WO1999059995A1

WO1999059995A1 - Heterocyclic compounds and their preparation and use

Info

Publication number: WO1999059995A1
Application number: PCT/DK1999/000257
Authority: WO
Inventors: Lone Jeppesen; Per Sauerberg
Original assignee: Novo Nordisk A/S
Priority date: 1998-05-15
Filing date: 1999-05-07
Publication date: 1999-11-25
Also published as: AU3700999A

Abstract

The present invention relates to therapeutically active azacyclic, azabicyclic and azatricyclic compounds of formula (I), a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in treating a disease in the central nervous system caused by malfunctioning of the muscarinic cholinergic system.

Description

Heterocyclic Compounds and their Preparation and Use

Field of the Invention

The present invention relates to therapeutically active azacyclic, azabicyclic or azatricyclic compounds, a method of preparing the same and to pharmaceutical or veterinary compositions comprising the compounds. The novel compounds are useful in treating a disease in the central nervous system caused by malfunctioning of the muscarinic cholinergic system.

Background of the Invention

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 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 degener- ate, the postsynaptic receptors in the forebrain and hippocampus still exist. Therefore cholinergic agonists are useful in the treatment of Alzheimer's disease, in halting progression of Alzheimer's disease, and in improving the cognitive functions of elderly people.

The compounds of this invention are also useful analgesic agents and therefore useful in the treatment of severe painful conditions.

Furthermore, the compounds of this invention are useful in the treatment of glaucoma, psychosis, mania, bipolar disorder, schizophrenia or schizophreniform conditions, depression, bladder dysfunctions, anxiety, sleeping disorders, epilepsy, cerebral ischemia and gastroin- testinal motility disorders. Summary of the Invention

It is an object of the invention to provide new muscarinic cholinergic compounds.

The novel compounds of the invention are heterocyclic compounds having the formula I

^R-Ar-^R3

F.< ,

wherein Ar is phenyl, thienyl, pyridyl, pyrimidinyl, thiazolyl or furyl; and

R\ R² and R³ independently are Z, hydrogen, halogen, CN, NO₂, C_1-3-alkyl, C_1-3-alkoxy or C, ₃-alkylthio wherein C^-alkoxy are optionally substituted with one or more halogens and at least two of the three R¹, R² or R³ substituents are a Z group, wherein

Z is a group of formula II

wherein A is C_1-10-alkylene, C₂.ι₀-alkenylene or C_2-10-alkynylene, and wherein

X and Y independently are oxygen or sulphur; and wherein

G is hydrogen, halogen or selected from the group of azacyclic, azabicyclic and azatricyclic ring systems consisting of:

wherein R⁴ is hydrogen or C_1-5-alkyl; and

n is 0,1 or 2; and

m is 0,1 or 2; or

a pharmaceutically acceptable salt or solvate thereof.

As used herein, the term "halogen" means F, Cl, Br, and I.

The term "C^.-alkyl" wherein n' can be from 2 through 5, as used herein, represents 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 and the like.

The term "C^-.-alkylene" wherein n' can be from 2 through 10, as used herein, represents a branched or straight alkylene group having from one to the specified number of carbon atoms. Examples of such groups include, but are not limited to, methylene, ethylene, trimethylene, propylene, tetramethylene, ethylethylene, pentamethylene, hexamethylene, and the like.

The term "C₂__n-alkenylene" wherein n' can be from 3 through 10, 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 limited to, ethenylene, propenylene, butenylene, pentenylene, hexenylene, butadienylene and the like.

The term "C_2-n.-alkynylene" wherein n' can be from 3 through 10, as used herein, represents an unsaturated 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, ethynylene, propynylene, butynylene, pentynylene, hexynylene, and the like. The term "C_1-3-alkoxy" as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a C_1-3-alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 4 carbon atoms. Examples of such groups include, but are not limited to, e.g. methoxy, ethoxy, propoxy, isopropoxy and the like.

The term "C_1-3-alkylthio" as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a C_1-3-alkyl group linked through a divalent sulfur atom having its free valence bond from the sulfur oxygen and having 1 to 4 carbon atoms. Examples of such groups include, but are not limited to, e.g. methylthio, ethylthio, pro- pylthio, isopropylthio and the like.

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 R¹, R² and R³ are Z.

In another preferred embodiment, the present invention is concerned with compounds of formula I wherein two of R¹, R² and R³ independently are Z and the third is hydrogen or halogen.

In another preferred embodiment, the present invention is concerned with compounds of formula I wherein Ar is phenyl.

