SK279168B6 - Bicyclic 1-azacycloalkanes, pharmaceutical agents containing thereof and use thereof - Google Patents

Abstract

Bicyclic 1-azacycloalkane derivatives having the formula (I), whereas the particular symbols are defined in the description, pharmaceutical agents containing thereof and use thereof. Compounds, according to invention, are suitable for the treatment of diseases associated with decreased functionality of the cholinometic system, e.g. in case of Alzheimer disease and senile dementia. Quaternary salts of these substances can be applied topically, e.g. in case of glaucoma.

Description

Technical field

The invention relates to bicyclic 1-azacycloalkanes, to a process for their preparation, and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

In European patent application no. No. 370,415 discloses quinuclidines of formula (I) wherein R is unsubstituted alkyl, alkenyl, or alkynyl. Also known are quinuclidines of formula (I) wherein R is a heterocyclic ring bonded through an oxygen atom. However, the European patent application describes these substances as 5-HT-antagonists. Substituted 1-azabicyclo [3.3.1] nonanes of the general formula (I) in which R represents an alkyl of 1 to 3 carbon atoms bonded via an oxygen atom are also known from the European patent application.

However, this European patent application does not explicitly mention optically active compounds of this type.

SUMMARY OF THE INVENTION

The present invention provides novel bicyclic 1-azacycloalkanes of formula (I)

wherein n = 0 or 1 and R is a radical of formula (R 1)

where

R 1 represents a hydrogen atom, C 1-4 alkyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, hydroxy, C 3-6 cycloalkyl, C = O, phenyl, which may be substituted with one, two or three substituents which are halogen, hydroxy, and / or straight or branched C 1-5 alkyl, C 1-8 cycloalkyl, C 1-5 hydroxyalkyl; amino, mono or disubstituted C 1-4 -alkylamino;

k is 1, 2 or 3, wherein when k is 1, all R 1 can be the same or different from each other;

R ² is H, Ci_4 alkyl, Ci_4-alkoxy, halogen, C = O;

represents the number 1 or 2, preferably 1, wherein in the case where 1 = 2, R ² may be the same or different from each other;

R ² is H or Ci-4-alkyl;

as well as the racemates thereof, their enantiomers, diastereomers and mixtures of these forms and, where appropriate, their pharmacologically acceptable acid addition salts as well as their quaternary salts, provided that if n = 0, R cannot be a pyridine radical which may be substituted with hydroxy, C 1-4 -alkyl, C 1-4 -alkoxy, amino, C 1-4 -alkylamino, di (C 1-4 -alkyl) amino with halogen or substituted or unsubstituted phenyl.

Preferred are the bicyclic 1-azacycloalkanes of formula (I) wherein

R are defined in which

R 1 is methyl or methoxy;

k is 1, 2 or 3, wherein when k is greater than 1, all R 1 can be the same or different from each other;

R ² is methyl or methoxy group;

R 3 represents a methyl group;

in the form of racemates, enantiomers, diastereomers and mixtures thereof, and in the form of pharmacologically acceptable acid addition salts and quaternary salts.

The separation of enantiomers starts as described in Example 3 for the first time from racemic compounds using optically active salts such as (+) or (-) tartaric acid in a known manner.

SK 279168 Β6

Based on binding experiments on rat muskerin subtypes H [, H2 and Hj] and on stimulation of phosphatidylsinsitol tumors (CHO cells in culture with human subtype m 1 receptor), potent (+) - (propargyloxymethyl) -l binding can be demonstrated in vitro -azabicyclo [2.2.2] octane compared to the racemate and the (-) enantiomer. The in vivo cholinomimetic activity of the same compound was studied in rabbits using EEG, where theta wines were multiplied.

The present invention provides a process for the preparation of compounds of formula (I) wherein the compound of formula (I) is formed

wherein each symbol is as defined above, the meaning is treated with a compound of formula

HOR where

R is defined in the presence of triphenylphosphine and an alkyl ester of azodicarboxylic acid.

During deprotonation and conversion of the hydroxy compound to a metal salt, which is preferably carried out at room temperature or at a slightly elevated temperature, the subsequent alkylation is preferably carried out under ice-cooling. Upon completion of the reaction, the protecting group is cleaved and the resulting product is optionally converted into its acid addition salt or quaternary salt. Reaction conditions are known, preferred quaternary compounds are methoiodide and metobromide.

Preferred deprotonating reactants are sodium hydride, sodium amide, alkali metal alkoxides such as potassium tert-butoxide.

Preferred addition salts are, for example, salts with hydrochloric, ethanesulfonic, toluenesulfonic, benzenesulfonic, lactic, malonic, succinic, maleic, fumaric, malic, tartaric, citric or benzoic acids.

