A METHOD OF TREATING HYPERCHOLESTEROLEMIA AND RELATED DISORDERS

Abstract: The invention relates to the use of a class of compounds (I) which are squalene synthetase inhibitors in the treatment of diseases associated with undesirable cholesterol levels in the body, and particularly diseases of the cardiovascular system, such as atherosclerosis. In said formula (I), G is selected from one of the azabicyclic rings (a) or (b) wherein the thiadazole ring can be attached at any carbon atom of the azabicyclic ring.

Description: A Method of Treating Hypercholesterolemia and related Disorders Field of the Invention The present invention relates to the use of a class of compounds which are squalene synthetase inhibitors in the treatment of diseases associated with un¬ desirable cholesterol levels in the body, and particularly diseases of the cardio¬ vascular system, such as atherosclerosis. Background of the Invention Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. An important risk factor for the development of atherosclerosis is an atherogenic lipid profile i.e. hyperlipidaemia with increased LDL-cholesterol and relatively decreased HDL-cholesterol. Typically, cholesterol is carried in the blood of warm blooded animals in certain lipid-protein complexes such as chylomicrons, very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). It is widely accepted that LDL functions in a way that directly results in deposition of the LDL cholesterol in the blood vessel wall and that HDL functions in a way that results in the HDL picking up the cholesterol from the vessel wall and transport¬ ing it to the liver where it is metabolized (Brown and Goldstone, Ann. Rev. Be¬ came. 52, 223 ( 1 983); Miller, Ann. Rev. Med. 31 , 97 (1 980)). It is generally ac- cepted by those skilled in the art that reduction of abnormally high LDL (low den¬ sity lipoprotein) cholesterol levels is effective therapy not only in the treatment of hypercholesterolemia but also in the treatment of atherosclerosis. The enzyme squalene synthase (also known as squalene synthetase) is the en- zyme involved in the first committed step in the de novo cholesterol biosynthe¬ sis. This enzyme is a microsomal enzyme that catalyses the reductive dimerization of two molecules of farnesyl diphosphate to form squalene. Squalene is utilized only for cholesterol biosynthesis whereas farnesyl diphosphate serves as the precur¬ sor to several other biologically important compounds. The inhibition of squalene synthase would thus hinder cholesterol biosynthesis while leaving unhindered other essential pathways to e.g dolichol, ubiquinone, isopentyl tRNA and preny- lated proteins. Even though there has already been discovered squalene synthetase inhibitors a need still remains for a more effective squalene synthetase inhibitor i.e. one that provides a better antihypercholesteremic effect and exhibits a good safety pro¬ file. We have discovered a new class of squalene synthetase inhibitors which have not previously been considered for the use in treating hypercholesterolemia and related disorders. Summary of the Invention The method of this invention comprises administering to a patient suffering from hypercholesterolemia and related disorders an effective amount of a compound of formula I wherein R is -Z'-R 4 , -Z'-R^-R 6 , -Z 1 -R 6 -Z 2 -R 7 -Z 3 -R 5 , -Z 1 -R 6 -CO-R 5 , -Z 1 -R 6 -CO 2 -R 5 , -Z^R^OaC-R 6 , -Z 1 -R 6 -CONH-R 5 , -Z'-R^NHCO-R 5 , -Z'-R^Y, -Z'-R^-Y or -Z'-R^Z^R'-Y, wherein Z\ Z 2 and Z 3 independently are -0-, -S- or -NH; and R 4 is C 3.15 -alkyl, C 2 . 15 -alkenyl, C 2 . 15 -alkynyl, each of which is optionally substituted with one or more halogen(s), C^-alkoxy, -CF 3 , -CN, -COOH, -OH, -SH, -NR 8 R 9 , C^-alkyl ester, C 3 . 10 -cycloalkyl, C 4 . 10 -cycloalkenyl, phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphthyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, -N0 2 , -CN, C^-alkyl, C,. 4 - alkoxy, -OCF 3 , -CF 3 , -CONH 2 , -CSNH 2 , -NH 2 , phenoxy or phenyl, or R 4 is C 1 . 2 -alkyl substituted with one or more halogen(s), C^-alkoxy, -CF 3 , -CN, -COOH, -OH, -SH, -NR 8 R 9 , C^-alkyl ester, C 3 . 10 -cycloalkyl, C 4 . 10 -cycloalkenyl, phenyl, benzy¬ loxycarbonyl, phenoxy, benzoyl, tetrahydronaphtyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, -N0 2 , -CN, C,. 4 -alkyl, C,. 4 -alkoxy, -OCF 3 , -CF 3 , -CONH 2 , -CSNH 2 , -NH 2 , phenoxy or phenyl; and R 5 is C 2 . 15 -alkenyl, C 2 . 15 -alkynyl, each of which is optionally substituted with one or more halogen(s), C^-alkoxy, -CF 3 , -CN, -COOH, -OH, -SH, -NR 8 R 9 , ester, C 3 . 10 -cycloalkyl, C 4 . 10 -cycloalkenyl, phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphtyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, -NO 2 , -CN, C 1-4 -alkyl, C 1-4 - alkoxy, -OCF 3 , -CF 3 , -CONH 2 , -CSNH 2 , -NH 2 , phenoxy or phenyl; and R 6 and R 7 independently are C 1-10 -alkylene, C 2 . 10 -alkenylene, C 2 . 10 -alkynylene, each of which is optionally substituted with one or more halogen(s), C^-alkoxy, -CF 3 , -CN, -COOH, -OH, -SH, -NR 8 R 9 , C^-alkyl ester, C 3 . 10 -cycloalkyl, C 4-10 -cycloalke- nyl, phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphtyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, -N0 2 , -CN, C^-alkyl, C^-alkoxy, -OCF 3 , -CF 3 , -CONH 2 , -CSNH 2 , -NH 2 , phenoxy or phenyl; and R 8 and R 9 independently are hydrogen or C,. 