DE2434015A1 - 1-PHENYL-6-AZABICYCLO SQUARE BRACKET ON 3,2,1 SQUARE BRACKET FOR OCTANE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THE SAME PRODUCT CONTAINED - Google Patents

Description

DR. MÜLLER-BORE dipl.-ing. GROENING DIPL.-CHEM. DR. DEUFEL

DIPL.-CHEM. DR. SCHÖN DIPL.-PHYS. HERTEL PATENT LAWYERS

1 5. JuIS

Tanabe Seiyaku Co., Ltd.

21, Doshomachi 3-chome, Higashi-ku

Osaka, Japan

1-phenyl-6-azabicyclo [3.2.1] octane derivatives, method too. their production and agents containing them

In the 1-phenyl-6-azabicyclo [3.2, i] octane derivatives according to the invention it is a compound of formula I.

"N-CH ₂ R

6098U / 1122

where mean:

R represents a hydrogen atom, a phenyl radical, an alkyl radical with 1 to 5 carbon atoms, a cycloalkyl radical with 3 or 4 carbon atoms, or an alkyl radical with 1 to 5 carbon atoms, which is substituted with a phenyl, benzoyl or 4-fluorobenzoyl radical,

R is a hydrogen atom or an alkyl radical with 1 to 3 carbon atoms, and

R- * is a hydrogen atom, an alkanoyl radical with 2 to 6 carbon atoms, a benzoyl radical or a nicotinoyl radical,

or a pharmaceutically acceptable acid addition salt thereof.

It was found that the compounds of the formula I according to the invention can be used as analgesic agents. The analgesic activity of compounds of the formula I is about twice or more than twice as strong as that of codeine. Is z. B. a 1 ige acetic acid solution injected intraperitoneally into mice in doses of 10 mg / kg after subcutaneous injection of a test compound and the number of writhes in pain per mouse counted for 5 minutes from a time beginning 10 minutes after injection of the acetic acid solution, the following is analgesic activity, expressed as TSD ₁ -Q, which produces a 50% reduction in acetic acid-induced pain writhing, found:

5 0 9 b U / I 1 2 2

link

5O (mg / kg)

1- (3-hydroxyphenyl) -6,7-dimethyl-6-azabicyclo-

[3.2.1] octane hydrobromide 4.5

1- (3-Hydroxyphenyl) -6- n -amyl-7-methyl-6-azabicyclo [3.2.1] octane hydrochloride 1.5

1- (3-hydroxyphenyl) -6-n-hexyl-7-methyl-6-aza-

bicyclo [3.2.1] octane hydrochloride 0.27

1- (3-Hydroxyphenyl) -6-cyclopropylmethyl-7-methyl-6-azabicyclo [3.2.1] octane hydrochloride 2.2

1- (3-Hydroxyphenyl) -6- [3- (4-fluorobenzoyl) propyl] -6-azabicyclo [3.2, i] octane hydrochloride 2.0

1- (3-hydroxyphenyl) -6-phenethyl-7-methyl-6-

azabicyclo [3.2.1] octane hydrochloride 0.61

(+) - 1- (3-Hydroxyphenyl) -6,7-dimethyl-6-azabi-

cyclo [3.2.1] octane hydrobromide 1.2

(+) - 1- (3-Hydroxyphenyl) -6-methyl-6-azabicy-

clo [3.2.1] octane hydrochloride 3.7

In contrast, the analgesic activity (ED ₁₅₀ ) of codeine, when tested under the specified conditions, is 9.5 mg / kg.

Compounds of the formula I indicated, in which R is an alkanoyl, Benzoyi or nicotinoyl radical are further examples for compounds with potent attachment activity. at Testun ^ under the same conditions as stated above

5098U / 1 1 22

ζ. B. for. 1- (3-Acetyloxyphenyl) - or 1- (3-Propionyloxyphenyl) derivatives of 6 _f 7-dimethyl-6-azabicyclo [3 _f 2, i] octane an analgesic activity (ED ₅₀ ) of 2.9 or 2.3 mg / kg found.

In addition, the toxicity of the compounds of the formula I according to the invention is remarkably low. So z. B. when administered subcutaneously to mice, the acute toxicity (LDcq) of 1- (3-hydroxyphenyl) -6,7-dimethyl-6-azabicyclo- [3 # 2, i] octane, its optically active (+) - isomer and from 1- (3 ^w propionyloxyphenyl) -6,7-dimethyl-6-azabicyclo [3.2.1] octane about 113 to 123 mg / kg.

The invention. Compounds of formula I are for pharmaceutical Purposes either in the form of a racemic modification or in an optically active form. Further the compounds of formula I can be used for pharmaceutical purposes either in the form of the free base or as a salt thereof be used. Pharmaceutically acceptable acid addition salts of compounds of the formula I are, for. B. the hydrochloride, Hydrobromide, perchlorate, nitrate, sulfate, phosphate, formate, acetate, propionate, glycolate, lactate, pyruvate, oxalate, Ascorbate, hydroxymaleate, phenyl acetate, aminobenzoate, Benzoate, methanesulfonate, malonate, succinate, maleate, fumarate, Malate, citrate, tartrate, ethanesulfonate, phthalate, benzenesulfonate, p-toluenesulfonate, sulfanilate, aspartate and glutamate.

The compounds of the formula I according to the invention are in the form of a pharmaceutical preparation for enteral or parenteral use Administration usable. The dosage of the compound of formula I suitable for pharmaceutical use can range from 5 to 5OO mg / body, especially 50 to 500 mg / body (for enteral Administration) or 10 to 60 mg / body (for parenteral administration). Furthermore, the compounds of the formula I according to the invention in connection with or admixture with a

5098U / 1 1 Il

pharmaceutical binders or carriers suitable for enteral or parenteral administration can be used. The carrier used should be one which does not react with the compound of the formula I according to the invention. Typical suitable carriers are e.g. B. gelatin, lactose, glucose, sodium chloride, starch, magnesium stearate, talc, vegetable oil, benzyl alcohol and gums. Other medical vehicles can also be used. The pharmaceutical preparation may be a solid dosage form for ₈ »B, a tablet, a coated tablet, a pill or a capsule, or a liquid dosage form z _t. B. a solution, a suspension or an emulsion. The pharmaceutical preparation can. be sterilized and / or contain additives, e.g. B. preservatives, stabilizers, wetting or emulsifying agents.

According to the invention, the compounds of formula I are thereby made that one

A) a) a 1- (3-methoxyphenyl) -6-azabicyclo [3 »2, i] octane der Formula II

1 2
wherein R and R have the meaning given, to a 1- (3-hydroxyphenyl) -6-azabicyclo [3.2, i] octane of the formula Ia

5098U / 1 122

1 2
where R and R di © have the given meaning, demethylated,

b) a 1- (3-hydroxyphenyl) -6-azabicyclo [3 »2, Ijoctan der Formula III

wherein R has the meaning given, with a compound of formula IV

R ¹ -CH

wherein X is a halogen atom or a radical of the formula

♦ 1

-N (CH,), J denotes and R denotes the meaning given has, to a 1- (3-hydroxyphenyl) -6-azabicyclo [3,2,1] -oetane (of the formula Ia) condensed or

c) a compound of the formula III with a carboxylic acid compound of the formula V

R ¹ -COOH

wherein R has the meaning given, or a functional Derivative thereof, condensed and the obtained N-acyl derivative of the compound III to a 1- (3-hydroxyphenyl) -6-azabicyclo [3.2, i] octane (of formula Ia) reduced, and optionally

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B) the compound of the formula Ia with a carboxylic acid compound of formula VI

R ⁴ -OH

wherein R represents an alkanoyl group having 2 to 6 carbon atoms, a benzoyl or nicotinoyl, or a functional derivative thereof, _s is acylated to a 1- (3-Acyloxyphenyl) -6-azabicyclo [3s> 2 _y 1] octane of formula Ib

N-CH ₂ R

12 4
wherein R, R and R have the meaning given.

Optionally, a compound according to the invention of the formula I, where R is a hydrogen atom by reductive methylation of a compound of the formula III to give a 1- (3-hydroxyphenyl) -6-methyl-6-azabicyclo [3 »2.1] octane of formula Ic

HO.

-CH.

wherein R has the meaning given and optionally through. Acylation of the compound of the formula Ic with a carboxylic acid compound of the formula VI or a functional derivative thereof.

509814/1122

To carry out the specified reactions according to the invention, the starting compounds of the formulas II and III can either be in the form of a racemic modification or in a optically active form can be used. Furthermore, all of the reactions indicated can be carried out without racemization. If the starting compounds II and III are used in a racemic or optically active form during the reactions, the compounds according to the invention are therefore the Formula I obtained in the corresponding racemic or optically active form.

The demethylation reaction of the compound of the formula II can be carried out in a conventionally known manner. So z. B. the compound of the formula Ia according to the invention prepared by treating the compound of the formula II with, for example, hydrobromic acid, hydroiodic acid, aluminum chloride, boron chloride, boron bromide or pyridine hydrochloride. The use of 47% hydrobromic acid has proven particularly advantageous for the reaction according to the invention. Be is convenient to carry out the reaction at a temperature from -20 to 200 ⁰ O.

The condensation reaction of the compounds of the formulas III and IV can be carried out in the presence of an acid acceptor. Typical suitable acid acceptors are e.g. B, organic and inorganic bases, e.g. B. triethylamine, fyridine, quinoline, alkali metal acetate (ζ. Β. Potassium acetate or sodium acetate), alkali metal hydroxide (ζ. E.g. potassium hydroxide or sodium hydroxide) and alkali metal carbonate (e.g. potassium carbonate or sodium carbonate) The condensation reaction can be carried out with or without a solvent will. Conveniently, the reaction is carried out at a temperature of 20 to 160 ⁰ C. Particularly suitable reaction solvents are e.g. B. acetone, toluene, dimethylformamide, dimethyl sulfoxide and short-chain alkenols (e.g. methanol, ethanol or propanol)

5098U / 1 122

-9- 2A3A015

The condensation reaction of the compound of the formula III with the carboxylic acid compound of the formula V or a functional derivative thereof can be effected in a conventionally known manner. Is z. If, for example, a functional derivative of the compound V is used to carry out the reaction, the condensation is preferably carried out in the presence of an acid acceptor. Typical functional derivatives of compound V suitable for carrying out the process of the invention are e.g. B. the corresponding acid anhydride, acid halide (z. B. chloride or taromide) and the corresponding acid esters (z. B. methyl ester, ethyl ester, propyl ester or benzyl ester). B. organic and inorganic bases, e.g. B. triethylamine, pyridine, quinoline, alkali metal acetate (ζ. B. potassium acetate or sodium acetate), alkali metal hydroxide (ζ. B. potassium hydroxide or sodium hydroxide) and alkali metal carbonate (e.g. potassium carbonate or sodium carbonate). The reaction can be carried out with or without a solvent. It has been found to be expedient to carry out the reaction at a temperature of from 0 to 120 ^° C. «Particularly suitable reaction solvents are, for. B. dichloromethane and dimethylformamide.

