CS235316B2 - Method of bicyclic compounds production - Google Patents

Description

The present invention relates to a process for the preparation of novel bicyclic compounds of the formula I

2 ^R \ Ν ³ / ^{* (I) * 3} in which 12

R and R are each C 1 -C 6 alkyl and

5

R is an esterified hydroxy group of the formula -OCO-R which it represents

-phenylacetoxy

-cinnamoyloxy group optionally containing a halogen substituent or at least one C 1 -C 4 alkoxy substituent,

a benzoyloxy group optionally containing a C1-C4 alkyl substituent, a phenyl or trihalomethyl substituent, or at least one C1-C4 alkoxy substituent, or at least one halogen substituent and / or a nitro substituent

- benzyloyloxy,

- xanthene-9-carbonyloxy,

- naphthoyloxy, or

furoyloxy, thenoyloxy or optionally halogen-substituted nicotinoyloxy, or stereoisomers or pharmaceutically acceptable acid addition salts thereof.

The novel compounds of the formula I are biologically active substances and have a particularly potent antiarrhythmic effect. These new compounds are derivatives of 3,7-diazabicyclo [3.3.1] nonane (bispidine) substituted at the 9-position.

The synthesis of simple compounds with a bispidine backbone that does not contain a substituent or is substituted by a keto group at the 9-position has been described by L. J. Anet et al. / Austral J. Sdi. Res. 34, 330 (1950) 7 and S. Chiavarelli et al. fQazz. 8him. Italian. 67, 109 (1957), compare Chem. Abstr. 52. 15 519d7, without mentioning the biological effects of the prepared compounds.

The structure of 3-methyl-7-alkyl-3,7-diazabicyclo (3,3,1] nonanes and the corresponding 9-one derivatives was analyzed based on the N 1 R spectrum and dipole moments by J. E. Douglass et al.

[j. Org. Chem. U, 355 (1966)] and based on the mass spectrum of P. C. Ruenitz et al.

[j. Herocyclic Chem. 14, 423 (1977)]. The relative configuration of the 9-carbon atom was investigated by P. Scheiber et al. [Acta Chim. Acad. Sci. Hung. 102 (3), 297 (1979)] on 9-keto and 9-hydroxy compounds which are asymmetrically substituted at positions 3 and 7. However, these publications only provide the results of structure investigation.

Bispidine compounds unsubstituted at the 9-position are disclosed in DOS 2,749,564 as central nervous system and antiparkinsonian stimulants and in DOS 3,727,571 as antiarrhythmic agents. Mixtures with antiarrhythmic effects comprising 9-substituted bispidine compounds together with calcium antagonists have been described in BOS Patent 2,744,248.

9-Keto and 9-unsubstituted bispidine compounds are also disclosed in Belgian Patent No. 830,153 (see also DOS Patent No. 2,428,792). Of these compounds, the 9-unsubstituted compounds have antiarrhythmic effects and the therapeutic breadth is twice as broad as that of lidocaine.

9-substituted 3,7-diazabicyclo [3.3.1] nonane derivatives or compounds containing such groups have been described in the following publications:

Smissman et al. [j. Copper. Chem. 19 (1). 186 (1976), Chem. Abstr. 84. 43995e.7 have described methylther and ethyl ester of 9-ol compounds as having analgesic effects.

Derivatives containing an oycloalkylene group or a methyl and phenyl group at the 9-position have been described in DOS No. 2,658,558 as central nervous system stimulating agents and analgesic agents.

Belgian Patent No. 867,086 (see also U.S. Pat. No. 2,821,058) discloses 6-aminepenicillanic acid derivatives having antiviral and antibacterial effects, which may, inter alia, contain N-formylbispidine as a substituent at the 6-position. the skeleton has no substituent at the 9-position.

It has now been found that novel compounds of formula I which can be prepared from the corresponding compounds of formula II

(II) in which 1 2

R and R have the above-mentioned meanings; This finding is very surprising since such an effect has not previously been observed with the known 9-substituted bispidine derivatives.

Biological effects of the novel compounds were determined as follows: In testing for antiarrhythmic effects, rats were pre-administered intravenously with 1 mg / kg of aconitine to induce irregular heartbeat / Med. Exp. (Basel) 10, 93 (1964)], then the test compound was administered intravenously and the dose required to restore regular rhythm was determined in 50% of cases (ED? Q mg / kg).