6 -alkyl; and Y is a 5 or 6 membered heterocyclic group containing one to four N, O or S atom(s) or a combination thereof, which heterocyclic group is optionally substi¬ tuted at carbon and/or nitrogen atom(s) with straight or branched C^-alkyl, phenyl or benzyl, or a carbon atom in the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group; and G is selected from one of the following azabicyclic rings wherein the thiadiazole ring can be attached at any carbon atom of the azabi¬ cyclic ring; and R 1 and R 2 may be present at any position including the point of attachment of the thiadiazole ring, and independently are hydrogen, C 5 -alkyl, C 2 . 5 -alkenyl, C 2 . 5 - alkynyl, C^^-alkoxy, C^-alkyl substituted with -OH, -OH, halogen, -NH 2 or -COOH; and R 3 is hydrogen, C^-alky!, C 2 . 5 -alkenyl or C 2 . 5 -alkynyl; and n is 0, 1 or 2; and m is 0, 1 or 2; and p is 0, 1 or 2; and q is 1 or 2; and is a single or double bond; or a pharmaceutically acceptable salt thereof. Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, ££, 2 ( 1 977) which are hereby in ¬ corporated by reference. Especially preferred salts include tartrate and hydrochloride. Preferred Y substituents include thienyl, tetrazolyl, thiadiazolyl, benzothiazolyl, phtalimido, pyridyl and 1 ,3-dioxolanyl. The terms alkyl, alkenyl, alkynyl, alkoxy, alkylene, alkenylene and alkynylene are intended to mean straight or branched alkyl, alkenyl, alkynyl, alkoxy, alkylene, alkenylene and alkynylene. It is to be understood that the invention extends to each of the stereoisomeric forms of the compounds of formula I as well as the racemates. As used herein, the term patient includes any mammal which could benefit from treatment of hypercholesterolemia and related disorders. The term particularly refers to a human patient, but is not intended to be so limited. The thiadiazole compounds used in the presently claimed method have been dis- closed and claimed in PCT/DK91 /00236, PCT/DK94/00092, PCT/DK94/00309 and PCT/DK94/00475 herein incorporated by reference in their entirety. The thiadiazole compounds are known to be useful in the treatment of presenile and senile dementia. The compounds are believed to be useful for treating Alzhei¬ mer's disease, glaucoma, painful conditions, psychosis and gastrointestinal dis- orders. Accordingly, there is no disclosure in these references of using the compounds to treat hypercholesterolemia and related disorders. Preferred compounds for use in treating hypercholesterolemia and related disor- ders include: 3-(3-Hexyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]-oct-2-ene; 3-Hexyloxy-3-(3-hexyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-Hexyloxy-1 ,2,5-thiadiazol-4-yl)-3-hydroxy-1 -azabicyclo[2.2.2]octane; 3-(3-Propoxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-Butoxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-Pentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-Butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-Hexylthio-1 ,2,5-thiadiazol-4- /l)-1 -azabicyclo[2.2.2]octane; 3-(3-(3-Phenylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(4-Cyanobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; Endo-6-(3-hexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]octane; Endo-6-(3-(5-hexenylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]octane; Endo-6-(3-butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-pentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Endo-6-(3-(3-phenylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Endo-6-(3-(4-cyanobenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Exo-6-(3-hexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Exo-6-(3-butylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Exo-6-(3-pentylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Endo-3-(3-pentylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Endo-3-(3-(3-phenylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Endo-3-(3-butylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Endo-3-(3-propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Exo-3-(3-pentylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Exo-3-(3-hexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Exo-3-(3-propylthio-1 , 2, 5-thiadiazol-4-yI)-1 -azabicyclo[2.2.1 Jheptane; Exo-3-(3-(3-phenylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Exo-3-(3-butylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; 3-(3-Hexyloxy-1 ,2, 5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(5-Hexenyloxy)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(3-Hexenyloxy)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-Pentyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-lsopentyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-Propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-Heptylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; Endo-6-(3-propylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-3-(3-hexylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Exo-6-(3-pentyloxy-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-pentyloxy-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; 4-Chloro-3-(3-propyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.3.1 Jnon-3ene; 4-Chloro-3-(3-pentyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.3.1 ]non3-ene; (-) 3-(3-Butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; ( + > 3-(3-Butγlthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 5-(3-Hexylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5S,6S)-6-(3-butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5R,6R)-6-(3-propylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5S,6S)-6-(3-propylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(2,2,3,3,4,4,4-heptafluorobutyloxy)-1 ,2,5-thiadiazol-4-yl)- 1 -azabicyclo- [3.2.1 