DD282228A5 - PROCESS FOR THE PREPARATION OF 3,7-DIAZABICYCLO [3,3,1] NONAN COMPOUNDS - Google Patents

Abstract

The invention relates to processes for the preparation of novel * of the general formula I wherein R 1 is alkyl, cycloalkylalkyl or benzyl, R 2 is lower alkyl, R 3 is lower alkyl or R 2 and R 3 together form an alkylene chain and R 4 is an optionally halogen, lower Alkoxy, lower alkyl, hydroxy or trifluoromethyl substituted benzhydryl group or represents an optionally substituted by halogen, lower alkyl, lower alkoxy, hydroxy, nitro or trifluoromethyl substituted cinnamyl group. The compounds have pharmacologically valuable, especially cardiac properties. Formula I {* Medicinal, heretical, phamacologically valuable}

Description

J-CH ₂ -CH = CH - / ^

la

wherein R ¹ , R ² , R ³ and R ^{11 have the} above meaning and R ⁹ and R ^{10 have} the meaning given above for R ⁹ and R ¹⁰ , but with any free hydroxy groups are provided with a protective group, compounds of general formula XIV

Z Ζ »

XIV

N-C-CPI = GH

in which R ¹ , R ² , R ³ , R ⁹ , R ¹⁰ and R ^{11 have the} above meaning, and Z and Z 'together are oxygen or Z is hydroxyl and Z' is hydrogen, then reduced, and subsequently any hydroxy protective groups are split off again, or, if desired, in resulting compounds of the formula I in which R ^{4 represents} a methoxy-substituted benzhydryl group, converts methoxy substituents into hydroxy and, if desired, converts free compounds of the formula I into their acid addition salts or converts the acid addition salts into the free compounds of the formula I.

2. The method according to claim 1, characterized in that compounds of general formula I are prepared wherein R ^{1 represents} an alkyl group having 1-6 carbon atoms or a cycloalkylalkyl group having 4-9 carbon atoms.

3. The method according to claim 1, characterized in that compounds according to claim 2, wherein the cycloalkylalkyl group contains 4-7 carbon atoms are prepared.

4. The method according to claim 1, characterized in that compounds of the general formula I are prepared, Jvorin R ^{4 is} a benzhydryl group of the formula a, wherein R ⁵ , R ⁶ , R ⁷ and R ^{8 have the} above meaning.

5. The method according to claim 1, characterized in that compounds are prepared according to claim 4, wherein R ⁶ and R ^{8 is} hydrogen.

6. The method according to claim 1, characterized in that compounds of the general formula I are prepared, wherein R ^{4 is} a cinnamyl group of the formula b, wherein R ⁹ , R ¹⁰ and R ^{11 have the} above meaning.

7. The method according to claim 1, characterized in that compounds are prepared according to claim 6, wherein R ^{11 is} hydrogen.

For this 6-page formulas

Field of application of the invention

The present invention relates to processes for the preparation of novel 3-Benzhydryl- and S-cinnamyl-α.y-diazabicyclop ^ .i] nonane compounds and their salts.

The compounds according to the invention are used in medicine as medicaments with cardioactive properties.

Characteristic of the known state of the art

DE-OS 2658558 discloses 3-alkanoyl and 3-aroyl-3,7-diazabicyclo | 3,3,1] nonane derivatives for which central analgesic effects are indicated. DE-OS 2428792 discloses 3,7-diazabicyclo [3,3,1-nonanane derivatives having antiarrhythmic properties which are substituted in the 3- and 7-position by alkyl or phenylalkyl radicals. In EP-A-O000074 7-8enzyl-3-phenylalkyl-3,7-diazabicyclo [3,3,1] nonane derivatives are also described with antiarrhythmic effects. Further 3,7-diazabicyclo [3,3,1 [nonane derivatives with antiarrhythmic properties are known from EP-A-0103833.

Object of the invention

The novel 3-substituted by a benzhydryl radical or a cinnamyl substituted 3,7-diazabicyclo [3,3,1] nonane compounds have valuable pharmacological properties, in particular valuable herzwirksnme properties. They are characterized by a favorable effect profile with heart rate lowering effects and antiarrhythmic properties.

Explanation of the essence of the invention

The object of the present invention is to develop new 3,7-diazabicyclo [3,3,1] nonane compounds having valuable pharmacological properties.

The present invention relates to processes for the preparation of therefore new 3,7-diazabicyclo3,3,1] nonane compounds of general formula I.

R ¹ J

V ^ - r3 W-

R 'is an alkyl group having 1-6 carbon atoms, a cycloalkylalkyl group having 4-9 carbon atoms or benzyl, R ^{2 is} lower alkyl and

R ^{3 is} lower alkyl or

R ² and R ³ together form an alkylene chain having 3-6 carbon atoms, and R ^{4 is} a Benzhydrylgi uppe of the general formula a

means, in which

R ^{5 is} hydrogen, halogen, lower alkoxy, lower alkyl, hydroxy or trifluoromethyl, R ^{6 is} hydrogen, lower alkyl, halogen or lower alkoxy,

R ^{7 is} hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl, and R ^{8 is} hydrogen, lower alkyl, halogen or lower alkoxy, or R ^{4 is} a cinnamyl group of the general formula b

(see formula b)

means, in which

R ^{9 is} hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, R ^{10 is} hydrogen, halogen, lower alkoxy, lower alkyl, hydroxy or, if R ^{9 is} hydrogen, also trifluoromethyl or nitro, and

R "hydrogen or, if R ⁹ and R ' ^{0 are} lower alkoxy, also lower alkoxy, and their acid addition salts.

If in the compounds of the formula IR ^{1 is} an alkyl group, this may be straight-chain or branched and contain 1 to 6, preferably 2 to 4, carbon atoms. A cycloalkylalkyl group R ¹ may contain 4 to 9, preferably 4 to 7, carbon atoms. Particularly suitable radicals R ¹ are alkyl and cycloalkylalkyl radicals, in particular branched alkyl radicals. If the substituents R ² and R ^{3 represent} lower alkyl, these alkyl groups may be straight-chain or branched and contain 1 to 4, preferably 1 to 3, carbon atoms. The alkyl groups R ² and R ³ are suitably the same, but may also be different. If R ² and R ³ together form an alkylene chain, this may contain 3 to 6, preferably 4 to 5 carbon atoms.

In the compounds of the formula I, the radical R ^{4 may represent} an optionally substituted benzhydryl group a. If the substituents R ^s to R ^{8 of} the benzhydryl group a represent or contain lower alkyl groups, these may contain 1 to 4, in particular 1 or 2, carbon atoms. Halogen substituents R ⁵ to R ⁸ preferably represent fluorine or chlorine. Preferably, the benzhydryl radical R ⁴ contains only 0-2 substituents in total. The radicals R ⁵ and R ⁷ are preferably hydrogen, halogen, in particular fluorine, or else lower alkyl, in particular methyl. The substituents R ⁶ and R ⁸ preferably represent hydrogen or else lower alkyl, in particular methyl.

In the compounds of the formula I, the radical R ^{4 may} also be an optionally substituted cynnamyl group b. If the substituents R ⁹ to R "of the cinnamyl group b are or contain lower alkylene groups, these may contain 1 to 4, in particular 1 or 2, carbon atoms. Halo substituents R ⁹ and / or R ¹⁰ are preferably chlorine.

