Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-01
2002-11-12
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S278000, C544S127000, C546S018000
Reexamination Certificate
active
06479486
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. §119 from GB Application No. 0108973.9, filed Apr. 10, 2001.
This invention relates to a class of azabicyclic compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are spiroether 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
Z is —CR
9
R
10
CH
2
— or —CH
2
CR
9
R
10
—;
R
1
represents hydrogen, hydroxy, C
1-6
alkyl, C
2-6
alkenyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
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
3-7
cycloalkoxy, C
3-7
cycloalkylC
1-4
alkoxy, phenoxy, benzyloxy, cyano, halogen, NR
a
R
b
, SR
a
, SOR
a
, SO
2
R
a
, OSO
2
R
a
, NR
a
COR
12
, COR
a
, CO
2
R
a
or CONR
a
R
b
where R
a
and R
b
each independently represent hydrogen, C
1-4
alkyl or fluoroC
1-4
alkyl;
R
2
represents hydrogen, halogen, C
1-6
alkyl or C
1-6
alkoxy;
or when R
2
is adjacent to R
1
, they may be joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two atoms selected from nitrogen, oxygen, sulphur, NH or NR
c
, which ring is optionally substituted by one, two or three groups selected from hydroxy, C
1-4
alkyl, C
1-3
alkoxyC
1-3
alkyl, fluoroC
1-4
alkyl, phenyl, ═O or ═S, where R
c
is C
1-4
alkyl, hydroxyC
1-4
alkyl, C
1-4
alkoxyC
1-4
alkyl, fluoroC
1-4
alkyl, phenyl or benzyl;
R
3
represents hydrogen, halogen, C
1-6
alkyl, fluoroC
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkoxy, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, cyano, SR
a
, SOR
a
, SO
2
R
a
, NR
a
R
b
, NR
a
COR
12
, COR
a
, CO
2
R
a
, CONR
a
R
b
or C
1-4
alkyl substituted by cyano, CO
2
R
a
or CONR
a
R
b
where R
a
and R
b
are as previously defined;
or R
3
represents a 5- or 6-membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which group is optionally substituted by one or two groups selected from C
1-6
alkyl, C
1-6
alkoxy, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, trifluoromethyl, OCF
3
, NO
2
, CN, SR
a
, SOR
a
, SO
2
R
a
, COR
a
, CO
2
R
a
, phenyl, —(CH
2
)
r
NR
a
R
b
, —(CH
2
)
r
NR
a
COR
b
, —(CH
2
)
r
CONR
a
R
b
, or CH
2
C(O)R
a
, where R
a
and R
b
are as previously defined and r is zero, 1 or 2;
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 optionally 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
1-4
alkyl, C
1-4
alkoxy, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, or C
2-4
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 hydroxy, 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 as previously defined;
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
, 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 R
1
is a C
1-6
alkoxy, fluoroC
1-6
alkoxy or C
3-7
cycloalkoxy group, or R
1
together with the group R
2
forms a 5-membered saturated ring containing one oxygen atom, which ring is optionally substituted by a methyl group.
A particularly preferred class of compound of formula (I) is that wherein R
1
is methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2-fluoroethoxy, cyclopropoxy or R
1
together with the group R
2
represents —OCH(CH
3
)CH
2
— or —N(CH
3
)C(O)C(CH
3
)
2
— to complete a 5-membered saturated ring, or —CH(OH)CH
2
OC(CH
3
)(CF
3
)—, —CH
2
CH
2
C(O)N(CH
3
)— or —CH(OH)CH
2
C(O)N(CH
3
)— to complete a 6-membered saturated ring. Most especially, R
1
is methoxy or cyclopropoxy.
Another preferred class of compound of formula (I) is that wherein R
2
is a hydrogen, fluorine or chlorine atom, especially a hydrogen atom.
A further preferred class of compound of formula (I) is that wherein R
3
is a hydrogen or halogen atom or a fluoroC
1-6
alkoxy group, especially fluorine, trifluoromethoxy or 2,2,2-trifluoroethoxy, or a 5-membered aromatic heterocyclic group as previously defined. Most preferably, R
3
is trifluoromethoxy or 5-(trifluoromethyl)tetrazol-1-yl, and especially trifluoromethoxy.
A particularly preferred class of compound of formula (I) is that wherein R
1
is attached at the 2-position of the phenyl ring and R
3
is attached at the 5-position of the phenyl ring.
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
Huscroft Ian Thomas
Kulagowski Janusz Jozef
Raubo Piotr Antoni
Merck Sharp & Dohme Ltd.
Powers Fiona T.
Theis J. Eric
Winokur Melvin
LandOfFree
Azabicyclic spiroether derivatives and their use as... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Azabicyclic spiroether derivatives and their use as..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Azabicyclic spiroether derivatives and their use as... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2962975