loctane; Exo-6-(3-propoxy-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-butoxy-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Exo-6-(3-pentyloxy-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-hexyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-isohexyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(2-butynyloxy)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(3-(2-thienyl)-1 -propylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; Endo-6-(3-(3-(2-thienyl)-1 -propylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]- octane; Endo-6-(3-(4,4,4-trifluorobutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]- octane; Endo-6-(3-(6,6,6-trifluoro-1 -hexylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]- octane; (5S,6S)-6-(3-(4,4,4-trifluoro-1 -butylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; Endo-3-(3-(2-phenoxyethylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Endo-3-(3-(2-thienyl)propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Endo-3-(3-(2-phenylthio)ethylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [2.2.1 Jheptane; Exo-6-(3-heptylthio- 1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-isohexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-isopentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(4-cyanobutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-cyanomethylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(2-cyanoethylthio)-1 , 2, 5-thiadiazol-4-yl)- 1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(3-cyanopropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(4-cyanobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(3-phenylpropylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(2-phenoxyethylthio)-1 , 2, 5-thiadiazol-4-yl)- 1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-benzylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-(2-phenoxyethylthio)-1 , 2, 5-thiadiazol-4-yl)- 1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-isopentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-isohexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-benzylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-cyanomethylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-(2-cyanoethylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-(3-cyanopropylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-(4-cyanobutylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; 4-Chloro-3-(3-butoxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.3. 1 ]non-3-ene; 4-Chloro-3-(3-hexyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.3.1 Jnon-3-ene; 3-(3-Butoxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.3.1 Jnon-3-ene; 3-(3-Propoxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.3.1 Jnon-3-ene; 3-(3-Hexyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.3. 1 ]non-3-ene; 3-(3-lsopentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-( 1 -Methylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-lsobutylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-(2-Phenoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-Cyanomethylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(3-(2-Thienyl)propylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(4-Chlorobutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-( 1 -Methyltetrazol-5-ylthio)butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [2.2.2Joctane; 3-(3-(2-Methyl-1 ,3,4-thiadiazol-5-ylthio)butylthio-1 ,2,5-thiadiazol-4-yl)-1 - azabicyclo[2.2.2Joctane; 3-(3-(4-(2-Benzothiazolyl)thio)butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2J- octane; 3-(3-(4-Ethylbenzyloxy)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(3-(2-Thienyl)propoxy)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; (5R,6R)-6-(3-butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; 3-(3-(N-(2-Ethylthio)phthalimide)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-(2-Methoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-(2-(1 ,3-Dioxolan-2-yl)ethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2J- octane; 3-(3-(4-Pyridylmethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-Cyclopropylmethylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(4-Fluorobenzylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; Exo-6-(3-(4-fluorobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(4-chlorobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(4-methylbenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(4-trifluoromethoxybenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; Exo-6-(3-(4-thiocarbamylbenzyIthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; Exo-6-(3-(4-methylsulfonylbenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; Exo-6-(3-(5,5,5-trifluoropentylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; Exo-6-(3-(3,3,3-trifluoropropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; Endo-6-(3-(4-trifluoromethoxybenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; Endo-6-(3-(4-methylbenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2. 