Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-01
2003-04-29
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S133000, C546S223000, C546S124000, C546S304000, C514S305000, C514S329000
Reexamination Certificate
active
06555552
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. §119 from GB Application No. 0108971.3, filed Apr. 10, 2001.
The present invention provides compounds of the formula (I):
wherein
X represents hydrogen or a C
1-4
alkyl group optionally substituted by a hydroxy group;
Y represents hydrogen, C
1-6
alkyl or C
3-7
cycloalkyl;
Z is —CR
9
R
10
CH
2
—or —CH
2
CR
9
R
10—;
R represents hydrogen, fluorine, hydroxy, Cl6alkyl or C
1-6
alkoxy;
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 R2 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
represents 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
COR12, 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
1-4
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 —W—NR
7
R
8
where
W 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 NRC 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 W, 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
R12, 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 X is hydrogen, methyl or hydroxymethyl, in particular, hydrogen.
Another preferred class of compound of formula (I) is that wherein Y is hydrogen or C
1-4
alkyl, in particular, hydrogen or methyl, especially hydrogen.
A further preferred class of compounds of formula (I) is that wherein R represents hydrogen or fluorine.
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 especially, R3 is trifluoromethoxy or 5-(trifluoromethyl)tetrazol-1-yl.
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 rin
Kulagowski Janusz Jozef
Raubo Piotr Antoni
Thomson Christopher George
Brown Baerbel R.
McKane Joseph K.
Merck Sharp & Dohme Ltd.
Shiao Rei-Tsang
Thies J. Eric
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