CZ75293A3 - 1-azabicycloalkane derivatives, process of their preparation and pharmaceutical preparations based thereon - Google Patents

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

(57) Azabicycloalkane derivatives and their stereoisomers of formula (I) wherein R ^{* 1} is phenyl substituted phenyl, naphthyl or thienyl, wherein the phenyl is optionally substituted by one or more halogen, methyl, methoxy, methylthio or trifluoromethyl, R ² , R ² , R ² or R ² or an aliphatic acyl group having 2 to 5 carbon atoms, R ³ is a hydrogen atom or a methyl group, n is an integer of 0 or 1, the dashed line shows the optional carbon-carbon bond present and the wavy line indicates that the substituent may be bonded to and any pharmaceutically acceptable acid addition salts thereof have valuable therapeutic, particularly antiamnesic, activity. Also described are methods of making these compounds and pharmaceutical compositions based thereon.

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The invention relates to 1-azabicycloalkane derivatives, to processes for their preparation and to pharmaceutical preparations based thereon. These compounds are novel and have not been described in the literature.

BACKGROUND OF THE INVENTION

In their structure, the compounds of the invention most closely resemble the 1-azabicyclo [3.3.1] non-6-ene derivatives disclosed in Japanese Patent Applications Nos. 75/49297 and 75/53518 (Kokai) as well as in Chem. Pharm. Bull. 24, 515 (1976) and Synthesis 440 (1975). Some of these compounds have an analgesic effect. 1-Azabicycloalkane derivatives as described in European patent applications no.

742, 94 744 and 239 321 contain benzamido substituents or benzamidoalkyl substituents and are 5HT receptor receptor antagonists.

European Patent Applications Nos. 257 741, 261 763 and 287 356 disclose 1-azabicycloalkane derivatives containing substituents at the 1,3-positions relative to the nitrogen atom, the latter being typically an acidic functional group or a heterocycle. According to the literature, these compounds exhibit muscarinic agonist activity and are useful for improving cholinergic functions.

One approach to the treatment of Alzheimer's type of dementia in the elderly is the attempt to stimulate a decreased cholinergic in various ways. neurotransmission by administering agonists to cholinergic receptors. Agonists that selectively bind to the muscarinic receptors M &lt; 4 &gt; seem to be suitable for this purpose [Science 217, 408 (1982); Drug Dev. Res. 5, 77 (1985); Neuropharmacol. 9, 53 (1986)].

Problems with absorption, selectivity and rapid metabolism have been reported with some muscarinic agonist compounds known in the literature.

As a result, no drug has been marketed in this field yet.

SUMMARY OF THE INVENTION

It has now surprisingly been found that the compounds of the invention bind to muscarinic receptors and, even in small doses, inhibit scopolamine-induced amnesia in rats. Thus, they are potential agents for the treatment of dementia or dementia of the Alzheimer type, especially in the elderly.

The present invention relates to 1-azabicycloalkane derivatives and their stereoisomers of formula (I)

where

R ¹ is phenyl, substituted phenyl, naphthyl or thienyl, wherein the phenyl is optionally substituted with one or more halogen, methyl, methoxy, methylthio or trifluoromethyl,

R represents a hydrogen atom or an aliphatic acyl group containing 2 to 5 carbon atoms,

R ³ is hydrogen or methyl, n is 0 or 1, the dashed line shows the optional carbon-carbon bond present, and the wavy line indicates that the substituent may be bonded to the carbon atom at any of two possible steric positions, and their pharmaceutically acceptable acid addition salts.

The compounds of formula I according to the invention have an asymmetric structure and all possible stereoisomers are defined by formula I. General formula la

it clearly shows the structure of those compounds of formula I wherein n is 1. The range of compounds of formula I is not limited to the enantiomers represented by formula Ia.

In the nomenclature of the compounds of formula I, the substituents R ² and R ³ 0 endo position when located in opposite position with respect to the methylene bridge with respect to the plane defined by the two bridgehead atoms and forming carbon atom bonded to the respective substituent. Accordingly, a substituent oriented in the same way as a methylene bridge is referred to as an exo substituent.

Of the compounds of formula I, the following are particularly preferred:

(±) endo-4-propionyloxy-6- (4-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride;

(+) endo-4-propionyloxy-6- (4-fluorophenyl) -1-azabicyclo [3.3.1.] non-6-ene hydrochloride;

(-) endo-4-propionyloxy-6- (4-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride;

(±) endo-4-acetoxy-6- (4-chlorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride;

(±) endo-4-hydroxy-6- (4-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride;

(±) endo-4-acetoxy-6-phenyl-1-azabicyclo [3.3.1] non-6-ene hydrochloride and (±) endo-4-hydroxy-6 (exo) -phenyl-1-azabicyclo [3.3] hydrochloride .1] nonane.

The present invention also provides a process for the preparation of 1-azabicycloalkane derivatives and their stereoisomers of formula (I)

rn <(CH ₂ ) _n ch ₂ (I) where

R ¹ is phenyl, substituted phenyl, naphthyl or thienyl, wherein the phenyl is optionally substituted with one or more halogen, methyl, methoxy, methylthio or trifluoromethyl,

R represents a hydrogen atom or an aliphatic acyl group containing 2 to 5 carbon atoms,

R ³ is hydrogen or methyl, n is 0 or 1, the dashed line shows the optional carbon-carbon bond present, and the wavy line indicates that the substituent may be bonded to the carbon atom at any of two possible steric positions, and also their pharmaceutically acceptable acid addition salts, characterized in that the 1,2,3,6-tetrahydropyridine derivatives of the general formula II or the piperidinol derivatives of the general formula III

^O R4-C- ^(C H ₂₎ - ^CH 2 OR ₅

Ri (II)

OH (III), R ₄ OC-ICH ₂₎ -CH ₂ OR ₅ wherein R ^1, R ^{3 and} n are as defined above, R ⁴ and R ⁵ are each alkyl having 1-4 carbon atoms or taken together are alkylene having from 2 to The compounds of the formula I, in which R @ ¹ , R @ ³ and n are as defined above and R @ ² represents a hydrogen atom, are acylated and / or saturated with a double bond and / or are saturated by an acid catalysed reaction. optionally resulting compounds of formula I wherein R 1 and n are as defined above and R ² and R ³ are each hydrogen are isomerized under acidic conditions and / or optionally obtained compounds of formula I wherein R ¹ , R ² , R ³ and ^{n are} are as defined above, subjected to optical resolution and / or converted to acid addition salts.

In a preferred embodiment of the process of the invention, the 1-alkyl-4-aryl-1,2,3,6-tetrahydropyridine derivative of the general formula II, wherein R ¹ , R ³ , R ⁴ , R ⁵ and n are as defined above, is heated in aqueous hydrochloric acid and then the resulting reaction mixture is evaporated and the resulting crystalline 1-azabicycloalkene derivative is isolated as the hydrochloride salt. The ring closure can also be carried out using another mineral acid, such as aqueous sulfuric acid. The reaction may preferably be carried out in a temperature range of 20 to 120 ° C. When sulfuric acid is used, the resulting reaction mixture is preferably treated with water and subsequent alkalinization, and the product is extracted with an organic solvent in the form of a base.

In another preferred embodiment of the process of the invention, the 1-alkyl-4-aryl-4-hydroxypiperidine derivative of formula III wherein R ¹ , R ³ , R ⁴ , R ⁵ and n are as hereinbefore defined is heated in a solution of aqueous hydrochloric acid or acid. sulfuric. The reaction mixtures are preferably worked up as described above.

The hydroxyl groups in the compounds of formula I obtained in the ring closure reactions of this invention have an endo (equatorial) position. Isomers that contain a hydroxy group in the exo (axial) position are formed only in minor amounts and can be detected in the recrystallization mother liquors. The compounds of the formula I, in which R @ ² and R @ ³ are each hydrogen and in which the hydroxy group is located in the endo position, can be isomerized by treatment with an acid, preferably aqueous perchloric acid. The resulting mixture of endo- and exo-hydroxy compounds can be resolved either in this form or after esterification by known methods.

If desired, the hydroxy group in the compounds of formula I obtained by the ring closure reaction can be esterified with an aliphatic carboxylic acid anhydride of 2 to 5 carbon atoms or the corresponding acyl chloride. This reaction is preferably carried out in the presence of an acid binding agent such as pyridine. The double bond may preferably be saturated by catalytic hydrogenation.

