Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-09-04
2003-02-11
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254090, C514S414000, C514S241000, C514S242000, C514S252020, C514S252190, C514S253090, C514S254020, C514S254030, C514S254040, C514S254050, C544S363000, C544S373000, C544S180000, C544S182000, C544S238000, C544S295000, C544S357000, C544S364000, C544S366000, C544S367000, C544S369000, C544S370000, C548S453000
Reexamination Certificate
active
06518273
ABSTRACT:
This invention relates to indole derivatives and their use as tachykinin antagonists, and in particular as neurokinin-1 receptor antagonists.
We have now found a class of indole 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
R
1a
and R
1b
each independently represent hydrogen, C
1-6
alkyl, 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 or naphthyl, wherein said phenyl, biphenyl or naphthyl 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 or C
1-4
alkoxyC
1-4
alkyl;
R
4
represents hydrogen, C
1-6
alkyl, carbonyl (═O), (CH
2
)
p
phenyl or a C
1-2
alkylene bridge across the piperazine ring;
R
5
represents C
1-6
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, C
2-6
alkenyl, phenyl, naphthyl, fluorenyl, heteroaryl, (CH
2
)
p
phenyl, (CH
2
)
p
heteroaryl, CH(phenyl)
2
, CH(C
1-6
alkyl)(phenyl), C
2-4
alkenyl(phenyl), (CH
2
)
p
NR
c
R
d
, (CH
2
)
p
CONR
c
R
d
, (CH
2
)
m
COR
c
, (CH
2
)
m
CO
2
R
c
or (CH
2
)
p
OH;
R
a
and R
b
each independently represent hydrogen, C
1-4
alkyl or fluoroC
1-4
alkyl;
R
c
and R
d
each independently represent hydrogen, C
1-4
alkyl, fluoroC
1-4
alkyl, C
2-4
alkenyl, 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, and 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—;
X represents an oxygen or a sulfur atom;
m is zero or an integer from 1 to 4;
n is an integer from 1 to 4;
p is an integer from 1 to 4;
or a pharmaceutically acceptable salt thereof.
A preferred group of compounds of formula (I) is that wherein R
1a
and R
1b
each independently represent hydrogen, C
1-6
aLkyl, fluoroC
1-6
alkoxy or halogen. Where R
1a
and R
1b
are both other than hydrogen, preferably R
1a
and R
1b
are the same. Where R
1a
is other than hydrogen and R
1b
is hydrogen, R
1a
is preferably attached to the indole ring at the 5-position.
A particularly preferred group of compounds of formula (I) is that wherein R
1a
and R
1b
each independently represent hydrogen, methyl, trifluoromethoxy, fluorine or chlorine.
As especially preferred group of compounds of formula (I) is that wherein R
1a
represents 5-methyl or 5-chloro, and R
1b
is hydrogen.
A further preferred group of compounds of formula (I) 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.
A particularly preferred group of compounds of formula (I) is that wherein 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 of formula (I) 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 or naphthyl (especially 2-naphthyl) wherein said phenyl 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 or naphthyl (especially 2-naphthyl) wherein said phenyl group is optionally substituted by one or two groups selected from chlorine, bromine, C
1-4
alkyl (especially isopropyl or tertiary butyl), methoxy, trifluoromethyl, trifluoromethoxy or vinyl.
An especially preferred group of compounds of formula (I) is that wherein R
3
represents phenyl optionally substituted by one or two groups selected from chlorine, bromine, C
1-4
alkyl (especially isopropyl or tertiary butyl), methoxy, trifluoromethyl, trifluoromethoxy or vinyl.
A further preferred group of compounds of formula (I) is that wherein R
4
represents hydrogen, methyl, carbonyl, benzyl or a methylene bridge across the 2,5-positions on the piperazine ring.
As especially preferred group of compounds of formula (I) is that wherein R
4
is hydrogen.
Another preferred group of compounds of formula (I) is that wherein R
5
represents C
1-6
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, C
2-6
alkenyl, phenyl, naphthyl, fluorenyl, heteroaryl, (CH
2
)
p
phenyl, (CH
2
)
p
heteroaryl, CH(phenyl)
2
, CH(C
1-6
alkyl)(phenyl), C
2-4
alkenyl(phenyl), (CH
2
)
p
NR
c
R
d
, (CH
2
)
p
CONRCR
d
, (CH
2
)
m
COR
c
or (CH
2
)
m
CO
2
R
c
wherein said phenyl or heteroaryl group is optionally substituted by one or two substituents selected from halogen, C
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkyl, fluoroC
1-6
alkoxy, NO
2
, cyano, SR
a
or —O(CH
2
)
1-2
O—.
A particularly preferred group of compounds of formula (I) is that wherein R
5
represents C
3-6
alkyl (especially propyl, isopropyl or isopentyl), C
5-7
cycloalkyl (especially cyclohexyl), C
3-7
cycloalkylC
1-2
alkyl (especially cyclopropylmethyl, cyclohexylmethyl or 2-cyclohexylethyl), C
2-4
alkenyl (especially vinyl), phenyl, naphthyl (especially 1-naphthyl), fluorenyl (especially 9-fluorenyl), heteroaryl, (CH
2
)
p
phenyl (especially wherein p is 1 or 2), (CH
2
)
p
heteroaryl (especially wherein p is 1), CH(phenyl)
2
, CH(C
1-2
alkyl)(phenyl), C
2-4
alkenyl(phenyl) (especially CH
2
—CH═CHphenyl), (CH
2
)
p
NR
c
R
d
(especially where R
c
and R
d
each represent C
2-4
alkenyl; and especially wherein p is 2), (CH
2
)
p
CONR
c
R
d
(especially wherein R
c
and R
d
each independently represent hydrogen, C
1-4
alkyl, C
2-4
alkenyl, phenyl or benzyl or R
c
and R
d
, together with the nitrogen atom to which they are attached, form a heteroaliphatic ring of 5 or 6 atoms to which ring there is fused a benzene ring; and especially wherein p is 1), (CH
2
)
m
COR
c
(especially wherein R
c
represents phenyl; and especially wherein m is zero) or (CH
2
)
m
CO
2
R
c
(especially wherein R
c
represents hydrogen or C
1-4
alkyl; and especially wherein m is zero or 1), wherein said phenyl or heteroaryl groups may be substituted by one or two groups independently selected from halogen, C
1-4
alkyl, C
1-4
alkoxy, fluoroC
1-4
alkyl, fluoroC
1-4
alkoxy, NO
2
, cyano and SR
a
(especially wherein R
a
represents C
1-4
alkyl), or said phenyl or heteroaryl group may be substituted by the group —O(CH
2
)
1-2
O—. Particularly preferred are compounds in which said phenyl groups are unsubstituted or substituted by one or two substituents independently selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, nitro, cyano and thiomethyl, or said phenyl is substituted by —OCH
2
O—. Also preferred are compounds in which said heteroaryl groups are unsubstituted or are monosubstituted by methyl or trifluoromethyl.
Another preferred group of compounds of formula (I) is that wherein X represents an oxygen atom.
A further preferred group of compounds of formula (I) is that wherein n is 2, 3 or 4, and especially wherein n is 2.
When any variable occurs more than one time in formula (I) or in any substituent, its definition on each occurrence i
Chapman Kevin Tyler
Dinnell Kevin
Elliott Jason Matthew
Hollingworth Gregory John
Hutchins Steven Michael
Bernhardt Emily
Merck Sharp & Dohme Ltd.
Thies J. Eric
Winokur Melvin
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