Preferably, the cinnamyl radical R ^{4 is} unsubstituted or mono- or disubstituted by halogen or methoxy. According to the invention, the new SJ-DiazabicyclolS ^ ilnonan compounds of general formula I and their acid addition salts are obtained by reacting in a conventional manner

a) compounds of the general formula II

(see formula II)

wherein R ¹ , R ² and R ^{3 have the} above meaning, with compounds of general formula III, R ⁴ -X III

wherein R ^{4 has} the meaning given above for R ⁴ , but any free hydroxyl groups are provided with a protective group, and X is an aminolytically cleavable group, reacting or

b) For the preparation of compounds of general formula I a

(see formula la)

wherein R ¹ , R ² , R ³ and R "have the above meanings and R ⁹ and R ^{10 have} the meaning given above for R ⁹ and R ¹⁰ , but with any free hydroxy groups being provided with a protective group Compounds of the general formula XIV

(see formula XIV)

in which R ¹ , R ² , R ¹ , R ⁹ , R ' ⁰ and R "have the above meaning, and Z and Z' together are oxygen or Z is hydroxyl and Z 'is hydrogen,

and then optionally splits off any hydroxy protecting groups, or if desired in resulting compounds of formula I, wherein R ^{4 represents} a methoxy-substituted Benzhydrylgruppo converted Methoxysubstituenten in hydroxy and optionally converted free compounds of formula I into their acid addition salts or converted the acid addition salts into the free compounds of formula I. ,

The reaction of compounds of the formula II with compounds of the formula III can be carried out in a manner known per se under customary conditions for the alkylation of amines. Thus, the reaction is conveniently carried out in an inert under the reaction conditions orpanic solvent under basic conditions. As aminolytic cleavable radicals in the compounds of formula III are preferably halogens such as chlorine or bromine or organic Sultonsäurereste in question, for example, the radical of Niederalkansulfonsäuren such. For example, methanesulfonic odar of aromatic sulfonic acids such as benzenesulfonic acid or substituted by lower alkyl or halogen benzenesulfonic acids, for example, toluenesulfonic acids or bromobenzenesulfonic acids. Suitable inert organic solvents are in particular aprotic solvents such as ethers, in particular cyclic ethers such as tetrahydrofuran, dimethylformamide, aromatic hydrocarbons such as benzene or toluene, or mixtures of the abovementioned solvents. Conveniently, the reaction is carried out in the presence of at least an equivalent amount of a base. Examples of suitable bases are alkali metal carbonates, alkali metal amides, alkali metal hydrides, organolithium compounds such as lower alkyl lithium or phenyl lithium. Thus, for example, the use of potassium carbonate in dimethylformamide or n-Biityllithium in tetrahydrofuran or of lithium amide in tetrahydrofuran or dimethylformamide proves to be useful. The reaction temperature can vary depending on the type of base used and between about 0 ° C and boiling point of the solvent, in particular between about 0 ° C and 8O ⁰ C are selected. The Reaklionsdauer can be depending on the type of reaction conditions selected between 2 and 12 hours. If the radical R ^{4 of} the compounds of the formula III contains free hydroxy substituents, they must be protected during the reaction with the compounds of the formula II in a manner known per se by readily cleavable protective groups. Suitable after the reaction If not again cleavable protecting groups for phenolic OH groups are, for. As known from E. McOmie, "Protective Groups in Organic Chemistry" Plenum Press, 1971. For example, are suitable for protecting a hydroxyl esters, for. Example, acetates and easily cleavable ether, in particular tetrahydropyranyl or readily cleavable carbonates such as benzyl carbonates. If R ⁴ is a are hydroxy-substituted cinnamyl, such protective groups must be selected, which are then readily cleavable under conditions under which the double bond of Cinnamylrestes is not attacked.

The reduction of compounds of the formula XIV according to process variant b can be carried out by methods customary per se for the reduction of amides and aminocarbinols. Suitable reducing agents are complex metal hydrides. Thus, for example, for the reduction of amides of the formula XIV complex Aluniiniumhydride, such as lithium aluminum hydride or sodium bis (2-methoxyethhoxy) dihydroaluminate in a Reaktionsbedingtingen inert solvent, such as an open-chain or cyclic ether such as diethyl ether or tetrahydrofuran, optionally in admixture with aromatic hydrocarbons such as benzene or toluene as suitable. In addition, sodium borohydride is also suitable for the reduction of aminocarbinols of the formula XIV. The reduction with sodium borohydride can be carried out in a lower alcohol, for example methanol, optionally in admixture with other inert organic solvents. The reaction temperature may vary depending on the type of reducing agent used. Temperatures between O ⁰ C and room temperature are favorable.

Compounds of the formula I in which R ^{4 is} a benzyl radical a containing a free hydroxy substituent can be obtained from corresponding methoxy-substituted compounds of the formula I by ether cleavage. Dia release of Kydroxygrup ever can be done by conventional methods for Phenolätherspaltung. For example, the ether cleavage proves to be favorable by treating the compounds with hydriodic acid in a solvent which is inert under the reaction conditions.

The compounds of the formula I can be isolated and purified from the reaction mixture in a manner known per se. Acid addition salts can be converted into the free bases in the customary manner and, if desired, these can be converted in known manner into pharmacologically acceptable acid addition salts. As pharmacologically a-mehmbare acid addition salts of the compounds of formol I eijnen, for example, their salts with inorganic acids, eg. As hydrohalic acids, in particular hydrochloric acid, sulfuric acid or phosphoric acids, or with organic acids, for example lower aliphatic mono- or dicarboxylic acids such as lactic acid, maleic acid, fumaric acid, tartaric acid or acetic acid, or sulfonic acids, for example N: ederalkylsulfonsäuren such as methanesulfonic acid or optionally in Bunzol ring by halogen or lower alkyl substituted benzenesulfonic acids such as p-toluenesulfonic acid or cyclohexylaminosulfonic acid.

In the event that R ² and R ^{3 are} different, the compounds can occur in two stereoisomeric forms. The present invention encompasses both the isomer mixtures and the pure isomers of these compounds of the formula I. Isomer mixtures can be separated in a manner known per se at the stage of the end compounds or at an intermediate stage into the individual isomers, for example by fractional crystallization or by column chromatography separation.

If R ^{4 represents} an optionally substituted cinnamyl radical b, this radical may have cis or trans configuration. The 3,7-diazabicyclo | 3,3,1) nonane compounds of the formula II used as starting compounds are known from EP-A-0103833 and DE-OS 2658558 and / or can be prepared by the methods described in these publications or analogously to the methods described in these documents are prepared in a conventional manner. For example, compounds of the formula II can be obtained by reacting compounds of the formula IV

(see formula IV)

wherein R ', R ² and R ^{3 have the} above meaning and R' ² benzyl hedeutet, the benzyl group R ¹² hydrogenolysis in a known per se. The hydrogenolytic cleavage of the group R ¹² can be carried out with hydrogen in the presence of a palladium / carbon Katfilysators in an organic protic polar solvent, such as a lower alcohol such as ethanol, conveniently in the presence of catalytic amounts of glacial acetic acid. The hydrogenation may conveniently be carried out at room temperature and a hydrogen pressure of about 5 to 6 atmospheres. Starting compounds of the formula IV can be prepared, for example, starting from compounds of the formula V

(see formula V)

wherein R ¹ , R ² and R ^{3 have the} above meaning, can be obtained. For this purpose, the tetraoxo compounds of the formula V are first reacted with benzyl halides of the formula VI

(see formula VI)

wherein R ^{12 has the} above meaning and Hal is halogen, in particular chlorine or bromine, to the N, N'-disubstituted tetraoxo compounds of the formula VII

(see formula VII)

wherein R ', R ² , R ³ and R ^{12 have the} above meaning, reacted and then reduced to the compounds of formula IV. The reaction of the diimide compounds of the formula V with the compounds of the formula VI can be carried out by methods customary per se for the alkylation of imides.