The compounds of the invention obtained by the ring closure reaction are racemate in nature. If desired, the racemate can be resolved by separating the diastereomeric pair formed with an optically active acid, after which the optically active base of Formula I is liberated from the corresponding diasteromeric salt by treatment with alkali. camphenesulfonic acid or amino acids. Preferably, camphensulfonic acid and tartaric acid mono-4-chloroanilide are used. The pairs of diastereomeric salts are preferably separated by crystallization.

For therapeutic purposes, it is preferable to prepare acid addition salts thereof from the compounds of formula (I). In addition to the above-mentioned hydrochloric acid, all organic or inorganic acids which are suitable for therapeutic use, such as oxalic acid, fumaric acid, malonic acid, methanesulfonic acid, sulfuric acid, phosphoric acid etc. are suitable for this purpose.

The preparation of the starting compounds of the general formula (II) used in the process according to the invention is described in the following examples. The compounds of formula (II), the preparation of which is not described in the examples, can be prepared from the corresponding 4-aryl-substituted-1,2,3,6-tetrahydropyridines by methods analogous to those described in the examples. The resulting compounds of the general formula (II) are generally oils which can be used directly in the process according to the invention.

The compounds of the formula III according to the invention are novel. They can be prepared by the methods described in the respective examples.

Known derivatives of 4-arylsubstituted 1,2,3,6-tetrahydropyridine which are used for the preparation of the compounds of the formulas II and III are inter alia: described in British Patent Publication No. 881,893, Dutch Patent Publication No. 6,510,107, and U.S. Patent Publication No. 6,980,519. No. 2,973,363 and CS Patent Publication No. 218,028. The preparation of the unknown 4-aryl-substituted 1,2,3,6-tetrahydropyridine derivatives is described in the respective examples.

Compounds of formula I according to the invention were studied by the test of binding to muscarinic receptors, using tritiated chinuklidinylbenzoátu ^[(3H) -QNB] as the ligand further potentiation of oxotremorine trials and tests with the amnesia induced by scopolamine.

( ³ H) -QNB Receptor Binding Assay

A membrane preparation of cortex cerebri of a male OFA rat weighing 180-250 g is made by the Yamamura Snyder method [Proc. Nati. Acad. Sci. USA 71, 1725 (1974)], modified by Hershkowitz et al. [Eur. J. Pharmacol. 86, 229 (1983)]. Proteins were determined by the Peterson method [Anal. Biochem. 83, 346 (1977)]. The 0.2 mg / ml protein is incubated in the presence of 0.2 nm ( ³ H) -QNB (44 Ci / mmol, Amersham) and the test compound (at eight different concentrations ranging from 0.1 to 300 μΜ) in total volume of 1 ml of 50 nM TRIS-HCl buffer (pH 7.4) at 25 ° C for 60 minutes. The reaction is stopped by adding 5 ml of ice-cold buffer solution and the reaction mixture is filtered through a Whatman GF / B filter under reduced pressure. The filter was washed twice with an equal volume of buffer solution. Non-specific binding is determined in the presence of ΙμΜ concentrations of atropine. All determinations are performed in triplicate. Bound radioactivity is determined in a toluene cocktail using Packard liquid scintillation spectrometry. IC ₅₀ values are obtained by linear regression analysis and the dissociation constant (K _D ) is calculated

Scatchard analysis.

Oxotremorine potentiation assay

Rathbun and Slater's methods [Psychopharmacology

4, 114 (1963)], modified by Ogren et al. [Psychopharmacology 86, 258 (1985)]. Groups of mice (5-15 mice per dose) are administered ip at 1, 3 and 10 mg / kg followed by 3, 10 and 30 mg / kg of the test compound. Treatment is performed 15 minutes prior to administration of oxotremorine, which is then administered at a dose of 0.125 mg / kg (ED ₁₆ ). In a semi-quantitative manner, the intensity of tremor and hypersalivation was evaluated in comparison with control groups of mice. The dose of the test compound inducing a 50% effect (minimum effective dose) is determined.

Test in rats with scopolamine-induced amnesia

The assay is carried out in a Skinner box on naive male rats - OFA weighing 100-120 g as described by Cumin et al. [Psychopharmacology 78, 104 (1982)]. The animals are placed in a box where they receive an electrical shock of 0.8 mA. This shock can be avoided if they remain on a plastic plate placed on a grid that is under power. In this way, the animals develop a passive avoidance reflex. After three consecutive trainings, rats are selected for the test and remain on the plastic plate for 1 minute without entering the grid. Groups are formed from these rats to give the following treatment:

control group I: control group II: test group:

solvent i.p. and p.o. scopolamine i.p. scopolamine i.p. + test compound

Treatment with the test compound is performed immediately after the last workout. After two hours, the animals are repeatedly placed on a plastic plate and the number of animals remaining on it for 1 minute, ie the number of animals with improved memory, is determined. Statistical evaluation is performed with probe X ² . The results are shown in Table 1.

Table 1

Compound of Example no. ( ³ H) -QNM Receptor Binding _Assay [50 _5θ (μΜ) Potentiation value of oxotremorine in mice the minimum effective dose [mg / kg] i.p. after. 2 1.6 > 10 > 10 4 2.3 3 3 9 29.5 0.3 1 32 0.5 10 30 59 1,8 3 10 60 1,8 10 10 61 15.4 10 > 10 64 30.5 10 > 30 67 1.1 10 30 68 2,0 10 > 30 oxotremorin 0.8 - - arecholine 6.3 3 > 30

Table 1 - continued

Compound from the rat test of Example No. 2 with scopolamine-induced amnesia, minimum effective dose [mg / kg] p.o.

acute toxicity in mice

LD ₅₀ [mg / kg]

i.p. after.

2 0.62 3-100 30-100 4 0.62 39 87 9 0.62 20 May 60 32 0.16 <- 53.8 114.5 59 0.62 29 49 60 > 2,5 30-100 > 100 61 > 2,5 30-100 > 100 64 0.31 30-100 > 100 67 0.04 30-100 > 100 68 0.16 30-100 > 100 oxotremorin 0.1 - - arecholine > 20 - -

The data presented in Table 1 show that the compounds of the invention exhibit significant pharmacological effects and are capable of exerting central cholinergic activity when administered both parenterally and orally.

The compounds of the invention and their pharmaceutically acceptable acid addition salts can be formulated into pharmaceutical compositions. The pharmaceutical preparations may take the form of tablets, coated tablets, powders, granules or capsules, or they may be in liquid form, such as in the form of solutions or suspensions, and in the form of sterile solutions or suspensions suitable for parenteral administration.

In the manufacture of oral preparations, lactose or starch, as binders or granulating agents of gelatin, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or starch resin, as disintegrating agents of potato starch or microcrystalline cellulose, and as antiadhesives of talc, colloidal silicic acid, stearin, etc. can be used as vehicles. Tablets which are manufactured in a manner known per se may optionally contain conventional protective coatings with the addition of flavoring and coloring agents, as is conventionally used in pharmaceutical manufacture. In the case of capsules, the mixture of active ingredients and excipients is filled into suitable capsules.

Liquid oral preparations are prepared in the form of solutions, syrups or dry substances which are mixed with water or some other carrier before immediate use.

For parenteral administration, the active ingredient is formulated as a sterile solution or suspension, wherein the sterile vehicle may contain additional adjuvants such as anesthetics or stabilizers and buffers.

The invention is illustrated by the following examples. These examples are illustrative only, and are not intended to limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

(±) Endo-4-hydroxy-6-phenyl-1-azabicyclo [3.3.1] non-6-ene hydrochloride

Method A

14.2 g (54.8 mmol) of 1- [3,3- (ethylenedioxy) propyl] -4-phenyl-1,2,3,6-tetrahydropyridine, isolated as a crude product, are dissolved in 70 ml of concentrated hydrochloric acid and the resulting solution was refluxed for 4 hours. The reaction mixture was evaporated to dryness, acetone containing 5-10% isopropanol was added to the residue, and the resulting crystalline product was filtered off (9.35 g). Recrystallization from ethanol gave 8.06 g of product, m.p. 263-264 ° C.

Method B

1.00 g (3.6 mmol) of 1- [3,3- (ethylenedioxy) propyl] -4-phenyl-4-hydroxypiperidine was refluxed in 10 ml of a 2: 1 mixture of concentrated hydrochloric acid and water for 3 hours. The reaction mixture was evaporated, acetone was added to the residue and the resulting product was filtered off (yield: 0.88 g; mp: 256-257 ° C). After recrystallization, the melting point of the product rose to 263 ° C. The product obtained is identical to the compound synthesized according to Method A.

