Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-19
2003-04-15
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253010, C514S255030, C514S256000, C514S277000, C514S325000, C514S372000, C544S298000, C544S358000, C544S383000, C544S392000, C544S402000, C544S406000, C546S207000, C546S225000, C546S229000, C546S235000, C548S122000, C548S125000, C548S146000, C548S262200, C548S300100, C548S400000
Reexamination Certificate
active
06548504
ABSTRACT:
This invention relates to novel compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders.
EPA 0 021 580 and EPA 0 076 072 describe naphthyl sulphonamide derivatives which are disclosed as having antiarrhythmic activity. European patent application EP 0815861 discloses a series of aryl sulphonamide compounds that are said to possess 5HT
6
receptor activity and are useful in the treatment of various CNS disorders. A structurally distinct class of compounds has now been discovered, which also have been found to have 5HT
6
receptor antagonist activity.
The present invention therefore provides, in a first aspect, a compound of formula (I) or a salt thereof:
in which the group D is selected from a group of formula (A), (B) or (C) below:
in which
P is a monocyclic, bicyclic or tricyclic alicyclic ring containing up to 20 carbon atoms in the ring(s);
A is a single bond, a C
1-6
alkylene or a C
2-6
alkenylene group;
R
1
is halogen, C
1-6
alkyl optionally substituted by one or more fluorine atoms, C
3-6
cycloalkyl, C
1-6
alkoxy, OCF
3
, hydroxy, hydroxyC
1-6
alkyl, hydroxyC
1-6
alkoxy, C
1-6
alkoxyC
1-6
alkoxy, C
1-6
alkanoyl, amino, alkylamino or dialkylamino, SR
11
where R
11
is hydrogen or C
1-6
alkyl or R
1
is aryl, arylC
1-6
alkyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;
n is 0, 1, 2 or 3; and
R
2
is hydrogen, C
1-6
alkyl, aryl, arylC
1-6
alkyl or C
3-6
cycloalkyl; or
in which R
a
is an alkyl group containing 1 to 20 carbon atoms or is an arylC
1-6
alkyl group, and R
b
is hydrogen or C
1-6
alkyl;
in which Q is a mono-, bi- or tricyclic group containing a nitrogen heteroatom bonded to the adjacent SO
2
group or Q is a 5-7 membered heterocyclic ring containing a nitrogen heteroatom bonded to the adjacent SO
2
group and a further heteroatom selected from nitrogen, oxygen or sulphur, and R
1
and n are as defined above;
R
3
is a group R
5
or together with R
5
forms a group (CH
2
)
2
O or (CH
2
)
3
O optionally substituted with 1 or more C
1-6
alkyl groups;
R
4
is an optionally substituted piperazine ring; and
R
5
is hydrogen, halogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
1-6
alkoxy optionally substituted with one or more fluorine atoms, hydroxy, hydroxyC
1-6
alkyl, hydroxyC
1-6
alkoxy, C
1-6
alkoxyC
1-6
alkoxy, C
1-6
alkanoyl, trifluoromethyl, or aryl.
Alkyl groups, whether alone or as part of another group, may be straight chain or branched. The term ‘halogen’ is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine. The term ‘aryl’ is used herein to describe, unless otherwise stated, a group such as phenyl or naphthyl. Such aryl groups may be optionally substituted by one or more C
1-6
alkyl or halogen.
Within the Definition of Group D Formula (A)
The group P may be saturated or unsaturated and includes bridged and unbridged bicyclic or tricyclic alicyclic rings, containing saturated and/or unsaturated rings. Examples of the group P which contain both a saturated and an unsaturated ring include indanyl and tetrahydronaphthyl. With such examples the group A is attached to the group P via a carbon atom of the unsaturated ring. When P is a monocyclic ring, suitable examples include cycloalkyl groups containing 4 to 10 carbon atoms e.g. cyclopentyl, cyclohexyl or cycloheptyl. Bicyclic and tricyclic rings may contain, for example, 10 to 20 carbon atoms. Examples of bridged bicyclic groups include bicyclo[2.2.1]heptyl or born-2-yl and examples of bridged tricyclic groups include adamantyl. Preferably P is cyclohexyl.
