WO1997039753A1

WO1997039753A1 - Heterocyclic compounds

Info

Publication number: WO1997039753A1
Application number: PCT/US1997/006678
Authority: WO
Inventors: Richard L. Simon; Celia A. Whitesitt
Original assignee: Eli Lilly And Company
Priority date: 1996-04-23
Filing date: 1997-04-23
Publication date: 1997-10-30
Also published as: AU2738397A; EP0912183A4; CA2252573A1; EP0912183A1; JP2000509043A

Abstract

The present invention provides heterocyclic compounds which are useful for modulating a muscarinic receptor.

Description

HETEROCYCLIC COMPOUNDS

The present invention relates to therapeutically active heterocyclic compounds having surprising potency at a muscarinic receptor. The novel compounds are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals.

Due to the generally improved health situation in the western world, elderly-related diseases are much more common now than in the past and are likely to be even more common in the future.

One of the elderly-related symptoms is a reduction of the cognitive functions. This symptom is especially pronounced in the pathophysiological disease known as Alzheimer's disease. This disease is combined with, and also most likely caused by, an up to 90% degeneration of the muscarinic cholinergic neurons in nucleus basalis, which is part of substantia innominata. These neurons project to the prefrontal cortex and hippocampus and have a general stimulatory effect on the cognitive functions of the

forebrain as well as of hippocampus, namely learning, association, consolidation, and recognition.

It is a characteristic of Alzheimer's disease that although the cholinergic neurons degenerate, the postsynaptic muscarinic receptors in the forebrain and hippocampus still exist. Therefore, muscarinic cholinergic agonists are useful in the treatment of

Alzheimer's disease, in halting its progression, and in improving the cognitive functions of elderly people.

Compounds active at a muscarinic cholinergic receptor are also useful analgesic agents and therefore are useful in the treatment of severely painful conditions. Furthermore, muscarinic cholinergic receptor active compounds are useful in the treatment of glaucoma, psychosis, anxiety, mania, bipolar disorder, schizophrenia or schizophreniform conditions, depression, sleeping disorders, epilepsy, cerebral ischemia, and gastrointestinal motility disorders.

Therefore, new compounds having muscarinic cholinergic activity are desired. Some muscarinic cholinergic receptor active compounds are associated with side effects attributed to undesired modulation of the muscarinic cholinergic receptors, for example, such undesired modulation may cause excessive salivation and gastrointestinal upset. Thus, the most desired muscarinic cholinergic compounds shall have high potency and at the same time a favorable side effect profile, including a low incidence of excessive salivation. The presently claimed compounds having a thiobenzyl substituent have surprisingly good bioavailability and long duration of action and provide a favorable side effect profile. Studies of compounds claimed herein suggest that the compounds will be particularly desired muscarinic receptor active compounds which can be especially useful pharmaceutically active compounds . Summary of the Invention

This invention provides compounds of the formula I:

;D wherein

R is selected from the group consisting of hydrogen, methyl, ethyl, chloro, fluro, and -CF3;

G is 1-azabicyclo [3.2.1] octyl; or a pharmaceutically acceptable salt or solvate thereof.

G is preferredly

It is an object of the invention to provide new muscarinic cholinergic compounds having surprising good bioavailability and long duration of action and a favorable side effect profile.

It is to be understood that the invention extends to each of the stereoisomeric forms of the compounds of the present invention as well as the pure diastereomeric, pure enatiomeric, and racemic forms of the compounds of this invention.

Detailed Description

As used herein the term "treating" includes prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been established or alleviation of the characteristic symptoms of such condition.

As used herein the phrase "interacting with a muscarinic cholinergic receptor" shall include compounds which block muscarinic cholinergic receptors or modulate such receptors. The phrase shall include the effect observed when compounds act as agonists, partial agonists and/or antagonists at a muscarinic cholinergic receptor. As used herein, the term "halogen" means Cl, Br, F, and I.