The starting material used was prepared by the reaction of 1.71 g (9.7 mmol).

4-phenyl-4-hydroxypiperidine [B.G. Boggiano et al., J. Chem. Soc. (1959), 1143] with 2.00 g (11 mmol) of 2- (2-bromoethyl) -1,3-dioxolane in 20 mL of dimethylformamide at 80 ° C, in the presence of 2.06 g of sodium carbonate as the acid-binding agent. After 90 minutes, the reaction mixture was poured into water and the product was extracted with ethyl acetate. The extract was evaporated and the residue (3.1 g of oil) was recrystallized under cooling. After mixing with diisopropyl ether, 1.56 g of 1- [3,3 (ethylenedioxy) propyl] -4-phenyl-4-hydroxypiperidine are obtained, m.p. 84-86 ° C.

Example 2

(±) Endo-4-acetoxy-6-phenyl-1-azabicyclo [3.3.1] non-6-ene hydrochloride

1.76 g (7 mmol) of the compound of Example 1 were dissolved in a mixture of 3 ml of pyridine, 5 ml of dichloroethane and 2 ml of acetic anhydride and the mixture was refluxed for 7 hours. The mixture was evaporated and the residue was dissolved in a mixture of aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, dried and evaporated. A mixture of hydrochloric acid in isopropyl alcohol and ether was added to the residue to give 1.62 g of the corresponding hydrochloride. Recrystallization from methyl ethyl ketone gives 1.1 g of product, m.p. 274 DEG-276 DEG C. (transformation to 216 DEG C.).

Example 3

(±) Endo-4-hydroxy-6- (4-chlorophenyl-1-azabicyclo [3.3.1] non-6-ene hydrochloride)

Method A

15.60 g (53 mmol) of 1- [3,3- (ethylenedioxy) propyl] -4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine are refluxed in 120 ml of 1: 1 concentrated hydrochloric acid. and water for 6 hours. The reaction mixture was evaporated to dryness to give

13.6 g of crystalline product, from which 10.4 g of the final product are obtained after recrystallization from ethanol, m.p. 291-293 ° C.

Method B

10 g (32 mmol) of 1- [3,3- (ethylenedioxy) propyl] -4- (4-chlorophenyl) -4-hydroxypiperidine were refluxed in 100 ml of 24% hydrochloric acid for 4 hours and then the mixture was reduced under reduced pressure. pressure evaporates. Acetone was added to the residue and the product was filtered off. 7 g of product are obtained, which is recrystallized from 150 ml of ethanol. Yield: 5.8 g. M.p. 290-292 ° C.

The starting material used in this method was prepared by reacting 4.49 g (16.5 mmol) of 4- (4-chlorophenyl) -4-hydroxypiperidine (CA 98, 160.556) in 25 ml of pre-distilled dimethylformamide with 3.6 g (2.33). ml, 20 mmol) of 2- (2-bromoethyl) -1,3-dioxolane in the presence of 2.12 g (20 mmol) of sodium carbonate, at 90-100 ° C. The reaction is carried out for 3 hours, then cooled, diluted with 74 ml of water, stirred for 1 hour and the precipitated substance is filtered off (yield: 3.28 g). This product is recrystallized from 30 ml of isopropanol to give 2. 33 g of product, m.p. 134-136 ° C.

Example 4

(±) Endo-4-acetoxy-6- (4-chlorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

5.0 g (17.5 mmol) of the product prepared as described in Example 3 were acetylated as described in Example 2.

The crude product (4.8 g) obtained in this analogous manner was recrystallized from ethanol. 4.2 g of the title compound of melting point 276 DEG-278 DEG C. (after rearrangement at about 220 DEG C.) are obtained.

AND

- 17 Example 5

(±) Endo-4-hydroxy-6- (3-chlorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

10.1 g (43.8 mmol) of 4- (3-chlorophenyl) 1,2,3,6-tetrahydropyridine hydrochloride in 80 ml of dimethylformamide were treated with 10.0 g (54 mmol) in the presence of 11.6 g of sodium carbonate. 2- (2-bromoethyl) -1,3-dioxolane at 80 ° C for 10 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated. 14.8 g of crude 1- [3,3- (ethylenedioxy) propyl] -4- (3-chlorophenyl) -1,2,3,6-tetrahydropyridine are obtained. This product was reacted as described in Example 3. Treatment of the reaction mixture yielded 5.84 g of crude product which was recrystallized from ethanol. 5.2 g of the final product are obtained, 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) -lazabicyclo [3.3.1] non-6-en-4 (endo) ol (B)

6.64 g (21.5 mmol) of [3,3- (ethylenedioxy) butyl] -4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine are dissolved in 26 ml of 85% sulfuric acid and the resulting solution is allowed to stand at room temperature for 10 days. The reaction mixture was poured into ice water and adjusted to pH 9. The precipitated product was extracted with ethyl acetate, the organic layer was washed with 10% sodium chloride solution, dried and evaporated. Recrystallization of the crystalline residue obtained from 55 ml of ethyl acetate gave 2.81 g of product A, m.p. 191-192 ° C.

The mother liquor obtained by filtration of product A is evaporated and 2.0 g of the residue obtained is flash chromatographed using a chloroform / methanol (8: 2) mixture containing 1 drop of triethylamine for every 20 ml of this mixture. Fractions with _Rf value = 0.8 were combined and evaporated. 0.8 g of crystalline 1- (3-oxobutyl) -4- (4-chlorophenyl) 1,2,3,6-tetrahydropyridine (having a melting point of 96 DEG-97 DEG C. after recrystallization from isopropyl ether) is obtained. The elution was continued and the uniform fractions having _Rf value of 0.2 to 0.3 is evaporated. 0.44 g of product B is obtained. Recrystallization is induced by scraping against the walls. After recrystallization from ethyl acetate, the product has a melting point of 132-133 ° C.

Example 7 (±) endo-4-methyl-6-phenyl-1-azabicyclo [3.3.1] non-6-en4 (exo) ol (A) and (±) exo-4-methyl-6-phenyl-1 -azabicyclo [3.3.1] non-6-en-4 (endo) ol (B)

13.19 g (67.4 mmol) of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride in 110 ml of dimethylformamide is reacted in the presence of 17.8 g of sodium carbonate with 15.8 g (80.8 mmol) of 2- (2-bromoethyl) -2-methyl-1,3-dioxolane at 70 ° C for 24 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The extract was evaporated to give crude oily 1- (3,3- (ethylenedioxy) butyl] 4-phenyl-1,2,3,6-tetrahydropyridine, 10 g of this product was added dropwise to 50 ml of 85% sulfuric acid with stirring. 90 DEG C. After 24 hours of reaction time, the mixture is poured into water and the pH of the mixture is adjusted to 9. The product is extracted with ethyl acetate and the organic layer is washed and evaporated. The resulting residue is mixed with isopropyl ether and the crystalline product formed is filtered. Recrystallization of 2.3 g of crude product from ethyl acetate gave 2.0 g of product A, m.p. 179-182 ° C.

The mother liquor obtained by filtration of product A was evaporated and 4.3 g of the resulting oily residue were subjected to flash chromatography using the mixture described in Example 6 as eluent. Evaporation uniform fractions having _Rf value of about 0.6, 0.46 g of oily (±) 4-methyl-6-phenyl-l-azabicyclo [3.3.l] nona-3,6-diene (the hydrochloride of m.p. Mp 194-196 ° C). The elution was continued and the fractions having _Rf value of about 0.2 is evaporated. The crystalline residue is recrystallized from isopropyl alcohol to give 0.28 g of product B, m.p. 160-161 ° C.

Example 8

1/2 (±) endo-4-hydroxy-6- (3-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene fumarate

2.7 g (12.6 mmol) of 4- (3-fluorophenyl) 1,2,3,6-tetrahydropyridine hydrochloride in 25 ml of dimethylformamide are reacted in the presence of 3.05 g of sodium carbonate with 2.77 g (15, 3 mmol) 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 was washed, dried and evaporated to give 3.4 g of crude 1- [3,3- (ethylenedioxy) propyl] -4- (3-fluorophenyl) -1,2,3,6-tetrahydropyridine which was then refluxed for 1 hour in 50 ml of a 2: 1 mixture of concentrated hydrochloric acid and water. The reaction mixture was evaporated to dryness, the oily residue was dissolved in water and neutralized with sodium bicarbonate solution. The product was extracted with ethyl acetate and the organic layer was dried and evaporated. 1.76 g of the residue obtained are dissolved in 20 ml of ethanol and 0.88 g of fumaric acid dissolved in 40 ml of ethanol is added. The resulting solution is evaporated to dryness and the residue is recrystallized from 80 ml of isopropyl alcohol. To give L / ⁵⁵ 9 of the desired product, mp 193-195 ° C.

