DE4116582A1 - New bi:cyclic 1-aza-cycloalkane 5HT antagonists - for treating Alzheimer's disorders, and for improving memory - Google Patents

Abstract

Bicyclic 1-aza-cycloalkane derivatives of formula (I), their enantiomers, racemates, diastereomers, acid addition salts and quaternary salts are new. R = 1-6C alkyl, 3-6C alkenyl or 3-6C alkynyl (all optionally substituted by phenyl, bipheny, oxetan or 5-7 membered heterocycle, themselves optionally substituted). R may also be phenyl, biphenyl or 5-7 membered heterocycle (all optionally substituted). X = O or S. A, B, C = independently CH2 or a direct bond. n = 0-2. (+)-propargyloxymethyl) -1-azabicyclo(2.2.2)octane is specifically claimed. (I) is prepared by reacting the corresponding alcohol or thiol (whose ring N atom is protected) with an alkylating reagent of formula R-Y, where Y is a leaving gp.. USE/ADVANTAGE - As 5HT receptor antagonists for the treatment of Alzheimer's disease, senile dementia and cognitive disorders, and for improving memory. Unit dose is 1-100 mg., administered orally or by injection.

Description

The invention relates to bicyclic 1-aza-cycloalkanes the general formula I, method for their Production and its use as a medicinal product.

The new compounds correspond to the general ones formula

wherein
R is an alkyl radical having 1 to 6 carbon atoms, an alkenyl radical having 3 to 6 carbon atoms, an alkynyl radical having 3 to 6 carbon atoms, wherein the alkyl, alkenyl or alkynyl radical is phenyl, substituted phenyl, optionally substituted biphenyl, an optionally substituted oxetane or an optionally substituted 5-, 6- or 7-membered heterocycle may be substituted, or
R is an optionally substituted phenyl, optionally substituted biphenyl, an optionally substituted 5-, 6- or 7-membered heterocycle;
X oxygen or sulfur,
A, B and C independently CH₂ or a single bond and
n = 0, 1 or 2
optionally, in the form of their racemates, their enantiomers, their diastereomers and their mixtures and optionally their pharmacologically acceptable acid addition salts as well as their quaternary salts.

As alkyl groups in the context of this invention branched or unbranched alkyl radicals having 1 to 6 Carbon atoms, such as. Methyl, ethyl, propyl, Butyl, pentyl and hexyl as well as their branched Isomers, such as. Iso-propyl, isobutyl, tert-butyl, sec-butyl u. a., understood; under alkenyl groups become branched or unbranched alkenyl radicals with 3 to 6 carbon atoms - such. For example, propenyl, butenyl, Pentenyl and hexenyl - with one double bond; and alkynyl groups are branched or unbranched alkynyl radicals having 3 to 6 carbon atoms - such. As propynyl, butynyl and pentynyl - with a Triple bond understood. Preferred are such Alkenyl or alkynyl radicals in which the double or Triple bond is arranged terminally.

As substituted phenyl are - if not otherwise - understood phenyl radicals, the one-, two- or triply by halogen, hydroxy and / or branched or unbranched alkyl having 1 to 5 Carbon atoms, C₃-C₆-cycloalkyl, C₁-C₅- Hydroxyalkyl, amino, mono- or disubstituted C₁-C₄-alkylamino are substituted. Optionally substituted cycloalkyl, biphenyl, wherein the second phenyl ring is also as indicated above, may be substituted.  

Examples are:
2-chlorophenyl, 2,6-dichlorophenyl, 2-bromophenyl, 3-fluorophenyl, 2,3-dichlorophenyl, 4-hydroxyphenyl, 2-methylphenyl, 4-methylphenyl, 3-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4- Butylphenyl, 4-tert-butylphenyl, 4-pentylphenyl, 2,4-dimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 2-propoxyphenyl, 4-butoxyphenyl, 2,4 Dimethoxyphenyl, 3,4,5-trimethoxyphenyl.

Heterocycle within the definition given above stands inter alia for a 5- to 7-membered ring, as heteroatoms oxygen, sulfur and / or Contains nitrogen and the optionally one another aromatic ring, preferably a phenyl ring, may be condensed.