The reaction expediently takes place in a solvent which is inert under the reaction conditions in the presence of a base at elevated temperature, for example the boiling point of the solvent. For example, alkali metal carbonates, amides or hybrids in dimethylformamide or alkali metal alcoholates in a lower alcohol are suitable. Conveniently, the benzyl halide is used in excess.

The 2,4,6,8-tetraoxo-3,7-diazabicyclo [3,3 _/ 1) nonane compounds of the formula V are known and / or can be prepared by the method described by Hörlein (Eur. J. Med. Chem. 12, 301-305) are prepared by ring closure of 2,6-dioxo-3,5-dicyanopiperidine compounds of formula VIII

(see formula VIII)

wherein R ¹ , R ² and R ^{3 have the} above meaning, in high-percentage acid-water mixtures. The 2,6-dioxo-3,5-dicyanopiperidine VIII are in turn obtained in a known manner by condensation of appropriately substituted Alkalidencyanessigestern of formula IX

(see formula IX)

in which R ² and R ^{3 have the} above meaning, with cyanoacetamides of the formula X (see formula X)

wherein R ^{1 has the} above meaning

 Compounds of the formula Ha

(see formula Ha)

wherein R ² and R ^{3 have the} above meaning and R 'has the meaning given for R ¹ with the exception of benzyl, can also be obtained by reacting compounds of formula II, wherein R ^{1 is} benzyl, with compounds of formula Xl

(see formula Xl)

wherein R '' and X have the above meaning, alkylated and then cleaved off the benzyl hydrogenolytically. The alkylation is carried out in a manner known per se e.g. under the conditions specified for the reaction of the compounds of the formula II with compounds of the formula III

 Compounds of the formula XIV

(see formula XIV)

wherein R ¹ , R ² , R ³ , R ⁹ , R ¹⁰ , Z and Z 'have the meaning given above for formula XIV, and R "is hydrogen or, if R ⁹ and R ^{10 are} lower alkoxy and R ² and R ³ The compounds of the formula XIV are valuable intermediates for the preparation of pharmacologically active compounds, for example compounds of the formula I. According to the invention, the compounds of the formula XIV are valuable intermediates for the preparation of pharmacologically active compounds, for example compounds of the formula I.

The amides of the formula XIVa (see formula XIVa)

wherein R ', R ² , R ³ , R ⁹ , R ¹⁰ and R "have the above meaning, can be obtained in known manner by n ~ cn acids of the formula XV

(see formula XV)

wherein R ⁹ , R ¹⁰ and R "have the above meanings or react their reactive acid derivatives with compounds of the formula II The reaction of acids of the formula XV and their reactive derivatives with compounds of the formula II can be carried out according to conventional methods for amide formation by aminoacylation For example, acid halides, in particular chlorides or bromides, lower alkyl esters or mixed anhydrides, for example anhydrides with lower alkanecarboxylic acids or acid derivatives, are used as reactive acid derivatives For example, lower alkanesulfonic acids, in particular acetic acid or methanesulfonic acid, are suitable, for example compounds of the formula XVa are suitable for the reaction with the compounds of the formers

(see formula XVa)

in which R ⁹ , R ¹⁰ and R "have the above meaning and Y is hydroxy, lower alkoxy, halogen or an acyloxy group -OY ', where Y' is lower alkylcarbonyl or lower alkylsulfonyl The conversion of the free acids of formula XV into reactive acid derivatives Thus, acid halides of formula XVa can be obtained, for example, by reacting the acids of formula XV with a halogenating agent, for example phosphorus trichloride, phosphorus pentabromide or thionyl chloride If desired, the reaction can be carried out in the presence of pyridine or another tertiary organic base For example, mixed acid anhydrides may be prepared by reacting acids of formula XV or their alkali metal salts with a corresponding organic acid chloride in an inert organic solvent, for example a halohydrocarbon, optionally in the presence of a tertiary organic base e, for example pyridine are obtained.

The reaction of the acid derivatives of the formula XVa with the compounds of the formula II can be carried out in a solvent which is inert under the reaction conditions at temperatures between -30 ° C. and the boiling point of the solvent. Suitable solvents are halogenated hydrocarbons such as dichloromethane or chloroform, aromatic hydrocarbons such as benzene or toluene, cyclic ethers such as tetrahydrofuran or dioxane or mixtures of these solvents. If desired, the reaction can be carried out in the presence of an acid-binding reagent. Suitable acid-binding agents are inorganic bases, in particular alkali metal carbonates and organic bases, in particular tertiary lower alkylamines and pyridines.

Aminocarbinol compounds of the formula XIVb (see formula XIVb)

wherein R ¹ , R ² , R ³ , R ⁹ , R ¹⁰ and R "have the above meaning, form, for example, when compounds of formula II with an aldehyde of formula XVI

(see formula XVI)

wherein R ⁹ , R ¹⁰ and R "have the above meaning condensed, and are conveniently further reduced directly in situ according to process variant b to compounds of formula la.

The reaction of the aldehydes of the formula XVI with the compounds of the formula II can be carried out by methods customary per se for the preparation of amino alcohols. For example, the condensation of the aldehyde compounds of the formula Xv ^- I with the cyclic amine compounds of the formula II can be carried out by heating in a polar solvent which is inert under the reaction conditions, for example a lower alcohol such as methanol.

The acids of the formula XV and the aldehydes of the formula XVI are known and / or can be prepared in a manner known per se.

The compounds of the formula III are known and / or can be obtained in a manner known per se.

The starting compounds of the formula III in which R ^{4 is} an optionally substituted benzhydryl radical can be obtained, for example, in a manner known per se by reacting with carbinol compounds of the formula XII

(see formula XII)

wherein R ⁶ and R ^{7 have} the meaning given above for R ⁵ and R ⁷ , wherein, however, any free hydroxy groups are provided with a protective group, and R ⁶ and R ^{8 have the} above meaning, in a conventional manner, the alcoholic hydroxy group in an aminolytic split off group X transferred. To introduce a halide radical X, the carbinol compounds of the formula XII can be reacted, for example, with the appropriate hydrohalic acid. For this purpose, the compound of formula XII is conveniently in an inert organic solvent, for. As an ether or an aromatic hydrocarbon such as benzene, reacted with gaseous hydrohalic acid at room temperature or le'cht elevated temperature, optionally in the presence of a drying agent. If the halide radical X represents chlorine, it is z. B. advantageous to add CaCl ₂ as a drying agent. For the introduction of a sulfonic acid radical X, the compounds of the formula XII are expediently reacted with the corresponding sulfonyl chloride. The reaction may, for example, in an inert solvent, for. As a cyclic ether such as tetrahydrofuran or a halogenated hydrocarbon such as dichloromethane at room temperature.

