NEW 1-AZABICYCLOALKANE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR PREPARING SAME

Abstract: The invention relates to new 1-azabicycloalkane derivatives and their stereoisomers of general formula (I), wherein R<1> représents a phenyl, substituted phenyl, naphthyl or thienyl group, wherein the phenyl group can be substituted by one or several halogen atom(s), methyl, methoxy, methylthio or trifluoromethyl group(s), R<2> represents a hydrogen atom or a C2-5 aliphatic acyl group, R<3> represents a hydrogen atom or a methyl group, n can be zero or one, the dotted line can optionally represent a further C-C bond and the wavy line means that the respective substituent can be bound to the carbon atom in either of the two steric positions, furthermore their pharmaceutically acceptable acid addition salts. Furthermore, the invention relates to a process for preparing the above compounds and pharmaceutical compositions containing the same. The compounds of general formula (I) have valuable therapeutic, mainly antiamnesic, activity.

Description: NEW 1-AZABICYCLOALKANE DERIVATIVES, PHARMACEUTICAL COMPOSI¬ TIONS CONTAINING THEM AND PROCESS FOR PREPARING SAME The invention relates to new 1-azabicycloalkane deriva¬ tives and their stereoisomers of the general formula (I) , wherein R 1 represents a phenyl, substituted phenyl, naphthyl or thienyl group, wherein the phenyl group can be substituted by one or several halogen atom(s) , methyl, methoxy, methylthio or trifluoromethyl group(s) , R 2 represents a hydrogen atom or a C 2 -5 aliphatic acyl group, R 3 represents a hydrogen atom or a methyl group, n can be zero or one, the dotted line can optionally represent a further C-C bond and the wavy line means that the respective substituent can be bound to the carbon atom in either of the two steric posi¬ tions, furthermore their pharmaceutically acceptable acid- addition salts. The compounds of the general formula (I) of the inven¬ tion have valuable therapeutic, i.e. antia nesic activity. The compounds of the general formula (I) have asymmetric structure and the general formula (I) represents all possible stereoisomers. The general formula (la) clearly demonstrates the structure of those compounds of the general formula (I) wherein n = 1 without limiting the range of compounds of the general formula (I) to enantiomerε represented by the general formula (la) . In the nomenclature of the compounds of the general formula (I) the R 0 and R 3 substituents have endo positions if they are opposite to the methylene bridge as regards the plane formed by the two bridgehead atoms and the carbon atom linked to the respective substituent. Accordingly, the substituent positioned in the same direction as the methylene bridge is designated as exo one. Particularly preferred compounds of the general formula (I) are: (±)endo-4-propionyloxy-6-(4-fluorphenyl)-l-azabicyclo[3.3.1]- non-6-ene hydrochloride, (+)endo-4-propionyloxy-6-(4-fluorphenyl)-l-azabicyclo[3.3.1]- non-6-ene hydrochloride, (.-)endo-4-propionyloxy-6-(4-fluorphenyl)-l-azabicyclo[3.3.1]- non-6-ene hydrochloride, (±)endo-4-acetoxy-6-(4-chlorophenyl)-l-azabicyclo[3.3.1]- non-6-ene hydrochloride, (±)endo-4-hydroxy-6-(4-fluorophenyl)-l-azabicyclo[3.3.1]- non-6-ene hydrochloride, (±)endo-4-acetoxy-6-phenyl-l-azabicyclo[3.3.1]-non-6-ene hydrochloride and (±)endo-4-hydroxy-6(exo)-phenyl-l-azabicyclo[3.3.l]nonane hydrochloride. The compounds of the general formula (I) are not described in the literature. Compounds which have structures nearest to the com¬ pounds of the invention are l-azabicyclo[3.3.l]non-6-ene derivatives described in the Japanese patent applications Nos. 75/49297 and 75/53518 (Kokai) as well as in Chem. Pharm. Bull. 2Λ_, 515 (1976) and Synthesis 440 (1975). Some of these compounds exert analgetic effect. The 1-azabicycloalkane derivatives described in the European patent specifications Nos. 94,742, 94,744 and 239,321 have benzamido or benzamido- alkyl substituents and are 5HT-receptor antagonists . . European patent specifications Nos. 257,741, 261,763 and 287,356 cover 1-azabicycloalkane derivatives with substi¬ tuents in positions 1,3 in relation to the nitrogen atom wherein the latter substituent is mostly an acidic function or a heterocycle. These compounds exert muscarinic agonist activity and are suitable to improve cholinergic functions according to the literature. According to one of the options for the treatment of Alzheimer type dementia of elderly people it was attempted to stimulate the distinctly reduced cholinergic neurotrans- mission by applying cholinergic receptor agonists. Agonists binding selectively to ^ muscarinic receptors seem to be suitable for this purpose [Science 217. 408 (1982) ; Drug Dev. Res. 5 , 77 (1985); Neurophar acol. 9., 53 (1986)]. During the study of some of the muscarinic agonist compounds known from the literature difficulties concerning absorption, selectivity and rapid metabolism, etc. arose. Consequently, no drug has been circulated yet in this area. Now it has been unexpectedly found that the compounds of the general formula (I) of the invention are bound by muscarinic receptors and are inhibiting even in low doses scopolamine-induced amnesia in rats, thus they are potential agents for the treatment of dementia or Alzheimer-type dementia, resp., in elderly people. According to a further feature of the present invention there is provided a process for the preparation of the novel compounds of the general formula (I) , wherein R 1 represents a phenyl, substituted phenyl, naphthyl or thienyl group, wherein the phenyl group can be substituted by one or several halogen atom(s) , methyl, methoxy, methylthio or trifluoromethyl group(s) , R 2 represents a hydrogen atom or a C2-5 aliphatic acyl group, R 3 represents a hydrogen atom or a methyl group, n can be zero or one, the dotted line can optionally represent a further C-C bond and the wavy line means that the respective substituent can be bound to the carbon atom in either of the two steric posi¬ tions, furthermore their pharmaceutically acceptable acid-addition salts, which comprises submitting a 1,2,3,6-tetrahydropyri- dine derivative of the general formula (II) or a piperidinol derivative of the general formula (III) , wherein R 1 , R 3 and n are as defined above, R 4 and R 5 represent a ^-4 alkyl group, or together they stand for a C2- 3 alkylene group, to acid-catalyzed ring closure, then, if desired, the resulting compound of the general formula (I) , wherein R 1 , R 3 and n are as defined above and R 2 represents a hydrogen atom, is acylated and/or the double bond is saturated and/or, if desired, the resulting compound of the general formula (I) , wherein R 1 and n have the same meaning as above and R 2 and R 3 represent hydrogen atoms, is isomerized under acidic conditions and/or, if desired, the obtained compound of the general formula (I), wherein R 1 , R 2 , R 3 and n have the same meaning as above, is resolved and/or converted to an acid-addition salt. According to a preferred process of the invention a 1- -alkyl-4-aryl-l,2,3,6-tetrahydropiridine derivative of the general formula (II), wherein R 1 , R 3 , R 4 , R 5 and n are as defined above, is heated in an aqueous solution of hydro¬ chloric acid, then the reaction mixture is evaporated and the resulting crystalline 1-azabicycloalkene derivative is isolated as hydrochloride salt. The ring closure may be performed also by an other mineral acid, for instance aqueous suifuric acid. The reaction can preferably be performed in a temperature range of 20 to 120 °C. If suifuric acid is applied, the reaction mixture is preferably mixed with water, then made alkaline and the product is extracted in base form with an organic solvent. According to a further preferred process of the inven¬ tion a l-alkyl-4-aryl-4-hydroxypiperidine derivative of the general formula (III), wherein R 1 , R 3 , R 4 , R 5 and n are as defined above, is heated in a solution of aqueous hydro- chloric or suifuric acid. The reaction mixtures are prefer¬ ably processed as described above. The hydroxy groups of the compounds of