The acute toxicity of the compounds was tested in mice after intranational administration and the doses found to cause 50% deaths (LD ≥ q mg / kg). In both tests lidocaine was used as reference. The results of the pharmacological tests are summarized in the following table. Therapeutic data (BD? Q / LD? Q) as well as the index ratio (new compound therapeutic index: lidocaine therapeutic index) are also shown in the table.

Compound

ED,

LDjq Therapeutic index

Index ratio

3,7-dimethyl-9-benzoyloxy-3,7-diazabicyclo [3.3.1] nonane

3-methyl-7-ethyl-9- (4'-chlorobenzoyloxy) -3,7-diazabicyclo [3.3.1] nonanedihydrochloride hydrate 3,7-diethyl-9- (4'-chlorobenzoyloxy) -r3,7- diazabicyclo [3.3.1] nonane dihydrochloride

3,7-di-n-butyl 9- (4'-chlorobenzoyloxy) -3,7-diazabicyclo [3.3.1] nonanfumarate

3,7-dimethyl-9-phenoxy-3,7-diazabicyclo [1,3.1] nonanofumarate

3,7-dimethyl-9- (4'-chlorophenoxy) -3,7-diazabicyclo [3.3.1] nonanfumarate

3,7-Dimethyl-9-benzhydryloxy-3,7-diazabicyclo [3.3.1] nonanfumarate

3-Methyl-7-ethyl-9- (4 = -chlorophenoxy) -3,7-diazabicyclo [3.3.1] nonane dihydrochloride

3-Methyl-7-ethyl-9 '- (2'-chlorophenoxy) -3,7-diazabicyclo [3.3.1] nonane dihydrochloride

3-Methyl-7-ethyl-9 '' - (2 ', 4'-dichlorobenzoyloxy) -3,7-diazabicyclo [3.3.1] nonane dihydrochloride

3-Methyl-7-ethyl-9H- (4'-phenylbenzoyloxy) -3,7-diazabicyclo [3.3.1] nonane

3,7-Dimethyl-9- (xanthene-9'-carbonyloxy) -3,7-diazabicyclo [3.3.1] nonane

0.8 9.0 0.009

0.6 26.0 0.023

0.4. 11.0 0.036

0.25 5.0 0.050

1.15 39.0 0.029

0.9 52.0 0.017

1.2 21.0 0.057

1.25 41.0 0.030

1.15 28.0 0.041

1.1 20.0 0.055

1.2 19.5 0.061

0.27 14.0 0.019

Compound “ ₅ 0 “ ₅ 0 Therapeutic index Ratio indexes 3,7-dimethyl-9- (2'-naphthoyloxy) -3,7-diazabicyclo [3.3.1] nonane bis (methanesulfonate) 0.11 17.0 0.006 58 3,7-Dimethyl-9- (3'-methoxy-4'-ethoxybenzoyloxy) -3,7-diazabicyclo [3.3.1] nonane 1.0 13.5 0,074 5 lidocaine 10.0 28.5 0.351 1

The data in the table show that the novel compounds have five to 58 times more favorable therapeutic effects than lidocaine.

Similarly good results were observed when the effects of suppressing heart rhythm irregularity were tested by the novel compounds in guinea pigs pretreated intravenously with 1 mg / kg ouabain to induce heart rhythm irregularity.

The novel compounds of the invention do not have β-receptor blocking effects, while their local anesthetic effects are close to lidocaine. In view of the mechanism of action, it is particularly favorable that the novel compounds also have calcium antagonistic effects (pAg). These effects of 3-methyl-7-ethyl-9 '- (4'-chlorobenzpyloxy) -3,7-diazabicyclo [3.3.1] nonane dihydrochloride are about as great as those of verapramil, a compound used successfully in therapy (4, ( 4.33 to 4.6 for the first and 4.58 to 4.7 for the second).

IN

It was also determined how the novel compounds affect the electropsychological parameters of the heart. It has been found that the novel compounds have irritating effects and increase the pacing threshold, lead time impulse, and immunity period that affect the pacing-inducing and pulse-guiding heart system in a direction that is particularly beneficial to eliminate regular rhythm disturbances.