In another preferred embodiment, the present invention is concerned with compounds of formula I wherein A is C₂.₅-alkynylene, preferably C₃-alkynylene.

In another preferred embodiment, the present invention is concerned with compounds of formula I wherein G is selected from the group of azacyclic or azabicyclic ring systems consisting of

wherein R⁴, n and m are as defined as above.

In another preferred embodiment, the present invention is concerned with compounds of formula I wherein X is oxygen.

In another preferred embodiment, the present invention is concerned with compounds of formula I wherein Y is sulphur.

In another preferred embodiment, the present invention is concerned with compounds of formula I wherein n is 1 and m is 2.

In another preferred embodiment, the present invention is concerned with compounds of formula I wherein n is 2 and m is 1.

In another preferred embodiment, the present invention is concerned with compounds of formula I wherein R⁴ is hydrogen or methyl.

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 enanti- omeric, 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.

The invention also relates to methods of preparing the above mentioned compounds, com- prising: a) reacting a compound of formula

wherein L is a leaving group e.g. chlorine or SO₂R⁵ wherein R⁵ is alkyl or phenyl and wherein G and Y are defined as above, with an alcohol of formula IV

HO _/OH

A^ Λ

Ar

RC

IV

wherein A and Ar are defined as above and wherein R⁶ is hydrogen, halogen, CN, NO₂, C_1-3- alkyl, C_1-3-alkoxy, C_1-3-alkylthio or -A-OH, wherein A is defined as above, to obtain a compound of formula I wherein Ar, R\ R² and R³ is defined as above except that X is O,

b) reacting a compound of formula III

wherein L is a leaving group e.g. chlorine or SO₂R⁵ wherein R⁵ is alkyl or phenyl and wherein G and Y are defined as above with sodium hydrosulfide in an aprotic solvent such as dimethyl formamide followed by an appropriate halide of formula VI

wherein A, Ar and Hal is defined as above and wherein R⁵ is hydrogen, halogen, CN, NO₂, C,.₃-alkyl, C_1-3-alkoxy, C^-alkylthio or -A-Hal, wherein A and Hal are defined as above, to obtain a compound of formula wherein I wherein Ar, R¹, R² and R³ is defined as above except that X is S.

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.

The invention further provides a formulation comprising a compound of formula I and one or more pharmaceutically acceptable diluents, carriers or excipients therefor. Such compositions are preferably in the form of an oral dosage unit or parenteral dosage unit.

The invention provides a method for treating a condition associated with a malfunction of the cholinergic muscarinic receptor system comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound according to the invention. Such conditions which may be treated using a compound of this invention include, but are not limited to Alzheimer's Disease, cognitive dysfunction, severely painful conditions, glaucoma, psychosis, schizophrenia, bladder dysfunction, anxiety, sleep disorders, and other such conditions associated with the modulation of a muscarinic receptor. 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 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.

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.

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 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 labelled 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 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 μl of test solution and 25 μl of ³H- Oxotremorine (1.0 nM, final concentration) mixed and incubated for 30 min. at 25°C. Nonspecific 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 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).

Table 1 Compound ³H-Oxo ICso, nM

1 1.4

2 2.3 3 2.7

4 11.0

5 0.70

6 0.74

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 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, transder al, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution 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 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 ex- ample, 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 ex- amples of suitable 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, pentaerythritol fatty acid esters, hydroxymethyl- cellulose and polyvinylpyrrolidone. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring 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 colouring 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.

A typical tablet, appropriate for use in this method, may be prepared by conventional tablet- ting 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.

The compounds according to 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 preferably, the animal is a vertebrate. Most preferably, a compound according to 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 or in bulk form.

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) 1,3 Bis-(3-[(6-azabicycIo[3.2.1]octanyl)-1,2,5-thiadiazol-4-yloxy]-1-propyn-1- yl)benzene, 2 L-(+)-tartrate

a)

A mixture of 1 ,3 dibromobenzene (7.1 g, 30.0 mmol), cupper(l)iodide (114 mg, 0.6 mmol) and bis (triphenylphosphine)palladium(ll)chloride (98%) (210 mg, 0.3 mmol) in triethylamine (25 ml) and diisopropylamine (75 ml) was stirred under nitrogen at room temperature for 1 . Propargyl alcohol (5.25 ml, 93.8 mmol) was added and the reaction mixture was heated at 60°C for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The product was purified by flash chromatography using toluene/ethyl acetate (9:1) graduated to toluene/ethyl acetate (4:1) as eluent to give 4.1 g (73%) of 1 ,3-bis(3-hydroxy-propyn-1- yl)benzene as an oil.

