CS273650B2 - Preparation of new derivatives azabicyclo-/3,3,1/nonane - Google Patents

Abstract

New compounds with pharmacological, particularly antiarrhythmic action of general formula I, where R<1>, R<2> and R<3> represent the same or different C1-C4 alkyl group or one of these symbols represents the benzyl group and the others represent C1-C4 alkyl group, R<4> represents a esterified hydroxyl group of general formula -OOC-R<6>, where R<6> represents the C1-C4 alkyl group or C5-C6 cycloalkyl group or possibly halogen or one or more C1-C4 alkyl groups or C1-C4 alkoxy groups, nitro groups, phenol groups, phenoxy groups or trifluoromethyl groups substituted phenol or benzyl group or naphthyl group, which is possibly halogenised or hydrogenised, or cinnamyl group, which is possibly substituted by halogen or C1-C4 alkoxy groups, or benzhydryl group or 1,1-diphenylhydroxymethyl group or, as a heterocyclic substituent, the thenyl or 9-xanthenyl group, and their pharmaceutically suitable additive salts with acids are prepared by leaving a new alcohol of general formula VIII to react, where R<1>, R<2> and R<3> have the abovementioned meaning, with a derivative of general formula R<6>-COX, where R<6> has the abovementioned meaning and X represents halogen or the C1-C4 alkoxy group, in the presence of a reagent of weighting acid or organic solvent and catalyst and the acquired ester derivative of general formula I is possibly divided into its alloisomers and/or it is transformed to its additive salts with acids.<IMAGE>

Description

(57) Novel compounds having a pharmacological, in particular antiarrhythmic, action of the general formula I, where M is

3

R, R and R are the same or different C 1 -C 6 alkyl or one of these is benzyl and the other is C-C, alkyl, R is an esterified hydroxyl group of the formula -00C-R °, where RC is C 1 -C 4 alkyl or C 1 -C 4 cycloalkyl or optionally halogen or one or more C 1 -C 4 alkyl groups or C 1 -C 6 alkyl; alkoxy, nitro, phenyl, phenoxy or trifluoromethyl substituted phenyl or benzyl or naphthyl optionally halogenated or hydrogenated, or cinnamyl optionally substituted by halogen or C.-C. alkoxy, or benzhydryl or 1,1-diphenylhydroxymethyl or as a heterocyclic substituent with thenyl or 9-xanthenyl, and their pharmaceutically acceptable acid addition salts are prepared by reacting a novel alcohol of formula VIII wherein R, R and R is as defined above, with a derivative of the formula R-COX, wherein R 0 is as defined above, and .X is halogen or a C 1 -C 6 alkoxy group, in the presence of an acid binding agent or an organic solvent and a catalyst; of formula (I) is optionally separated into its stereoisomers and / or converted into its acid addition salts.

CS 273550 B2

The invention relates to a process for the preparation of novel azabicyclo [3.3.1] nonane derivatives and pharmaceutically acceptable acid addition salts thereof.

The compounds of formula I are thus prepared by the process of the invention

where it means

3

R, R and ^{RJ are the} same or different C 1 -C 4 alkyl or one of these is benzyl and the other C 1 -C 4 alkyl esterified hydroxyl group of the formula -OOC-R 6 where R is C 1 -C 4 alkyl or C 5 -C 5 cycloalkyl or optionally halogen or one or more C 1 -C 4 alkyl or alkoxy, nitro, phenyl, phenoxy or trifluoromethyl substituted phenyl groups or a benzyl or naphthyl group which is optionally halogenated or hydrogenated, or a cinnamyl group which is optionally substituted by a halogen atom or a (C 1 -C 4) alkoxy group, or a benzhydryl group or 1,1-diphenylhydroxymethyl group, or a thenyl group as a heterocyclic substituent; 9-xanthenes and alpha- or beta- chemical bond by selins.

and the pharmaceutically acceptable acid addition salts of azabicyclo (3,3,3,13 nonane) have the 6-position as defined above and a dialkylamino or N-alkyl-N-benzylamino group, which have excellent antiarrhythmic activity.

The azabicyclo [3,3,13 nonane] derivatives known from the literature, on the other hand, have a heterocyclic substituent at the 5-position and their field of application is different or not mentioned at all from the compounds prepared by the process according to the invention. This is illustrated by the following citations: A.Z. Britten and J. O'Sullivan (Chem. And Ind. 15, 335, 1972 and Tetrahedron 29, 1331, 1973) describe only new research results to determine the chemical structure of these compounds. Antipyretic and analgesic azabicyclo [3,3,13 nonanes] are known from Japanese Kokai Spring No. 42-25895, and French azabicyclo L 3,3,1 3 nonanes are known to reduce blood sugar and stimulate blood sugar. central nervous system.

The present invention provides a process for the preparation of novel, pharmaceutically active compounds of formula (I) wherein each symbol is as defined above. SUMMARY OF THE INVENTION The novel alcohol of formula VIII (VIII) is reacted

Wherein R, R, R and '-' are as defined above, with a carboxylic acid derivative of the general formula R 6 -COX, wherein R is as defined above, and X represents a halogen atom or a C 1 -C 4 alkoxy group, in the presence of an acid binding agent or an organic solvent and a catalyst, and the ester derivative of the formula I obtained is optionally separated into its stereoisomers and / or converted into its acid addition salts.

Acyl halides are preferably used to acylate the alcohol of formula (VIII) and acid binding agents are used during the reaction. If the acylation is carried out with an acid ester suitable for transesterification, a transesterification promoting catalyst may optionally also be used. The acylation is optionally selective, that is to say, 6-6, 9-9 = 4-6 is not acylated when the isomer mixture is acylated. This can also be used for the separation of isomers.

Thus, when acylating the isomeric direction in chloroform, the 6-00-ol remains unchanged and can be isolated as its salt. The other compounds react to the ester mixture and can be separated from the unchanged 6- ω -9-, δ -ol by extraction. After acylation, the reaction mixture is extracted with ether at pH 7.5 to 8.5 and then the extract is evaporated. A mixture of the 6-O-9- / 3-ester and the 6-E, 3-9-ester with hydrochloric acid can be separated from the residue. These esters are separated, the mother liquor is evaporated and the residue is washed with alcohol, whereupon the 6- (3,9-ester) may crystallize. The ester obtained may optionally be hydrolyzed to the corresponding 9-ol and converted to another ester.

The product obtained can be isolated in a manner known per se and optionally converted into its pharmaceutically acceptable acid addition salt.

The starting compound of formula VIII can be prepared from a tetrahydropyridine derivative of formula V

(IN)

Wherein R, R and R are as defined above through a compound of formula IV

S ¹ -N (IV)

in

Wherein R, R and R are as defined above. Compounds of formula (V) may be prepared by reacting an amine of formula (VII):

Wherein R and R are as defined above, with the piperidone of formula VI (VI) wherein r 1 is R 1; is as defined above.

The tetrahydropyridine derivative of general formula V is reacted with acrylaldehyde.

The thus obtained azabicyclo [1,3,3] nonan-9-one derivative of formula (IV) is reduced to give compounds of formula (VIII) wherein R, R and R are as defined above.

The process for preparing starting materials for the process of the invention is described in detail in the Examples.