When using the compound V in the form of the free acid, the N-acyl derivative of the compound III is optionally prepared by reacting the compound III with an approximately equal amount of the compound V in the presence of a dehydrating agent at a temperature of -10 to 80 ⁰ O * As De - Hydrating agents are e.g. B. N, N ^t -dicyolohexylcarbodiimide or N-cyclohexyl-N'-morpholinomethylcarbodiimide can be used *. Tetrahydrofuran and dimethylformamide are suitable as reactive solvents. The obtained N-acyl derivative of the compound III can be easily converted into the compound Ia by reacting the N-acyl derivative with a conventionally known reducing agent in a solvent. Typical suitable reducing agents are % · BT-f thi v ^ i ^ i.Ti h ^ hTflriifl, aluminum-

5 Ö 9 81 47 11 2 2 originally inspected

hydride and diborane. Preferably, the reduction is carried out at a temperature of 25 to 70 ⁰ C. Tetrahydrofuran and ether prove to be suitable reaction solvents

Furthermore, the reductive methylation of the compound III can be brought about by condensation of the compound III with formaldehyde or alkyl chloroformate (e.g. methyl chloroformate, ethyl chloroformate or propyl chloroformate) in a solvent, and subsequent reduction or catalytic hydrogenation of the condensation product obtained. The condensation reaction of the compound III with formaldehyde or alkyl chloroformate is preferably carried out at a temperature of 0 to 100 ⁰ C. A short-chain alkenol (ζ. Β. Methanol, ethanol or propanol), chloroform or dimethylformamide are suitable as reaction solvents. The subsequent reduction of the condensation product is carried out by treatment with alkali metal borohydride or lithium aluminum hydride in a solvent. Sodium borohydride, potassium borohydride and lithium borohydride are used as the alkali metal borohydride. Particularly suitable reaction solvents are e.g. Tetrahydrofuran, ether, dioxane, and short-chain alkenols (e.g.. Methanol, ethanol, or propanol) · Preferably, the reduction at a temperature of 20 to 80 ⁰ C is performed. In contrast, the catalytic hydrogenation of the condensation product is carried out in the presence of a catalyst in a hydrogen atmosphere in a solvent. Particularly suitable catalysts are, for. B. platinum dioxide, platinum, palladium-carbon and Raney-Hlckel · Typical suitable reaction solution ·! are z. B. a short-chain alkenol, ζ. Β. Methanol, ethanol or propanol · The catalytic hydrogenation is preferably carried out at a temperature of 20 to 40 ⁰ C.

OFHGJNAL INSPECTED

• 80381 U Π 2 2

The compounds Ia and Ic according to the invention, which can be prepared in the manner indicated, can, if necessary, be acylated with a carboxylic acid compound of the formula VI or a functional derivative thereof. This acylation reaction is easy to carry out. If, for example, a functional derivative of the compound VI is used, the acylation reaction is carried out in the presence of an acid acceptor. Typical suitable functional derivatives of the compound VI are e.g. B. the corresponding acid anhydride and acid halide (e.g. chloride or bromide). Typical suitable acid acceptors are e.g. B. organic and inorganic bases, e.g. B. triethylamine, pyridine, quinoline, alkali metal acetate (ζ. B. potassium acetate or sodium acetate), "alkali metal hydroxide (ζ. B. potassium hydroxide or sodium hydroxide) and alkali metal carbonate (eg. Potassium carbonate or sodium carbonate). The reaction can be carried out with or without a solvent. Conveniently, the acylation is carried out at a temperature of O to 180 ⁰ C. Particularly suitable reaction solvents are e.g. B. benzene, toluene and dichloromethane. When the compound VI in the form of the free acid, the acylation reaction is optionally carried out by treatment of compound Ia or Ic with an approximately equal amount of the compound VI in the presence of a dehydrating agent at a temperature of -10 to 80 ^0C. For example, NjN'-dicyclohexylcarbodiimide or N-cyclonexyl-N'-morpholinomethylcarbodiimide are used as the dehydrating agent. Tetrahydrofuran and dimethylformamide are suitable as reaction solvents.

All starting compounds of the formulas II and III which are used according to the invention in process stages (A) a) to (B) and for the reductive methylation are new compounds. These new starting compounds can be prepared according to various methods, which are illustrated by the following reaction scheme:

509814/1122 ORIGINAL INSPECTED

£ 434015

. R.

N-CH ₀ R ¹

(Ha)

CH ₃ O

-CH ₂ O ₆ H ₅

(XII)

NH

(IHb)

(XI)

(Hb) (HIa)

5098U / 1 122

In the formulas given, R ^ denotes an alkyl radical with 1 to 3 carbon atoms and R has the meaning given.

The reactions given are explained below «

1- (3-Methoxyphenyl) -6-azabicyclo [3.2.1] octan-7-one (VIII) becomes produced in a 6-step process by (1) hydrolysis of 4- (3-methoxyphenyl) -4-cyano-1,1-ethylenedioxy-cyclohexane (VII) with an alkali metal hydroxide (e.g. sodium hydroxide or potassium hydroxide) with heating in a solvent (e.g. methanol, ethanol, ethylene glycol or a mixture from one of these solvents and water) with formation of 4- (3-methoxyphenyl) -4-carbamoyl-1,1-ethylenedioxy-cyclohexane, (2) Reaction of the carbamoyl-cyclohexane obtained with an acid (e.g. hydrochloric acid, sulfuric acid or acetic acid) under Heating, (3) bromination of the 4- (3-methoxyphenyl) -4-carbamoyl-cyclohexanone obtained with bromine or pyridinium-hydrobromidr-perbromide (σ, -Η-Ν ^ ΒΓ *) at room temperature in a solvent (e.g. acetic acid or tetrahydrofuran), (4) reaction of the 2-bromo-4- (3-methoxyphenyl) -4-carbamoyl-cyclohexanone obtained with an alkali metal hydride (e.g. sodium hydride) or an alkali metal alkoxide (e.g. sodium methoxide, Potassium methoxide, sodium ethoxide or potassium ethoxide) at room temperature in a solvent (e.g. methanol, ethanol, or dimethoxyethane) with formation of 1- (3-methoxyphenyl) -6-azabicyclo [3.2, i] octane-4,7-dione, (5) reflux heating a mixture of the product obtained and hydrazine hydrate in a solvent (e.g. ethanol or ethylene glycol) and finally (6) heating the 1- (3 - & * thoxyphenyl) -6-azabicyclo [3.2.1] octane 4,7-dione-4-hydrazory in the presence of an alkaline agent (e.g. potassium hydroxide or potassium tert-butoxide) in a solvent (e.g. toluene)

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An i- (3-methoxyphenyl) -6-azabicyclo [3.2.1] octan-7-one derivative (X) is produced by condensation of the compound VIII or an alkali metal salt thereof (e.g. the sodium, or potassium salt) with the compound IV. This condensation reaction is carried out in the same way as the condensation of compounds III and IV carried out. Optionally, the 1- (3-methoxyphenyl) -6-azabicyclo [3.2.1] octane X after a 4-step process produced by (1) reacting 1- (3-methoxyphenyl) -cyclohexen-3-one (IX) with an alkali metal cyanide (e.g. potassium cyanide or sodium cyanide) in the presence of acetic acid, ammonium chloride or triethylamine hydrochloride with heating in a solvent (e.g. methanol, Ethanol, propanol or dimethylformamide), (2) reflux of a mixture of the 3- (3-methoxyphenyl) -3-cyano-cyclohexanone obtained and an alkanol (e.g. methanol or ethanol) in an acidic medium to form an alkyl 1- (3-methoxyphenyl) -3-oxo-cyclohexane-1-carboxylate, (3) catalytic ^ hydrogenation of a mixture of the carboxylate obtained and an alkylamine (e.g. methylamine, ethylamine, propylamine or butylamine) at room temperature in the presence of a catalyst (e.g. platinum, platinum dioxide, Raney-Niekel, or palladium-carbon) in a solvent (e.g. methanol, ethanol or propanol) and finally (4) heating the resulting alkyl 1- (3-methoxyphenyl) -3-alkylamino-cyclohexane-1-carboxylate in a solvent (e.g. toluene or xylene).

The compound Ha is prepared by refluxing a mixture of the compound X and an alkyl lithium or Alkyl magnesium halide in a solvent (e.g. ether, benzene or tetrahydrofuran) to form a 7-alkylidene derivative of compound X, and reduction of this alkylidene derivative with an alkali metal borohydride (e.g. sodium borohydride) at room temperature in a solvent (e.g. methanol or ethanol)

5098U / 1 122

The reduction of compound VIII with lithium aluminum hydride, Aluminum hydride or diborane gives 1- (3-methoxyphenyl) -6-azabicyclo [3.2.1] octane (XC). This reduction is carried out in the same way as the reduction of the N-acyl derivative of Compound III.

The compounds Ha and XI are prepared according to the procedures given always obtained in the form of a racemic modification and, if desired, can be converted optically into the two active enantiomers are split. The cleavage of the compounds II or XC into each of their optically active enantiomers can be effected by reacting the racemic modification of compound II or XC with a resolving agent in a solvent to form the diastereoisomeric salt thereof, and separate the diastereoisomers into the individual components through selective crystallization. Typical suitable splitting agents are e.g. B. d-tartaric acid or their derivatives (e.g. dibenzoyl-d-tartaric acid, monobenzoyl-dartaric acid, or Diacetyl-d-tartaric acid), d-camphorsulfonic acid, d-oc-bromocamphor sulfonic acid, 1-mandelic acid, quinic acid or Glutamic acid or its derivatives (e.g. N-carbobenzyloxyglutamic acid). Suitable solvents are e.g. B. water, a short-chain alkenol (ζ. B. methanol, ethanol, propanol or Butanol), ethyl acetate, dimethylformamide or a mixture of water and one of the specified short-chain alkanols or Dimethylformamide. The selective crystallization can preferably be carried out at room temperature.

The compound XC can easily be converted into a 1- (3-methoxyphenyl) -6-azabicyclo [3.2, i] octane Hb in the same way as the conversion of the compound III into the compound Ia or Ic. On the other hand, demethylation of compound XC gives 1- (3-hydroxyphenyl) -6-azabicyclo [3.2.1] octane (HIa). This demethylation is carried out in the same way as the demethylation of compound II.

50981 4/1122

1- (3-Methoxyphenyl) -ö-benzyl-T-alkyl-ö-azablcyclot 3.2.1] octane (XII) is produced according to a 3-step process by (1) condensation of the compound VIII or an alkali metal salt thereof ( e.g. the sodium or potassium salt) with benzyl halide with heating in a solvent (e.g. dioxane), (2) refluxing a mixture of the 1 - (3-Hethoxyphenyl) -obenzyl-T-oxo- o-azabicycloC 3,2, i}> ctane and an alkyl lithium or alkyl magnesium halide in a solvent (e.g. ether , benzene or tetrahydrofuran) to form 1- (3-methoxyphenyl) -6-benzyl-7-alkylidene-6 azabicyclo [3.2.1] octane, and finally (3) reduction of the resulting alkylidene derivative with an alkali metal borohydride (e.g. sodium borohydride) at room temperature in a solvent.

