# Patent

## Title
Heteroaryl diol acids as leukotriene antagonists

## Abstract

The present invention relates to a novel method for treating a mammal suffering from hypercholesterolemia and related disorders.

## Background
This application claims priority under 35 U.S.C. 119 of Danish application serial No. 0002/96 filed Jan. 4, 1996, the contents of which are fully incorporated herein by reference.

The present invention relates to the use of a class of compounds 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.

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 transporting it to the liver where it is metabolized (Brown and Goldston, Ann. Rev. Became 52, 223 (1983); Miller, Ann. Rev. Med. 31, 97 (1980)). It is generally accepted by those skilled in the art that reduction of abnormally high LDL (low density lipoprotein) cholesterol level 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 enzyme involved in the first committed step in the de novo cholesterol biosynthesis.

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 precursor 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 prenylated 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 profile.

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.

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 ##STR1## wherein R is --Z.sup.1 --R.sup.4, --Z.sup.1 --R.sup.6 --Z.sup.2 --R.sup.5, --Z.sup.1 --R.sup.6 --Z.sup.2 --R.sup.7 --Z.sup.3 --R.sup.5, --Z.sup.1 --R.sup.6 --CO--R.sup.5, --Z.sup.1 --R.sup.6 --CO.sub.2 --R.sup.5, --Z.sup.1 --R.sup.6 --O.sub.2 C--R.sup.5, --Z.sup.1 --R.sup.6 --CONH--R.sup.5, --Z.sup.1--R.sup.6 --NHCO--R.sup.5, --Z.sup.1 --R.sup.6 --Y, --Z.sup.1 --R.sup.6 --Z.sup.2 --Y or --Z.sup.1 --R.sup.6 --Z.sup.2 --R.sup.7 --Y, wherein Z.sup.1, Z.sup.2 and Z.sup.3 independently are --O--, --S --or --NH; and R.sup.4 is C.sub.3-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more halogen(s), C.sub.1-6 -alkoxy, --CF.sub.3, --CN, --COOH, --OH, --SH, --NR.sup.8 R.sup.9, C.sub.1-6 -alkyl ester, C.sub.3-10 -cycloalkyl, C.sub.4-10 -cycloalkenyl, phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphthyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, --NO.sub.2, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2, --CSNH.sub.2, --NH.sub.2, phenoxy or phenyl, or R.sup.4 is C.sub.1-2 -alkyl substituted with one or more halogen(s), C.sub.1-6 -alkoxy, --CF.sub.3, --CN, --COOH, --OH, --SH, --NR.sup.8 R.sup.9, C.sub.1-6 -alkyl ester, C.sub.3-10 -cycloalkyl, C.sub.4-10 -cycloalkenyl, phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphtyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, --NO.sub.2, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2, --CSNH.sub.2, --NH.sub.2, phenoxy or phenyl; and R.sup.5 is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkenyl, each of which is optionally substituted with one or more halogen(s), C.sub.1-6 -alkoxy, --CF.sub.3, --CN, --COOH, --OH, --SH, --NR.sup.8 R.sup.9, C.sub.1-6 -alkyl ester, C.sub.3-10 -cycloalkyl, C.sub.4-10 -cycloalkenyl, phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphtyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, --NO.sub.2, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2, --CSNH.sub.2, --NH.sub.2, phenoxy or phenyl; and R.sup.6 and R.sup.7 independently are C.sub.1-10 -alkylene, C.sub.2-10 -alkenylene, C.sub.2-10 -alkynylene, each of which is optionally substituted with one or more halogen(s), C.sub.1-6 -alkoxy, --CF.sub.3, --CN, --COOH, --OH, --SH, --NR.sup.8 R.sup.9, C.sub.1-6 -alkyl ester, C.sub.3-10 -cycloalkyl, C.sub.4-10 -cycloalkenyl phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphtyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, --NO.sub.2, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2, --CSNH.sub.2, --NH.sub.2, phenoxy or phenyl; and 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 substituted at carbon and/or nitrogen atom(s) with straight or branched C.sub.1-6 -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 ##STR2## wherein the thiadiazole ring can be attached at any carbon atom of the azabicyclic ring; and attachment of the thiadiazole ring, and independently are hydrogen, C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, C.sub.1-5 -alkyl substituted with --OH, --OH, halogen, --NH.sub.2 or --COOH; and -alkynyl; and

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, 66, 2 (1977) which are hereby incorporated 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 disclosed 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 Alzheimer's disease, glaucoma, painful conditions, psychosis and gastrointestinal disorders.