The starting materials required for carrying out the synthesis, corresponding to the hydroxyazabicycloalkanes, are known from the literature.

Said substances are, when n = 0, known from JACS 74, 2215 (1952) (Ha), J. Org. Chem. 33 4376 (1968) (IIb) from European patent application no. 307,140 (III) and J. Pharm. Science 52: 331 (1954) (IV). Starting materials in which R represents a hydrogen atom and n = 1 or 2 can be obtained by reduction of the corresponding alkyl esters in which X - R represents a COOalkyl group. Starting from the corresponding ketones, thiols of formula (II) and (III) can be obtained according to J. Chem. 43.1965.

When R in formula (I) is an aromatic or heteroaromatic radical, compounds of formula (I) may be obtained according to O. Mitusunobu, Synthesis 1, 1981, Georg Thieme Verlag, Stuttgart, J. C. Perkin I, p. 462, 1975 by reaction of the corresponding hydroxy-substituted reactants (I) in which R = H, HOR reactants in which R is phenyl or a heterocyclic radical in the presence of diethyl azodicarboxylic acid and triphenylphosphinate. The reaction is generally carried out in an inert organic solvent at room temperature.

The compounds of formula (I) have valuable pharmacological properties. In binding assays, their affinity for muscarinic receptors and agonist CTP-receptors (CTP = guanosine triphosphate) can be demonstrated according to Birdsall, N.I.M., E. C. Hulme and I. M. Stockton 1984, T.I.P.S. Supplement, Proc. Internat. Symposium on Subtypes of Muscarinic Receptor, Ed. Hirschowitz, Hammer, Ciacchetti, Klims, Levine, Elsevier p. 4 to 8.

Receptor binding experiments were performed according to A. Closse, H. Bittiger, O. Langenegger, and A. Wahner, Naunyn-Schmiedeberg's Arch. Pharmacol. 335, 372-377, 1987.

Table A: Receptor Binding Experiments

The radiolabeled ligand used was L (+) cis- [2-methyl-3H] -N, N, N-trimethyl-1,3-dioxolane-4-methanammonium iodide NET 647, (NEN, New England Nuclear DU PONT). ).

Rat cerebral cortex was used as the test organ.

T a b at 1 k and A

example R Ki [nnol / 2] 1 -0 120 4 -O-phenyl-CH 229 9 -0-c ₆ h ₅ 89

As substances acting similarly to muscarin, i. j. cholinomimetics, the compounds of the invention can be used in the treatment of diseases in which the function of the cholinergic system is reduced.

Based on pharmacological tests, the compounds can be used, for example, for the treatment of the following diseases: Alzheimer's disease, senile dementia, cognitive disorders, and in addition, the compounds can be used to improve thought processes.

The quaternary compounds of formula (I) are particularly suitable for topical administration, for example in the treatment of glaucoma.

The compounds of formula (I) may be used as such or in combination with other compounds of the invention or else in combination with other pharmacologically active substances, for example brain tissue activating agents and / or peripheral cholinergic blockers. Suitable forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders.

Tablets can be obtained, for example, by mixing one or more active ingredients with excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or milk sugar, and thickening agents such as corn starch or alginic acid, binders such as starches or gelatin; glidants such as magnesium stearate or talc; and / or slow release agents such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also consist of a plurality of layers.

In a similar manner, dragees can also be obtained by coating cores whose composition corresponds to that of tablets, using the means commonly used on the coating.

2796 dragees such as collidone or shellac, acacia, talc, titanium dioxide or sugar. To achieve a depot effect or to prevent incompatibilities, the core may also be formed by a plurality of layers. Also, the coating may be formed to achieve a depot effect by a plurality of layers; it is possible to use excipients as mentioned in the manufacture of tablets.

Syrups may contain, in addition to the active ingredient or active ingredient combination, sweetening agents, such as saccharin, cyclamate, glycerol or sugar, and a flavor enhancer, for example, flavoring agents such as vanillin or orange extract. In addition, they may contain suspending or thickening agents, such as sodium carboxymethylcellulose, a crosslinking agent, such as condensation products of aliphatic alcohols with ethylene oxide, or preservatives, such as p-hydroxybenzoate.

Injectable solutions may be prepared in conventional manner, for example by the addition of a preservative such as p-hydroxybenzoate or stabilizers, such as the alkali salts of ethylenediaminetetraacetic acid, then the solutions are filled into bottles or ampoules.

Capsules containing one or more active ingredients are obtained by mixing the active ingredients with inert carriers such as milk sugar or sorbitol and filling the resulting mixture into gelatin capsules.

