IL44765A - 3-substituted 6,7-diaza-(3,2,2)-bicyclononane derivatives - Google Patents

Abstract

1460019 Derivatives of 6,7-diaza-[3,2,2]- bicyclononane ASSIA CHEMICAL LABORATORIES Ltd 21 May 1974 [31 May 1973] 26017/73 Heading C2C The invention comprises compounds of formula including the optical isomers and other stereoisomers, and the physiologically active and pharmaceutically acceptable salts, wherein R 1 is O = or R being H, tropoyl, acetyltropoyl, atropoyl, benzoyl, p-aminobenzoyl, benziloyl, mandeloyl, cinnamoyl, propylvaleroyl, diarylacryloyl or benzhydryl; and R 2 , R 3 are each H, C 1-7 alkyl, C 2-4 alkenyl, C 3-7 cycloalkyl, carboxy-C 1-4 - alkyl, aryl-C 1-4 -alkyl, #-alkoxycarbonylethyl (possibly α-Ph-substituted), or C 1-4 alkyl substituted by mono- or dialkylamino, piperidino, morpholino or pyrrolidino. In examples, the ketones are prepared by reacting R 2 NHNHR 3 with cyclohepta-2,6-dienone or with succinaldehyde + an acetonedicarboxylic acid derivative, and may be reduced to the alcohols, which in turn may be esterified. Stereoisomers of the alcohols (or their derivatives) may be selectively formed by choice of reducing agent and may be interconverted. Therapeutic compositions which may have atropine-like activity and may be antispasmodics, anticholinergics and histamine antagonists, comprise compounds of the above formula (other than the ketones). Forms suitable for oral, parenteral, rectal and topical administration are mentioned. [GB1460019A]

Description

7,6 "Assia" Chemical Laboratories Ltd.

The present invention consists in new 6,7-diaza 27-bicyclononane derivatives of general formula I in which R± stands either for =0 or for H,0R' in which R* stands either for hydrogen atom or for a radical selected among the group consisting of tropoyl, acetyl-tropbyl , atro-poyl and benzoyl radicals; and g and R^ stand for hydrogen or for different or identical straight or branched alkyl (having up to 7 carbon atoms), cyclo-alkyl, (having 3-7 5.V.74 carbon atoms), benzoyl phenethyl, lower alkoxy carbonyl 5.V.74 (phenyl) alkyl and lower alkenyl groups) and in the physiologically active and pharmaceutically acceptable quarter-nary acid addition salts, such as hydrohalides, sulfates, nitrates, tartrates and the alkylhalide or alkylsulfonate addition salts such as methiodides, methobromides, metho-chlorides, methonitrates and methylmethanesulfonates.

The alcohols, esters and ethers embraced by general formula I may exist in two stereoisomeric forms named 3a-and 3β-. The present invention protects both the stereoisomers and the mixtures thereof, if any, or the optical antipodes and their reacemates, if any.

The alcohols, ethers and esters embraced by general formula I are useful as therapeutic agents. Certain alcohols, ethers and esters exhibit exceptionally high atropine-like activity. Some of these compounds are powerful antispasmodics and anticholinergi-β and also show activity as histamine antagonists.

The present invention also, consists in a process for the preparation of the compounds of general formula , wherein R^ stands for H, OR', R' having the same meaning as above wherein a compound of general formula II 0 in which and R^ have the same meaning as above is reduced to yield a compound of general formula I, in. which R^ stands for Η,ΟΗ, having the 3a- or 3β- form or being a mixture thereof, and said compound, if desired, is esterified or etherified to yield a compound of general formula I in which ^ stands for H,OR' , R' standing for aiiy of the radicals indicated above, having the 3a- or 3β- form or being a mixture thereof.

The reducing agent may be chosen in such a manner that the desired 3a- or 3β- alcohol is obtained. Thus, for instance, if on palladium or platinum -©r charcoal, Raney Nickel, in a solvent, e.g. an alcohol is chosen the 3a-alcohol is the main product obtained by said reduction. On the other hand, in case that sodium borohydride in water is chosen the 3§-alcohol is mainly obtained.

Other catalysts, e.g. sodium borohydride in ethanol, sodium in ethanol, lithium aluminium hydride in ether yield mixtures of both alcohols in various ratios. Said mixture can be separated b methods known per se, e.g. by chromatography or may eventually out be subjected to the next reaction step with/any prior separation.

By refluxing the 3a-alcohol with sodium amyloxide dissolved in amyl alcohol it may be converted into the 3 -alcohol.

The salts of the alcohols may be prepared by methods known per se.

The esterification or the etherification step is performed by methods known per se either with the free base or with the acid addition salt, preferably the hydrochloride. Whenever the acid moiety possesses a hydroxyl group it may be protected, for example, by acylation and liberated by acid hydrolysis at a later stage.