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 disorders include: tane; ane; ptane; tane; cyclo3.2.1!octane; .2.1!octane; 3.2.1!octane; 2.1!octane; 3.2.1!octane; col3.2.1!octane; ptane; eptane; !heptane; e; e; ne; ne; ane; ane; tane; ne; ane; ne; tane; lo2.2.2!octane; -azabicyclo2.2.2!octane; o2.2.2!octane; e; !octane; .2.2!octane; ; ; ane; ane; ane; 3.2.1!octane; .1!octane; .2.1!octane; 2.1!octane; 2.1!octane; o3.2.1!octane; tane; tane; octane; octane; 3.2.1!octane; 3.2.1!octane; octane; octane; o3.2.1!octane; 3.2.1!octane; 3.2.1!octane; o3.2.1!octane; ane; tane; clo3.2.1!octane; tane; ane; tane; .1!octane; ctane; ctane; tane; 3.2.1!octane; -azabicyclo3.2.1!octane; clo3.2.1!octane; octane; !octane; ane; ane; ne; ne; e; e; e; e; ne; ne; 3.2.1!octane; 3.2.1!octane; ane; -azabicyclo2.2.2!octane; ne; ctane; 1!octane; !octane; !octane; 2.1!octane; 1!octane; 3.2.1!octane; 3.2.1!octane; o3.2.1!octane; o3.2.1!octane;

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 10 ml icecold 0.25M sucrose, 2 mM EDTA and 50 mM Tris, HCl buffer pH 7.4. The liver was homogenized in 3.times.volume buffer relative to weight using a glass teflon Potter-Elvehjem homogenizer set to 1000 rpm.

The homogenate was then centrifuged for 15 min. at 12,000.times.g at 4.degree. C. The resultant supernatant was gently decanted into 10 ml ultracentrifuge vials and treated at 100,000.times.g for 60 min. at 4.degree. C. The microsomal pellet was resuspended in a final volume of 1 ml icecold 0.1M 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.degree. C. until further use in the squalene synthetase inhibition assay.

b) Assay procedure

To begin the assay, 20 .mu.l of the compound of this invention or vehicle solution is added to each 16.times.150 screw-cap culture tube on ice. Then 580 .mu.l of N.sub.2 flushed assay buffer is pipetted into each tube. 100 .mu.l of cofactor is next added to each tube, followed by 1 00 .mu.l of a dilution of microsomal enzyme (approximately 80 .mu.g protein). The tubes are preincubated for 10 min. at 37.degree. C., and 200 .mu.l of the .sup.3 H-FPP (200,000 dpm, 10 .mu.M final conc.) is added to each tube at two second intervals. The tubes are then incubated for exactly 10 min., shaking at 150 oscillations per min. After the 10 min. incubation, the reaction is stopped by the addition of 1 ml of 15% KOH in ethanol, and the tubes are incubated for 30 min. in a 65.degree. C. water bath for saponification of lipids and solubilization 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 10 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 16 .times.150 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.RTM. 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: __________________________________________________________________________ SQUALENE SYNTHETASE INHIBITION G          R                 IC50 uM % max __________________________________________________________________________ ##STR3## ##STR4##         12.4  55 ##STR5## ##STR6##          0.89 92 ##STR7## ##STR8##          0.90 89 ##STR9## ##STR10##        0.3   83 ##STR11## ##STR12##        3.9   60 ##STR13## ##STR14##        5.1   72 ##STR15## ##STR16##        1.1   80 __________________________________________________________________________

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 10 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 10 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 parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular, topical, intranasal or an ointment, the oral route being preferred.

Typical compositions include a compound of formula I or a pharmaceutically acceptable 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 liquid material which acts as a vehicle, excipient, or medium for the active compound. 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, lactose, 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 suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated 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 tablets, 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 100 mg in a pharmaceutically acceptable carrier per unit dosage.