Future therapeutic doses of the novel compounds when administered in clinical treatment are about 0.5 to 1 mg / kg for intravenous administration and about 10 mg / kg for oral administration.

This amount of active agent can be administered to the cell in a single dose or in multiple doses per day, depending on the disease being treated.

For oral administration, 3-methyl-7-ethyl-9- [4- (4-chlorobenzoyloxy) -3,7-diazabioyklo [3.3.1] nonane dihydrochloride, a compound having an ED50 ratio of 0.25%, appears to be particularly suitable. . = 16.7.

The principle of the preparation of the novel bicyclic compounds of the above-mentioned general formula (I) by the process according to the invention is that the compound of the general formula (II)

R @ ¹ -N @ ² \ | ^X OH /

2 wherein R and R are as defined above, reacted with a carboxylic acid of formula IV

R ⁵ - COOH (IV), wherein the -O-CO-R group is as defined above, or a reactive derivative thereof, optionally in the presence of an acid binder or in the presence of an alkali metal or other transesterification catalyzing agent. Optionally, the isomeric mixture is separated into its individual isomers and / or the compound of formula I obtained as the free base is converted into its pharmaceutically acceptable acid addition salt, or the base of formula I is liberated from its salt.

2

The starting compounds of formula II, in which R and R are the same and are ethyl or n-butyl, are novel compounds. These compounds can be prepared by catalytic hydrogenation of the respective 9-one derivatives.

With respect to the starting compounds of the formula II, there is also a novel process for the preparation of 3-methyl-7-ethyl-3,7-diazabicyclo [3.3.1] nonan-9-ol, as well as the 9-* -ol and 9β-resolution. -ο1 isomers.

According to the invention, the compound of formula II is acylated at the hydroxy group at the 9-position to obtain an ester of formula I.

When the free carboxylic acids of formula (IV) are used as the acylalcohol, the reaction is preferably carried out in the presence of a dehydrating agent and / or a carboxyl group activating agent.

However, it is preferable to use a functional derivative of a compound of formula (IV), such as an anhydride, halide or aliphatic alkyl of 1 to 5 carbon atoms, as the acylating agent.

When an acid halide, preferably chloride, of the acid of formula IV is used as the acylating agent, the reaction is preferably carried out in the presence of an acid binding agent. If the reaction solvent is a base such as pyridine, excess solvent may also act as an acid binding agent. Conversely, an inert organic solvent that suitably dissolves the starting material and the product can also be used as the reaction medium, in combination with any acid binder such as triethylamine.

In the case where the acid binder is not used in the reaction, it is recommended to use an aprotic organic solvent in which the starting material and the product are well soluble as the reaction medium. Such solvents are chlorinated hydrocarbons, especially chloroform. The reaction is preferably carried out at room temperature or under moderate cooling, at a temperature of 3 to 10 ° C.

It is preferred to use the acylating agent in excess and to carry out the reaction in the presence of an alkali metal or other transesterification catalyst as acylating agent of an aliphatic C 1 -C 5 ester.

As catalysts, for example, alkali metals or its alcoholates, hydrides or amides can be used. Sodium metal has proven to be a particularly preferred catalyser. In the reaction, usually 0.01 to 0.1 mol of catalyst is used, based on one mole of the diazabicyclic compound. The reaction is carried out under reduced pressure at a temperature of about 80 to 100 ° C; under such conditions the reaction takes place in 1 to 24 hours.

The reaction mixture is preferably processed as follows:

Excess solvent was evaporated under reduced pressure and if the reaction was carried out in the presence of a catalyst, the residue was worked up to decompose traces of catalyst. At the end, the residue is taken up in aqueous acid, the non-basic substances are removed from the mixture by extraction, the acidic aqueous phase is rendered alkaline, the free base of formula I is separated from the aqueous mixture by extraction and the extract is worked up in a manner known per se. The free bases of formula (I) are generally obtained in high purity, so that there is no need to purify the product before it is converted to a salt. Bases are usually crystalline solids which can be purified if recrystallization is required. If desired, the free bases can be converted into their acid addition salts by methods known per se, preferably to the dihydro chloride, dihydrobromides, dimethanesulfonates and the like.