the general formula (I) , obtained in the ring closure reactions according to the invention, have endo (equatorial) position. The isomers having a hydroxy group with exo (axial) position are formed only in minor amounts and are detectable in the recrystallization mother liquors. The compounds of the general formula (I) , wherein R 2 and R 3 each represent hydrogen atoms and the hydroxy group has endo position, can be isomerized by treatment with an acid, preferably with aqueous perchloric acid, and the resulting endo-exo mixture can be separated either in this form or after esterification by known methods. If desired, the hydroxy groups of the compounds of the general formula (I) , obtained in the ring closure reaction, are esterified by a C2-5 aliphatic carboxylic acid anhydride or acyl chloride. The reaction is preferably carried out in the presence of an acid-binding agent, e.g pyridine. The double bond can preferably be saturated by catalytic hydrogenation. The compounds of the invention obtained by ring closure are racemates. If desired, the racemate can be resolved by separating the diastereomer pair formed with an optically active acid, thereafter the optically active base of the general formula (I) is liberated from the respective diastereomer salt by an alkali. Tartaric acid, lactic acid, camphenesulfonic acid or amino acids can be used as optically active acids. Preferably camphenesulfonic acid and tartaric acid mono-4-chloroanilide are used. The diastereomer salt pairs are preferably separated by crystallization. For therapeutic purposes it is advantageous to prepare acid-addition salts from the compounds of the general formula (I) . In addition to the already mentioned hydrochloric acid, all organic or inorganic acids can be utilized which are compatible with therapeutic use, i.e. oxalic acid, fumaric acid, alonic acid, methansulfonic acid, suifuric acid, phosphoric acid etc. The starting compounds of the general formula (II) , applied in the process of the invention, can be prepared, if their preparation is not described in the Examples, from the respective 4-aryl-substituted-l,2,3,6-tetrahydropyridines by processes analogous to those described in the Examples. The resulting compounds of the general formula (II) are usually oils which can be used directly in this form in the process of the invention. The compounds of the general formula (III) of the in¬ vention are new. They are prepared by processes described in the respective Examples. The known 4-aryl-substituted-l,2,3,6-tetrahydropyridine derivatives, serving for the preparation of the compounds of general formulas (II) and (III) , are described, among others, by the British patent specification No. 881,893, Dutch paten specification No. 6,510,107, US patent specification No. 2,973,363 and Czech patent specification No. 218,028. The preparation of unknown 4-aryl-substituted-l,2,3,6-tetrahydro pyridine derivatives is described in the respective Examples. The compounds of the general formula (I) of the inven¬ tion were studied by the muscarine receptor-binding test, using tritiated quinuclidinylbenzoate [( 3 H)-QNB] as ligand, furthermore by the oxotremorine potentiating test and the scopolamine amnesia test. ( 3 H)-QNB receptor-binding test The membrane preparation was obtained from the cerebra cortex of male OFA rats, weighing 180 to 250 g, by the Yamamura-Snyder method [Proc. Natl. Acad. Sci. USA 21, 1725 (1974)], modified by Hershkowitz et al. [Eur. J. Pharmacol. 86, 229 (1983)]. Proteins were assayed by Peterson's method [Anal. Biochem. _82, 346 (1977)]. Amounts of 0.2 mg/ml of protein were incubated in the presence of 0.2 nm of ( 3 H)-QNB (44 Ci/mmole, Amersham) and the test compound (in 8 con¬ centrations: 0.1 - 300 μM) in a total volume of 1 ml of 50 nM TRIS-HC1 buffer (pH 7.4) at 25 °C for 60 minutes. The reac¬ tion was stopped by adding 5 ml of ice-cold buffer solution and filtering on a Whatman GF/B filter at reduced pressure. The filters were washed twice with the same volumes of the buffer solution. Non-specific binding was determined in the presence of 1 μM of atropine. All determinations were per¬ formed three times. Bound radioactivity was assayed in a toluene " cocktail by Packard liquid scintillation spectro- metry. IC50 values were obtained by linear regression analysis, while the dissociation constant (Kp) was calculated by Scatchard analysis. Oxotremorine potentiation test The method of Rathbun and Slater [Psychopharmacology 4., 114 (1963), modified by Ogren et al. (Psychopharmacology 86, 258 (1985) ] was applied. Groups of mice (5-15 mice/dose) were treated by i.p. doses of 1, 3 and 10 mg/kg and p.o. doses of 3, 10 and 30 mg/kg, resp. Treatment was performed 15 minutes before the addition of oxotremorine, then 0.125 mg/kg of oxotremorine (ED 16 ) was applied* Both tremor intensity and hypersalivation were assessed by semiquantitative "scores" compared to the control mouse groups. The dose of the test compounds inducing 50 % effect (minimum effective dose) was determined. Scopolamine amnesia test in rats The test was performed in a Skinner box on naive male OFA rats weighing 100 to 120 g by the method of Cumin et al. [Psychopharmacology 2ϋ, 104 (1982)]. The animals were placed in the box where they received electric shock of 0.8 A. Thi could be avoided if they remained on the plastic platform placed on the grid under current. In this way passive avoidance reflex was developed. After three consecutive training sessions the rats remaining on the platform for one minute without stepping on the grid were selected and groups were formed which received the following treatment: Control group I: solvent i.p. and p.o. Control group II: scopolamine i.p. Treated group: scopolamine i.p. + test compound Treatment with the test compound was performed immediately after the last training session. After two hours the animals were repeatedly placed on the platform, and the number of animals_ remaining on the platform for one minute, i.e. with improved memory, was determined. Statistical evaluation was performed by the X 2 probe. - The results are presented in Table 1. Table 1 Compound ( 3 H)-QNM receptor Oxotremorine potentiation Scopolamine amnesia Acute toxici Example No. binding test test in mice, minimum test in rats, min. in mice IC 50 (μM) effective dose, mg/kg effective dose, mg/kg ( D50 mg/kg i.p. p.o. p.o. i.p. p >10 >10 3 3 0.3 1 10 30 3 10 10 10 10 >10 10 >30 10 30 10 >30 >30 The data of Table 1 demonstrate that the compounds of the invention possess significant pharmacological effects and are able to exert central cholinergic activity at both parenteral and oral application. The compounds of the invention and their acid-addition salts can be transformed into pharmaceutical compositions. The latter may be formulated as tablets, coated tablets, powders, granulates or capsules or in liquid form as solutions or suspensions, furthermore as sterile solutions or suspensions for parenteral applications. For preparing oral formulations lactose or starch can be used as vehicle, gelatine, carboxymethylcellulose sodium, methyl cellulose, polyvinylpyrrolidone or starch gum as binding or granulating agent, potato starch or microcrystal- line cellulose as disintegrator, finally talc, colloidal silicic acid, stearine, etc. as antiadhesives. Tablets are formed by known methods by using, if desired, usual protective coatings, flavouring and colouring agents applied in the manufacture of pharmaceuticals. In case of capsules the mixture of active ingredients and auxiliary materials is filled into capsules. Liquid oral formulations are prepared in the form of solutions, syrups or a dry substance which is mixed with " water or some other carrier before use. For parenteral application the active ingredient is formulated as sterile solution or suspension, wherein the sterile vehicle can contain additional adjuvants such as local anaesthetic or stabilizing agents or buffers. The invention is elucidated in detail with the aid the following non-limiting Examples. Example 1 (±)Endo-4-hydroxy-6-phenyl-l-azabicyclo[3.3.l]non-6- -ene