Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-09-01
1994-06-28
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514242, 544182, 540585, C07D40304, A61K 3153
Patent
active
053247248
DESCRIPTION:
BRIEF SUMMARY
This invention relates to compounds having pharmaceutical activity, to a process for their preparation and their use as pharmaceuticals.
EP-0327155 discloses certain substituted pyrazines, pyrimidines and pyridazines useful in the treatment of senile dementia.
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: ##STR1## in which one of X and Y represents hydrogen and the other represents Z, where Z is a group ##STR2## where R is selected from hydrogen, OR.sub.1 , SR.sub.1 , N (R.sub.1 ).sub.2, NHCOR.sub.1, NHCOOCH.sub.3, NHCOOC.sub.2 H.sub.5, NHOR.sub.1, NHNH.sub.2, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, cyclopropyl or C.sub.1-2 alkyl optionally substituted with OR.sub.1, N(R.sub.1).sub.2, SR.sub.1, CO.sub.2 R.sub.1, CON(R.sub.1).sub.2 or one, two or three halogen atoms, in which each R.sub.1 is independently hydrogen or C.sub.1-2 alkyl; r represents an integer of 2 or 3, s represents an integer of 1 or 2 and t represents 0 or 1, with the proviso that when Y is hydrogen s is 1.
Certain compounds of formula (I) are capable of existing in a number of stereoisomeric forms including 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.
In compounds of formula (I) having two assymmetric centres where Y is other than hydrogen, the stereochemical configuration in which the group Y and the (CH.sub.2)s bridge are on the same side of the plane of the molecule which contains both bridgehead atoms and the ring carbon atom bonded to the group Y will herein be referred to as the exo configuration. Similarly, the configuration of compounds in which the group Y and the bridge (CH.sub.2)s are on opposite sides of the above-mentioned plane of the molecule will herein be referred to as the endo configuration. Preferably compounds of formula (I) have the exo configuration. 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.
Preferred combinations of (r, s, t) include (2, 2, 0) , (3, 1, 0) , (2, 1, 0) , (2, 1, 1) and (3, 1, 1) .
Preferably R.sub.1 is hydrogen or methyl. Preferably R when C.sub.1-2 alkyl is unsubstituted. Preferred values for R include hydrogen, C.sub.1-2 alkyl, cyclopropyl, OR.sub.1 , SR.sub.1 or N (R.sub.1 ).sub.2.
Examples of R include hydrogen, methyl, ethyl, methoxy, methylthio, cyclopropyl, amino and dimethylamino.
R is preferably methyl or ethyl.
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) cyclising a compound of formula (II): ##STR3## in which (i) A represents Z or a group convertible thereto and B represents --(CH.sub.2).sub.j L.sub.1 where L.sub.1 is a leaving group or A and L.sub.1 together represent --COO--; one of j, k and l is 1 and the other two independently represent an integer of 2 or 3, and R.sub.5 represents hydrogen or an N-protecting group; to give a compound of formula (IIa): ##STR4## in which A' represents Z or a group convertible thereto, x-is an anion and the remaining variables are as previously defined;
or (ii) A represents an electron withdrawing group, B represents hydrogen and R.sub.5 represents --(CH2).sub.j L.sub.2 where L.sub.2 is a leaving group; one of k and l is 1 and the other and j independently represent an integer of 2 or 3; to give a compound of formula (IIb): ##STR5## in whic
Faulkner Richard E.
Orlek Barry S.
Beecham Group p.l.c.
Ford John M.
Hall Linda E.
Lentz Edward T.
Suter Stuart R.
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