Suppositories may be obtained by mixing the active ingredient with a carrier, for example a neutral fat or polyethylene glycol, or a derivative thereof.

An effective single dose of the compounds of the invention is in the range of 1 to 100 mg.

The invention will be explained by the following example section, in which examples of the composition of the individual dosage forms are given, as well as processes for the manufacture of certain active substances.

DETAILED DESCRIPTION OF THE INVENTION

Examples of pharmaceutical compositions

A) Tablets active ingredient mg / tablet active substance 80 milk sugar 140 maize starch 240 polyvinylpyrrolidone 15 magnesium stearate 5

480 mg

The finely divided active ingredient, milk sugar and part of the corn starch are mixed. The mixture was passed through a sieve, moistened with a solution of polyvinylpyrrolidone in water, mixed, granulated wet and dried. The granulate, the corn starch residue and the magnesium stearate are passed through a sieve and mixed. The mixture is compressed into tablets of suitable shape and size.

B) Tablets

active ingredient mg / tablet active substance 60 maize starch 190 milk sugar 55

Microcrystalline cellulose 35 Polyvinylpyrrolidone 15 Carboxymethyl starch sodium 23 Magnesium stearate 2

380 mg

The finely divided active ingredient, corn starch fraction, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed. The mixture is passed through a sieve and treated with the rest of the corn starch and water to form a granulate which is dried and sieved again. Sodium carboxymethyl starch and magnesium stearate are added, the ingredients are mixed, and the mixture is compressed into tablets of appropriate size.

C) Ampoules

active ingredient 20 mg sodium chloride 10 mg bidestilled water to 1.0 ml

The active ingredient and sodium chloride are dissolved in bidistilled water, and the solution is then filled into ampoules under sterile conditions.

D) Drops active ingredient 5.0 g methyl ester of the acid p-hydroxybenzoic acid 0.1 g propyl ester of an acid p-hydroxybenzoic acid 0.1 g demineralized water to 100.0 ml

To do this, the active ingredient and preservatives are dissolved in demineralised water, the solution is filtered and then filled into 100 ml vials.

Example 1

3-Propargyl-1-azabicyclo [2.2.1] heptene

5.6 g (0.05 mol) of 1-azabicyclo [2.2.1] heptan-3-ol are dissolved in 150 ml of absolute tetrahydrofuran under nitrogen and treated at 50C with 50 ml of 1M borane-tetrahydrofuran complex THF. After the addition was complete, the mixture was stirred at room temperature for 1 hour, then evaporated to dryness, the residue was dissolved in saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic phases are combined, evaporated to dryness, the residue is dissolved in 120 ml of absolute THF and then 2.08 g (0.052 mol) of sodium hydride are added in portions under a nitrogen atmosphere. The mixture was allowed to stand for 1 hour, then cooled to 0 ° C and 17.55 g of propargyl bromide as a 50% solution in tetrahydrofuran was added dropwise at this temperature. The resulting mixture was stirred at room temperature for 12 hours, then the excess hydride was quenched by the addition of ethanol, the solution was evaporated, the residue was dissolved in saturated aqueous sodium chloride solution and extracted with dichloromethane. After drying and evaporating the combined organic phases obtained in this way, oily liquid which was distilled under high vacuum, Κρ] θθ _and P = 45-46 ° C. Addition of one equivalent of fumaric acid yields a fumarate which is recrystallized from a mixture of ethanol and ether and then dried under vacuum. this

2.1 g of the title compound are obtained in the form of colorless crystals, m.p. 121-123 ° C.

1 H-NMR (250 MHz, CO 3 OD, TMS): δ 6.68 (2H, s, fumaric acid), 4.47 (1H, m, H-3), 4.21 (2H, m, CH 2 - 8) 3.73 2.86 (7H, m, CH 2 -2, 6.7, H-4), 2.95 (1H, t, J = 3 Hz, H-9), 2.30, 1.96 (2H, m, _CH2 -5).

Example 2

3-phenoxy-l-azabicyclo [2.2.2] octane

3.82 g, 0.03 mol of 3-hydroxyquinuclidine, 2.82 g, 0.03 mol of phenol, and 7.96 g, 0.03 mol of triphenylphosphine with 5.22 g, 0.03 mol of azabicarboxylic acid diethyl ester are dissolved in 150 ml of absolute THF and stirred at room temperature for 2 days. The mixture is evaporated to dryness, the residue is taken up in 20 ml of 6 N hydrochloric acid and 50 ml of water and extracted with ether. The aqueous phase is basified, shaken with ethyl acetate, the organic phases are combined and evaporated. After distillation, 3.6 g of a colorless oil are obtained having a Kp10 Pa = 104-105 ° C.

