Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-12-21
2001-11-06
Morris, Patricia L. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S256000
Reexamination Certificate
active
06313145
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.
PCT/EP96/00368 (SmithKline Beecham plc) describes indole and indoline derivatives which are described as possessing 5HT
2C/2B
receptor antagonist activity. A novel class of compounds has now been discovered which fall within the generic scope of PCT/EP96/00368, but are not specifically disclosed therein, and have been found to exhibit a surprisingly enhanced 5HT
2C
receptor antagonist activity profile (enhanced activity and duration of action after oral dosing). 5HT
2
C receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, 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) as well as microvascular diseases such as macular oedema and retinopathy.
The present invention therefore provides, in a first aspect, a compound of formula (I) or a salt thereof:
wherein:
R
1
is hydrogen or C
1-6
alkyl;
R
2
, R
3
and R
4
groups are independently hydrogen, halogen or C
1-6
alkyl optionally substituted by one or more fluorine atoms.
C
1-6
Alkyl groups, whether alone or as part of another group, may be straight chain or branched.
Suitably R
1
is hydrogen or C
1-6
alkyl, preferably R
1
is hydrogen.
Suitably R
2
, R
3
and R
4
groups are independently hydrogen, halogen or C
1-6
alkyl optionally substituted by one or more fluorine atoms. Preferably R
2
is C
1-6
alkyl substituted by one or more fluorine atoms, particularly CF
3
and R
3
is C
1-6
alkyl, particularly methyl or R
2
is hydrogen and R
3
is halogen, particularly bromine or C
1-6
alkyl substituted by one or more fluorine atoms, particularly CF
3
. Preferably R
4
is hydrogen or C
1-6
alkyl, in particular methyl.
Particular compounds of the invention include:
5-Methyl-1-[2-(pyridin-2-ylmethyloxy)pyridin-5-ylcarbamoyl]-6-trifluoromethylindoline,
1-[2-(pyridin-2-ylmethyloxy)pyridin-5-ylcarbamoyl]-5-trifluoromethylindoline, 5-Methyl-1-[2-(pyridin-2-ylmethyloxy)-3-methylpyridin-5-ylcarbamoyl]-6-trifluoromethylindoline,
5-Bromo-1-[2-(pyridin-2-ylmethyloxy)pyridin-5-ylcarbamoyl]-indoline,
1-[2-(Pyridin-2-ylmethyloxy)pyridin-5-ylcarbamoyl]-6-trifluoromethyl-indoline, 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 methanesulphonic.
Compounds of formula (I) may also form N-oxides or 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 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 compounds of the invention can be prepared using standard procedures such as those of PCT/EP96100368. for example by the coupling of a compound of formula (II);
with a compound of formula (III);
in which R
1
, R
2
, R
3
and R
4
are as defined in formula (I) and A and B contain the appropriate functional group(s) necessary to form the moiety —NHCO— when coupled and thereafter optionally forming a pharmaceutically acceptable salt thereof Suitable examples of groups A and B include:
(i) A is —N═C═O and B is hydrogen,
(ii) A is —NHCOL and B is hydrogen,
(iii) A is —NH
2
and B is COL, or
(iv) A is halogen and B is —CONH
2
wherein L is a leaving group. Examples of suitable leaving groups L include halogen such as chloro, bromo, imidazole, or phenoxy or phenylthio optionally substituted, for example, with one or more halogens.
Compounds of formula (II) and (III) may be prepared according to known methods or analogous to known methods, for example using the procedures described in WO 95/01976 and PCT/EP96/00368.
Novel intermediates of formula (II) and (III) also form part of the invention.
Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative. N-oxides may be formed conventionally by reaction with hydrogen peroxide or percarboxylic acids.
Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT
2C
receptor antagonist activity and are believed to be of potential use for the treatment or prophylaxsis of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders (including disturbances of Circadian rhythym), 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 disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
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 administ
King William T.
Kinzig Charles M.
Morris Patricia L.
Simon Soma G.
SmithKline Beecham p.l.c.
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