Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-02-23
1994-05-24
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546329, 546330, 546334, 546335, C07D21357, A61K 3144
Patent
active
053149017
DESCRIPTION:
BRIEF SUMMARY
This invention relates to compounds having pharmaceutical activity, to a process for their preparation and their use as pharmaceuticals.
EP-0271798, EP-0288394 and U.S. Pat. No. 4,710,508 disclose certain 1,2,5,6-tetrahydropyridin-3-yl oxime ethers.
A novel group of compounds has now been discovered which 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: ##STR2## wherein R.sub.1 represents a 1,2,5,6-tetrahydropyridin-3-yl group N-substituted by R.sub.10 wherein R.sub.10 represents hydrogen, C.sub.1-2 alkyl, prop-2-enyl, prop-2-ynyl or cyclopropyl; 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 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, --SH or --SCH.sub.3 and n is 0 or 1, with the proviso that when n is 0, R.sub.9 is not --SH.
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, for certain compounds, 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.
Examples of R.sub.10 include hydrogen, methyl and ethyl. Preferably R.sub.10 is methyl.
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 methoxy, chloro, fluoro, bromo, CF.sub.3, CHF.sub.2, CFH.sub.2 and when R.sub.3 is a group (CH.sub.2).sub.n R.sub.9 and n is 0, an example of R.sub.9 is --CN. 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: ##STR3## 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; ##STR4## with a compound of formula (V): represents 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 forming a pharmaceutically acceptable salt; ##STR5## wherein R.sub.1 ' is R.sub.1 or a group convertible thereto and wherein R.sub.1 and R.sub.2 are as defined in formula (I), with a chlorinating, brominating or fluorinating agent, converting R.sub.1 ' when other than R.
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Bromidge Steven M.
Dabbs Steven
Orlek Barry S.
Beecham Group p.l.c.
Davis Zinna N.
Hall Linda E.
Ivy C. Warren
Lentz Edward T.
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