DE2426105A1 - 8,9 DIAZA ANGULAR CLAMP ON 3,2,2 ANGLE CLAMP FOR BICYCLONONANE DERIVATIVES, THEIR SALT, METHOD FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS - Google Patents

Description

"8,9-DIaZa-T ^, 2,27-bicyclononane derivatives, their salts, processes for their manufacture and medicinal products "

Priority: May 51, 1973, Great Britain, No. 26 017/73

The invention relates to 8,9-diaza / 3,2,27-bicyclononane-3-derivatives of the general formula I.

(D

2 "3

in which R is either a carbonyl oxygen atom or together with the ring carbon atom is the group ^ CHOR ^ in which R ^ a hydrogen atom or a tropoyl, acetyltropoyl, atrop.oyl, Benzoyl-j p-aminobenzoyl, benzilyl, mandelyl, cinnamoyl, propylvaleroyl, Represents diarylacryloyl or benzhydryl group and

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unbranched R2 and R, hydrogen atoms or / or branched alkyl radicals with 1 to 7 carbon atoms, cycloalkyl radicals with 5 to 7 carbon atoms, lower aralkyl, lower carboxyalkyl, lower mono- or dialky! aminoalkyl-, piperidino-lower-alkyl-, Morpholino lower alkyl, pyrrolidino lower alkyl or lower Alkenyl radicals mean their stereoisomers and their mixtures and the optical antipodes and racemates and their salts with Acids.

The salts are derived, for example, from hydrohalic acids, Sulfuric acid, nitric acid or tartaric acid. Furthermore, quaternary ammonium salts come into consideration, which by reacting with Alkyl halides or sulfonic acid alkyl esters are produced, such as the iodine methylates, bromomethylates, chloromethylates, methonitrates and methyl methanesulfonates.

The alcohols, esters and ethers of the general formula I can exist in two stereoisomeric forms, namely the J></ - and 3-β form.

The compounds of general formula I in which R ,. a carbonyl oxygen atom means »are valuable starting compounds for the preparation of the other compounds of the general formula I.

Special compounds of the general formula I are: 8,9-Dimethy1-8,9-diaza- / 3,2,2 / -bicyclononan-3-one, 8,9-dicyclopentyl-8,9-diaza - / $, 2,27-bicyclononan-3-one,

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8,9-benzyl, methyl 1-8,9-diaza / B, 2,27-bicy clononan-3-one, 8,9-dibenzy1-8,9-diaza- / 3,2,27-bicyclononan-3-one, 8,9-Diisopropy1-8,9-diaza-Z3,2,27-bicyclononan-3-one,

8,9-diallyl-8,9-diaza- / 3,2,2,7-bicyclononan-3-one, 8,9-methyl , 3 <methyl-3 ~ phenylpropionate) -8,9-diaza-73.2, 27-bicyclononan-3-one (diasteromer A),

8,9-methyl, 3- (methyl 1-3-phenyl-propionate) -8,9-diaza- / 3,2,27-bicyclononan-3-one (Diasteromer B),

8,9-dimethyl 1-8,9-diaza-Z3,2,27-bicyclononan-3ot - ol, 8,9-dimethyl-8,9-diaza- / 5,2,27-bicyclononan-3ß- ol, 8,9-dimethyl-8,9-diaza- / 3,2,27-bicyclononan-3 oc / β-ol, 8,9-dicyclopentyl-8,9-diaza- / 3i2,27-bicyclononan-3oc -ol, 8,9-dicyclopentyl-8,9-diaza- / 3,2,27-bicyclononan-3β-ol, · 8,9-benzyl, methyl-8,9- <iiaza- / 3 ^ 2.27 -bicyclononan-3oC-ol, 8,9-benzyl, methy1-8,9-diaza-Z3,2,27-bicyclononan-3ß-ol, 8,9-dibenzyl-8,9-diaza- / 3,2, 27-bicy clononan-3 <*. -ol, 8,9-dibenzyl-8,9-diaza-7B, 2,27-bicyclononan-3ot / β-ol> 8,9-dimethyl-8,9-diaza-Z3,2,2 / -bicyclononan -3 c <- yl-tropat _# 8,9-dimethy 1-8,9-diaza- / 3 »2,27-bicy clononan-3 ot-y 1-acety ltropat, e ^ -dicyclopentyl-e, 9 -diaza-73,2,27-bicyclononan-3 d (.- yl-tropate, 8,9-dicyclopentyl-8,9-cliaza-73i 2, ^ / - bicyclononan-Jß-yl-tropate,.