The compounds of formula I, wherein the individual symbols are as defined above, prepared by the process according to the invention, have an excellent pharmacological action. In particular, the compounds of formula I have a beneficial effect on heart rhythm disorders. Antiarrhythmic activity was investigated, as usual, by the removal of aconitine-induced cardiac rhythm disorders in Wistar rats (Fekete M. and Borsy J .: Med. Exp. Basel, 10: 93, 1964). Lidocaine, which has already been used successfully in therapy, has been used as a comparator. The active ingredients were administered intravenously. Toxicity values were also determined in some cases in mice also intravenously to obtain a therapeutic index. The following table lists the doses that eliminate arrhythmias in 50% (Εϋ ^ θ) and cause 50S mortality (LD ^ q). Thereafter, the therapeutic indices and index ratio, which is the ratio to the therapeutic index of lidocaine, which is considered to be 1, are also listed.

TABLE

Number according to compound and example number mg / kg ^{ED50 LD} 5 0 which the compound is obtained lidocaine 7.7 25.1 1528 (example 10) 0.68 1529 (example 11c) 0.15 35.2 1530 (example people) 1,8 1531 (example Uf) 1.0 1541 (example 16; 6- oG, 9- / 0-isomer) 3.5 1542 (example 12) 0.43 21.7 1543 (example 13) 0.6 1547 (example 17; 6- oC, 9- / 5 -isomer) 0.71 36.3 1658 (example 15a) 2.3 1797 (example lig) 0.45 1799 (example 11a) 1.1 1800 (example 11b) 0.75 1801 (example lle) 0.7 1840 (example 15b) 0.95 1641 (example llh), 0.55

Table continuation:

the compound number and the example number by which the compound is obtained mg / kg ^ED50 ·,. ...... rfX i »- ·. • ... LD ₅₀ .rfjrfrfrf: -. ···. ·· 1642 (example lli) 0.5 ř - - 1643 (example lij, 1,2 1644 (example llk, 1.4 1645 (Example 111) 1,2 IN 1648 (example lim) 1.0 · - - .rfi-rf- compound number and example number therapeutic index index - '' ratio 'in comparison ^: · · wherein the 3e compound is obtained ^{LD50 / ED50} to lidocaine - - / - lidocaine , ........ 3.26 ...... ., ... .. -¾. ". ' 1529 (Example 11c) 234.0 71.8 · - 1542 (Example 12) 50.5 15.5. _r , 1547 (Example 16; 6- ° C, 9- / 3- ·; · - '. '«. · * · *»? ·. . , ... · x - », T t C, * i. -isomer) 51.1 15.7,, "

Oral efficacy was also investigated in the aconithin-arrhythmia model, where the compounds of formula I also exhibit efficacy. The compounds of formula (X) prepared according to the process of the invention, and in particular compound number 1529, exhibit a sustained -anthetic arrhythmia in the case of Wistar rats at a dose of 20 mg / kg after r, x, * ♦ '' - 1 »·> ¹¹ * J

All of the compounds of formula X, prepared by the process of the invention, also have a strong local anesthetic action (examined on an isolated nerve of an ischiadious frog). Compound No. 1542 is four times more potent than lidocaine. The compounds of formula (I) do not act as beta-receptor blockers. The action of the compounds of the formula Ϊ on the electrophysiological parameters of the heart resulting from the mechanism of action of the compounds of the formula I was investigated in the guinea pig heart (the rate of irritation transfer and the refractory period increase). In this respect, almost all of the compounds of formula (I) prepared by the process of the invention are more potent than quinidine. The strong local anesthetic action of compound number 1542 exceeds the electrophysiological efficacy of quinidine by about five times. _(; * _t and cl *% Λ «

The expected therapeutic dose of the compounds of formula (1) prepared by the method of the invention is, when administered clinically, 0.5 to 1 mg / kg for intravenous administration and 10 mg / kg for oral administration. , in <rf »'

The invention is illustrated by the following examples, which are not intended to limit the invention in any way. '/ _t . ¾. }. ..

The percentages given are by weight unless otherwise indicated p, ' ^f ' ⁽ · ^? /

Example 1.

Dissolve 139 g of freshly distilled 1-methyl-4-dimethylamino-1,4-dioxane in 300 ml of dioxane. -1,2,5,6-tetrahydropyridine and a solution of 77 g of acrylaldehyde in 300 ml of dioxane was added dropwise to the obtained solution with stirring over 5 hours. The reaction mixture is allowed to stand overnight at room temperature, then the solvent is distilled off and the residue is distilled under vacuum to give a pale yellow oil in 74.7% yield, which is an isomeric mixture, and contains 70 to rf. 1-6C-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-one and 20-30% 6- / 3-dimethylamino-3-methyl-3-azabicyclo [3.3- 1J nonan-9-one (stereoisomers of formula IV). The boiling point is 80 to 100 ° C / 10 Pa. The corresponding starting material is prepared as follows:. '/, ¾' ^ r-Wrf · - ;; ,. ·· - 'yy'

To 1000 g of molecular sieve (Klinosorb-4) was added 500 ml of anhydrous diethyl ether and 226 g of 1-methyl-4-piperidone, then the reaction mixture was continuously purged with dimethylamine at a rate to achieve a gentle reflux. Dimethylamine gas is introduced for three days three times for 8 hours, then Klinosorb-4 is filtered off and washed with ether. The obtained ether filtrate and wash liquor were combined, evaporated in vacuo and the residue e purified by vacuum distillation to give 1-methyl-4-dimethylamino-1,2,5,6-tetrahydropyridine in a yield of 70.0%. 82 ° C / 2.66 kPa.

Example 2.

Similar to Example 1, a freshly distilled 1-ethyl-4-dimethylamino-1,2,5,6-tetrahydropyridine with acrylaldehyde yielded a colorless oil in a yield of 48.8% containing 80% 6-oC, -dimethylamino- 3-ethyl-3-azabicyclo [3.3.1.0] nonan-9-one and 20% 6- / 5-dimethylamino-3-ethyl-3-azabicyclo [3.3.1] nonan-9-one at boiling point 90 to 95 * C / 2.6 Pa and η _β ²⁰ = 1.4980.

Similar to Example 1, the starting material of formula V, 1-ethyl-4-dimethyl amino-1,2,5,6-tetrahydropyridine, is obtained in a yield of 73.5% from 90 g of 1-ethyl-4-piperidone by introducing of dimethylamine gas for three days over a total of 20 hours. The boiling point is 90 to 90 °. 2 0

C / 1.47 kPa, = 1.4931.

Example 3

Similar to Example 1, from freshly distilled 1-butyl-4-dimethylamino-1,2,5,6-tetrahydropyridine (prepared from 1-butyl-4-plperidone and dimethylamine in 77.9% yield, boiling point 103- 106 C (1.5 kPa) by reaction with acrylaldehyde to give a pale yellow oil in a yield of 44.2% which contains a mixture of 75% of 6-dimethylamino-3-butyl-3-azabicyclo 1,3,3,1j nonane- 9-one and 25% of 6- / 3-dimethylamino-3 'butyl-3-azabicyclo £ 3.3, LJ nonan-9-one with a melting boiling point 110-116 ° C / 7 mbar n _Q ^ ² = 1.4933 .

