Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-03-19
1994-11-08
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546112, A61K 31435, C07D47108
Patent
active
053627393
DESCRIPTION:
BRIEF SUMMARY
This invention relates to compounds having pharmaceutical activity, to a process for their preparation and their use as pharmaceuticals.
EP-0338723 and EP-0392803 (published 17 Oct. 1990) disclose certain azabicyclic compounds which enhance acetylcholine function via an action at muscarinic receptors.
A novel group of compounds has now been discovered which also enhance acetylcholine function via an action at muscarinic receptors within the central nervous system and are therefore of potential use in the treatment and/or prophylaxis of dementia in mammals.
According to the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR3## wherein R.sub.1 represents ##STR4## in which p represents 2 or 3;
R.sub.2 is a group OR.sub.4, where R.sub.4 is C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, a group OCOR.sub.5 where R.sub.5 is hydrogen or R.sub.4, or a group NHR.sub.6 or NR.sub.7 R.sub.8 where R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-2 alkyl; and
R.sub.3 is hydrogen, chloro, fluoro, bromo, cyclopropyl, C.sub.1-4 alkyl, C.sub.1-3 alkyl substituted by one, two or three halogen atoms, or R.sub.3 is a group (CH.sub.2).sub.n R.sub.9 where R.sub.9 is --CN, --OH, --OCH.sub.3, --SH, --SCH.sub.3, --C.tbd.CH or --CH.dbd.CH.sub.2 and n is 0 or 1, with the proviso that when n is 0, R.sub.9 is not --OH or --SH, or, when, R.sub.2 is OCOR.sub.5 or NHR.sub.6, R.sub.3 may not be hydrogen.
The term halogen includes bromine, chlorine, fluorine and iodine, preferably fluorine.
Compounds of formula (I) are capable of existing in a number of stereoisomeric forms including geometric isomers such as syn and anti and enantiomers. 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 compounds of formula (I) can form acid addition salts with acids, such as the conventional pharmaceutically acceptable acids, for example hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, oxalic and methanesulphonic.
The term pharmaceutically acceptable salt encompasses solvates and hydrates. Thus where compounds of formula (I) or pharmaceutically acceptable salts thereof form solvates or hydrates, these also form an aspect of the invention.
Preferably, p represents 2.
The groups R.sub.4 and R.sub.5 in R.sub.2 are preferably selected from methyl, ethyl, allyl and propargyl. R.sub.6, R.sub.7 and R.sub.8 are preferably methyl. Suitable values for R.sub.2 include methoxy, ethoxy, allyloxy, propargyloxy, acetoxy and dimethylamino, preferably methoxy.
Suitable examples for R.sub.3 include hydrogen, methyl, cyclopropyl, chloro, fluoro and bromo and when R.sub.3 is a group (CH.sub.2).sub.n R.sub.9 and n is 0, suitable examples of R.sub.9 include --CN, --OCH.sub.3 or --C.tbd.CH. When n is 1, an example of R.sub.9 is CN.
The invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises:
(a) reacting a compound of formula (II): ##STR5## with a compound of formula (III): R.sub.2 ' represents R.sub.2 or hydroxy, and R.sub.3 ' represents R.sub.3 or a group convertible thereto, converting R.sub.2 ' to R.sub.2 when hydroxy, converting R.sub.1 ' and R.sub.3 ' when other than R.sub.1 and R.sub.3 to R.sub.1 and R.sub.3, wherein R.sub.1, R.sub.2 and R.sub.3 are as defined in formula (I), and thereafter optionally forming a pharmaceutically acceptable salt;
(b) reacting a compound of formula (IV): ##STR6## with a compound of formula (V): R.sub.1 or a group convertible thereto, R.sub.3 ' represents R.sub.3 or a group convertible thereto, converting R.sub.1 ' and R.sub.3 ' when other than R.sub.1 and R.sub.3 to R.sub.1 and R.sub.3, wherein R.sub.1, R.sub.2 and R.sub.3 are as defined in formula (I), and thereafter optionally formi
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Bromidge Steven M.
Faulkner, deceased Richard E.
Orlek Barry S.
Beecham Group p.l.c.
Dentz Bernard
Hall Linda E.
Lentz Edward T.
Suter Stuart R.
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