Example 9

(±) Endo-4-hydroxy-6- (4-fluorophenyl) -1-azabicyclo (3.3.1) non-6-ene hydrochloride

Method A

As described in Example 1, from 4.8 g (17.3 mmol),

Of 1- [3,3- (ethylenedioxy) propyl] -4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine, 2.9 g of crude product are obtained, after recrystallization from ethanol, 2.50 g of product are obtained. mp 216-218 ° C.

Method B

26.58 g (90 mmol) of 1- [3,3- (ethylenedioxy) propyl] -4- (4-fluorophenyl) -4-hydroxypiperidine were heated with 130 ml of 24% hydrochloric acid at 70 ° C for 30 minutes. The resulting mixture was evaporated under reduced pressure and the residue was recrystallized from isopropyl alcohol. Yield: 20.77 g of product, m.p. 213 DEG-218 DEG.

The starting material for the above process was prepared by refluxing 30.1 g (130 mmol) of 4- (4-fluorophenyl) -4-hydroxypiperidine hydrochloride (see Dutch Patent No. 6,510,107;

C.A. 65, P 7154 e) in anhydrous acetone, in the presence of 37.3 g of potassium carbonate, with 24.70 (136.5 mmol) of 2- (2-bromoethyl) -1,3-dioxolane. The precipitated salt is filtered off, the filtrate is evaporated and the residue is recrystallized from isopropanol. 27.43 g of 1- [3,3- (ethylenedioxy) propyl] -4- (4-fluorophenyl) -4-hydroxypiperidine, m.p. 110 DEG-112 DEG C., are obtained.

Example 10

(±) Endo-4-acetoxy-6- (4-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

2.0 g of the product produced in Example 9 were acetylated as described in Example 2. Recrystallization from isopropyl alcohol gave 1.93 g of product which was rearranged at 264-268 ° C and had a final melting point of 280 ° C.

Example 11

(±) Endo-4-hydroxy-6- (2-methylphenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

3.46 g (16.5 mmol) of 4- (2-methylphenyl) 1,2,3,6-tetrahydropyridine hydrochloride in 25 ml of dimethylformamide were treated with 3.6 g (19.9 mmol) in the presence of 4 g of sodium carbonate. 2- (2-bromoethyl) -1,3-dioxolane at 90 ° C for 3 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was washed, dried and evaporated. 5.2 g of crude 1- [3,3- (ethylenedioxy) propyl] -4- (2-methylphenyl) -1,2,3,6-tetrahydropyridine are obtained, which is then refluxed in 60 ml of a 2: 1 mixture. concentrated hydrochloric acid and water for 1 hour. The product obtained after evaporation of the reaction mixture is recrystallized from ethanol. The product (1.9 g) has a melting point of 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 mmol) of the product obtained in Example 11 are acetylated as described in Example 2. The crude product which is isolated as a base is converted by treatment with hydrochloric acid in isopropanol and ether into 1 g of hydrochloride, from which recrystallization from 20 ml of isopropyl alcohol gave 0.7 g of product, m.p. 222-223 ° C.

Example 13

(±) Endo-4-hydroxy-6- (3-methylphenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

9.0 g (43 mmol) of 4- (3-methylphenyl) 1,2,3,6-tetrahydropyridine hydrochloride in 50 ml of dimethylformamide are reacted in the presence of 13.8 g of potassium carbonate with 9.05 g (50 mmol) of 2. - (2-bromoethyl) -1,3-dioxolane at 70 ° C for 2.5 hours. The reaction mixture was poured into water and the product was extracted with methylene chloride. The organic layer was washed, dried and evaporated. Crude 1- [3,3- (ethylenedioxy) propyl] -4- (3-methylphenyl) -1,2,3,6-tetrahydropyridine is obtained, which is dissolved in 60 ml of a 2: 1 mixture of concentrated hydrochloric acid and water. . The mixture was stirred at 60 ° C for 2 hours and then evaporated to dryness. Isopropyl alcohol is added to the residue and the resulting crystals are filtered off. 8.51 g of product, m.p. 227 DEG-230 DEG C., are obtained.

Example 14

(±) endo-4-acetoxy-6- (3-methylphenyl) -1-azabicyclo [3.3.1] non-6-ene fumarate

From the product prepared according to Example 13, the base is obtained by treatment with potassium hydroxide. 2.52 g (11 mmol) of this base were dissolved in 25 ml of pyridine and treated with 1.57 g (20 mmol) of acetyl chloride at 25 ° C for 3 hours. The reaction mixture was worked up as described in Example 2, and the residue was dissolved in ethanol and fumaric acid was added. The resulting salt is recrystallized from isopropyl alcohol. Yield: 2.20 g, m.p. 155-159 ° C.

Example 15

(±) Endo-4-hydroxy-6- (4-methylthiophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

1.0 g (3.3 mmol) of 1- [3,3- (ethylenedioxy) propyl] -4 (methylthiophenyl) -1,2,3,6-tetrahydropyridine was refluxed in 15 ml of concentrated acid for 4 hours. hydrochloric acid and water (2: 1). The resulting reaction mixture was evaporated to dryness and the crude product (0.6 g) thus obtained was recrystallized from ethanol. 0.4 g of product is obtained, m.p. 222-225 ° C.

1- [3,3- (ethylenedioxy) propyl] -4- (4-methylthiophenyl) 1,2,3,6-tetrahydropyridine, which serves as the starting material for this example, was prepared as follows:

A Grignard reagent was prepared from 0.64 g (0.026 mol) of magnesium and 5.07 g (26 mmol) of 4-bromothioanisole in 15 ml of tetrahydrofuran, and a solution of 3 g (17.5 mmol) was added thereto at 0-10 ° C. -ethoxycarbonyl-4-piperidone in 10 mL of tetrahydrofuran. The mixture was stirred overnight at room temperature and then quenched by the addition of 20 mL of 10% ammonium chloride solution in ice water. The reaction mixture was extracted with ethyl acetate and the organic layer was dried and evaporated. The residue, 5.4 g of crude 1-ethoxycarbonyl-4- (424 methylthiophenyl) -4-hydroxypiperidine, was refluxed with 3 g of potassium hydroxide in 25 ml of isopropanol for 3 days. The mixture was evaporated, the residue was dissolved in water and extracted with ethyl acetate. The organic layer was evaporated and to the residue was added hydrochloric acid in ether. 1.5 g of hydrochloride are obtained, which is recrystallized from 40 ml of isopropyl alcohol. There was thus obtained 4- (4-methylthiophenyl) -4-hydroxypiperidine hydrochloride (0.9 g), m.p. 188-190 ° C.

0.5 g (2 mmol) of 4- (4-methylthiophenyl) -4-hydroxypiperidine hydrochloride was refluxed with 3 ml of a 2: 1 mixture of concentrated hydrochloric acid and water. The reaction mixture is evaporated to dryness and the residue is recrystallized from 30 ml of ethanol. 0.2 g of 4- (4-methylthiophenyl) -1,2,3,6-tetrahydropyridine hydrochloride is obtained, m.p. 255-256 ° C.

1.63 g (6.74 mmol) of 4- (4-methylthiophenyl) 1,2,3,6-tetrahydropyridine hydrochloride in 20 ml of dimethylformamide are reacted in the presence of 1.43 g of sodium carbonate with 1.46 g of (8, 1 mmol) of 2- (2-bromomethyl) -1,3-dioxolane at 90 ° C for 3 hours. The reaction mixture is poured into water, the precipitated substance is filtered off and 1.2 g of the crude product thus obtained are recrystallized from 25 ml of isopropyl alcohol. 1.0 g of 1- [3,3- (ethylenedioxy) propyl] -4- (4-methylthiophenyl) -1,2,3,6-tetrahydropyridine is obtained, m.p. 98-99 ° C.