1- (3-hydroxyphenyl) -7-alkyl-6-azabicyelo [3.2.1] octane (IHb) is produced by catalytic hydrogenation of compound XII and subsequent demethylation of the same. The catalytic hydrogenation is carried out at room temperature in the presence of a catalyst (e.g. platinum, platinum dioxide or Palladium) in a solvent (e.g. methanol, ethanol or acetic acid). The subsequent demethylation is carried out in carried out in the same way as the demethylation of compound II.

Practical and presently preferred embodiment / method of the invention are illustrated in the following examples.

1- (3-methoxyphenyl) -6-azabicyolor 3.2.iiootan-7-one (a) A mixture of 3 »5 g 4- (3-methoxyphenyl) -4-cyano-1,1-

5098U / 1 122

ethylenedioxy-cyclohexane, 70 ml of 5 # aqueous potassium hydroxide solution and 70 ml of ethanol were heated under reflux for 22 hours. After cooling, the mixture was diluted with water and then extracted with chloroform. The chloroform extract was dried and evaporated to remove the solvent. The residue obtained in this way was recrystallized from a mixture of ethyl acetate and η-hexane. 2.32 g of 4- (3-methoxyphenyl) -4-earbamoyl-1,1-ethylenedioxy-cyclohexane were obtained. F = 135 to 138 ⁰ C.

(b) A mixture of 8.7 g of 4- (3-methoxyphenyl) -4-carbamoyl-1,1-ethylenedioxy-cyclohexane and 170 ml of acetic acid was refluxed for 15 hours. After the reaction, the mixture was reduced under reduced pressure evaporated to remove the acetic acid. The residue obtained was dissolved in benzene. The benzene solution was washed with aqueous sodium bicarbonate, dried and then evaporated to remove the benzene. The residue thus obtained was recrystallized from ethyl acetate. 5 _{tons of} 4 g of 4- (3-methoxyphenyl) -4-carbamoyl-cyclohexanone were obtained. P = 120 to 122 ⁰ C.

(c) 50.5 g of 4- (3-methoxyphenyl) -4-carbamoyl ~ cyelohexanon were dissolved in 500 ml of acetic acid and to the resulting solution, a solution of 32.7 g bromine in 500 ml of acetic acid was added dropwise at 20 ⁰ C under Stirring added. The mixture was then poured into bis water and extracted with chloroform.The chloroform extract was washed with water, dried and then evaporated to remove the solvent.Based 69.8 g of 2-bromo-4- (3-methoxyphenyl) -4-carbamoyl- cyolohexanone obtained in the form of a crude oil.

(d) 69.8 g of the 2-bromo-4- (3-methoxyphenyl) -4-carbamoyl-cyclohexanone obtained were dissolved in 250 ml of methanol The solution obtained was a solution composed of 18.8 g of sodium and 500 ml of M

5098 U / 1122 *

Sodium methoxide solution prepared ethanol was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. 1000 ml of water was added to the obtained residue, and the aqueous mixture was extracted with chloroform. The chloroform extract was washed with an aqueous solution saturated with sodium chloride. The chloroform extract was then dried and evaporated to remove the solvent. The residue thus obtained was recrystallized from ethyl acetate. 25.2 g of 1- (3-methoxyphenyl) -6-azabicyclo [3.2, i] octane-4,7-dione were obtained. P ■ 138 to 139 ⁰ C.

(e) A mixture of 21.73 g of i- (3-methoxyphenyl) -6-azabicyclo- [3.2.1] octane-4,7-dione _f 4.9 g of hyidrazine hydrate and 170 ml of ethanol was added for 1 hour heated to reflux. After cooling, the mixture was evaporated under reduced pressure to remove the solvent. The residue obtained was dispersed in benzene and then filtered, yielding 21.64 g of 1- (3-methoxyphenyl) -ö-azabicyclo-C 3.2.1 ] octane-4,7-dione-4-hydrasone were obtained in the form of crude crystals. A mixture of 21.64 g of 1- (3- * ethoxyphenyl) -6-azabicyclo [3.2, i] octane-4,7-dione-4-hydrazone, 17.1 g of potassium tert-butoxide and 400 ml of toluene was refluxed for 2 hours. After cooling, water was added to the mixture and the aqueous mixture was extracted with ether. The ether extract was washed with water, dried and then evaporated to remove the solvent. The residue thus obtained was made from a mixture of ethyl acetate and η-hexane recrystallized. 17 _f 54 g of 1- (3-methoxyphenyl) -6-azal) icyclo- [3.2, i] octan-7-one were obtained. F = 109 to 111 ⁰ O.

509814/1122

Example 2

i- (3-Methoxyphenyl) -6-methyl-6-azabicyclor 3.2.11octan-7-one

0.36 g of 69% sodium hydroxide solution was added to 40 ml of dimethyl sulfoxide. The resulting mixture was heated at 70 ⁰ C for 30 Hinuten in a nitrogen atmosphere. 2 g of 1- (3-methoxyphenyl) -6-azabicyclo [3 »2, i] octan-7-one were added to the mixture at 10 to 15 ^° C. Thereafter, the mixture was stirred at room temperature for 1 hour. 2.1 g of methyl iodide was added to the mixture and the resulting mixture was further stirred for 2 hours at room temperature. The reaction mixture was poured into ice water and extracted with ether. The ether extract was washed with water, dried and then evaporated to remove the solvent β. The residue obtained in this way was recrystallized from η-hexane. 2 g of 1- (3-methoxyphenyl) -o-methyl-ö-azabicydoC 3 »2.1] octan-7-one were obtained. F = 68 to 70 ⁰ C.

Example 3

1- (3-methoxyphenyl) -e-methyl-o-azabicyclof 3.2.11octan-7-one

(a) Its solution of 8.0 g of potassium cyanide in 28 ml of water was stirred into a mixture of 4.04 g of 1- (3-ethoxyphenyl) -cyclohexen-3-one, 120 ml of 95 tiger ethanol and 3 »6 g Acetic acid added. The resulting mixture was ^{stirred at 35 0} O for 80 hours. After the completion of the reaction, the mixture was added with 260 ml of water and the resulting aqueous mixture was extracted with chloroform. The chloroform extract was washed with water, dried and then evaporated to remove the solvent. The residue obtained was distilled under reduced pressure, whereby 3 g of 3- (3-methoxyphenyl) -3-cyano-cyclohexanone were obtained in the form of an oil

5098U / 1 1 22

boiled at 175 ° C / 0.8 mmHg. F "48-48.5 ⁰ C (after Umkristalliaation from isopropyl ether).

(b) A mixture of 4 g of 3- (3-methoxyphenyl) -3-cyano-cyclohexanone and 45 ml of a 36 JCigen hydrogen chloride -ethanol solution was refluxed for 4 hours. To When the reaction was completed, the mixture was concentrated under reduced pressure. Water was added to the residue and the aqueous mixture was extracted with ether. The ether extract was washed with water, dried and then evaporated to remove the solvent. The residue obtained was distilled under reduced pressure, where 4.1 g of methyl 1- (3-aethoxyphenyl) -3-oxo-cyclohexane-1-carboxylate in the form of an oil with a boiling point of 176 ° C / 2-3 nmHg were obtained.

(c) A mixture of 0.52 g of methyl 1- (3-methoxyphenyl) -3-oxocyclohexane-1-carboxylate, 0.5 ml of 30% aqueous methylamine, 8 ml of methanol and O ₉ 025 g of platinum oxide was allowed to dry for 48 hours shaken in a hydrogen atmosphere. After the reaction had ended, the mixture was filtered only to remove the catalyst. The filtrate was concentrated under reduced pressure to remove the solvent, yielding methyl-1- (3-aiethoxyphenyl) ^ HBethylasino-cyclohexane-1-carboxylate were obtained in the form of a crude oil. 7 ml of xylene was added to the crude oil and the resulting mixture was refluxed for 20 hours. Then the mixture was concentrated under reduced pressure to remove the solvent. The residue obtained was dissolved in ether. The ether solution was washed successively with 10 ^ hydrochloric acid and water, dried and then evaporated to remove the solvent. The residue thus obtained was recrystallized from η-hexane. 0.33 g of 1- (3-Hethoxyphenyl) -6-methyl-6-azabicyclo [3,2,1joctan-7-one was obtained. F - 68 to 70 ⁰ C.

5098U / 1122

Example 4

1 - (3-Methoxrphenyl) -6-methyl-6- azal3ic yclo | '. 3 _f 2.11 octan-7-one

(a) A mixture of 6.06 g of 1 <- (3-Metho2 £ yphyl) -eyclohexen-3-one, 4.02 g of potassium cyanide, 4.33 g of erimethylaniine hydrochloride, 21 ml of water and 120 ml of dimethylformamide was added 93 to 94 ⁰ C stirred for 6 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure. Benzene was added to the residue and the insoluble material was filtered off. The filtrate obtained was washed successively with water, 10% hydrochloric acid and water. The filtrate was then dried and evaporated to remove the solvent. The residue obtained was distilled under reduced pressure ₉ with 5.26 g of 3- (3-M @ thoxyphenyl) -. 3-cyano-cyclohexanone in the form of an oil _f which boiled at 175 ° C / 0 _f 8 mmHg were obtained. F = 48 to 48.5 ⁰ C (after crystallization with isopropyl ether).

(b) A solution of 9.5 g of 3- (3 ^ra methoxyphenyl) -3 ^ra cyano-cyclohexanone in 95 ml of methanol was saturated with hydrogen chloride gas while cooling with ice. The resulting solution was refluxed for 4 hours. Thereafter, the solution was concentrated under reduced pressure. Water was added to the residue and the aqueous mixture was extracted with benzene. The benzene extract was washed successively with water, aqueous sodium bicarbonate and water, then dried in the oven and then evaporated to remove the solvent distilled ρ whereby 9.55 g of methylol (3-methoxypb, enyl) -3-o: cyclohexane-1-carboxylate in Worm, a colorless oil with a boiling point of 176 ° C / 2-3 mmHg were obtained «

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(c) A mixture of 9.29 S methyl 1- (3-methOxyphenyl) -3-oxocyclohexane-1-carboxylate, 5.5 ml of 40% aqueous methylamine and 0.13 g of platinum oxide was at room temperature for 5 hours in shaken in a hydrogen atmosphere under atmospheric pressure. The mixture absorbed about 790 ml of hydrogen. After the reaction was over, the mixture was filtered to remove the catalyst. The piled up was concentrated under reduced pressure. ^{The residue obtained was heated to 100 to 110 °} C. under reduced pressure for 2 hours and then dissolved in benzene. The benzene solution was washed successively with 10 liters of hydrochloric acid and water. Then the benzene solution was evaporated to remove the solvent. The residue thus obtained was recrystallized from isopropyl ether. There was added 5.8 g of 1- (3-methoxyphenyl) -o-methyl-ö-azabicyeloC 3,2,1] octan-7-one was obtained · F = 68 to 70 ⁰ C.