Compounds of formula XII can be prepared in a manner known per se by reduction of corresponding benzophenones of formula XIII

(see formula XIII)

wherein R ⁵ , R ⁶ , R ⁷ and R ^{8 have the} above meaning, are obtained. Suitable reducing agents are, for example, borohydrides, such as sodium borohydride or metallic zinc / sodium hydroxide solution. The benzophenones of the formula XIII are known and / or can be obtained in a manner known per se by reacting a correspondingly substituted benzonitrile or a benzoic acid ester with a correspondingly substituted phenylmagnesium halide in a Grignard reaction. Compounds of formula XII can also be obtained by reacting appropriately substituted benzaldehydes with appropriately substituted phenylmagnesium halides in a Grignard reaction in a manner known per se to the carbinol compounds of formula XII.

Compounds of the formula III in which R ^{4 is} an optionally substituted cinnamyl radical can be obtained, for example, starting from acids of the formula XV or their lower alkyl esters or aldehydes of the formula XVI, by first converting these into carbinol compounds of the formula XVII

(see formula XVII)

wherein R ⁹ , R ¹⁰ and R "have the above meaning, reduced and then converted in a conventional manner, the alcoholic hydroxy group in an aminolytic cleavable group X. As a reducing agent for reducing the acids of formula XV or lower alkyl esters and the aldehydes of the formula Complex metal hydrides, for example lithium aluminum hydrides and, in the case of aldehydes, also sodium borohydride, are suitable for the carbools of the formula XVII The carbinol compounds of the formula XVII can be reacted with the corresponding hydrochloric acid, for example, to introduce a halide radical X. The introduction of a chloride can also be carried out in a manner known per se by reaction with thionyl chloride To introduce a sulfonic acid residue X, the compounds of the formula XVII are expediently reacted reacted with the corresponding sulphonyl chloride. The reaction can be carried out, for example, in an inert solvent, for. As a cyclic ether such as tetrahydrofuran or a halogenated hydrocarbon such as dichloromethane at room temperature.

The novel compounds of the formula I according to the invention and their pharmacologically acceptable acid addition salts have interesting pharmacological properties, in particular cardiovascular active properties. The compounds are characterized by pronounced heart rate lowering effects with a favorable effect profile. Thus, in addition to bradycardic effects, the compounds also have antiarrhythmic properties without adversely affecting the oxygen demand of the heart and blood pressure.

The cardiogenic properties of the compounds can be demonstrated in standard pharmacological test methods in vitro and in vivo.

I. In vitro detection of the heart rate lowering effect and the antiarrhythmic effect.

The direct effect of the active ingredients on the heart rate (FRQ) was tested on spontaneously beating, isolated right atria of 250-350g male pirbright-white guinea pigs. In the following Table I is given as FRQ 75 that concentration in μπιοΙ / Ι, in which it comes 20 minutes after substance administration to a decrease in frequency to 75% of the initial value.

The antiarrhythmic effects of the test substances were demonstrated experimentally by determining the functional refractory period (= FRP) of the lint * .n electrically challenged (1 Hz) atrium of male Pirbright-white guinea pigs of the weight class 250-30Og with the aid of paired electrical stimulation to the method of Govier (WCGovier, J.Pharmacol.Exp.Ther.148 [1] [1965], 100-105). In the following Table I is given as FRP + 25ms that concentration in μπιοΙ / Ι, at which it comes 18 minutes after the substance appli cation an extension of the functional refractory period by 25 ms.

The example numbers given for the surfactants in Table I refer to the following Preparation Examples.

Table I

test substance Cardiac properties FRP + 25 ms the formula I Effective concentration in 4.1 substance μηιοί / Ι to achieve 3.5 Example no. FRQ 75% 3.5 2 4.3 4.9 4th 1.6 4.3 3 1.4 7.9 •;O 2.4 8.9 36 0.74 33 0.89 37 1.2

il. Investigations in vivo in the anesthetized rat.

The effect of the substances on heart rate and blood pressure in i.V. continuous infusion in anesthetized rats was determined by the method v: n Buschmann et al. (J. Cardiovascular Pharmacol. 2, [1980J].

Male Wistar rats (330-37Og body weight) were anesthetized by i.p. application of 1.25 g / kg urethane and tracheotomized. After a 10 minute equilibration period, measurements are started. In a precedent phase of 5 minutes, the output values are measured.

Subsequently, the test substances are dissolved in isotonic sodium chloride solution (optionally with the addition of a solubilizer) as a continuous infusion i. v. applied, starting with the lowest dose. The dose is increased 10-fold every 10 minutes without increasing the volume of infusion. The systolic and diastolic blood pressure (Ps and Pd) are measured and from this the mean blood pressure (Pm) is determined. At the same time, the heart rate is determined from the R-R distance from the electrocardiogram (ECG). In the following table Il, the measured starting values (= initial values) for the heart rate (FRQ) and the diastolic blood pressure (Pd) as well as the values measured at a test substance dose ve η 10 pmol / kg are given for each test animal group and the change of these parameters is calculated in% ,

Table II

Influence on heart rate (FRQ) and diastolic blood pressure (Pd)

Test substance Example no. Dose μΓηοΙ / kg FRQ min '' % Change FRQ Pd mm Hg % Change Pd Prevalues 17 0 10 413 303 -27 72 77 + 7 Prevalues 12 0 10 340 249 -27 95 35 -11 Prevalues 1 0 10 405 208 -49 64 71 + 11 Prevalent 5 0 10 395 241 -39 96 91 -5 Prevalues 13 0 10 360 196 -46 79 81 + 3

As can be seen from Table II, the test substances reduce the heart rate without significantly affecting the diastolic blood pressure in the dose range of the heart rate lowering effects.

Due to the pharmacological properties described above, in particular the pronounced heart rate lowering effects in combination with antianhythmic properties, the substances are suitable for the prophylaxis and treatment of cardiovascular diseases. Due to their favorable effect profile, the substances are also suitable for the treatment of ischemic heart disease.

The doses to be used may vary individually and, of course, vary depending on the nature of the condition to be treated, the substance used and the mode of administration.

For example, parenteral formulations will generally contain less drug than oral preparations. In general, however, are suitable for applications in larger mammals, especially humans drug forms with an active ingredient content of 0.1-10mg per single dose.

As a remedy, the compounds of formula I and their physiologically acceptable acid addition salts with conventional pharmaceutical excipients in galenic preparations such. As tablets, capsules, suppositories or solutions may be included. These galenic preparations can be prepared by methods known per se using conventional solid carriers such. As lactose, starch or talc or liquid diluent such. B.

Water, fatty oils or liquid paraffins and using pharmaceutically conventional excipients, such as disintegrants, solubilizers or preservatives.

embodiments

The following examples are intended to illustrate the invention in more detail, but do not limit its scope in any way. If the compounds prepared in the following examples are not characterized by their melting point, they are characterized by the retention time in the gas chromatograph.

The retention time measurement was carried out under the following conditions:

Gas chromatograph used:

Gas chromatograph from Hewlett Packard with the type designation 5750G, detector used: flame ionization detector,

Detector temperature: 300 ° C,

Injection temperature: 290 ° C,

Heating rate from 80 to 280 ⁰ C: 15 ° C / min.