Example 4

Similar to Example 1, a mixture containing 80% of 6-C-diethylamino-3-methyl-3-azabicyclo [beta] 3 is prepared from freshly distilled 1-methyl-4-diethylamino-1,2,5,6-tetrahydropyridine by treatment with acrylaldehyde. 3,1] nonan-9-one and 20% 6- / 3-diethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-one and 20% 6- / 3-diethylamino 3-methyl-3-azabicyclo [3.3.1] nonan-9-one in 26.4% yield, boiling point 95 DEG-108 DEG C./0.3 mbar; η _β ² θ = 1.9897.

The preparation of the starting material is as follows:.

To 1000 g of Klinosorb-4 molecular sieve are added 1000 ml of anhydrous diethyl ether, 226% of 3-methyl-4-piperidone and 2X9 g of baxy anhydrous diethylamine. for four days at room temperature, then Klinosorb-4 is filtered off and washed with ether. The ether filtrate and washings were combined, the solvent was distilled off and the residue was purified by vacuum distillation. There was thus obtained 1-methyl-4-diethylamino-1,2,5,6-tetrahydropyridine in a yield of 59.9% with a boiling point of 88 DEG-106 DEG C./15 mbar; η _β ²⁰ »1.4825.

Example 5

Similar to Example 1, the product is prepared from freshly distilled 1-methyl-4-dibutylamino-1,2,5,6-tetrahydropyridine by reaction with acrylaldehyde.

After working up the reaction mixture, a pale yellow oil is obtained which contains a mixture of stereoisomers consisting of 80% 6-C-dibutylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-one and 20% 6- [3]. -Dibutylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-one. >

1 ·

The corresponding starting material is prepared as follows:

226 g of 1-methyl-4-piperidone and 310.2 g of dibutylamine are mixed with 800 ml of toluene, then 0.5 g of 4-toluenesulphonic acid is added and the reaction mixture is heated under reflux using a water-separating handpiece for eight hours. During this time, the calculated amount of water is collected in the water separator. The solvent was distilled off and the residue was purified by vacuum distillation. There was thus obtained 1-methyl-4-dibutylamino-1,2,5,6-tetra20 hydropyridine in 50.1% yield; boiling point 130-138 ° C; _Q n = 1.480.

Example 6

240 g of a 75: 25 mixture of 6-i-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-one and 6-dimethylamino-3-methyl-3-azabicyclo [3.1.1] are mixed. A solution of 233.0 g of 70% sodium dihydrogen-bis- (2-methoxyethoxy) aluminate in 100 ml is added dropwise over three hours at 15 ° C. The reaction mixture is treated with 500 ml of 20% aqueous sodium hydroxide, then the organic phase is separated and the aqueous phase is extracted twice with 100 ml of ether each time, the extract is combined with the separated organic phase, dried over magnesium sulphate and the solvent is evaporated. is dissolved in 300 ml of diisopropyl ether with heat, then, after cooling, a mixture of 6- [deg.] C.-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonane-9-O-ol and 6-dimethylamino- is precipitated. 3-methyl-3-azabicyclo [3.3.1 (1 nonan-9-beta-ol). The crystalline product is recrystallized from about 4 times the amount of diisopropyl ether to give 6- [alpha] -dime. thylamino-3-methyl-3-azabicyclo [3.3.1] (1 nonan-9-10-ol), which contains no 9-, β-isomer and has a melting point of 119 ° C.

The structure's accuracy of 6- ού-dimethyl-3-methyl-3-azabicyclo [3.3.1 (1-honan-9-ol) was shown by NMR and Eu (fod) ₃ · ¹ H reagents. NMR: θ '. (CDCl); 3.8 ppm, t, C / 9 / H; 2.19 ppm, s, C / 6 / N / CH _3/2; 2.07 ppm, s, N / 3 / CH _3;

3.25-1.5 ppm, m, CH, CH ₂ · (Eu (fod) ₃ = tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5) (octanediol) europium.

Example 7

Similar to Example 6, 6- (3-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-04) -ol was prepared from the mother liquor after recrystallization from diisopropyl ether after first reduction. The mother liquor was evaporated and the residue was fractionated under vacuum in a 30 cm long metal gauze column. After distillation, 6-, β-dimethylamino-3-methyl-3-azabicyclo-3,3,1-dnonan-9-ol is crystallized with a boiling point of 74 to 75 c / 2.7 Pa and a melting point of 38 to 40 c. .

The correctness of the structure of 6- / 3-Dimethylamino-3-methyl-3-azabicyclo £ 3.3.1] nonan-9-ol was demonstrated by NMR spectrum and NMR spectra taken with the reagent Eu (fod) ₃ · ^x H NMR : δ '(CDCl ₃ ) 3.61 ppm, t, C / 9-H; 2.27 ppm, s, C / 6 / N / CH _3/2! 2.07 ppm, s, N / 3 / CH _3; 3.09 to 1.25 ppm, m, CH, CH 2.

Example 8

6- was prepared from the benzoyl ester by the method of Example 16. Α-dimethylamino-3-methyl-4-azabicyclo [3.3.1] nonane-9-. / 3 -ol in pure, isomer-free state as follows:

Dissolve 4.0 g of 6- N -dimethylamino-3-methyl-9- [3-benzoyloxy-3-azabicyclo [3.3.1] nonane dihydrochloride in 25 ml of ethanol, then add 20 ml of a 25% aqueous solution. sodium hydroxide. The reaction mixture is allowed to stand for three hours at room temperature, then the alcohol is distilled off and the residue is saturated with potassium carbonate and extracted three times with 30 ml of chloroform each. The extract was dried over magnesium sulphate and filtered to remove evaporate. A white, crystalline material is obtained which, after vacuum sublimation, has a melting point of 111 DEG C .; the yield is 94.7%.

The dihydrochloride salt of the compound obtained by known methods has a melting point of 256 DEG C. with decomposition (from alcohol). The structure of 6-cy-dimethylamino-3-methyl-3-azabicyclo-nonan-9-beta-ol was confirmed by NMR ^and Eu (fod) ₃ .

¹ H-NMR: δ (CDCl ₃ ) 3.46 ppm, t, C (9) -H; 2.19 ppm, s, C (6) (N (CH ₃ )); 2.09 ppm, s, N (3) -CH ₃

2.81-1.5 ppm, m, CH, CH 2 ·

Example 9

6- (3-Dimethylamino-3-methyl-3-aza-bicyclo [3.3.1] nonane-9- [beta] -ol) is obtained in pure, isomer-free state from the 4-nitrobenzoyl ester of Example 18 as follows:

In 20 ml of water was dissolved 4.0 g of 6- / 3-Dimethylamino-3-methyl-9- / 3 - (4 ¹ -nitrobenzoyloxy) -3-azabicyclo (.3,3,1J nonandihydrochloridu and then adding 5, 6 g of potassium chloride and 15 ml of alcohol to dissolve the precipitated ester base The reaction mixture is left to stand for one hour at room temperature, after distillation of the alcohol, the residue is extracted three times with 30 ml of chloroform, dried over magnesium sulphate and filtered. This leaves a colorless, very thick oil, n _Q = 1.5125, the yield is 96%.

The 6-, -dimethylamino-3-methyl-3-azabicyclo-3,3,13-nonan-9-beta-ol dihydrochloride prepared in a manner known per se had a melting point of 286 to 288 DEG C. with decomposition (from alcohol).

