US 5,691,349 A · Quinclidine derivatives as squalene synthase inhibitors

Abstract

Quinuclidine derivatives of formula, and their pharmaceutically acceptable salts, in which: R.sup.1 is hydrogen or hydroxy; R.sup.2 is hydrogen; pr 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.dbd.C--, --CH.sub.2 O--, --OCH.sub.2 --, --CH.sub.2 NH--, NHCH.sub.2 --, --CH.sub.2 CO--, --COCH.sub.2 --, --CH.sub.2 S(O).sub.n -- and --S(O).sub.n CH.sub.2 -- wherein n is 0, 1 or 2; and AR is phenyl which may be optionally unsubstituted or substituted by one or more substituents such as halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, dialkylamino, N-alkylcarbamoyl, N,N-di-alkylcarbamoyl, alkoxycarbonyl, alkythio, alkylsulphinyl, alkylsulphonyl, halogeno alkyl, alkanoylamino, alkylenedioxy, alkanoyl and oxime derivatives thereof and O-alkyl ethers of said oximes; provided that when X is selected from --OCH.sub.2 --, --NHCH.sub.2 --, and SCH.sub.2 --, R.sup.1 is not hydroxy; inhibit squalene synthase and are useful in treating diseases or medical conditions in which inhibition of squalene synthase is desirable. The use of such heterocyclic derivatives in treating conditions such as hypercholesterolemia, and atherosclerosis is referred to as well as novel compounds, processes for their preparation and pharmaceutical compositions containing them.

Claims19

Dependent claims

A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R.sup.1 and R.sup.2 are 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.sub.2 S(O).sub.n -- and --S(O).sub.n CH.sub.2 -- wherein n is 0, 1 or 2;
and
Ar is phenyl which may be optionally unsubstituted or substituted by one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino, N-(1-6C)alkylcarbamoyl, N,N-di-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, (1-6C)alkanoylamino, (1-4)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and O-(1-6C)alkyl ethers of said oximes;
but excluding those compounds in which:
X is --CH.sub.2 CO-- and Ar is phenyl which is unsubstituted or substituted by one or more groups selected from trifluoromethyl, halogeno and (1-6C)alkoxy;
R.sup.1 and R.sup.2 are hydrogen and X is selected from --CH.sub.2 O--, --OCH.sub.2 --, --CH.sub.2 S(O).sub.n -- and --S(O).sub.n CH.sub.2 --;
R.sup.1 and R.sup.2 are hydrogen and X is --NHCH.sub.2 --, and Ar is phenyl substituted by one or more groups selected from (1-6C)alkoxy and halogeno;
R.sup.1 and R.sup.2 are hydrogen, X is --CH.dbd.CH-- and Ar is phenyl which is unsubstituted or substituted by one or more halogeno groups;
R.sup.1 and R.sup.2 are hydrogen, X is --CH.sub.2 NH-- and Ar is unsubstituted phenyl;
and
R.sup.1 and R.sup.2 are hydrogen, X is --CH.sub.2 CH.sub.2 -- and Ar is phenyl which is unsubstituted or substituted by a halogeno, hydroxy, alkyl, alkoxy, amino, cyano, nitro, alkanoylamino carbamoyl, alkylsulphonyl or alkylcarbamoyl substituent.

10 more elements

A method for the inhibition of cholesterol biosynthesis in a warm blooded animal in need thereof comprising the administration of a cholesterol biosynthesis inhibiting amount of a compound of formula I:

##STR4## or a pharmaceutically acceptable salt 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;
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.sub.2 S(O).sub.n -- and --S(O).sub.n CH.sub.2 -- wherein n is 0, 1 or 2;
and
Ar is phenyl which may be optionally unsubstituted or substituted by one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino, N-(1-6C)alkylcarbamoyl, N,N-di-(1-6C)alkyl!carbamoyl, (1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, (1-6C)alkanoylamino, (1-4C)alkylenedioxy, (1-6C)alkanoyl and oxime derivatives thereof and O-(1-6C)alkyl ethers of said oximes;
provided that when X is selected from --OCH.sub.2 --, --NHCH.sub.2 --, and --S(O).sub.n CH.sub.2 --, R.sup.1 is not hydroxy.

5 more elements

Dependencies are inferred from the claim text.

Quinclidine derivatives as squalene synthase inhibitors

Life of this patent

Quinclidine derivatives as squalene synthase inhibitors

Life of this patent

Abstract

Claims19