The following two types of columns were used:

Column type A *: 30 m length, 0.75 mm inner diameter, methyl silicone inner coating with a film thickness of 1 μηι;

Carrier gas nitrogen, flow rate 12 ml / min. Column Type B **: 6 feet in length, Ve inches inside diameter, filled with SiO ₂ -based filler having a grain size of 80/100 ***; Carrier gas nitrogen, flow rate 22 m '/ min.

• = column type SPB1 of the company Supelco ·· = column type 3% OVI of the company Supelco ··· = Supelcoport "of the company Supelco

Example 1:

7-diphenylmethyl-3-butyl-9,9-dimethyl-3,7-diazabicyclo [3.3.1] nonane.

4.3 g of 3-butyl-9,9-dimethyl-3,7-diazabicyclo [3,3,1] nonane are allowed to react together with 6.06 g of diphenylmethylbromide and 4.2 g of potassium carbonate in 50 ml of dimethylformamide at room temperature for 12 hours. For work-up, the reaction mixture is filtered and the filtrate containing the title compound is concentrated under reduced pressure. For further purification, the residue containing the crude title compound is taken up in aqueous citric acid solution, the title compound dissolving as the citric acid salt. The solution is washed with diethyl ether and then made alkaline by the addition of dilute sodium hydroxide solution, the title compound is released again as the base. This is extracted with diethyl ether. After drying the Ätherextraktes over magnesium sulfate, the ethereal solution is filtered and distilled off the ether. There are obtained 3.9 g of 7-diphenyl-ethyl-3-n-butyl-9,9-dimethyl-3,7-diazabicyclo [3,3,1-inonane as Ölipe base

 Gct chromatography: column B, retention time: 6.82 min.

Example 2:

7-diphenylmethyl-3-cyclohexylmethyl-9,9-tetramethylene-3,7-diazabicyclo [3.3.1] nonane.

1.5 g of 3-cyclohexylmethyl-9,9-tetramethylene-3,7-diazabicyclo [3,3,1] nonane are dissolved in 30 ml of tetrahydrofuran and stirred at ⁰ ° C with 3.64 ml of a 1.5 molar solution of n-butyl lithium in Hexane spiked. The reaction mixture is kept for 1 hour at this temperature and then 1.47 g of diphenylmethyl bromide are dissolved in 20 ml of tetrahydrofuran to the reaction mixture dropwise at 0 ⁰ C. The reaction mixture is allowed to warm with stirring to room temperature and the mixture is stirred for a further 12 hours.

For workup, the reaction mixture is first treated with dilute aqueous citric acid solution and worked up by the method described in Example 1 by an acid-base separation. This gives 1.7 g of 7-diphenyl-methyl-3-cyclohexylmethyl-9,9-tetramethylene-3,7-diazabicyclo [3,3,1-inonane as an oily base.

Gas chromatography: column A, retention time: 21.84 min.

Example 3:

7-diphenylmethyl-3-cyclopropylmethyl-9,9-dimethyl-3,7-diazabicyclo [3.3.1 inonane.

1 g of 3-cyclopropylmethyl-9,9-dimethyl-3,7-diazabicyclo- (3,3,1-inone are dissolved in 25 ml of absolute tetrahydrofuran and the solution is mixed with 0.2 g of lithium amide and stirred for 1 hour at 6O ⁰ C. and allowed to cool then. After cooling, a solution of 3 g diphenylmethyl bromide in 25 ml of absolute tetrahydrofuran is slowly added dropwise and the reaction mixture 90 min at a temperature of 4O ⁰ C weitergerühri. then the reaction mixture is acidified with aqueous citric acid solution, and as described in example 1, worked up 1.5 g of 7-diphenylmethyl-3-cyclopropylmethyl-9,9-dimethyl-3,7-diazabicyclo [3.3.1] -nonane are obtained as oily base.

Gas chromatography: column A, retention time: 14.66 min.

For the conversion into the hydrogen tartrate, 1.5 g of the oily basic title compound obtained above are dissolved in 10 ml of ethyl acetate, and the solution is mixed with 1.2 g of tartaric acid in 10 ml of acetone with stirring. The reaction solution thus obtained is strongly concentrated on a rotary evaporator and then allowed to cool. The precipitate formed on cooling is filtered off and dried at 50 ° C in Vakuumt- .ockenschrank. There are obtained 1.2 g of 7-diphenylmethyl-3-cyclopropylmethyl-9,9-dimethyl-3,7-diazabicyclo [3,3,1] no'nan monohydrogen tartrate having a melting point of 216-217 ⁰ C.

Example 4:

7- [bis (4-fluorophenyl) methyl] -3-cyclopropylmethyl-9,9-dimethyl-3,7-diazabicyclo (3.3.1 inonan.

3.5 g of 3-cyclopropylmethyl-9,9-dimethyl-3,7-diazabicyclo [3,3,1-inonane are dissolved in 25 ml of dimethylformamide, and 0.8 g of lithium amide are added to the solution. Then, the reaction mixture is kept for one hour at a temperature of 6O ⁰ C and then allowed to cool.

After cooling, a solution of 8 g of bis (4-fluorophenyl) methyl chloride in 10 ml of dimethylformamide is added dropwise and the reaction mixture is stirred at 40 ° C. for 4 hours. Subsequently, the reaction mixture is treated with aqueous citric acid solution and worked up as described in Example 1. There are obtained 5.8 g of 7- [bis (4-fluorophenyl) methyl] -3-cyclo (o-methyl-9,9-dimethyl-3,7-diazabicyclo [3,3,1] -nonane as an oily base.

Gas chromatography: column A, retention time: 14.24 min.

Example 5:

7-cinnamyl-3-n-butyl-9,9-dimethyl-3,7-diazabicyclo | 3,3,1lnonan.

1.5 g of 3-butyl-9,9-dimethyl-3,7-diazabicyclo [3.3.1] nonane are dissolved in 20 ml of dichloromethane and to the solution is added a solution of 1.2 g of cinnamyl chloride in 20 ml of dichloromethane , The reaction mixture is allowed to react for one hour at room temperature.

For working up and further treatment, the residue containing the crude title compound is taken up in aqueous citric acid solution, the title compound dissolving as the citric acid salt. To remove non-basic impurities, the solution is extracted with diethyl ether. Subsequently, the aqueous solution is made alkaline with dilute aqueous sodium hydroxide, dig titled compound is released again as the base. This is extracted with diethyl ether. After drying the Ätherextraktes over magnesium sulfate, the ethereal solution is filtered and distilled off the ether. There are obtained 1.4 g of 7-cinnamyl-3-n-butyl-9,9-dimethyl-3,7-diazabicyclo [3,3,1) nonane as an oily base.

Gas chromatography: column B, retention time: 6.21 min.

Example 6:

7-cinnamyl-3-isobutyl-9,9-dimethyl-3,7-diazabicycloI3,3,1) nonane.

3 g of 3-isobutyl-9,9-dimethyl-3,7-diazabicyclo [3.3.1] nonane are dissolved in 25 ml of dimethylformamide and the solution is treated with 0.6 g of lithium amide and then for 60 minutes at a temperature of 60.degree further stirred. After cooling the solution, a solution of 4.1 g of cinnamyl chloride is added dropwise in 25 ml of dimethylformamide and the reaction mixture stirred for a further 2 hours at 4O ⁰ C.

