Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-05-29
2003-07-29
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253060, C514S254030, C514S254090, C514S254110
Reexamination Certificate
active
06599904
ABSTRACT:
This invention relates to 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 sulphonamide derivatives which are disclosed as having antiarrhythmic activity. A structurally distinct class of compounds has now been discovered, which have been found to have 5HT
6
receptor antagonist activity. 5HT
6
receptor antagonists are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, cognitive memory enhancement e.g. for the treatment Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Compounds of the invention are also expected to be of use in the treatment of certain GI (gastrointestinal) disorders such as IBS (Irritable Bowel Syndrome).
The present invention therefore provides, in a first aspect, a compound of formula (I) or a salt thereof:
wherein:
P is phenyl, naphthyl, 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;
A is a single bond, a C
1-6
alkylene or a C
1-6
alkenylene group;
R
1
is halogen, C
1-6
alkyl optionally substituted by one or more halogen atoms, C
3-6
cycloalkyl, COC
1-6
alkyl, 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, nitro, amino, C
1-6
alkylamino or diC
1-6
alkylamino, cyano or R
1
is phenyl, naphthyl, 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, 3, 4, 5 or 6,
R
2
is hydrogen, C
1-6
alkyl or aryl C
1-6
alkyl;
R
3
is a group R
5
or together with R
5
forms a group (CH
2
)
2
O or (CH
2
)
3
O or R
3
is linked to R
2
to form a group (CH
2
)
2
or (CH
2
)
3
;
R
4
is —X(CH
2
)
p
—R
6
where X is a single bond, CH
2
, O, NH or N—C
1-6
alkyl and p is 0 to 6 and R
6
is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or R
6
is NR
7
R
8
where R
7
and R
8
are independently hydrogen, C
1-6
alkyl or aryl C
1-6
alkyl; and
R
5
is hydrogen, halogen, C
1-6
alkyl, C
3-6
cycloalkyl, COC
1-6
alkyl, C
1-6
alkoxy, hydroxy, hydroxyC
1-6
alkyl, hydroxyC
1-6
alkoxy, C
1-6
alkoxyC
1-6
alkoxy, C
1-6
alkanoyl, nitro, trifluoromethyl, cyano or aryl.
C
1-6
Alkyl groups, whether alone or as part of another group, may be straight chain or branched. Preferred alkyl groups are generally methyl and ethyl. As used herein the term aryl includes optionally substituted phenyl and naphthyl.
When P is a bicyclic heterocyclic ring suitable examples include benzothiophene, quinoline or isoquinoline. When P is a 5 to 7-membered heterocyclic ring suitable examples include thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl, 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. Suitable substituents for these rings include R
5
groups as defined above.
Preferably P is phenyl, thiophene, benzothiophene or naphthyl. Preferably A is a single bond, an ethylene group or a —CH═CH— group. Most preferably A is a single bond.
When R
1
is a heterocyclic group suitable examples include those listed above. Preferably R
1
is halogen or C
1-6
alkyl optionally substituted by one or more halogen atoms, for example methyl or trifluoromethyl.
Preferably n is 0, 1, 2 or 3, particularly 1 or 2.
Suitably R
2
is hydrogen or C
1-6
alkyl. Preferably R
2
is hydrogen.
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 sulphonamide linkage. Preferably X is a bond, p is 0 and R
6
is an optionally substituted 5- to 7-membered heterocyclic ring. The heterocyclic rings can be linked to the remainder of the molecule via a carbon atom or, when present, a nitrogen atom. Optional substituents for these rings, which can be present on carbon and/or nitrogen atoms, include C
1-6
alkyl, in particular methyl. More preferably R
4
is N-piperazine optionally substituted by C
1-6
alkyl, particularly unsubstituted piperazine.
Preferably R
5
is C
1-6
alkoxy, most preferably methoxy. Preferably R
5
is para with respect to the sulphonamide linkage.
A preferred meaning for P-A is benzo[b]thiophen-2-yl or benzo[b]thiophen-3-yl optionally substituted by one or two R
1
groups, especially 5-chloro-3-methylbenzo[2]thiophen-2-yl.
Particular compounds of the invention include:
4-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-thiophenesulfonamide,
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-5-(pyridin-2-yl)-2-thiophenesulfonamide,
2,5-Dichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-thiophenesulfonamide,
4-Bromo-5-chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-thiophenesulfonamide,
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,
3-Bromo-5-chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-thiophenesulfonamide,
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzylsulfonamide,
2-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,
3-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,
3-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-methylbenzenesulfonamide,
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-trans-styrenesulfonamide,
3,4-Dichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,
3,5-Dichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-[2,1,3]benzothiadiazole-4-sulfonamide,
5-Chloro-N-[4methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-2-benzothiophenesulfonamide,
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-methyl-5-nitrobenzenesulfonamide,
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-trifluoromethylbenzenesulfonamide,
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-trifluoromethylbenzenesulfonamide,
2,5-Dimethoxy-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-benzenesulfonamide,
4-Fluoro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,
4-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,
4-Iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,
4-Ethyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,
4-tert-Butyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,
4-Isopropyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,
4-tert-Amyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-trifluoromethoxybenzenesulfonamide,
4-n-Butoxy-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide,
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-methylbenzenesulfonamide,
5-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-thiophenesulfonamide,
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1-naphthalenesulfonamide,
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-naphthalenesulfonamide
Bromidge Steven Mark
King Francis David
Wyman Paul Adrian
Bernhardt Emily
Kinzig Charles M.
McCarthy Mary E.
Simon Soma G.
SmithKline Beecham p.l.c.
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