As used herein the phrase "one or more selected from" shall more preferredly refer to from 1-3 substituents. The term shall further preferredly refer to from 1-2 substituents.

The terms "Cι-C_n' alkyl" wherein n'can be from 2 through 15, as used herein, represent a branched or linear alkyl group having from one to the specified number of carbon atoms. Typical Ci-Ce alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

As used herein the term "carboxy" refers to a substituent having the common meaning understood by the skilled artisan, wherein the point of attachment may be through the carbon or oxygen atom of the group.

Examples of pharmaceutically acceptable 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 known to the skilled artisan. The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.

The compounds of this invention can be prepared using the chemical processes illustrated in Scheme I. The starting materials for the illustrated process are commercially available or may be prepared using methods known to the skilled artisan. SCHEME I

As described above by the Scheme I, the term [3.2.1]" means an p of the formula:

As described above by Scheme I, the term R^4" means a group of the formula:

The term "Hal" means Cl, Br, and R⁹S0₂. R⁹ is Cι-₈ alkyl or aryl.

As described in the following Schemes, the following substituents have the meanings defined above unless otherwise indicated. Preferred oxidizing agents for the process of Scheme I include oxone and sodium periodate. Oxone is an especially preferred oxidizing agent for the process of Scheme I. Compounds of Formula 3, as illustrated in Scheme I wherein the OR group is replaced by an R⁴ group, can be prepared using methods well known in the art. See for example, U.S. Patent Number 5,043,345.

Further, compounds of Formula I may be prepared using the process illustrated in the following Scheme II

SchemeII

As used in Scheme II, Q may be N, 0 or S; R²⁴ is selected from the group consisting of hydrogen, R⁴, R⁵, R⁶, and R^7; R²⁵ is selected from the group consisting of SOR⁴ and SO₂R⁴; all other meanings are as defined supra . As used in Scheme II, G(CH)₂W- shall mean a [3.2.1] -O- group. QR shall mean

Certain intermediates of the present invention may be prepared using the process illustrated in Scheme IV. Scheme IV

9 10 11

As used in Scheme IV, R⁸ is Li, Na, or K; Si means silyl; R¹⁰,!*¹¹, R¹², R¹³, R¹⁴ and R¹⁵' are independently selected from the group consisting of (Cι~ Cβ) -alkyl, aryl, and aryl (C₁-C₃) alkyl; R¹⁵ and R¹⁶ are independently selected from the group consisting of hydrogen, R¹⁰RⁿR¹²Si, and R¹³R¹⁴R¹⁵'Si. R is selected from the group consisting of hydrogen, amino, halogen, NHR⁶, NR⁶R⁷, R⁴, -OR⁴, -SR⁴, -SOR⁴, -S0₂R⁴, C3-10- cycloalkyl, C₄-₁₂- (cycloalkylalkyl) , -Z-C₃-ιo-cycloalkyl and -Z-C₄-₁₂- (cycloalkylalkyl) wherein R⁴ is Cι-₁5-alkyl, C2-i5^_alkenyl, C2-i5~alkynyl, each of which is optionally substituted with one or more halogen (s), -CF₃, -CN, Y, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, Cι-₄-alkyl, Cι-₄-alkoxy, - OCF₃, -CF₃, -CONH₂ or -CSNH₂; or

R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, Cι-₄-alkyl, Ci- ₄-alkoxy, -OCF3, -CF3, -C0NH₂ or -CSNH₂; or R is -OR⁵Y, -SR⁵Y, OR⁵-Z-Y, -SR⁵ZY, -0-R⁵-Z-R⁴ or -S-R⁵-Z- R⁴ wherein Z is oxygen or sulphur, R⁵ is Cι-₁₅-alkyl, C2- 15-alkenyl, C2-I5~alkynyl, and Y is a 5 or 6 membered heterocyclic group;

R⁶ and R⁷ independently are hydrogen, Cι-₆~alkyl; or R⁶ and R⁷ together with the nitrogen atom optionally form a 4- to 6-member ring;