8,9-dicyclopentyl-8,9-diaza- / 3i2,27-bicyclononan-3ß-yl-benzoate, 8,9-Benzy1, methy1-8,9-diaza-ZB, 2,27-bicyclononane-3 oC-y1-tropat, 8,9-Benzyl, methyl-e ^ -diaza-ZB ^ j ^ -bicyclononan ^ ß-yl-benzoate, 8,9-dibenzyl-8,9-diaza- / B, 2,2 / -bicyclononan-3oC-yl-tropate and 8,9-dibenzy1-8,9-diaza- / 3,2,27-bicyclononane-3β-y1-benzoate.

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The alcohols, ethers and esters of the general formula I are valuable medicinal substances. Some of the connections show one off Spoken high atropine-like effect, other compounds are strong anti-spasmodic and anticholinergic compounds and some compounds also act as histamine antagonists.

The invention also relates to a process for the preparation of the compounds of the general formula I, in which R. together with the ring carbon atom denotes the group) CHOR ₂ , and R.sup.4 has the meaning given above, which is characterized in that in per se known manner a compound of the general formula II

(II)

in the r _? and R-, which have the above meaning, reduced and optionally the resulting compound of the ^ cL- and / or 3ß-form with a carboxylic acid of the general formula R ¹ ^ COOH, in which R ¹ ^ -CO has the same meaning as R ^ , or .- "their" reactive derivative esterified or _{etherified an alcohol R 4} -OH or its reactive derivative.

The reduction can, for example, be carried out with palladium- or platinum-on-carbon or Raney nickel in a solvent, for example an alcohol. In this case, the 3 ⁰ ^ -AlkOhOl is obtained as the main product. When using

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Sodium borohydride as a reducing agent in water is mainly the result of the α-alcohol. Other reducing agents such as sodium borohydride in ethanol, sodium in ethanol or lithium aluminum hydride in an ether produce mixtures of the two alcohols in different proportions. These mixtures can be separated into the components in a manner known per se, for example by chromatography. The mixtures can also be used directly in the next reaction stage without prior separation. The corresponding 3β alcohol is obtained by refluxing the 3 ¹ ^ alcohol with sodium amyloxide in amyl alcohol.

The salts with acids and the quaternary ammonium salts of the alcohols can be prepared in a manner known per se.

The "esterification or etherification can also be known per se Way either with the free base or with the salt, preferably the hydrochloride. Unless the acid used for acylation contains a hydroxyl group in the molecule, it can be protected, for example by acylation, and set free again at a later stage by acid hydrolysis.

The esters of the general formula I ,. which are often oils can be cleaned in a manner known per se, for example by chromatography, distillation or by conversion into the salts with acids or into quaternary ammonium salts Reacting the free base with the corresponding acid or the

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Alkylating agents. 2 A2 6 1 O 5

The ketones of the general formula II can, for example, according to following processes can be produced:

1) A 1,2-disubstituted hydrazine of the general formula III

in which R2 and R, have the above meaning, or its .Salt is reacted with cyclohepta-2i6-dien-1-one. This connection can for its part according to the von.E.W. Garbisch, J. Org. Chem., Vol. 30 (1965), p. 2109 can be prepared. The reaction can be carried out in the absence or in the presence of an inert solvent such as an alcohol, for example methanol or ethanol. The disubstituted hydrazine of the general formula III can be known per se Wise can be prepared, for example, by reducing a hydrazone or amine in the presence of a catalyst.

2) The 1,2-disubstituted hydrazine of the general formula III or its salt can with an acetone dicarboxylic acid ester and succinic acid dialdehyde or its intermediate, for example 2,5-dimethoxytetrahydrofuran, are implemented.

The alcohols, esters and ethers of the general formula I can. processed into common medicinal preparations such as tablets, capsules, injection preparations, tinctures, suppositories, ointments or solutions will. To produce the medicinal products, customary auxiliaries, such as binders, extenders, emulsifiers, Carriers, solvents or other drugs are used.