Examples of saturated heterocyclic 6-membered rings include, for example:
1,4 and 1,3-dioxane, morpholine, thiomorpholine, piperidine, piperazine, 4-C₁ to C₄-alkylpiperazine, N-hydroxy-C₁ to C₄-alkylpiperazine, 2,5-diketopiperazine, tetrahydropyran. Examples of saturated heterocyclic 5-membered rings include, for example, tetrahydropyrrole, tetrahydrofuran, proline, tetrahydropyrazole, imidazolidine, hydroxyproline, pyrrolidine, pyrazolidine, pyrrolidone, thiolane, butyrolactone, 1,2-oxathiolane.

As examples of 5-, 6- and 7-membered mono- and polyunsaturated heterocyclic rings, mention may be made, for example:
Imidazole, imidazoline, 1,2,4- and 1,2,3-triazole, tetrazole, isothiazole, furan, dihydrofuran, thiophene, pyridine, pyrimidine, pyran, 2,5-dihydropyrrole, thiazole, thiadiazine, azepine, 1,2 -Oxathiepan, pyrrole, pyrroline, pyrazoline, dimethylpyrrole, 2-acylfuran, dihydrothiophene. Examples of further heteroaryl radicals which may be mentioned are pyrazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, thiazolyl, benzothiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl and indolyl.

Preferred heterocyclic radical is, for example the pyridine radical, this may be 1 to 4 times, preferred 1 to 2 times the same or different by hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, NH₂, mono or di (C₁-C₄) alkylamino, halogen, CF₃, CN or Nitro be substituted.

As a 5, 6 or 7-membered heterocyclic ring bonded via a nitrogen atom, there are also mentioned by way of example:
Phenantridin-6-one, quinolin-2-one, isoquinoline-1,3-dione, benz [c, d] indole, 1,4-benzoxazin-3-one, indole-2,3-dione, indole-2 on, 1,2,4-triazolo [4,3-a] pyridin-3-one, 1,2-benzisothiazol-3-one, 1H-indazole, 1H-benzimidazole, 1H-benzotriazole, benzothiazin-3-one, Benz [d, e] isoquinoline-1,3-dione, 4-quinazolinone, isoindol-1-one, pyrrolo [1,2-c] imidazole-1,3-dione, 1,3-dihydro-2H-indole 2-one, tetrahydro-1H-isoindole-1,3-dione, 3,7-dihydro-1H-purine-2,6-dione, indole, indazole, benzimidazole, benzimidazol-2-one, 1,4-benzothiazine 3-one, 1H-isoindole-1,3-dione.

The heterocycle may be mono- or polysubstituted by halogen, Hydroxy, branched or unbranched C₁ to C₄ Alkyl, C₁ to C₄ hydroxyalkyl and / or C₁ to Be substituted C₄ alkoxy. The heterocycle can contain a keto function, such as. B. Dihydrotetrafuranon.

Preferred compounds of the general formula I are those in which X is oxygen, n = 0 or 1 and the substituent (CH₂) _n -XR in α or β position to the carbocyclic bridgehead, and R is an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 3 or 4 carbon atoms, an alkynyl group having 3 or 4 carbon atoms, an optionally substituted phenyl group, an optionally substituted 5- or 6-membered aromatic heterocycle.

Preferred compounds of general formula I are Quinuclidines, wherein n = 0 or 1, X = oxygen and R = an optionally substituted pyridine, Thiophene, furan, pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetane, tetrahydrofuran, pyrrolidine or Oxolane, an optionally substituted phenyl radical, is an optionally substituted benzyl radical, wherein the side chain in the 3-position of quinuclidine Systems is arranged.

Preferred 1-azabicyclo [2.2.1] heptanes of the general Formula I are those wherein X = oxygen, n = 0 or 1 and R is an alkyl group having 1-3 carbon atoms, an alkenyl group having 3 or 4 carbon atoms or an alkynyl group having 3 or carbon atoms optionally substituted pyridine, thiophene, furan, Pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetane,  Tetrahydrofuran, pyrrolidine or oxolane optionally substituted phenyl radical optionally substituted benzyl radical, wherein the Side chain in the 3-position of the bicyclic system is arranged.