Example 5 1- (3-itetho3nn) lienyl) -6T7-dimethyl-6-azabicyclor 3.2.1 "! Octane

0.17 g of lithium were added to 8 ml of absolute ether in a nitrogen atmosphere and a solution of 1.6 g of methyl iodide was added j in 3 ml absolute ether at 0 to -5 ⁰ C. The resulting mixture was stirred at the indicated temperature for 30 minutes. Then a solution of 1.0 g of 1 - (3-Hethoxyplieiiyl) -ö-methyl-e-azabicycloC 3,2,1] ootan-7-one in 30 ml of benzene was added dropwise to the mixture within 5 minutes.

wisely admitted. The resulting mixture was refluxed for 3 hours. Water was added to the mixture under ice cooling and the aqueous mixture was extracted with ether. The ether extract was washed with water, dried and then evaporated to remove the solvent, whereby 1.0 g of 1 - (3-Methoxyphenyl) -6-methyl-7-methylidene-6-arabicyclo [3.2.1] octane. The product obtained was dissolved in 60 ml of ethanol. The ethanol solution was

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300 mg sodium borohydride are added at 10 to 15 ^{° C.} Thereafter, the mixture was stirred at room temperature for 20 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure. Water was added to the residue and the aqueous mixture was extracted with chloroform. The chloroform extract was washed with water, dried and then evaporated to remove the solvent. To the residue was added methanolic hydrogen bromide in ether and the crystalline precipitate formed was collected by filtration. The precipitate was recrystallized from a mixture of ethanol, acetone and ether. 1.1 g of 1- (3-4hethoxyphenyl) -6,7-dimethyl-6-azabicyclo- [3.2, i] octane hydrobromide were obtained. F «175 to 177 ^° C

Example 6

1 - (3-rMe thoxyphenyl) -6-methyl-7-ethyl-6-azabicyclo [3.2.11 octane

0.17 g of lithium were added to 8 ml of absolute ether in a nitrogen atmosphere and a solution of 1.8 g of ethyl iodide in 3 ml of absolute ether was added dropwise at 0 to -5 ° 0. The resulting mixture was stirred at the indicated temperature for 30 minutes. The mixture was then treated with a solution of 0.8 g of 1 - (3-methoxyphenyl) -6-methyl-6-azabicyclo [3.2, i] ootan-7-one in 30 ml of benzene at room temperature dropwise over the course of 5 minutes offset. The resulting mixture was refluxed for 3 hours. To the mixture was added water while cooling with ice, and the resulting aqueous mixture was extracted with ether. The ether extract was washed with water, dried and then evaporated to remove the solvent, 0.8 g of 1- (3-methoxyphenyl) -6-methyl-7-ethylidene-6-azabicyclo [3 »2.1] octane being obtained . The product obtained was dissolved in 60 ml of ethanol. The ethanol solution was at 10 to 15 ⁰ O with 300 mg

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Sodium borohydride was added. The mixture was then stirred at room temperature for 20 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure. Water was added to the residue and the aqueous mixture was extracted with chloroform. The chloroform extract was washed with water, dried and then evaporated to remove the solvent. To the residue in ether was added methanolic hydrogen chloride and the crystalline precipitate formed was collected by filtration. The precipitate was recrystallized from a mixture of ethanol and ether. 0.4 g of 1- (3-methoxyphenyl) -6-methyl-7-ethyl-6-azabicyclo [3.2.1] octane hydrochloride were obtained. P = 176 to 178 ⁰ C.

Example 7

Optically active 1- (3-methoxyphenyl) ~ 6,7-dimethyl-6 ~ azabicyclo- ~ 3.2.1! Octane

8.5 g of 1- (3-methoxyphenyl) -6,7-dimethyl-6-azabieyclo- [3,2,1] octane and 5.3 g of d-tartaric acid were dissolved in 50 ml of ethanol with heating. The resulting solution was evaporated to dryness under reduced pressure. The residue was then recrystallized twice from 25 ml of methanol. 6.01 g of (-) - 1- (3-methoxyphenyl) -6,7-dimethyl-6-azabicyclo [3.2.1] octane tartrate were obtained in the form obtained from crystals. P a 174 to 176 ⁰ C. Ca] Jp + 22.3 ° (c »1.6, methanol)

Free base: [a] | ³ - 10.4 ° (c = 0.76, methanol)

That after isolation of (-) - 1- (3-methoxyphenyl) -6,7-dimethyl-6-azabicycloC 3.2.1] octane-d-tartrate obtained methanol filtrate was evaporated to dryness. The residue thus obtained was recrystallized from 15 ml of methanol 5.45 g (+) - 1- (3-methoxyphenyl) -6,7-dimethyl-6-azabieyolo-

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Obtained [3.2, i] octane-d-tartrate. P = 143 Ms 146 ⁰ O.

[oc] jp + 0.5 ° (c = 1.205, methanol)

Free base: [a] {p + 10.3 ° (c = 0.75, methanol)

Example 8

1 - (3-methoxyphenyl) -6-azabicyclo [3 # 2 ₁ 1 octane!

A mixture of 3 g of 1- (3-methoxyphenyl) -6-azabieyclo [3,2,1] octan-7-one, 2.7 g of lithium aluminum hydride and 150 ml of tetrahydrofuran was refluxed for 5 hours cooling, to the mixture β ml water eye is to decompose lithium aluminum hydride to _e su Then the aqueous mixture was added 100 ml of ether was added and the resulting mixture was filtered to remove insoluble iron © !! Material filtered. "The filtrate obtained was dried and then evaporated to remove the solvent" A methanolic oxalic acid solution was added to the residue in ether and the crystalline precipitate formed was collected by filtration. The precipitate was recrystallized from ethanol. 3 »65 g of 1- (3-methoxyphenyl) -6-azabicyclo [3.2, i] octane oxalate were obtained. F = 173 to 175 ⁰ C »

Example 9

Optically active 1 -C 3-M® tho3c grphenyl) -6-azabicycloi 3.2.1 toctane

8.7 g of 1- (3-Kethoxyph®nyl) -6-azabicyclo [3f2 ₉ i] octane and 6.2 g of d-tartaric acid were added to 30 ml of boiling ethanol. The resulting mixture was left to stand overnight. The crystalline precipitate formed was collected by filtration

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243A015

and then recrystallized from methanol. 5.65 g of (-) - 1- (3-methoxyphenyl) -6-azabieyolo [3.2.1] octane-d-tartrate were obtained. F = 190 to 192 ⁰ G.

Free base: [a] jp - 15.3 ° (c «0.64, methanol

The methanol filtrate obtained after isolating (-) - 1- (3-methoxyphenyl) -6-azabieyclo- [3.2.1] octane-d-tartrate was concentrated under reduced pressure. Aqueous ammonia was added to the residue and the resulting mixture was extracted with ether. The ether extract was washed with water, dried and then evaporated to remove the solvent. The residue thus obtained was dissolved in 30 ml of ethanol and the resulting solution was mixed with 4 g of 1-malic acid are added. The resulting solution was left to stand overnight. The formed crystalline precipitate was collected by filtration and then recrystallized from ethanol · Ss, 5.2 g of (+) - 1- (3-methoxyphenyl) -6-azabicyclo [3,2,1] -oetane-1-malate was obtained. F = 132 to 133 ⁰ C.

Free base: [oc] S ³ + 15.3 ° (c - 0.69, methanol). Example 10

1 - (3-Methoxyphen.vl) -e-methyl-e-azabieyclor 3.2.11 octane

0.85 g of 1- (3-methoxyphenyl) -6-azabioyclo [3.2.1] octane were in 10 al of ethanol were dissolved and 0.34 g of 37% formalin were added to the resulting solution. The resulting solution was heated on a water bath for 30 minutes. After cooling, the Solution mixed with 0.54 g of sodium borohydride. The solution was stirred at room temperature for 2 hours and then under concentrated under reduced pressure to remove the solvent. Water was added to the residue and the aqueous mixture was extracted with chloroform. The chloroformex

• 5098U / 1 122

The tract was washed with water, dried and then evaporated to remove the solvent. The residue in the ether was treated with methanolic hydrogen bromide and the crystalline precipitate formed was collected by filtration. The precipitate was recrystallized from a mixture of ethanol and ether. B. 0.81 g of 1- (3-methoxyphenyl) -6-methyl-6-azabicyclo [3.2.1] octane hydrobromide was obtained. F = 169 to 171 ⁰ G.

The following connections were made in the same way as described above:

(+) - 1- (3-Methoxyphenyl) -6-methyl-6-azabicyclo [3.2.1] octane picrate: F = 140 to 142 ⁰ Gj [a] Jp + 67.5 ° (c = 0.4 , Chloroform)

(-) - 1- (3-methoxyphenyl) -6-methyl-6-azabicyclo [3,2,1] octanpicrat: F = 140 to 142 ⁰ Oj [a] § ^3-68.2 ° (c = 0 * , 39; chloroform)

Example 11

1- (3-methoxyphenyl) -6- (3-benzqylpropyl) -6-azabicyclo [3.2.1] octane

A mixture of 0.8 g of 1- (3-methoxyphenyl) -6-azabicyclo [3,2, i] octane, 0.74 g 3-benzoylpropyl chloride, 0.8 g potassium carbonate, 0.05 g of potassium iodide and 20 ml of toluene was under for 24 hours Heated to reflux. After cooling, water was added to the mixture and the aqueous mixture was extracted with ether. The ether extract was washed with old water, dried and then evaporated to remove the solvent. The on residue thus obtained was dissolved in 2 ml of benzene. The benzene solution was applied to a column of 50 g of alumina upset. The column was then eluted with a mixture of 400 ml of benzene and 400 ml of η-hexane, and the eluate became

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243A015

evaporated to remove the solvent. To the residue in ether was added methanolic hydrogen chloride and the crystalline precipitate formed was collected by filtration. The precipitate was recrystallized from a mixture of ethanol and ether. 0.485 g of 1- (3-methoxyphenyl) -6- (3-benzoylpropyl) -6-azabicyclo- [3.2, i] octane hydrochloride were obtained. P ■ 167 to I69 ⁰ C.

Example 12

1- (3-methoxyphenyl) -6- [3y (4-fluorobenzoyljpropylj-ö-aza bicycloC 3.2.11octane

A mixture of 0.8 g of 1- (3-methoxyphenyl) -6-azabicyclo [3.2.1] octane, 0.81 g of 3- (4-fluorobenzoyl) propyl chloride, 0.8 g of potassium carbonate, 0.03 Potassium iodide and 20 ml of toluene were refluxed for 48 hours. After cooling, the mixture was treated in the same way as described in Example 11. 0.65 g of 1- (3-methoxyphenyl) -6- [3- (4-fluorobenzoyl) -propyl] -S-azabicyclo [3.2.1] octane hydrochloride were obtained. P = 195 to 196 ⁰ C (after recrystallization from a mixture of ethanol and ether).

