Spirocyclic ketones and their use as tachykinin antagonists

Details Spirocyclic ketones and their use as tachykinin antagonists Spirocyclic ketones and their use as tachykinin antagonists

2001-08-08

2002-04-16

Aulakh, Charandit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S016000

Reexamination Certificate

active

06372754

ABSTRACT:

This invention relates to a class of spirocyclic ketone compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are 3-spiro-cyclopentanone piperidine derivatives.
International (PCT) patent specification no. WO 97/49710 (published Dec. 31st, 1997) discloses spiro-piperidine derivatives as substance P antagonists. In particular, WO 97/49710 relates to spirocyclic piperidine derivatives containing a 1-oxa-7-aza-spiro[4.5]decane core.
We have now found a further class of non-peptides which are potent antagonists of tachykinins, especially of the neurokinin-1 (substance P) receptor.
The present invention provides compounds of the formula (I):
wherein
R
1
represents hydroxy, C
1-6
alkyl, fluoroC
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, C
1-6
alkoxyC
1-4
alkyl, C
1-6
aralkoxyC
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, cyano, halogen, NR
a
R
b
, SR
a
, SOR
a
, SO
2
R
a
, OSO
2
R
a
, NR
a
COR
14
, 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 and sulphur, which ring is optionally substituted by a group selected from C
1-4
alkyl, CF
3
, ═O or ═S;
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
14
, 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, 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
12
, CONR
13
C
2-6
alkenyl, CONR
13
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 ZNR
7
R
8
where
Z is C
1-6
alkylene or C
3-6
cycloalkyl;
R
7
is 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
is 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, hydroxyl 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 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 optionally substituted by hydroxy or C
1-4
alkoxy;
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 Z, 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
and R
10
each independently represent hydrogen, halogen, C
1-6
alkyl, CH
2
OR
e
, oxo, CO
2
R
a
or CONR
a
R
b
where R
a
and R
b
are as previously defined and Re represents hydrogen, C
1-6
alkyl or phenyl;
R
12
represents OR
a
, CONR
a
R
b
or heteroaryl;
R
13
represents hydrogen or C
1-6
alkyl; and
R
14
represents C
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkyl or phenyl;
and pharmaceutically acceptable salts thereof.
According to a first aspect of the present invention, phenyl ring A is preferably a 2,5-disubstituted phenyl ring.
According to a second alternative aspect of the present invention, phenyl ring A is preferably a 3,5-disubstituted phenyl ring.
A preferred class of compound of formula (I) is that wherein R
1
is hydroxy, C
1-6
alkyl, fluoroC
1-6
alkyl, C
2-6
alkenyl, C
1-6
alkoxy, fluoroC
1-6
alkoxy, C
2-6
alkeny oxy, C
3-7
cycloalkoxy, C
3-7
cycloalkylC
1-4
alkoxy, cyano, NR
a
R
b
, SR
a
, OSO
2
R
a
, or R
1
together with the group R
2
form a 5-membered saturated ring containing one oxygen atom.
A particularly preferred class of compound of formula (I) is that wherein R
1
is C
1-6
alkyl, fluoroC
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkoxy, C
3-7
cycloalkoxy or C
3-7
cycloalkoxyC
1-4
alkyl, especially methyl, trifluoromethyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, cyclopropoxy or cyclopropylmethoxy.
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 hydrogen, halogen, fluoroC
1-6
alkyl, fluoroC
1-6
alkoxy, cyano, NR
a
R
b
, NR
a
COR
14
(where R
14
is preferably methyl, methoxy, trifluoromethyl or phenyl), or a 5-membered aromatic heterocyclic group as previously defined.
Also preferred is the class of compound of formula (I) in which R
3
is C
1-6
alkyl, fluoroC
1-6
alkyl, fluoroC
1-6
alkoxy or a 5-membered aromatic heterocyclic group as previously defined, especially methyl, trifluoromethyl, trifluoromethoxy or 5-trifluoromethyl-1,2,3,4-tetrazol-1-yl.
Certain particularly apt compounds of the present invention include those wherein R
3
is a group selected from pyrrole, furan, thiene, pyridine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, triazine, and tetrazole, each heteroaryl group being optionally substituted as previously defined.
Preferred compounds of the present invention are those wherein R
3
is a group selected from furan, pyridine, pyrazole, imidazole, oxazole, isoxazole, pyrazine, pyrimidine, thiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and tetrazole, each heteroaryl group being optionally substituted as previously defined.
Particularly preferred compounds of the present invention are those wherein R
3
is a group selected from furan, pyridine, pyrimidine, 1,2,3-triazole, 1,2,4-triazole and tetrazole, each heteroaryl group being optionally substituted as previously defined.
An especially preferred class o

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