The novel compounds of the invention can be converted into pharmaceutical compositions by methods well known in the art using conventional pharmaceutical carriers, diluents and / or other ingredients.

The invention is illustrated in more detail by means of the following non-limiting examples.

EXAMPLE 1 g of 3,7-dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-ol is dissolved in 10 ml of dry pyridine and a solution of 11.24 g is added dropwise to the resulting solution stirred at 5-10 ° C. benzoyl chloride in 50 ml dry pyridine over 30 minutes. The reaction mixture was then stirred at room temperature for 3 hours and the bulk of the pyridine was distilled off under reduced pressure. The residue is taken up in 30 ml of water, acidified with 20 ml of concentrated hydrochloric acid solution and extracted with 50 ml of ether each time to remove non-basic substances. The aqueous phase was made basic with potassium carbonate and extracted three times with 50 ml of chloroform each. The chloroform solutions were combined, dried over magnesium sulfate, filtered, and the filtrate was evaporated. The residue was crystallized from n-hexane to give 3,7-dimethyl-9-benzoyloxy-3,7-diazabicyclo [3.3.1] nonane in 42.5% yield, mp 100-102 ° C.

The base is converted to its hydrochloride in a manner known per se. The crystalline salt melts at 260 ° C after recrystallization from isopropyl alcohol.

Example 2

3,7-Dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-ol is reacted with suitable acyl halides as described in Example 1 to obtain the following compounds:

(a) When 4-nitrobenzoyl chloride is used as reactant, 3,7-dimethyl-9- (4 ' -nitrobenzoyloxy) -3,7-diazabicyclo [3.3.1] nonane is obtained in a yield of 80.6%. This product melts at 150 ° C after recrystallization from glycol dimethylether.

The dihydro chloride of the above compound is separated as a hemihydrate after recrystallization from methanol. Mp 272 ° C.

b) When 4-chlorcinnamoyl chloride is used as a reactant, a yield of 75.3% is obtained.

3,7-dimethyl-9- (4'-chlorocinnamoyloxy) -3,7-diazabicyclo [3.3.1] nonane. This product melts at 111-112 ° C after recrystallization from diisopropyl ether.

c) When 4-methoxycinnam (ayl chloride) was used as a reactant, a yield of 87.2% was obtained.

3,7-dimethyl-9- (4'-methoxycinnamoyloxy) -3,7-diazabioyklo [3.3.1] nonane. The resulting viscous yellow oil was converted directly to dihydro chloride. The salt melts at 230 ° C (with decomposition) after recrystallization from alcohol.

d) It is used as a reactant of 3,4,5-trimethoxycinnamoyl chloride, in a yield of 61.5% of 3,7-dimethyl-9- (3 ', 4 *, 5'-trimethoxycinnamoyloxy) -3,7-diazabicyclo [3] is obtained. 3.1] nonane. This product had a melting point of 130 ° C after recrystallization from diisopropyl ether. The base dichloride melts at 248 ° C (dec.) After recrystallization from aqueous alcohol.

Example 3 g of 3-methyl-7-ethyl-3,7-diazabicyclo [3.3.1] nonan-9-ol is reacted with 9.16 g of benzoyl chloride as described in Example 1. 3-methyl is obtained. -7-ethyl-9-benzoyloxy7,353.6

-3,7-diazabicyclo [3.3.1] nonane in 60.7% yield. The oily product has a boiling point of 175-178 ° C / 1.2 kPa; m / z = 1.5275. The free base dihydrochloride monohydrate melts at 26-237 ° C, after recrystallization from isopropyl alcohol.

Example 4

The following 3-methyl-7-ethyl-9ol-aroyloxy-3,7-diazabicyclo [3.3.1] nonane derivatives are prepared from the appropriate starting materials by the method described in the previous examples:

a) 1-Methyl-7-ethyl-90- (2'-dichlorobenzoyloxy) -3,7-diazabicyclo 3,3,1 nonane dihydrochloride, m.p. 105 DEG-07 DEG C. (after recrystallization from ethanol / ether), yield 48.1% <·

b) 3-methyl-7-ethyl-9 '- (4'-chlorobenzoyloxy) -3,7-diazabicyclo [3.3.1] nonane dihydrochloride, m.p. 140-142 ° C (after recrystallization from a mixture of ethanol; and ether, yield 48.2%.

c) 3-Methyl-7-ethyl-9o- (4'-phenylbenzoyloxy) -3,7-diazabicyclo [3.3.1] nonane; m.p. 9 DEG-92 DEG C. (after recrystallization from n-hexane), yield 50%. The dihydrochloride melts at 83 DEG-185 DEG C. after recrystallization from a mixture of ethanol and ether.