hydrochloride Method A 14.2 g (54.8 mmoles) of l-[3,3-(ethylenedioxy)propyl -4-phenyl-l,2,3,6-tetrahydropyridine, isolated as raw product, are dissolved in 70 ml of concentrated hydrochlor acid and refluxed for 4 hours. The reaction mixture is eva orated to dryness, the residue is mixed with acetone conta ing 5 - 10 % of isopropanol and the crystalline product is filtered; weight 9.35 g. Recrystallized from ethanol 8.06 of the product are obtained, m.p. 263-264 °C. Method B 1.00 g (3.6 mmoles) of l-[3,3-(ethylenedioxy)propyl] -4-phenyl-4-hydroxy-piperidine are refluxed in 10 ml of a mixture of concentrated hydrochloric acid and water for 3 hours. The residue obtained after evaporation is mixed wit acetone and filtered; weight 0.88 g (m.p. 256-257 °C) . Aft recrystallization the m.p. of the product raises to 263 °C and is identical with that of the compound synthesized by Method A. The above starting material is prepared by reacting 1.71 g (9.7 mmoles) of 4-phenyl-4-hydroxypiperidine (B. G". Boggiano et al.: J. Chem. Soc. 1959, 1143) with 2.00 g (11 mmoles) of 2-(2-bromoethyl)-l,3-dioxolane in 20 ml of SUBSTITUTE SHEET dimethylformamide at 80 °C, in the presence of 2.06 g of sodium carbonate as acid-binding agent. After 90 minutes the reaction mixture is poured on water and the product is extracted with ethyl acetate. After evaporation the residue (3.1 g of oil) is recrystallizing upon cooling. Mixed with diisopropylether 1.56 g of l-[3,3-(ethylenedioxy)propyl]-4- -phenyl-4-hydroxypiperidine (m.p.: 84-86 °C) are obtained. Example 2 (±)Endo-4-acetoxy-6-phenyl-l-azabicyclo[3.3.1]non-6- -ene-hydrochloride 1.76 g (7 mmoles) of the compound prepared by the process of Example 1 are dissolved in a mixture of 3 ml of pyridine, 5 ml of dichloroethane and 2 ml of acetic anhydride and refluxed for 7 hours. The mixture is evaporated and the residue is dissolved in a mixture of aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer is washed with a saline solution, dried and evaporated. Applying hydro¬ chloric acid in isopropanol and ether the residue is converted to 1.62 g of the hydrochloride. Recrystallized from ethyl-methylketone 1.1 g of the product are obtained, m.p. 274-276 °C (transformation after 216 °C) . Example 3 (±)Endo-4-hydroxy-6-(4-chlorophenyl)-ι-azabicyclo- [3.3.1]non-6-ene hydrochloride Method A 15.60 g (53 mmoles) of l-[3,3-(ethylenedioxy)propyl]-4- (4-chlorophenyl)-l,2,3,6-tetrahydropyridine are refluxed in 120 ml of a 1:1 mixture of concentrated hydrochloric acid and water for 6 hours. The reaction mixture is evaporated to dryness yielding 13.6 g of a crystalline product which, recrystallized from ethanol, gives 10.4 g of the final product, m.p. 291-293 °C. Method B 10 g (32 mmoles) of l-[3,3-(ethylenedioxy)propyl]-4-(4- -chlorophenyl)-4-hydroxypiperidine are refluxed with 100 ml of 24 % hydrochloric acid for 4 hours, then the mixture is evaporated at reduced pressure, the residue is mixed with acetone and filtered. The resulting 7 g of product is re¬ crystallized from 150 ml of ethanol. Yield 5.8 g, m.p. 290-292 °C. The above starting material is prepared by reacting 3.49 g (16.5 mmoles) of 4-(4-chlorophenyl)-4-hydroxypipe- ridine (C. A. 9£, 160,556) in 25 ml of distilled dimethyl- formamide with 3.6 g (2.33 ml, 20 mmoles) of 2-(2-bromo- ethyl)-l,3-dioxolane in the presence of 2.12 g (20 mmoles) of sodium carbonate at 90 - 100 °C for 3 hours. After cooling the mixture is diluted with 74 ml of water, the precipitated compound is filtered after stirring for 1 hour (weight: 3.28 g) and crystallized from 30 ml of isopropanol. Yield: 2.33 g, m.p. 134-136 °C. Example 4 (+)Endo-4-acetoxy-6-(4-chlorophenyl)-l-azabicyclo- [3.3.1]non-6-ene hydrochloride 5.0 g (17.5 mmoles) of the product prepared by the pro¬ cess of Example 3 are acetylated according to Example 2. The crude product (4.8 g) obtained by this analogous method is recrystallized from ethanol yielding 4.2 g of the final prod¬ uct, m.p. 276-278 °C after a rearrangement at around 220 °C. Example 5 (±)Endo-4-hydroxy-6-(3-chlorophenyl)-1-azabicyclo- [3.3.1]non-6-ene hydrochloride 10.1 g (43.8 mmoles) of 4-(3-chlorophenyl)-1,2,3,6- tetrahydropyridine hydrochloride in 80 ml of dimethylform- amide are reacted in 1zϊ_e presence of 11.6 g of sodium car¬ bonate with 10.0 g (54 mmoles) of 2-(2-bromoethyl)-l,3-di- oxolane at 80 °C for 10 hours. The reaction mixture is poured into water and the product is extracted with ethyl acetate. The ethyl acetate extract is dried and evaporated to yield 14.8 g of crude l-[3,3-(ethylenedioxy)propyl]-4-(3-chloro- phenyl)-1,2,3,6-tetrahydropyridine which are reacted accord- ing to Example 3. The 5.84 g of crude product, obtained by working up the reaction mixture, is recrystallized from ethanol yielding 5.2 g of the final product, m.p. 237-239 °C. Example 6 (±)Endo-4-methyl-6-(4-chlorophenyl)-1-azabicyclo- [3.3.1]non-6-en-4(exo)-ol (A) and (±)exo-4-methyl-6- -(4-chlorophenyl)-l-azabicyclo-[3.3.l]non-6-en- -4(endo)-ol (B) 6.64 g (21.5 mmoles) of [3,3-(ethylenedioxy)-butyl]-4- -(4-chlorophenyl)-l,2,3,6-tetrahydropyridine are dissolved in 26 ml of 85 % suifuric acid and- the solution is left to stand at room temperature for 10 days. Then the reaction mixture is poured over icewater and its pH is adjusted to 9. The pre¬ cipitated product is extracted with ethyl acetate, the organic layer is washed with 10 % sodium chloride solution, dried and evaporated. Recrystallizing the crystalline resid obtained from 55 ml of ethyl acetate yields 2.81 g of produ A, m.p. 191-192 °C. The mother liquor obtained after filtering the above product is evaporated and the 2.0 g residue obtained is submitted to flash-chromatography (eluant: 8:2 mixture of chloroform-methanol containing 1 drop of triethylamine for each 20 ml of the mixture). The fractions having R ∑ . 0.8 are pooled, evaporated, yielding 0.8 g of crystalline l-(3-oxo- butyl)-4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (re¬ crystallized from isopropylether, m.p. 96-97 °C) . Elution is continued and the uniform fractions at Rp 0.2-0.3 are evaporated yielding 0.44 g of product B. Upon scratching th product recrystallizes. Recrystallized from ethyl acetate t product has a m.p. of 132-133 °C. Example 7 (±)Endo-4-methyl-6-phenyl-l-azabicyclo[3.3.1]non-6- -en-4(exo)-ol (A) and (±)exo-4-methyl-6-phenyl-l-aza- bicyclo[3.3.l]non-6-en-4-(endo)-ol (B) 13.19 g (67.4 mmoles) of 4-phenyl-l,2,3,6-tetrahydro- pyridine hydrochloride in 110 ml of dimethylformamide are reacted in the presence of 17.8 g of sodium carbonate with 15.8 g (80.8 mmoles) of 2-(2-bromoethyl)-2-methyl-l,3-dio- xolane at 70 °C for 24 hours. Then the reaction mixture is poured into water and the product is extracted with ethyl acetate. After evaporating the extract a crude oil of l-[3,3 -(ethylenedioxy)butyl]-4-phenyl-l,2,3,6-tetrahydropyridine i obtained. 10 g of it are added dropwise at constant stirring to 50 ml of 85 % suifuric acid at 90 °C. After a reaction period of 24 hours the mixture is poured into water and its pH is adjusted to 9. The product is extracted with ethyl acetate, the organic layer is washed and evaporated. The resulting residue is mixed with isopropyl ether and the crystalline product formed is filtered. Recrystallizing 2.3 of the crude product from ethyl acetate 2.0 g of product "A" are obtained, m.p. 179-182 °C. The mother liquor, obtained after filtering the above product, is evaporated and the 4.3 g of oily residue are sub mitted to flash-chromatography, applying the mixture described in Example 6 as eluant. Evaporating the uniform fraction having an Rp of about 0.6, 0.46 g of oily (±)4- -methyl-6-phenyl-l-azabicyclo[3.3.1]nona-3,6-diene is ob¬ tained (m.p. of hydrochloride 194-196 °C) . Elution is con¬ tinued and the fraction having an Rp value of about 0.2 is evaporated. The crystalline residue is recrystallized from isopopanol to yield 0.28 g of product "B", m.p. 160-161 °C. Example 8 (±)Endo-4-hydroxy-6-(3-fluorophenyl)-1-azabicyclo- [3.3.1]non-6-ene 1/2 fumarate 2.7 g (12.6 mmoles) of 4-(3-fluorophenyl)-1,2,3,6- -tetrahydropyridine hydrochloride in 25 ml of dimethyl- formamide