Example 16

(±) Endo-4-hydroxy-6- (3-trifluoromethylphenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

3.8 g (14.4 mmol) of 4- (3-trifluoromethyl25-phenyl) -1,2,3,6-tetrahydropyridine hydrochloride in 30 ml of dimethylformamide are reacted in the presence of 3.8 g of sodium carbonate with 3.13 g ( 17.2 mmol) of 2- (2-bromoethyl) -1,3-dioxolane at 60 ° C for 6 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was washed, dried and evaporated. The remaining crude 1- [3,3- (ethylenedioxy) propyl] -4 (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine was heated to reflux in a mixture of 60 ml concentrated hydrochloric acid and water (2: 1). ) for 2 hours. The reaction mixture was evaporated to dryness, acetone was added to the residue and the resulting crystals were filtered off. 1.38 g of product are obtained, after recrystallization from isopropyl alcohol, 1.24 g of the title compound of melting point 230 DEG-233 DEG C. are obtained, after rearrangement at 217 DEG-220 DEG.

Example 17

(±) Endo-4-hydroxy-6- (4-trifluoromethylphenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

4.48 g (17 mmol) of 4- (4-trifluoromethylphenyl) 1,2,3,6-tetrahydropyridine hydrochloride was treated with 2- (2-bromoethyl) -1,3-dioxolane as described in Example 13.

The reaction mixture is diluted with 250 ml of water and the precipitated crystals of 1- [3,3- (ethylenedioxy) propyl] -4- (4-trifluoromethylphenyl) 1,2,3,6-tetrahydropyridine are filtered off (4.60 g, m.p. 106). to 109 ° C) and stirred in 20 mL of concentrated hydrochloric acid / water (2: 1) for 3 hours at 60 ° C. The reaction mixture was evaporated and the residue was recrystallized from ethanol. 3.07 g of product are obtained, 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 mmol) of 1- [3,3- (ethylenedioxy) propyl] -4-hydroxy-4- (2-methoxyphenyl) piperidine are dissolved in 40 ml of a 2: 1 mixture of concentrated hydrochloric acid and water. The mixture was stirred at room temperature for 4 hours. Then the reaction mixture is evaporated to dryness and the residue is recrystallized from ethanol. 4.20 g of product are obtained, m.p. 263-268 ° C.

1- [3,3- (ethylenedioxy) propyl] -4-hydroxy-4- (2-methoxyphenyl) piperidine, which serves as starting material in the above-described process, is prepared as follows:

3.15 g (0.13 mol) of magnesium shavings are treated in 140 ml of tetrahydrofuran with 24.24 g (130 mmol) of 2-bromoanisole and the resulting solution is mixed with a solution of 17.1 g (100 mmol) at 0 ° C. of 1-ethoxycarbonyl-4-piperidone in 100 mL of tetrahydrofuran. The mixture was allowed to stand overnight at room temperature and then quenched by the addition of 20% ammonium chloride solution. The product was extracted with chloroform and the organic layer was washed, dried and evaporated. The residue is mixed with 20 ml of ether and the crystals of 1-ethoxycarbonyl-4-hydroxy-4- (2-methoxyphenyl) piperidine are filtered off (yield 17.66 g, m.p. 125-127 ° C). These crystals were dissolved in 155 ml of methylcellosolv and the solution was refluxed for 26 hours with 12.36 g (220 mol of potassium hydroxide). The resulting reaction mixture was diluted with water, extracted with methylene chloride, and the organic layer was washed with brine and dried. The methylene chloride was evaporated and the residue was recrystallized from ethyl acetate. 7.37 g of 4-hydroxy-4- (2-methoxyphenyl) piperidine, m.p. 121 DEG-124 DEG C., is obtained.

7.37 g (35.5 mmol) 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 mmol) of 2- Of (2-bromoethyl) -1,3-dioxolane at 80 ° C for 1 hour, followed by the procedure described in Example 13. The crude product obtained is recrystallized from isopropyl alcohol. 7.77 g of 1- [3,3- (ethylenedioxy) propyl] -4-hydroxy are obtained

190 DEG-193 DEG C., 4- (2-methoxyphenyl) piperidine.

Example 19

(±) Endo-4-hydroxy-6- (4-methoxyphenyl) -1-azabicyclo (3.3.1) non-6-ene hydrochloride

0.5 g (1.72 mmol) of 1- [3,3- (ethylenedioxy) propyl] -4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridine is allowed to stand in 15 ml of a concentrated hydrochloric acid / water mixture (2: 1) at room temperature for 30 minutes. The reaction mixture is evaporated to dryness and the residue is recrystallized from 10 ml of ethanol. 0.21 g of product is obtained, m.p. 235-236 ° C.

1- [3,3- (ethylenedioxy) propyl] -4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridine, which serves as the starting material in this example, was prepared as follows:

0.8 g (3.6 mmol) of 4- (4-methoxyphenyl) 1,2,3,6-tetrahydropyridine hydrochloride in 10 ml of dimethylformamide is reacted in the presence of 0.8 g of sodium carbonate with 0.77 g (4, 2 mmol) 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 off. 0.56 g of product is obtained, m.p. 98-100 ° C.

Example 20

(±) Endo-4-acetoxy-6- (4-methoxyphenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

1.0 g (3.6 mmol) of the product prepared as described in Example 19 was acetylated as described in Example 2. 0.9 g of the crude product obtained was recrystallized from 15 ml of isopropyl alcohol to give 0.8 g. 235-237 ° C.

Example 21

(±) Endo-4-hydroxy-6- (2-thienyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

5.66 g (20 mmol) of 1- [3,3- (ethylenedioxy) propyl] -4-hydroxy-4- (2-thienyl) piperidine are dissolved in 30 ml of a 2: 1 mixture of concentrated hydrochloric acid and water, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated and the residue was mixed with methanol. 2.49 g of product, m.p. 267 DEG-269 DEG C., are filtered off.

1- [3,3- (ethylenedioxy) propyl] -4-hydroxy-4- (2-thienyl) piperidine, which serves as starting material in this example, was prepared as follows:

3.15 g (0.13 mol) of magnesium shavings were treated with 21.18 g (130 mmol) of 2-bromothiophene in 130 ml of tetrahydrofuran, and a solution of 17.1 g (100 mmol) of l was added to the resulting solution at 0 ° C. -ethoxycarbonyl-4-piperidone in 100 mL of tetrahydrofuran. The resulting mixture was allowed to stand overnight at room temperature and then worked up as described in Example 18. The crude product was recrystallized from ethyl acetate. It is obtained

16.85 g of 1-ethoxycarbonyl-4-hydroxy- (2-thienyl) piperidine, m.p. 152-153 ° C.

A solution of this compound in 100 ml of isopropyl alcohol was refluxed for 40 hours with 12.9 g (230 mmol) of potassium hydroxide, and then the resulting mixture was worked up as described in Example 18. The crude product was recrystallized from ethyl acetate. 9.65 g of 4-hydroxy-4- (2-thienyl) piperidine of melting point 145 DEG -146 DEG C. are obtained.

9.56 g (52 mmol) of the above product is reacted in 70 ml of dimethylformamide in the presence of 11.0 g of potassium carbonate with 10.86 g (60 mmol) of 2- (2-bromoethyl) 1,3-dioxolane at 80 ° C, for 1 hour. The resulting mixture was then worked up as described in Example 13. The crude product was recrystallized from isopropyl alcohol to give 10.51 g of 1- [3,3- (ethylenedioxy) propyl] -4-hydroxy-4- (2-thienyl) piperidine. mp 110-112 ° C.

Example 22

(±) 4-Phenyl-endo-6-hydroxy-1-azabicyclo (3.2.1) oct-3-ene hydrochloride

9.78 g (0.05 mol) of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride is reacted in 130 ml of dimethylformamide in the presence of 10.6 g of sodium carbonate with 11.3 g (0.055 mol) of bromoacetaldehyde diethyl acetal at 80 ° C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed, dried and evaporated.

13.7 g of an oily residue are obtained, which consists mainly of 1- (2,2-diethoxyethyl) -4-phenyl-1,2,3,6-tetrahydropyridine.

11.3 g of this intermediate are refluxed with 100 ml of 1: 1 concentrated hydrochloric acid / water for 4 hours, the reaction mixture is evaporated and the residue is mixed with acetone. The crude product (6.7 g) was recrystallized first from ethanol and then from isopropyl alcohol. 3.2 g of product are obtained, m.p. 228 DEG-230 DEG.

Example 23

(±) 4-Phenyl-endo-6-acetoxy-1-azabicyclo [3.2.1] oct-3-ene hydrochloride

1.76 g (7.4 mmol) of the product prepared as described in Example 22 was acetylated as described in Example 2.

1.16 g of the crude product, which is isolated in the form of a base, is converted into the hydrochloride with hydrochloric acid in ether and the salt formed is recrystallized from isopropyl alcohol. 0.74 g of product is obtained, m.p. 178-180 ° C.