/ 7X ^ ^OC 6 ^H 5

Cv

1 H-NMR (250 MHz, CDCl 3, TMS): δ 7.26, 6.87 (5H, m, aryl-H), 4.36 (1H, m, H-3), 3.34-2.63 (6H, m, CH ₂ -2, 6.7), 2.19-1.27 (5H, m, CH-4, CH ₂ -5, 8).

The base obtained is converted in ethanol solution to fumarate, which is then precipitated by addition of ether and recrystallized from acetonitrile.

4.1 g of the title compound are obtained in the form of a colorless crystalline substance, m.p. 122-124 ° C.

Example 3 ± acetic acid (+) - and (-) - 3- (Propargyloxymethyl) -1-azabicyclo [2.2.2] octane 3-quinuclidinylmethyl ester

Racemic 3-quinuclidinylmethanol is obtained by a method known in the literature, for example via cyanohydrin from quinuclidin-3-one according to Helv. Chim. Acta 37, 1695 (1954) and then acylated with acetyl chloride in a mixture of triethylamine and chloroform at room temperature to give racemic acetic acid 3-quinuclidinylmethyl ester of boiling point 130-134 ° C at 3 kPa in 82% yield.

(-) - 3-Quinuclidinylmethanol

26.5 g of racemic 3-quinuclidinylmethyl acetate and 21.7 g of L - (+) - tartaric acid are heated to boiling in 275 ml of 95% ethanol, followed by slow cooling to give a crystalline tartaric salt which is left to stand still. recrystallize five times from 95% ethanol. Crystallization is carried out until a constant rotation angle is reached. 13.5 g of a salt with an optical rotation of [alpha] / [beta] - are obtained. 16.93 ° (c - 2, H ₂ O), stirred for 2 hours at room temperature in 80 ml of 2 N sodium hydroxide, then treated with 80 g of potassium carbonate and repeatedly extracted with chloroform. A total of 5.6 g of the resulting (-) - 3-quinuclidinylmethanol is obtained in the form of a light-colored oily substance having an optical rotation of [α] D at -66 ° (c = 1.2 in 1 N hydrochloric acid). ).

Analytical control of the purity of the obtained enantiomer was carried out after derivatization of phenyl isocyanate by high pressure liquid chromatography on a Chiralcel-OD column, the mixture was shown to contain 98.6% (-) - form and 1.4% (+) - form.

All mother liquors resulting from the preparation of (-) - 3-quinuclidinylmethanol were evaporated in vacuo. The residue was dissolved in a small amount of water, basified with potassium carbonate and then extracted with chloroform. 19.5 g of optically enriched 3-quinuclidinylmethyl acetic acid ester were obtained, which was treated with 16.0 g of D - (+) - tartaric acid in 200 ml of 95% ethanol on the diastereomeric salt. This salt was recrystallized five times from 95% ethanol to give 12.7 g of a salt with an optical rotation of [alpha] j = 20.8 ° (c = 2, water) and was obtained similarly to ( -) - enantiomer by treatment with 75 ml of 2 N sodium hydroxide in an amount of 4.7 g of (+) - 3-quinuclidinylmethanol as a light oily substance having an optical rotation of [.alpha.] D @ 20 = + 66.5 DEG (c = 1; 1 N hydrochloric acid).

The purity of the enantiomer was determined after derivatization with phenyl isocyanate by high pressure liquid chromatography on a Chiralcel-OD column, it was shown to contain 97.4% (+) - form and 2.6% (-) - form.

(A) (+) - 3- (Propargyloxymethyl) -1-azabicyclo [2.2.2] octane

5.6 g of (+) - 3-quinuclidinylmethanol hydrochloride, 1.32 g of sodium borohydride and 100 ml of tetrahydrofuran are stirred overnight. The mixture was filtered, the filtrate was evaporated, the residue was dissolved in ethyl acetate and the solution was washed with saturated aqueous sodium chloride solution. The solution was dried and the solvent was evaporated, yielding 3.4 g of the resulting complex of (+) - 3-quinuclidinylmethanol and borane as a light colored oil.