A typical tablet, appropriate for use in this method, may be prepared by conventional tabletting techniques and contains: Active compound    5.0    mg Lactosum           67.8   mg Ph. Eur. Avicel .RTM.       31.4   mg Amberlite .RTM.    1.0    mg Magnesii stearas   0.25   mg Ph. Eur. ______________________________________

## Claims

1. A method of inhibiting squalene synthetase or treating hypercholesterolemia in a subject in need thereof comprising administering to the subject an effective amount of a compound of formula I ##STR17## wherein R is --Z.sup.1 --R.sup.4, --Z.sup.1 --R.sup.6 --Z.sup.2 --R.sup.5, --Z.sup.1 --R.sup.6 --Z.sup.2 --R.sup.7 --Z.sup.3 --R.sup.5, --Z.sup.1 --R.sup.6 --CO--R.sup.5, --Z.sup.1 --R.sup.6 --CO.sub.2 --R.sup.5, --Z.sup.1 --R.sup.6 --O.sub.2 C--R.sup.5, --Z.sup.1 --R.sup.6 --CONH--R.sup.5, --Z.sup.1 --R.sup.6 --NHCO--R.sup.5, --Z.sup.1 --R.sup.6 --Y, --Z.sup.1 --R.sup.6 --Z.sup.2 --Z or --Z.sup.1 --R.sup.6 --Z.sup.2 --R.sup.7 --Y, wherein Z.sup.1, Z.sup.2 and Z.sup.3 independently are --O--, --S-- or --NH--; R.sup.4 is C.sub.3-15 -alkyl, C.sub.2-15 -alkenyl, or C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more halogen(s), C.sub.1-6 -alkoxy, --CF.sub.3, --CN, --COOH, --OH, --SH, --NR.sup.8 R.sup.9, C.sub.1-6 -alkyl ester, C.sub.3-10 -cycloalkyl, C.sub.4-10 -cycloalkenyl, phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphthyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, --NO.sub.2, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2, --CSNH.sub.2, --NH.sub.2, phenoxy or phenyl, or R.sup.4 is C.sub.1-2 -alkyl substituted with one or more halogen(s), C.sub.1-6 -alkoxy, --CF.sub.3, --CN, --COOH, --OH, --SH, --NR.sup.8 R.sup.9, C.sub.1-6 -alkyl ester, C.sub.3-10 -cycloalkyl, C.sub.4-10 -cycloalkenyl, phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphtyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, --NO.sub.2, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2, --CSNH.sub.2, --NH.sub.2, phenoxy or phenyl; R.sup.5 is C.sub.1-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more halogen(s), C.sub.1-6 -alkoxy, --CF.sub.3, --CN, --COOH, --OH, --SH, --NR.sup.8 R.sup.9, C.sub.1-6 -alkyl ester, C.sub.3-10 -cycloalkyl, C.sub.4-10 -cycloalkenyl, phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphtyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, --NO.sub.2, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2, --CSNH.sub.2, --NH.sub.2, phenoxy or phenyl; R.sup.6 and R.sup.7 independently are C.sub.1-10 -alkylene, C.sub.2-10 -alkenylene, C.sub.2-10 -alkynylene, each of which is optionally substituted with one or more halogen(s), C.sub.1-6 -alkoxy, --CF.sub.3, --CN, --COOH, --OH, --SH, --NR.sup.8 R.sup.9, C.sub.1-6 -alkyl ester, C.sub.3-10 -cycloalkyl, C.sub.4-10 -cycloalkenyl, phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphtyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, --NO.sub.2, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2, --CSNH.sub.2, --NH.sub.2, phenoxy or phenyl; R.sup.8 and R.sup.9 independently are hydrogen or C.sub.1-6 -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 substituted at carbon and/or nitrogen atom(s) with straight or branched C.sub.1-6 -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 ##STR18## wherein the thiadiazole ring can be attached at any carbon atom of the azabicyclic ring; R.sup.1 and R.sup.2 may be present at any appropriate position and independently are hydrogen, C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl, C.sub.2-5 -alkynyl, C.sub.1-10 -alkoxy, C.sub.1-5 -alkyl substituted with --OH, --OH, halogen, --NH.sub.2 or --COOH; R.sup.3 is hydrogen, C.sub.1-5 -alkyl, C.sub.2-5 -alkenyl or C.sub.2-5 -alkynyl; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; q is 1 or 2; and ..... is a single or double bond; or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein Z.sup.1 is sulphur.

3. The method according to claim 2, wherein G is ##STR19## wherein m, n and p are 1.

4. The method according to claim 3, wherein R is --Z.sup.1 --R.sup.4, --Z.sup.1 --R.sup.6 --Z.sup.2 --R.sup.5, --Z.sup.1 --R.sup.6 --Z.sup.2 --R.sup.7 --Z.sup.3 --R.sup.5, --Z.sup.1 --R.sup.6 --CO--R.sup.5, --Z.sup.1 --R.sup.6 --CO.sub.2 --R.sup.5, --Z.sup.1 --R.sup.6 --O.sub.2 C--R.sup.5, --Z.sup.1 --R.sup.6 --CONH--R.sup.5, or --Z.sup.1 --R.sup.6 --NHCO--R.sup.5.