Preferred 1-azabicyclo [3.2.1] octanes of the general Formula I are those wherein X = oxygen, n = 0 or 1 and R is an alkyl group having 1-3 carbon atoms, an alkenyl group having 3 or 4 carbon atoms or an alkynyl group having 3 or 4 carbon atoms optionally substituted pyridine, thiophene, furan, Pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetane, Tetrahydrofuran, pyrrolidine or oxolane optionally substituted phenyl radical optionally substituted benzyl radical, wherein the Side chain in the 3- or 6-position of the bicyclic nerve is arranged.

Preferred 1-azabicyclo [3.3.1] nonanes of the general Formula I are those wherein X = oxygen, n = 0 or 1 and R is an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 3 or 4 carbon atoms, one Alkynyl group having 3 or 4 carbon atoms, a optionally substituted pyridine, thiophene, furan, Pyrimidine, imidazole, pyrazole, 1,2,4-triazole, oxetane, Tetrahydrofuran, pyrrolidine or oxolane optionally substituted phenyl radical optionally substituted benzyl radical, wherein the Side chain prefers in the 3-position of the bicyclic is arranged.  

Particularly preferred are compounds of the general formula

wherein n = 0 or 1; and
R is a radical of the formula

wherein
R₁ is hydrogen, C₁-C₄-alkyl, preferably methyl, C₁-C₄-alkoxy, preferably methoxy, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino, halogen, hydroxy, C₁-C₆-cycloalkyl, optionally substituted phenyl, = 0;
k 1, 2 or 3, where k <1 all R₁ may be the same or different,
R₂ is hydrogen, C₁-C₄-alkyl, preferably methyl, C₁-C₄-alkoxy, preferably methoxy, halogen, = 0;
l is 1 or 2, preferably 1, wherein when 1 = 2 R₂ may be the same or different;
R₃ is hydrogen, C₁-C₄-alkyl, preferably methyl.

Preference is furthermore given to radicals of the general formula

wherein
n = zero or 1, preferably zero;
R = C₃-alkynyl, C₃-alkenyl, a radical of the general formula

wherein
R₁, R₂, k and l are as previously defined;
furthermore preferred radicals of the general formula

wherein
n = zero or 1;
R = C₃-alkynyl, C₃-alkenyl, methyl, ethyl, propyl,

wherein
R₁, R₂, k and l are as defined above, in the form of their racemates, their enantiomers, their diastereomers and their mixtures and their pharmacologically acceptable acid addition salts as well as their quaternary salts.

From the prior art are certain compounds the general formula I described. For example from the non-pre-published European Patent Application 3 70 415, from the quinuclidines of general formula I, wherein R is unsubstituted Alkyl, alkenyl or alkynyl radical is known are. These links are to be disclaimed. In the European patent application, the optical However, active compounds of this type are not named by name.

The separation of the enantiomers is carried out as in Example 3 now described for the first time, starting from the racemic compounds using optically active salts, eg. B. (+) or (-) tartaric acid, after known methods.  

Based on the binding studies on the muscarinic subtypes M₁, M₂ and M₃ (rat) and based on the stimulation of the phosphatidylinositol turnover (CHO cell cultures with human-m₁ receptor subtype) proved in vitro the Compound (+) - (propargyloxymethyl) -1-aza-bicyclo- [2.2.2] octane towards the racemate and the (-) - Enantiomer as more effective. The cholinomimetic in vivo efficacy of (+) - (propargyloxymethyl) -1-aza-bicyclo [2.2.2] octane was in the rabbit by EEG (Thetawellenzunahme) demonstrated.

Also known are quinuclidines of the general Formula I, wherein R is an oxygen linked heterocyclic ring is defined. The British Patent Application 22 08 385 describes these compounds however, as 5-HT antagonists. From the European Patent Application 2 57 741 are substituted 1-azabicyclo [3.3.1] -nonanes of general formula I. in which R is an oxygen-linked C₁-C₃ alkyl group.