Z is oxygen or sulphur, R⁵ is Cι-₁₅-alkyl, C2-i5-alkenyl,

C2-i5~alkynyl, and Y is a 5 or 6 membered heterocyclic group; For example, R⁸N[ (R¹⁰R^1:LR¹²Si) (R¹³R¹⁴R¹⁵'si) may be, but is not limited to lithium bis(tri-2- propylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium bis(tri-2- propylsilyl) amide, sodium bis (ethyldimethylsilyl) amide, potassium bis (1-propylethylmethylsilyl) amide, lithium bis (tri-phenylsilyl) amide, sodium bis(tri- phenylmethylsilyl) amide, potassium bis (2-butyl-2- propylmethylsilyl) amide, lithium (tri-2-propylsilyl) (2- butyldiethylsilyl) amide, sodium (trimethylsilyl) (triphenylsilyl) amide, potassium (dimethyl phenylsilyl) (ethyldimethylsilyl) amide, and the like. Most preferably, R¹⁵ and R¹⁶ are each hydrogen when the process of Scheme III is used for preparing a compound of 11 from a compound of 10. The intermediate 10 may be nitrosated using standard nitrosating procedures. A preferred nitrosating agent is isoamyl nitrite; however, other known nitrosating agents are appropriate.

The concentration of the reactants is not critical. The art worker can alter the concentration of the reactants to achieve the desired rate of reaction and product yield.

The length of time for carrying out the processes described are not critical. As is always the case in chemistry, the rate of the reaction depends on a variety of factors, such as the temperature and the exact compound which is to be prepared. The course of the reaction may be followed using methods such as thin layer chromatography (TLC) , high performance liquid chromatography (HPLC) , gas chromatography (GC) and nuclear magnetic resonance spectroscopy (NMR) to detect the degree of completion of the reaction. The operator may obtain maximum yields using the process by extending the reaction time. Alternatively, the operator may wish to obtain maximum throughput by cutting off the reaction at the point at which it reaches an economical degree of completion.

When the product of a step in the following process is an oil, it may be isolated by standard methods. Such methods include distillation, flash chromatography, HPLC and the like.

As used herein the term "malfunctioning of the muscarinic cholinergic system" shall have the meaning accepted by the skilled artisan. For example the term shall refer to, but is not in any way limited to, conditions such as glaucoma, psychosis, schizophrenia or schizophreniform conditions, depression, sleeping disorders, epilepsy, and gastrointestinal motility disorders. Other such conditions include Alzheimer's Disease and incontinence.

The pharmacological properties of the compounds of the invention can be illustrated by determining their capability to inhibit the specific binding of ³H- Oxotremorine-M (³H-Oxo) . Birdsdall N.J.M., Hulme E.C., and Burgen A.S.V. (1980) . "The Character of Muscarinic Receptors in Different Regions of the Rat Brain". Proc. Roy. Soc. London (Series B) 207,1.

³H-Oxo labels muscarinic receptor in the CNS

(with a preference for agonist domains of the receptors) . Three different sites are labeled by ³H-Oxo. These sites have affinity of 1.8, 20 and 3000 nM, respectively. Using the present experimental conditions only the high and medium affinity sites are determined.

The inhibitory effects of compounds on ³H-oxo binding reflects the affinity for muscarinic acetylcholine receptors.

All preparations are performed at 0-4°C unless otherwise indicated. Fresh cortex (0.1-1 g) from male Wistar rats (150-250 g) is homogenized for 5-10 seconds in 10 mL 20 nM Hepes pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer is rinsed with 10 mL of buffer and the combined suspension centrifuged for 15 min. at 40,000 x g. The pellet is washed three times with buffer. In each step the pellet is homogenized as before in 2 x 10 mL of buffer and centrifuged for 10 min. at 40, 000 x g.