3.4 g of the borane complex are stirred in 100 ml of tetrahydrofuran for 30 minutes with 2.63 g of 60% sodium borohydrate at room temperature, then 4.89 g of 80% propargyl bromide are added and the mixture is further stirred for 6 hours. The reaction mixture is carefully quenched with alcohol, the solvent is evaporated, the residue is dissolved in 150 ml of ethyl acetate, the solution is washed with saturated aqueous sodium chloride solution and the solvent is evaporated again. To remove the borane protecting group, the residue is dissolved in 50 ml of acetone and stirred with 20 ml of 3 N hydrochloric acid overnight. After evaporation of the acetone, the aqueous phase is washed with ethyl acetate, basified with potassium carbonate and then extracted with ethyl acetate. The residue is subjected to flash chromatography on silica gel, eluting with ethyl acetate: methanol: ammonia (18: 15: 1) to give 4.3 g of propargyl ether which is converted in alcohol by treating the fumarate with the calculated amount of fumaric acid, which precipitates with alcohol and ether. In this way, 3.9 g of fumarate having a melting point of 132 DEG-133 DEG C. and an optical rotation of [.alpha.] D @ 20 = + 28.47 DEG (c = 1, methanol) are obtained.

3.b) (-) - 3- (propargyloxymethyl) -1-azabicyclo [2.2.2] octane

Similar to Example 3.a), a borane protecting group is introduced into (-) - 3-quinuclidinylmethanol, etherified by propargyl bromide and, after cleavage of the borane protecting group, the free base is converted to a fumarate with an optical rotation of [alpha] i). _{2 2} 8.4 ° (c = 1, methanol) and mp 132-133 ° C.

SK 279168 Β6

The following compounds of formula (I) can be obtained in an analogous manner to the foregoing examples.

example

R * melting point ’C

10a Example R * Melting point * C

10b

1 - 0— / \. 2 HCl N 236 (decomposition) 2 -Ό 164-166 fumarate 3 -ABOUT 160-161 fumarate 4 - ° - ^c 135-136 fumarate

| alpha _O | _D - +27.5 (c - 1, H ₂ O)

| Alpha | _D. -25, S (Cl, H ₂ O)

110 (dec.) Fumarate

C1

110 - 112 fumarate

112 - 114 fumarate

100-110 fumarate

14 OCH ^ 128 - 131 (fumarate) 15 Q ock ₃ 16 ABOUT 5 17 - in ^C '3 18 -about

122-124 fumarate

197-19B fumarate

alpha | _D = +22.2 (C-2 H ₂ O)

| «Lf. | _D - -22.9 (c = 2, K ₂ O)

147-149 fumarate

example

R * melting point * C example

R * melting point * C

29 D ^^ b-CH 30 ABOUT 31 -O-O-N- ^CH 3 32 -c _V ^ 0 117-118 fuearát 33 189-191 ťumaclt 33a -ck ₂ -o ^ 2} 158-160 fumarate II. about 34 -O-CH ₂ -C = CH 121-127 Fumaca 3S -O-CH = CH-CH

36 37 •about 114-116 oxalate 38 "'ABOUT 39 ABOUT 40 -Ό III. ABOUT 41 _endo-0-CH2-C 'CH 121-124 oxalate 42 exo-O-CH = CH-C oil oxalate 43 -O-CH-C = CH_ ² 1 ² H 93-95 oxalate 44 45 -oc " ₂ _θ 46 -n 47 48 -Ό IV. \ <Z 49 endo-O-CH ₂ -CSCH 148-149 fumarate 49a exo C-CH _2-C-CH 147-148 fumarate 50 exo-0-CH ₂ -CR = CH ₂ 99-101

example R mp 50a _{endo-0-CH2-CH} = _CH2 113-114 fumarate 51 Xo-O-CH ₂ -CH ₃ 147-148 funaráe 51a endo-o-CH ₂ -CH ₃ 115-117 fumarate

- ^C 6 ^H 5

_{-O-CH2-C g} H ₅

-OCH ₂ -C ₈ H _s

O-CH ₂ -CH ₃

Δ and & performs for inversions.