1 Joctane; Endo-6-(3-(4-fluorobenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5R,6R)-6-(3-(4-cyanobenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joct¬ ane; (5S,6S)-6-(3-(4-cyanobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]oct- ane; (5S,6R)-6-(3-propylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5R,6R)-6-(3-isohexylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5S,6S)-6-(3-isohexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; <5R,6S)-6-(3-isohexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5S,6R)-6-(3-(4,4,4-trifluorobutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]- octane; (5R,6S)-6-(3-(4,4,4-trifluorobutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; (5S,6R)-6-(3-(4-cyanobenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joct¬ ane; (5R,6S)-6-(3-(4-cyanobenzylthio)- 1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]oct- ane; (5R,6S)-6-(3-propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5R,6R)-6-(3-(3,3,3-trif luoropropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]- octane; (5R,6R)-6-(3-(3-(2-thienyl)propylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 l- octane; (5R,6R)-6-{3-(4,4,4-trifluorobutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; (5R,6S)-6-(3-(3,3,3-trifluoropropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; Exo-3-(3-(4-cyanobenzylthio)-1 , 2, 5-thiadiazol-4-yl)- 1 -azabicyclo[2.2.1 Jheptane; Exo-6-(3-cyclopropylmethylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2. 1 Joctane; Exo-6-(3-(2-( 1 ,3-dioxolan-2-yl)-ethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; Exo-6-(3-(4-methoxybenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(2-methoxyethylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(3-hydroxypropylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Exo-6-(3-(4,4,4-trifluorobutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; Endo-6-(3-cyclopropylmethylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-(4-methoxybenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; Endo-6-(3-(2-methoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-(4-trifluoromethylbenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 loctane; 5-(3-(4-Cyanobenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; ( + )-Exo-6-(3-pentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; { -H-Exo-6-(3-hexylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (-)-Exo-6-(3-pentγlthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (-)-Exo-6-(3-hexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane: ( + )-Endo-6-(3-pentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; ( + )-Endo-6-(3-hexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (-)-Endo-6-(3-pentylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (-)-Endo-6-(3-hexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; ( + )-Exo-6-(3-(4-trifluoromethylbenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 loctane; ( + )-Exo-6-(3-(4-nitrobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; ( + )-Exo-6-(3-(2-hydroxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]- octane; Endo-2-methyl-6-(3-propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2. 1 loctane; Endo-8-methyl-6-(3-propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2. 1 loctane; Exo-2-methyl-6-(3-propylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Exo-8-methyl-6-(3-propylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-2-methyl-6-(3-butylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-8-methyl-6-(3-butylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Exo-2-methyl-6-(3-hexylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Exo-8-methyl-6-(3-hexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(2-cyanobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(3-cyanobenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Exo-6-(3-(2-trifluoromethylbenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 loctane; Exo-6-(3-(3-trifluoromethylbenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 loctane; Endo-6-(3-(2-cyanobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; 3-(3-(2-Hydroxybutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(2-Butanonylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(3-Phenoxybenzyloxy)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-(4-Carboxybutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(3-Hydroxybutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-(4-Hydroxybutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; ( + ) 3-(3-(2-Butanonylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; ( + ) 3-(3-(2-Hydroxybutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; ( + )-Exo-6-(3-(2-propanonylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; ( + )-Exo-6-(3-(2-hydroxypropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; ( + )-Exo-6-(3-(3-phenylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicycio[3.2.1 l- octane; (-)-Exo-6-(3-(3-phenylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; ( + )-Endo-6-(3-(3-phenylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; (-)-Endo-6-(3-(3-phenylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; ( + )-Exo-6-(3-(4-fluorophenoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 loctane; (-)-Exo-6-(3-(4-fluorophenoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; ( + }-Endo-6-(3-(4-fluorophenoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; (-)-Endo-6-(3-(4-fluorophenoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; or a pharmaceutically acceptable salt thereof. Methods Squalene synthease inhibition assay in vitro a) Rat liver microsomal preparation Male rats weighing 200 to 300 g were decapitated and the liver removed and placed in 1 0 ml icecold 0.25 M sucrose, 2mM EDTA and 50 mM Tris, HCI buffer pH 7.4. The liver was homogenized in 3 x volume buffer relative to weight using a glass teflon Potter-Elvehjem homogenizer set to 1 000 rpm. The homogenate was then centrifuged for 1 5 min. at 1 2,000 x g at 4°C. The re¬ sultant supernatant was gently decanted into 1 0 ml ultracentrifuge vials and treated at 1 00,000 x g for 60 min. at 4°C. The microsomal pellet was resus¬ pended in a final volume of 1 ml icecold 0.1 M phosphate buffer pH 7.4 per gram liver tissue by gentle homogenization in a glass Potter-Elvehjem at 800 rpm. Aliquots of 0.5 ml (approx. 