The compounds of general formula I can, if R is an aliphatic radical, in analogy to L. Stotter et al. in Heterocycles, Vol. 25 (1987), Page 25 described procedures. Starting from the appropriate - if necessary N-protected (that is, the nitrogen atom of the bicyclic is by a protecting group Z, e.g. B. BH₃, blocked) Derivatives (R = H) of the general formula I are obtained Compounds according to the invention by deprotonation with strong bases and subsequent implementation with a Alkylating reagent of the general formula Y-R, wherein R as previously defined and Y is an easily cleavable one Leaving group - such. As halogen, p-toluenesulfonate u. a. - means. The reaction turns into polar inert organic solvents, such. B. dimethylformamide, Tetrahydrofuran, dioxane and the like a., performed.  

While the deprotonation and conversion of the Hydroxy compound in a metal salt, preferably at Room temperature or slightly elevated temperature is carried out, the subsequent takes place Alkylation preferably with ice cooling. After the reaction, the protective group cleaved and the compounds optionally in their Acid addition salts or quaternary compounds transferred, the reaction conditions are known, preferred quaternary compounds are the Methoiodides and Methobromides.

Preferred reagents for deprotonation are Sodium hydride, sodium amide, alkali metal such as. B. Potassium tert-butylate.

Preferred acid addition salts are, for example Salts with hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, methanesulfonic acid, Ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, Lactic acid, malonic acid, succinic acid, maleic acid, Fumaric acid, malic acid, tartaric acid, citric acid or Benzoic acid.

The starting compounds necessary for the synthesis, corresponding hydroxyazabicycloalkanes are known from the Known in the art,

so z. For n = 0 from JACS 74, 2215 (1952) (IIa), J. Org. Chem. 33, 4376 (1968) (IIb), European Patent Application 3 07 140 (III) and J. Pharm. Science 52, 331 (1954) (IV). Starting compounds (R = H) in which n = 1 or 2 means are by reduction of corresponding alkyl esters (X-R = COOAlkyl) available. Starting from the corresponding ketones can be the thiols of general formulas II and III in Analogous to that described in J. Chem. 43, 1965 Produce process.

R in the general formula I is an aromatic or heteroaromatic radical, the compounds of the general formula I using the Mitsunobu Reaction (O. Mitusunobu in Synthesis, 1, 1981, Georg Thieme Verlag, Stuttgard; J.C.S. Perkin I, page 462, 1975) by implementation of the appropriate hydroxy-substituted reactants (formula I R = H, reagent HOR, R = phenyl, heterocycle) in the presence of Diethyl azodicarboxylate and triphenylphosphine to be obtained. The implementation is generally in inert organic solvents Room temperature.

The compounds of the general formula I possess valuable pharmacological properties. So show the Compounds in binding studies have affinities too muscarinic receptors and muscarinic agonist GTP shifts (GTP = guanosine triphosphate). (Birdsall, N.I.M., E.C. Hulme and I.M. Stockton 1984 in T.I.P.S. Supplement, Proc. Internat. Symposium on subtypes of Muscarinic Receptors, Ed. Hirschowitz, Hammer, Giacchetti, Klirns, Levine; Elsevier p. 4-8).

Receptor binding studies were performed according to the following quotation [A. Closse, H. Bittiger, D. Langenegger and A. Wahner; Naunyn-Schmiedeberg's Arch. Pharmacol. 335, 372-377 (1987)].  

Table A Receptor binding studies

radioligand:
L (+) - cis- [2-methyl-3 H] -N, N, N-trimethyl-1, 3-dioxolane-4-methanammonium iodide NET-647, NEN (New England Nuclear DU PONT). Organ:
Cerebral cortex (rat)

Table A

As muscarinic agonists (cholinomimetics) are the Substances for the treatment of diseases in one Subfunction of cholinergic system suitable.

Due to pharmacological findings are the Connections z. B. for treatment mentioned below Diseases suitable: Alzheimer's disease, senile dementia, cognitive disorders and, in addition, the Compounds for improving memory be used.