The correctness of the structure of 6- / 3-Dimethylamino-3-methyl-3-azabicyclo [3,3,1J nonan-9-ol was confirmed by NMR spectra and NMR spectra taken with the reagent Eu (fod) ₃ · ^X H-NMR: 7 ÍCDC1 ₃₎ 3.92 ppm, t, C / 9-H; 2.17 ppm, s, C (6) N (CH 2) ₂ ; 2.11 ppm, s, N / 3 / CH _3; 2.81-1.35 ppm, m, CH, CH 2.

Example 10

Dissolve 7.0 g of 6-cis-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-c-ol in 50 ml of anhydrous pyridine and add dropwise to the solution dropwise at 5 to 10 with stirring. A solution of 8.0 g of benzoyl chloride in 50 ml of anhydrous pyridine. The reaction mixture is stirred at room temperature for 1 to 3 hours and then most of the pyridine is distilled off in vacuo. The residue is extracted with 50 ml of diethyl ether. The aqueous phase was basified with potassium carbonate and extracted three times with 50 ml of chloroform. The combined chloroform extracts were dried over magnesium sulfate, filtered, and evaporated. The dihydrochloride salt is prepared from the remaining phase in a manner known per se by means of hydrogen chloride dissolved in ether. Yield 92.8%. The resulting 6-dimethylamino-3-methyl-9-cis-benzoyloxy-3-azabicyclo [3.3.1] nonane dihydrochloride is sintered at a temperature above 160 c and melts at 166-168 c with decomposition after recrystallization from methanol.

Example 11

Similar to Example 10, the following compounds were prepared from 6-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-o-ol by reaction with various acid halides:

a) 6-O-D-Dimethylamino-3-methyl-9- [N - (4'-methyl benzoyloxy) -3-azabicyclo [3.3.1] nonane dihydrochloride is obtained with 4-methylbenzoyl chloride in a yield of 62.9 after recrystallization from ethanol, m.p. 153 DEG-155 DEG C. with decomposition. The base had a melting point of 65-67 ° C.

b) With 4-chlorobenzoyl chloride, 6- pi is prepared. -dimethylamino-3-methyl-9-. what? - (4'-chlorobenzoyloxy) -3-azabicyclo [3.3.1] nonane dihydrochloride in 24.4% yield. The compound has a melting point after recrystallization from ethanol 192 DEG-194 DEG C. and decomposes.

c) Preparation of 6-, 10-dimethylamino-3-methyl-9-methyl-3,4,5-trimethoxybenzoyl chloride;

- (3 ', 4, ^1, 5'-trimethoxybenzoyloxy) -3-azabicyclo [3.3] nonane with a yield of 66.4%. After recrystallization from 2-butanone, it has a melting point of 122 to 123 ° C.

of

d) Preparation of 6-C? -dimethylamino-3-methyl-9-η 4 - (4'-phenylbenzoyloxy) -3-azabicyclo [3.3.1.1] nonane in 72.2% yield. After recrystallization from diisopropyl ether, the compound has a melting point of 121-122 ° C. The dihydrochloride prepared in a manner known per se has a melting point after recrystallization from ethanol of 252 to 253 ° C.

e) With 6-naphthoyl chloride, 6- eyes are prepared. -dimethylamino-3-methyl-9-? - (2'-naphthoyloxy) -3-azabicyclo [3.3.1] nonane in 82.3% yield. After recrystallization from acetone, the compound has a melting point of 128-130 ° C. The dihydrochloride prepared in a manner known per se has a melting point after recrystallization from diethylene glycol monomethyl ether of 287 DEG-289 DEG C. with decomposition.

f) With 6-octyl-dimethylamino-3-methyl-9-chloro-xanthene-9-carboxylic acid in the form of chloride. .- (xanthene-9'-carbonyloxy) -3-azabicyclo [3.3.1] nonane dihydrochloride in 72.7% yield. After recrystallization from isopropyl alcohol, the compound has a melting point of 211-215 ° C with decomposition.

g) 6-N-Dimethylamino-3-methyl-9-ol is prepared with thenoyl chloride; (2'-thenoyloxy) -3-azabicyclo [3.3.1] nonane in 93.1% yield, m.p. 81-83 ° C. The dihydrochloride prepared in a manner known per se is sintered at a temperature above 190 DEG C. and melts at 206 DEG-208 DEG C. with decomposition after recrystallization from ethanol.

h) Preparation of 6-octyl-dimethylamino-3-methyl-9-octyl- (4'-fluorobenzoyloxy) -3-azabicyclo [3.3.1] nonane dihydrochloride monohydrate in 51.5% yield with 4-fluorobenzoyl chloride. After recrystallization from aqueous ethanol, the compound has a melting point of 255-257 c with decomposition.

(i) 6-N, N-Dimethylamino-3-methyl-9-O- (3 &apos; -fluorobenzoyloxy) -3-azabicyclo [3.3.1] nonanedihydrochloride monohydrate was prepared with fluorobenzoyl chloride in a yield of 87.8%. After recrystallization from aqueous methanol, the compound has a melting point of 180 DEG-184 DEG C. with decomposition.

j) Preparation of 6-N, N-dimethylamino-3-methyl-9- (3 ', 4'-dichlorobenzoyloxy) -3-azabicyclo [3.3.1] nonane dihydrochloride monohydrate with 3,4-dichlorobenzoyl chloride yield 94.4%. After recrystallization from aqueous methanol, the compound has a melting point of 266 DEG-267 DEG C. with decomposition. The base has a melting point of 99-100 ° C (ethanol).

k) 6- tert -Dimethylamino-3-methyl-9- is prepared with chlorobenzoyl chloride. - (2'-chlorobenzoyloxy) -3-azabicyclo [3.3.1] nonanedihydrochloride monohydrate in a yield of 68.6%. After recrystallization from aqueous methanol, the compound has a melting point of 170-175 c with decomposition.

l) 6-00-Dimethylamino-3-methyl-9-N - (3'-chlorobenzoyloxy) -3-azabicyclo [3.3.1] nonanedihydrochloride monohydrate was prepared with 3-chlorobenzoyl chloride in 77.0% yield. After recrystallization from aqueous methanol, the compound has a melting point of 175-177 ° C with decomposition.

m) Preparation of 6- (dimethylamino-3-methyl-9-ai) with trifluoromethylbenzoyl chloride

- (3'-Trifluoromethylbenzoyloxy) -3-azabicyclo [3.3.1] nonane dihydrochloride monohydrate in 90.0% yield. After recrystallization from aqueous ethanol, the compound has a melting point of 169-172 DEG C. with decomposition. The base had a melting point of 97-98 ° C after recrystallization from hexane.

n) With cinnamic acid chloride, 6-. oit-dimethylamino-3-methyl-9-, N-einnamoyl CS 273650 B2 oxy-3-azabicyclo [3.3.1] nonane dihydrochloride in 79.7% yield. After recrystallization from ethanol, the compound has a melting point of 196 to 201 DEG C. with decomposition.

o) 6-, 10-Dimethylamino-3-methyl-9-β- (4'-chlorocinnamoyloxy) -3-azabicyclo [3.3.13] nonanedihydrobromide was prepared in 68.6% yield with 4-chloro-cinnamic acid chloride.