b)

To a icecooled solution of (5R,6R) 6-(3-propylsulfonyl-1 ,2,5-thiadiazol-4-yl)-1- azabicyclo[3.2.1]octane (Olesen, P. H. et al, Chirality, 9, 1997, 739-749) (603mg, 2.0 mmol) in tetrahydrofurane (20 ml) was under nitrogen added 1 ,3-bis-(3-hydroxy-propyn-1- yl)benzene (186 mg, 1.0 mmol) in tetrahydrofurane (10 ml) followed by sodiumhydride (80%) (360 mg, 12.0 mmol). The mixture was stirred under nitrogen at 0°C for 6 h and at room temperature for 48h. The reaction mixture was quenched with ice water and added 4 N HCI to pH 2-3. The tetrahydrofurane was evaporated and the residue washed with ether (2 x - discared). The solution was made basic with potassium carbonate (pH 9-10) and the product isolated by extraction with dichloromethane (3 x). The organic phases were dried (MgSO₄), filtered and evaporated . The residue was purified by HPLC on a Source RPC column equilibrated in ethanol/20 mM 1 ,3 diaminopropane (3:7) and eluated with 30%-65% acetonitril. The pure fractions were pooled and the acetonitrile was evaporated. The residue was extracted with diethylether (3 x). The organic phases were dried (NaSO₄) filtered and concentrated in vacuo. The purified product was crystallised with L-(+)-tartaric acid in isopropanol to give 130 mg (7 %) of the title compound. M.p. 100-105°C. Compound 1.

The following compound was made in the same manner using the appropriate amine (Olesen, P. H. et al, Chirality, 9, 1997, 739-749).

(3S) 1 ,3-Bis-(3-[(3-azabicyclo[2.2.2]octanyl)-1 ,2,5-thiadiazol-4-yloxy]-1 -propyn-1 -yl)benzene, 2 L-(+)-tartrate. M.p. 97-105°C. Compound 2.

Example 2

(5R,6R) 1,4 Bis-(3-[(6-azabicyclo[3.2.1]octanyl)-1,2,5-thiadiazol-4-yloxy]-1 -propyn-1 - yl)benzene, 2 HCI

a)

A mixture of 1 ,4-dibromobenzene (11.8 g, 50.0 mmol), cupper(l)iodide (300 mg, 1.6 mmol) and bis-(triphenylphosphin)palladium(ll)chloride (98%) (720 mg, 1.0 mmol)in triethylamine (30 ml) and diisopropylamine (150 ml) was stirred at room temperature under nitrogen for 1 h. Propargyl alcohol (6.4 ml, 110 mmol) was added and the stirring was continued at 55°C for another 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The product was purified by flash chromatography using dichloromethane graduated to di- chloromethane/methanol (19:1) as eluent to give 2.9 g (32%) of 1 ,4-bis-(3-hydroxy-propyn-1- yl)benzene as an oil.

b)

To a solution of 1 ,4-bis-(3-hydroxy-propyn-1-yl)benzene (372 mg, 2.0 mmol) in dry tetrahy- drofuran (30 ml) under nitrogen was added (5R,6R) 6-(3-propylsulfonyl-1 ,2,5-thiadiazol-4-yl)- 1-azabicyclo[3.2.1]octane (1.2 g, 4.0 mmol) in dry tetrahydrofuran (20 ml). The mixture was cooled on ice and added sodium hydride (720 mg, 24.0 mmol). Stirring under nitrogen at 40°C for 3 days. The reaction mixture was quenched with ice-water and added 4 N HCI to pH 2.0. The tetrahydrofuran was evaporated and the residue washed with diethylether (2 x 75 ml - discard). The solution was made basic with NH₃ to pH 10-11 and the product isolated by extraction with dichloromethan (3 x). The residue was disolved in warm 0.5 N HCI and the product allowed to precipitate under cooling. 650 mg (82%) of the title compound was iso- lated by filtration. M.p. >200°C. Compound 3.

The following compound was made in the same manner using the appropriate amine. The product was isolated as described for compound 5 and purified by HPLC on a Source RPC 15 column equilibrated in ethanol/20 mM 1 ,3 diaminopropane (3:7) and eluated with 15-20% acetonitril. The title compound was precipitated as an tartrate.

