The present invention relates to therapeutically active quaternary azacyclic and azabicyclic compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds.

The novel compounds are useful as stimulants in the peripheral cholinergic system or for treatment of a cholinergic deficit in the peripheral system.

From basic pharmacology it is known that cholinergic agonists effect the cardiovascular sys¬ tem, the gastrointestinal system, and the urinary tract. They also stimulate secretion by exo- crine glands that receive parasymphatic innervation and that include the lacrimal, tracheobron- chial, salivary, digestive and sweat glands. Cholinergic agonists also evoke bronchoconstriction and when instilled to the eye produce miosis.

The recent elucidations of the existence and distinct tissue distribution of several subtypes of muscarinic cholinergic receptors has renewed interest in synthetic analogs that enhance the tissue selectively of muscarinic agonist.

It is an object of the invention to provide new muscarinic cholinergic compounds for treatment of glaucoma, gastrointestinal motility disorders, irritable bowel syndrome (IBS), urinary bladder disorders and respiratory disorders.

The novel compounds of the invention are quaternary compounds of formula

(I)

wherein X is oxygen or sulfur and wherein G is selected from the group of azacyclic or azabi¬ cyclic ring systems consisting of

wherein the oxadiazole or thiadiazole ring can be attached at any position; and

R ⁵ and R ^β may be present at any possible position, including the point of attachment of the oxadiazole or thiadiazole ring, and independently are H, straight or branched C _1-5 -alkyl, straight or branched C _2-5 -alkenyl, straight or branched C ₂ . ₅ -alkynyl, straight or branched C,. ₁₀ -alkoxy, straight or branched hydroxyalkyl, -OH, halogen, -NH ₂ or carboxy; and R ⁷ and R ^B independently are straight or branched C^-alkyl, straight or branched C ₂ . ₅ -alkenyi, straight or branched C ₂ . ₅ -alkynyl, C _M -cycloalkyl or C ₃ . ₅ -cycloalkylC,. ₂ -alkyl; and n and p independently are 0, 1, 2, 3, or 4; and is a single or double bond ; and

R is hydrogen, halogen, -NR'R ² , -R ³ , -OR ³ , -SR ³ , -SOR ³ , -SO ₂ R ³ , C _M -cycloalkyl, C^- (cycloalkylalkyl), -Z-C ₃ . ₁₀ -cycloalkyl and -Z-C<. ₁₂ -(cycloalkylalkyl) wherein R ³ is straight or branched C,. ₁₅ -alkyl, straight or branched C ₂ . ₁₅ -alkenyl, straight or branched C ₂ . ₁₅ -alkynyl, or straight or branched C^-alkenynyl, each of which is optionally substituted with one or more halogen(s), -CF ₃ , -CN, -OH, Y, phenyl or phenoxy wherein phenyl or phenoxy is optionally sub¬ stituted with halogen, -OH, -CF ₃ , -CN, C _M -alkyl, C^-alkoxy, C _M -alkylthio, -SCF ₃ , -OCF ₃ , -CONH ₂ or -CSNH ₂ ; or

R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -OH, -CF _3l -CN, C _M -alkyl, C _M -alkoxy, C -alkylthio, -SCF ₃ , -OCF ₃ , -CONH ₂ or -CSNH ₂ ; or R is -OR ⁴ Y, -SR ⁴ Y, -OR ⁴ ZY, -SR ⁴ ZY, -OR ⁴ ZR ³ or -SR ⁴ ZR ³ wherein Z is oxygen or sulphur, R ⁴ is straight or branched C^s-alkylene, straight or branched C ₂ . ₁₅ -alkenylene, straight or branched C ₂ . ₁₅ -alkynylene or straight or branched C ₄ . ₁₅ -alkenynylene; and

Y is a 5 or 6 membered heterocyclic group , which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with halogen,-OH, -CF ₃ , -CN, C^-alkyl, C^-alkoxy, C^-alkylthio, -SCF _3l -OCF ₃ , -CONH ₂ , -CSNH ₂ , phenyl, benzyl or thienyl, or a carbon atom in the heterocy¬ clic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group; and

R ¹ and R ² independently are hydrogen, Cβ-alkyl, or R ¹ and R ² together with the nitrogen atom optionally form a 4- to 6-membered ring; and

A is a negative radical of a pharmaceutically acceptable salt; or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or a prodrug thereof.