Quaternary compounds of general formula I are suitable especially for peripheral use, such. B. for Glaucoma treatment.  

The compounds of the general formula I can be used alone or in combination with other inventive Active ingredients, optionally in combination with other pharmacologically active agents, eg. B. Cerebroviruses and / or peripheral cholinergic blocker, are used. suitable Application forms are, for example, tablets, Capsules, suppositories, solutions, juices, emulsions or dispersible powder.

Corresponding tablets, for example, by Mixing the active substance (s) with known ones Auxiliaries, for example inert Diluents, such as calcium carbonate, Calcium phosphate or lactose, Disintegrants, such as cornstarch or alginic acid, Binders such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents for Achieving the depot effect, how Carboxymethyl cellulose, cellulose acetate phthalate, or Polyvinyl acetate can be obtained. The tablets can also consist of several layers.

Correspondingly, coated tablets can be prepared by coating analogously cores made with the tablets, usually in Drageeüberzügen used means, for example Kollidone or shellac, gum arabic, talc Titanium dioxide or sugar. to Achieving a depot effect or avoidance of Incompatibilities, the core can also consist of several Layers exist. Likewise, the Dragee cover to achieve a depot effect consist of several layers, with the above at the Tablets mentioned adjuvants can be used.  

Juices of the active compounds according to the invention or In addition, active ingredient combination can be one more Sweetening agents, such as saccharin, cyclamate, glycerol or Sugar as well as a taste-improving agent e.g. B. Flavorings, such as vanillin or orange extract, contain. You can also use suspending aids or thickening agents, such as sodium carboxymethylcellulose, Wetting agents, for example condensation products of Fatty alcohols with ethylene oxide, or protective substances, such as p-hydroxybenzoates.

Injection solutions are in the usual manner, for. B. under Addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as Alkali salts of ethylenediaminetetraacetic acid prepared and in injection bottles or ampoules bottled.

The one or more active substances or Capsules containing active ingredient combinations can be used For example, be prepared by the Active ingredients with inert carriers, such as lactose or Sorbitol, mixed and encapsulated in gelatine capsules.

Suitable suppositories can be, for example, by Mix with appropriate carriers, such as Neutral fats or polyethylene glycol or its derivatives.

The therapeutically effective single dose is in the range between 1 and 100 mg.

The following examples illustrate the present invention without, however, in its scope to restrict:  

Pharmaceutical Formulation Examples

A) tablets per tablet active substance 80 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate  5 mg 480 mg

The finely ground active ingredient, lactose and a part the cornstarch are mixed together. The Mixture is sieved, followed by a solution of polyvinylpyrrolidone moistened in water, kneads, wet granulated and dried. The granules, the rest cornstarch and magnesium stearate are sieved and mixed together. The mixture becomes too Tablets of suitable shape and size pressed.

B) tablets per tablet active substance 60 mg corn starch 190 mg lactose 55 mg Microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg Sodium carboxymethyl starch 23 mg magnesium stearate  2 mg 380 mg

The finely ground active substance, a part of the maize starch, Lactose, microcrystalline cellulose and Polyvinylpyrrolidone are mixed together, the Mixture sieved and with the rest of the cornstarch and Water processed into a granulate, which is dried and sieved. To do this you give the Sodium carboxymethyl starch and the magnesium stearate, mixed and pressed the mixture into tablets suitable size.

C) ampoules active substance 20 mg sodium chloride 10 mg bidistilled water q. s. ad 1.0 ml

manufacturing

The active ingredient and the sodium chloride are in dissolved in bidistilled water and the solution in Ampoules filled sterile.

D) drops active substance 5.0 g p-hydroxybenzoate 0.1 g p-hydroxybenzoate 0.1 g demineralised water q. s. ad 100.0 ml

manufacturing

The active ingredient and the preservatives are dissolved in demineralized water and the solution filtered and bottled to 100 ml.