are reacted in the presence of 3.05 g of sodium carbonate with 2.77 g (15.3 mmoles) of 2-(2-bromoethyl)-1,3- -dioxolane at 90 °C for 3 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is washed, dried and evaporated to yield 3.4 of crude l-[3,3-(ethylenedioxy)-propyl]-4-(3-fluorophenyl)- 1,2,3,6-tetrahydropyridine which thereafter is refluxed in 5 ml of a 2:1 mixture of concentrated hydrochloric acid and water for one hour. The reaction mixture is evaporated to dryness, the oily residue is dissolved in water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is evaporated after drying, the 1.76 g residue are dissolved in 20 ml of ethanol and mixed with a solution of 0.88 g of fumaric acid in 40 ml of ethanol. The solution is. evaporated and the residue is recrystallized from 80 ml of isopropanol to yield 1.55 g of the aimed product, m.p. 193-195 °C. Example 9 (±)Endo- -hydroxy-6-(4-fluorophenyl)-l-azabicyclo- [3.3.i]non-6-ene hydrochloride Method A Applying the proces described in Example 1 2.9 g of crude product are obtained from 4.8 g (17.3 mmoles) of 1- -[3,3-(ethylenedioxy)propyl]-4-(4-fluorophenyl)-1,2,3,6- tetrahydropyridine which, recrystallized from ethanol, yield 2.50 g of the product, m.p. 216-218 °C. Method B 26.58 g (90 mmoles) of l-[3,3-(ethylenedioxy)propyl]-4- -(4-fluorophenyl)-4-hydroxypiperidine are heated with 130 ml of 24 % hydrochloric acid at 70 °C for 30 minutes, the mixture is evaporated at reduced pressure and the residue is recrystallized from isopropanol. Yield: 20.77 g, m.p. 213-218 ° C . The above starting material is prepared by refluxing 30.1 g (130 mmoles) of 4-(4- luorophenyl)-4-hydroxypiperidin hydrochloride (Dutch patent specification No. 6,510,107; C. A. §5., P 7154 e) in anhydrous acetone, in the presence of 37.3 g of potassium carbonate with 24.70 (136.5 mmoles) of 2-(2-bromoethyl)-1,3-dioxolane. The precipitated salt is fil¬ tered, the filtrate is evaporated and the residue recrystallized from isopropanol. Yield 27.43 g of l-[3,3- (ethylenedioxy)propyl]-4-(4-fluorophenyl)-4-hydroxy- piperidine, m.p. 110-112 °C. Example 10 (±)Endo-4-acetoxy-6-(4-fluorophenyl)-i-azabicyclo- [3.3.l]non-6-ene hydrochloride 2.0 g of the product prepared according to Example 9 are acetylated by the process defined in Example 2. Re¬ crystallized from isopropanol, 1.93 g of the product are ob¬ tained, which is rearranged at 264-268 °C and has a final m.p. of 280 °C. Example 11 (±)Endo-4-hydroxy-6-(2-methylphenyl)-1-azabicyclo- [3.3.1]none-6-ene hydrochloride 3.46 g (16.5 mmoles) of 4-(2-methylphenyl)-l,2,3,6- tetrahydropyridine hydrochloride in 25 ml of dimethyl- formamide are reacted in the presence of 4 g of sodium carbonate with 3.6 g (19.9 mmoles) of 2-(2-bromoethyl)-1,3- -dioxolane at 90 °C for 3 hours. The reaction mixture is poured into water and the product is extracted with ethyl acetate. The organic layer is washed, dried and evaporated yield 5.2 g of crude l-[3,3-(ethylenedioxy)propyl]-4-(2- -methylphenyl)-l,2,3,6-tetrahydropyridine which thereafter i refluxed in 60 ml of a 2:1 mixture of concentrated hydro- chloric acid and water for one hour. The product obtained after evaporating the reaction mixture is recrystallized fro ethanol to yield 1.9 g of the product, m.p. 293-295 °C. Example 12 (±)Endo-4-acetoxy-6-(2-methylphenyl)-1-azabicyclo- [3.3.1]non-6-ene hydrochloride 2.0 g (7.5 mmoles) of the product prepared according t Example 11 are acetylated by the process described in Exampl 2. The crude product, isolated as the base, is converted wit hydrochloric acid in isopropanol and ether to 1 g of the hydrochloride which, recrystallized from 20 ml of isopropa¬ nol, yields 0.7 g of the product, m.p. 222-223 °C. Example 13 (±)Endo-4-hydroxy-6-(3-methylphenyl)-l-azabicyclo- [3.3.1]non-6-ene hydrochloride " 9.0 g (43 mmoles) of 4-(3-methylphenyl)-1,2,3,6-tetra- hydropyridine hydrochloride in 50 ml of dimethylformamide ar reacted in the presence of 13.8 g of potassium carbonate with 9.05 g (50 mmoles) of 2-(2-bromoethyl)-l,3-dioxolane at 70 °C for 2.5 hours. The reaction mixture is poured into water and extracted with methylenechloride. The organic laye is washed, dried and evaporated to yield crude l-[3,3- -(ethylenedioxy)propyl]-4-(3-methylphenyl)-1,2,3,6-tetra- hydropyridine which, dissolved in 60 ml of a 2:1 mixture of concentrated hydrochloric acid and water, is stirred at 60 for 2 hours. The reaction mixture is evaporated to dryness the residue is mixed with isopropanol and the crystals for are filtered to yield 8.51 g of the product, m.p. 227-230 Example 14 (±)Endo-4-acetoxy-6-(3-methylphenyl)-l-azabicyclo- [3.3.1]non-6-ene 1/2 fumarate A base is prepared from the product prepared accordi to Example 13 by applying potassium hydroxide. 2.52 g (11 mmoles) of this base are dissolved in 25 ml of pyridine an reacted with 1.57 g (20 mmoles) of acetyl chloride at 25 ° for 3 hours. The reaction mixture is worked up according t the process defined in Example 2. the evaporation residue dissolved in ethanol and treated with fumaric acid. The re suiting salt, recrystallized from isopropanol, yields 2.20 of the product, m.p. 155-159 °C. Example 15 (±)Endo-4-hydroxy-6-(4-methylthiophenyl)-l-aza¬ bicyclo[3.3.l]non-6-ene hydrochloride 1.0 g (3.3 mmoles) of l-[3,3-(ethylenedioxy)propyl]- -(methylthiophenyl)-l,2,3,6-tetrahydropyridine are refluxe in 15 ml of a mixture of concentrated hydrochloric acid an water (2:1) for 4 hours. The reaction mixture is evaporate to dryness and the 0.6 g crude product obtained is recry- stallized from ethanol to yield 0.4 g of the product, m.p. : 222-225 °C. 1-[3,3-(Ethylenedioxy) ropyl]-4-(4-methylthiophenyl) -1,2,3,6-tetrahydropyridine serving as starting material f * » *<-'•_»•-> E a L _ .___ the Example is prepared by the following process. Grignard reagent is prepared from 0.64 g (0.026 g atom) of magnesium and 5.07 g (26 mmoles) of 4-bromo- thioanisole in 15 ml of tetrahydrofuran then a solution of 3 g (17.5 mmoles) of 1-ethoxycarbony1-4-piperidone in 10 ml of tetrahydrofuran is added at 0 - 10 °C. The mixture is stirred at room temperature overnight then is decomposed wit 20 ml of a 10 % solution of ammonium chloride in ice-water. The reaction mixture is extracted with ethyl acetate, the organic layer is dried and evaporated. The residue, 5.4 g of crude l-ethoxycarbonyl-4-(4-methylthiophenyl)-4-hydroxy- piperidine, is refluxed with 3 g of potassium hydroxide in 25 ml of isopropanol for 3 days. Thereafter the mixture is evaporated, the residue is dissolved in water and extracted with ethyl acetate. After evaporating the organic layer 1.5 of hydrochloride are formed with hydrochloric acid in ether. Recrystallization from 40 ml of isopropanol yields 0. g of 4-(4-methylthiophenyl)-4-hydroxypiperidine hydro¬ chloride, m.p. 188-190 °C. 0.5 g (2 mmoles) of 4-(4-methylthiophenyl)-4-hydroxy- piperidine hydrochloride is refluxed with a mixture of 3 ml of concentrated hydrochloric acid and water (2:1). Re- crystallization of the residue, obtained by evaporating the reaction mixture to dryness from 30 ml of ethanol, yields 0.2 g of 4-(4-methylthiophenyl)-1,2,3,6-tetrahydropyridine hydro¬ chloride, m.p. 255-256 °C. 1.63 g (6.74 mmoles) of 4-(4-methylthiophenyl)-1,2,3,6- tetrahydropyridine hydrochloride in 20 ml of dimethyl- formamide are reacted in the presence of 1.43 g of sodium carbonate with 1.46 g (8.1 mmoles) of 2-(2-bromoethyl)-l,3- -dioxolane at 90 °C for 3 hours. The reaction mixture is poured into water, the precipitated material is filtered, then the 1.2 g of crude product are recrystallized from 25 of isopropanol to yield 1.0 g of l-[3,3-(ethylenedioxy)- propyl]-4-(4-methylthiophenyl)-1,2,3,6-tetrahydropyridine, m.p. 98-99 °C. Example 16 (±)Endo-4-hydroxy-6-(3-trifluoromethylphenyl)-l-aza¬ bicyclo[3.3.1]non-6-ene hydrochloride 3.8 g (14.4 mmoles) of 4-(3-trifluoromethylphenyl)- -1,2,3,6-tetrahydropyridine hydrochloride in 30 ml of di- methylformamide are reacted in the presence of 3.8 g of sodium carbonate with 3.13 g (17.2 mmoles) of 2-(2-bromo- ethyl)-1,3-dioxolane at 60 °C for 6 hours. The reaction mixture is poured into water