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-7- The examples illustrate the invention. '2 4 2 OIUO

example 1

10.8 g of cyclohepta-2,6-dien-1-one are added to a solution of 6 g of 1,2-di] thyme-hydrazine in 100 ml of methanol at room temperature and while stirring. After 1 hour the reaction mixture is evaporated to dryness. 15 g of 8,9-dimethyl-8,9-diaza- / 3,2,2 / -bicyclononan-3-one remain. The crude product can be purified by distillation (bp 62 to 65 ° C / 0.15 Torr) or via its hydrochloride (p. 160 to 161 ° C). The crude product can be used immediately in the next stage.

B) 20 g of 2,5-dimethoxytetrahydrofuran are dissolved in 100 ml of water / water and 12 ml of 1 η hydrochloric acid. The solution is refluxed for 50 minutes, then cooled to room temperature and neutralized with 12 ml of 1 n sodium hydroxide solution. The solution obtained is added to a solution of 40 g of 1,2-dimethylhydrazine dihydrochloride, 44 g of acetone dicarboxylic acid and 92.5 g of sodium acetate in 250 ml of water. The mixture is heated to 55 "to 60 ^° C. for 90 minutes, then cooled, 45 g of sodium carbonate and 62 g of sodium chloride are added and the mixture is extracted four times with 100 ml of diethyl ether each time. The ether extracts are combined and evaporated. Crude 8,9-dimethyl remains -8,9-diaza- / 3,2,2 / -bicyclononan-3-one, which can be purified according to (A) The products are identical in every respect.

"Example- 2

A solution of 10 g of S ^ -Di

3-one in 100 ml of water or ethanol is used with a hydrogen

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Pressure of 1 "to 2 atm hydrogenated in the presence of 1 g of Raney nickel. After the uptake of hydrogen has ended, the catalyst is filtered off and the filtrate is evaporated. There remains 10 g 8,9-Dimethyl-8,9-diaza- / 3,2,27-bicyclononan-3oL-ol, which is about its hydrochloride can be purified. The hydrochloride melts at 195 to

Example 3

A) A solution of 10 g of e ^ -dimethyl-S ^ nonan-3-one in 100 ml of water is partially mixed with 3 g of sodium borohydride while stirring. After 4 hours of implementation the reaction mixture acidified with acetic acid, evaporated and the residue extracted with chloroform. The chloroform extract is evaporated. It left behind. 9.8 g of an oil, the main consists of 8,9 ~ dimethyl-8,9-diaza- / 3,2,27-bicyclononan-3β-ol. The crude product is used immediately in the next stage. It can be purified via its hydrochloride.

B) A solution of 10 g of S ^ -
nonane-3 ^ci --ol in 100 ml of amyl alcohol is treated with a solution which has been prepared by dissolving 10 g of sodium in 200 g of amyl alcohol at 120 ⁰ C. The mixture is refluxed for 48 hours, allowed to cool and poured into 500 ml of water. After acidification with hydrochloric acid, the mixture is extracted with diethyl ether. The aqueous solution is then made alkaline with potassium carbonate and extracted with chloroform. The chloroform extract is dried over potassium carbonate and evaporated. What remains is an oil, which is mainly out

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" ⁹ V 2-26-05

8,9-dimethyl-8,9-diaza-Z5 »2,27-" bicyclononan-3ß-ol ordered that can be used immediately in the next stage. The cleaning can be done via the hydrochloride.

Example 4

10 g e ^ -Dimethyl-S ^ -diazabicyclo-ZB ^ j ^ -nonan ^ -one are in a solution of 2.5 g of lithium aluminum hydride in 200 ml of diethyl ether registered. The mixture is refluxed for 3 hours. After cooling, the reaction mixture is saturated with 10 ml aqueous sodium sulfate solution is added, and the crystals formed are filtered off and washed thoroughly with diethyl ether washed out. The filtrate is evaporated to dryness. There remain 10 g of a 1: 1 isomer mixture of 8,9-dimethyl-8,9-diaza- / 3,2,27-bicyclononane-3oi> .- or -3ß-ol, which can be separated from one another by chromatography. The connections are with the alcohols prepared in Examples 2 and 3 identical.

The mixture of alcohols can be converted into a mixture of hydrochlorides by reacting with hydrochloric acid can be used in the next stage, in which they can be separated from one another in the form of the isomeric esters.