Example 1 3-propargyloxy-1-azabicyclo [2.2.1] heptane

5.6 g (0.05 mol) of 1 azabicyclo [2.2.1] heptan-3-ol are dissolved under nitrogen atmosphere in 150 ml of absolute tetrahydrofuran and treated at 0 ° C with 50 ml of 1M borane-THF complex. After completion of the addition, the mixture is stirred for one hour at room temperature, concentrated to dryness, the residue is taken up in saturated brine and extracted with dichloromethane. The combined organic phases are dried and concentrated, the residue is dissolved in 120 ml of absolute THF and treated under nitrogen atmosphere in portions with 2.08 g (0.052 mol) of sodium hydride. After one hour, the batch is cooled to 0 ° C and at this temperature 17.55 g of propargyl bromide are added dropwise as a 50% solution in THF. It is stirred for 12 hours at room temperature, then decomposed with excess hydride with ethanol, concentrated, the residue is taken up in saturated brine and extracted with dichloromethane. After drying and concentrating the combined organic phases, an oil is obtained, which is distilled under high vacuum Kp _{1 mbar} = 45-46 ° C). With one equivalent of fumaric acid, the fumarate is prepared, recrystallized from ethanol / ether and i. V. dried. This gives 2.1 g of colorless crystals of the title compound, mp. 121-123 ° C.
1 H NMR (250 MHz, CD₃OD, TMS): δ = 6.68 (2H, s, fumaric acid); 4.47 (1H, m, H-3); 4.21 (2H, m, CH₂-8); 3.73-2.86 (7H, m, CH₂-2, 6, 7; H-4); 2.95 (1H, t, J = 3Hz, H-9); 2.30; 1.96 (2H, m, CH₂-5).

Example 2 3-phenoxy-1-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 and 5.22 g (0.03 mol) of diethyl azodicarboxylate dissolved in 150 ml of absolute THF and stirred for 2 days at room temperature. It is concentrated to dryness, the residue is taken up in 20 ml of 6N-HCl and 50 ml H₂O and extracted with ether. The aqueous phase is made alkaline and shaken with ethyl acetate, the combined ethyl acetate phases are dried and concentrated. After distillation, 3.6 g of colorless oil (bp _{0.1 mbar} = 104-105 ° C).

1 H-NMR (250 MHz, CDCl₃, TMS): δ = 7.26; 6.87 (5H, m, aryl-H); 4.36 (1H, m, H-3); 3.34-2.63 (6H, m, CH₂-2, 6, 7); 2.19-1.27 (5H, m, CH-4, CH₂ 5, 8).

The base is in ethanolic solution in the fumarate converted, which precipitated with ether and from acetonitrile is recrystallized.

This gives 4.1 g of colorless crystals of mp. 122-124 ° C.  

example 3 (+) - and (-) - 3- (propargyloxymethyl) -1-azabicyclo- [2.2.2] octane ± -Acetic acid (3-chinuclidinylmethyl) ester

Racemic 3-quinuclidinylmethanol is after literature known methods, eg. B. by means Cyanohydrin synthesis from quinuclidin-3-one by Helv. Chim. Acta 37, 1695 (1954) and with Acetyl chloride and triethylamine in chloroform as Solvent at room temperature acylated, the racemic acetic acid (3-quinuclidinylmethyl) esters in 82% yield and a boiling point of 130-134 ° at 30 mbar.

(-) - 3-Chinuclidinylmethanol

26.5 g ± acetic acid (3-quinuclidinylmethyl) ester and 21.7 g of L - (+) - tartaric acid are dissolved in 275 ml of 95 percent Ethanol heated to boiling; at the subsequent Slow cooling gives crystalline Tartaric acid salt made from 95% ethanol about 5 × is recrystallized to the rotation angle constancy. The thus obtained 13.5 g salt from the rotation (c = 2, H₂O) are in 80 ml of 2N sodium hydroxide solution Stirred for two hours at room temperature, the solution then mixed with 80 g of potash and the approach worked up extractively with chloroform. In this way is set with simultaneous ester saponification 5.6 g (-) - 3-Chinuclidinylmethanol as a light oil with  (c = 1, 2, in 1N-HCl) free.  