For working up, the solvent is distilled off and the residue containing the title compound is treated with aqueous citric acid solution and worked up as described in Example 5. There are obtained 3.1 g of 7-cinnamyl-3-isobutyl-9,9-dimethyl-3,7-diazabicyclo [3,3,1] nonane as an oily base.

Gas chromatography: column A, retention time: 12.45 min.

Example 7: 7-Cinnamyl-3-benzyl-9,9-dimethyl-3,7-diazabicyclo [3,3,1-nonanone.

A) 3.9 g of cinnamic acid chloride are dissolved in 20 ml of dichloromethane and to this solution, under ice-cooling, a solution of 5.5 g of 3-benzyl-9,9-dimethyl-3,7-diazabicyclo [3,3,1] nonane in 10 ml of dichloromethane added. Subsequently, the reaction mixture is stirred for 3 hours at room temperature. The solvent is then distilled off for working up and the residue containing 7-cinnamoyl-3-benzyl-9,9-dimethyl-3,7-diazabicyclo [3,3,1] nonane is taken up in water. To remove non-basic components, extract with ethyl acetate. Then, the aqueous phase is made alkaline with dilute sodium hydroxide solution and the reaction product extracted with Essicnster. The ethyl acetate extract is dried over magnesium sulfate, filtered and the solvent distilled off. The residue obtained is 5 g of 7-cinnamoyl-3-benzyl-9,9-dimethyl-3,7-diazabicyclo [3,3,1] nonane.

Gas chromatography: column A, retention time: 19.96 min.

B) 0.8 g of the above product are dissolved in 20 ml of toluene, and to the! Solution are added dropwise at room temperature 0.9 ml of a 3.4 molar solution of sodium bis (2-methoxyethoxy) dihydroaluminate (Red-Al ^R ) in toluene. Subsequently, the reaction mixture is stirred for a further 12 hours. For working up the reaction mixture containing the title compound, 5 ml of water, 5 ml of 20% strength aqueous sodium hydroxide solution and again 15 ml of water are added successively. From the formed Aluminatniederschlag is filtered off, and the filtrate is extracted with ethyl acetate. After drying over magnesium sulfate and concentrating the solution, rr.an as residue 0.5 g of 7-cinnamyl-3-benzyl-9,9-dimethyl-3,7-diazabicyclo [3,3,1] nonane as an oil.

Gas chromatography: column A, retention time: 15.39min.

Example 8:

7- [1- (4'-hydroxyphenyl) -1-phenylmethyll-3-hexyl-9,9-psntamethylen-3,7-diaz. jicyclo [3.3.1] nonane To 1.2 g of 7- [1- (4'-methoxyphenyl) -1-phenylmethyl-3-hexyl-9,9-pentamethylene-3,7-diazabicyclo [3,3,1 ] Nonane (see Example 32) in 4 ml of acetic anhydride is allowed to drip slowly 8 ml of 57% hydriodic acid. The batch is then heated under reflux for 4 hours. After cooling, the reaction mixture is carefully added to ice-water and performs an acid-base separation analogous to Example 1 by. From the alkaline aqueous phase, the reaction product is extracted by means of methylene chloride. The methylene chloride extract is dried over magnesium sulfate and the solvent is distilled off. From the residue, the 7- [1- (4'-hydroxyphenyl) -1-phenylmethyl-S-hexyl-g-pentamethylene-SJ-diazabicycloS ^ .I] nonane is isolated by Kugelrohr distillation under reduced pressure

 Gas chromatography: column A, retention time:

Example 9:

7- (4'-Nitrocinnamyl) -3-cyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo [3,3,1] nonane To a solution of 1.24 g of 3-cyclopropylmethyl-9,9-tetramethylene-3,7 -diazabicyclo [3,3,1] nonane in 50 ml of methanol, 0.8 g of p-nitrocinnamaldehyde is added and the reaction mixture allowed to react for one hour at room temperature. Then, 0.8 g of sodium borohydride is slowly added to the reaction mixture containing 7- (4'-nitrocinnamyl) -3-cyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo [3.3.1] -nononane, and the reaction mixture is added a further 2 Allowed to react at room temperature for hours. Subsequently, the solvent is distilled off and the residue taken up in methylene chloride. The methylene chloride solution is washed with water, dried over magnesium sulfate and concentrated. From the residue, the 7- (4'-nitrocinnamyl) -3-cyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo [3,3,1] nonane is isolated by Kugelrohr distillation under reduced pressure.

Gas chromatography: column A, retention time: 19.92 min.

Analogously to the processes described in the preceding examples, the compounds of the formula I listed in Tables 1 a and 1 b below can also be obtained.

TABLE 1a R ² R ³ R ⁴ R ⁵ = diphenylmethyl Major-h R ⁰ Remarks Mp in ⁰ C subst. R ' Gaschromat: Salzfoim at R ^e retention time game CH ₃ - CH ₃ - H H RT of the base No. R ¹ CH ₃ - CH ₁ - 4-F H H in min nC ₃ H _r nC ₃ H7- H H 4-F H (SäuleAoderB) CH ₃ - CH ₃ - 4-F H H H RT: 14.29 (A) 10 (CH ₃ ) jCH-CH ₂ - - (CHj) ₄ - H H 4-F H RT: 14.30 (A) B: 82 11 (CH ₃ ) JCH-CHj- - (CHj) ₄ - 4-F H H H RT: 16.90 (A) 8: 67-68 12 nC ₄ H ₃ - - (CH ₂ ) ₄ - 4-F H 4-Γ H B: 102 13 nC ₄ H ₉ - CH ₃ - CH ₃ - H H 4-F H RT: 15.34 (A) 14 (CH ₃ ) jCH- - (CHj) ₄ - H H H H RT: 15.27 (A) 15 (CH ₃ I ₂ CH- - (CH ₂ ) * - 4-F H H H RT: 19.99 (A) B: 101 16 Cyclohex-CH ₂ - - (CH ₂ ) * - H H 4-F H RT: 17.41 (A) 17 Cyclohex-CH _? - - (CHj) ₄ - 4-F H H H RT: 16.62 (A) 1HBr: 180 18 (CH ₃ I ₂ CH-CH ₂ - - (CHj) ₄ - H H 4-F H RT: 15.47 (A) B: 103 19 (CH ₃ I ₂ CH-CH ₂ - - (CH ₂ ) * - 4-F H H H RT: 18.23 (A) 20 Cycloprop-CHj- CH ₃ - CH ₃ - H H 1-F H RT: 16.22 (A) 21 Cycloprop-CH / - CH ₃ - CH ₃ - H H 4-CI H Rl: 23,27 (A) 22 Benz CH ₃ - CH ₃ - 4-CI H 4-CH ₃ H RT: 22.04 (A) 23 Benz - (CHj) ₆ - H H 4-CI H RT: 15.87 (A) 24 Cycloprop-CHj- - (CHj) ₅ - 4-CI H 4-CI H RT: 15.11 (A) 25 Cycloprop-CHj- - (CH ₂ I ₅ - H H 4-CI H RT: 17.98 (A) 26 Cycloprop-CHj- - (CH ₂ I ₅ - H H 4-CH ₃ 4-CH ₃ RT: 29.01 (A) 27 Benz - (CHj) ₅ - H H 3-CH ₃ H RT: 36.88 (A) 28 Benz - (CHj) ₅ - H H 4-CFj H RT: 25.00 (A) 29 Benz -I 4-OCH ₃ RT: 23.48 (A) 30 nc ₆ H _l3 ;H RT: 18.35 (A) 31 nC ₆ H, ₃ RT: 17,43 (A) 32 PC ₆ H ₁₃