Example 13

1- (3-Hydroxyphenyl) -fr-azabicyclof 3.2.11octane

A mixture of 9 g of 1- (3-methoxyphenyl) -6-azabicycloC3,2,1] octane oxalate and 90 ml of aqueous 48 # hydrobromic acid was refluxed for 1.5 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure. The residue obtained was recrystallized from a mixture of ethanol and ether · 7.7 g of 1- (3-hydroxyphenyl) -6-

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243A015

azabicyclo- [3.2, i] octane-hydrobromide. F = 239 to 242 ⁰ C.

Example 14

1- (3-methoxyphenyl) -e-benzyl ^ -methyl-a-azabicyclof, 3.2.11octane

(a) A mixture of 2.31 g of 1- (3-methoxyphenyl) -6-azabicyclo- -T-On, 0.418 g of 69 tiger sodium hydride and 30 ml

Dioxane was stirred at 60 to 62 ^° C. for 1 hour. After cooling, 1.52 g of benzyl chloride were added to the solution. The solution ^{was then stirred at 100 °} C. for a further 3 hours. After cooling, water was added to the solution. The resulting solution was evaporated to remove the solvent. Then water was added to the residue and the aqueous mixture was extracted with ether. The ether extract was dried and then evaporated to remove the solvent. The residue thus obtained was distilled under reduced pressure, whereby 3 »17 g of 1- (3-methoxyphenyl) -6-benzyl-6-azabicyclo [3.2.1] octan-7-one were obtained in the form of a viscous oil were, which ^{boiled at 195 0} C (bath temperature) / 0.05 mmHg.

(b) 0.262 g of lithium were added to 10 ml of absolute ether in a nitrogen atmosphere and a solution of 2.8 g of methyl j ο did in 5 ml of absolute ether at 0 to 5 ⁰ O was added dropwise to this. The resulting mixture was stirred at the indicated temperature for 50 minutes. Then the mixture was washed with a solution of. 1.5 g of 1- (3-Methoxyphenjrl) -6-benzyl-6-azabicyclo [3,2, i] octan-7-ott in 30 ml of absolute benzene at 5 to 10 ⁰ C. In a Stlckstoffatmosphärs dropwise. The mixture obtained was stirred at room temperature overnight. After adding water to the mixture, the bensol ether layer was washed with water and dried

5098U / 1122 owinal «s

and then evaporated to remove the solvent. The residue obtained was dissolved in 60 ml of ethanol and the ethanol solution 0.355 g sodium borohydride was added thereto at 8 to 10 ⁰ C. The ethanol solution was stirred at room temperature for 2 hours. Then the ethanol solution was concentrated under reduced pressure to remove the solvent. Water was added to the residue and the aqueous mixture was extracted with ether. The ether extract was extracted with 10 ^ aqueous hydrochloric acid. The aqueous extract was washed with ether, made alkaline with ammonia and extracted again with ether. The ether extract obtained was dried and evaporated to remove the solvent. The residue obtained was dissolved in 5 ml of chloroform. The chloroform solution was applied to a column containing 100 g of silica gel. Then the column was eluted with a mixture of 2850 ml of chloroform and 150 ml of methanol. The resulting eluate was evaporated to remove the solvent »whereby 0.59 g of 1- (3-methoxyphenyl) -6-benzyl-7-methyl-6" -azabicyclo [3 »2» 1] oetane were obtained.

Picrat: F * 184 to 186 ⁰ C (after recrystallization from methanol)

Example 15

1 - (^ - hydroxyrhenyl) -7-methrl-6-az »bicyclor3.2.1! Octane

(a) Kn OeBiSOh au »7 _f 21 g of 1- (3-methoxyphenyl) -6-benzyl-7- ■ * ethyl-6-asabicyclo [3.2.1] octane, 2.2 g of colloidal palladium and 165 si Acetic acid was shaken at room temperature for 2 hours in a minmr fasseretoffatmosphäre under atmospheric pressure. When the reaction had ended, the mixture was filtered off the catalyst. The filtrate was

■ - ■ '. "509814/1122 originally inspected

then evaporated to remove the solvent. Water was added to the residue and the aqueous mixture was made alkaline with ammonia. Then the aqueous mixture was extracted with ether. The ether extract was dried and evaporated to remove the solvent. 4.94 g of 1- (3-methoxyphenyl) -7-methyl-6-azabicyolo- [3.2 _f i] octane were obtained.

Hydrochloride: P = 174 Ms 176 ⁰ C (after recrystallization from a mixture of acetone, ethanol and ether).

(b) A mixture of 5.22 g of 1- (3-methoxyphenyl) -7-methyl-6-azabicyclo [3.2, i] octane hydrochloride and 52 ml of 47% aqueous hydrobromic acid was refluxed for 1 hour . After cooling, the crystalline precipitate formed was collected by filtration. The precipitate was recrystallized from a mixture of methanol and ether. 5.48 g of 1- (3-hydroxyphenyl) -7-methyl-6-azabicydoC3,2,1] octane hydrobromide were obtained. F β 282 to 284 ⁰ C.

Example 16

1- (3-hydroxyphenyl) -6-methyl-6-azabicyclo [3.2.1 "! Octane

A mixture of 0.4 g of 1- (3-methoxyphenyl) -6-methyl-6-azabicyclo [3.2.1] octane hydrobromide and 4 ml of aqueous 48? (Iger Hydrobromic acid was refluxed for 1.5 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure. Aqueous ammonia was added to the residue and the aqueous mixture was extracted with chloroform. The chloroform extract was washed with water, dried and then evaporated to remove the solvent. The residue obtained was recrystallized from ethyl acetate. 0.245 g of 1- (3-hydroxyphenyl) -6-methyl-6-azabicyclo [3.2, i] octane were obtained. F «144.5 to 145.5 ° C.

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_32- 243A015

The following connections were made in the same way as described above:

(+) - 1- (3-Hydroxyphenyl) -6-methyl-6-azabicyclo [3.2.1] octane: F - 150 to 152 ^° C; [a] | p + 19.5 ° (c = 0.37, 1N-HC1)

(-) - 1- (3-Hydroxyphenyl) -6-methyl-6-azabicyclo [3.2.1] octane: F = 150 to 152 ^° C; [α] | ³ - 19.0 ° (c = 0.4, 1N-HC1)

Example 17

1- (3-hydroxyphenyl) -6.7-dimethyl-6-azabicyclo [3.2.11octane

A mixture of 3.1 g of 1- (3-methoxyphenyl) -6,7-dimethyl-6-azabicyclo [3.2, i] octane hydrobromide and 30 ml of 48 # aqueous hydrobromic acid was under for 1.5 hours Heated to reflux. After the completion of the reaction, the mixture was concentrated under reduced pressure. Aqueous ammonia was added to the residue and the aqueous mixture was extracted with chloroform. The chloroform extract was washed with water, dried and then evaporated to remove the solvent. The residue obtained was recrystallized from ethyl acetate. 2.1 g of 1- (3-hydroxyphenylίο, 7-dimethyl-6-azabicyclo [3.2.1] octane were obtained. F = 182 to 183 ^° C

Hydrobromide F = 231 to 234 ^° C

Hydrochloride F = 238 to 240 ⁰ C (recrystallized from ethanol)

Sulphate F a 192 to 194 ⁰ C (recrystallized from ethanol)

Methanesulfonati F = 198 to 199 ⁰ C (recrystallized from ethanol)

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Acetats P = 123 to 125 ⁰ C (recrystallized from acetone ether)

Citrate P = 161 to 165 ⁰ C (recrystallized from methanol)

Oxalate: P = 201 to 202 ⁰ C (decomp.) (Recrystallized from methanol)

Maleate: P - 169 to 170 ⁰ C (recrystallized from methanol) Pumarate: P = 227 to 230 ⁰ C (recrystallized from methanol) Succinate: P = 152 to 154 ⁰ C (recrystallized from ethanol)

Phthalate: P = 136 to 142 ⁰ O (recrystallized from acetone-ether)

p-Toluenesulfonate: P = 168 to 170 ⁰ O (recrystallized from ethanol-ether)

Benzoats P «175 to 177 ⁰ C (recrystallized from methanol ether)

The following connections were made in the same way as described above:

(+) - 1- (3-hydroxyphenyl) -6, 7-dimethyl-6-azabioyclo [3 '2,1] octani P "152-153 ⁰ C; Hydrobromide: P * 261 to 263 ⁰ J [a] | p + 9.9 ° (c »0.79, water)} Hydrochloride: P - 254 to 256 ⁰ G

(-) -1 - (3-hydroxyphenyl) -6,7-dimethyl-6-a8abicyclo [3 '2,1] octan s P β 152-153 ° C »hydrobromide: P" 261-263 ⁰ C; [a] | ³ - 9.7 ° (c »0.79, water)

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Example 18

1 - (3-Hydroxyphenyl) -o-methyl ^ -ethyl-e-azapicyclof 3.2.11 octane.

1- (3-Methoxyphenyl) -6-methyl ^ -ethyl-ö-azabicycloC 3 »2.1] octane was treated as described in Example 16, with 1- (3-hydroxyphenyl) -6-methyl-7-ethyl -6-azabicyelo [3, 2 , 1] octane was obtained. Yield: $ 83.3> * Hydrobromide: P = s 245 to 247 ⁰ C

Example 19

1- (3-Hydroxyphenyl) ~ 6 »benzyl-» 7 ^ methyl ~ 6-azabic.ycloC 3.2.11 octane

A mixture of 0.3 g of 1- (3-methoxyphenyl) -o-benzyl- ^ - methyl-6-azabicyclo [3 »2, i] octane and 3 ml of 48% aqueous hydrobromic acid was refluxed for 30 minutes . The mixture was concentrated under reduced pressure. Water was added to the residue and the aqueous mixture was made alkaline with ammonia. Then the aqueous mixture was extracted with chloroform. The chloroform extract was washed with water, dried and then evaporated to remove the solvent. The residue in ether was treated with methanolic hydrogen chloride and the crystalline precipitate formed was collected by filtration. The precipitate was recrystallized from ethanol. 0.22 g of 1- (3-hydroxyphenyl) -6-benzyl-7-methyl-6-azabicyclo- [3.2, i] octane hydrochloride were obtained. P = 226 to 230 ⁰ C.

Example 20

1- (3-Hydroxyphenyl) -6- (3-benzoylpropyl) -6-azabicyclo [ ^ ₉ 2r ₉ \\ " octane

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A mixture of 0.42 g of 1- (3-methoxyphenyl) -6- (3-benzoylpropyl) -6-azabicyelo [3.2, i] octane and 4 ml of 47% aqueous hydrobromic acid was refluxed for 45 minutes heated. The mixture was concentrated under reduced pressure. The residue obtained was washed with aqueous Ammonia neutralized and extracted with ether. The ether extract was dried and then dried to remove the solvent evaporated.-Then the residue in ether was treated with methanol! Collected precipitate by filtration. 0.3 g of 1- (3-hydroxyphenyl) -6- (3-benzoylpropyl) -6-azabicyclo [3,2,1] octane hydrochloride were obtained obtained in the form of an amorphous powder.