The analytical verification of the enantiomeric purity was carried out after derivatization with phenyl isocyanate by HPLC on a Chiralcel OD column and gave a Enantiomeric distribution of 98.6% (-): 1.4% (+) - enantiomer.

3-Chinuclidinylmethanol

The collected mother liquors used in the production of (-) - 3-quinuclidinylmethanol are obtained in Vacuum concentrated. The residue is taken in a little Water, alkaline and alkaline with potash extracted with chloroform. The thus obtained 19.5 g of optically enriched acetic acid (3-quinuclidinylmethyl) - esters are treated with 16.0 g of D - (+) - tartaric acid in 200 ml of 95% ethanol in the diastereomer salt transferred. Recrystallization is obtained after 5 times from 95% ethanol 12.7 g of salt from the rotation  (c = 2, H₂O), from the analog as with (-) - enantiomer by means of 75 ml 2N sodium hydroxide solution 4.7 g (+) - 3-quinuclidinylmethanol as a light oil with  (c = 1, in 1N HCl) becomes.

After derivatization with phenyl isocyanate was Enantiomeric purity by HPLC on a Chiralcel OD column 97.4% (+) -: 2.6% (-) Enantiomer determined.

3a: (+) - 3- (propargyloxymethyl) -1-azabicyclo [2.2.2] - octane

5.6 g of (+) - 3-quinuclidinylmethanol hydrochloride, 1.32 g Sodium borohydride and 100 ml of tetrahydrofuran are over Night stirred. From the filtrate, the solvent is withdrawn, the residue was taken up in ethyl acetate and the solution obtained with saturated sodium chloride solution washed. After drying and removal of the solvent remain 3.4 g of (+) - 3-quinuclidinylmethanol borane complex back as light oil.  

3.4 g of the borane complex are dissolved in 100 ml Tetrahydrofuran for 30 minutes with 2.63 g of 60% strength Sodium hydride stirred at room temperature, then reacted with 4.89 g of 80% propargyl bromide and 6 stirred for another few hours. The reaction mixture is with Alcohol carefully decomposed, the solvent withdrawn, the Residue taken up in 150 ml of ethyl acetate, the solution washed with saturated saline and the Solvens withdrew again. To destroy the Borane protective group takes the residue in 50 ml Acetone and stirred with 20 ml of 3N-HCl overnight. To The evaporation of the acetone, the aqueous phase with Washed ethyl acetate, made alkaline with potash and extracted with ethyl acetate. The extraction residue is on silica gel with ethyl acetate: methanol: NH₃ = 85: 15: 1 as Eluens flash chromatographed and gives 4.3 g of propargyl ether, which in alcohol with the calculated amount of fumaric acid in the fumarate is transferred, which is reprecipitated from alcohol-ether and in 3.9 g yield with mp. 132-133 ° C and = + 28.47 ° (c = 1, methanol) is obtained.

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

Analog 3a in (-) - 3-Chinuclidinylmethanol the Boranschutzgruppe introduced the etherification with Propargyl bromide performed and after cleavage the borane protecting group releases the free base into the fumarate converted with mp 132-133 ° C and (c = 1, methanol).  

In analogy to the general ones described Synthetic methods and examples may be as follows Compounds of general formula I prepared become.

Claims (12)