Example 5

3-Methyl-7-ethyl-3,7-diazabicyclo [3.3.1] nonan-9-ol is reacted with 4-chlorobenzoyl chloride as described in Example 1. 3-Methyl-7-ethyl- N - (4'-chlorobenzoyloxy) -3,7-diazabicyclo [3.3.1] nonane in 70% yield. The base had a melting point of 66-67 ° C after recrystallization from petroleum ether (boiling point 120 ° C).

The dihydrochloride of the above base, prepared in a manner known per se, is a colorless crystalline solid, m.p. 175 DEG C., after recrystallization from isopropyl alcohol.

Example 6

9.9 g of 3,7-diethyl-3,7-diazabicyclo [3.3.1] nonan-9-ol is reacted with 4-chlorobenzoyl chloride as described in Example 1 to give 3,7- Diethyl-9- (4 ^of -chlorbenzoyloxy) -3,7-diazabicyclo [3.3] nonane with a yield of 53.8%; mp 116-120 ° C.

The starting material can be obtained as follows:

1-Ethyl-4-piperidone is reacted with paraformaldehyde and ethylamine. In a yield of%, 3,7-diethyl-3,7-diazabicyclo [3.3.1] nonan-9-one is obtained; boiling point 87 ° C / 1.3 Pa, n _D = 1.4935; 76 g of the title compound are dissolved in 300 ml of dry alcohol, 0.6 g of platinum oxide (Adams catalyst) is added and the mixture is hydrogenated at a pressure of 70 bar for about 7 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was recrystallized from heptane to give 54 g (7%) of 3,7-diazabicyclo [3.3.1] nonan-9-ol, mp 61.5 ° C.

Example7

10.18 g of 3,7-di-n-butyl-3,7-diazabicyclo [3.3.1] nonan-9-ol was reacted with 7.7 g of 4-chlorobenzoyl chloride as described in Example 1. with 3,7-di-n-butyl 9- (4-chlorobenzoyloxy) -3,7-diazabicyclo [3.3.1] nonane, which is converted to its fumarate. The salt, m.p. 180 DEG -8.8 DEG C., is obtained in a yield of 57.5%.

The starting material is prepared from 3,7-di-n-butyl-3,7-diazabicyclo [3.3.1] nonan-9-one (boiling point 123 ° C / 7 Pa, = 1.4883) by catalytic reduction, according to the method described in Example 6. The resulting 3,7-di-K-butyl-3,7-diazabicyclo-3,3,11-nonan-9-ol is recrystallized from petroleum ether (boiling point 120 ° C) and then subjected to sublimation under reduced pressure. pressure. The colorless crystalline solid had a melting point of 31-32 ° C.

Example g of 3,7-dimethyl-3,7-diazabicyclo [3.3.1-naphthalen-9-ol was reacted with 19.57 g of xanthene-9-carbonyl chloride as described in Example 1. 3,7-dimethyl- 9- (xanthene-9'-carbonyloxy) -3,7-diazabioylclo [3.3.1] nonane in 58.3% yield. The free base has a melting point of 10 108 ° C, after recrystallization from n-hexane. The corresponding fumarate has a melting point of 191-193 ° C, after recrystallization from a mixture of ethanol and ether.

Example 9

To a solution of 8.5 g of 3,7-dimethyl-3,7-diazabicyclo [3.3.1.0] nonan-9-ol in 100 ml of chloroform was added 13.3 g of 2-naphthoyl chloride at a temperature below 20 ° C and then The reaction mixture was allowed to stand at room temperature for one hour. The chloroform solution is evaporated under reduced pressure and the residue is taken up in 100 ml of water. The aqueous solution was acidified with 10 ml of hydrochloric acid and then extracted twice with 50 ml of ether each time. The aqueous phase was made basic with potassium carbonate and the liberated base was extracted three times with 50 ml of chloroform each. The chloroform extracts were combined, dried over magnesium sulfate and filtered, and the filtrate was evaporated. The crystalline residue has a melting point of 76-78 ° C after recrystallization from 2-butanone. Yield 99%. Resultant

3,7-Dimethyl-9- (2'-naphthoyloxy) -3,7-diazabicyclo [3.3.0 nonane] is converted to its di (methanesulfonate) in a manner known per se. The salt was heated to 212 ° C after recrystallization from ethanol.