Infrared absorption spectrum:

( _cm -1). ₃₂ 00 (0H), 2300 - 2800 (= NH *)

1680 (C = O)
Mass analysis: 349 (M ⁺ )

Example 21

1- (3-Hydroxyphenyl) -6- [3 = - (4 ^m fluorobenzoyl) propyl] -6-aza bicyclo [3.2.11 octane __

A mixture of 0.5 g of 1- (3 ™ methoxyphenyl) -6- [3- (4-fluorobenzoyl) propyl] -6-azabieyclo [3.2 ₉ i] octane and 5 ml of 47% aqueous hydrobromic acid was added for 1 hour heated under reflux for a long time. The ßemiseh was then treated as described in Example 20. O ₉ 34 g of 1- (3-hydroxyphenyl) -6- [3- (4-fluorobenzoyl) propyl] -6-azabieyclo [3.2, i] octane hydrochloride were obtained obtained in the form of an amorphous powder.

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Infrared absorption spectrum:

ν chloroform (cm- ¹ ): 3200 (0H), 2300

1680 (0 = 0)

Mass analysis: 367 (M ⁺ )

Example 22

1- ( 3- Hydroxyphenyl) -6.7-dimethyl-6-azabicyclo [3 * 2.11octane

A mixture of 1.1 g 1- (3-hydroxyphenyl) -7-methyl-6-azabicyclo [3.2, i] octane, 0.7 g methyl 3odide, 0.6 g sodium bicarbonate and 10 ml dimethylformamide was added at 70 to 80 ⁰ C for 2 hours. After cooling, the mixture was added with water and the aqueous mixture was extracted with chloroform. The chloroform extract was washed with water, dried and then evaporated to remove the solvent. The residue in ether was treated with methanolic hydrogen chloride and the crystalline precipitate which had formed was collected by filtration. The precipitate was recrystallized from ethanol. 0.6 g of 1- (3-hydroxyphenyl) -6,7-dimethyl-6-azabicyclo [ 3 , 2.1] octane hydrobromide was obtained. P = 231 to 233 ⁰ C

Example 23 1- (3-hydroxyphenyl) -6.7-dimethyl-6-azabicyclor 3.2.11octane

0.37 g of 37% formalin was added to a solution of 0.5 g of 1- (3-hydroxyphenyl) -7-methyl-6-azabicyclo [3.2.1] octane in 10 ml of ethanol. The solution was ^{heated at 50 °} C. for 30 minutes. After cooling, 0.3 g was added to the solution

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Sodium borohydride added * The resulting mixture was stirred at room temperature for 2 hours. Then the mixture was concentrated under reduced pressure. Water was added to the residue and the aqueous mixture was extracted with a mixture of 50 ml of chloroform and 5 ml of ethanol. The chloroform-ethanol extract was dried and then evaporated to remove the solvent. The residue in ether was treated with methanolic hydrogen chloride and the crystalline precipitate formed was collected by filtration. The resulting precipitate was recrystallized from ethanol. 0.2 g of 1- (3-hydroxyphenyl) -6,7-dimethyl-6-azabicyclo [3 »2.1] octane hydrobromide was obtained. F = 231 to 233 ⁰ C.

Example 24

1- (3-Hydroxyphenyl) -6.Y-dimethyl-e-azabicycloC 3 «2.11octane

A mixture of 0.3 g of 1- (3-hydroxyphenyl) -7-methyl-6-azabi- cycloC3,2,1] octane and 10 ml of ethyl formate was refluxed for 4 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in 5 ml of tetrahydrofuran and the tetrahydrofuran solution was added dropwise to 10 ml of tetrahydrofuran containing 0.3 g of lithium aluminum hydride. The mixture was refluxed for 2 hours. Then water was added to the mixture to decompose lithium aluminum hydride. The aqueous mixture was then acidified with 10% hydrochloric acid. After the aqueous mixture was made alkaline with ammonia, it was extracted with a mixture of 50 ml of chloroform and 5 ml of methanol. The extract was dried and then evaporated to remove the solvent. The residue in ether was treated with methanolic hydrogen chloride and the crystalline

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line precipitate collected by filtration. The precipitate was recrystallized from ethanol. 0.16 g of 1 - (3-hydroxyphenyl) -6,7-dimethyl-6-azabicyclo [3.2.2] octane hydrobromide was obtained. F = 231 to 233 ⁰ C.

Example 25

1- (3-hydroxyphenyl) -6,7-dimethyl-6-azabicyclo [3.2.1! Octane

A solution of 0.25 g Äthylchloroformiat in 5 ml of chloroform was added dropwise at 5 to 10 ⁰ C to a mixture of 0> 5 g of 1- (3-hydroxyphenyl) -7-methyl-6-azabicyclo [3,2, i] octane, 0.5 g potassium carbonate and 20 ml. Dimethylformamide were added. The resulting mixture was stirred for 2 hours. Then water was added and the aqueous mixture was extracted with chloroform. The chloroform extract was dried and then evaporated to remove the solvent. The residue thus obtained was dissolved in 5 ml of tetrahydrofuran, and the tetrahydrofuran solution was added dropwise to 10 ml of tetrahydrofuran containing 0.4 g of lithium aluminum hydride. The resulting mixture was refluxed for 3 hours and then treated in the same manner as described in Example 24. 0.28 g of 1- (3-hydroxyphenyl) -6,7-dimethyl-6-azabicyclo-C3,2,1] octane hydrobromide were obtained. F = 231 to 233 ⁰ C.

Example 25

ί- (3-hydroxyphenyl) -6-ethy-yl-7-methyl-6-azabicycloC 3.2.11 octane

A mixture of 0.35 g of 1- (3-hydroxyphenyl) -7-methyl-6-azabicycloC3,2,1] octane, 0.31 g of ethyl iodide, 0.31 g of sodium bicarbonate and 5 ml of dimethylformamide was at 70 to 80 ⁰ C 2 hours

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stirred for a long time. After cooling, water was added to the mixture and the aqueous mixture was extracted with ether. The ether extract was washed with water, dried and then evaporated to remove the solvent. The residue in ether was treated with methanolic hydrogen chloride and the crystalline precipitate formed was collected by filtration. The precipitate was recrystallized from isopropanol. 0.38 g of 1- (3-hydroxyphenyl) -6-ethyl-7-methyl-6-azabicyclo [3.2.1] octane hydrochloride were obtained. F = 228bis 231 'C ⁰

Example 27

1- (3-hydroxyphenyl) -6-propyl-7-methyl-6-azabicyclo [3.2.11 octane

A mixture of 0.35 g of 1- (3-hydroxyphenyl) -7-methyl-6-azabicyclo [3.2.1] octane, 0.34 g of propyl iodide, 0.34 g of sodium bicarbonate and 5 ml of dimethylformamide was added at 70 to 80 ^° C. for 2 hours. After cooling, the mixture was treated as described in Example 26. 0.32 g of 1- (3-hydroxyphenyl) -6-propyl-7-methyl-6-azabicyclo [3.2.1] octane hydrochloride was obtained. F = 244 to 248 ⁰ C.

Example 28

1- (3-Hydroxyphenyl) -ö -cyclopropylmethyl ^ -methyl-e-azabicyclo- [3.2.i "loctane

A mixture of 0.35 g of 1- (3-hydroxyphenyl) -7-methyl-6-azabicyclo [3.2, i] octane, 0.23 g of cyclopropylmethyl bromide, 0.2 g of sodium bicarbonate and 5 ml of dimethylformamide was added at 70 to 80 ^° C. for 2 hours. After cooling, the mixture was treated as described in Example 26. It was 0.3 g

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1- (3-Hydroxyphenyl) -ö -cyclopropylmethyl ^ -methyl-ö -azabicyclo [3.2.1] octane hydrochloride was obtained. F = 216 to 219 ⁰ (recrystallized from a mixture of ethanol and ether).

Example 29

1- (3-Hydroxyphenyl) ~ 6-n ~ amyl-7-meth.vl-6-azabicyclo [3 «2.11 octane

A mixture of 0.35 g of 1- (3-hydroxyphenyl) -7-methyl-6-azabicyclo [3.2, i] octane, 0.3 g of n-amyl bromide, 0.3 g of lithium bicarbonate and 5 ml of dimethylformamide was added 100 ^° C. for 2 hours. After cooling, the mixture was treated in the same way as described in Example 26. 0.39 g of 1- (3-hydroxyphenyl) -6-n-amyl-7-methyl-6-azabicyclo- [3.2.1] octane hydrochloride were obtained. P = 151 to 154 ^° C. (recrystallized from acetone).

Example 30

1- (3-Hydroxyphenyl) -6- n -hexyl-Y-methyl-e-azabicycloE 3,2,1] octane

A mixture of 0.35 g of 1- (3-hydroxyphenyl) -7-methyl-6-azabicyclo [3.2, i] octane, 0.32 g of n-hexyl bromide, 0.17 g of sodium bicarbonate and 5 ml of dimethylformamide was added 70 to 80 ⁰ C

Stirred for 2 hours. After cooling, the mixture was treated as described in Example 26. 0.5 g of 1- (3-hydroxyphenyl) -6-n-hexyl-7-methyl-6-azabicyclo [3.2.1] octane hydrochloride was obtained. F = 164 to 165 ^° C. (recrystallized from ethanol).

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Example 31

1- (3-Hydroxyphenyl) -6 ~ n -hexyl-6-azabicyclo [3.2.11 octane

0.73 g of n-caproyl chloride were added to a mixture of 0.5 g of 1- (3-hydroxyphenyl) -6-azabicyclo [3.2, i] octane, 0.62 g of triethylamine and 10 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 4 hours. Then water was added to the mixture and the aqueous mixture was extracted with chloroform. The chloroform extract was washed with water, dried and then evaporated to remove the solvent. The residue obtained was dissolved in 40 ml of tetrahydrofuran. To the solution was added 0.9 g of lithium aluminum hydride and the resulting solution was refluxed for 12 hours. After cooling, the reaction solution was added with water to decompose lithium aluminum hydride. The reaction solution obtained was acidified with hydrochloric acid. Thereafter, the reaction solution was made alkaline with aqueous ammonia and extracted with chloroform. The chloroform extract was washed with water, dried and then evaporated to remove the solvent. The residue was dissolved in 5 ml of chloroform. The chloroform solution was applied to a column containing 50 g of silica gel. Then the column was eluted with a mixture of 950 ml of chloroform and 50 ml of methanol, and the eluate was evaporated to remove the solvent. The residue obtained was distilled under reduced pressure, giving 0.48 of 1- (3-Hydr.oxyphenyl) -6-n-hexyl-6-azabicyclo [3.2.1] octane in the form of a viscous oil with a boiling point of 250 ⁰ C (bath temperature) / 0.1 mmHg were obtained.