Example 63

3- (2-Propinyloxy) -1-azabicyclo [2.2: 2] octane

OH 1. NaH, second 0R-CH ₂ -C = C

3. HCl

X BMj

14.1 g, 0.1 mol of 3-hydroxy-1-azabicyclo [2.2.2] octane-borane complex is converted in 140 ml of dimethylformamide at room temperature under nitrogen by treatment with 4 g of sodium hydride in oil (60% dispersion) dispersion. to sodium salt. As soon as the evolution of hydrogen is complete, a solution of 14.28 g, 0.12 mol of propargyl bromide in 10 ml of toluene is added to the reaction mixture under ice-cooling, the mixture is stirred for 3 hours at room temperature, 5 ml of ethanol are added and evaporated. vacuum on a rotary evaporator. The residue is partitioned between 10% sodium chloride solution and ether. The organic phase is dried over anhydrous sodium sulphate and then evaporated. The residual dark brown oil was dissolved in a mixture of 75 ml of tetrahydrofuran and 15 ml of acetone. 30 ml of a 4 N hydrochloric acid solution were added dropwise to the resulting solution under ice-cooling, which resulted in the evolution of gas. The reaction was allowed to proceed for 1 hour at room temperature and the organic solvent was distilled off. The residue is diluted with a small amount of water and then shaken with petroleum ether, b.p. 40-60 ° C and ether. The aqueous phase was made basic by the addition of a 40% potassium carbonate solution and then extracted with ether. The ether solution was dried over anhydrous sodium sulfate and evaporated. 6.9 g of free 3- (2-propynyloxy) -1-azabicyclo [2.2.2] octane are obtained in a yield of 41.8% of theory, which is then converted by treatment with an equivalent amount of fumaric acid after recrystallization. mp 138-140 ° C.

Analysis for C | Found: C, 59.86; H, 6.76; N, 4.95%. Found: C, 59.86; H, 6.76; N, 4.95%.

1 H-NMR (CH 3 OD): 6.66 (s, 2H, FU C = CCH), 4.25 (d, 2H, J = 3Hz, OCH ₂ ), 4.11 (m, 1H, OCH), 3.67-3.12 (m, 6H, 3 NCH ₂ ), 2.93 (t, 1H, J = 3 Hz, = CH), 2.46-1.70 (m, 5H, -CH 2 -CH CH2).

The compounds of the following example may also be prepared in an analogous manner:

Example 64

3- (N-propoxy) -1-azabicyclo [2.2.2] octane Melting point: 120 to 121 ° C (CH 3 CN), fumarate.

The compound contains 1.5 moles of fumaric acid according to microanalysis and NMR spectra.

H, 7.34; N, 4.08%. Found: C, 55.67; H, 7.51; N, 4.09%.

Example 65

3-Methoxy-1-azabicyclo [2.2.2] octane Melting point: 72-74 ° C (ethyl acetate / ether), maleate.

According to the microanalysis and NMR spectra, the compound contains 1.5 moles of maleic acid.

H, 6.73; N, 4.83%. Found: C, 53.33; H, 6.71; N, 4.44%.

Example 66

3-Ethoxy-1-azabicyclo [2.2.2] octane Melting point: 96-98 ° C (acetone / ether), maleate. N, 5.16%. Found: C, 57.40; H, 8.01; N, 5.18%.

1 H-NMR (CD 3 OD): 6.23 (s, 2H, MA = CH), 3.55 (qu, 2H, J = 7Hz, OCH 2), 3.98-3.08 (m, 7H, 3 N) -CH 2, 1 CHO), 2.43-1.68 (m, 5H, -CH ₂ -CH-CH ₂ ).

Example 67

3-Allyloxy-1-azabicyclo [2.2.2] octane Melting point: 129-132 ° C (methanol / ether), fumarate. H, 7.47; N, 4.94%. Found: C, 59.19; H, 7.64; N, 5.03%.

1 H-NMR (CD 3 OD): 6.66 (s, 2H, FU = CH), 5.90 (m, 1H, = CH), 5.21, 9m, 2H, = CH ₂ ), 4.03 (m , 2H, _OCH2), 4.14 to 3.09 (m, 7H, 3 _N-CH2), 2.45 to 1.69 (m, 5H, _{-CH2 -CH-CH2).}

Example 68

Separation of the 3- (2-propynyloxy) -1-azabicyclo [2.2.2] octane racemate

a) (+) - 3- (2-propinyloxy) -1-azabicyclo [2.2.2] octane fumarate g, 96.82 mmol of free 3- (2-propinyloxy) -1-azabicyclo [2.2.2] octane and 18, 22 g (48.41 mmol) of (-) - dibenzoyl-L-tartaric acid monohydrate were dissolved in 160 ml of acetonitrile with heating. Repeated crystallization gave the corresponding dibenzoyltartrate, m.p. 146-150 ° C with decomposition.

[.alpha.] _D @ ²⁰ = -43.1 DEG (c = 1, water).

The salt thus obtained was dissolved in a small amount of water, basified with a 40% aqueous potassium carbonate solution and shaken twice with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulphate and evaporated.

0.8 g (4.9 mmol) of the colorless oil thus obtained and 0.56 g (4.9 mmol) of fumaric acid are dissolved in a small amount of ethanol. Addition of ether affords the title compound, m.p. 145-147 ° C. [alpha] f) = 20 + 35 _{J 2} ^c (c = 1, water).