and extracted with ethyl ace¬ tate. The organic layer is washed, dried and evaporated. Th residual crude l-[3,3-(ethylenedioxy)propyl]-4-(3-trifluoro methylphenyl)-1,2,3,6-tetrahydropyridine is refluxed in a mixture of 60 ml of concentrated hydrochloric acid and wate (2:1) for 2 hours. The reaction mixture is evaporated to dryness, the residue is mixed with acetone and the crystals formed are filtered to give 1.38 g of the product which, re crystallized from isopropanol, yields 1.24 g of the aimed compound, m.p. 230-233 °C, after rearrangement at 217-220 ° Example 17 (±)Endo-4-hydroxy-6-(4-trifluoromethylphenyl)-l-aza¬ bicyclo[3.3.1]non-6-ene hydrochloride 4.48 g (17 mmoles) of 4-(4-trifluoromethylphenyl)- -1,2,3,6-tetrahydropyridine hydrochloride are reacted with -(2-bromoethyl)-l,3-dioxolane according to the process described in Example 13. The reaction mixture is diluted with 250 ml of water and the precipitated crystals of l-[3, -(ethylenedioxy)-propyl]-4-(4-trifluoromethylphenyl)-1,2,3, -tetrahydropyridine are filtered (4.60 g, m.p. 106-109 °C) , then stirred in 20 ml of- a mixture of concentrated hydro¬ chloric acid and water (2:1) at 60 °C for 3 hours. The reaction mixture is evaporated. Recrystallization of the residue from ethanol yields 3.07 g of the product, m.p. 255-265 °C. Example 18 (±)Endo-4-hydroxy-6-(2-methoxyphenyl)-1-azabicyclo- [3.3.1]non-6-ene hydrochloride 7.77 g (25.3 mmoles) of l-[3,3-(ethylenedioxy)propyl]- 4-hydroxy-4-(2-methoxyphenyl)-piperidine are dissolved in 40 ml of a mixture of concentrated hydrochloric acid and water (2:1) and stirred at room temperature for 4 hours. The reac¬ tion mixture is evaporated to dryness and the residue is re¬ crystallized from ethanol to yield 4.20 g of the product, m.p. 263-268 °C. l-[3,3-(Ethylenedioxy)propyl]-4-hydroxy-4-(2-methoxy- phenyl)-piperidine serving as starting material is prepared by the following process. 3.15 g (0.13 g atom) of magnesium chips are reacted in 140 ml of tetrahydrofuran with 24.24 g (130 mmoles) of 2- bro oanisole, and the resulting solution is combined at 0 °C with a solution of 17.1 g (100 mmoles) of 1-ethoxy- carbonyl-4-piperidone in 100 ml of tetrahydrofuran then left to stand overnight at room temperature. Thereafter the reaction mixture is decomposed with a 20 % solution of ammonium chloride and the product is extracted with chloro¬ form. The organic layer is washed, dried and evaporated. The evaporation residue is mixed with 20 ml of ether and the crystals of l-ethoxycarbonyl-4-hydroxy-4-(2-methoxyphenyl)- -piperidine are filtered (17.66 g, m.p. 125-127 °C) . The crystals are dissolved in 155 ml of methylcellosolve and refluxed with 12.36 g (220 moles) of potassium hydroxide for 26 hours. Then the reaction mixture is diluted with water, extracted with methylenechloride, the organic layer is washe with saline solution and dried. The methylenechloride is evaporated and the evaporation residue is recrystallized fro ethyl acetate to yield 7.37 g of 4-hydroxy-4-(2-methoxy- phenyl)-piperidine, m.p. 121-124 °C. 7.37 g (35.5 mmoles) of 4-hydroxy-4-(2-methoxyphenyl)- -piperidine in 45 ml of dimethylformamide are reacted in the presence of 8.28 g of potassium carbonate with 8.04 g (44.4 mmoles) of 2-(2-bromoethyl)-l,3-dioxolane at 80 °C for 1 hour, thereafter the process described in Example 13 is followed. The crude product obtained is recrystallized from isopropanol to yield 7.77 g of 1-[3,3-(ethylenedioxy)propyl] -4-hydroxy-4-(2-methoxyphenyl)-piperidine, m.p. 190-193 °C. Example 19 (±)Endo-4-hydroxy-6-(4-methoxyphenyl)-l-azabicyclo- [3.3.1]non-6-ene hydrochloride 0.5 g (1.72 mmoles) of l-[3,3-(ethylenedioxy)propyl]- -(4-methoxyphenyl)-l,2,3,6-tetrahydropyridine is left to stand in 15 ml of a mixture of concentrated hydrochloric ac and water (2:1) at room temperature for 30 minutes. The reaction mixture is evaporated to dryness and the residue i recrystallized from 10 ml of ethanol to yield 0.21 g of the product, m.p. 235-236 °C. l-[3,3-(Ethylenedioxy)propyl]-4-(4-me hoxypheny1)- -1,2,3,6-tetrahydropyridine serving as starting material of the example is prepared according to the following method. 0.8 g (3.6 mmoles) of 4-(4-methoxypheny1)-1,2,3,6- tetrahydropyridine hydrochloride in 10 ml of dimethyl- formamide is reacted in the presence of 0.8 g of sodium carbonate with 0.77 g (4.2 mmoles) of 2-(2-bromoethyl)-1,3- dioxolane at 90 °C for 3 hours. The reaction mixture is poured into water and the precipitate formed is filtered to yield 0.56 g of the product, m.p. 98-100 °C. Example 20 (±)Endo-4-acetoxy-6-(4-methoxypheny1)-1-azabicyclo- [3.3.1]non-6-ene hydrochloride 1.0 g (3.6 mmoles) of the product prepared by the process described in Example 19 is acetylated according to Example 2. 0.9 g of the crude product obtained is recrystal¬ lized from 15 ml of isopropanol to yield 0.8 g of the aimed product, m.p. 235-237 °c. Example 21 (±)Endo-4-hydroxy-6-(2-thienyl)-l-azabicyclo[3.3.1]- non-6-ene hydrochloride 5.66 g (20 mmoles) of l-[3,3-(ethylenedioxy)propyl]-4- -hydroxy-4-(2-thienyl)-piperidine are dissolved in 30 ml of mixture of concentrated hydrochloric acid and water (2:1) an stirred at room temperature for one hour. The reaction mixture is evaporated, the evaporation residue is mixed with methanol and filtered to yield 2.49 g of the product, m.p. 267-269 °C. l-[3,3-(Ethylenedioxy)propyl]-4-hydroxy-4-(2-thienyl)- piperidine serving as starting material of the example is prepared by the following process. 3.15 g (0.13 g atom) of magnesium chips are reacted with 21.18 g (130 mmoles) of 2-bromothiophene in 130 ml of tetrahydrofuran then the solution is combined at 0 °C with a solution of 17.1 g (100 mmoles) of l-ethoxycarbonyl-4-pipe- ridone in 100 ml of tetrahydrofuran and left to stand at roo temperature overnight. The reaction mixture is worked up according to the method described in Example 18. The crude product is recrystallized from ethyl acetate to yield 16.85 of 1-ethoxycarbony1-4-hydroxy-(2-thienyl)-piperidine, m.p. 152-153 °C. The solution of this compound in 100 ml of isopropanol is ref.luxed with 12.9 g (230 mmoles) of potassium hydroxide for 40 hours, then it is worked up according to the method described in Example 18. The crude product is recrystallized from ethyl acetate to yield 9.65 g of 4-hydroxy-4-(2- -thienyl)-piperidine, m.p. 145-146 °C. 9.56 g (52 mmoles) of the above product are reacted i 70 ml of dimethylformamide, in the pesence of 11.0 g of potassium carbonate, with 10.86 g (60 mmoles) of 2-(2-bromo ethyl)-1,3-dioxolane at 80 °C for one hour. Thereafter the mixture is worked up as described in Example 13. The crude product is recrystallized from isopropanol to yield 10.51 g of 1-[3,3-(ethylenedioxy)propyl]-4-hydroxy-4-(2-thienyl)-pi peridine, m.p. 110-112 °C. Example 22 (±)4-Phenyl-endo-6-hydroxy-l-azabicyclo[3.2.l]oct-3- -ene hydrochloride 9.78 g (0.05 mole) of 4-phenyl-l,2,3,6-tetrahydro- pyridine hydrochloride are reacted in 130 ml of dimethyl- formamide, in the presence of 10.6 g of sodium carbonate, with 11.3 g (0.055 mole) of bromoacetaldehyde diethyl acetal at 80 °C for 16 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer i washed, dried and evaporated yielding 13.7 g of an oily residue consisting mainly of l-(2,2-diethoxy-ethyl)-4- -phenyl-1,2,3,6-tetrahydropyridine. 11.3 g of this inter¬ mediate product are refluxed with 100 ml of a mixture of concentrated hydrochloric acid and water (1:1) for 4 hours, then the reaction mixture is evaporated and the residue mixe with acetone. 6.7 g of the crude product are recrystallized first from ethanol then from isopropanol to yield 3.2 g of the product, m.p. 228-230 °C. Example 23 (±)4-Phenyl-endo-6-acetoxy-l-azabicyclo[3.2.l]oct-3- -ene hydrochloride 1.76 g (7.4 mmoles) of the product prepared by the process described in Example 22 are acetylated according to Example 2. 