Example 24 (+) - 4- (4-Chloro-phenyl) -endo-6-hydroxy-1-azabicyclo [3.2.1] oct-3-ene

11.4 g (50 mmol) of 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride in 90 ml of dimethylformamide are reacted in the presence of 10.6 g of sodium carbonate with 11.3 g (55 mmol) of bromoacetaldehyde diethyl acetal at 80 ° C for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed, dried and evaporated. 15.6 g of crude resinous 1- (2,2-diethoxyethyl) -4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine are obtained.

This intermediate was added with constant stirring to 230 mL of 85% sulfuric acid at room temperature. Stirring is continued for 2 hours and then the reaction mixture is poured onto ice and adjusted to pH 9 with sodium hydroxide. The product is extracted with ethyl acetate and after evaporation of the organic layer the residue is chromatographed (flash, eluent: benzene: methanol: triethylamine). 2: 1: 0.1). The main fraction, which is obtained when the R value of about 0.3 _F (4.3 g) was recrystallized from methyl ethyl ketone. 2.9 g of product are obtained, m.p. 145-148 ° C.

Example 25

(±) 4- (4-Chloro-phenyl) -endo-6-acetoxy-1-azabicyclo [3.2.1] oct-3-ene hydrochloride

4.9 g of the product prepared as described in Example 24 are acetylated as described in Example 2. 3.6 g of the base thus obtained are converted to the hydrochloride by treatment with hydrochloric acid in isopropanol and ether. 2.12 g of this product is recrystallized from isopropyl alcohol. 1.77 g of pure product, m.p. 253 DEG-256 DEG C., are obtained.

Example 26

(±) 4- (4-Methoxyphenyl) -endo-6-hydroxy-1-azabicyclo [3.2.1] oct-3-ene hydrochloride

3.54 g (14.4 mmol) of 4- (4-methoxyphenyl) 4-hydroxypiperidine hydrochloride in 25 ml of dimethylformamide was reacted in the presence of 3.07 g of sodium carbonate with 3.3 g (16 mmol) of bromoacetaldehyde diethyl acetal at 90 °. C for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed, dried and evaporated.

4.6 g of crude 1- (2,2-diethoxyethyl) -4- (4-methoxyphenyl) -4-hydroxypiperidine are obtained. To this was added 50 mL of a 2: 1 mixture of concentrated hydrochloric acid and water at room temperature and the reaction was allowed to proceed for 2 hours. The reaction mixture is evaporated and the residue is recrystallized from 200 ml of ethanol. 1.58 g of the expected product are obtained, m.p. 265 DEG-267 DEG.

The 4- (4-methoxyphenyl) -4-hydroxypiperidine hydrochloride used as starting material in this example was prepared as follows:

37.4 g (0.2 mol) of 4-bromoanisole are added dropwise to a mixture of 4.86 g (0.2 mol) of magnesium and 60 ml of tetrahydrofuran. After dissolution of magnesium, a mixture of 24 g (0.14 mol) of 1-ethoxycarbonyl-4-piperidone and 60 ml of tetrahydrofuran is added dropwise over a temperature range of 0 to 10 ° C and the mixture is stirred at room temperature overnight. The mixture was then quenched by the addition of 160 ml of ice-cold 10% ammonium chloride solution, extracted with ethyl acetate, and the organic layer was dried and evaporated. Diisopropyl ether was added to the residue to give 23.38 g of 1-ethoxycarbonyl-4- (4-methoxyphenyl) -4-hydroxypiperidine, m.p. 110-112 ° C.

This intermediate was boiled under reflux in 160 ml of isopropyl alcohol for 12 days using 12 g of potassium hydroxide. The mixture was evaporated, the residue was taken up in water and extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was treated with hydrochloric acid in ether. There were obtained 6.2 g of 4- (4-methoxyphenyl) 4-hydroxypiperidine hydrochloride, m.p. 218-220 ° C.

Example 27 (±) 4- (3-Methylphenyl) -endo-6-hydroxy-1-azabicyclo [3.2.1] oct-3-ene

9.0 g (43 mmol) of 4- (3-methylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride in 50 ml of dimethylformamide are reacted in the presence of 13.8 g of potassium carbonate with 10.3 g (50 mmol) of bromoacetaldehyde diethyl acetal. at 80 ° C for 3 hours. The reaction mixture was poured into water and extracted with methylene chloride. The organic layer was washed and chromatographed (flash, eluent: benzene: methanol: triethylamine, 95: 5: 0.1). 7.60 g of 1- (2,2-diethoxyethyl) -4- (3-methylphenyl) -1,2,3,6-tetrahydropyridine are obtained.

This intermediate was dissolved in 30 mL of concentrated hydrochloric acid / water (2: 1) and stirred at room temperature for 20 hours. The reaction mixture was then poured onto ice and adjusted to pH 9 with sodium hydroxide. The product was extracted with ether and after evaporation of the organic layer the residue was recrystallized from ethyl acetate. 2.70 g of the desired product are obtained, m.p. 144 DEG-147 DEG.

Example 28

(±) Endo-4-hydroxy-6 (exo) -phenyl-1-azabicyclo [3.3.1] nonane hydrochloride

1.25 g (5 mmol) of endo-4-hydroxy-6-phenyl-azabicyclo [3.3.1] non-6-ene hydrochloride prepared according to Example 1 was subjected to hydrogenolysis in 80 ml of a mixture of methylene chloride and ethanol ( 1: 1), in the presence of 0.10 g of 10% palladium on carbon catalyst. The consumption of the calculated amount of hydrogen is complete after about 5 hours, the catalyst is filtered off, the filtrate is evaporated and the crystalline residue is recrystallized. 0.85 g of product is obtained. M.p. 284-285 ° C (rearrangement at 245-268 ° C).

Example 29

(±) Endo-4-hydroxy-6 (exo) - (3-methylphenyl) -lazabicyclo [3.3.1] nonane hydrochloride

A solution of 2.0 g (7.52 mmol) of (±) endo-4-hydroxy-6- (3-methylphenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride from Example 13 was hydrogenated in the presence of 0. 2 g of 10% palladium on activated carbon catalyst for 8 to 10 hours. The catalyst is filtered off, the filtrate is evaporated and the residue is recrystallized from isopropanol. 1.33 g of the expected product are obtained, m.p. 238 DEG-245 DEG.

Example 30

(±) Endo-4-hydroxy-6 (exo) - (4-trifluoromethylphenyl-1-azabicyclo [3.3.1] nonane) hydrochloride

The (±) endo-4-hydroxy-6- (trifluoromethylphenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride of Example 17 (1.59 g, 5 mmol) was hydrogenated as described in Example 29 to give the title compound. is recrystallized from ethanol. 1.19 g of product, m.p. 299 DEG-303 DEG C., is obtained.

Example 31

(±) Endo-4-hydroxy-6 (exo) - (2-methoxyphenyl) -1-azabicyclo [3.3.1] nonane hydrochloride

1.97 g (7 mmol) of (±) endo-4-hydroxy-6- (2-methoxyphenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride (Example 18) was hydrogenated as described in Example 29 and the obtained the material is recrystallized from isopropyl alcohol. 0.92 g of product is obtained, m.p. 258-262 ° C.

Example 32

(±) Endo-4-propionyloxy-4- (4-fluorophenyl) -lazabicyclo [3.3.1] non-6-ene hydrochloride

To 2.50 g (10.7 mmol) of (±) endo-4-hydroxy-6- (4-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride prepared according to Example 9 was added aqueous potassium carbonate solution, then the base obtained is extracted with ether. The extract was evaporated and the resulting crystalline product was stirred at 60 ° C in 13.5 ml of propionic anhydride for 8 hours. Excess anhydrides were removed by quenching with 20 mL of water and then evaporating to dryness. The residue was treated with hydrochloric acid in methanol to give 3.35 g of product, m.p. 233-235 ° C.

Example 33

(±) Endo-4-isobutyroyloxy-6- (3-chlorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

2.25 g (7.86 mmol) of (±) endo-4-hydroxy-6- (3-chlorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride, prepared according to Example 5, are treated with 4. % sodium hydroxide solution. The resulting base was extracted with chloroform and the organic extract was evaporated. The residue was dissolved in 20 mL of anhydrous methylene chloride and a solution of 1.63 mL (15.72 mmol) of isobutyroyl chloride in 10 mL of methylene chloride was added at 0 to 5 ° C in the presence of 1.27 mL of anhydrous pyridine. The reaction mixture was stirred at room temperature for 3 hours and then evaporated. The residue was diluted with concentrated sodium carbonate solution and extracted with benzene. The organic layer was evaporated and to the resin residue was added hydrochloric acid in isopropanol. 1.39 g of product, m.p. 233 DEG-235 DEG C., are obtained.