In a similar way, mixtures of isomers are obtained by reducing 8,9-Dimethyl-8,9- <iiaza- / 3,2,27-bieyclononan-3-one with sodium borohydride obtained in ethanol or sodium in ethanol.

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Example 5

10 g of ajg-dimethyl-e ^ -diaza-Z ^ j ^ y-bicyclononan ^ oL-ol hydrochloride are mixed with 14.5 g of acetyltropoyl chloride, and the mixture is ^{heated to 80 °} C. for 3 hours. Then, 30 ml of dioxane and 50 ml of aqueous hydrochloric acid 1,5prozentige are added and the mixture is heated for 4 hours at 50 ⁰ C, then extracted with Diäthylather, making the aqueous solution alkaline with Natriuinbicarbonat and extracted with chloroform. The chloroform extract is evaporated. There remain 12 g of crude 8,9-dimethyl-8,9-diaza- / 3,2,27-bicyclononan-3oc-yl-tropate, which can be purified by chromatography.

NMR Spectrum (CDCl4) 2.44 (S, N-CH ₃₅ 6H), 2.86 (M, 'h> ,, H ₅ ), 3.46 to 4.30 (ABC, CH-CH-O -3H), 5.34 (quin., J = 6.0 Hz, H), 7.27 (M, Ph, 5H).

A solution of 1 g of the ester in 5 ml of acetone is mixed with 2 ml of methyl iodide added and heated under reflux for 24 hours. The crystals formed are then filtered off. It will be 1.1 g of iodine methylate were obtained in white crystals with a melting point of 123 to 125 ° C. (decomp.).

Example 6

10 g 8,9-dimethyl-8,9-diaza- / 3, 2.27-bicyclononane-3o (.- ol hydrochloride are added to 14.5 g Acetyltropoylchlorid, and the mixture is heated for 3 hours at 8O ⁰ C The reaction mixture is then extracted with diethyl ether, made alkaline with sodium bicarbonate and extracted with chloroform.

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extract is evaporated. 13 g of crude 8,9-dimethyl-S ^ -diaza-ZBiSigZ-bicyclononan-Joc-yl-acetyltropate remain as an oil that can be purified by chromatography.

NMR Spectrum (CDCI) 1.99 (S, CH ₅ OOO, 3H), 2.44 (S, N-CH ₅ , 6H), 2.88 (M, H ₁ , H ₅ ), 3.73 to 4.80 (ABC, CH-CH ₂ -O-, 3H), 5.34 (quin., J = 6.0 Hz, H ₅ ), 7.27 (M, Ph, '5H).

Example 7 1 * level:

A solution of 20.4 g of dicyclopentylhydrazine dihydrochloride in 100 ml of methanol is mixed with 10.6 g of anhydrous sodium carbonate at room temperature while stirring. Then 10.8 g of cyclohepta-2,6-dien-1-one are introduced. After 16 hours of reaction, the solid is filtered off. The filtrate is evaporated. 23.6 g of almost pure S ^ -dicyclopentyl-e ^ - diaza-r3 _r 2,27-bicyclononan-3-one remain as an oil, which crystallizes quickly. F. 69 to 71 ⁰ O. The hydrochloride melts at 147 to 153 ° C.

2nd stage: ■

10 g of 8,9-dicyclopentyl-8,9-diaza- ^ 3,2,27-bicyclononan-3-one are reduced according to Example 2. 9 * 8 g of 8,9-dicyc'lopentyl-8,9-diaza- _/ 3> 2.2 / -bicyclononan-3oi.-ol are obtained. A part is recrystallized from petroleum ether. F. 118 to 120 ^° C. The crude alcohol is converted into the hydrochloride and used in the next stage without purification ".

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3rd stage:
9 »6 g S ^ -Di

hydrochloride are added to 8.14 g Acetyltropoylchlorid, and the mixture is heated to 100 ⁰ C 3 .Stunden. After adding 20 ml of dioxane and 36 ml of 1.5 percent hydrochloric acid, the mixture is extracted with ether, the aqueous solution is made alkaline with 10 percent aqueous sodium carbonate solution and extracted with chloroform. The chloroform extract is evaporated. The oily residue is chromatographed. The eluate is evaporated. Yield 12 g of pure S ^ -dicyclopentyl-e ^ -diaza-ZB ^ gZ-bicyclononane ^^ - ol-tropate.