8eni = benzyl, cyclohex = cyclohexyl, cycloprop = cyclopropyl, B = Baso HBr = hydrobromide

TABLE 1b R ² R ³ R ⁹ O R ¹ * = cinnamyl R " Remarks subst. by Gaschromat. at R ¹⁰ retention time game CH ₃ - CH ₃ - H H RT of the base No. R ¹ - (CH ₂ ) * - H H in min - (CHj) ₄ - H H H (SäuleAoderB) - (CHj) ₄ - H H H RT: 13.15 (A) 33 CyCIoPrOp-CH ₂ - - (CHj) ₄ - H H H RT: 13.87 (A) 34 (CH ₃ ) jCH- CH ₃ - CH ₃ - H H H RT: 14.81 (A) 35 (CH ₃ ) jCH-CH ₂ - CH ₃ - CH ₃ - 2OCH ₃ H H RT: 7.14 (B) 36 Cycloprop-CHj- - (CH ₂ ) S- 4-CI H H RT: 18.91 (A) 37 Benz - (CHj) ₅ - 3-CI H H RT: 15.04 (A) 38 Cyclohex-CHj- - (CHj) ₅ - 4-NO ₂ H H RT: 13.62 (A) 39 nC ₄ H ₉ - - (CH ₂ I ₄ - 3-CH ₃ 4-CI H RT: 18.82 (A) 40 NC ₆ H ₁₃ - - (CHj) ₄ - 4-CF ₃ H H RT: 21.69 (A) 41 NC ₆ H ₁₃ - - (CH ₂ I ₄ - H RT: 23.91 (A) 42 nC ₆ H, ₃ - H RT: '5.99 (A) 43 Cycloprop-CHR , 4,5-tri OCH ₃ - RT: 15.65 (A) 44 Cycloprop-CHj- RT: 45 Cycloprop-CHj-

Benz - benzyl, cycloprop = cyclopropyl, cyclohex = cyclohexyl

The starting materials used were prepared according to the following general working instructions:

A) General procedure for the preparation of 3,7-disubstituted 2,4,6,8-tetraoxo-3,7-diazabicyclo [3,3,1] nonane compounds of the formula VII by reacting 2,4,3,8-tetraoxo 3,7-diazabicyclo [3,3,1 Inon.in Vsrbindungen of formula V with benzyl halides of the formula Vl.

a) Reaction of N-monosubstituted compounds of the formula V in which R 'is not H.

A mixture of 0.1 mole of the imide compound of formula V, 0.1 mole of potassium carbonate and 0.15 mole of benzyl halide of formula VI in 390 ml of dimethylformamide is heated at reflux for 3 to 7 hours. It is then filtered off from the precipitate of inorganic salts formed and the klaie solution concentrated to dryness. The remaining residue is dissolved in water and ethyl acetate. The organic solution is separated, washed twice with water, Ί, over magnesium sulfate

dried, filtered and concentrated. If the formed tetraoxo precursor of the formula VII is already obtained in crystalline form, a simple recrystallization is sufficient for further purification. Otherwise, it may be necessary to purify the resulting crude product by column chromatography on silica gel or alumina using ethyl acetate-hexane mixtures as eluent.

b) reacting compounds of the formula V in which R ¹ = H.

To disubstitute the compounds of formula V wherein R 'H is the benzyl halides of formula VI, the above general procedure for monosubstituting the compounds of formula V wherein R ^{1 is} not = H, is modified. Instead of the above-mentioned reaction mixture, a mixture of 0.1 mol of the tetraoxo compound of the formula V, 0.25 mol of potassium carbonate and 0.3 mol of benzyl halide of the formula VI is used in 300 ml of dimethylformamide.

According to the general working instructions above, the following compounds listed in Table A were used

manufactured.

TABLEA R ¹ R ² - (CH ₂ ), - R ³ R " Remarks nC ₄ H ₉ CH ₃ - (CH ₂ ), - CH ₃ Benz FpJn ⁰ C Compounds of the formula VII n-C, Hg nC ₃ H ₇ - (CH ₂ ), - nC ₃ H ₇ Benz Mp: 110 Sub Cycloprop-CH? - CH ₃ - (CH ₂ ), - CH ₃ Benz Oil" punching Cycloprop-CH ₂ - CH ₃ - (CH ₂ ), - CH ₃ Benz Mp: 129-131 No. (CH ₃ I ₂ CH-CH ₂ - CH ₃ - (CH ₂ I ₆ - CH ₃ Benz Oil" A1 (CHA) ₂ CH- Benz Oil' A2 Cycloprop-CHR - (CH ₂ I ₆ - Benz Oil* A3 (CHA) ₂ CH-CH ₂ - Benz Oil* A4 Cyclohex-CH ₂ - Benz Oil" A5 Benz Benz Oil· A6 nC ₆ H, a Benz Oil* A7 Benz CH ₃ CH ₃ Benz Oil* A8 Benz Benz Mp: 155-157 A9 Mp: 150-154 A10 A11 A12 A13

Benz = benzyl, cyclohex = cyclohexyl, cycloprop = cyclopropyl • oil = was further processed as an oil

B) General procedure for the reduction of 2,4,6,8-Te * .raoxo-3,7-diazabicyclo [3,3,1] nonane compounds of the formula VIi to 3,7-diazabicyclo [3,3,1 [Nonane compounds of the formula IV.

In a three-necked flask, 0.1 mol of lithium aluminum hydride in 100 ml of a solution of 70 ml of absolute tetrahydrofuran and 30 ml of absolute toluene are heated to an oil bath temperature of 80 ⁰ C. Then, 0.025 mol of the tetraoxo compound in 100 ml of a mixture of tetrahydrofuran / toluene 70/30 are added dropwise slowly. The reaction mixture is allowed to react for 2 to 4 hours at 120 ° C.

It is then hydrolyzed under basic conditions and extracted with methylene chloride. The organic phase is separated, dried over magnesium sulfate and concentrated. The formed 3,7-diazabicyclo [3,3,1] nonane compounds crystallize out or are separated by Kugelrohr distillation under reduced pressure.

Still in this general work instruction for the reduction by means of lithium aluminum hydride, the 3,7-diazabicyclo [3,3, V] nonane compounds of the formula IV indicated in Table B below were prepared.