Examples 34 and 35

The following Table 2 describes the compounds of formula I in which n is 1 and R ² and R ³ are hydrogen atoms, with a broken line showing the additional bond CC. The symbol R ¹ has the meaning given in the table. These compounds are prepared from the appropriately substituted 1,2,3,6-tetrahydropyridine as described in Example 1.

Table 2

Example number R ¹ melting point of hydrochloride (° C) 34 4-methylphenyl 253-257 35 α-naphthyl 309-321

Examples 36 and 37

In Table 3, compounds of formula I are characterized in which n is 1 and R ² and R ³ are hydrogen, with the broken line showing the additional bond CC. The symbol R ¹ has the meaning given in the table. These compounds were prepared by hydrogenation from the corresponding starting materials as described in the Example

29. The product obtained is converted on a base in a manner known per se and then recrystallized from isopropyl alcohol.

Table 3

Example of starting material R ¹ mp Example number No. Of base (C)

34 4-Methylphenyl 124-126

9 4-Fluorophenyl 173-175

Examples 38 to 50

The following Table 4 describes compounds of formula I wherein R ³ is hydrogen, with the dotted line depicting the additional bond CC. The symbols n, R ¹ and R ² have the meanings indicated in the table.

These compounds are prepared by acylating the base obtained from the corresponding starting material and optionally converting the product to an acid addition salt.

Table

ex. C. starting material z př.č. n L R ¹ R ² method z př.č. m.p. HCl sol (° C) 38 3 1 4-chlorophenyl propionyl 32 258-260 39 3 1 4-chlorophenyl isobutyroyl 33 268-270 40 3 1 4-chlorophenyl pivaloyl 32 258-260 41 26 0 4-methoxyphenyl acetyl 32 202-203 42 34 1 4-methylphenyl acetyl 32 253-256 43 5 1 3-chlorophenyl acetyl 32 238-240 44 5 1 3-chlorophenyl propionyl 32 210-212 45 5 1 3-chlorophenyl pivaloyl 32 229-231 46 9 1 4-fluorophenyl pivaloyl 32 235-238 47 17 1 5-Trifluoromethyl · - propionyl 32 256-263 48 18 1 phenyl 2-methoxyphenyl acetyl 32 216-219 49 1 1 phenyl propionyl 2 254-258 50 35 1 α-naphthyl propionyl 32 115-116 ^a a = base

Examples 51 to 58

In the following Table 5, compounds of formula I are characterized in which n is 1, R ³ is hydrogen, with the dotted line showing the additional bond CC. The symbols R and R ² have the meanings indicated in the table.

These compounds are prepared by acylating the base obtained from the corresponding starting material and possibly ^- transforming the product into an acid addition salt.

Table 5

ex. C. Eastern substance z př. R ¹ R ² method from ex. m.p. Hydrochl. (° C) 51 28 phenyl acetyl 2 262-263 52 28 phenyl propionyl 2 113 ^a 53 28 phenyl pivaloyl 2 116-117 54 31 2-methoxyphenyl acetyl 32 276-281 55 29 3-methylphenyl acetyl 32 258-263 56 37 4-fluorophenyl acetyl 32 276 (subl 57 37 4-fluorophenyl propionyl 32 255 (subl 58 30 4-trifluoromethyl- - propionyl 32 239 (subl

phenyl a = base

Example 59

(+) Endo-4-acetoxy-6- (4-chlorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

The base prepared from Example 3 is treated with sodium bicarbonate solution, which is then extracted with ethyl acetate and isolated as a solid foam. To a solution of 9.95 g (40 mmol) of this base in 5 mL of ethyl acetate was added dropwise over 2 hours 4.41 g (19 mmol) of (+) - camphen-10-sulfonic acid in 120 mL of ethyl acetate. The resulting suspension was stirred for 24 hours and then the precipitated diastereomeric salt (8.16 g) was filtered off. This salt is recrystallized first from 10% and then from 5% isopropyl alcohol in methyl ethyl ketone and the resulting crystalline mass is stirred at least 16 hours at room temperature each time. After this treatment, which may be followed by optional further crystallization, the specific rotation of the salts is in the range of [α] _D +109.3 to 111.7 ° (c = 0.5, ethanol). To check the optical purity of this product, a salt sample is acylated with (+) - camphen-10-sulfonyl chloride in _5- pyridine and the diastereomeric impurity is determined by ¹ H-NMR.

From 2.28 g of this product (having a diastereomeric salt content above 99%), the base (1.18 g) was formed as a foam by stirring with a mixture of aqueous sodium bicarbonate and ethyl acetate. This base was first converted to the acetyl derivative and then to the hydrochloride as described in Example 2. Recrystallization from isopropyl alcohol gave 0.89 g of product, m.p. 264-268 ° C; recrystallization at 238-250 ° C; [α] _D - + 233.3 ^O (c = 0.5, ethanol).

Example 60

(-) Endo-4-acetoxy-6- (4-chlorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

The base was liberated from the recrystallization mother liquors of the diastereomer of Example 59 by stirring with aqueous 10% sodium bicarbonate solution and ethyl acetate. To a solution of 8.58 g (34 mmol) of the base obtained in 40 ml of ethyl acetate at room temperature with stirring is added dropwise a solution of 3.76 g (16.2 mmol) of (-) - camphen-10-sulfonic acid in 100 ml. ml of ethyl acetate and the resulting suspension was stirred for an additional 16 hours. The diastereomeric salt was filtered off and recrystallized from ethyl acetate containing first 2% and then 3% isopropyl alcohol. 1.88 g of salt, [a] _D = -115.3 ⁰ (c = 0.5, ethanol).

The base (0.98 g of a solid foam) was released from this product, which was converted first to the acetylderivative and then to the hydrochloride as described in Example 2. Yield 0.50 g, m.p. 264 DEG-263 DEG C. (recrystallization at 220 DEG C.); [a] _D

-229.1 ° (c = 0.5, ethanol).

Example 61

1/2 (±) exo-4-acetoxy-6- (4-chlorophenyl) -1-azabicyclo [3.3.1] non-6-ene fumarate

1.5 g of the compound prepared in Example 3 was heated at 80 ° C in 5 ml of 70% perchloric acid for 4 hours to give a mixture of endo and exo isomers. The exo form can be isolated from this mixture as follows:

The reaction mixture was poured into ice-water, adjusted to pH 8 with sodium bicarbonate solution and then extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated. The white crystalline product (1.4 g) thus 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 was worked up as described in Example 2 and the oil obtained (0.7 g) was collected using a 8: 2 mixture of benzene and methanol on a silica gel 60 column (Macherey-Nagel). In the elution, the endo (equatorial) isomer is exited first, followed by the exo (axial) isomer (0.25 g, Rp = 0.3 to 0.4). The latter isomer is dissolved in 5 ml of ethanol and mixed with an alcoholic solution of 0.04 g of fumaric acid. After evaporation, the salt is recrystallized from 15 ml of ethanol. 0.21 g of product is obtained, m.p. 219-221 ° C. According to gas chromatography analysis, 96% of this product is the axial (exo) isomer.

Example 62

(±) Endo-4-isobutyroyl-6- (4-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

3.6 g (13.3 mmol) of the compound prepared according to Example 9 were converted on the base with potassium carbonate solution and this base was extracted with ethyl acetate. The solvent was evaporated and the residue was dissolved in anhydrous pyridine. The solution was cooled to 0 ° C and a solution of 2.12 g (20 mmol) of isobutyryl chloride in 5 mL of anhydrous dioxane was added. The mixture was allowed to stand overnight and then poured onto ice and extracted with chloroform. The chloroform extract was evaporated and isopropanolic hydrogen chloride was added to the residue. 2.86 g of product are obtained, which sublimates at 225 ° C.