20 mg/ml protein) was stored at -80°C until fur¬ ther use in the squalene synthetase inhibition assay. b) Assay procedure To begin the assay, 20 μl of the compound of this invention or vehicle solution is added to each 1 6 x 1 50 screw-cap culture tube on ice. Then 580 μl of N 2 flushed assay buffer is pipetted into each tube. 100 μl of cofactor is next added to each tube, followed by 1 00 μl of a dilution of microsomal enzyme (approximately 80 μg protein). The tubes are preincubated for 10 min. at 37°C, and 200 μl of the 3 H-FPP (200,000 dpm, 1 0 μM final cone.) is added to each tube at two second intervals. The tubes are then incubated for exactly 10 min., shaking at 1 50 oscillations per min. After the 1 0 min. incubation, the reaction is stopped by the addition of 1 ml of 1 5% KOH in ethanol, and the tubes are incu¬ bated for 30 min. in a 65°C water bath for saponification of lipids and solubiliza- tion of proteins. The tubes are cooled on ice for five min. The samples are next extracted with 5 ml of petroleum ether by shaking for 1 0 min. at low speed on a metabolic shaker. Each lower aqueous layer is frozen in a dry ice/alcohol bath (2- propanol/methanol, 1 : 1 ), and each organic layer is poured into another set of 1 6 x 1 50 screw-top culture tubes containing 2 ml of deionized water. Each ether layer is washed by vortexing each tube for 5 sec. The aqueous layers are again frozen in the dry ice/alcohol bath, and the ether is poured into scintillation vials. 10 ml of AquaSol * is next added to each vial, and the vials are counted for 5 min. in a scintillation counter. Percent inhibitions are calculated from the counts obtained. Test results obtained by testing some compounds of the present invention will appear from the following Table 1 : TABLE 1 SQUALENE SYNTHETASE INHIBITION G R IC50 uM % max 12.4 r ^ ^ 1 - 4 5 5 N endo s 0 0.89 92 s^ /^ 3.9 60 • The compounds used in this method are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used. A most preferable dosage is about 1 0 mg to about 70 mg per day. In choosing a regimen for patients suffering from hypercholesterolemia and related disorders it may frequently be necessary to begin with a dosage of from about 30 to about 70 mg per day and when the condition is under control to reduce the dosage as low as from about 1 to about 1 0 mg per day. The exact dosage will depend upon the mode of administration, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge. The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or par¬ enteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular, topi¬ cal, intranasal or an ointment, the oral route being preferred. Typical compositions include a compound of formula I or a pharmaceutically ac¬ ceptable acid addition salt thereof, associated with a pharmaceutically acceptable carrier. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liq¬ uid material which acts as a vehicle, excipient, or medium for the active com¬ pound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lac¬ tose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone. The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds. For parenteral application, particularly suitable are injectable solutions or suspen¬ sions, preferably aqueous solutions with the active compound dissolved in poly- hydroxylated castor oil. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tab¬ lets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed. Generally, the compounds are dispensed in unit form comprising from about 1 to about 1 00 mg in a pharmaceutically acceptable carrier per unit dosage. A typical tablet, appropriate for use in this method, may be prepared by conven¬ tional tabletting techniques and contains: Active compound 5.0 mg Lactosum 67.8 mg Ph.Eur. Avicel ® 31 .4 mg Amberlite ® 1 .0 mg Magnesii stearas 0.25 mg Ph. Eur.

Claims: CLAIMS L A method of inhibiting squalene synthetase in a subject in need thereof comprising administering to said subject an effective amount of a compound of formula I wherein R is -Z'-R 4 , -Z'-R^Z'-R 5 , -Z'-R^-R'-Z'-R 5 , -Z 1 -R 6 -CO-R 5 , -Z 1 -R 6 -C0 2 -R 5 , -Z 1 -R 6 -Z 2 -Y or -Z'-R'-Z^R'-Y, wherein Z 1 , Z 2 and Z 3 independently are -0-, -S- or -NH-; and R 4 is C 3 . 15 -alkyl, C 2 . 15 -alkenyl, C 2 . 15 -alkynyl, each of which is optionally substituted with one or more halogen(s), C,. 6 -alkoxy, -CF 3 , -CN, -COOH, -OH, -SH, -NR 8 R 9 , phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronap thyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, -N0 2 , -CN, C,. 4 -alkyl, C,^- alkoxy, -OCF 3 , -CF 3 , -CONH 2 , -CSNH 2 , -NH 2 , phenoxy or phenyl, or R 4 is C^-alkyl substituted with one or more halogen(s), C,. 6 -alkoxγ, -CF 3 , -CN, -COOH, -OH, - SH, -NR 8 R 9 , C^-alkyl ester, C 3 . 10 -cycloalkyl, C^^-cycloalkenyl, phenyl, benzy¬ loxycarbonyl, phenoxy, benzoyl, tetrahydronaphtyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, -NO 2 , -CN, C,. 4 -alkyl, C,. 4 -alkoxy, -OCF 3 , -CF 3 , -CONH 2 , -CSNH 2 , -NH 2 , phenoxy or phenyl; and R 5 is C,. 15 -alkyl, C 2 . 15 -alkenyl, C 2 .., 5 -alkynyl, each of which is optionally substituted with one or more halogen(s), C^-alkoxy, -CF 3 , -CN, -COOH, -OH, -SH, -NR 8 R 9 , C 1-6 -alkyl ester, C 3 . 10 -cycloalkyl, C 4 . 10 -cycloalkenyl, phenyl, benzy ¬ loxycarbonyl, phenoxy, benzoyl, tetrahydronaphtyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, -NO 2 , -CN, C,. 4 -alkyl, C^-alkoxy, -OCF 3 , -CF 3 , -CONH 2 , -CSNH 2 , -NH 2 , phenoxy or phenyl; and R 6 and R 7 independently are C,. 10 -alkylene, C 2 . 