Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-01
2004-04-27
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S323000, C514S252180, C514S318000, C544S362000, C544S323000, C546S183000
Reexamination Certificate
active
06727249
ABSTRACT:
This invention relates to a class of azabicyclic compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are substituted benzylether derivatives of 1-phenyl-8-azabicyclo[3.2.1]octane, which are useful as neurokinin 1 (NK-1) receptor antagonists.
The present invention provides compounds of the formula (I):
wherein
X represents hydrogen, C
1-4
alkyl optionally substituted by a hydroxy, methoxy or benzyloxy group, or CO
2
(C
1-2
alkyl);
Z is —CR
9
R
10
CH
2
— or —CH
2
CR
9
R
10
—;
R
1
is hydrogen, halogen, C
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkyl, fluoroC
1-6
alkoxy, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, NO
2
, CN, SR
a
, SOR
a
, SO
2
R
a
, CO
2
R
a
, CONR
a
R
b
, C
2-6
alkenyl, C
2-6
alkynyl or C
1-4
alkyl substituted by C
1-4
alkoxy, wherein R
a
and R
b
each independently represent hydrogen or C
1-4
alkyl;
R
2
is hydrogen, halogen, C
1-6
alkyl, fluoroC
1-6
alkyl or C
1-6
alkoxy substituted by C
1-4
alkoxy;
R
3
is hydrogen, halogen or fluoroC
1-6
alkyl;
R
4
represents hydrogen, halogen, C
1-6
alkyl, C
1-6
alkoxy, CF
3
, OCF
3
, NO
2
, CN, SR
a
, SOR
a
, SO
2
R
a
, CO
2
R
a
, CONR
a
R
b
, C
2-6
alkenyl, C
2-6
alkynyl or C
1-4
alkyl substituted by C
1-4
alkoxy, where R
a
and R
b
are as previously defined;
R
5
represents hydrogen, halogen, C
1-6
alkyl, CF
3
or C
1-6
alkoxy substituted by C
1-4
alkoxy;
R
6
represents hydrogen, hydroxy, COR
a
, CO
2
R
a
, COCONR
a
R
b
, COCO
2
R
a
, C
1-6
alkyl, C
2-6
alkenyl, or C
1-6
alkyl substituted by a group selected from CO
2
R
a
, CONR
a
R
b
, hydroxy, CN, COR
a
, NR
a
R
b
, C(NOH)NR
a
R
b
, CONHphenyl(C
1-4
alkyl), COCO
2
R
a
, CONHNR
a
R
b
, C(S)NR
a
R
b
, CONR
a
C
1-6
alkylR
14
, CONR
11
C
2-6
alkenyl, CONR
11
C
2-6
alkynyl, COCONR
a
R
b
, CONR
a
C(NR
b
)NR
a
R
b
, CONR
a
heteroaryl, and phenyl optionally substituted by one, two or three substituents selected from C
1-6
alkyl, C
1-6
alkoxy, halogen and trifluoromethyl;
or R
6
represents a group of the formula —CH
2
C≡CCH
2
NR
7
R
8
where R
7
and R
8
are as defined below;
or R
6
represents C
1-6
alkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms optionally substituted by ═O or ═S and optionally substituted by a group of the formula —Y—NR
7
R
8
where
Y is C
1-6
alkylene or C
3-6
cycloalkyl;
R
7
represents hydrogen or C
1-4
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, or C
2-4
alkyl substituted by C
1-4
alkoxy or hydroxyl;
R
8
represents hydrogen or C
1-6
alkyl, C
1-6
alkoxy, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, phenyl or C
1-4
alkyl substituted by a group selected from C
1-4
alkoxy, hydroxyl, CO
2
R
a
, NR
a
R
b
, aryl, aryloxy, heteroaryl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R
7
, R
8
and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from methyl, hydroxy, CO
2
(C
1-2
alkyl), phenyl, benzyl or C
1-4
alkoxy optionally substituted by a C
1-4
alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)
2
or a second nitrogen atom which will be part of a NH or NR
c
moiety where R
c
is C
1-4
alkyl, hydroxyC
1-4
alkyl, C
1-4
alkoxyC
1-4
alkyl, phenyl or benzyl;
or R
7
, R
8
and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Y, R
7
and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R
9
represents hydrogen, hydroxy, oxo, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, fluoroC
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkoxy, hydroxyC
1-6
alkyl, C
1-6
alkoxyC
1-4
alkyl, C
1-6
alkoxyC
1-4
alkoxy, fluoroC
1-6
alkoxyC
1-4
alkyl, C
2-6
alkenyloxy, C
2-6
alkynyloxy, C
3-7
cycloalkoxy, C
3-7
cycloalkylC
1-4
alkoxy, aryl, aryl(CH
2
), aryloxy, aryl(CH
2
)oxy, cyano, halogen, NR
7
R
8
, CH
2
NR
7
R
8
, SR
12
, SOR
12
, SO
2
R
12
, OSO
2
R
12
, NR
a
COR
12
, CH(OH)R
12
, COR
12
, CO
2
R
12
, CONR
7
R
8
, CONHNH
2
, CH
2
OR
13
, heteroaryl or heteroarylC
1-4
alkyl, wherein R
a
is as previously defined;
R
10
represents hydrogen, halogen or hydroxy;
R
11
represents hydrogen or C
1-6
alkyl;
R
12
represents hydrogen, C
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkyl or phenyl optionally substituted by one, two or three substituents selected from C
1-6
alkyl, C
1-6
alkoxy, halogen or trifluoromethyl;
R
13
represents C
1-4
alkyl substituted by a group selected from hydroxy, COR
a
, CO
2
R
a
, CONR
a
R
b
and heteroaryl, where R
a
is as previously defined;
R
14
represents OR
a
, CONR
a
R
b
or heteroaryl;
and pharmaceutically acceptable salts or N-oxides thereof.