After recrystallization from methanol, the compound has a melting point of 226-229 ° C.

p) 6,4'-Dimethylamino-3-methyl-9-oG (3 ', 4', 5'-trimethoxycinnamoyloxy) -3-azabicyclo [3 '] is prepared with 3,4,5-trimethoxycinnamic acid in the form of chloride. 3.1] nonanedihydrochloride in 28.5% yield. After recrystallization from ethanol, the compound has a melting point of 223-225 DEG C. with decomposition.

q) 6-O-Dimethylamino-3-methyl-9-β- (1'-naphthoyloxy) -3-azabicyclo [3.3.1] nonane dihydrochloride was prepared with 1-naphthoyl chloride in a yield of 64.9%. After recrystallization from methanol, the compound has a melting point of 195-198 DEG C. with decomposition.

r) with 6-chloro-2-naphthoyl chloride was prepared 6- C4'-dimethylamino-3-methyl-9-cC ^/ - (6'-chloro-2'-naphthoyloxy) -3-azabicyclo [3.3.1 ] nonanedihydrochloride in 94.5 ^? O. After recrystallization from methanol, the compound has a melting point of 254 DEG-257 DEG C. with decomposition.

s) 6- N, N-Dimethylamino-3-methyl-9-O- (1 ', 2', 3 ', 4'-Tetrahydro) was prepared with 1,2,3,4-tetrahydro-2-naphthoyl chloride. -2'-naphthoyloxy) -3-azabicyclo [3.3.1] nonane dihydrochloride in 92.2% yield. After recrystallization from ethanol, the compound has a melting point of 160-170 ° C with decomposition.

t) 6- O -Dimethylamino-3-methyl-9- was prepared with phenoxyacetyl chloride. cis, - (phenoxyacetyloxy) -3-azabicyclo [3.3.1] nonane dihydrobromide in 75% yield. After recrystallization from methanol, the compound has a melting point of 257-259 DEG C. with decomposition.

Example 12

Similar to Example 10, from a solution of 7.0 g of 6- [5-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-oG -ol in 50 ml of anhydrous pyridine with a solution of 8.0 g of benzoyl chloride in 50 ml of anhydrous pyridine prepared 6- [beta] -dimethylamino-3-methyl-9- from 1-benzoyloxy-3-azabicyclo [3.3.1] nonane. The compound obtained is reacted in a manner known per se to the dihydrochloride, m.p. 300 DEG C. (dec., Methanol-water) in a yield of 86.8%.

Example 13

Similar to Example 10, 6- was prepared from 6-. 5-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-o (1-ol with xanthene-9-carboxylic acid chloride). / 3-dimethylamino-3-methyl-9 oG .- ⁽¹ xanthene-9 carbonyloxy) -3-azabicyclo [3.3.1] nonane. a compound in a known manner is reacted to the dihydrochloride salt, mp 195 C. (dec., methanol) Yield 85.5%.

Example 14

To a solution of 5.0 g of 6- / 3-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonane-9-OC-ol in 50 ml of chloroform is added a solution of 4.7 g of 4-methylbenzoyl chloride in 10 ml of chloroform at a temperature below 20 DEG C., then the reaction mixture is allowed to stand for one hour at room temperature. The chloroform solution is evaporated in vacuo, the residue is taken up in 50 ml of water, acidified with 5 ml of concentrated aqueous hydrochloric acid, then extracted twice with 50 ml of diethyl ether each time to remove non-basic products. The aqueous phase was basified with potassium carbonate and the liberated base was extracted three times with 50 ml of dichloromethane each time. The combined dichloromethane phases were dried over magnesium sulfate, filtered, and the filtrate was evaporated.

The dihydrochloride is prepared from the remaining base using hydrogen chloride in anhydrous ether in a manner known per se. The yield based on dihydrochloride is 83.1%. After recrystallization from methanol, the melting point of the obtained 6- [3-dimethylamino-3-methyl-9- <-> - (4'-methylbenzoyloxy) -3-azabicyclo [3.3.1] nonane dihydrochloride is 286 DEG C. with decomposition. .

Example 15

The following compounds were prepared from 6- / 3-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonane-9-O-ol using various acid halides:

a) 6- (3-Dimethylamino-3-methyl-9-PO- (4'-chlorobenzoyloxy) -3-azabicyclo [3.3.1] nonanedihydrochloride) was prepared with 4-chlorobenzoyl chloride in a yield of 66.0%. After recrystallization from methanol, the compound has a melting point of 291-292 ° C with decomposition.

b) 6- (O-Dimethylamino-3-methyl-9-) was prepared with 2-naphthoyl chloride. oO- (2'-naphthoyloxy) -3-azabicyclo [3.3.1] nonane dihydrochloride in 88.2% yield. After recrystallization from a mixture of methanol and water, the compound has a melting point of 294 zaC with decomposition.

Example 16

14.0 g of a mixture of approximately 1: 1 6-o-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-o-ol and 6-o-dimethylamino- are dissolved in 100 ml of chloroform. 3-methyl-3-azabicyclo [3.3.1] nonane-9-Z 3 -ole, then 12 g of benzoyl chloride is added at a temperature below 20 ° C. The reaction mixture was allowed to stand at room temperature overnight. The chloroform solution is evaporated in vacuo, the residue is taken up in 100 ml of water, acidified with 20 ml of concentrated hydrochloric acid and extracted twice with 50 ml of ether each time to remove non-basic products. The aqueous phase was basified with potassium carbonate to pH 8 and the liberated base was extracted three times with 50 ml of chloroform each. At this pH, the resulting 6- PO -dimethylamino-3-methyl-9- [3-benzoyloxy-3-azabicyclo [3.3.13] nonane can be selectively extracted from the reaction mixture from unreacted 6-. N -dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-o-ol. The combined chloroform extracts were dried over magnesium sulfate, filtered, and evaporated. The dihydrochloride is prepared from the remaining base in a manner known per se. Yield 52.1%. After recrystallization from alcohol, the melting point of the obtained 6-O-dimethylamino-3-methyl-9- is obtained. (5-benzoyloxy-3-azabicyclo [3.3.1] nonane dihydrochloride 144-146 c) with decomposition.

Example 17

Similar to Example 16, from a mixture of approximately 1: 1 6-o-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonane-9- &lt; 4 &gt; -ol and 6-dimethylamino-3-methyl Of 3-azabicyclo [3.3.1] nonan-9- [3-ol] with xanthene-9-carboxylic acid chloride to prepare 6- C 3 -dimethylamino-3-methyl-9- / 3t- (xanthene-9) ^1- carbonyloxy) -3-azabicyclo [3.3.1] nonane in 91.6% yield. After recrystallization from diisopropyl ether, the compound has a melting point of 132 DEG-133 DEG C. The dihydrochloride prepared in a known manner has a melting point of 284 DEG C. with decomposition after recrystallization from methanol.

Example 18

To 145 g of a mixture of about 80:20 6-O-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-one and 6-. N-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-one is added 250 ml of ethanol and 0.7 g of platinum oxide monohydrate (PtO 3 .H 2 O) as a catalyst. The reaction mixture is hydrogenated at an initial pressure of 7.6 MPa and a temperature of 80 C. The aminoketone receives the calculated amount of hydrogen over three hours. The catalyst was filtered off and the solvent was evaporated, yielding 144 g of a colorless oil containing a mixture of four possible stereochemical isomers.