10 -alkenylene, C 2 . 10 -alkynylene, each of which is optionally substituted with one or more halogen(s), C^-alkoxy, -CF 3 , -CN, -COOH, -OH, -SH, -NR 8 R 9 , C,. 6 -alkyl ester, C 3 . 10 -cycloalkyl, nyl, phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphtyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, -N0 2 , -CN, C^-alkyl, C^-alkoxy, -OCF 3 , -CF 3 , -CONH 2 , -CSNH 2 , -NH 2 , phenoxy or phenyl; and R a and R 9 independently are hydrogen or C,. 6 -alkyl; and Y is a 5 or 6 membered heterocyclic group containing one to four N, O or S atom(s) or a combination thereof, which heterocyclic group is optionally substi¬ tuted at carbon and/or nitrogen atom(s) with straight or branched C,. 6 -alkyl, phenyl or benzyl, or a carbon atom in the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group; and G is selected from one of the following azabicyclic rings wherein the thiadiazole ring can be attached at any carbon atom of the azabi¬ cyclic ring; and R 1 and R 2 may be present at any position including the point of attachment of the thiadiazole ring, and independently are hydrogen, C 1-5 -alkyl, C 2 . 5 -alkenyl, C 2 . 5 - alkynyl, C^ Q -alkoxy, C,. 5 -alkyl substituted with -OH, -OH, halogen, -NH 2 or -COOH; and R 3 is hydrogen, C^-alkyl, C 2 . 5 -alkenyl or C 2 . 5 -alkynyl; and n is 0, 1 or 2; and m is 0, 1 or 2; and p is 0, 1 or 2; and q is 1 or 2; and is a single or double bond; or a pharmaceutically acceptable salt thereof. Z J . The method according to claim 1 wherein the compound is selected from the following: 3-(3-Hexyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]-oct-2-ene; 3-Hexyloxy-3-(3-hexyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2)octane; 3-{3-Hexyloxy-1 ,2,5-thiadiazol-4-yl)-3-hydroxy-1 -azabicyclo[2.2.2]octane; 3-(3-Propoxy-1 ,2,5-thiadiazol-4-yI)-1 -azabicyclo[2.2.2]octane; 3-(3-Butoxy-1 ,2,5-thiadiazol-4-yl)- 1 -azabicyclo[2.2.2Joctane; 3-(3-Pentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-Butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-Hexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(3-Phenylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(4-Cyanobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; Endo-6-(3-hexylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-(5-hexenylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-butylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-pentylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Endo-6-(3-(3-phenylpropylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Endo-6-(3-(4-cyanobenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Exo-6-(3-hexylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-pentylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-3-(3-pentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Endo-3-(3-(3-phenylpropylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Endo-3-(3-butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Endo-3-(3-propylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Exo-3-(3-pentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Exo-3-(3-hexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Exo-3-(3-propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Exo-3-(3-(3-phenylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Exo-3-(3-butylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; 3-(3-Hexyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2loctane; 3-(3-(5-Hexenyloxy)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(3-Hexenyloxy)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2)octane; 3-(3-Pentyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-lsopentyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-Propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-Heptylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; Endo-6-(3-propylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-propylthio-1 , 2, 5-thiadiazol-4-yl)- 1 -azabicyclo[3.2.1 Joctane; Endo-3-(3-hexylthio- 1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Exo-6-(3-pentyloxy-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-pentyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; 4-Chloro-3-(3-propyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.3.1 ]non-3ene; 4-Chloro-3-(3-pentyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.3.1 Jnon3-ene; {-) 3-(3-Butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; ( + ) 3-(3-Butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 5-(3-Hexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5S,6S)-6-(3-butylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; <5R,6R)-6-(3-propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5S,6S)-6-(3-propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(2,2,3,3,4,4,4-heptafluorobutyloxy)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 loctane; Exo-6-(3-propoxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-butoxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-pentyloxy-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-hexyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-isohexyloxy-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(2-butynyloxy)-1 , 2, 5-thiadiazol-4-yl)- 1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(3-(2-thienyl)-1 -propylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; Endo-6-(3-(3-(2-thienyl)-1 -propylthio)- 1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; Endo-6-(3-(4,4,4-trifluorobutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; Endo-6-(3-(6,6,6-trifluoro-1 -hexylthio)- 1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; <5S,6S)-6-(3-(4,4,4-trifluoro-1 -butylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; Endo-3-(3-(2-phenoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Endo-3-(3-(2-thienyl)propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.1 Jheptane; Endo-3-(3-(2-phenylthio)ethylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [2.2.1 Jheptane; Exo-6-(3-heptylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-isohexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-isopentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(4-cyanobutylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-cyanomethylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(2-cyanoethylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(3-cyanopropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(4-cyanobenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(3-phenylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(2-phenoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-benzylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Endo-6-(3-(2-phenoxyethylthio)-1 , 2, 5-thiadiazol-4-yl)- 1 -azabicyclo[3.2.1 loctane; Endo-6-(3-isopentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Endo-6-(3-isohexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Endo-6-(3-benzylthio- 1 , 2, 5-thiadiazol-4-yl)- 1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-cyanomethylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-(2-cyanoethylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-(3-cyanopropylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-(4-cyanobutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; 4-Chloro-3-(3-butoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.3.1Jnon-3-ene; 4-Chloro-3-(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.3.1]non-3-ene; 3-(3-Butoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.3.1]non-3-ene; 3-(3-Propoxy-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.3.1 Jnon-3-ene; 3-(3-Hexyloxy-1 ,2,5-thiadiazol-4-yl)-1-azabicyclo[3.3.1]non-3-ene; 3-(3-lsopentylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane; 3-(3-(1 -MethylpropylthioH ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-lsobutylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane; 3-(3-(2-Phenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane; 3-(3-Cyanomethylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane; 3-(3-(3-(2-Thienyl)propylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane; 3-(3-(4-Chlorobutylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2Joctane; 3-(3-(1-Methyltetrazol-5-ylthio)butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo- [2.2.2]octane; 3-(3-(2-Methyl-1 ,3,4-thiadiazol-5-ylthio)butylthio-1 ,2,5-thiadiazol-4-yl)-1- azabicyclo[2.2.2Joctane; 3-(3-(4-(2-Benzothiazolyl)thio)butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2J- octane; 3-(3-(4-Ethylbenzyloxy)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-(3-(2-Thienyl)propoxy)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; (5R,6R)-6-(3-butylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; 3-(3-(N-(2-Ethylthio)phthalimide)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-(2-Methoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-(2-( 1 ,3-Dioxolan-2-yl)ethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2J- octane; 3-(3-(4-Pyridylmethylthio)-1 ,2,5-thiadiazol-4-yl)- 1 -azabicyclo[2.2.2]octane; 3-(3-Cyclopropylmethylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(4-Fluorobenzylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; Exo-6-(3-(4-fluorobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Exo-6-(3-(4-chlorobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(4-methylbenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(4-trifluoromethoxybenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; Exo-6-(3-(4-thiocarbamylbenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]- octane; Exo-6-(3-(4-methylsulfonylbenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; Exo-6-(3-(5,5,5-trifluoropentylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; Exo-6-(3-(3,3,3-trifluoropropylthio)- 1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; Endo-6-(3-(4-trifluoromethoxybenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; Endo-6-(3-(4-methyIbenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-(4-fluorobenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; (5R,6R)-6-(3-(4-cyanobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loct¬ ane; (5S,6S)-6-(3-(4-cyanobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joct- ane; (5S,6R)-6-(3-propylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5R,6R)-6-(3-isohexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5S,6S)-6-(3-isohexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5R,6S)-6-(3-isohexylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5S,6R)-6-(3-(4,4,4-trifluorobutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]- octane; (5R,6S)-6-(3-(4,4,4-trifluorobutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]- octane; (5S,6R)-6-(3-(4-cyanobenzylthio)-1 , 2, 5-thiadiazol-4-yl)- 1 -azabicyclo[3.2.1 Joct¬ ane; (5R,6S)-6-(3-(4-cyanobenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicγclo[3.2.1 Joct¬ ane; (5R,6S)-6-(3-propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (5R,6R)-6-(3-(3,3,3-trifluoropropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 l- octane; (5R,6R)-6-(3-(3-(2-thienyl)propylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]- octane; (5R,6R)-6-(3-(4,4,4-trifluorobutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 l- octane; (5R,6S)-6-(3-(3,3,3-trifluoropropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; Exo-3-(3-(4-cyanobenzylthio)-1 , 2, 5-thiadiazol-4-yl)- 1 -azabicyclo[2.2.1 Jheptane; Exo-6-(3-cyclopropylmethylthio-1 ,2,5-thiadiazol-4-yl)- 1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(2-( 1 ,3-dioxolan-2-yl)-ethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; Exo-6-(3-(4-methoxybenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(2-methoxyethylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(3-hydroxypropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(4,4,4-trifluorobutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]- octane; Endo-6-(3-cyclopropylmethylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-(3-(4-methoxybenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; Endo-6-(3-(2-methoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Endo-6-{3-(4-trifluoromethylbenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; 5-(3-(4-Cyanobenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; ( + )-Exo-6-(3-pentylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; ( + )-Exo-6-(3-hexylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (-)-Exo-6-(3-pentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; (-)-Exo-6-(3-hexylthio-1 , 2, 5-thiadiazol-4-yl)- 1 -azabicyclo[3.2.1 Joctane: ( - )-Endo-6-(3-pentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]octane; ( + )-Endo-6-(3-hexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; (-)-Endo-6-(3-pentylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; (-)-Endo-6-(3-hexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; ( + )-Exo-6-(3-(4-trifluoromethylbenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 loctane; ( + )-Exo-6-(3-(4-nitrobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; ( + )-Exo-6-(3-(2-hydroxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 l- octane; Endo-2-methyl-6-(3-propylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Endo-8-methyI-6-(3-propylthio-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Exo-2-methyl-6-(3-propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Exo-8-methyl-6-(3-propylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 loctane; Exo-2-methyl-6-(3-butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-8-methyl-6-(3-butylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-2-methyl-6-(3-hexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2. 1 Joctane; Exo-8-methyl-6-(3-hexylthio-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(2-cyanobenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(3-cyanobenzylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; Exo-6-(3-(2-trifluoromethylbenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; Exo-6-(3-(3-trifluoromethylbenzylthio)- 1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; Endo-6-(3-(2-cyanobenzylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; 3-(3-(2-Hydroxybutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(2-Butanonylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(3-Phenoxybenzyloxy)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; 3-(3-(4-Carboxybutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(3-Hydroxybutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; 3-(3-(4-Hydroxybutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; ( + ) 3-(3-(2-Butanonylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2Joctane; ( + ) 3-(3-(2-Hydroxybutylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[2.2.2]octane; ( + )-Exo-6-(3-(2-propanonylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; ( -I- )-Exo-6-(3-(2-hydroxypropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; ( + )-Exo-6-(3-(3-phenylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; (-)-Exo-6-(3-(3-phenylpropylthio)-1 , 2, 5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 Joctane; ( + )-Endo-6-(3-(3-phenylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 J- octane; (-)-Endo-6-(3-(3-phenylpropylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo[3.2.1 ]- octane; ( + )-Exo-6-(3-(4-fluorophenoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; (-)-Exo-6-{3-(4-fluorophenoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; ( + )-Endo-6-(3-(4-fluorophenoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 Joctane; (-)-Endo-6-(3-(4-fluorophenoxyethylthio)-1 ,2,5-thiadiazol-4-yl)-1 -azabicyclo- [3.2.1 ]octane; or a pharmaceutically acceptable salt thereof. i. A method of treating hypercholesterolemia in a subject in need thereof comprising administering to said subject an effective amount of a compound ac¬ cording to claim 1 . 4 x method of treating hypercholesterolemia in a subject in need thereof comprising administering to said subject an effective amount of a compound ac¬ cording to claim 2. IL. The use of a compound according to claim 1 or a pharmaceutically ac- ceptable salt thereof for the preparation of a medicament for inhibiting squalene synthetase. i The use of a compound according to claim 1 or a pharmaceutically ac¬ ceptable salt thereof for the preparation of a medicament for treatment of hypercholesterolemia. 2 * The use of a compound according to claim 2 or a pharmaceutically ac¬ ceptable salt thereof for the preparation of a medicament for inhibiting squalene synthetase. S The use of a compound according to claim 2 or a pharmaceutically ac¬ ceptable salt thereof for the preparation of a medicament for treatment of hypercholesterolemia.

Inventors: HANSEN KRISTIAN TAGE, SAUERBERG PER, HANSEN, KRISTIAN, TAGE, SAUERBERG, PER
Applicants: NOVONORDISK AS, NOVO NORDISK A/S
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, A61P3, A61P9, C07D453, C07D471, C07D487