He did

3,7-Dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-ol is reacted with a suitable acylating agent as described in Example 9. The following compounds are obtained:

a) 3,7-Dimethyl-9- (4'-methylbenzoyloxy) -3,7-diazabicyclo [3.3.1] nonane; yield 83%, mp 59-60 ° C (after sublimation in vacuo). The dihydrobromide produced in a manner known per se has a melting point of 231-233 [deg.] C. after recrystallization from methanol.

b) 3,7-Dimethyl-9- (4 ^{<-ethylbenzoyloxy)} -3,7-diazabicyclo [3.3.1] nonane; yield 90%, mp 62-63 ° C (after sublimation in vacuo). The dihydrobromide produced in a manner known per se has a melting point of 233-234 [deg.] C. (with decomposition) after recrystallization from ethanol.

c) 3,7-Dimethyl-9- (4'-chlorobenzoyloxy) _-3) 7-diazabicyklot3,3, Únonan; 87 DEG-89 DEG C. (after sublimation under vacuum). The dihydrobormide produced in a known manner has a melting point of 260 DEG C. after recrystallization from aqueous acetone.

d) 3,7-Dimethyl-9- (2'-chloro-4'-nitrobenzoyloxy) -3,7-diazabicyclo [3.3.1] nonane; Yield 73%, mp 116-117 ° C (after recrystallization from acetone). The dihydrobromide produced in a known manner has a melting point of 237 DEG-238 DEG C. (with decomposition) after recrystallization from aqueous acetone.

e) 3,7-Bimethyl-9- (3'-methoxy-4'-ethoxybenzoyloxy) -3,7-diazabicyclo [3.3.1] nonanone yield 93%, mp 72-73 ° C (after sublimation at vacuum). The dihydrobromide produced in a manner known per se has a melting point of 178 DEG-180 DEG C. (with decomposition) after recrystallization from ethanol.

f) 3,7-Dimethyl-9- (2'-furoloxy) -3,7-diazabicklo [3.3.1] nonane yield 71.9%, mp 131-132 ° C (after recrystallization from acetone). The dihydrobromide produced in a manner known per se has a melting point of 239 DEG-241 DEG C. (with decomposition) after recrystallization from methanol.

g) 3,7-Dimethyl-9- (2'-chloronicotinoyloxy) -3,7-diazabicyclo [3.3.1] nonane 85% yield, m.p. 123-125 ° C (after recrystallization from methyl ethyl ketone). Dihydrobromide production- ^; m.p. 260 DEG C. (dec.) after recrystallization from aqueous methanol.

h) 3,7-Dimethyl-9- (2'-thenoyloxy) -3,7-diazabicyclo [3.3.1] nonane; yield 83%, m.p. 96-97 ° C. The dihydrobromide prepared in a manner known per se has a melting point of 260 DEG-262 DEG C. (with decomposition) after recrystallization from methanol.

They did

To a mixture of 8 g of 3,7-dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-ol and 22 g (excess 185%) of phenylacetic acid ethyl ester is added 0.3 g of sodium metal in the form of small chips. . The reaction mixture is kept 6 hours under reduced pressure of 3 kPa for vddní bath heated to 90 ^{ΰ Β.} The pressure is then adjusted to atmospheric pressure, the reaction mixture is diluted with 50 ml of ether and the basic material is extracted twice with 75 ml of 10% aqueous hydrochloric acid each time. The aqueous phases were combined, basified with potassium carbonate and the product separated as an oil was extracted three times with 50 ml of chloroform each. The chloroform extracts were combined, dried over magnesium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was distilled in vacuo.

3.7-Dimethyl-9-phenylacetoxy-3,7-diazabicyclo [3.3.1] nonane was obtained in a yield of 88.5%.

o 25

The substance has a boiling point of 168 DEG C. at 20 Pa, = 1.5310. The dihydrobromide produced in a manner known per se has a melting point of 230 DEG C. after recrystallization from methanol.