The esters of general formula I which are very often oils, may be purified by methods known per se, for example by chromatography, distillation or by their conversion to acid 1 addition salts or alkyhalide or alkyl sulphonate derivatives by reacting the free base with the corresponding acid, or alkyl derivative.

The ketones of general formula II may be prepared, for example, by one of the following methods i (1) by the reaction of a 1,2-disubstituted hydrazine of general formula III R2NH-NHR3 in which and have the same meaning as in general formula I or one of its salts with cyclohepta-2,6-dien-l-one . (The latter compound may be prepared as described by E. ¥. Garbisch, J. Org.

Chem. 30, 2109 (1965).) Said reaction may be performed without any solvent or in an inert solvent, such as an alcohol, e.g. methanol or ethanol.

The disubstituted hydrazine of general formula III may he prepared by methods known per se, for example, by the reduction of a hydrazone or azine i the presence of a catalyst. (2) By reacting a 1,2-disubstituted hydrazine of general formula III or one of its salts with acetone-dicarboxylate and succindi- aldehyde or an intermediate thereof, for example ,2, 5-dimethoxy- tetrahydrofuran.

The alcohols, esters and ethers of general formula I which are useful as therapeutic agents may be administered as such or as an active ingredient of a composition, i.e. in the form of tablets, capsules, ampules, tinctures, suppositories, ointments or solutions. Said compositions are prepared in a conventional manner, i.e. by the addition of suitable binders, extenders, emulsifyers, carriers solvents, other therapeutic compounds and the like.

The invention will now be illustrated with reference to the following Examples without being restricted by them. (All temperatures herein are indicated in degrees centigrade. NMB units are in ppm downfield from TMS (^scale) . Coupling constants are given in Hz) .

Example 1 A. To 6 g of 1 , 2-dimethylhydrazine in 100 ml of methanol are added 10.8 g of cyclohepta-2,6-dien-l-one while stirring at room temperature.. After one hour, the mixture is evaporated to dryness, yielding 15 g of ■e79-dimethyl-*|--diaza-/3,2,2 -bicyclclononan-3-one. The crude reaction product may be purified by distillation (b.p. 62-65°/°· 15 mm Hg) or by conversion to its hydrochloride (m.p. 160-1°). Alternatively, the crude product may be used directly in the next step. The analysis of Calculated t , C 52.80$; H 8.31 } N 13.70 Pound I C 52,61%j H 8.29%} N 13.56% B. 20 g of 2,5-dimethoxytetrahydrofuran are dissolved in 100 ml of water and 12 ml of IN HC1, the solutioneis refluxed for half an hour, then allowed to cool to room temperature and neutralised with 12 ml of IN NaOH. The resulting solution is added to a solution of 40 g of 1,2-dimethylhydrazine dihydrochloride , 44 g of acetone dicarboxylate and 92.5 g of sodium acetate in 250 ml of water, the mixture is heated to 55-60° for 90 minutes, allowed to cool, then 45 g of and 62 g of NaCl are added and the product is extracted with ether (?,J- - (4 x 100 ml). On evaporation of the etheral extracts, crude &9-dimethyl-^r9-diaza-/5,2,2/- bicyclononan-3-one is obtained which can be purified as described under A above, the products obtained by the two methods being identical in all respects.

Example 2 A solution of 10 g of 2,27-bicyclononan-3-one in 100 ml of water or ethanol, is hydrogenated at 1-2 atm in the presence of 1 g of Raney Nickel. After the hydrogen uptake has ceased, the catalyst if filtered off and the solvent evaporated to yield 10 g of 8>9-dimethyl-8,9-diaza /3,2, 2/-bicyclononan-3 Example 3 6,7 6,7 A. To a solution of 10 g of •8y9-dimethyl-*r9-diazabicyclio /3,2,27 nonan-3-one in 100 ml of water, are added portionwise while stirring 3 g of sodium borohydride. After four hours, the mixture is acidified with acetic acid, concentrated and extracted with chloroform. On evaporating the chloroform extracts, 9.8 g of an oil are obtained, 6,7 6,7 consisting mainly of ■8-}-9-dimethyl-8-j-9-diaza /3,2,2/bicyclononan- 3β-ο1. The crude product is purified by conversion to the hydrochloride wn cn used directly in the next step* 6,7 6,7 B. To a solution of 10 g of -&-,- -dimethyl-*-^diaza /3,2,2/bicyclo- nonan-3ct-ol in 100 ml of amyl alcohol is added a solution prepared by adding 10 g of sodium to 200 g of amyl alcohol at 120°, the mixture is refluxed for |48 hours, allowed to cool and poured into 500 ml"of water. The mixture is acidified with HCl and extracted with ether, then it is made basic with potassium carbonate and extracted with chloroform. The chloroform extracts are dried on potassium carbonate and evaporated to give an oil which consists 6,7 6,7 ._ _ mainly of ■e7^idimethyl«-e7'9,!adiaza-/3,2,2/-bicycl5nonan-3p-ol, which may be used in the next stage, after conversion to the hydrochloride.