HMR spectrum (CDC1,) 1.50 (M, 2C ₅ H ₉ 12H), 3.18 (M, H ₁ , H ₅ ), 3.6 to 4.2 (ABC, CH-CH ₂ O-, 3H), 5.4 (quin., J = 6.0 Hz, H ₅ ), 7.1 (S, Ph, 5H).

Example 8

1st stage :

10 g of 8,9-dicyclopentyl-8,9-diaza- / 3,2,2 / -bicyclononan-3 ^ -ol are according to Example 3 B) in the 8,9 ~ dicyclopentyl-8,9-diaza-ZB, 2,27-bicyclononan-3β-ol converted. Yield 10 g of white crystals with a melting point of 125 to 127 ^° C. The crude product is converted into the hydrochloride and used in the next stage without further purification.

2nd stage:

10 g of the hydrochloride are mixed with 9 g of acetyltropoyl chloride according to Example 7, step 3 implemented. Yield 13 g of 8,9-dicyclopenty1-8,9-diaza- / 3,2,27-bicyclononan-3β-y1-tropate.

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NMR Spectrum (CDCl3) 1.50 (M, C ₅ H ₉ 18H), 3.18 (M, H ₁ , H ₅ ), 3.59 to 4.20 (ABC, CH-CH ₂ OH, 3H) , 5.20 (quin., J = 10.0, H ₃ ), 7.12 (S, Ph, 5H).

Example 9

9.6 g of the 8,9-dic; yclopent; yl-8,9-diaza-Z3,2,2 / -bicyclononan-3β-ol hydrochloride prepared according to Example 8 are mixed with 4.29 g of benzotrichloride and 2 hours heated to 100 ^{° C.} Then 30 ml of dioxane and 15 ml of water are added and the mixture is extracted with diethyl ether. The aqueous solution is neutralized with sodium carbonate and extracted with chloroform. The chloroform extract is evaporated. This leaves 12 g of almost pure 8,9-dicyclopentyl-8,9-diaza- / 3,2,27-bicyclononane-3β-3'lbenzoate. After recrystallization from isopropanol, the white crystals melt at 136 to 138 ° C. "·

NMR Spectrum (CDCl ₅ ) 1.58 (M, 2C ₅ H ₉ 18H), 3.35 (M, H ₁ , H ₅ ), 5.52 (quin., J = 10.0, H), 7 , 20 to 7.50 (M, Ph, 3H), 7.80 to 8.00 (M _t Ph, · 2Η).

Example 10

1st stage :

A solution of 13.6 g of 1-benzyl-2-methylhydrazine in 100 ml of methanol 10.8 g of cyclohepta-2,6-dien-1-one are added at room temperature with stirring. After 2 hours of implementation, the Lö solvent distilled off and the crude 8,9-Ββηζν1 ^ βΐ ^ 1-8,9-diaza-Z5,2, '27 ^ bicyclononan-3-one used in the next stage without further purification. The hydrochloride melts at 181 bis

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2nd stage:

10 g of 8,9-benzyl, methyl-8,9-diaza- / 3,2,27-bicyclononan-3-one are hydrogenated with Raney nickel in water according to Example 2. The crude 8,9-benzyl, methyl-8,9-diaza-Z5 »2,27-bicyclononan-3oL-ol obtained is converted with hydrochloric acid into the hydrochloride, which melts at 183 to 184 ° C (decomp.).

3rd stage:

10 g of acetyltropoyl chloride are added to 10 g of the hydrochloride and the mixture is heated ^{to 100 ° C. for 2 hours.} Then, 40 ml of dioxane and 50 ml 1,5prozentige hydrochloric acid was added, and the mixture is heated for 6 hours at 50 ⁰ C. After cooling, the reaction mixture is extracted with diethyl ether, the aqueous solution is made alkaline with sodium carbonate and extracted with chloroform. The chloroform extract is evaporated. Yield 13 g of 8,9-benzyl, methyl 8,9-diaza- / 3,2,27-bicyclononan-3 oC-yl-tropate. The product is a mixture of 2 diastereomers.

NMR Spectrum (CDCl3) 2.75 (S, CH ₃ , 3H), 2.90 (M, H ₁ , H ₅ ) 3.40 to 4.30 (ABC CH-CH ₂ -O-, 3H), 3.78 (S, CH ₂ , 2H), 5.70 (quin., J = 6.0, H ₃ ), 7.0 to 7.4 (M, Ph, 5H), 7.0 to 7, 4 (M, Ph, 5H).

