Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-08-30
1996-04-16
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514314, 546143, 546163, A61K 31475, C07D40104
Patent
active
055082882
DESCRIPTION:
BRIEF SUMMARY
This application is the National Phase of PCT/GB93/00449 filed on Mar. 4, 1993.
This invention relates to compounds having pharmacological activity, to a process for their preparation, to compositions containing them and to their use in the treatment of mammals.
P. Fludzinski et al. J. Med. Chem. 1986 29 2415-2418 describes N-(1,2-dimethyl-3-ethyl-1H-indol-5-yl)-N'-(3-trifluoromethylphenyl)urea which shows selectivity for the rat stomach fundus seretonin receptor.
A class of compounds has now been discovered which have been found to have 5HT.sub.1C receptor antagonist activity. 5HT.sub.1C receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, obsessive compulsive disorders, migraine, anorexia, Alzheimers disease, sleep disorders, 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.
Accordingly, the present invention provides a compound of formula (I) or a salt thereof: ##STR2## wherein: P represents a quinoline or isoquinoline residue or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur; C.sub.1-6 alkyl, or R.sub.10 and R.sub.11 together form a bond, or R.sub.2 and R.sub.10 or R.sub.3 and R.sub.11 together form a C.sub.2-6 alkylene chain; or COOR.sub.12, where R.sub.8, wherein the urea moiety is attached at the 4-, 5- or 6-position of the indole or indoline ring, provided that P is not pyridyl when R.sub.10 and R.sub.11 form a bond.
Alkyl moieties within the variables R.sub.1 to R.sub.12 are preferably C.sub.1-3 alkyl, such as methyl, ethyl, n- and iso-propyl, most preferably methyl.
Suitable R.sub.4 and R.sub.7 halogens include chloro and bromo.
Examples of R.sub.1 include hydrogen, methyl, ethyl and n-propyl, preferably methyl.
R.sub.2 and R.sub.3 are preferably hydrogen. R.sub.10 and R.sub.11 are preferably a bond so as to form an indole structure. In an indoline structure, R.sub.10 and R.sub.11 are preferably hydrogen.
Preferably R.sub.4 is hydrogen or methyl, most preferably hydrogen.
Preferably R.sub.5, R.sub.6 and R.sub.7 are hydrogen.
The urea moiety can be attached to a carbon or nitrogen atom of the ring P, preferably it is attached to a carbon atom.
Suitable moieties when the ring P is a 5- or 6-membered aromatic heterocyclic ring include pyrazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl. When P is a quinoline or isoquinoline residue, the urea moiety can be attached at any position of the ring, preferably to the 4-position.
The urea moiety is preferably attached at the 5-position of the indole or indoline ring.
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 acids.
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.
When R.sub.1 (in an indole) and/or R.sub.5 and/or R.sub.6 are hydrogen or when R.sub.4 is hydroxy or NR.sub.8 R.sub.9 and at least one of R.sub.8 and R.sub.9 are hydrogen the compounds of formula (I) may exist tautomerically in more than one form. The invention extends to these and any other tautomeric forms and mixtures thereof.
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 present invention also provides a process f
REFERENCES:
Fludzinski, et al., "2,3-Dialkyl(dimethylamino)indoles: Interaction with 5HT.sub.1, 5HT.sub.2, and Rat Stomach Fundal Serotonin Receptors", J. Med. Chem. 29: 2415-2418 (1986).
Forbes Ian T.
Jones Graham E.
Martin Roger T.
Hall Linda E.
Huang Evelyn
Ivy C. Warren
Lentz Edward T.
SmithKline Beecham p.l.c.
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