5. The method according to claim 4, wherein R is --Z.sup.1 --R.sup.4.

6. The method according to claim 5, wherein R.sup.4 is C.sub.3-15 -alkyl, C.sub.2-15 -alkenyl, or C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphthyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, --NO.sub.2, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2, --CSNH.sub.2, --NH.sub.2, phenoxy or phenyl.

7. The method according to claim 3, wherein R is --Z.sup.1 --R.sup.6 --Y wherein Y is a heterocyclic group selected from the group consisting of thienyl, tetrazolyl, thiadiazolyl, benzothiazolyl, phthalimido, pyridyl and 1,3-dioxolanyl wherein the heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched C.sub.1-6 -alkyl, phenyl or benzyl, or a carbon atom of the heterocyclic group together with an oxygen atom form a carbonyl group.

8. The method according to claim 3, wherein the compound is: pharmaceutically acceptable salt thereof.

9. The method according to claim 3, wherein the compound is: ptane; tane; ptane; eptane; 1!heptane; ane; or a pharmaceutically acceptable salt thereof.

10. The method according to claim 2, wherein G is ##STR20## wherein m is 1, n is 2, and p is 1.

11. The method according to claim 10, wherein R is --Z.sup.1 --R.sup.4, --Z.sup.1--R.sup.6 --Z.sup.2 --R.sup.5, --Z.sup.1 --R.sup.6 --Z.sup.2 --R.sup.7 --Z.sup.3 --R.sup.5, --Z.sup.1 --R.sup.6 --CO--R.sup.5, --Z.sup.1 --R.sup.6 --CO.sub.2 --R.sup.5, --Z.sup.1 --R.sup.6 --O.sub.2 C--R.sup.5, --Z.sup.1 --R.sup.6 --CONH--R.sup.5, or --Z.sup.1 --R.sup.6 --NHCO--R.sup.5.

12. The method according to claim 11, wherein R is --Z.sup.1 --R.sup.4.

13. The method according to claim 12, wherein R.sup.4 is C.sub.3-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphthyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, --NO.sub.2, --CN, C.sub.1- -alkyl, C.sub.1- -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2, --CSNH.sub.2, --NH.sub.2, phenoxy or phenyl.

14. The method according to claim 10, wherein R is --Z.sup.1 --R.sup.6 --Y wherein Y is a heterocyclic group selected from the group consisting of thienyl, tetrazolyl, thiadiazolyl, benzothiazolyl, phthalimido, pyridyl and 1,3-dioxolanyl wherein the heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched C.sub.1-6 -alkyl, phenyl or benzyl, or a carbon atom of the heterocyclic group together with an oxygen atom form a carbonyl group.

15. The method according to claim 10, wherein the compound is: ane; tane; .2.1!octane; 3.2.1!octane; 2.1!octane; 3.2.1!octane; clo3.2.1!octane; e; e; ne; ane; ane; tane; ne; ane; ne; 2.1!octane; 2.1!octane; -isohexylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octane; 3.2.1!octane; 3.2.1!octane; o3.2.1!octane; 3.2.1!octane; 3.2.1!octane; o3.2.1!octane; tane; -dioxolane-2-yl)-ethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octa ne; ane; tane; .1!octane; ctane; tane; !octane; ane; ane; ne; ne; e; e; e; e; ctane 1!octane; !octane; !octane; 1!octane; 1!octane; 3.2.1!octane; -(4-fluorophenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!octa ne; o3.2.1!octane; o3.2.1!octane; or a pharmaceutically acceptable salt thereof.

16. The method according to claim 10, wherein the compound is: ane; ne; ane; ane; ane; 3.2.1!octane; .1!octane; o3.2.1!octane; tane; tane; octane; octane; octane octane; tane; ctane; 3.2.1!octane; clo3.2.1!octane; octane; ne; ne; 3.2.1!octane; -(3-trifluoromethylbenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo3.2.1!o ctane; ane; or a pharmaceutically acceptable salt thereof.

17. The method according to claim 10, wherein the compound is: cyclo3.2.1!octane; or a pharmaceutically acceptable salt thereof.

