Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-02-10
1995-09-05
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142328, 514254, 544126, 544361, 546 80, A61K 3144, C07D49504
Patent
active
054479371
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB92/01487 filed Aug. 11, 1992.
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.
EP-A-0327223 and WO91/17165 (filed 1st May 1991) disclose certain tetrahydrobenzothienopyridines which have CNS activity, in particular anxiolytic and/or anti-depressant activity.
A class of compounds has now been discovered, which compounds have been found to have CNS activity, in particular anxiolytic and/or anti-depressant and/or anticonvulsant activity and/or possess activity useful in the treatment of sleep disorders.
Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof. ##STR2## wherein:
R.sub.1 is hydrogen, C.sub.1-6 alkyl, phenyl or phenyl C.sub.1-4 alkyl wherein the phenyl moiety is optionally substituted by one or more C .sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, hydroxy, C.sub.2-7 alkanoyl, halo, trifluoromethyl, nitro, amino optionally substituted by one or two C.sub.1-6 alkyl groups or by C.sub.2-7 alkanoyl, cyano, carbamoyl or carboxy groups;
R.sub.2 and R.sub.3 are independently selected from hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-4 alkyl, C.sub.3-6 alkenyl, C.sub.1-7 alkanoyl, C.sub.1-6 alkylsulphonyl, di-(C.sub.1-6 alkyl)amino C.sub.1-6 alkyl, 3-oxobutyl, 3-hydroxybutyl, phenyl, phenyl C.sub.1-4 alkyl, benzoyl, phenyl C.sub.2-7 alkanoyl or benzenesulphonyl any of which phenyl moieties are optionally substituted by one or two halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, amino or carboxy, or R.sub.2 and R.sub.3 together are C.sub.2-6 polymethylene optionally interrupted by oxygen or NR.sub.6 wherein R.sub.6 is hydrogen or C.sub.1-6 alkyl optionally substituted by hydroxy;
R.sub.5 is hydrogen or C.sub.1-6 alkyl and R.sub.8 is hydrogen or R.sub.5 and R.sub.8 together form a C.sub.1-6 alkylidene group at the 8-position;
R.sub.9 is hydrogen or C.sub.1-6 alkyl; and --CO.sub.2 R.sub.4 is a pharmaceutically acceptable ester group.
Alkyl moieties within the variables R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6 and R.sub.9 are preferably C.sub.1-3 alkyl, such as methyl, ethyl and n- and iso-propyl.
Values for R.sub.1 include hydrogen, methyl, ethyl, n- and iso-propyl, phenyl and benzyl. Preferably, R.sub.1 is methyl.
It will be appreciated in selecting variables R.sub.2 and R.sub.3 that the nitrogen atom is not directly attached to unsaturated aliphatic carbon.
Values for R.sub.2 and R.sub.3 include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, n-, sec, iso- and neo-pentyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentyl-C.sub.1-4 alkyl, cyclohexyl-C.sub.1-4 alkyl and cycloheptyl-C.sub.1-4 alkyl, where values for C.sub.1-4 alkyl include methylene and ethylene, but-2-enyl, but-3-enyl, 1-methylprop-2-enyl, formyl, acetyl, propionyl, methylsulphonyl, 3-dimethylaminobutyl, 3-oxobutyl, 3-hydroxybutyl, phenyl, benzyl, benzoyl, benzylcarbonyl and benzenesulphonyl, or R.sub.2 and R.sub.3 together form --(CH.sub.2).sub.r --X--(CH.sub.2).sub.s -wherein r and s are independently 1, 2 or 3 and X is a bond, O or NR.sub.6, for example C.sub.4 or C.sub.5 polymethylerie, --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2 -- or --(CH.sub.2).sub.2 -NR.sub.6 --(CH.sub.2).sub.2 -where R.sub.6 is preferably methyl.
Preferably R.sub.2 is hydrogen and R.sub.3 is hydrogen or C.sub.1-6 alkyl, for example methyl.
Most preferably R.sub.2 and R.sub.3 are hydrogen.
Suitable examples of pharmaceutical esters of the compounds of formula (I) include C.sub.1-6 alkyl esters wherein the alkyl moiety is optionally substituted by up to three halo atoms selected from chloro, fluoro and bromo, such as methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl and 2,2,2-trifluoroethyl esters, C.sub.2-6 alkenyl esters such as vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-3-enyl, pent-4-enyl, 1-methylenepropyl and 1-methylprop-2-enyl,
REFERENCES:
patent: 3767659 (1973-10-01), Suh
patent: 5093493 (1992-03-01), Thompson
patent: 5126448 (1992-06-01), Ueki
Davies David T.
Forbes Ian T.
Thompson Mervyn
Chang Ceila
Hall Linda E.
Lentz Edward T.
SmithKline Beecham p.l.c.
Suter Stuart R.
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