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243A015

Example 32

1- (3-hydroxyphenyl) -6-cyclobutylmethyl-6-azabicyclo [3.2.1] octane '

0.52 g of cyclobutylcarbonyl chloride were added to a mixture of 0> 43 g of 1- (3-hydroxyphenyl) -6-azabicyclo [3.2, i] octane, 0.51 g of diethylamine and 8 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 15 hours. Then water was added to the mixture and the aqueous mixture was extracted with chloroform. The chloroform extract was washed with water, dried and then evaporated to remove the solvent. The residue obtained was dissolved in 25 ml of tetrahydrofuran. To the solution, 0.6 g of lithium aluminum hydride was added and the resulting solution was refluxed for 3 hours. After cooling, the reaction solution was added with water to decompose lithium aluminum hydride. The reaction solution was then acidified with hydrochloric acid. Then the reaction solution was made alkaline with aqueous ammonia and extracted with chloroform. The chloroform extract was washed with water, dried and then evaporated to remove the solvent. The residue was dissolved in 5 ml of chloroform. The chloroform solution was applied to a column of 30 g of silica gel. The column was then eluted with a mixture of 500 ml of chloroform and 25 ml of methanol and the eluate was evaporated to remove the solvent. The obtained residue was distilled under reduced pressure to give 0.42 g iO HydroxyphenylJ-ö-cyclobutyl-methyl-ö-azabiqyclo [3,2,1] octane in the form of a viscous oil having a boiling point of 240 ⁰ C (bath temperature) / 0.1 mmHg were obtained.

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Example 33

1 * ■ (3-hydroxyphenyl) -o-phenethyl-T-methyl-o-azabieycloC 3 _y 2.1] octane

0.62 g of phenylacetyl chloride was added dropwise with ice cooling to a mixture of 0.35 g of T- (3-hydroxyphenyl) -7-methyl-6-azabicyclo [3.2, i] octane, 1 ml of triethylamine and 7 ml of methylene dichloride. The resulting mixture was stirred at room temperature for 20 hours. Then the mixture was concentrated under reduced pressure. Water was added to the residue and the aqueous mixture was extracted with benzene. The benzene extract was washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate and water. The benzene extract was dried and evaporated to remove the solvent. The residue obtained was dissolved in 12 ml of tetrahydrofuran. The TetrahydrofU SiJdsund ¹ was mixed with 0.6 g of lithium aluminum hydride and the resulting solution was heated under reflux for 1.5 hours. After cooling, the reaction solution was added with dilute hydrochloric acid to decompose lithium aluminum hydride. Then the reaction solution was made alkaline with aqueous ammonia, whereupon it was extracted with chloroform. The chloroform extract was washed with water, dried and then evaporated to remove the solvent. The residue was dissolved in 5 ml of chloroform. The chloroform solution was applied to a column containing 20 g of silica gel. Then the column was eluted with a mixture of 300 ml of chloroform and 50 ml of methanol and the eluate was evaporated to remove the solvent. The residue in ether was treated with methanolic hydrogen chloride and the crystalline precipitate which had formed was collected by filtration. The precipitate was recrystallized from acetone. 0.09 g of 1- (3-hydroxyphenyl) -ö-phenethyl-T-methyl-ö-azabicyclot 3 »2.1] octane hydrochloride were obtained. P = 231 to 233 ° C.

5098U / 1 122

Example 34

1- (3-Hydroxyphenyl) -6- (2-benzoylethyl) -6-azabicyclo [3.2.1] octane

A mixture of 0.4 g of 1- (3-hydroxyphenyl) -6-azabicyclo [3,2,1] octane, 0.4 g of 2-benzoylethyl chloride, 0.4 g of potassium carbonate, 0.03 g of potassium iodide and 5 ml of dimethylformamide was stirred for 4 hours at 100 ⁰ C in a Stickstoffat / gas atmosphere. After cooling, the mixture was added with water and the aqueous mixture was extracted with chloroform. The chloroform extract was washed with water, dried and then evaporated to remove the solvent. The residue obtained was dissolved in 5 ml of chloroform. The chloroform solution was applied to a column containing 40 g of silica gel. Then the column was eluted with a mixture of 300 ml of chloroform and 15 ml of methanol, and the eluate was evaporated to remove the solvent. The residue in ether was treated with methanolic hydrogen chloride and the crystalline precipitate which had formed was collected by filtration. The precipitate was recrystallized from a mixture of methanol and ether. 0.1 g of 1- (3-hydroxyphenyl) -6- (2-benzoylethyl) -6-azabicyclo [3 »2.1] octane hydrochloride were obtained. P β 187 to 189 ⁰ C

Example 35

1 - (3-Hydro3-cyphenyl) -6- (2-benzoylethyl) -6-azabicyclor 3.2.11 octane

A mixture of 0.4 g of 1- (3-hydroxyphenyl) -6-azabicyelo [3,2, i] octane, 0.69 g of N- (2-benzoylethyl) -N, N, N-trimethylaminoium; iodide, 0.24 g of potassium carbonate and 5 ml of dimethylformamide was added to Stirred at room temperature in a nitrogen atmosphere for 5 hours. After the completion of the reaction, the mixture was washed with water

5098U / 1122

added and the aqueous mixture extracted with ether. The ether extract was dried and then evaporated to remove the solvent. The residue in ether was treated with methanolic hydrogen chloride and the crystalline precipitate which had formed was collected by filtration. The precipitate was recrystallized from a mixture of methanol and ether. 0.64 g of 1- (3-hydroxyphenyl) -6- (2-benzoylethyl) -6-azate> icyclo [3.2.1] octane hydrochloride were obtained. F = 187 Ms 189 ⁰ C.

Example 36

1 -. (3-Acetyloxyphenyl) -6. 7-dimethyl-6-azabicrclor 3.2.11 octane

A mixture of 0.5 g of 1- (3-hydroxyphenyl) -6 _> 7-dimethyl-6-azabicydo [3f2, i] octane hydrobromide, 10 ml of acetic anhydride and 0.3 g of potassium acetate was heated on a water bath for 1 hour . After the reaction had ended, the mixture was concentrated under reduced pressure. Ajither and water were added to the residue and the aqueous mixture was made alkaline with 5% aqueous sodium bicarbonate. The aqueous mixture was then extracted with ether. The ether extract was washed with water, dried and then evaporated to remove the solvent. The residue in ether was treated with methanolic hydrogen chloride and the crystalline precipitate which had formed was collected by filtration. The precipitate was recrystallized from a mixture of ethanol and ether. 0.37 g of 1- (3-acetyloxyphenyl) -6,7-dimethyl-6-azabicyclo [3.2, i] octane hydrochloride were obtained. F = 250 to 252 ⁰ C.

The following connections were made in the same way as described above:

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(+) - 1- (3-Acetyloxyphenyl) -6,7-dimethyl-6-azabicyclo [3,2,1] octane hydrochloride: F = 207-211 ⁰ C; [α] | ⁴ + 9.9 ° (c = 0.45, methanol)

(-) - 1- (3-Aeetyloxyphenyl) -6,7-dimethyl-6-azabicyclo [3,2,1] octane hydrochloride: F = 208 to 21O ⁰ C; [α] ^ ⁴ - 9.9 ⁹ (c = 0.38, methanol)

Example 37

1- (3-Acetyloxyphenyl) -6-methyl-7-ethyl-6-azabicyclo [3.2.1] octane

1- (3-Hydroxyphenyl) -6-methyl-7-ethyl-6-azabicyclo [3.2.1] octane was treated as described in Example 36, with 1- (3-acetyloxyphenyl) -6-methyl-7- ethyl-6-azabicyclo [3.2.1] octane hydrobromide was obtained, yield: 65 #, F = 237 to 240 ⁰ C,

Example 38

1- (3-propionyloxyphenyl) -6.7-dimethyl-6-azabicyclo [3.2.11octane

A mixture of 0.25 g of 1- (3-hydroxyphenyl) -6,7-dimethyl-6-azabicyclo [3.2.1] octane hydrobromide, 5 ml of propionic anhydride and 0.3 ml of pyridine was at 80 to 90 ⁰ C heated for 2 hours. After cooling, the crystalline precipitate formed was collected by filtration, washed with acetone and then recrystallized from a mixture of chloroform and ether , 4.1] octane hydrobromide. F = 226 to 228 ⁰ C ₄

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Example 39

1- (3-n-Hexanoyloxyphenyl) -6,7-dimethyl-6-azabicyclo [3, 2,1] octane

A mixture of 0.25 g of 1- (3-hydroxyphenyl) -6,7-dimethyl-6-azabicyclo [3.2, i] octane hydrobromide, 8 ml of n-hexanoic anhydride, and 0.1 ml of pyridine was added at 120 ⁰ C heated for 3 hours. After the reaction had ended, the equipment was concentrated under reduced pressure. Ether was added to the residue and the crystalline precipitate which had formed was collected by filtration. The precipitate was recrystallized from a mixture of chloroform and ether. There were 0.155 g of 1- (3-n-Hexanoyloxyphenylj-e ^ -dimethyl-ö-azabicyclot 3,2, i] octane obtained. F = 95 to 97 ⁰ C.

Example 40

1- (3-Benzoyloxyphenyl) -6,7-dimethyl-6-azabicyclo [3 * 2.11 octane

0.35 g of 1- (3-hydroxyphenyl) -6,7-dimethyl-6-azabicyclo [3,2,1] octane was dissolved in 4 ml of fyridine, and the resulting solution was mixed with a solution of 0.28 g of benzoyl chloride in 2 ml of benzene are added. The resulting mixture was stirred for 45 minutes. Then the mixture was concentrated under reduced pressure. The residue obtained was washed with ether and then recrystallized from a mixture of ethyl acetate and acetone. 0.43 g of 1- (3-benzoyloxyphenyl) -6,7-dimethyl-6-azabicyclo [3.2.1] octane hydrochloride was obtained. F = 207 to 209 ⁰ C.

5098U / 1 122

Example 41

1- (3-Ni cotinoyloxyphenyl) -6,7-dimethyl-6-azabicyclo [3.2.1] octane

To a solution of 0.231 g of 1- (3-hydroxyphenyl) -6,7-dimethyl-6-azabicyclo [3.2, i] octane in 4 ml of pyridine, 0.376 g of nicotinoyl chloride hydrochloride was added while cooling with ice. The resulting solution was stirred at room temperature overnight. Then the solution was concentrated under reduced pressure. The residue obtained in this way was washed with ether and then recrystallized from a mixture of ethanol, acetone and ether. 0.17 g of 1- (3-nicotinoyloxyp / henyl) -6,7-dimethyl-6-azabicyclo [3,2,1-octane dihydrochloride hemihydrate was obtained. P = 210 to 218 ⁰ C.

