Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-04-17
2003-12-30
Aulakh, C. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S225000, C546S214000, C546S196000, C514S326000, C514S318000
Reexamination Certificate
active
06670379
ABSTRACT:
This application is a 371 of PCT/EP01/07941 filed Jul. 10, 2001, now WO 02/04420 Jan. 17, 2002.
This invention relates to organic compounds, their preparation and their use as pharmaceuticals.
In one aspect, the invention provides compounds of formula
in free or salt form, where
Ar
1
is phenyl substituted by one or more halogen atoms,
Ar
2
is phenyl or naphthyl which is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxy, nitro, C
1
-C
8
-alkyl, C
1
-C8-haloalkyl, C
1
-C
8
-alkoxy or C
1
-C
8
-alkoxycarbonyl,
R
1
is hydrogen or C
1
-C
8
-alkyl optionally substituted by hydroxy, C
1
-C
8
-alkoxy, acyloxy, —N(R
2
)R
3
, halogen, carboxy, C
1
-C
8
-alkoxycarbonyl, —CON(R
4
)R
5
or by a monovalent cyclic organic group,
R
2
and R
3
are each independently hydrogen or C
1
-C
8
-alkyl, or R
2
is hydrogen and R
3
is acyl or —SO
2
R
6
, or R
2
and R
3
together with the nitrogen atom to which they are attached denote a 5- or 6-membered heterocyclic group,
R
4
and R
5
are each independently hydrogen or C
1
-C
8
-alkyl, or R
4
and R
5
together with the nitrogen atom to which they are attached denote a 5- or 6-membered heterocyclic group,
R
6
is C
1
-C
8
-alkyl, C
1
-C
8
-haloalkyl, or phenyl optionally substituted by C
1
-C
8
-alkyl, and n is 1, 2,3 or 4,
with the proviso that when Ar
1
is p-chlorophenyl and R
1
is hydrogen, Ar
2
is not phenyl or p-nitrophenyl.
Terms used in the specification have the following meanings:
“C
1
-C
8
-alkyl” as used herein denotes straight chain or branched C
1
-C
8
-alkyl, which may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight or branched pentyl, straight or branched hexyl, straight or branched heptyl, or straight or branched octyl. Preferably, C
1
-C
8
-alkyl is C
1
-C
4
-alkyl.
“C
1
-C
8
-alkoxy” as used herein denotes straight chain or branched C
1
-C
8
-alkoxy which may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight or branched pentoxy, straight or branched hexyloxy, straight or branched heptyloxy, or straight or branched octyloxy. Preferably, C
1
-C
8
-alkoxy is C
1
-C
4
-alkoxy.
“C
1
-C
8
-haloalkyl” as used herein denotes C
1
-C
8
-alkyl as hereinbefore defined substituted by one or more halogen atoms, preferably one, two or three halogen atoms.
“Acyl” as used herein denotes alkylcarbonyl, for example C
1
-C
8
-alkylcarbonyl where C
1
-C
8
-alkyl may be one of the C
1
-C
8
-alkyl groups hereinbefore mentioned, optionally substituted by one or more halogen atoms; cycloalkylcarbonyl, for example C
3
-C
8
-cycloalkylcarbonyl where C
3
-C
8
-cycloalkyl may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; 5- or 6-membered heterocyclylcarbonyl having one or two hetero atoms selected from nitrogen, oxygen and sulfur in the ring, such as furylcarbonyl or pyridylcarbonyl; arylcarbonyl, for example C
6
-C
10
-arylcarbonyl such as benzoyl; or aralkylcarbonyl, for example C
6
to C
10
-aryl-C
1
-C
4
-alkylcarbonyl such as benzylcarbonyl or phenylethylcarbonyl. Preferably acyl is C
1
-C
4
-alkylcarbonyl.
“Acyloxy” as used herein denotes alkylcarbonyloxy, for example C
1
-C
8
-alkylcarbonyloxy where C
1
-C
8
-alkyl may be one of the C
1
-C
8
-alkyl groups hereinbefore mentioned, optionally substituted by one or more halogen atoms; cycloalkylcarbonyloxy, for example C
3
-C
8
-cycloalkylcarbonyloxy where C
3
-C8-cycloalkyl may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; 5- or 6-membered heterocyclylcarbonyloxy having one or two hetero atoms selected from nitrogen, oxygen and sulfur in the ring, such as furylcarbonyloxy or pyridylcarbonyloxy; arylcarbonyloxy, for example C
6
-C
10
-arylcarbonyloxy such as benzoyloxy; or aralkylcarbonyloxy, for example C
6
to C
10
-aryl-C
1
-C
4
-alkylcarbonyloxy such as benzylcarbonyloxy or phenylethylcarbonyloxy. Preferably acyloxy is C
1
-C
4
-alkylcarbonyloxy.