The final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 mL per g of original tissue) and used for binding assay. Aliquots of 0.5 mL is added 25 μL of test solution and 25 μL of ³H-Oxotremorine (1.0 nM, final concentration) mixed and incubated for 30 min. at 25°C. Non-specific binding is determined in triplicate using arecoline (1 μg/mL, final concentration) as the test substance. After incubation samples are added 5 mL of ice-cold buffer and poured directly onto Whatman GF/C glass fiber filters under suction and immediately washed 2 times with 5 mL of ice-cold buffer. The amount of radioactivity on the filters are determined by conventional liquid scintillation counting. Specific binding is total binding minus non specific binding.

Test substances are dissolved in 10 mL water

(if necessary heated on a steam-bath for less than 5 min.) at a concentration of 2.2 mg/mL. 25-75% inhibition of specific binding must be obtained before calculation of IC₅₀. The test value will be given as IC₅₀ (the concentration (nM) of the test substance which inhibits the specific binding of ³H-oxo by 50%) . IC₅₀ = (applied test substance concentration) x (C_x/C₀- C_x)nM where C_D is specific binding in control assays and C_x is the specific binding in the test assay. (The calculations assume normal mass-action kinetics) .

Furthermore the pharmacological properties of the compounds of the invention can also be illustrated by determining their capability to inhibit ³HPRZ (pirenzepine, [N-methyl-³H] ) binding to rat cerebral cortex membranes. Pirenzepine binds selectively to subtype of muscarinic receptors. Historically the type is named the Mi-site, whereas pirenzepine sensitive site would be more appropriate. Although selective for Mχ-sites pirenzepine also interact with M₂~sites.

All preparations are performed at 0-4°C unless otherwise indicated. Fresh cortex (0.1-1 9) from male Wistar rats (150-200 g) is homogenized for 5-10 s in 10 mL 20 mM Hepes pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer is rinsed with 2 x 10 mL of buffer and the combined suspension centrifuged for 15 min. at 40,000 x g. The pellet is washed three times with buffer. In each step the pellet is homogenized as before in 3 x 10 mL of buffer and centrifuged for 10 min. at 40,000 x g.

The final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 mL per g of original tissue) and used for binding assay. Aliquots of 0.5 mL is added 20 μl of test solution and 25 μL of ³HPRZ (1.0 nM, final cone), mixed and incubated for 60 min. at 20°C. Non-specific binding is determined in triplicate using atropine (1 ,μg/mL, final cone.) as the test substance. After incubation samples are added 5 mL of ice-cold buffer and poured directly onto Whatman GF/C glass fiber filters under suction and immediately washed 2 times with 5 mL of ice- cold buffer. The amount of radioactivity on the filters are determined by conventional liquid scintillation counting. Specific binding is total binding minus non-specific binding.

Test substances are dissolved in 10 mL water, at a concentration of 0.22 mg/mL. 25-75% inhibition of specific binding must be obtained before calculation of ICso. The test value will be given as IC₅₀ (the concentration (nM) of the test substance which inhibits the specific binding of ³HPRZ by 50%) . IC₅₀ = (applied test substance concentration) x(C_x/C₀- C_x)nM where C₀ is specific binding in control assays and C_x is the specific binding in the test assay. (The calculations assume normal mass-action kinetics) .

Additionally, the pharmacological activity and tendency to produce salivation can be determined using the following methods:

Salivation in mice:

Mice weighing 20 to 30 g were used for salivation testing. Mice, in groups of five, were injected i.p. with 10 mg/kg doses of compound dissolved in distilled water. After, 30 min, salivation and tremor were scored on a scale of 0, 1, or 2, where 0 = no effect, 1 = moderate salivation or tremor, and 2 = marked salivation or tremor. Those compounds producing an average score of 1 were tested at half log lower doses until a score lower than 1 was achieved. The lowest dose of compound producing a score of 1 was expressed at the minimum effective dose (MED) .