As used herein, the term "halogen" means F, CI, Br, and I. Especially preferred halogens in¬ clude CI, Br, and F.

The term "C _h alky!" wherein n' can be from 2 through 15, as used herein, represent a branched or straight alkyl group having from one to the specified number of carbon atoms. Typical C^-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.

The term "C^-alkenyl" wherein n' can be from 3 through 15, as used herein, represents an olefinically unsaturated branched or straight group having from 2 to the specified number of carbon atoms and at least one double bond. Examples of such groups include, but are not lim¬ ited to, 1-propenyl, 2-propenyl, 1 ,3-butadienyl, 1 -butenyl, hexenyl, pentenyl, and the like.

The term "C _2-n -alkynyl" wherein n' can be from 3 through 15, as used herein, represent an un- saturated branched or straight group having from 2 to the specified number of carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like.

The term ^,, C ₄ _ _n .-alkenynyl" wherein n' can be from 5 through 15, as used herein, represent an unsaturated branched or straight hydrocarbon group having from 4 to the specified number of carbon atoms and both at least one double bond and at least one triple bond. Examples of such groups include, but are not limited to, 1-penten-4-yne, 3-penten-1-yne, 1 ,3-hexadiene-5- yne and the like.

The term "C^-cycloalkyl" wherein n=4-10, as used herein, represents e.g. cyclopropyl, cyclob- utyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and the like.

As used herein the term "C^^^cycloalkylalkyl)" represents a branched or straight alkyl group substituted at a carbon with a cycloalkyl group. Examples of such groups include, but are not limited to, cyclopropylethyl, cyclobutylmethyl, 2-(cyclohexyl)ethyl, cyclohexylmethyl, 3- (cyclopentyl)-l -propyl, and the like.

The term "C _1-n -alkoxy" wherein n" can be from 2 through 10, as used herein, alone or in com- bination, refers to a straight or branched monovalent substituent comprising an alkyl group having from one to the specified number of carbon atoms linked through an ether oxygen hav¬ ing its free valence bond from the ether oxygen. Examples of such groups include, but are not limited to, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

The term "C, ^-alkylthio" wherein n" can be from 2 through 10, as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising an alkyl group having from one to the specified number of carbon atoms linked through a divalent sulfur atom having its free valence bond from the sulfur oxygen. Examples of such groups include, but are not limited to, e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like.

As used herein, the phrase "R ¹ and R ² together with the nitrogen atom optionally form a 4- to 6- membered ring" for example, include, but are not limited to:

As used herein, the phrase "5 or 6 membered heterocyclic group" means a group containing from one to four N, O or S atom(s) or a combination thereof, which heterocyclic group is op¬ tionally substituted at carbon or nitrogen atom(s) with halogen, -OH, -CF ₃ , -CN, C _M -alkyl, C^- alkoxy, C^-alkylthio, -SCF ₃ , -OCF ₃ , -CONH ₂ , -CSNH ₂ , phenyl, benzyl or thienyl, 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. The phrase "5 or 6 membered het¬ erocyclic group" includes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. thiophenes, pyrroles, furans); 5-membered heterocycles having two heteroatoms in 1,2 or 1,3 positions (e.g. oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heterocycles having three heteroatoms (e.g. triazoles, thiadiazoles); 5-membered heterocycles having four heteroatoms; 6-membered heterocycles with one heteroatom (e.g. pyridine, quino- line, isoquinoline, phenanthridine, cyclohepta[b]pyridine); 6-membered heterocycles with two heteroatoms (e.g. pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines); 6-membered heterocycles with three heteroatoms (e.g. 1,3,5-triazine); and 6-membered het¬ erocycles with four heteroatoms. Particularly preferred are thiophenes, pyridines, and furans, more preferred is thiophenes.