Example12

3.7-Dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-ol is reacted with a 100% excess of a suitable carboxylic acid ester as described in Example 11. The following compounds are obtained:

(a) 3,7-Dimethyl-9-benzyloyloxy-3,7-diazabicyclo [3.3.1] nonane; yield 57.8%, mp 119 ° C (after recrystallization from diisopropyl ether). The fumarate has a melting point of 205 ° C, after recrystallization from a mixture of methanol and ethanol.

b) 3,7-Dimethyl-9-nicotinoyloxy-3,7-diazabicyclo [3.3.1] nonane; boiling point 183 ° C / 140 Pa, melting point 70-75 ° C. The trihydrobromide prepared in a manner known per se has a melting point of 262 [deg.] C. after recrystallization from methanol.

Claims (9)

SUBJECT OF THE INVENTION A process for the preparation of bicyclic compounds of the general formula (I) ^: N-R * (I) wherein 1 2 R and R are each C 1 -C 6 alkyl and are esterified hydroxy of the formula OCO-R 6 which represents -phenylation of the toxic group, -cinnamoyloxy group optionally containing a halogen substituent or at least one C 1 -C 4 alkoxy substituent, - a benzoyloxy group optionally containing a C 1 -C 4 alkyl substituent, a phenyl or trihalomethyl substituent, or at least one C 1 -C 4 alkoxy substituent, or at least one halogen substituent and / or a nitro substituent, - benzyloyloxy, - xanthene-9-carbonyloxy, - naphthoyloxy, or - furoyloxy, thenoyloxy or optionally halogen-substituted nicotinoyloxy, or stereoisomers or pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula II 1 / P tf-N C. N-FC OH (II) Wherein R and R are as defined above, reacted with a carboxylic acid of formula IV R ⁵ - COOH (IV) wherein the -O-CO-R group is as defined above, or a reactive derivative thereof, optionally in the presence of an acid binder or in the presence of an alkali metal or other transesterification catalyst, optionally separating the isomeric mixture obtained to the individual isomers and / or the compound of formula I obtained as the free base is converted into its pharmaceutically acceptable acid addition salt, or the base of formula I is liberated from its salt. 2. A process according to claim 1, wherein the reactive carboxylic acid derivative of the formula IV is an acid halide. 3. Process according to claim 1 or 2, characterized in that the reaction is carried out in the presence of an acid binding agent. 4. The process according to claim 1, wherein the reactive carboxylic acid derivative of the formula IV is an alkyl ester of 1 to 5 carbon atoms. 5. The process of claim 1, wherein the reaction is carried out in the presence of a transesterification catalysing agent. 6. The process of item 1, for the preparation of 3,7-dimethyl-9-benzoyloxy-3,7-diazabicyclo [3.3.11] nonane, characterized in that 3,7-diazabicyclo [3.3.1] nonane is The 9-ol is reacted with benzoyl chloride. 7. Method according to claim 1 for producing 3-methyl-7-ethyl-9 - (4 -chlorbenzoyloxy) -3,7-diazabicyclo [3 _t 3.1] nonane and its dihydrochloride, characterized in that 3-Methyl-7-ethyl-3,7-diazabicyclo [3.3.1.0] nonane-9-ol is reacted with 4-chlorobenzoyl chloride and optionally the resulting base is converted to its dihydrochloride. n 8. A process according to claim 1, for the preparation of 3,7-diethyl-9- (xanthene-9'-carbonyloxy) -3,7-diazobicyclo [3.3.1] nonane and its fumarate, characterized in that it comprises: N -dimethyl- and N -diazabicyclo [1,3.1] nonan-9-ol is reacted with xanthene-9-carbonyl chloride and optionally the resulting base is converted to its fumarate. 9. A process according to claim 1 for the preparation of 3,7-dimethyl-9- (2'-naphthoyloxy) -3,7-diazabicyclo [3.3.1] nonane and its di (methanesulfonate), characterized in that: The 3,7-dimethyl-3,7-diaza-bicyclo [3.3.1] nonan-9-ol is reacted with 2-naphoyl chloride and optionally the resulting base is converted to its di (methanesulfonate).