Example 11 The 8,9-benzyl, methyl-8,9-diaza- / 3,2,2 / -bicyclononan-3ß-ol prepared according to Example 3 is converted into the benzoic acid ester according to Example 9. Έ. 114 to 115 ° C.

NMR Spectrum (CDCl ₃ ) 2.45 (S, CH ₃ , 3H), 2.94 (M, H ₁ , H ₅ ), 3.83 ^L A09881 / 1218 ^J

(S, CH ₂ , 2H), 5.40 (quin., J = 1O, O, H ₃ ), 7.0 to 7.5 (M, Ph, 7.8 to 8.0 (M, Ph, 2H).

Example 12

1st stage:

A solution of 21.2 g of 1,2-dibenzylhydrazine in 100 ml of methanol is at room temperature with stirring with 10.8 g of cyclohepta-2,6-dien-1-one offset. After 4 hours of reaction, the solvent becomes distilled off. What remains is crude 8,9-dibenzyl-8,9-diaza- / 3,2,2 / -bicyclononan-3-one. Melts after recrystallization the pure compound at 60 to 62 ° C. The hydrochloride melts at 168 to 169 ° C (dec.).

2nd stage:

10 g of S ^ -dibenzyl-S ^ -diaza-ZB ^ j ^ -bicyclononan-J-one are hydrogenated with Raney nickel in ethanol according to Example 2. Yield 10 g of 8,9-dibenzyl-8,9-cLiaza- / 3i2,27-bicyclononan-3o ^f --ol, which is converted into its hydrochloride and used in the next stage.

3rd stage:

10 g of the hydrochloride are according to Example 5 in the tropoyl ester convicted. Yield 4 g of 8,9-dibenzyl-8,9-diaza- / 3,2,27-bicyclononan-3 o «-yl-tropate, which is purified by chromatography can be.

NMR Spectrum (CDCl ₃ ) 2.92 (M, H ₁ , H ₅ ), 3.6 to 4.30 (ABC, CH ₂ O-, 3H); 3.80 (S, CH _2, 4H), 5.38 (quin., J = 6.0, H _5), 7,0 to 7,3 (m, Ph, 10H).

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Example 13

1st stage :

8,9-Dibenzyl-8,9-cLiaza- / 3,2,2 / -bicyclononan-3-one is reduced according to Example 4 with lithium aluminum hydride. A mixture is obtained of S ^ -dibenzyl-S ^ -diaza-ZB ^ jSZ-bicyclononan-Jo ^ - and -3ß-ol in a proportion of about 1 _; :1.

2nd stage:

The mixture of alcohols obtained in the first stage is converted into the benzoic acid esters according to Example 9. After recrystallization the two isomeric benzoic acid esters can be separated from isopropanol. The S ^ -dibenzyl-e ^ -diaza-ZBiS ^ Z-bicyclononan-3c? C-yl-benzoate melt at 114 to 115 ° C.

NMR Spectrum (CDCl ₃ ) 3.04 (M, H ₁ , H ₅ ), 3.91 (S, CH ₂ , 4H), 5.67 (quintet-like J = 6.0, H ₃ ), 7.1 up to 7.55 (M, Ph, 3H), 7.1 to 7.55 (M, Ph, 10H), 7.25 to 8.0 (M, Ph, 2H).

The 8,9-dibenzyl-8,9-diaza- / 3,2,2 / -bicyclononan-3β-yl-benzoate melts at 80 to 82 ° C).

NMR Spectrum (CDCl ₃ ), 3.05 (M, H ₁ , H ₅ ), 3.91 (S, CH ₃ , 4H), 5.4-6 (quin., J = 10.0, H) , 7.1 to 7.6 (M, Ph, 3H), 7.1 to 7.6 (M, Ph, 10H), 7.9 to 8.16 (M, Ph, 2H).

Example 14

1,2-Diisopropylhydrazine monohydrochloride is prepared according to Example 7 reacted with cyclohepta-2,6-dien-1-one. The 8,9-diiso-

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propyl-8,9-diaza-Z3i2,2 / -t) icyclononan-3-one from ί ¹ . 64 to 65 ° C (recrystallized from petroleum ether).