Example 4 10 g of e 9-dimethyl-e79-diazabicyclo /3,2,2/nonan-3-one are added to 2.5 g of lithium aluminium hydride in 200 ml of ether.

The mixture is refluxed for 3 hours, 10 ml of a saturated aqueous solution of sodium sulfate are added and the solid is filtered off. The etheral filtrate is evaporated to dryness, affording 10 g of a < · 6,r 1:1 mixture of the isomeric mixture of T& -dimethyl-"8>-9-diaza- /3,2,2/bicyclononan-3a/p-ol, which can be separated by chromatography, each of them being identical to the single alcohols described in examples 2 and 3.

The mixture of alcohols may be converted to a mixture of hydrochlorides which may be used directly in the next step whereby they may be separated in the form of the isomeric esters. of -8'j--dimethyl-8'j-9^-diaza-/3,2,2/-bicyclononan-3-one with Sodium borohydride in ethanol, sodium in ethanol, etc.

Example 5 6,7 6,7 _ ' To 10 g of^r -dimethyl-8-^diaza-/3,2,2/-bicyclononan-3a-ol hydrochloride are added 14.5 g of acetyltropolychloride , and the 8 ° m diox n nd 0 ml of with chloroform. The chloroform extracts afford 12 g of crude ftj-y- 6,7 ... dimethyl-8-r9-diaza-/3,2,2/-bicyclononan-3o-yl tropate, which may be purified by chromatography.

NMR (C.DCI3) 2.44 (*Τ,N-CH-j , 6H) 2.86 (m,^,^) 3.46-4.30(ABC,CH-CH2-0.3H) , 5.34 (quin., J = 6.0Hz,H3>, 7.27 (m,Ph,5H). 1 g of the ester in 5 ml of acetone is treated with 2 ml of methyl iodide at reflux. After 24 hours, the solid is filtered off, to give 1.1 g of white methiodide, m.p. 123-5°(dec . ) .

The analysis was caluulated for I Calculated : C 49.60 ; H 6.30#j N 6.O87S; I 27.60$ Found i C 49,55#j H 6.34#} N 6.19 * I 27.70 Example 6 6,7 6,7 To lO g of 8^^dimethyl-8-ir9-diaza^ 5,2,2/-bicyclononan-3a-ol-hydro-i hloride are added 14.5 g of acetyltropoyl chloride and the mixture is heated for 3 hours at 80°. The mixture is extracted with ether, made basic with sodium bicarbonate and extracted with chloroform. The chloroform extracts afforded 13 g of crude 8,9-dimethyl-8,9-diaza /5, 2,2/-bicyclononan-3o-yl-acetyl tropate (an oil) which may be purified by chromatography.

NMR (CDC13) 1.99 (I.CH-jCOO, 3H) 2.44 («,Ν-CILj, 6H) , 2.88 (m,!^,!^), 3.73-4.80 (ABC, CH-CH20, 3H), 5.34 (quin., J=6.0Hz, R*3), 7.27 (m, Ph, 5H).

Example % Step 1. 20.4 g of 1 ,2-dicyclopentyl hydrazine dihydrochloride are dissolved in 100 ml of methanol, 10.6 g of anhydrous sodium carbonate are added while stirring at room temperature, then 10.8 g of cyclohepta-2,6-dien-l-one are added. After 16 hours, the solid is filtered off, and the filtrate afforded on evaporation 23.6 g of oil which is almost 6'7 6,7 The hydrochloride had an m.p. of 147-3°. The analysis was calculated for Calculated : C 65.80$ H 8.70 ; N 9.03 ; CI llf42% Pound : C 65.54%; H 8.87 ; N 9.04%; CI 11.38$ Step 2 6,7 6,7 „, 10 g of "e-j-^-dicyclopentyl—87"9-diaza-/3 , 2>£/ bicyclononan-3-one are reduced under the same conditions as described in Example 2 to yield 9.8 g of 8,9-dicyclopentyl-8,9-diaza- J,2,27 bicyclononan-3a-ol .

An aliquot recrystallized from petroleum ether had m.p. 118-120°.

The crude alcohol was converted to hydrochloride and used without purification in the next step.