1. New bicyclic 1-aza-cycloalkanes of the general formula wherein
R is an alkyl radical having 1 to 6 carbon atoms, an alkenyl radical having 3 to 6 carbon atoms, an alkynyl radical having 3 to 6 carbon atoms, wherein the alkyl, alkenyl or alkynyl radical is phenyl, substituted phenyl, optionally substituted biphenyl, an optionally substituted oxetane or an optionally substituted 5-, 6- or 7-membered heterocycle may be substituted, or
R is an optionally substituted phenyl, an optionally substituted biphenyl, an optionally substituted 5-, 6- or 7-membered heterocycle;
X oxygen or sulfur,
A, B and C independently CH₂ or a single bond and
n = 0, 1 or 2
optionally, in the form of their racemates, their enantiomers, their diastereomers and their mixtures and optionally their pharmacologically acceptable acid addition salts as well as their quaternary salts. 2. A novel bicyclic 1-Azacycloalkane of the general formula I according to claim 1 wherein X is oxygen, n = 0 or 1 and the substituent (CH₂) _n -XR in α or β position to the carbocyclic bridgehead, and R is an alkyl group with 1 to 3 carbon atoms, an alkenyl group having 3 or 4 carbon atoms, an alkynyl group having 3 or 4 carbon atoms, an optionally substituted phenyl group, an optionally substituted 5- or 6-membered aromatic heterocycle, optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures and optionally their pharmacologically acceptable acid addition salts as well as their quaternary salts. 3. New bicyclic 1-Azacycloalkane according to claim 1 of the general formula wherein
n = 0 or 1; and
R is a radical of the formula wherein
R₁ is hydrogen, C₁-C₄-alkyl, preferably methyl, C₁-C₄-alkoxy, preferably methoxy, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino, halogen, hydroxy, C₁-C₆-cycloalkyl, optionally substituted phenyl, = 0;
k 1, 2 or 3, where k <1 all R₁ may be the same or different,
R₂ is hydrogen, C₁-C₄-alkyl, preferably methyl, C₁-C₄-alkoxy, preferably methoxy, halogen, = 0;
l is 1 or 2, preferably 1, wherein when 1 = 2 R₂ may be the same or different;
R₃ can be hydrogen, C₁-C₄-alkyl, preferably methyl,
or the general formula wherein
n = zero or 1, preferably zero;
R = C₃-alkynyl, C₃-alkenyl, a radical of the general formula wherein
R₁, R₂, k and l are as previously defined; or the general formula wherein
n 0 is zero or 1;
R = C₃-alkynyl, C₃-alkenyl, methyl, ethyl, propyl, wherein
R₁, R₂, k and l are as defined above, in the form of their racemates, their enantiomers, their diastereomers and their mixtures and their pharmacologically acceptable acid addition salts as well as their quaternary salts. 4. Use of quinuclidines of the general Formula I according to claim 1, 2 or 3 optionally in the form of their racemates, theirs Enantiomers, their diastereomers and their Mixtures as well as their pharmacological harmless acid addition salts as well as theirs Quaternary salts as medicines. 5. Pharmaceutical preparation containing a Compound of the general formula I according to Claim 1, 2 or 3 as well as customary auxiliary and / or carriers. 6. Process for the preparation of pharmaceutical Preparations according to claim 5, characterized characterized in that compounds of the general formula I with conventional galenic Auxiliaries and / or carriers mixes. 7. A process for the preparation of compound of general formula 1, according to claim 1, 2 or 3, characterized in that a compound of the general formula wherein
n and X which have been defined above and Z is a protective group (in the case of X = S, can be dispensed with the protective group Z), and deproniert with an alkylating reagent of the formula Y-Rworin
R is as defined above and Y is a readily cleavable group means, then cleaves the protecting group and optionally converted in their acid addition salts or quaternary salts and / or optionally separated into their optically active compounds. 8. A process for the preparation of compounds of general formula I, according to claim 1, 2 or 3, wherein
R is optionally substituted phenyl, optionally substituted biphenyl, an optionally substituted 5-, 6- or 7-membered heterocycle, characterized in that a compound of the formula with a compound of the formula HOR (R = phenyl, heterocycle) in the presence of triphenylphosphine and Azodicarbonsäurealkylester. 9. (+) - (propargyloxymethyl) -1-aza-bicyclo- [2.2.2] octane, its acid addition salts as well its quaternary salts.   10. Use of a compound of general formula I. according to any one of claims 1, 2, 3 or 9 to Preparation of a medicament for the treatment of Conditions or diseases on one Subfunction of the cholinergic system. 11. Use of a compound of general formula I. according to any one of claims 1, 2, 3 or 9 to Preparation of a medicament for the treatment of Alzheimer's, senile dementia or for improvement the memory power. 12. Use of compounds of general formula I. according to any one of claims 1, 2, 3 or 9 to Production of a drug with 5-HT antagonistic properties.