“Halogen” as used herein may be fluorine, chlorine, bromine or iodine; preferably it is fluorine, chlorine or bromine.
In Ar
1
, the phenyl group may be substituted by one, two or three, preferably one or two halogen atoms, preferably selected from fluorine and chlorine atoms. When there is one halogen substituent, it is preferably para to the indicated carbonyl group. When there are two or three halogen substituents, preferably one is para to the indicated carbonyl group and at least one of the others is ortho to the indicated carbonyl group.
Ar
2
as substituted phenyl may, for example, be substituted by one, two, three, four or five, preferably by one, two or three, of the abovementioned substituents. Ar
2
may be, for example, monosubstituted phenyl in which the substituent, preferably halogen, cyano, nitro or C
1
-C
4
-alkoxy, is preferably ortho or meta to the indicated —CH═CH— group. Ar
2
may alternatively be, for example, disubstituted phenyl in which the substituents are preferably selected from halogen, cyano, hydroxy, nitro, C
1
-C
4
-alkoxy, C
1
-C
4
-alkyl and C
1
-C
4
-haloalkyl, especially two halogen substituents (same or different halogen), two C
1
-C
4
-alkoxy groups, two C
1
-C
4
-alkyl groups, two C
1
-C
4
-haloalkyl groups, one halogen and one cyano, one halogen and one C
1
-C
4
-alkoxy, one halogen and one nitro, one halogen and one hydroxy, one halogen and one C
1
-C
4
-haloalkyl, one cyano and one C
1
-C
4
-alkoxy, one hydroxy and one C
1
-C
4
-alkyl, or one hydroxy and one C
1
-C
4
-alkoxy group. Ar
2
may alternatively be, for example, trisubstituted phenyl in which the substituents are preferably selected from halogen, hydroxy, C
1
-C
4
-alkoxy and C
1
-C
4
-alkoxycarbonyl, especially three halogen substituents (same or two or three different halogens), or two C
1
-C
4
-alkoxy and one halogen, hydroxy or C
1
-C
4
-alkoxycarbonyl. Ar
2
may alternatively be, for example, penta-substituted phenyl in which the substituents are preferably halogen, especially fluorine. Especially preferred groups Ar
2
are cyanophenyl, particularly meta-cyanophenyl, and disubstituted phenyl where one substituent is C
1
-C
4
-alkoxy, preferably ortho to the —CH═CH— group, and the other, preferably para to the C
1
-C
4
-alkoxy group, is C
1
-C
4
-alkoxy, halogen, cyano or C
1
-C
4
-alkyl.
R
1
as optionally substituted C
1
-C
8
-alkyl is preferably optionally substituted C
1
-C
4
-alkyl, especially C
1
-C
4
-alkyl or substituted methyl or ethyl. When R
1
is substituted by a cyclic organic group, the latter may be a carbocyclic or heterocyclic group, for example a C
3
-C
15
-carbocyclic group or a 5- to 7-membered heterocyclic group having one or more, preferably one, two or three, ring hetero atoms selected from nitrogen, oxygen and sulfur. The C
3
-C
15
-carbocyclic group may be, for example, a cycloaliphatic group having 3 to 8 carbon atoms, preferably C
5
- or C
6
-cycloalkyl such as cyclopentyl, methylcyclopentyl or cyclohexyl. The C
3
-C
15
-carbocyclic group may alternatively be, for example, a C
6
-C
15
aromatic group, such as phenyl, which is unsubstituted or substituted by C
1
-C
8
-alkyl, C
1
-C
8
-alkoxy, halogen, cyano, —CON(R
4
)R
5
, —SO
2
N(R
4
)R
5
or C
1
-C
8
-alkylsulfonylamino where R
4
and R
5
are a hereinbefore defined. The heterocyclic group may have one nitrogen, oxygen or sulfur atom in the ring or it may have two nitrogens, or one oxygen and one or two nitrogens, or one sulfur and one or two nitrogens in the ring. The heterocyclic group is preferably a heterocyclic aromatic group, especially a 5- or 6-membered heterocyclic group such as furyl, imidazolyl, thiazolyl or pyridyl. In especially preferred compounds, R
1
is C
1
-C
4
-alkyl substituted by hydroxy, phenyl, or a 5-or 6-membered heterocyclic aromatic group having one or two ring hetero atoms selected from nitrogen, oxygen and sulfur.
Preferred compounds of formula I in free or salt form include those in which
Ar
1
is phenyl substituted by fluorine or chlorine para to the indicated carbonyl group
Bhalay Gurdip
Howe Trevor John
Le Grand Darren Mark
Storz Thomas
Aulakh C. S.
Brouillette D. Gabrielle
Hess Susan L.
Novartis AG
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