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

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

In a preferred embodiment, the present invention is concerned with compounds of formula I wherein G is selected from

and wherein n, p, R ^b , R ⁶ , R ⁷ , R ⁸ and A ^" are as defined above.

In another preferred embodiment, the present invention is concerned with compounds of for¬ mula I wherein G is selected from

and wherein n, p, R ^s , R ⁶ , R ⁷ , R ^β and A are as defined above.

In another preferred embodiment, the present invention is concerned with compounds of for¬ mula I wherein n is 1 or 2.

In another preferred embodiment, the present invention is concerned with compounds of for¬ mula I wherein p is 1 or 2.

tn another preferred embodiment, the present invention is concerned with compounds of for¬ mula I wherein R is halogen, -OR ³ , -SR ³ or -SO ₂ R ³ , wherein R ³ is as defined above.

In another preferred embodiment, the present invention is concerned with compounds of for¬ mula I wherein R ³ is straight or branched C _1-15 -alkyl, straight or branched C ₂ . ₁₅ -alkenyl, straight or branched C _2-15 -alkynyl or straight or branched C^s-alkenynyl, each of which is optionally substituted with one or more halogen(s), -CN, -SCF ₃ , -OCF ₃ , Y or phenyl, wherein phenyl or Y is optionally substituted with halogen(s), -CN, C _M -alkyl, C -alkoxy, C _M -alkylthio, -SCF ₃ or -OCF ₃ .

In another preferred embodiment, the present invention is concerned with compounds of for¬ mula I wherein R is -OR ³ or -SR ³ , wherein R ³ is propynyl substituted with phenyl or thienyl, wherein phenyl or thienyl is optionally substituted with halogen(s), -CN, C -alkyl, C -alkoxy, C^-alkylthio, -SCF ₃ or -OCF ₃ .

In another preferred embodiment, the present invention is concerned with compounds of for¬ mula I wherein the oxadiazole or thiadiazole is attached at the 3 position of G.

In another preferred embodiment, the present invention is concerned with compounds of for¬ mula I wherein R ⁵ and R ^β are H.

In another preferred embodiment, the present invention is concerned with compounds of for¬ mula I wherein R ⁷ is C,. ₂ -alkyl.

In another preferred embodiment, the present invention is concerned with compounds of for¬ mula I wherein R ^β is C _1-2 -alkyl.

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

The starting materials for the illustrated process are, if nothing else mentioned, commercially available or may be prepared using methods known to the skilled artisan.

Pharmaceutical salts suitable as acid addition salts and also as providing the anions of cyclic amine salts are those from acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, triflouracetic, trichloracetic, oxalic, maleic, pyruvic, malonic, succinic, citric, mandetic, benzoic, cinnamic, methanesulfonic, ethane sulfonic, picric and the like, and include acids re¬ lated to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 6_6_, 2 (1977) and incoφorated herein by reference.

The invention also relates to methods of preparing the above mentioned compounds, charac¬ terized in:

reacting a compound of formula II

(ll)

(prepared according to methods described in EP 384288, PCT/DK91/00234, PCT/DK91/00235 and PCT/DK91/00236) wherein G' is selected from the azacyclic or azabicyclic ring systems consisting of

wherein X, R, R ⁵ , R ^β , R ⁷ , C _n and C _p have the meanings defined above with an active quatern- izing agent of the formula

Rt

wherein R ⁸ has the meaning defined above and L is a leaving group (e.g. a halogen ion), whereafter L optionally can be exhanged with A which is as defined above e.g. by ion exhange to give compounds of formula I.

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.

The pharmacological properties of the compounds of the invention can be illustrated by deter¬ mining their capability to inhibit the specific binding of ³ H-Oxotremorine-M ( ³ H-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.