H, 6.81; N, 4.98%. Found: C, 59.75; H, 6.99; N, 5.15.

b) (-) - 3- (2-Propynyloxy) -1-azabicyclo (2.2.2) octane fumarate

The mother liquor remaining in step a) is evaporated to give a base. 8 g (0.048 mol) of this base and 9.11 g (0.024 mol) of (+) - dibenzoyl-D-tartaric acid monohydrate are dissolved in acetonitrile. Analogous to step a), benzoyltartrate is obtained having a melting point of 145-150 ° C with decomposition with an optical rotation of [α] D 40 = + 43.4 ° (c = 1, water) and from this tartrate 2.1 g of the title compound, m.p. 145-147 ° C. [alpha] p20 =. 35 DEG (c = 1, water).

H, 6.81; N, 4.98%. Found: C, 59.79; H, 7.05; N, 4.97%.

EXAMPLE 69 3- (2-Butinyloxy) -1-azabicyclo [2.2.2] octane Melting point: 131 to 132 ° C (acetonitrile) fumarate. Analysis for C 13 H 17 NO x C 4 H 4 O 4 (295.34) calculated C 61.00, H, 7.17; N, 4.74%. Found: C, 60.92; H, 7.40; N, 4.70%.

Example 70 3- (2-Methylpropyloxy) -1-azabicyclo [2.2.2] octane Melting point: 120 to 122 ° C (methanol / ether), fumarate.

According to microanalysis and NMR spectra, this compound contains 1.5 moles of fumaric acid. Analysis for C] [H ₂ JnO x 1.5 C4H4O4 (357.41) calculated C 57.13, H 7.61, N 3.92% found C, 57.48, H, 7.66, N, 4.10% .

Example 71

3-Methoxymethyl-1-azabicyclo [2.2.2] octane Melting point 133-136 ° C (ethanol / ether), fumarate. H, 7.80; N, 5.15. Found: C, 57.20; H, 7.87; N, 5.12%.

Example 72

3-Ethoxymethyl-1-azabicyclo [2.2.2] octane Melting point: 73-77 ° C (ethanol / ether), fumarate. H, 8.31; N, 4.62. Found: C, 55.15; H, 8.19; N, 4.52%.

Example 73

3- (2-Propionyloxymethyl) -1-azabicyclo [2.2.2] octane Melting point: 88-90 ° C (acetonitrile) oxalate

The compound crystallizes together with 1.5 moles of oxalic acid.

H, 6.41; N, 4.46%. Found: C, 53.67; H, 6.66; N, 4.59.

Example 74

3-Allylmercapto-1-azabicyclo [2.2.2] octane

2.86 g, 0.02 mole of 3-mercapto-1-azabicyclo [2.2.2] octane are dissolved in 30 ml of dimethylformamide and converted into potassium salt by adding 2.24 g, 0.02 mole of potassium tert-butylate under nitrogen. . Finally, allyl bromide (2.42 g, 0.02 mol) was added with stirring and ice-cooling. The reaction mixture was stirred at room temperature for 45 minutes, then acidified with dilute hydrochloric acid and evaporated in vacuo. The residue was dissolved in a small amount of water, basified with 40% potassium carbonate solution and extracted with ether. The organic phase is dried and evaporated. The methanol solution of the residue was passed through a silica gel column. After evaporation of the solvent, 2.9 g of base are obtained, which is converted into the oxalate.

Melting point: 90 to 92 ° C (acetonitrile / ether) Analysis for C ₁₀ H 17 NS x 1.5 C ₂ H ₂ O ₄ (318.38) calculated C 49.04, H 6.33, N 4.10, S 10.07 Found: C 48.89, H 6.42, N 4.44, S 10.21%.

Example 75

3-ethyl mercaptan 1-azabicyclo [2.2.2] octane Melting point: 101 DEG-102 DEG C. (acetonitrile / ether), oxalate Anal C9H17NS x 1.5 _{C2 H2} O4 (306.37) calculated C 47.05 Found: C, 47.16; H, 6.92; N, 4.70; S, 10.63.

Example 76 (-) - 3- (Propinyloxy) -1-azabicyclo [2.2.2] octane

A suspension of 12.72 g (0.1 mole) of (R) -3-quinuclidinol described in B. Ringdahl et al., Acta Pharma Sueg., 16, 281 ff, 1979 in 200 ml of absolute tetrahydrofuran was stirred under nitrogen at 0 ° under nitrogen. C was mixed with 100 mL of a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran. The reaction solution is stirred for an additional hour at room temperature and then evaporated in vacuo. The oily residue was partitioned between methylene chloride and saturated sodium chloride solution. The organic phase is dried over anhydrous sodium sulphate and then evaporated. The residual resin was crystallized from cyclohexane. In this way, 12 g of (R) -3-quinuclidinol-borane complex are obtained in a yield of 85.1% of theory.