Ex vi vo receptor binding. The cerebral cortex from the brains of Sprague-Dawley rats was weighed and homogenized in 10 vol of 20 mM Tris Cl, pH 7.4, containing 1 mM MnCl₂ and the suspension was preincubated for 10 min at 25°C to remove endogenous ligands. For detemination of ex vivo binding, 0.1 ml of whole homogenates w_s added to 1 ml of buffer containing either 3 nM of [³H]oxotrmorine-M (87.0 Ci/mmol) or 1 nM [³H]pirenzepine (86.2Ci/mmol) . The homogenates were incubated at 25° C for 15 or 60 min for [³H] ocotramorine-M or [³H]pirenzepine binidng, respectively. To terminate the incubation, the homogenates were filtered by vacuum through GF/c glass filters that had been soaked for 1 hr in 0.1% polyethylenimine. After rinsing the filters three times with 2 ml of cold buffer, they were placed inscintillation vials containing 10 ml of scintillation fluid for determination of radioactivity, nonspecific binding was determined by addition fo 1 μM atropine.

The compounds of the invention 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 0.1 mg to about 70 mg per day. In choosing a regimen for patients suffering from diseases in the central nervous system caused by malfunctioning of the muscarinic cholinergic system it may frequently be necessary to begin with a dosage of from about 20 to about 70 mg per day and when the condition is under control to reduce the dosage as low as from about 0.1 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 prescribing caregiver 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, depot, subcutaneous, intravenous, intramuscular or intranasal, 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 excipient which may be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, or other container. 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 formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.

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 0.1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.

The compounds of this invention may be suitable for administration to an animal. Such animals include both domestic animals, for example livestock, laboratory animals, and household pets, and non-domestic animals such as wildlife. More preferredly, the animal is a vertebrate. Most preferredly, a compound of this invention shall be administered to a mammal. It is especially preferred that the animal is a domestic mammal or a human. The most preferred mammal is a human. For such purposes, a compound of this invention may be administered as a feed additive.

In order to more fully illustrate the operation of this invention, the following formulation examples are provided. The examples are illustrative only, and are not intended to limit the scope of the invention in any way. Formulation 1 A typical tablet, appropriate for use in this method, may be prepared using conventional techniques and may contain:

Amount per Concentration Tablet by Weight

(%) a compound of this invention 5.0 mg 4.7

Lactosum 67.8 mg Ph Eur. 64.2

Avicel^® 31.4 mg 29.8

Amberlite^® .0 mg 1.0 magnesium stearate 0.25 mg 0.3 105.45 mg 100

Formulation 2

Hard gelatin capsules are prepared using the following ingredients:

Amount per Concentration Tablet by Weight (%)

a compound of this invention 0.1 mg 0.05 starch dried 200 mg 95.2 magnesium stearate 10 mg 4.8 210.1 mg 100

The above ingredients are mixed and filled into hard gelatin capsules in 210.1 mg quantities. Formulation 3 Suspensions each containing 1 mg of medicament per 5 mL dose are as follows:

Amount per 5mL of suspension a compound of this invention 1 mg sodium carboxymethyl cellulose 50 mg

syrup 1.25 mL benzoic acid solution 0.10 mL flavor q.v. color q.v. water q.s. to 5 mL

The medicament is passed through a No. 45 mesh

U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color is diluted with some of the water and added to the paste with stirring. Sufficient water is then added to produce the required volume.

The compounds of the present invention have useful muscarinic receptor activity. Certain compounds and conditions withm the scope of this invention are preferred. The following conditions, invention embodiments, and compound characteristics listed in tabular form may be independently combined to produce a variety of preferred compounds and process conditions. The following list of embodiments of this invention is not intended to limit the scope of this invention in any way.

Some prefered characteristics of compounds of formula I are:

A) G is 1-azabιcyclo [3.2. ljoctyl;

B) R is F; C) R is methyl;

D) R is trifluoromethyl; G) R is H H ) R i s Cl

The invention will now be described in further detail with reference to the following examples. The examples are provided for illustrative purposes, and are not to be construed as limiting the scope of the invention in any way.