The inhibitory effects of compounds on ³ H-Oxo binding reflects the affinity for muscarinic ace¬ tylcholine 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 s in 10 ml 20 mM 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 ul of test solution and 25 ul of ³ H- 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 ug 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 liq¬ uid 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 ob¬ tained before calculation of IC _∞ .

The test value will be given as IC ₅₀ (the concentration (nM) of the test substance which inhibits the specific binding of ³ H-Oxo by 50%).

ICa, = (applied test substance concentration)

where C ₀ is specific binding in control assays and C„ 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 il- lustrated by determining their capability to inhibit ³ H-PRZ (pirenzepine, [N-methyl- ³ H]) binding to rat cerebral cortex membranes.

Pirenzepine binds selectively to subtype of muscarinic receptors. Historically the type is named the M site, whereas pirenzepine sensitive site would be more appropriate. Although selective for M _r sites pirenzepine also interact with M ₂ -sites.

All preparations are performed at 0-4°C unless otherwise indicated. Fresh cortex (0.1-1 g) 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 rinzed with 2 x 10 ml of buffer and the com¬ bined suspension centrifuged for 15 min at 40,000 xg. 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 xg.

The final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 ml per g of original tissue) and used for binding assay. Aiiquots of 0.5 ml is added 20 μl of test solution and 25 μl of ³ H- Pirenzepine (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 incu¬ bation samples are added 5 ml of ice-cold buffer and poured directly onto Whatman GF/C glass fiber filters inder 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% inhibi¬ tion of specific binding must be obtained before calculation of IC _K ,.

The test value will be given as ICg, (the concentration, nM) of the test substance which inhibits the specific binding of ³ H-PRZ by 50%.

IC ₅₀ = (applied test substance concentration)

where C ₀ is specific binding in control assays and C _x is the specific binding in the test assay. (The calculations assume normal mass-action kinetics).

Test results obtained by testing some compounds of the present invention will appear from the following table 1.

IABLE1

ICso, nM Compound ³ H-Oxo-M ³ H-Pz

1 3.4 6.0

2 3.3 9.0 3 0.59 4.5

4 1.50 4.9

5 3.3 8.8

6 4.8 2.3

7 4.9 135.0 8 3.5 28.0

9 1.6 26.0

10 15.5 56.0

11 35

12 63 13 13

The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, sus¬ pensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without ad-

ditional active compounds or principles, and such unit dosage forms may contain any suitable effective muscarinic cholinergic agonistic amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing ten (10) milligrams of the active ingredient or, more broadly, one (1) to hundred (100) milligrams, per tablet, are accord¬ ingly suitable representative unit dosage forms.

The compounds of this invention can thus be used for the formulation of pharmaceutical prepa¬ rations, e.g. for oral and parenteral administration to mammals including humans, in accor¬ dance with conventional methods of galenic pharmacy.

Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier sub¬ stances suitable for parenteral or enteral application which do not deleteriously react with the active compounds.

Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhy- droxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, epntaerythritol fatty acid esters, hydroxy- methylcellulose 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, prefera- bly aqueous solutions with the active compound dissolved in polyhydroxyiated castor oil.

Ampoules are convenient unit dosage forms.

Tablets, dragees, or capsules having talc and/or a carbo-hydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch, are particularly suitable for oral application. A syrup, elixir or the like can be used in cases where a sweetened vehicle can be employed.

Generally, the compounds of this invention are dispensed in unit form comprising 1-100 mg in a pharmaceutically-acceptable carrier per unit dosage.

The dosage of the compounds according to this invention is 1-100 mg/day, preferably 10-70 mg day, when administered to patients, e.g. humans, as a drug.

A typical tablet which may be prepared by conventional tabletting techniques 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.