TABLE B

Substance IV

Remarks Gas Chrom. boiling point retention time in ° C in min (0.01 Torr) (Column A or B) Mp in ⁰ C Bp: 170 Bp: 200 13.23 (A) Bp: 170 11.54 (A) 9.85 (B) 10.84 (A) 6.29 (B) 12.67 (A) Fp .: 58 7.23 (B) Mp .: 54 7.24 (B) Mp .: 54 14,70 (A) 13.47 (A) Fp .: 58 16.66 (A) Mp: 60

B1 B2 B3 B4 B5 B6 B7 B8 B9 B10 B11 B12 B13

nC, H ₉ CH ₃ - (CH ₂ ), - CH ₃ Benz nC, H ₉ nC ₃ H ₇ - (CH ₂ ), - nC ₃ H ₇ Benz Cyclohex-CHz- CH ₃ - (CH ₂ ), - CH ₃ Benz Cycloprop-CH ₂ - CH ₃ - (CH ₂ ), - CH ₃ Benz (CH ₃ I ₂ CH-CH ₂ - CH ₃ - (CH ₂ ), - CH ₃ Benz (CH ₃ I ₂ CH- - (CH ₂ ), - Benz Cydoprop CH ₂ - Benz - (CH ₃ I ₂ CH-CH ₂ - (CH,), - Benz Cyclohex-CHj- Benz Benz Benz nc ₆ H ₁₃ Benz Benz CH ₃ CH ₃ Benz Benz Benz

Cycloprop = cyclopropyl, benz = benzyl, cyclohex = cyclohexyl,

C) General procedure for the debenzylation of 3,7-disubstituted 3,7-diazabicyclo | 3,3,1-ynonane compounds of the formula IV to N-monosubstituted 3,7-diazabicyclo | 3,3,1-jnonan compounds of the formula

0.2 mol of a compound of formula IV are dissolved in 600 ml of ethanol with the addition of 5 ml of glacial acetic acid and the solution is mixed with 10 g of palladium / carbon catalyst. The reaction mixture is hydrogenated at room temperature under a hydrogen pressure of 5 atmospheres for about 6 hours. After completion of the hydrogenation, the solution is separated from the catalyst and concentrated. The compounds of the formula II formed can be further purified by means of Kugelrohr distillation under vermtndprtem pressure.

According to the above general procedure for the denzylation, the 3,7-diazabicyclo [3,3,1] nonane compounds of the formula II indicated in Table 3 below were prepared.

TableC R ' R ² R ³ - (CHj) ₄ - CH ₃ - (CH,), - Remarks boiling point Gas Chrom. - (CH ₂ I ₄ - in ° C retention time Compounds of the formula II - (CH ₂ J ₄ - (0.01 Torr) in min - (CH ₂ ), - Mp in ⁰ C (SäuleAoderB) Sub nC ₄ H ₉ CH ₃ CH ₃ - (CH ₂ ), - Bp: 145 punching nc ₄ Hg nC ₃ H ₇ nC ₃ H; - (CH ₂ J ₅ - Bp: 220 (1,5Torr) IV Cyclohex-CH ₂ - CH ₃ CH ₃ n.d. No. Cycloprop-CHj- CH ₃ CH ₃ 7.74 (A) C1 (CHA) ₂ CH-CH ₂ - CH ₃ CH ₃ 5.78 (B) C2 Cycloprop-CH ₂ - 2 WS: Mp. 75 4.59 (B) C3 (CHA) ₂ CH- 2WS: Fp.115 8.71 (A) C4 (CHA) ₂ CH-CH ₂ 9.32 (A) C5 CyClOhOX-CH ₂ - 1HCI: mp 185 11.83 (A) C6 Benz 12.38 (A) C7 nC ₆ H, a 11.58 (A) C8 Benz CH ₃ Bp: 180 C9 Benz 12.62 (A) C10 C11 C12 C13

Cycloprop = cyclopropyl, WS = hydrogentartrate, benz = benzyl, cyclohex = cyclohexyl, HCl = hydrochloric) n.b. = not determined, further processed without cleaning

Example I:

7-Diphenylmethyl-3-cyclopropylmethyl-9,9-dimethyl-3,7-diazabicyclo [3,3,1] nonane monohydrogen tartrate-containing tablets.

Tablets are prepared in the following composition per tablet:

20mg

60mg

135mg

6mg

7-Diphenylmethyl

diazabicyclo [3,3,1nonan monohydrogen tartrate cornstarch

lactose

Gelatin (as a 10% solution)

animal, corn starch and lactose are thickened with the 10% gelatin solution. The paste is crushed and the resulting granules are placed on a suitable plate and dried. The dried granules are passed through a crusher and mixed in a blender with the following additional auxiliaries:

talc

magnesium stearate

corn starch

and then pressed into tablets of 240 mg.

5mg 5mg 9mg

Example II:

7-Cinnamyl-3-isobutyl-9,9-dimethyl-3,7-diazabicyclo [3,3,1] nonane-containing tablets.

Tablets are prepared in the following composition per tablet:

7-cinnamyl-3-isobutyl-9,9-dimethyl ·

3,7-diazocyclo [3,3,1] nonane

corn starch

lactose

Gelatin (as a 10% solution)

20 mg

60 mg

135mg

6mg

The active ingredient, corn starch and milk sugar are thickened with the 10% gelatin solution. The paste is crushed and the resulting granules are placed on a suitable plate and dried. There? dried granules are passed through a crusher and mixed in a mixer with the following additional excipients:

Talcum 5 mg

Magnesium Stearate 5mg

Corn starch 9mg

and then pressed into tablets of 240mg.

2 82 p 2?

R-N

NO

N-CH ₂ -CH = CH

R ^ 10

11

-CH ₂ -CH = CH-

11

28

RM ^a \ NR

III

ο o

⁸ ^ 2 28

R ¹² -hal

VI

N-R 12

VII

R ¹ -N

VIII

CN

COOC ₂ H ₅

R ¹ -NH-CO-CH ₂ -CN IX

X.

CH-OH

XII

C = O nil

-X XI

- 43-

N-CO-CH = CH- "

R-

10

R'-N

R-N-CH0H - CH = CH- <f

R-

11

- 10

-CK = MC COOK

R ¹

2 2 2 β

XV

R '

CK = CK-CO-Y

11

XVa

- R

-CH = CK-CHO

11

XVI

7-CH = CH-CH ₉ -OK XViI

Claims (1)

1. A process for the preparation of 3,7-dia ^ abicyclo [3,3,1-ionone compounds of the general formula I. R ¹ -N R ^{1 is} an alkyl group having 1-6 carbon atoms, a cycloalkylalkyl group having 4-9 Carbon atoms or benzyl,
R ^{2 is} lower alkyl and
R ^{3 is} lower alkyl or R ² and R ³ together form an alkylene chain of 3-6 carbon atoms, and R ^{4 is} a benzhydryl group of general ^r -cmelene a means, in which R ^{5 is} hydrogen, halogen, lower alkoxy, lower alkyl, hydroxy or trifluoromethyl, R ^{6 is} hydrogen, lower alkyl, halogen or lower alkoxy, R ^{7 is} hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl, and R ^{8 is} hydrogen, lower alkyl, halogen or lower alkoxy, or R ^{4 is} a cinnamyl group of the general formula b -CK ₂ -CH = CH- / 10 , 11 means, in which R ^{9 is} hydrogen, lower alkyl, halogen, lower alkoxy or hydroxy, and R ^{10 is} hydrogen, halogen, lower alkoxy, lower alkyl, hydroxy or, if R ^{9 is} hydrogen, also trifluoromethyl or nitro, and R ^{11 is} hydrogen or, if R ⁹ and R ^{10 are} lower alkoxy, also lower alkoxy, and their acid addition salts, characterized in that a) compounds of the general formula II wherein R ¹ , R ² and R ^{3 have the} above meaning, with compounds of general formula III R ⁴ - X III wherein R ^{4 has} the meaning given above for R ⁴ , but any free hydroxyl groups are provided with a protective group, and X is a ai ninolytisch Abspaltb'.re group, umsefzt or
b) for the preparation of compounds of general formula I a