This invention relates to polycyclic compounds containing two mono- and/or bicyclic rings and a basic tertiary amino group capable of forming an ammonium ion at biological pH and which reduces levels of serum cholesterol in the body without significantly reducing mevalonic metabolite synthesis. This invention relates also to pharmacological compositions and method of treatment for lowering serum cholesterol levels using the compounds of this invention.
BACKGROUND OF THE INVENTION
This is a divisional of application Ser. No. 07/959,898 filed Oct. 13, 1992 now U.S. Pat. No. 5,385,912 which is a continuation-in-part application of U.S. patent application Ser. No. 07/667,686, now abandoned, filed Mar. 8, 1991 and a continuation-in-part application of PCT Application having Serial Number PCT/US92/01773, filed Mar. 3, 1992.
The present invention relates to 1-aza-bicycloalkyl derivatives of formula I, ##STR00001## wherein X is CH.sub.2 or a single bond; Y is a group of formula ##STR00002## and wherein R has the meanings as defined in the specification, which compounds are alpha 7 nicotinic acetylcholine receptor (nAChR) agonists; to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.
Quinuclidine compounds of the formula I: ##STR1## R.sup.1 is hydrogen or hydroxy; R.sup.2 is hydrogen; or R.sup.1 and R.sup.2 are joined together so that CR.sup.1 --CR.sup.2 is a double bond; X is selected from --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C--, --CH.sub.2 O--, --OCH.sub.2 --, --CH.sub.2 NH--, --NHCH.sub.2 --, --CH.sub.2 CO--, --COCH.sub.2 --, --CH.dbd.N--, --N.dbd.CH--, --CH.sub.2 S--, --SCH.sub.2 --, wherein the sulphur atom in the latter two groups may optionally bear one or two oxygen atoms; and wherein one or both of ring A and ring B may be optionally unsubstituted or independently substituted by one or more substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, alkyl, alkenyl, alkoxy, alkylamino, di-alkyl]amino, N-alkyl]carbamoyl, N,N-di-alkyl]carbamoyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl and halogeno-alkyl; are inhibitors of squalene synthase and are hence useful in treating diseases or medical conditions such as hypercholesterolemia, atherosclerosis and fungal diseases. Methods of using these compounds to treat such conditions, novel compounds, processes for making these compounds and pharmaceutical compositions containing them are claimed.
Biphenylylquinuclidine compounds of the formula I: ##STR1## and pharmaceutically-acceptable salts thereof; wherein R.sup.1 is hydrogen or hydroxy; R.sup.2 is hydrogen; or R.sup.1 and R.sup.2 are joined together so that CR.sup.1 -CR.sup.2 is a double bond; and one or both ring A and ring B may be optionally unsubstituted or independently substituted by one or more substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-[(1-6C)alkyl]carbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl and halogeno-(1-6C)alkyl; are inhibitors of squalene synthase and are hence useful in treating diseases or medical conditions such as hypercholesterolemia, atherosclerosis and fungal diseases. Methods of using these compounds to treat such conditions, novel compounds, processes for making these compounds and pharmaceutical compositions containing them are claimed.
Quinuclidine compounds of the formula I: ##STR1## R.sup.1 is hydrogen or hydroxy; R.sup.2 is hydrogen; or R.sup.1 and R.sup.2 are joined together so that CR.sup.1 --CR.sup.2 is a double bond; X is selected from --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C--, --CH.sub.2 O--, --OCH.sub.2 --, --CH.sub.2 NH--, --NHCH.sub.2 --, --CH.sub.2 CO--, --COCH.sub.2 --, --CH.dbd.N--, --N.dbd.CH--, --CH.sub.2 S--, --SCH.sub.2 --, wherein the sulphur atom in the latter two groups may optionally bear one or two oxygen atoms; and wherein one or both of ring A and ring B may be optionally unsubstituted or independently substituted by one or more substituents selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, alkyl, alkenyl, alkoxy, alkylamino, di-alkyl!amino, N-alkyl!carbamoyl, N,N-di-alkyl!carbamoyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl and halogeno-alkyl; are inhibitors of squalene synthase and are hence useful in treating diseases or medical conditions such as hypercholesterolemia, atherosclerosis and fungal diseases. Methods of using these compounds to treat such conditions, novel compounds, processes for making these compounds and pharmaceutical compositions containing them are claimed.