Example 15

According to Example 1, 1-methyl-2-allylhydrazine is reacted with cycloheptar-2,6-dien-1-one. The 8,9-methyl, allyl-8,9-diaza- / 3,2,2 / -bicyclononan-3-one is obtained. The picrate melts at 156 "to 160 ⁰ C (after recrystallization from a mixture of equal parts" acetone and methanol).

Example 16

1,2-Diallylhydrazine is mixed according to Example 1 with cyclohepta-2,6-dien-1-one implemented. The 8,9-diallyl-8,9-diaza- / 3,2,27-Mcyclononan-J-one is obtained. The Picrat s.chmili at 14-5 to 47 ° C (from methanol recrystallized).

Example 17

3- (2-Methylhydrazine) -3-pheny! Propionic acid is prepared according to Example 1 reacted with cyclohepta-2,6-dien-1-one. After "evaporating the Solvent, the residue is mixed with an ethereal solution of diazomethane. As a result of the presence of two asymmetrical Centers in the molecule can be two diastereomers of 8,9-methyl-3- (methyl-3-phenylpropionate) -8,9-diaza- / 3i2,2 / ~ bicyclononan-3-one that are isolated with. Diastereomer A and B are designated. The diastereomers are grounded by chromatography separated from each other on aluminum oxide. Compound A melts at 89 to 91 ° C, compound B at 115 to 117 ° C.

409881/1218

Claims (6)

Claims 8,9-diaza / 3,2,27-bicyclononane-3-derivatives of the general Formula I. (D in the R _x . either a carbonyl oxygen atom or, together with the ring carbon atom, the group ^ CHOR ^, means in the R. a hydrogen atom or a tropoyl, acetyltropoyl, atropoyl, benzoyl - ^ - amino benzoyl, benzilyl, mandelyl, cinnamoyl, propylvaleroyl -, diarylacryloyl or benzhydryl / represents two qte groups and R ₂ ^{and R} 3 V / water st off atoms or unbranched / branched alkyl radicals with 1 to 7 carbon atoms, Cycloalkylreste.mit 3 to 7 carbon atoms, lower aralkyl, lower carboxy alkyl, lower mono- or Dialkylaminoalkyl-, piperidino-lower-alkyl-, morpholino-lower-alkyl- ,. Pyrrolidino-lower-alkyl or lower alkenyl radicals mean their stereoisomers and their mixtures and the optical antipodes and racemates and their salts with acids. 2. Compounds according to claim 1, characterized in that the salts are from hydrohalic acids, sulfuric acid, Nitric acid, tartaric acid, alkyl halides or alkyl sulfonates derive. 409881/1218, 3. Compounds according to claim 2, characterized in that the salts are derived from iodine, bromine or chloromethylates, methonitrates or derive methyl methanesulfonates. 4. A process for the preparation of the compounds of general formula I according to claim 1, in which R ₁ together with the ring carbon atom denotes the group ^ .. GEOR ^ and R ^ has the meaning given in claim 1, characterized in that in in a manner known per se, a compound of the general formula II || (H) in which R ₂ and R, which have the meaning given in claim 1, are reduced and, if appropriate, the compound of the 3c ^ - and / or ~ 3ß-form obtained with a carboxylic acid of the general formula R'COOH, in which R '.- CO the same meaning v / ie R ^ has, or, esterified its reactive derivative. Or etherified an alcohol R ₄ -OH or its reactive derivative optionally the compound obtained by reacting with an inorganic or organic acid into a salt or converted into a quaternary ammonium salt with an alkylating agent. 5. Process for the preparation of the compounds of the general Formula I according to claim 1, in which R ^ is a carbonyl oxygen atom means, characterized in that either a) a 1,2-disubstituted hydrazine of the general formula ¹¹¹ A 0 9 8 8 1/1 2 1 8 ₂ (III) in which Rp and R ^ have the meaning given in claim Λ or reacts its salt with cyclohepta-2,6-dien-1-one or b) with acetone dicarboxylic acid and succinic acid dialdehyde or its intermediate. 6. Medicament, consisting of a compound according to claim 1, in which R ^ together with the ring carbon atom is the group ^> CHOIR. and R ^ has the meaning given in claim 1 has, and usual carriers and / or diluents and / or auxiliaries. AÜ9881 / 1218 - ¹