(3S) 1 ,4-Bis-(3-[3-azabicyclo[2.2.2]octanyl)-1 ,2,5-thiadiazol-4-yloxy]-1 -propyn-1 -yl)benzene, 2 L-(+)-tartrate. M.p. 123-126°C. Compound 4.

Example 3

(3S) 1 ,3- Bis-(3-[(3-azabicyclo[2.2.2]octanyl)-1 ,2,5-thiadiazol-4-yloxy]-1 -propyn-1 -yl)-5- fluorobenzene, 2 L-(+)-tartrate

a)

A mixture of 1 ,3-dibromo-5-fluorobenzene (15.0 g, 59.0 mmol), cupper(l)iodide (380 mg, 142.0 mmol) and bis-(triphenylphosphine)-palladium(ll)chlorid (98%) (840 mg, 1.2 mmol) in triethylamin (50 ml) and diisopropylamin (200 ml) was stirred ar room temperature under nitrogen for 1 h. Propargyl alcohol (8.3 ml, 142.0 mmol) was added and the reaction mixture was stirred over night at 55°C. More propargyl alcohol (4.1 ml, 70.0 mmol) was added and the stirring was continued at 55°C for another 16 h. The mixture was filtered and the filtrate concentrated in vacuo. The product was purified by flash chromatography using di- chloromethan / methanol (19:1) as eluent to give 12.0 g (99%) of 1 ,3-bis-(3-hydroxy-propyn- 1-yl)-5-fluorobenzene as an oil.

b)

To a ice cooled solution of 1 ,3-bis-(3-hydroxy-propyn-1-yl)-5-fluorobenzene (408 mg, 2.0 mmol) and (3S) 3-(3-butylsulfonyl-1 ,2,5-thiadiazol-4-yl]-1-azabicyclo[2.2.2]octane (1.3 g, 4.0 mmol) in tetrahydrofuran (50 ml) was under nitrogen added sodium hydride (80%) (180 mg, 6.0 mmol). The mixture was stirred under nitrogen at 0°C for 6 h and at room temperature for 48 h. The reaction mixture was quenched with ice water and added 4 N HCI to pH 2-3. The tetrahydrofuran was evaporated and the residue washed with ether (2 x - discared). The solution was made basic with NH₃ to pH 10-11 and the product isolated by extraction with dichloromethan (3 x). The organic phases was purified by HPLC on a Source RPC 15 column equilibrated in ethanol/20 mM 1 ,3 diaminopropane (3:7) and eluated with 50-80% acetonitril.The pure fractions was pooled and the acetonitril was evaporated and the residue extracted with dichloromethane (3 x). The organic phases were washed with water and saturated sodium chloride solution, dryed (MgSO₄), filtered and concentrated in vacuo. The residue was disolved in isopropanol and crystasllised with L-(+)-tartaric acid in isopropanol to give 204 mg (12%) of the title compound. M.p. 102-104°C. Compound 5.

The following compound was made in then same manner using the appropriate amine. (5R.6R) 1 ,3-Bis-(3-[(6-azabicyclo[3.2.1]octanyl)-1 ,2,5-thiadiazol-4-yloxy]-1 -propyn-1 -yl)-5- fluorobenzene, 2 L-(+)-tartrate, M.p. 99-102°C. Compound 6.

Claims

1. A compound of formula I

R .R^J ^{^}Ar

R'

wherein Ar is phenyl, thienyl, pyridyl, pyrimidinyl, thiazolyl or furyl; and

R¹, R² and R³ independently are Z, hydrogen, halogen, CN, NO₂, C_1-3-alkyl, C_1-3-alkoxy or C^ ₃-alkylthio wherein C_1-3-alkoxy are optionally substituted with one or more halogens and at least two of the three R¹, R² or R³ substituents are a Z group, wherein

Z is a group of formula II

wherein A is C_1-10-alkylene, C_2-10-alkenylene or C₂.₁₀-alkynylene, and wherein

X and Y independently are oxygen or sulphur; and wherein

wherein R⁴ is hydrogen or C_1-5-alkyl; and

n is 0,1 or 2; and

m is 0,1 or 2; or

a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1 wherein R¹, R² and R³ are Z.

3. A compound according to claims 1 or 2 wherein two of R\ R² and R³ independently are Z and the third is hydrogen or halogen.

4. A compound according to anyone of the preceding claims wherein Ar is phenyl.

5. A compound according to anyone of the preceding claims wherein A is C_2-5- alkynylene, preferably C₃-alkynylene.

6. A compound according to anyone of the preceding claims wherein G is selected from the group of azacyclic or azabicyclic ring systems consisting of

wherein R⁴, n and m are as defined as in claim 1.