The oil obtained is mixed with 900 ml of chloroform, and a solution of 144 g of 4-nitrobenzoyl chloride in 700 ml of chloroform is added dropwise while cooling. The reaction mixture is allowed to stand for three days at room temperature, then evaporated in vacuo and the residue π

CS 273650 Β2 is extracted three times with 100 ml of 10% aqueous hydrochloric acid each. The aqueous hydrochloric acid solution was basified with potassium carbonate to pH 8 and extracted three times with 100 ml of ether each time. The combined ether extracts were dried (MgSO 4) and filtered. The solvent was evaporated, the light brown oil obtained was dissolved in 500 ml of methanol and acidified with hydrogen chloride dissolved in anhydrous alcohol. The reaction mixture was allowed to stand for one hour at room temperature and the precipitated crystalline fraction was filtered off (mixture of 4-nitrobenzoyl ester with 6-O (.beta.- 3- and 5-6- and 9-o-configurations). The residue was dissolved in 300 ml of ethanol and allowed to stand overnight at 0-10 DEG C. The precipitated crystalline material was filtered off (9.1 g) to give 6--dimethylamino-3-methyl-9- [2]. - (4'-Nitrobenzoyloxy) -3-azabicyclo [3.3.1] nonane dihydrochloride has a melting point after recrystallization from methanol 297-298 ° C.

Example 19

To a mixture of 7.0 g of N, N -dimethylamino-3-methyl-3-azabicyclo [3.3.13 nonane-9-c-ol and 20.0 g of ethyl benzyl ester is added 0. 2 g of metallic sodium in the form of tiny chips. The reaction mixture is maintained at a pressure of 6 to 10 Pa and a temperature of 90 to 100 ° C for 13 hours. After adjusting the vacuum, 50 ml of 10% aqueous hydrochloric acid are added, then the excess ethyl benzyl ester is extracted twice with 50 ml of ether each time. The aqueous phase was made basic with potassium carbonate and the precipitated ester base was extracted three times with chloroform. The combined chloroform extracts were dried over magnesium sulfate, filtered, the solvent was distilled off from the filtrate, and the residue was recrystallized from heptane. There was thus obtained 6- (N-dimethyl-3-methyl-9- < / RTI &gt; -benzoyloxy-3-azabicyclo [3.3.1] nonane in 86.0% yield, m.p. 115 [deg.] C. the dihydrochloride prepared above had a melting point after recrystallization from methanol-water of 245-247 DEG C. with decomposition.

Example 20

39 g of a mixture of approximately 80:20 6-N, N-diethylamino-3-methyl-2-azabicyclo [3.3.1] nonan-9-one and 6-diethylamino-3-methyl-3-azabicyclo are mixed. [3,3,1] nonan-9-one with 200 ml of isopropyl alcohol containing 35 g of aluminum isopropylate. The reaction mixture was slowly distilled through a Vigreux column (rate about 5 drops per minute). After distillation for 3.5 hours, the reaction mixture was refluxed for half an hour and then slowly distilled again for half an hour. The reaction mixture is evaporated in vacuo and the residue is mixed with 100 ml of 30% sodium hydroxide solution and extracted four times with 50 ml of dichloromethane. The combined extract was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue is a pale yellow, thick liquid containing a mixture of approximately 1: 1 6-diethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-ol / ol and 6-. N -diethylamino-3-methyl-3-azabicyclo [3.3.1] nonane-9- [1,3] -ol, b.p. 107-110 DEG C./0.4 mbar in a yield of 81%.

Example 21

Dissolve 30 g of a mixture of approximately 1: 1 6-06-diethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-ol and 6-diethylamino-3-methyl-3- The azabicyclo [3.3.1] nonane-9 -? - 3-ol, prepared as described in Example 20, in 300 ml of chloroform and while cooling with cold water, was added 18.65 g of benzoyl chloride. The reaction mixture was allowed to stand for 24 hours at room temperature and then evaporated in vacuo. The residue is dissolved in 300 ml of water, acidified to pH 3 with hydrochloric acid, and the non-basic impurities are extracted three times with 100 ml of ether each time. The aqueous phase was basified by addition of potassium carbonate to pH 8 and extracted three times with 100 ml of dichloromethane each time. The extract contains an ester component. After addition of additional potassium carbonate, the aqueous phase was basified to pH 10 and extracted three more times with dichloromethane. The extracts obtained at pH 10 are combined, dried over magnesium sulphate and the solvent is distilled off in vacuo. The rest is a thick oil which crystallizes on standing. The product obtained is 6- cZ? -diethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-c-ol having a melting point of 72 ° C (after recrystallization in heptane and vacuum sublimation). The yield is 82% based on 50% starting isomer content.

Structure accuracy 6-. [eta] -diethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-eta]

1 ^u

confirmed by CNMR and 1 H-NMR spectra.

¹ H-NMR: θ '(CDC1 _3); C / 6 / N ₂ / CH CH _3/2, t, 0.93 ppm; C / 6 / N ₂ / CH CH _3/2, q, 2.59 ppm;

N (3) -CH ₃ , s, 2.04 ppm; C (9) -H, t, 3.78 ppm

Example 22

The extracts obtained in the selective benzoylation reaction of Example 21 by extraction at pH 8 are combined, dried over magnesium sulfate and the solvent is distilled off in vacuo. The hydrobromide salt is prepared from the remaining thick oil in a manner known per se and recrystallized from methanol. There was thus obtained 6- 04 N -diethylamino-3-methyl-9- [N -benzoyloxy-3-azabicyclo [3.3.1] nonane dihydrobromide in 80% yield (based on 50% of the starting isomer content), m.p. 246 C with decomposition.

Example 23

Dissolve 4.0 g of 6-tert-diethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-ol / ol in 50 ml of anhydrous pyridine and add to the solution over 10 minutes. minutes at a temperature below 15 DEG C. of 3.1 g of cyclohexanecarboxylic acid chloride. The reaction mixture is kept for one hour at room temperature and then most of the pyridine is distilled off in vacuo. The residue was dissolved in 50 mL of water and extracted with 50 mL of diethyl ether to remove non-basic portions. The aqueous phase was made basic with potassium carbonate and extracted three times with 50 ml of dichloromethane each time. The combined dichloromethane extracts were dried over magnesium sulfate and filtered. The filtrate was evaporated and the dihydrobromide salt was prepared in 92.5% yield from the remaining base in a manner known per se. Obtained 6-. N-diethylamino-3-methyl-9- N -cyclohexanoyloxy-3-azabicyclo [3.3.1] nonane dihydrobromide has a melting point after recrystallization from ethanol 242-244 ° C.

Example 24

30 g of a mixture of approximately 80:20 6-N-dimethylamino-3-ethyl-3-azabicyclo [3.3.1] nonan-9-one and 6- are dissolved. 3-Dimethylamino-3-ethyl-3-azabicyclo [3.3.13 nonan-9-one (according to Example 2) in 100 ml of anhydrous ether, then 27 g at a temperature below 15 ° C is added dropwise over about one hour. 70% solution of sodium dihydrobis (2-methoxyethoxy) aluminate in 50 ml of anhydrous ether. The reaction mixture is treated with 70 ml of 20% aqueous sodium hydroxide solution, the organic phase is separated and the aqueous phase is extracted twice with 50 ml of ether each time. The extract was combined with the separated organic phase, dried over magnesium sulfate and the solvent was distilled off. The residual thick oil is dissolved in 50 ml of diisopropyl ether while warming, and then, upon cooling, 6-N- (dimethylamino-3-ethyl-3-azabicyclo [3.3.1] nonan-9-O) -ol crystallizes. The compound was recrystallized from diisopropyl ether and after vacuum sublimation, melting point 88 ^- C.