A preferred class of compound of formula (I) is that wherein X is hydrogen, methyl or hydroxymethyl.
Another preferred class of compound of formula (I) is that wherein R
1
is hydrogen, C
1-4
alkyl, C
1-4
alkoxy, halogen or CF
3
.
Another preferred class of compounds of formula (I) is that wherein R
2
is hydrogen, C
1-4
alkyl, C
1-4
alkoxy, halogen or CF
3
.
Also preferred is the class of compounds of formula (I) wherein R
3
is hydrogen, fluorine, chlorine or CF
3
.
A particularly preferred class of compounds of formula (I) is that wherein R
1
is fluorine, chlorine or CF
3
.
Another particularly preferred class of compounds of formula (I) is that wherein R
2
is hydrogen, fluorine, chlorine or CF
3
.
Also particularly preferred is the class of compounds of formula (I) wherein R
3
is hydrogen, fluorine, chlorine or CF
3
.
Preferably R
1
and R
2
are in the 3 and 5 positions of the phenyl ring.
More preferably R
1
is 3-fluoro or 3-CF
3
.
More preferably R
2
is 5-fluoro or 5-CF
3
.
More preferably R
3
is hydrogen.
Most preferably R
1
is 3-F or 3-CF
3
, R
2
is 5-CF
3
and R
3
is hydrogen.
A further preferred class of compound of formula (I) is that wherein R
4
is a hydrogen atom or a fluorine atom.
Another preferred class of compound of formula (I) is that in which R
5
is a hydrogen atom.
A further preferred class of compound of formula (I) is that wherein R
6
is a hydrogen atom or a C
1-6
alkyl group (especially methyl) or a C
1-3
alkyl group, in particular CH
2
, CH(CH
3
) and CH
2
CH
2
and especially CH
2
, substituted by a 5-membered heterocyclic ring containing 2 or 3 nitrogen atoms as previously defined.
In particular, the 5-membered ring is a heterocyclic ring selected from 1,3-imidazol-4-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl, 2-oxo-1,3-imidazol-4-yl and 3-oxo-1,2,4-triazol-5-yl, any of which rings being optionally substituted by the group —Y—NR
7
R
8
.
Particularly preferred heterocyclic rings are selected from:
Most especially, the 5-membered heterocyclic ring is a 1,2,4-triazol-3-yl or 3-oxo-1,2,4-triazol-5-yl group.
Another preferred class of compound of formula (I) is that wherein R
9
represents hydrogen, hydroxy, oxo, C
1-6
alkoxy, C
1-6
alkoxyC
1-4
alkyl, hydroxyC
1-4
alkyl, cyano, NR
7
R
8
, CH
2
NR
7
R
8
, SO
2
R
d
, CH(OH)R
12
, COR
12
, CO
2
R
12
, CONR
7
R
8
, phenyl, heteroaryl, heteroarylC
1-4
alkyl or CH
2
OR
13
, where said phenyl is optionally substituted by one or two substituents selected from C
1-4
alkyl, C
1-4
alkoxy, halogen or trifluoromethyl.
A further preferred class of compound of formula (I) is that wherein R
9
represents hydrogen, hydroxy, C
1-4
alkoxyC
1-2
alkyl (especially methoxymethyl), hydroxyC
1-2
alkyl (especially hydroxymethyl), cyano, CH
2
NR
7
R
8
, SO
2
R
12
(especially where R
12
is phenyl), CH(OH)R
12
(especially where R
12
is phenyl), COR
12
(especially where R
12
is phenyl), CO
2
R
12
(especially where R
12
is C
1-2
alkyl, e.g. methyl), CONR
7
R
8
, heteroaryl, or CH
2
OR
13
.
When the group R
9
represents NR
7
R
8
, CH
2
NR
7
R
8
or CONR
7
R
8
, R
7
is preferably hydrogen, or C
1-4
alkyl (especially methy
Curtis Neil Roy
Huscroft Ian Thomas
Kulagowski Janusz Jozef
Raubo Piotr Antoni
Merck Sharp & Dohme Ltd.
Robinson Kinta
Thies J. Eric
Winokur Melvin
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