Example 1

(5R, 6R) -endo-3- (4-Fluorobenzylthiol) -4- (1- azabicyclo[3.2.1]octyl-6-oxγ-l,2,5-thiadiazole

p-Fluorobenzylthiol (3.8 mmol) was added at -40° C. to a stirred solution of potassium t-butoxide (3.8 mmole) in 70 ml of THF. After stirring for 15 min, (5R, 6R)-endo-3- propylsulfonyl-4- (1-azabicyclo [3.2.1] octyl-6-oxy) -1,2,5- thiadiazole (1.9 mmol) (prepared using methods taught herein) was added and the solution stirred for an additional 30 min. The reaction was quenched with water and the product extracted with EtOAc, dried and condensed. The product was purified by HPLC over silica gel eluted with CHCl₃/EtOH/NH₄OH, 50/49/1 and converted to the maleate salt to yield 380 mg, 42% of product (m.pt. 114-115°C) .

Similarly prepared were

(5R,6R) p-Chlorobenzylthiol, hydrochloride salt m pt 199-200, yield 70%

(5R, 6R) benzylthiol, maleate, m pt 89-90, yield 46 %

(5R, 6R) p-methylbenzylthiol, maleate, m pt 119-121, yield 37%

(5R, 6R) p-trifluoromethylbenzylthiol, maleate, m pt

124-126, yield 16%

The compounds claimed herein have been tested in an ex vivo receptor binding assay for the percent inhibition in the brain 3 hours after oral administration of 10 mg/kg and have demonstrated surprising bioavailability. Further, the compounds provided a more favorable side effect profile than comparable oxygen bridged compounds as demonstrated using methods taught herein.

Claims

We Cl aim :

A of the formula I

wherein

R is selected from the group consisting of hydrogen, methyl Cl, F, and -CF₃;

G is 1-azabicyclo [3.2.1]octyl; or a pharmaceutically acceptable salt or solvate thereof. 2. A compound of Claim 1 wherein R is CH₃.

3. A compound of Claim 1 wherein R is selected from the group consisting of Cl and F.

A compound of Claim 3 wherein R is F,

1 wherein G is

6. A compound of Claim 5 wherein R is selected from the group consisting of CH₃, Cl, and F. 7. A compound of Claim 6 wherein R is CH₃.

8. A formulation comprising a compound of Claim 1 associated with one or more carriers, diluents, or excipients therefor.

9. A method for modulating a muscarinic receptor comprising administering an effective amount of a compound of Claim 1 to a patient in need thereof.

10. A method of Claim 9 wherein the compound acts as a muscarinic receptor antagonist.

11. A method of Claim 9 wherein the compound acts as a muscarinic receptor agonist.

12. A method for treating a condition selected from the group consisting of Alzheimer's disease, anxiety, glaucoma, a psychotic condition, or a severely painful condition comprising administering an effective amount of a compound of Claim 1.

13. A compound as claimed by Claim 1 wherein the compound is selected from the group consisting of (5R, 6R)-endo-3- (4-Fluorobenzylthiol) -4- (1- azabicyclo [3.2.1]octyl-6-oxy-l, 2, 5-thiadiazole, (5R, 6R) - endo-3- (4-methylbenzylthiol) -4- (1-azabicyclo [3.2.1] octyl- β-oxy-l, 2, 5-thiadiazole, (5R, 6R) -endo-3- (4- ethylbenzylthiol) -4- (1-azabicyclo [3.2.1] octyl-6-oxy- 1,2, 5-thiadiazole, (5R, 6R) -endo-3- (4- trifluoromethylbenzylthiol) -4- (1-azabicyclo [3.2.1] octyl- β-oxy-l, 2, 5-thiadiazole, and (5R, 6R) -endo-3- (benzylthiol) -4- (1-azabicyclo [3.2.1]octyl-β-oxy-l, 2,5- thiadiazole. 14. A compound as claimed by Claim 1 for use in the manufacture of a medicament.