Structure Accuracy 6-cis-Dimethylamine, o-3-ethyl-3-azabicyclo [3.3.1] nonane-9-o4> 13 1

confirmed by CNMR and 1 H-NMR spectra.

¹ H-NMR: θ '(CDC1 _3); N (3) -CH ₂ -CH ₃ , t, 0.98 ppm; C (9) -H, t, 3.83 ppm; C / 6 / N / CH _3/2, s, 2.22 ppm, CH _2, CH, m, 1.5 to 3.3 ppm

Example 25

To a solution of 15 g of an isomeric mixture of 6-dimethylamino-3-ethyl-3-azabicyclo [3.3.1] nonan-9-ol (6- [4], 9- & J, 6-, 9- (2 >) and 6- The .3-, 9-oc., Isomers obtained in the reduction described in Example 24 from the mother liquor after recrystallization of the 6-cis-dimethylamino-3-ethyl-3-azabicyclo [3.3.1] of nonan-9-ol / -ol) in 100 ml of chloroform was added 9.93 g of benzoyl chloride at a temperature below 15 ° C over 10 minutes. The reaction mixture was allowed to stand at room temperature for 12 hours. The solvent was distilled off, the residue was dissolved in 100 ml of water and acidified to pH 3 with concentrated hydrochloric acid, then the non-basic products were extracted three times with 50 ml of dichloromethane each time. The aqueous phase was basified with potassium carbonate to pH 8 and extracted three times with 50 ml of dichloromethane each time. The combined extracts were dried over magnesium sulphate and the solvent was distilled off after filtering off the desiccant. The residue is a thick oil which contains two isomeric esters.

The dihydrochloride is prepared from a mixture of isomeric esters in a manner known per se, which is recrystallized three times from methanol. There was thus obtained 6- N -dimethylamino-3-ethyl-9-N-benzoyloxy-3-azabicyclo [3.3.1] nonane dihydrochloride, m.p. 276-278 ° C with decomposition.

Example 26

To a mixture of 2.3 g of 6-dimethylamino-3-ethyl-3-azabicyclo [3.3.13 nonan-9-c-ol and 3.3 g of ethyl phenylacetic acid is added 0.1 g of sodium metal in in the form of small chips, then the reaction mixture is maintained at 90-100 [deg.] C. under a pressure of 1.7 kPa for 4 hours. After adjusting the vacuum, 50 ml of 10% aqueous hydrochloric acid are added and the excess ethyl phenylacetic ester is extracted twice with 50 ml of ether each time. The aqueous phase was made basic with potassium carbonate and the precipitated ester base was extracted three times with 50 ml of dichloromethane each time. The combined dichloromethane extract was dried over magnesium sulfate, filtered, and the solvent was distilled off. The residue is reacted in a manner known per se to the dihydrobromide salt. There was thus obtained 6-cis-dimethylamino-3-ethyl-9-O-phenylacetyloxy-3-azabicyclo [3.3.1] nonanedihydrobromide, which had a melting point of 225-227 ° C with decomposition after recrystallization from methanol. Yield 84.6%.

Example 27

Similar to Example 24, 32 g of a mixture of approximately 80:20 6-dimethylamino-3-butyl-3-azabicyclo [3.3.1] nonan-9-one and 6- / 3-dimethylamino-3-butyl-3- azabicyclo [1,3.3.1] nonan-9-one (according to Example 5) reduces 24.8 g of 70% sodium dihydrobis (2-methoxyethoxy) aluminate. After working up the reaction mixture, a thick oil is obtained which is distilled under vacuum. There was thus obtained a colorless oil (29.5 g, 92.2%) which contained a mixture of 6-dimethylamino-3-butyl-3-azabicyclo [3.3.1] nonan-9-ol-ol, 6-cis-dimethylamino-3-butyl-3-azabicyclo [3.3.1] nonan-9- (3-ol) and 6- (3-dimethylamino-3-butyl-3-azabicyclo [3,3,1] J nonan-9-, 10-ol. The boiling point is 120 to 126 ° C / 13 Pa. The mixture of isomers does not crystallize even after prolonged standing.

Example 28

To 18.5 g of a mixture of stereoisomers (6- oO, 9-oO, 6-eis 9 · 5, and 6- / 3-, 9'-isomers) 6-dimethylamino-3-butyl-3-azabicyclo [b] 3,3,1J of nonan-9-ol (Example 27) is added with 100 ml of chloroform, then 10.82 g of benzoyl chloride are added under cooling with cold water. The reaction mixture was allowed to stand for 12 hours at room temperature and then evaporated in vacuo. The residue is dissolved in 150 ml of water, acidified to pH 3 with concentrated hydrochloric acid, and the non-basic impurities are extracted three times with 50 ml of ether each time. The aqueous phase was basified to pH 8 with potassium carbonate and extracted three times with 50 ml of dichloromethane each time. The extract contains an ester component. The aqueous phase was basified to pH 10 by further addition of potassium carbonate and again extracted three times with 50 ml of dichloromethane each time. The extracts obtained at pH 10 are combined, dried over magnesium sulphate and the solvent is distilled off in vacuo. The residue is a thick oil which crystallizes on standing. The obtained 6-alpha-dimethylamino-3-butyl-3-azabicyclo [3.3.1] nonan-3-alpha-ol has a melting point after recrystallization from diisopropyl ether and vacuum sublimation of 72-73 ° C.

Structure Accuracy 6-Dimethylamino-3-butyl-3-azabicyclo [3.3.11 nonane-9-

1

ol confirmed by C NMR and H-NMR spektrem.14 ¹ H NMR delta (CDCl j H / 3 / - / CH _2/3 -CH _3, s, 0.85 ppm / C / 6 / N / CH _3/2, s, 2.22 ppm;

C (9) -H, t, 3.82 ppm, CH 3, CH, m, 1.0-3.3 ppm

Example 29

The extracts obtained in the selective benzoylation reaction of Example 28 by extraction at pH 8 are combined, dried over magnesium sulphate and the solvent is distilled off, the residue being a thick oil containing two isomeric esters.

The dihydrochloride is prepared from a mixture of ester isomers in a manner known per se, which is recrystallized twice from methanol. There was thus obtained 6- (N-dimethylamino-3-butyl-9-oc) -benzoyloxy-3-azabicyclo [3.3.1] nonane dihydrochloride, m.p. 273 DEG-275 DEG C. with decomposition.

Example 30

Dissolve 2.8 g of 6-. [eta] -dimethylamino-3-butyl-3-azabicyclo [3.3.1] nonan-9-ol; -ol in 30 ml of anhydrous pyridine, then a solution of 3.22 g of diphenylacetyl chloride is added over 5 minutes at a temperature below 15 ° C. The reaction mixture is allowed to stand for two hours at room temperature, then treated as in Example 23. The dihydrobromide salt is prepared in a manner known per se from the crude base obtained in the work-up. Thus, after recrystallization from ethanol, 6- O? -dimethylamino-3-butyl-9-c0-diphenylacetyloxy-3-azabicyclo [3.3.1] nonanedihydrobromide in a yield of 86.7% which sintered from 160 ° C and at a temperature of 165 to 170 ° C with melting of the foam.

