Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-18
2001-05-01
Rotman, Alan L. (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
06225320
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. 371 from PCT/GB98/01541, filed May 27, 1998, which claims priority from Great Britain Application No. 9711114.0, filed May 29, 1997.
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 piperidine 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.
The present invention provides compounds of the formula (I):
wherein
ring A represents a 6-membered aromatic heterocyclic group containing one, two or three nitrogen atoms;
X represents —CH
2
— or —CH
2
CH
2
—;
Y represents —CH
2
—, —CH
2
CH
2
—, —CH═ or —CH
2
CH═, with the proviso that the sum total of carbon atoms in X and Y is 2 or 3;
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, 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
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 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
, NR
a
SO
2
R
14
, or C
1-4
alkyl substitued by cyano or CO
2
R
a
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 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
, 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
each independently represent hydrogen or C
1-4
alkyl;
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
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;
R
14
represents C
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkyl or phenyl;
q is 1 or 2; and
when Y is —CH═ or —CH
2
CH═, the broken line represents a double bond;
and pharmaceutically acceptable salts thereof.
Preferably, R
1
is attached to a carbon atom in ring A that is adjacent to the point of attachment of ring A to the remainder of the molecule.
Preferably R
3
is attached to a carbon atom in ring A that is two atoms away from the point of attachment of ring A to the remainder of the molecule and, where a susbtituents R
1
is present, R
3
is preferably not adjacent to R
1
.
R
2
, where present, is attached to any available carbon atom.
Suitable aromatic heterocyclic groups represented by ring A include pyridine, pyridazine, pyrimidine, pyrazine and 1,3,5-triazine.
Preferred compounds of the present invention are those wherein the ring A is a 6-membered aromatic heterocyclic group containing one or two nitrogen atoms, especially a pyridyl group.
Particularly preferred compounds of the present invention are those wherein the ring A is a 2,3,5- or 2,3,6-trisubstituted pyridine ring.
A preferred class of compound of formula (I) is that wherein R
1
is hydrogen, C
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkoxy, C
3-7
cycloalkoxy, halogen or NR
a
R
b
; in particular a hydrogen atom or a methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, cyclopropoxy or cyclobutoxy group; and especially a hydrogen atom or a methoxy or cyclopropoxy group.
Another preferred class of compound of formula (I) is that wherein R
2
is a hydrogen atom.
Also preferred is the class of compound of formula (I) in which R
3
is halogen, C
1-6
alkyl, fluoroC
1-6
alkyl, C
1-6
alkoxy, fluoroC
1-6
alkoxy, cyano or a 5-membered aromatic heterocyclic group as previously defined.
Particularly preferred is the class of compound of formula (I) in which R
3
is halogen or fluoroC
1-6
alkoxy, especially fluorine, trifluoromethoxy or 2,2,2-trifluoroethoxy, or a 5-membered aromatic heterocyclic group as previously defined.
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
Kulagowski Janusz Jozef
Raubo Piotr Antoni
Swain Christopher John
Thomson Christopher George
Desai Rita
Merck Sharp & Dohme Ltd.
Rose David L.
Rotman Alan L.
Thies J. Eric
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