Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-05
2001-07-24
Bernhardt, Emily (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S326000, C514S227800, C514S235500, C514S252050, C514S316000, C514S217040, C540S597000, C544S360000, C544S372000, C544S058500, C544S141000, C544S238000, C544S364000, C546S208000, C546S187000, C546S191000, C546S146000, C546S149000, C546S172000, C546S112000, C546S125000
Reexamination Certificate
active
06265408
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
7
receptor antagonist activity. 5HT
7
receptor antagonists are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, sleep disorders, and schizophrenia.
The present invention therefore provides, in a first aspect, a compound of formula (I) or a salt thereof:
wherein:
Ar is an optionally substituted mono- or bicyclic aromatic or heteroaromatic ring;
R
1
and R
2
are independently hydrogen, C
1-6
alkyl, arylC
1-6
alkyl or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring optionally containing a further heteroatom selected from nitrogen, sulphur or oxygen, the nitrogen atom being substituted by hydrogen, C
1-6
alkyl, cycloC
3-7
alkyl, or an optionally substituted aryl, heteroaryl or arylC
1-6
alkyl group;
R
3
is hydrogen or C
1-6
alkyl;
X is oxygen, sulphur or a bond;
n is 2 or 3; and
m is 1 or 2.
C
1-6
Alkyl groups, whether alone or as part of another group, may be straight chain or branched.
Optional substituents for aromatic and heteroaromatic groups include C
1-6
alkyl optionally substituted by NR
7
R
8
, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
alkylthio, cyano, nitro, halogen, CF
3
, C
2
F
5
, NR
7
R
8
, CONR
7
R
8
, NR
7
COR
8
, S(O)
p
NR
7
R
8
, CHO, OCF
3
, SCF
3
, COR
9
, CH
2
OR
9
, CO
2
R
9
or OR
9
where p is 1 or 2 and R
7
, R
8
and R
9
are independently hydrogen, C
1-6
alkyl, optionally substituted aryl or optionally substituted arylC
1-6
alkyl. More than one substituent can be present and in the case of multiple substituents these can be the same or different.
Suitably Ar is an optionally substituted mono- or bicyclic aromatic or heteroaromatic ring. Preferably Ar is an optionally substituted naphthyl, phenyl or thienyl group. Most preferably Ar is naphthyl, phenyl or thienyl substituted by one or more halogen, in particular 2,3-di-bromothienyl.
In R
1
and R
2
optional substituents for the heterocyclic rings include C
1-6
alkyl. Preferably R
1
and R
2
form an optionally substituted 5- to 7-membered heterocyclic ring, in particular an optionally substituted 6-membered ring. Most preferably R
1
and R
2
form a piperidine ring optionally substituted by one or two methyl groups, or R
1
and R
2
form a piperazine ring substituted on nitrogen with an optionally substituted aryl ring.
Preferably R
3
is hydrogen.
Preferably X is a bond.
Preferably n and m have values such that, together with X, they form part of a 5- or 6-membered ring.
Particular compounds of the invention include:
(±)-N-(1-Naphthylsulfonyl)-2-[1-(piperidinyl)ethyl]piperidine,
(±)-N-[(4,5-Dibromo)-thienyl-2-sulfonyl]-2-[1-(piperidinyl)ethyl]piperidine,
1-(2-[1-(Naphthalene-1-sulfonyl)-piperidin-2-yl]-ethyl)-4-pyrid-2-yl piperazine,
1-(2-[1-(Naphthalene-1-sulfonyl)-piperidin-2-yl]-ethyl)-4-phenyl piperazine,
(R)-4-Methyl-1-(2-(1-(3-methylphenylsulfonyl)-pyrrolidin-2-yl)-ethyl)-piperidine
and pharmaceutically acceptable salts thereof.
The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulfonic.
Compounds of formula (I) may also form solvates such as hydrates, and the invention also extends to these forms. When referred to herein, it is understood that the term ‘compound of formula (I)’ also includes these forms.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms including diastereomers and enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.
The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises
(a) the coupling of a compound of formula (II):
ArSO
2
L (II)
in which Ar is as defined in formula (I) and L is a leaving group with a compound of formula (III):
in which n, m, X, R
1
, R
2
and R
3
are as defined in formula (I);
or (b) the coupling of a compound of formula (IV):
in which Ar, n, m, X, and R
3
are as defined in formula (I) and L
1
is a leaving group with a compound of formula (V):
HNR
1
R
2
(V)
and optionally thereafter (a) or (b):
forming a pharmaceutically acceptable salt.
Suitable leaving groups L and L
1
include halogen in particular chloro. The reaction of a compounds of formulae (II) and (III) is preferably carried out in an inert solvent such as dichloromethane optionally in the presence of a base such as triethylamine.
Compounds of formulae (II) and (III) are commercially available or may be prepared according to known methods or analogous to known methods.
Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT
7
receptor antagonist activity and are believed to be of potential use for the treatment or prophylaxis of CNS disorders such as anxiety, depression, sleep disorders, including instances of Circadian rhythym and schizophrenia.
Thus the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders.
The invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of the above disorders.
The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
For parenteral ad
Forbes Ian Thomson
King Francis David
Rahman Shirley Katherine
Bernhardt Emily
King William T.
Kinzig Charles M.
Simon Soma G.
SmithKline Beecham Plc
LandOfFree
Sulphonamide derivatives and their use in the treatment of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Sulphonamide derivatives and their use in the treatment of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Sulphonamide derivatives and their use in the treatment of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2436756