18. The method according to claim 2, wherein G is ##STR21## wherein m and n are 2 and p is 1.

19. The method according to claim 18, wherein R is --Z.sup.1 --R.sup.4, --Z.sup.1 --R.sup.6 --Z.sup.2 --R.sup.5, --Z.sup.1 --R.sup.6 --Z.sup.2 --R.sup.7 --Z.sup.3 --R.sup.5, --Z.sup.1 --R.sup.6 --CO--R.sup.5, --Z.sup.1 --R.sup.6 --CO.sub.2 --R.sup.5, --Z.sup.1 --R.sup.6 --O.sub.2 C--R.sup.5, --Z.sup.1 --R.sup.6 --CONH--R.sup.5, or --Z.sup.1 --R.sup.6 --NHCO--R.sup.5.

20. The method according to claim 19, wherein R is --Z.sup.1 --R.sup.4.

21. The method according to claim 20, wherein R.sup.4 is C.sub.3-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphthyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, --NO.sub.2, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2, --CSNH.sub.2, --NH.sub.2, phenoxy or phenyl.

22. The method according to claim 18, wherein R is --Z.sup.1 --R.sup.6 --Y wherein Y is a heterocyclic group selected from the group consisting of thienyl, tetrazolyl, thiadiazolyl, benzothiazolyl, phthalimido, pyridyl and 1,3-dioxolanyl wherein the heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched C.sub.1-6 -alkyl, phenyl or benzyl, or a carbon atom of the heterocyclic group together with an oxygen atom form a carbonyl group.

23. The method according to claim 18, wherein the compound is: ; pharmaceutically acceptable salt thereof.

24. The method according to claim 2, wherein G is ##STR22## wherein m and n are 1 and p is 2.

25. The method according to claim 24, wherein R is --Z.sup.1 --R.sup.4, --Z.sup.1 --R.sup.6 --Z.sup.2 --R.sup.5, --Z.sup.1 --R.sup.6 --Z.sup.2 --R.sup.7 --Z.sup.3 --R.sup.5, --Z.sup.1 --R.sup.6 --CO--R.sup.5, --Z.sup.1 --R.sup.6 --CO.sub.2 --R.sup.5, --Z.sup.1 --R.sup.6 --O.sub.2 C--R.sup.5, Z.sup.1 --R.sup.6 --CONH--R.sup.5, or --Z.sup.1 --R.sup.6 --NHCO--R.sup.5.

26. The method according to claim 25, wherein R is --Z.sup.1 --R.sup.4.

27. The method according to claim 26, wherein R.sup.4 is C.sub.3-15 -alkyl, C.sub.2-15 -alkenyl, C.sub.2-15 -alkynyl, each of which is optionally substituted with one or more phenyl, benzyloxycarbonyl, phenoxy, benzoyl, tetrahydronaphthyl, naphtyl, indanyl or indenyl, wherein each aromatic ring is optionally substituted with halogen, --NO.sub.2, --CN, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, --OCF.sub.3, --CF.sub.3, --CONH.sub.2, --CSNH.sub.2, --NH.sub.2, phenoxy or phenyl.

28. The method according to claim 24, wherein R is --Z.sup.1 --R.sup.6 --Y wherein Y is a heterocyclic group selected from the group consisting of thienyl, tetrazolyl, thiadiazolyl, benzothiazolyl, phthalimido, pyridyl and 1,3-dioxolanyl wherein the heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched C.sub.1-6 -alkyl, phenyl or benzyl, or a carbon atom of the heterocyclic group together with an oxygen atom form a carbonyl group.

29. The method according to claim 24, wherein the compound is: !octane; or a pharmaceutically acceptable salt thereof.

30. The method according to claim 24, wherein the compound is: e; or a pharmaceutically acceptable salt thereof.

31. The method according to claim 24, wherein the compound is: pharmaceutically acceptable salt thereof.

32. The method according to claim 24, wherein the compound is: -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; or a pharmaceutically acceptable salt thereof.

33. The method according to claim 24, wherein the compound is: tane; lo2.2.2!octane; -azabicyclo2.2.2!octane; o2.2.2!octane; .2.2!octane; ; a pharmaceutically acceptable salt thereof.

34. A method of inhibiting squalene synthetase or treating hypercholesterolemia in a subject in need thereof comprising administering to the subject an effective amount of Exo-6-(3-(4-methylsulfonylbenzylthio)-1,2,5-thiadiazol-4-yl)-1-azabicyclo 3.2.1!octane or a pharmaceutically acceptable salt thereof.