Due to the high muscarinic cholinergic receptor agonistic activity, the compounds of the inven¬ tion are extremely useful in the treatment of symptoms related to a cholinergic deficit in the pe¬ ripheral system. The compounds of the invention may accordingly be administered to a sub- ject, e.g., a living animal body, including a human, in need of stimulation of the cholinergic system, and if desired in the form of a pharmaceutically acceptable salt (such as the hydrobromide, hydrochloride, or sulfate, in any event prepared in the usual or conventional manner) ordinarily concurrently, simultaneously, or together with a pharmaceuti¬ cally acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective stimulating amount, and in any event an amount which is effective for improving the symptoms related to a cholinergic deficit of mammals due to their muscarinic cholinergic re¬ ceptor agonistic activity. Suitable dosage ranges are 1-100 milligrams daily, 10-100 milligrams daily, and especially 30-70 milligrams daily, depending as usual upon the exact mode of ad- ministration, form in which administered, the indication towards which the administration is di¬ rected, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.

The invention will now be described in further detail with reference to the following examples:

EXAMPJJ l

3-(3-Hexylthio-1 ,2,5-thiadiazol-4-yl)-1 ,2,5,6-tetrahydro-1 , 1 -dimethylpyridinium iodide

3-(3-hexylthio-1,2,5-thiadiazol-4-yl)-1 _l 2,5,6-tetrahydro-1-methylpyridine (0.59 g, 2 mmol) was dissolved in acetone (10 ml), lodomethane (1.15 g, 8 mmol) was added, and the reaction mix¬ ture stirred for 2 h at room temperature. Ether (10 ml) was added. The precipitated title com- pound was filtered and dried. Yield: 0.5 g. M.p. 138-139°C. Compound 1.

EXAMPLE 2

In exactly the same manner the following compounds were made using the appropriate alkyl- halogenide:

3-(3-Hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1 ,1 -dimethylpyridinium iodide. M.p. 159- 160°C. Compound 2.

3-(3-Ethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1 ,1 -dimethylpyridinium iodide. M.p. 235- 236°C. Compound 3.

3-(3-Butylthio-1 ,2,5-thiadiazol-4-yl)-1-methyl-1-azabicyclo[2.2.2]octane iodide. M.p. 106-108°C. Compound 4.

Endo 6-(3-Butylthio-1,2,5-thiadiazol-4-yl)-1-methyl-1-azabicyclo[ 3.2.1]octane iodide. M.p. 179- 180°C. Compound 5.

Endo 6-(3-Pentylthio-1,2,5-thiadiazol-4-yl)-1-methyl-1-azabicyclo [3.2.1]octane iodide. M.p. 164- 166°C. Compound 6.

Exo 6-(3-Pentylthio-1 ,2,5-thiadiazol-4-yl)-1-methyl-1-azabicyclo[3.2.1]octane iodide. M.p. 130- 132°C. Compound 7.

3-(3-Ethylthio-1 ,2,5-thiadiazol-4-yl)-1 ,2,5,6-tetrahydro-1-ethyl-1-methylpyridinium iodide. M.p. 153-154°C. Compound 8.

3-(3-Ethylthio-1,2,5-thiadiazol-4-yl)-1 ,2,5,6-tetrahydro-1 _l 1 -dimethylpyridinium iodide. M.p. 216- 217°C. Compound 9.

3-(3-Ethoxy-1 ,2,5-thiadiazol-4-yl)-1 ,2,5,6-tetrahydro-1-ethyl-1-methyl-pyridinium iodide. M.p. 171-172°C. Compound 10.

Exo(+) 6-(3-(3-(3-Thienyl)-2-propyn-1-yloxy)-1,2,5-thiadiazol-4-yl) -1-azabicyclo[3.2.1]- octane iodide. M.p. 153-155°C. Compound 11.

Exo(+) 6-(3-(3-(2-Thienyl)-2-propyn-1-yloxy)-1,2,5-thiadiazol-4-yl) -1-azabicyclo[3.2.1]- octane iodide. M.p. 122-124°C. Compound 12.

Exo(+) 6-(3-(3-(3-Phenyl)-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl) -1-azabicyclo[3.2.1]- octane iodide. M.p. 190-192°C. Compound 13.