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Claims (40)

Claims 1.'1-Phenyl-δ-azabicyclof3,2,1] octanes of the formula where mean: -R is a hydrogen atom, a phenyl radical, an alkyl radical
with 1 to 5 carbon atoms, a cycloalkyl group with 3 or 4 carbon atoms, or an alkyl group with 1
up to 5 carbon atoms, which is substituted with a phenyl, benzoyl or 4-fluorobenzoyl radical, R is a hydrogen atom or an alkyl radical with 1 to 3
Carbon atoms, and R- * is a hydrogen atom, an alkanoyl radical with 2 to 6 Koh fuel atoms, a benzoyl radical or a nicotinoyl radical, or a pharmaceutically acceptable acid addition salt
the same. 2. A compound according to claim 1, characterized in that in the formula given: R is a hydrogen atom or a methyl, ethyl, butyl, amyl, cyclopropyl, cyclobutyl, phenyl, benzyl, benzoylmethyl, 2-benzoylethyl or 2- (4-pluorobenzoyl) - ethyl residue, J _{5 0} 9 β 1 4/1 1 2 2- so 2
R is a hydrogen atom or a methyl or ethyl radical, and R ^ a hydrogen atom or an acetyl, propionyl, Hexanoyl, benzoyl or hicotinoyl radical. 3. A compound according to claim 1 ", characterized in that in the given formula mean: R is a hydrogen atom or an η-butyl, n-amyl, Cyclopropyl, benzyl-y 2-benzoylethyl or 2- (4-pluorobenzoyl) ethyl radical, 2
R is a hydrogen atom or a methyl radical, and R ^ is a hydrogen atom or an acetyl, propionyl, benzoyl or nicotinoyl radical. 4. Compound according to Claim 3, characterized in that R, R and R ^J denote hydrogen atoms. " 5. A compound according to claim 3 »characterized in that R ¹ υ th. 1 λ 2 R and R ^J hydrogen atoms and R denotes a methyl radical 6. A compound according to claim 3, characterized in that 12 "\ R is an n-butyl radical, R is a methyl radical and R ^{J is} a hydrogen atom. 7 »Compound according to claim 3» characterized in that R is an n-amyl radical, R
mean hydrogen atom. R ^{1 is} an n-amyl radical, R ^{2 is} a methyl radical and R ^ is a water 8. A compound according to claim 3 »characterized in that 1 2 ^ R ^{1 is} a cyclopropyl radical, R is a methyl radical and R- * is a hydrogen atom. 0U30II * / I UZ 9. A compound according to claim 3 »characterized in that 1 ? R eilen benzyl radical, R mean hydrogen atom. 1 ? · Λ R is benzyl, R is methyl and R ^{J is} water 10. A compound according to claim 3, characterized in that 1 2 ^ R is a 2-benzoylethyl radical and R and R ^{J are} hydrogen atoms. 11. A compound according to claim 3, characterized in that R ^{1 is} a 2- (4-fluorobenzoyl) ethyl radical and R ² and R ^ are hydrogen atoms. 1 2 λ R is hydrogen, R is methyl and R ^{J is} 1 2} R is a hydrogen atom, R is a methyl radical and R is a 12. A compound according to claim 3, characterized in that R ^{1 is} a hydrogenate
Mean acetyl radical. 13. Compound according to Claim 3, characterized in that R is a hydrogen atom
Mean propionyl radical 14. A compound according to claim 3 »characterized in that R ^{1 is} a hydrogenate ' Mean benzoyl radical 15. A compound according to claim 3, characterized in that R is a hydrogen atom, Mean nicotinoyl radical. 1 2 "\ R is hydrogen, R is methyl and R is R is a hydrogen atom, R is an ethyl radical and R ^{J is} a 16. A compound according to claim 1, characterized in that the compound is in the form of an optically active (+) - isomer is present. 17. A compound according to claim 2, characterized in that the compound is in the form of an optically active (+) - isomer is present. 5098U / 1 1 22 18. A compound according to claim 3, characterized in that the compound is in the form of an optically active (+) isomer. 19. A compound according to claim 4, characterized in that the compound is in the form of an optically active (+) isomer. 20. A compound according to claim 5, characterized in that the compound is in the form of an optically active (+) - isomer is present. 21. Process for the preparation of a 1-phenyl-6-azabicyclo [3,2, i] · Octanes according to Claims 1 to 20 of the formula I where mean: R ^{1 is} a hydrogen atom, a phenyl radical, an alkyl radical with 1 to 5 carbon atoms, a cycloalkyl radical with 3 or 4 carbon atoms, or an alkyl radical with up to 5 carbon atoms which is substituted with a phenyl, benzoyl or 4-fluorobenzoyl radical, R ^{2 is} a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms, and R ^ is a hydrogen atom, an alkanoyl radical with 2 to 6 carbon atoms, a benzoyl radical or a nicotinoyl radical, 5098U / 1122 Sl characterized in that one A) a) a compound of the formula II 1 2
wherein R and R have the meaning given, to a compound of the formula Ia N-CJH ₂ R 1 2
where R and R have the meaning given, demethylated, * b) a compound of the formula III wherein R has the meaning given, with a compound of the formula IV 5098U / 1122 wherein X is a halogen atom or a radical of the formula -N ^# (CH.J, J ^e "and R has the meaning given, condensed to a compound of the formula Ia, or c) a compound of the formula III given with a compound of the formula V R ¹ -COOH wherein R has the meaning given, or a functional derivative thereof, condensed and that obtained N-acyl derivative of the compound III to one Compound of the given formula Ia reduced, and optionally B) the compound of the formula Ia given with a compound of the formula VI R ⁴ -OH wherein R ^ ^{- is} an alkanoyl radical having 2 to 6 carbon atoms, a benzoyl or a nicotinoylrean, or a functional derivative thereof, acylated to give a compound of the formula where R, R and R ^ have the meaning given 5098U / 1 122 SS 22. The method according to claim 21, characterized in that the demethylation is carried out by treating the Compound II with hydrobromic acid, hydroiodic acid, aluminum chloride, boron chloride, boron bromide or pyridine hydrochloride. 23 · The method according to claim 21 ,. characterized in that the demethylation is carried out at a temperature of -20 to 200 ^° C. 24. The method according to claim 21, characterized in that the condensation of the compounds III and IV is carried out at a temperature of 20 to 160 ^° C. in the presence of an acid acceptor. 25. The method according to claim 24, characterized in that the acid acceptor triethylamine, pyridine, quinoline, Alkali metal acetate, alkali metal hydroxide or alkali metal carbonate used. 26. The method according to claim 21, characterized in that the condensation of the compound III with a functional derivative of the compound V is carried out at a temperature of 0 to 120 ⁰ C in the presence of an acid acceptor, and the subsequent reduction of the resulting N-acyl derivative of the compound III by treating the same with lithium aluminum hydride, aluminum hydride or diborane. 27. The method according to claim 26, characterized in that the functional derivative is the corresponding acid anhydride , the corresponding acid halide or the corresponding acid ester, and triethylamine as the acid acceptor, Pyridine, quinoline, alkali metal acetate, alkali metal hydroxide or alkali metal carbonate are used, and the reduction is used 5098U / 1 1 22 at a temperature of 25 Ms 70 ⁰ G 28. The method according to claim 21, characterized in that the condensation of the compound III with the compound V at a temperature of -10 to 80 ⁰ G in the presence of STjSP-dicyelohexylcarbodiimide or N-cyclohexyl-N'-morpholino-methylearbodiimide in one Carries out solvent, and the subsequent reduction of the obtained Bf-acyl derivative of the compound ΙΙΪ by treating the same with lithium aluminum hydride, aluminum hydride or diborane at a temperature of 25 Ms 70 ⁰ G is carried out. 29 · Tsrfahren according to claim 21, characterized in that the acylation of the compound Ia with a functional derivative of the compound VI bsi a temperature of 0 ⁰ Ms 180 G in the presence of a Säuy AKZ @ @ ptors performs. 30. The method according to claim 29 »characterized in that the corresponding acid anhydride or acid halide is used as the fractional derivative, and pyridine as the acid acceptor, Triethylaaing quinoline, alkali metal acetate, alkali metal hydroxide or alkali metal carbonate is used. Process according to Claim 21, characterized in that the acylation of the compound Ia of the compound VI is carried out at a temperature of -10 to 80 ⁰ C in the presence of NjiP-dicyclohexylcarbodiimide or 2MJyelohexyl-N * -morpholinomethylearbodiimide in a solvent. 32. Process for the preparation of a compound of formula I. 5098U / 1122 wherein "means;
ρ R is a hydrogen atom or an alkyl radical with 1 "to 3 Carbon atoms -and R- ^ a hydrogen atom or an alk & üoylrest with 2 to 6 carbon atoms © of a benzoyl or nicotinoyl residue, characterized in that a compound of the formula III wherein R has the meaning given, reductively methylated to a compound of the formula Ic N-CH. where R has the meaning given ©, and then given optionally the compound of the formula Ic is acylated with a compound of the formula VI. R ⁴ -OE wherein R ^ is an alkanoyl radical having 2 to 6 carbon atoms or a benzoyl or nicotinoyl radical, or with a functional derivative thereof. 5098U / 1122 33. The method according to claim 32, characterized in that the reductive methylation by condensation of the Compound III with formaldehyde or alkyl chloroformate, and subsequent reduction of the condensation product obtained with alkali metal borohydride or lithium aluminum hydride performs. 34. The method according to claim 33, characterized in that the condensation is carried out at a temperature of 0 to 100 ⁰ C in a solvent and the subsequent reduction is carried out at a temperature of 20 to 80 ⁰ C in a solvent. 35. The method according to claim 32, characterized in that the reductive methylation durch.Kondensation der Compound III with formaldehyde or alkyl chloroformate and subsequent catalytic hydrogenation of the condensation product formed in the presence of a catalyst in a hydrogen atom in a solvent. 36. The method according to claim 35, characterized in that the condensation is carried out at a temperature of 0 to 100 ⁰ C in a solvent and the subsequent catalytic hydrogenation is carried out at a temperature of 20 to 40 ⁰ C, .and as a catalyst platinum dioxide, platinum, Palladium-carbon or Raney nickel is used. 37. The method according to claim 32, characterized in that . the acylation of the compound Ic with a functional derivative of the compound VI is carried out at a temperature of from 0 to 180 ^° C. in the presence of an acid acceptor. 5098U / 1 122 38 ", method according to claim 37? characterized in that the corresponding acid anhydride or acid halide is used as the functional derivative and pyridine triethylamine, quinoline ₉ alkali metal acetate, alkali metal hydroxide or alkali metal all carbonate is used as the acid peak septor «, 39 »Process according to claim 32 _9, characterized in that the acylation of the compound Ic with the compound VI is carried out at a temperature of -10 to 80 ⁰ C in the presence of N _? N ^S -dicyclohexylcarbodiimide or M ^ GyelQiiaxyl-N ¹ -morpholinomethylcarbodiimid in a solvent. 40. Therapeutic agent ₉ identified by the content of a compound of the formula what mean! R is a hydrogen atom, a phenyl radical, an alkyl radical with 1 to 5 carbon atoms ^ a Gyeloalkylrest with 3 or 4 carbon atoms, or an alkyl radical with up to 5 carbon atoms, which is substituted with a phenyl, benzoyl or 4-I "luorobenzoyl radical, R is a hydrogen atom or an alkyl radical with 1 to 3 Carbon atoms, and _R 3 is a hydrogen atom, an alkanoyl radical with 2 to 6 carbon atoms, a benzoyl radical or a Nico- 5098U / 1 122 1.0 tinoyl radical, or a pharmaceutically acceptable acid addition salt thereof, as an active component, optionally alongside a pharmaceutically acceptable carrier therefor. 5098U / 1122