Example 31

To a solution of 5.95 g of (-) - 6? -Dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-o (i -ole) in 50 ml of anhydrous pyridine was added at a temperature below 50 ° C. Add 15 c over 10 minutes

9.23 g of 3,4,5-trimethoxybenzoyl chloride. The reaction mixture was allowed to stand for one hour at room temperature and then worked up as in Example 23. (+) - 6-. about £ / dimethylamino-3-methyl-9 oC /. (* 3, ^4, 5 ^Ι -trimethoxybenzoyloxy) -3-azabicyclo [3.3.1] nonane crystallized. The compound has a melting point after recrystallization from ethanol of 147-150 [deg.] C., [.alpha.] D = + 23 (c = 3, dichloromethane).

Hydrochloric acid salt of the above compound, prepared in a manner known per se, (+) - 6-dimethylamino-3-methyl-9-O- (3 ', 4', 5'-trimethoxybenzoyloxy) -3-azabicyclo [3,3,1] nonanedihydrochloride hahydrate (1/2 H10) crystallizes and has a melting point of 170-180 ° C after recrystallization from a mixture of ethanol and diisopropyl ether with successive foaming and [eU] 573 = + 9.0 (c = 3, water) .

Example 32

To a solution of 4.96 g of (+) - 6-oc-dimethylamino-3-methyl-3-azabicyclo [3.3.1] nonan-9-O-ol in 50 ml of anhydrous pyridine was added at 10 min. temperature below 15 ° C

6.92 g of 3,4,5-trimethoxybenzoyl chloride. The reaction mixture was allowed to stand for two hours at room temperature and then worked up as described in Example 23. After treatment, the (-) - 6-O, N-dimethylamino-3-methyl-9-ol was obtained after work-up. (3 ', 4', 5'-trimethoxybenzoyloxy) -3-azabicyclo [3.3.1] nonane crystallizes. This compound has a melting point after recrystallization from ethanol of 146-147 [deg.] C. [.alpha.] D = -22 (c = 3, dichloromethane). Yield 68.8%.

Hydrochloric acid addition salt of this compound, prepared in a manner known per se, (-) - 6-dimethylamino-3-methyl-9-o- (3 ', 4', 5'-trimethoxybenzoyloxy) -3-azabicyclo [3] , 3,1] nonanedihydrochloride hemihydrate (1/2 H ₂ O) crystallizes and has a melting point after recrystallization from ethanol-diisopropyl ether system 160-175 ° C with gradual foaming, [α] gyg = - 8.7 '(c = 3, water).

Example 33

Freshly distilled 1-benzyl-4-dimethylamino-1,2,5,6-tetrahydropyridine was reacted with the acrylaldehyde of Example 1.

After working up the reaction mixture, a pale yellow oil is obtained in 43% yield consisting of a mixture of approximately 80% 6-dimethylamino-3-benzyl-3-azabicyclo [3.3.1] nonan-9-one and 20% 6- [3-dimethylamino-3-benzyl-3-azabicyclo [3.3.1] nonan-9-one.

Boiling point 140-145 ° C / 23 Pa, n = ⁵ = 1.5430

The corresponding starting material was prepared from 1-benzyl-4-piperidine in the presence of a Klinosorb molecular sieve by introducing gaseous dimethylamine as described in Example 1. 1-Benzyl-4-dimethylamino-1,2,5,6-tetrahydropyridine was obtained in 64¾ yield.

Boiling point 130 DEG-140 DEG C./0.5 mbar.

Example 34

138 g of 80:20 6-oes-dimethylamino-3-benzyl-3-azabieyclo [3.3.1] nonan-9-one and 6- / 3-dimethylamino-3-benzyl-3 are taken up in 350 ml of dry ether. -azabicyclo [3.3.1] nonan-9-one and reduce 156.5 g of 70% sodium dihydrobis (2-methoxyethoxy) aluminate dissolved in 100 mL of ether as described in Example 24.

The isomeric amino alcohol mixture obtained after working up the reaction mixture was dissolved in 200 ml of n-heptane with heat. Upon cooling, a substance consisting predominantly of 6-dimethylamino-3-benzyl-3-azabicyclo [3.3.1] nonan-9-e. Recrystallization from acetone several times afforded pure isomer-free 6-N, N-dimethylamino-3-benzyl-3-azabicyclo [3.3.1] nonane-9-O-, in a 33% yield based on the isomeric mixture of amino alcohols. Melting point: 118-120 ° C.

The structure of 6-, N-dimethylamino-3-benzyl-3-azabicyclo [3.3.1] nonane-9-ol was confirmed by NMR and NMR spectra obtained with the reagent ( ¹ H ⁾ -1H- NMR: δ (CDCl 3); 7.26 ppm, s, Ar-H; 3.83 ppm, t, C (9) -H; 3.66 ppm, d, 3.00 ppm, d,

Sheet,,; 2.18 ppm, s, C (6) N / CH 2 Z 2; 3.40-1.50 ppm, m, CH 2, CH

Example 35

To a solution of 10.98 g of 6- (2-dimethylamino-3-benzyl-3-azabicyclo [3.3.1] nonan-9-ol) in 60 ml of dry pyridine is added dropwise over 15 minutes at a temperature below 15 C 5.06 g of benzoyl chloride. The reaction mixture was stirred at room temperature for two hours. The resulting reaction mixture was worked up as described in Example 23.

After work-up, the base obtained in 73% yield is converted in a known manner to the dihydrobromide salt, which is purified by recrystallization from an alcohol / ether mixture. The resulting 6- (N) -dimethylamino-3-benzyl-9-benzoyloxy-3-azabicyclo [3.3.1] nonane dihydrobromide melts at 167-169 ° C.

Claims (3)

SUBJECT OF THE INVENTION A process for the preparation of novel azabicyclo 3,3,1 nonane derivatives of the general formula I 4> where it means R ² and R ^{3 are the} same or different C 1 -C 4 alkyl or one of these is benzyl and the other is C 1 -C 4 alkyl, an esterified hydroxyl group of the formula -00C-R ⁶ , where R ^{6 is} C 1 -C 4 alkyl or C 5 -C 6 cycloalkyl or optionally halogen or one or more C 1 -C 4 alkyl or alkoxy, nitro, phenyl, phenoxy or trifluoromethyl substituted phenyl or a benzyl or naphthyl group which is optionally halogenated or hydrogenated, or a cinnamyl group which is optionally substituted by a halogen atom or a (C 1 -C 4) alkoxy group, or a benzhydryl group or 1,1-diphenylhydroxymethyl group, or a thenyl group as a heterocyclic substituent; 9-xant henyl, and alpha or beta chemical bonds, and pharmaceutically acceptable acid addition salts thereof, characterized in that the novel alcohol of formula (VIII) Wherein R, R, R and / or j are as defined above, reacted with a carboxylic acid derivative of the formula R @ ⁶ -COX, wherein R @ ⁶ is as defined above and X is halogen or C1 -C4 alkoxy , in the presence of an acid binding agent or an organic solvent and a catalyst, and the resulting ester derivative of the formula I is optionally separated into its stereoisomers and / or converted into its acid addition salts. 2. A method according to claim 1, characterized in that the reaction using the carboxylic acid derivative of the formula R ⁶ -COX wherein R ⁶ is as defined in claim 1 and X represents halogen, and during the reaction using an acid binding agent. 3. A process according to claim 1, wherein the reaction is a carboxylic acid derivative of the formula R @ ⁶ -COX, wherein R @ ⁶ is as defined in item 1 and X is C1 -C4 alkoxy, uses alkali metal as a transesterification promoting catalyst.