Example 63

(±) Exo-4-hydroxy-6- (4-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

The ethanolic mother liquor obtained in Example 9 was evaporated and the residue was converted on a base. 5.0 g of this base (with an endo isomer to exo isomer ratio of about 4: 1) was heated to 80 ° C with 25 ml of 70% perchloric acid for 1 hour. The resulting solution was cooled, basified with 5N sodium hydroxide and extracted with chloroform. The extract was evaporated. In the resulting base, the endo / exo isomer ratio is about 2: 3. 3.80 g of this isomeric mixture were separated on a silica gel 60 (Macherey-Nagel) column (120 g) eluting with benzene / methanol (4: 1). The resulting crude product (1.85 g) was recrystallized from ethyl acetate. The crude product obtained (1.85 g) was recrystallized from ethyl acetate. 1.40 g of (±) exo-4-hydroxy-6- (4-fluorophenyl) -1-aza-bicyclo (3.3.1) non-6-ene base having a melting point of 133 DEG-137 DEG C. is obtained. isopropanol is converted to 1.47 g of product, m.p. 220-224 ° C.

Example 64

(±) Exo-4-propionyloxy-6- (4-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

0.65 g (2.79 mmol) of (±) exo-4-hydroxy-6- (4-fluorophenyl) -lazabicyclo [3.3.1] non-6-ene base, prepared as described in Example 63, was allowed to react. with propionic anhydride as described in Example 32 and converted to the hydrochloride. Yield 0.54 g, m.p. 174-179 ° C.

Example 65

(±) Endo-4-hydroxy-6- (4-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

The base prepared in the manner described in Example 9 was treated with potassium carbonate solution and extracted with ethyl acetate. The ethyl acetate extract was concentrated to give crystals. To a solution of 7.0 g (30 mmol) of this base (m.p. 119-122 ° C) in 50 mL of acetone was added a hot solution of 3.90 g (15 mmol) of L-tartaric acid 4-chloroanilide [T. A. Montzka, T. L. Pindell and J. D. Matiskell:

J. Org. Chem. 33, 3993 (1968)] in 100 ml acetone. The crystals formed are filtered off and recrystallized three times from isopropyl alcohol. The optical purity of the resulting diastereomeric salts was determined as described in Example 59.

From 3.10 g of product (optical purity above 99%) prepared as described above (m.p. 126-131 ° C; [α] _D = +145.8 (c = 1, methanol)] liberates the base by treatment with aqueous sodium bicarbonate. For 2.12 g of the obtained (+) endo-4-hydroxy-6- (4-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene [m.p. 154-157 ° C; [α] _D = +149.35 (c - 1, methanol)] is treated with hydrogen chloride gas in isopropyl alcohol. There were obtained 2.16 g of product, mp 253-255 ° C, [a] _Q »+155.0 DEG (c" 1, methanol).

Example 66

(-) Endo-4-hydroxy-6- (4-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

The acetone mother liquor from the salt production of Example 65 was evaporated and the resulting thick resin (4.9 g) was treated with water. The separated crystals were collected by filtration to give 2.39 g of base enriched in the (-) enantiomer [[a] _D -87.5 ⁰ (c 1, methanol)]. This material was dissolved in acetone and treated with a solution of 2.38 g of (-) - camphen-10-sulfonic acid in acetone. The precipitated salt was recrystallized from methyl ethyl ketone and the optical purity of the resulting diastereomeric salts was checked as described in Example 59.

From 1.66 g of the product obtained in the above manner, the optical purity of which is not less than 99%, the base is liberated by treatment with aqueous sodium carbonate solution. The obtained (-) endo-4-hydroxy-6- (4-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene [m.p. 154-157 ° C; [α] D = -148.5 ° (c = 1, methanol)] is treated with hydrogen chloride gas in isopropyl alcohol. 1.60 g of product are obtained, which sublimates at 252-254 ° C; [α] _D -156.8 ⁰ (c-1, methanol).

Example 67

(+) Endo-5-propionyloxy-6- (4-fluorophenyl) -1-aza-bicyclo [3.3.1] non-6-ene hydrochloride

0.75 g (3.2 mmol) of (+) endo-4-hydroxy-6- (4-fluorophenyl) -1-azabicyclo (3.3.1) non-6-ene, prepared as described in Example 65, was reacted with propionic anhydride as described in Example 32 and the resulting product was converted to the hydrochloride yield 0.84 g [sublime at 243 ° C; [α] _Q = +218.2 (c = 1, methanol)].

Example 68

(±) Endo-4-propionyloxy-6- (4-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene hydrochloride

0.57 g (2.44 mol) of (-) endo-4-hydroxy- (4-fluorophenyl) -lazabicyclo [3.3.1] non-6-ene, prepared as described in Example 66, is reacted with propionic anhydride of the acid and the resulting product is converted to the hydrochloride. Yield: 0.71 g of product which sublimes at 245 ° C. Its [α] _D = -223.5 (c = 1, methanol).

Claims (7)

PATENT CLAIMS 1. A compound 1-azabicycloalkane and stereoisomers thereof, ¹ '' of the formula I ^J OH J FJ Cl / - where _______ R ¹ is phenyl, substituted phenyl, naphthyl or thienyl, wherein the phenyl is optionally substituted with one or more halogen, methyl, methoxy, methylthio or trifluoromethyl, R ² represents a hydrogen atom or an aliphatic acyl group containing 2-5 carbon atoms; R ³ is hydrogen or methyl, n is 0 or 1, the dashed line shows the optional carbon-carbon bond present, and the wavy line indicates that the substituent may be bonded to the carbon atom at any of two possible steric positions, and their pharmaceutically acceptable acid addition salts. A compound selected from the group consisting of (±) endo-4-propionyloxy-6- (4-fluorophenyl) -147 azabicyclo [3.3.1] non-6-ene; (+) endo-4-propionyloxy-6- (4-fluorophenyl) -1-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-fluorophenyl) -1-azabicyclo [3.3.1] non-6-ene; (±) endo-4-acetoxy-6-phenyl-1-azabicyclo [3.3.1] non-6-ene; (±) endo-4-hydroxy-6 (exo) -phenyl-1-azabicyclo [3.3.1] nonane and their acid addition salts. A pharmaceutical composition comprising, as active ingredient, a 1-azabicycloalkane derivative of the formula I wherein R ¹ , R ² , R ³ , n, dashed lines and wavy lines are as defined in claim 1, or a pharmaceutically acceptable salt thereof. a suitable acid addition salt, in association with at least one carrier and / or excipient, which is usually used in the manufacture of medicaments. 4. A process for the preparation of 1-azabicycloalkane derivatives and their stereoisomers of the general formula I (i). where R ¹ is phenyl, substituted phenyl, naphthyl or thienyl, wherein the phenyl is optionally substituted with one or more halogen, methyl, methoxy, methylthio or trifluoromethyl, R ³ represents a hydrogen atom or an aliphatic acyl group containing 2-5 carbon atoms; R ³ is a hydrogen atom or a methyl group, n is a number of 0 or 1, the dashed line shows the optional carbon-carbon bond present, and the wavy line indicates that the respective substituent may be bonded to the carbon atom at any two possible steric positions; also pharmaceutically acceptable acid addition salts thereof, characterized in that in the 1,2,3,6-tetrahydropyridine derivatives of the general formula II or the piperidinol derivatives of the general formula III r ₄ 0-c- (ch ₂ ) -ch ₂ - n ORs R1 (II) R ₄ OC- (CH ₂ ) _n -CH ₂ -N (III) 0R ₅ OH R ¹ where R ¹ , R ³ and n are as defined above, R ⁴ and R ⁵ are each C 1 -C 4 alkyl, or both together are C 2 -C 3 alkylene, by an acid-catalysed reaction, the ring is closed, and optionally recovered compounds of formula I wherein R ¹ , R ³ and n are as defined above and R ² is hydrogen, acylated and / or saturated with a double bond thereof, and / or optionally the resulting compounds of formula I wherein R ¹ and n are as defined above and R and R are each hydrogen, isomerized under acidic conditions and / or optionally obtained compounds of formula I, wherein R ¹ , R ² , R ³ and n are as defined above, resolved by optical resolution and / or converted into addition salts with acids. Method according to claim 4, characterized in that the acid-catalysed ring closure is carried out by treatment with an aqueous mineral acid, preferably hydrochloric acid. Method according to claim 4 or 5, characterized in that the ring closure is carried out at a temperature in the range from 20 to 120 ° C. 7. A method of preparing a pharmaceutical composition that has particular efficacy antiamnesic, characterized in that a derivative of 1-azabicycloalkane general formula I wherein R ^1, R ^2, R ^3, n, the dotted line and the wavy line are as defined in of claim 1, or a pharmaceutically acceptable acid addition salt thereof, admixed with at least one carrier and / or excipient, which is usually used in the manufacture of medicaments.