a
, SOR
a
, SO
2
R
a
, COR
a
, CO
2
R
a
, CONR
a
R
b
, C
2-6
alkenyl, C
2-6
alkynyl, C
1-4
alkoxyC
1-4
alkyl or —O(CH
2
)
1-2
O—;
R
a
and R
b
each independently represents hydrogen, C
1-4
alkyl, fluoroC
1-4
alkyl or phenyl; or the group —NR
a
R
b
may form a 5- or 6-membered ring optionally substituted by ═O, ═S or a C
1-4
alkyl or hydroxy group, and optionally containing a double bond, which ring may optionally contain in the ring one or two heteroatoms selected from O and S, or groups selected from NR
c
, SO or SO
2
;
R
c
and R
d
each independently represents hydrogen, C
1-4
alkyl, fluoroC
1-4
alkyl, C
2-4
alkenyl, COR
a
, SO
2
R
a
, phenyl or benzyl or R
c
and R
d
, together with the nitrogen atom to which they are attached, form a heteroaliphatic ring of 4 to 7 atoms, to which ring there may optionally be fused a benzene ring;
m is zero or an integer from 1 to 4;
p is an integer from 1 to 4;
or a pharmaceutically acceptable salt thereof.
In the heterocyclic residues (a)-(e) represented by “Het”, pyridine rings completed by A or B may be fused to the 5-membered rings in any of the possible orientations. Thus, for example, (a) may represent a pyrrolo[2,3-b]pyridine system, a pyrrolo[2,3-C]pyridine system, a pyrrolo[3,2-c]pyridine system, or a pyrrolo[3,2-b]pyridine system.
In a subgroup of the compounds of formula I, B completes a fused benzene ring.
In another subgroup of the compounds of formula I, when Het represents (b), a double bond is present in the position indicated by the dotted line.
A preferred group of compounds of formula I is that wherein R
1a
and R
1b
each independently represent hydrogen, halogen, C
1-6
alkyl, C
2-6
alkenyl, fluoroC
1-6
alkoxy, NR
a
R
b
, COR
a
, CO
2
R
a
, or heteroaryl. When R
1a
and R
1b
are both other than hydrogen, preferably R
1a
and R
1b
are the same. When R
1a
is other than hydrogen and R
1b
is hydrogen, R
1a
is preferably attached to the 5-position when Het represents (a) or (e), to the 5- or 6-position when Het represents (b) or (d), and to the 6-position when Het represents (c).
A particularly preferred group of compounds of formula (I) is that wherein R
1a
and R
1b
each independently represent hydrogen, methyl, vinyl, trifluoromethoxy, fluorine, chlorine, bromine, pyrrolidinyl, piperidinyl, morpholino, acetyl, methoxycarbonyl, pyridyl (especially 3-pyridyl) or furyl (especially 2-furyl).
An especially preferred group of compounds of formula (I) is that wherein R
1a
represents methyl or chloro, and R
1b
is hydrogen.
A subclass of compounds of formula (I) is that wherein Het represents (a) or (e). Within this subclass, a preferred group of compounds is that wherein R
2
represents hydrogen, C
1-6
alkyl, fluoroC
1-6
alkyl, (CH
2
)
m
COR
a
, (CH
2
)
p
COR
a
, (CH
2
)
p
OH or (CH
2
)
m
phenyl. More preferably, R
2
represents C
1-3
alkyl (especially methyl, ethyl or isopropyl), fluoroC
1-3
alkyl (especially trifluoromethyl or 2,2,2-trifluoroethyl), COCH
3
, CH
2
CO
2
H, CH
2
CO
2
CH
3
, (CH
2
)
1-2
OH (especially CH
2
CH
2
OH) or benzyl. An especially preferred group of compounds within this subclass is that wherein R
2
is hydrogen or methyl.
Another preferred group of compounds of formula (I) is that wherein R
3
represents phenyl, biphenyl, naphthyl (especially 2-naphthyl) or heteroaryl (especially 2- or 3-pyridyl) wherein said phenyl, biphenyl, naphthyl or heteroaryl group is optionally substituted by one or two groups selected from halogen, C
1-6
alkyl, C
1-6
alkoxy, trifluoroC
1-6
alkyl, fluoroC
1-6
alkoxy or C
2-6
alkenyl.
A particularly preferred class of compounds of formula (I) is that wherein R
3
represents phenyl, biphenyl, naphthyl (especially 2-naphthyl) or heteroaryl (especially 2- or 3-pyridyl) wherein said phenyl, biphenyl, naphthyl or heteroaryl group is optionally substituted by one or two groups selected from fluorine, chlor

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