When R
1
is a bicyclic heterocyclic ring, suitable examples include benzothiophene, indole, benzimidazole, quinoline or isoquinoline. Suitable 5 to 7-membered heterocyclic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazoly, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrrolidinyl and pyrazinyl. The heterocyclic rings can be linked to the remainder of the molecule via any suitable carbon atom or, when present, a nitrogen atom. Preferably R
1
is a C
1-6
alkyl group such as methyl or ethyl. Preferably n is 0, 1 or 2.
When R
2
is a C
3-6
cycloalkyl group a preferred example is cyclohexyl. Preferably R
2
is hydrogen or a C
1-6
alkyl group such as methyl, ethyl or isopropyl.
Suitably A is a single bond, a methylene or ethylene group or a —CH═CH—group. Preferably A is a single bond or methylene.
Within the Definition of Group D Formula (B)
The alkyl group R
a
may be straight chain or branched. Preferably R
a
represents a C
1-8
alkyl group.
Preferably R
b
is hydrogen.
Within the Definition of Group D Formula (C)
When Q is a mono-, bi- or tricyclic group containing a single nitrogen heteroatom, suitable examples may be saturated or unsaturated including partially unsaturated groups for example bicyclic groups in which one ring is saturated and the other is unsaturated. Monocyclic groups preferably contain 4 to 8 atoms in the ring, advantageously six atoms, a preferred example of such a monocyclic group being piperidine. Bicyclic groups, which may be bridged or unbridged, preferably contain 8 to 12 atoms in the rings, advantageously 10 atoms, preferred examples of such bicyclic groups being decahydroquinoline or decahydroisoquinoline. Tricyclic groups, which may be bridged or unbridged, preferably contain 6 to 14 atoms in the rings. When Q is a 5-7 membered heterocyclic ring containing a further heteroatom, suitable examples include piperazinyl, morpholinyl or thiomorpholinyl.
When R
1
is a bicyclic heterocyclic ring or a 5-7 membered heterocylic ring suitable examples include those listed for R
1
within the definition of formula (A). Preferably R
1
is a C
1-6
alkyl group such as methyl or ethyl or an arylC
1-6
alkyl group such as benzyl. Preferably n is 0, 1 or 2.
R
3
is a group R
5
or together with R
5
forms a group (CH
2
)
2
O or (CH
2
)
3
O. It will be appreciated that when R
3
/R
5
groups are linked together the two groups must be attached to adjacent carbon atoms of the phenyl ring. Preferably R
3
is a group R
5
, in particular hydrogen.
Preferably R
4
is meta with respect to the SO
2
group. Optional substituents for the piperazine ring, which can be present on carbon and/or nitrogen atoms, include C
1-6
alkyl, in particular methyl. Most preferably R
4
is unsubstituted piperazine.
Suitably R
5
is C
1-6
alkoxy. Preferably R
5
is a methoxy group with a para relationship with respect to the SO
2
group.
Particular compounds of the invention include:
N-Cyclohexyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,
N-Indan-1-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,
N-Bicyclo[2.2.1]hept-2-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,
N-Adamantan-1-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,
N-Cycloheptyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,
N-Cyclohexyl-4-methoxy-N-methyl-3-piperazin-1-ylbenzenesulfonamide,
N-Adamantan-2-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,
N-Cyclopentyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,
1-[5-(4-Benzylpiperidine-1-sulfonyl)]-2-methoxyphenyl]piperazine,
N-Hexyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,
N-Indan-2-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,
1-[5-(3,3-Dimethylpiperidine-1-sulfonyl)]-2-methoxyphenyl]piperazine,
1-[5-(2-Ethylpiperidine-1-sulfonyl)]-2-methoxyphenyl]piperazine,
4-Methoxy-N-(1-methylbutyl)-3-piperazin-1-ylbenzenesulfonamide,
N-tert-Butyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,
(R)-4-Methoxy-3-piperazin-1-yl-N-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-benzenesulfonamide,
N-(4-tert-Butylcyclohexyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,
4-Methoxy-N-(2-methylcyclohexyl)-3-piperazin-1-ylbenzenesulfonamide,
4-Methoxy-N-(3-methylcyclohexyl)-3-piperazin-1-ylbenzenesulfonamide,
4-Methoxy-N-(4-methylcyclohexyl)-3-piperazin-1-ylbenzenesulfonamide,
N-(2,3-Di
Bromidge Steven Mark
Moss Stephen Frederick
Kinzig Charles M.
McCarthy Mary E.
Patel Sudhaker B.
Shah Mukund J.
Simon Soma G.
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