1.16 g of the crude product, isolated in the form of a base, are transformed into the hydrochloride with hydro chloric acid in ether and the salt is recrystallized from isopropanol to yield 0.74 g of the product, m.p. 178-180 °C. Example 24 (±)4-(4-Chlorophenyl)-endo-6-hydroxy-i-azabicyclo- [3.2.l]oct-3-ene 11.4 g (50 mmoles) of 4-(4-chlorophenyl)-1,2,3,6-tetra hydropyridine hydrochloride in 90 ml of dimethylformamide ar reacted in the presence of 10.6 g of sodium carbonate with 11.3 g (55 mmoles) of bromoacetaldehyde diethyl acetal at 80 °C for 24 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is washed, dried and evaporated to yield 15.6 g of crude resinous l-(2,2-diethoxyethyl)-4-(4-chlorophenyl)-1,2,3,6- tetrahydropyridine. This intermediate is added under constant stirring to 230 ml of 85 % suifuric acid at room temperature. Stirring i continued for 2 hours then the reaction mixture is poured on ice and its pH is adjusted with sodium hydroxide to 9. The product is extracted with ethyl acetate and after evaporatin the organic layer the residue is submitted to flash chromato graphy (eluant: mixture of benzene-methanol-triethylamine 2:1:0.1). The main fraction obtained at an Rp of about 0.3 ( ' 4.3 g) is recrystallized from ethylmethylketone yielding 2. g of the product, m.p. 145-148 °C. Example 25 (±)4-(4-chlorophenyl)-endo-6-acetoxy-l-azabicyclo- [3.2.1]oct-3-ene hydrochloride 4.9 g of the product prepared by the process described in Example 24 are acet lated accordiaig to Example 2. 3.6 g o the base obtained are converted to the hydrochloride by hydrochloric acid in isopropanol and ether. 2.12 g of this product are recrystallized from isopropanol to yield 1.77 g of the pure product, m. p. 253-256 °C. Example 26 (±)4-(4-Methoxyphenyl)-endo-6-hydroxy-l-azabicyclo- [3.2.1]oσt-3-ene hydrochloride 3.54 g (14.4 mmoles) of 4-(4-methoxyphenyl)-4-hydroxy- piperidine hydrochloride in 25 ml of dimethylformamide are reacted in the pesence of 3.07 g of sodium carbonate with 3. g (16 mmoles) of bromoacetaldehyde diethyl acetal at 90. °C for 5 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is washed, dried and evaporated to yield 4.6 g of crude l-(2,2-diethoxy ethyl)-4-(4-methoxyphenyl)-4-hydroxypiperidine which are treated with 50 ml of a mixture of concentrated hydrochloric acid and water (2:1) at room temperature for 2 hours. The reaction mixture is evaporated, the residue is recrystallize from 200 ml of ethanol to yield 1.58 g of the aimed product, m.p. 265-267 °C. 4-(4-Methoxypheny1)-4-hydroxypiperidine hydrochloride serving as starting material in the example is prepared by the following process. 37.4 g (0.2 mole) of 4-bromoanisole are added dropwise to a mixture of 4.86 g (0.2 g atom) of magnesium and 60 ml of tetrahydrofuran. After the dissolution of the magnesium a mixture of 24 g (0.14 mole) of l-ethoxycarbonyl-4-piperidone and 60 ml of tetrahydrofuran are added dropwise in a tempera¬ ture range of 0-10 °C and stirred at room temperature over- night. Then the mixture is decomposed by adding 160 ml of icy 10 % ammonium chloride solution, extracted with ethyl acetate and the organic layer is dried and evaporated. Treating the residue with diisopropyl ether yields 23.38 g of 1-ethoxy- carbonyl-4-(4-methoxypheny1)-4-hydroxypiperidine, m.p. 110-112 °C. This intermediate is refluxed in 160 ml of isopropanol with 12 g of potassium hydroxide for 3 days. Thereafter the mixture is evaporated, taken up in water and extracted with ethyl acetate. The organic layer is dried and evaporated. Treating the evaporation residue with hydrochloric acid in ether yields 6.2 g of 4-(4-methoxyphenyl)-4-hydroxypiperidine hydrochloride, m.p. 218-220 °C. Example 27 (±)4-(3-Methylphenyl)-endo-6-hydroxy-l-azabicyclo- [3.2.l]oct-3-ene 9.0 g (43 mmoles) of 4-(3-methylphenyl)-1,2,3,6-tetra- hydropyridine hydrochloride in 50 ml of dimethylformamide ar reacted in the presence of 13.8 g of potassium carbonate wit 10.3 g (50 mmoles) of bromoacetaldehyde diethyl acetal at 8 °C for 3 hours. The reaction mixture is poured into water a extracted with methylenechloride. The organic layer is washed, then submitted to flash chromatography (eluant: fixture of benzene-methanol-triethylamine 95:5:0.1), yieldi 7.60 g of l-(2,2-diethoxyethyl)-4-(3-methylphenyl)-1,2,3,6- -tetrahydropyridine. This intermediate is dissolved in 30 ml of a mixture of concentrated hydrochloric acid and water (2:1) and stirred at room temperature for 20 hours. Then the reaction mixture is poured on ice and the pH is adjusted to with sodium hydroxide. The solution is extracted with ether, the organic layer is evaporated and the residue is recrystal lized from ethyl acetate yielding 2.70 g of the aimed product, m.p. 144-147 °C. Example 28 (+)Endo-4-hydroxy-6(exo)-phenyl-l-azabicyclo[3.3.1]- nonane hydrochloride 1.25 g (5 mmoles) of (±)endo-4-hydroxy-6-phenyl-l-aza- bicyclo[3.3.l]non-6-ene hydrochloride, prepared according to Example l, are submitted to hydrogenolysis in 80 ml of a mixture of methylenechloride and ethanol (1:1) in the presence of 0.10 g of 10 % palladium charcoal catalyst. Uptake of the calculated amount of hydrogen gas is completed in about 5 hours. The catalyst is filtered, the filtrate is evaporated and the crystalline residue is recrystallized to yield 0.85 g of the product, m.p. 284-285 °C (rearrangement at 245-268 °C) . Example 29 (±)Endo-4-hydroxy-6(exo)-(3-methylphenyl)-l-aza¬ bicyclo[3.3.1] onane hydrochloride A solution of 2.0 g (7.52 mmoles) of (±)endo-4-hydroxy- 6-(3-_nethylphenyl)-l-azabicyclo[3.3.1]non-6-ene hydrochloride (Example 13) is hydrogenated in the presence of 0.2 g of 10 % palladium charcoal catalyst for 8-10 hours. The catalyst is filtered, the filtrate is evaporated and the residue is re¬ crystallized from isopropanol to yield 1.33 g of the aimed product, m.p. 238-245 °C. Example 30 (±)Endo-4-hydroxy-6(exo)-(4-trifluoromethylphenyl)-1- -azabicyclo[3.3.1] onane hydrochloride 1.59 g (5 mmoles) of (±)endo-4-hydroxy-6-(4-trifluoro- methylphenyl)-l-azabicyclo[3.3.l]non-6-ene hydrochloride .Example 17) are hydrogenated according to Example 29 and the substance is recrystallized from ethanol to yield 1.19 g of the product, m.p. 299-303 °C. Example 31 (±)Endo-4-hydroxy-6(exo)-(2-methoxypheny1)-l-aza¬ bicyclo[3.3.1]nonane hydrochloride 1.97 g (7 mmoles) of (±)endo-4-hydroxy-6-(2-methoxy- phenyl)-l-azabicyclo[3.3.1]non-6-ene hydrochloride (Example 18) are hydrogenated according to Example 29 and the substa-nce is recrystallized from isopropanol to yield 0.92 g of the product, m.p. 258-262 °C. Example 32 (±)Endo-4-propionyloxy-4-(4-fluorophenyl)-1-azabicycl [3.3.1]non-6-ene hydrochloride Applying an aqueous potassium carbonate solution the base is prepared from 2.50 g (10.7 mmoles) of (±)endo-4- hydroxy-6-(4-fluorophenyl)-l-azabicyclo[3.3.l]non-6-ene hydrochloride, prepared according to Example 9 f then it is extracted with ether and evaporated. The crystalline product obtained is stirred with 13.5 ml of propionic anhydride at 6 °C for 8 hours. Excess anhydride is removed by decomposition with 20 ml of water then it is evaporated to dryness. Treating the residue with hydrochloric acid in methanol yields 3.35 g of the product, m.p. 233-235 °C. Example 33 (±)Endo-4-isobutyroyloxy-6-(3-chlorophenyl)-l- -azabicyclo[3.3.l]non-6-ene hydrochloride Applying a 4 % solution of sodium hydroxide the base is prepared from 2.25 g (7.86 mmoles) of (±)endo-4-hydroxy-6 (3-chlorophenyl)-l-azabicyclo[3.3.l]non-6-ene hydrochloride, prepared according to Example 5. then the base is extracted with chloroform and the organic layer is evaporated. The residue is dissolved in 20 ml of anhydrous methylene chlorid and treated at 0-5 °C with a solution of 1.63 ml (15.72 mmoles) of isobutyroyl chloride in 10 ml of methylene- chloride, in the presence of 1.27 ml of anhydrous pyridine. The reaction mixture is stirred at room temperature for 3 hours then it is evaporated. The residue is diluted with a concentrated solution of sodium carbonate and extracted with b'enzene. The organic layer is evaporated and the resinous residue is treated with hydrochloric acid in isopropanol to yield 1.39 g of the product, m.p. 233-235 °C. Examples 34 and 35 Table 2 presents compounds of the general formula (I) wherein n = 1, R 2 and R 3 represent hydrogen atoms, the dotted line an additional C-C bond and R 1 a group