7. A compound according to anyone of the preceding claims wherein X is oxygen.

8. A compound according to anyone of the preceding claims wherein Y is sulphur.

9. A compound according to anyone of the preceding claims wherein n is 1 and m is 2.

10. A compound according to anyone of the preceding claims wherein n is 2 and m is 1.

11. A compound according to anyone of the preceding claims wherein R⁴ is hydrogen or methyl.

12. A compound according to anyone of the preceding claims which is selected from the following:

(5R,6R) 1 ,3 Bis-(3-[(6-azabicyclo[3.2.1 ]octanyl)-1 , 2, 5-thiadiazol-4-yloxy]-1 -propyn-1 - yl)benzene,

(3S) 1 ,3-Bis-(3-[(3-azabicyclo[2.2.2]octanyl)-1 , 2, 5-thiadiazol-4-yloxy]-1 -propyn-1 -yl)benzene,

(5R,6R) 1 ,4 Bis-(3-[(6-azabicyclo[3.2.1 ]octanyl)-1 ,2,5-thiadiazol-4-yloxy]-1 -propyn-1 - yl)benzene,

(3S) 1 ,4-Bis-(3-[3-azabicyclo[2.2.2]octanyl)-1 ,2,5-thiadiazol-4-yloxy]-1 -propyn-1 -yl)benzene,

(3S) 1 ,3- Bis-(3-[(3-azabicyclo[2.2.2]octanyl)-1 ,2,5-thiadiazol-4-yloxy]-1 -propyn-1 -yl)-5- fiuorobenzene,

(5R,6R) 1 ,3-Bis-(3-[(6-azabicyclo[3.2.1]octanyl)-1 ,2,5-thiadiazol-4-yloxy]-1 -propyn-1 -yl)-5- fluorobenzene,

or a pharmaceutically acceptable salt or solvate thereof.

13. A method of preparing a compound according to claim 1 , characterized in,

a) reacting a compound of formula III

HO^ _/OH

A^ ╬¢

Ar

R^b IV

wherein A and Ar are defined as above and wherein R⁶ is hydrogen, halogen, CN, NO₂, C_1-3- alkyl, C_1-3-alkoxy, C_1-3-alkylthio or -A-OH, wherein A is defined as above, to obtain a compound of formula I wherein Ar, R¹, R² and R³ is defined as above except that X is O,

b) reacting a compound of formula III

wherein A, Ar and Hal is defined as above and wherein R⁵ is hydrogen, halogen, CN, NO₂, C_1- -alkyl, C_1-3-alkoxy, C_1-3-alkylthio or -A-Hal, wherein A and Hal are defined as above, to obtain a compound of formula wherein I wherein Ar, R\ R² and R³ is defined as above except that X is S.

14. A pharmaceutical composition comprising a compound according to claims 1 to 12 together with one or more pharmaceutically acceptable carriers or diluents.

15. A pharmaceutical composition for use in treating a disease in the central nervous system caused by malfunctioning of the muscarinic cholinergic system comprising an effective amount of a compound according to claims 1 to 12 together with a pharmaceutically acceptable carrier or diluent.

16. The pharmaceutical composition according to claim 14 or 15 in the form of an oral dosage unit or parenteral dosage unit.

17. The pharmaceutical composition according to claim 16, wherein said dosage unit comprises from about 0.1 to about 100 mg of the compound according to claims 1 to 12 .

18. A method of treating a disease in the central nervous system caused by malfunctioning of the muscarinic cholinergic system comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound according to claims 1 to 12.

19. A method of treating a disease in the central nervous system caused by malfunc- tioning of the muscarinic cholinergic system comprising administering to a subject in need thereof a pharmaceutical composition according to claims 14 to 17.

20. The use of a compound according to claims 1 to 12 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treatment of a disease in the central nervous system caused by malfunctioning of the muscarinic cholinergic system.

21. A method for treating a condition associated with the modulation of a muscarinic cholinergic receptor comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound according to claims 1 to 12.

22. The use of a compound according to claims 1 to 12 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treatment of a condition associated with the modulation of a muscarinic cholinergic receptor.

23. A method for interacting with a muscarinic cholinergic receptor comprising administering to a subject in need thereof an effective amount of a compound according to claims 1 to 12.

24. The use of a compound according to claims 1 to 12 or a pharmaceutically acceptable salt hereof for the preparation of a medicament for interacting with a muscarinic cholinergic receptor.