Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-22
2001-01-09
Aulakh, Charanjit 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
06172077
ABSTRACT:
This invention relates to a class of azacyclic compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are spiro-substituted azacyclic derivatives.
International (PCT) patent specification no. WO 94/20500 (published Sep. 15, 1994) discloses spiroazacyclic derivatives as substance P antagonists. In particular, WO 94/20500 relates to spirocyclic piperdine derivatives containing a 1,8-diazaspiro[5.5]undecane core.
We have now found a further class of non-peptides which are potent antagonists of tachykinins, especially of substance P. In addition, the compounds of the present invention exhibit a high level of hepatic stability as measured by, for example, conventional liver microsome analysis.
The present invention provides compounds of the formula (I):
wherein
X represents —CH
2
, —CH
2
CH
2
— or —CH
2
CH
2
CH
2
—;
Y represents —CH
2
— or —CH
2
CH
2
—, with the proviso that the sum total of carbon atoms in X and Y is 2or 3;
R
1
represents halogen, hydroxy, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylthio, C
1-6
alkoxyC
1-4
alkyl, fluoroC
1-6
alkyl, fluoroC
1-6
alkoxy, fluoroC
1-6
alkylthio, fluoroC
1-6
alkoxyC
1-4
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, C
2-6
alkenyloxy, cyano, phenoxy, benzyloxy, NR
a
R
b
, SR
a
, SOR
a
, SO
2
R
a
, or OSO
2
R
a
, 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 oxygen atoms;
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 each independently hydrogen or C
1-4
alkyl 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
, 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, C
1-6
alkoxy substituted by C
1-4
alkoxy or CF
3 ;
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
d
, oxo, CO
2
R
a
or CONR
a
R
b
where R
a
and R
b
are as previously defined and R
d
represents hydrogen, C
1-6
alkyl or phenyl;
R
12
represents OR
a
, CONR
a
R
b
or heteroaryl;
R
13
represents H or C
1-6
alkyl;
p is zero or 1; and
q is 1 or 2;
and pharmaceutically acceptable salts thereof.
A preferred class of compound of formula (I) is that wherein R
1
is a C
1-4
alkoxy, fluoroC
1-4
alkoxy or C
3-5
cycloalkoxy group.
A particularly preferred class of compound of formula (I) is that wherein R
1
is a methoxy, isopropoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2-fluoroethoxy, cyclopropoxy or cyclobutoxy, group, especially a methoxy or cyclopropoxy group.
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
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.
Also preferred is the class of compound of formula (I) in which R
9
and R
10
are both hydrogen atoms.
A further preferred class of compound of formula (I) is that wherein R
6
is a hydrogen atom.
Also preferred is the class of compound of formula (I) in which R
6
is a C
1-6
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:
Particularly preferred heterocyclic rings are selected from:
A particularly preferred heterocyclic ring is:
Where R
1
and R
2
are attached to adjacent carbon atoms and are joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two oxygen atoms, there is formed a fused ring moiety such as 2,3-dihydrobenzofuran, benzofuran, 3,4-dihydro-2H-1-benzopyran, 2H-1-benzopyran, 1,3-benzodioxole or 1,4-benzodioxan. Particularly preferred is 2,3-dihydrobenzofuran where the oxygen atom corresponds to the position of R
1
.
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 of compound of formula (I) is that wherein R
3
is the group
where R
11
is hydrogen, halogen, C
1-6
alkyl, C
1-6
alkoxy, CF
3
, OCF
3
, NO
2
, CN, SR
a
,
Curtis Neil Roy
Elliott Jason Matthew
Hollingworth Gregory John
Jackson Philip Stephen
Kulagowski Janusz Jozef
Aulakh Charanjit S.
Merck Sharp & Dohme Ltd.
Rose David L.
Thies J. Eric
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