defined in the Table. The compounds are prepared, starting from the suitably substituted 1,2,3,6-tetrahydropyridine, according to the process described in Example 1. Table 2 Example No. R 1 M.p. (hydrochloride) , °C 34 4-Methylphenyl 253-257 35 Alpha-naphthyl 309-321 Examples 36 and 37 Table 3 presents compounds of the general formula (I) wherein n = 1, R 2 and R 3 represents hydrogen atoms, the dotted line does not define an additional C-C bond and R 1 represents a group defined in the Table. The compounds are prepared by hydrogenation from the respective starting material according to the process described in Example 29. then the product obtained is converted to the base by known methods and recrystallized from isopropanol. Table 3 Example No. Example No. of R l M.p. (base) starting material °C 36 34 4-Methylphenyl 124-126 37 4-Fluorophenyl 173-175 Examples 38 to 50 Table 4 presents compounds of the general formula (I) wherein R 3 represents a hydrogen atom, the dotted line an additional C-C bond, while n, R 1 and R 2 are defined in the Table. The compounds are prepared by acylating the base, prepared from the respective starting material, and, if desired, by transforming the product to its acid addition salt. Table 4 Example Starting material Method, M.p. (hydr No. example No. n R R2 example No. chloride) . 1 4-cholorophenyl propionyl 32 258-260 1 4-chlorophenyl isobutyroyl 33 268-270 1 4-chlorophenyl pivaloyl 32 258-260 0 4-methoxypheny1 acetyl 32 202-203 1 4-methylphenyl acetyl 32 253-256 1 3-chlorophenyl acetyl 32 238-240 1 3-chlorophenyl propionyl 32 210-212 1 3-chlorophenyl pivaloyl 32 229-231 1 4-fluorophenyl pivaloyl 32 235-238 1 5-trifluoromethylphenyl propionyl 32 256-263 1 2-methoxypheny1 acetyl 32 216-219 1 phenyl propionyl 2 254-258 1 alpha-naphthyl propionyl 32 115-116 base Examples 51 to 58 Table 5 presents compounds of the general formula (I) wherein n = 1, R 3 represents a hydrogen atom, the dotted line does not mean an additional C-C bond, furthermore R 1 and R 2 are defined in the Table. The compounds are prepared by acylating the base, prepared from the respective startin material, and, if desired, by transforming the product to its acid-addition salt. Table 5 Example Starting material Method, M.p. (hydro- le No. Ri R 2 exa ple No. chloride) . °C phenyl acetyl 2 262-263 phenyl propionyl 2 113 a phenyl pivaloyl 2 116-117 2-methoxypheny1 acetyl 32 276-281 3-methylphenyl acetyl 32 258-263 i 4-fluorophenyl acetyl 32 276 (subl.) o I 4-fluorophenyl propionyl 32 255 (subl.) 4-trifluoromethylphenyl propionyl 32 239 (subl.) base Example 59 (+) Endo-4-acetoxy-6- (4-chlorophenyl) -1-azabicyclo- [3.3.1]-non-6-ene hydrochloride From the compound prepared according to Example 3 th base is liberated with a sodium hydrogen carbonate soluti then it is extracted with ethyl acetate and isolated in t form of a solid foam. To a solution of 9.95 g (40 mmoles) this base in 5 ml of ethyl acetate 4.41 g (19 mmoles) of (+)-camphene-10-sulfonic acid in 120 ml of ethyl acetate added dropwise within 2 hours. The suspension formed is stirred for 24 hours, then the precipitated diastereomer salt (8.16 g) is filtered. This salt is recrystallized fi from 10 % then from 5 % isopropanol containing ethyl-meth ketone, and the crystal mass formed is stirred each time at least 16 hours at room temperature. After this procedu which may be followed eventually by further crystallizati the specific rotation of the salts is in the range of [C_] +109.3-111.7° (c = 0.5, ethanol). To control the optical purity of the product a sample of the salt is acylated by (+)-camphene-10-sulfonyl chloride in d5~pyridine and the diastereomer contaminant is assayed by the ^-N R method. A base is formed (1.18 g of a solid foam) from 2.28 of the above product (diastereomer salt content not less than 99 %) by stirring with a mixture of aqueous sodium h rogen carbonate solution and ethyl acetate, and the resul ing base is converted first to the acetyl derivative acco ing to Example 2, then to the hydrochloride. Recrystalliza tion from isopropanol yields 0.89 g of product, m.p. 264-2 °C; after recrystallization: 238-250 °C, [α] D : +233.3° (c = 0.5, ethanol). Example 60 (-)Endo-4-acetoxy-6-(4-chlorophenyl)-1-azabicyclo- [3.3.1]non-6-ene hydrochloride The base is liberated from the recrystallization mother liquors of diastereomers of Example 59 by stirring with a mixture of aqueous 10 % sodium hydrogen carbonate solution ■and ethyl acetate. To a solution of 8.50 g (34 mmoles) of the obtained base in 40 ml of ethyl acetate a solution of 3.76 g (16.2 mmoles) of (-)-camphene-lO-sulfonic acid in 100 ml of ethyl acetate are added dropwise at room temperature under stirring for 2 hours, and the suspension is stirred during 16 hours. The diastereomer salt is filtered and recrystallized from ethyl acetate containing first 2 %, then 3 % of isopropanol. Yield: 1.88 g of salt, [α] D : -115.3° (c = 0.5, ethanol). The base liberated from this product (0.98 g of a soli foam) is converted according to Example 2 first to the acetyl derivative, then to the hydrochloride salt. Yield 0.50 g, m.p. 264-268 °C (recrystallizing after 220 °C) [c_] D : -229.1° (c = 0.5, ethanol). Example 61 (±)Exo-4-acetoxy-6-(4-chlorophenyl)-1-azabicyclo- [3.3.1]non-6-ene 1/2 fumarate Heating 1.5 g of the compound prepared according to Example 3 in 5 ml of 70 % perchloric acid at 80 °C for 4 hours a mixture of endo and exo isomers is formed. The exo form can be isolated from the mixture according to the following procedure. The reaction mixture is poured into ice-water, its p is adjusted to 8 with sodium hydrogen carbonate solution, then it is extracted with ethyl acetate. The ethyl acetat extract is dried and evaporated. The 1.4 g white crystalli product obtained is refluxed in a mixture of 15 ml of dry dichloromethane, 15 ml of pyridine and 6 ml of acetic anhydride for 1.5 hours. The reaction mixture is processed according to Example 2 and the obtained 0.7 g of oil is separated with a mixture of benzene and methanol (8:2) on Kieselgel 60 (Macherey-Nagel) column. During elution the endo (equatorial) isomer is followed by the exo (axial) iso er (0.25 g, Rp = 0.3-0.4) which is dissolved in 5 ml o ethanol and mixed with the alcoholic solution of 0.04 g of fumaric acid. After evaporation the salt is recrystallize from 15 ml of ethanol. Yield 0.21 g, m.p. 219-221 °C. According to gas-chromatographic analysis 96 % of the product is the axial (exo) isomer. Example 62 (±)Endo-4-isobutyroyl-6-(4-fluorophenyl)-l-azabicyclo [3.3.1]non-6-ene hydrochloride 3.6 g (13.3 mmoles) of the compound prepared accordin to Example 9 is converted to the base with a potassium carbonate solution and extracted with ethyl acetate. The solvent is evaporated, the residue is dissolved in anhydro pyridine cooled to 0 °C and treated with a solution of 2.1 g (20 mmoles) of isobutyryl chloride in 5 ml of anhydrous dioxane. After standing overnight the reaction mixture is poured on ice, extracted with chloroform, evaporated and th residue-is treated with HC1 in isopropanol. Yield 2.86 g, sublimating at 225 °C. Example 63 (±)Exo-4-hydroxy-6-(4- luorophenyl)-1-azabicyclo- [3.3.1]non-6-ene hydrochloride The ethanol mother liquor obtained according to Example 9 is evaporated and the residue is converted to the base. 5.0 g of this base (endo-exo isomer ratio about 4:1) are heated with 25 ml of 70 % perchloric acid at 80 °C for 1 hour. The solution is cooled, made alkaline with 5 N sodium hydroxide, extracted with chloroform and evaporated. In the resulting base the ratio of endo-exo isomers amounts to about 2:3. 