Treatment with propargyl bromide according to Example 63 affords (-) - 3- (2-propynyloxy) -1-azabicyclo [2.2.2] octane. The crude base was purified by distillation at 121 ° C and 2 kPa and converted to hydrogen fumarate. To this end, the base is dissolved together with one equivalent of filmaric acid in methanol and the resulting salt is precipitated by addition of ether.

Mp: 149-151 ° C, [.alpha.] D @ 23 =. 36.3 ° (c = ζ water).

Example 77 (+) - 3- (Propinyloxy) -1-azabicyclo [2.2.2] octane

Starting from (S) -3-quinuclidinol, the title compound is obtained as the hydrogen fumarate analogously to Example 76.

Mp: 149-151 ° C, [α] D 23 = + 36.5 ° (c = 1, water).

Example 78 (-) - 3-Ethoxy-1-azabicyclo [2.2.2] octane

The title compound can be obtained according to the method of Example 76 from (R) -3-quinuclidinol and ethyl iodide. Boiling point 88-90 ° C at 2 kPa.

Melting point hydrogen fumarate 148 DEG-149 DEG C. [.alpha.] D @ 23 =. 27.2 ° (c = 1, water).

H, 7.80; N, 5.16 Found: C, 57.61; H, 7.96; N, 5.29%.

The (+) - rotating enantiomer is obtained correspondingly from (S) -3-quinuclidinol.

Melting point: 148-149 ° C, [α] _D 23 = + 27.4 ° (c = 1, water).

Claims (7)

PATENT CLAIMS Bicyclic 1-azacycloalkanes of general formula (I) wherein n = 0 or 1 a R is a radical of the formula ( ^CH 2 ^{(R 1))} wherein ^{R 1} is hydrogen, C 1-4 -alkyl, C 1-4 -alkoxy, amino, C 1-4 -alkylamino, C 1-4 -dialkylamino, halogen, hydroxy, C 3-8; C = O, phenyl, which may be substituted by one, two or three substituents which are halogen, hydroxy, and / or a straight or branched C 1-5 -alkyl radical, C 1-8 -cycloalkyl, C 1-5 -hydroxyalkyl, amino, mono or disubstituted C 1-4 -alkylamino; k is 1, 2 or 3, wherein when k is greater than 1, all R 1 can be the same or different from each other; r 2 is hydrogen, C 1-4 -alkyl, C 1-4 -alkoxy, halogen, C-O; 1 is the number 1 or 2, preferably 1, where in the case where 1 = 2, R 2 may be the same or different from each other; r 3 represents a hydrogen atom or C 1-6 .4 alkyl; as well as the racemates thereof, their enantiomers, diastereomers and mixtures of these forms and, where appropriate, their pharmacologically acceptable acid addition salts and their quaternary salts, provided that if n = 0, R must be a pyridine radical which: it may be substituted with hydroxy, C 1-4 -alkyl, C 1-4 -alkoxy, amino, C 1-4 -alkylamino, di (C 1-4 -alkyl) amino with halogen or substituted or unsubstituted phenyl. The bicyclic 1-azacycloalkanes of formula (I) according to claim 1, wherein R is as defined in claim 1 and wherein R 'is methyl or methoxy; k is 1, 2 or 3, wherein when k is greater than 1, all R 1 may be the same or different from each other; R 2 is methyl or methoxy; R 3 represents a methyl group. The bicyclic 1-azacycloalkane of formula (I) according to claim 1 which is (+) - (propargyloxymethyl) -1-azabicyclo [2.2.2] octane. The bicyclic 1-azacycloalkane of formula (I) according to claim 1 which is 3- (2-propynyloxy) -1-azabicyclo [2.2.2] octane. Pharmaceutical compositions, characterized in that they contain, as active ingredient, bicyclic 1-azacycloalkanes of the general formula (I) according to claim 1 or 2 and excipients and / or carriers. Use of the bicyclic 1-azacycloalkanes of formula (I) according to claim 1 for the manufacture of a medicament for the treatment of diseases caused by a reduced function of the cholinergic system. Ί. The use of (+) - (propargyloxymethyl) -1-azabicyclo [2.2.2] octane according to claim 3 for the manufacture of a medicament for the treatment of diseases caused by a reduced function of the cholinergic system. Use of (+) - (propargyloxymethyl) -1-azabicyclo [2.2.2] octane according to claim 7, for the manufacture of a medicament for the treatment of Alzheimer's disease, senile dementia, cognitive impairment, and amelioration of thought processes.