3.80 g of the isomer mixture are separated on a Kieselgel 60 (Macherey-Nagel) column (120 g) using benzene- -methanol (4:1) as eluant. The resulting crude product (1.85 g) is recrystallized from ethyl acetate. Yield 1.40 g of (±)exo-4-hydroxy-6-(4-fluorophenyl)-l-azabicyclo[3.3.1]non- -6-ene base, m. p. 133-137 °C. Treating this base with hydrochloric acid gas in isopropanol yields 1.47 g of the product, m.p. 220-224 °C. Example 64 (+)Exo-4-propionyloxy-6-(4-fluorophenyl)-l-azabicyclo- [3.3.1]non-6-ene hydrochloride 0.65 g (2.79 mmoles) of (±)exo-4-hydroxy-6-(4- -fluorophenyl)-l-azabicyclo[3.3.l]non-6-ene, prepared according to the process described in Example 63, is treate with propionic anhydride according to Example 32 and the product obtained is converted to the hydrochloride salt. Yield 0.54 g, m. p. 174-179 °C. Example 65 (±)Endo-4-hydroxy-6-(4-fluorophenyl)-l-azabicyclo- [3.3.1]non-6-ene hydrochloride The base is liberated from the. compound prepared according to Example 9 with potassium carbonate solution, extracted with ethyl acetate and the ethyl acetate extract is concentrated to yield crystals. To a solution of 7.0 g (30 mmoles) of this base (m. p. 119-122 °C) in 50 ml of acetone a hot solution of 3.90 g (15 mmoles) of L-tartaric acid 4-chloroanilide [T. A. Montzka, T. L. Pindell and J. D Matiskella: J. Org. Chem. 3J3, 3993 (1968)] in 100 ml of acetone are poured, the crystals formed are filtered and recrystallized 3 times from isopropanol. The optical purity of the resulting diastereomer salts is checked according to the method described in Example 59. The base is liberated from 3.10 g of the product (optical purity not less then 99 %) prepared above [m. p. 126-131 °C; [ ] ^ : +145.8° (c = 1, methanol)] with- aqueous sodium carbonate solution. The resulting 2.12 g of (+)endo- -4-hydroxy-6-(4-fluorophenyl)-l-azabicyclo[3.3,l]non-6-ene [m.p. 154-157 °C, [a] D : +149.35° (c = 1, methanol)] are treated with hydrochloric acid gas in isopropanol. Yield: 2.16 g, m.p. 253-255 °C, [α] D : +155.0° (c = 1, methanol). Example 66 (-)Endo-4-hydroxy-6-(4-fluorophenyl)-l-azabicyclo [3.3.1]non-6-ene hydrochloride The mother liquor of acetonic salt formation in Exampl 65 is evaporated and the resulting 4.9 g of thick resin is worked up with water. The solidified crystals are filtered to yield 2.39 g of the base enriched in the (-)enantiomer [[ α _D : -87.5° (c = 1, methanol)]. This is dissolved in acetone and reacted with the solution of 2.38 g of (-)- -camphene-10-sulfonic acid in acetone. The precipitated sal is recrystallized from ethyl-methylketone and the optical purity of the diastereomer salts formed is checked accordin to the method described in Example 59. The base is liberated from 1.66 g of the product, prepared by the above method and having an optical purity not less than 99 %, with an aqueous sodium carbonate solution. Treating the resulting 0.70 g of (-)endo-4- —hydroxy-6-( -fluorophenyl)-l-azabicyclo[3.3.1]non-6-ene [m.p. 154-157 °C; [α] D : -148.5° (c = l, methanol)] with hydrochloric acid gas in isopropanol, 1.60 g of the product are obtained which is sublimating at 252-254 °C; [α] D : -156.8° (c = 1, methanol). Example 67 (+)Endo-5-propionyloxy-6-(4-fluorophenyl)-l-azabicyclo [3.3.1]non-6-ene hydrochloride 0.75 g (3.2 mmoles) of (+)endo-4-hydroxy-6-(4-fluoro- -phenyl)-l-azabicyclo[3.3.l]non-6-ene, prepared according t the process described in Example 65, is treated with propionic anhydride according to Example 32 and the resulting product is converted to the hydrochloride salt. Yield 0.84 g [sublimating at 243 °C, [α] D : +218.2° (c = 1, methanol) ] . Example 68 (-)Endo-4-propionyloxy-6-(4-fluorophenyl)-l-azabicycl [3.3.1]non-6-ene hydrochloride 0.57 g (2.44 mmoles) of (-)endo-4-hydroxy-(4-fluoro¬ phenyl)-l-azabicyclo[3.3.l]non-6-ene, prepared according to the process described in Example 66, is treated with propionic anhydride and subsequently converted into the hydrochloride. Yield 0.71 g of the product sublimating at 245 °C, [ ] D : -223.5° (c = 1, methanol).

Claims: Claims 1. New 1-azabicycloalkane derivatives and their stereo¬ isomers of the general formula (I) wherein R 1 represents a phenyl, substituted phenyl, naphthyl or thienyl group, wherein the phenyl group can be substituted by one or several halogen atom(s) , methyl, methoxy, methylthio or trifluoromethyl group(s), R 2 represents a hydrogen atom or a C2-5 aliphatic acyl group, R3 represents a hydrogen atom or a methyl group, n can be zero or one, the dotted line can optionally represent a further C-C bond ■ and the wavy line means that the respective substituent can be bound to the carbon atom in either of the two steric pos tions, furthermore their pharmaceutically accaptable acid- addition salts. 2. A compound selected from the group consisting of (±)endo-4-propionyloxy-6-(4-fluorphenyl)-l-azabicyclo- [3.3.1]non-6-ene, (+)endo-4-propionyloxy-6-(4-fluorophenyl)-l-azabicyclo- [3.3.1]non-6-ene, (-)endo-4-propionyloxy-6-(4-fluorophenyl)-1-azabicyclo- [3.3.1]non-6-ene, (±)endo-4-acetoxy-6-(4-chlorophenyl)-1-azabicyclo- [3.3.1]non-6-ene, (±)endo-4-hydroxy-6-(4-fluorphenyl)-1-azabicyclo- [3.3.1]non-6-ene, (±)endo-4-acetoxy-6-phenyl-l-azabicyclo[3.3.1]non-6-ene and (±)endo-4-hydroxy-6-(exo)-phenyl-l-azabicyclo[3.3.l]nonane and their acid addition salts. 3. A pharmaceutical composition which comprises as active ingredient an 1-azabicycloalkane derivative of the general formula (I), wherein R 1 , R , R 3 , n, the dotted and wavy lines are as defined in claim 1, or pharmaceutically acceptable acid-addition salts thereof in admixture with carrier(s) and/or additive(s) usually applied in drug manufacturing. 4. A process for preparing new 1-azabicycloalkane derivatives and their stereoisomers of the general formula (I), wherein R 1 represents a phenyl, substituted phenyl, naphthyl or thienyl group, wherein the phenyl group can be substituted by one or several halogen atom(s) , methyl, methoxy, methylthio or trifluoromethyl group(s), R 2 represents a hydrogen atom or a C2-5 aliphatic acyl group, R 3 represents a hydrogen atom or a methyl group, n can be zero or one, the dotted line can optionally represent a further C-C bond and the wavy line means that the respective substituent can be bound to the carbon atom in either of the two steric pos tions, furthermore their pharmaceutically accaptable acid- addition salts, which comprises submitting a 1,2,3,6- -tetrahydropyridine derivative of the general formula (II) or a piperidinol derivative of the general formula (III) 0R 5 wherein R 1 , R 3 and n are as defined above, R 4 and R 5 represent a C^_ 4 alkyl group, or together they stand for a C2-3 alkylene group, to acid catalyzed ring closure, then, if desired, the resulting compound of the general formula (I) , wherein R 1 , R 3 and n are as defined above and R 2 represents a hydrogen atom, is acylated and/or the double bond is saturated and/or the obtained compound of the general formula (I) , wherein R 1 and n have the same meanin as above and R 2 and R 3 represent hydrogen atoms, is isomerized under acidic conditions and/or, if desired, the obtained compound of the general formula (I) , wherein R 1 , R 2 , R 3 and n have the same meaning as above, is resolved and/or converted to an acid-addition salt. 5. A process as claimed in claim 4 which comprises performing the acid-catalyzed ring closure with an aqueous mineral acid, preferably hydrochloric acid. 6. A process as claimed in claim 4 or 5 which comprises carrying out the ring closure in a temperature range of 20 to 120 °C. 7. A process for preparing a pharmaceutical compositi having mainly antiamnesic activity, which comprises trans¬ forming the compound of the general formula (I), wherein R 1 R 2 , R 3 , n, the dotted and wavy lines are as defined in clai 1, prepared by the process of claim 10, or a pharmaceutically acceptable acid-addition salts thereof to pharmaceutical composition by admixing it with carrier(s) and additive(s) usually applied in drug manufacturing.

Inventors: ABRAHAM GIZELLA, BORSI JOZSEF, CSUZDI EMESE, GOLDSCHMIDTNE HORVATH KATALIN, KARIMNE TAPFER MARIANN, LING ISTVAN, MATE GYOERGYNE, MIKLOSNE KOVACS ANIKO, SOLYOM SANDOR, SZABONE BADY ERZSEBET, SZOELOESSY MARTA, VITALIS BEATA, ABRAHAM, GIZELLA, BORSI, JOZSEF, CSUZDI, EMESE, GOLDSCHMIDTNE HORVATH, KATALIN, KARIMNE TAPFER, MARIANN, LING, ISTVAN, MATE, GYOERGYNE, MIKLOSNE KOVACS, ANIKO, SOLYOM, SANDOR, SZABONE BADY, ERZSEBET, SZOELOESSY, MARTA, VITALIS, BEATA
Applicants: GYOGYSZERKUTATO INTEZET, GYOGYSZERKUTATO INTEZET KV.
Application year: 1991
Main classification: C07D487
IPC codes: A61K31, C07D471