Step 3 C.T o,r To 9.6 g of 6 9-dicyclopentyl-8 9-diaza-/5,2,27-bicyclononan-2a-ol hydrochloride are added 8.14 g of acetyltropoyl chloride and the mixture is heated at 1θθ° for 3 hours. 20 ml of dioxane and 36 ml of 1.5 HC1 are added, then extracted with ether, made basic with 10$ aqueous Na^O^ and extracted with chloroform. The chloroform extracts afford an oil, which is purified by chromatography to give 12 g of ■ 6,7 6,7 pure 8T9—dicyclopentyl &τ9—diaza-/3, 2,2 -bicyclononan-3a-»l-tropate . MR (CDC<<3) 1.50m (m,2C5H912H), 3.18 (ιη,Ι^,Η..), 3.6-4.2(ABC,CH-CH20,3H) 6.0 5.4 (quin., J = 6fr,H3) , 7.1 (S,Ph,5H).

Example 8 Step 1. 6,7 6,7 10 g of &79¾-dicyclopentyl-8,f9-diaza- 3,2,2 bicyclononan-3 -ol are converted to 8,9-dicyelopentyl-8, 9-diaza-/3 , 2,2/bicyclononan-3a-61 in the same manner as described in Example 3B affording 10 g of white solid, m.p. 125-127°. The orude reaction product is converted into the hydrochloride and used in the next step without further purification 10 - 44765/2 Step 2 10 g of 6,7-dicyelopentyl-6,7-diaza-^3,2,i7bicyclononan--3β-ο1 hydrochloride are reacted with 9 g of acetyl tropoyl chloride in the same manner as described in step 3 of Example 7 for the 3a-isomer to yield 13 g of 6,7-dicyclopentyl-6,7-diaza-^3,2,27bicyclononan-3p-yl-tropate.

NMR (CDCi3) 1.50 (πι,Ο^ΙβΗ), 3.18 (m,^, H5), 3.59-4.20 (ABC,CH-CH2OH, 3H) , 5.20 (quin. , J = 10.0, H3), 7.12 (s, Ph, 5H).

Example 9 To 9.6 g of 6,7-dicyclopentyl-8,9-diaza- 5,2,27bicyclo-nonan-3p-ol- hydrochloride prepared as described in Example 8 are added 4.29 g of benzoylchloride and the mixture is heated at 100° for 2 hours. 30 ml of dioxane and 15 ml of water are added, and the mixture is extracted with ether. The aqueous layer is neutralized with and extracted with chloroform. On evaporation, the chloroform extracts afford 12 g of a white solid which is almost pure 6,7-dicyclopentyl-6,7-diaza-^5,2,27bicyclononan-3p-yl-benzoate, m.p. 136-8° (recryetallized from isopropanol).

NMR (CDC13) 1.58 (m, 2C,.H918H), 3.35 (m, Ηχ, 5.52 (quin.,J=10,0 H?) , 7.20-7.50 (m,Ph,3H) 7.80-8.00 (m,Ph,2H).

Example 10 Step 1 10.8 g of cyclohepta-2,6-diene-l-one are added to a solution of 13.6 g of l-benzyl-2-methyl-hydrazine in 100 ml of methanol , while stirring at roo$ temperature. After 2 44765/2 bicyclononan-3-one is used in the next step vith or without purification, in the form of hydrochloride: m.p. 181-2°.

The analysis was calculated for C^H^N^d .

Calculated t N. 9.98 CI 12.67 Found I N. 9.71 CI 12.46$ Step 2 10 g of the racemic mixture of 6-methy1-7-benzyl*- and 6-benzyl-7-methyl-6,7^5,2,27bicyclononan-3-on§ are reduced with Raney Nickel in water in the same manner as described in Example 2. The crude racemic mixture of 6-methyl-7-benzyl-and 6-benzyl-7-methyl-6f75,2,27bicyclononan-3o-ol obtained is converted to the hydrochloride, m.p. 183-4° (dec.) and used in the next step.

Step 3 To 10 g of the racemic mixture of 6-methyl-7-benzyl-and 6-benzyl-7-methyl-6,7^*2,27bicyclonona-3a-ol hydrochloride are added 10 g of acetyl tropoyl chloride and the mixture is heated at 100° for two hours. 40 ml of dioxane and 50 ml of 1.5 aqueous HCl are added and the mixture is then heated at 50° for 6 hours. The mixture is extracted with ether, then made basic with and extracted with chloro form. The chloroform extracts afford 13 goof a racemic mixture of 6-methyl-7-benzyl" and 6-benzyl-7-methyl-6,7-diazai- 5,2t 27bieye1ononan-3o-y1-tropate .

The product is a mixture of 2 diasteromers.

NMR (CDC13) 2.75 (s,Me,3H), 2.90 (πι,Η^Η,-), 3.40-4.30 (ABC CH-CH20, 3H) 3.78 (s, CH2, 2h), 5.70 (quin., J = 6.0, - - Said crude compound is either used in the next step as such, or purified 2 Θ by way of crystallization (m.p. 60-6 ) or by conversion to the hydrochloride m.p. 168-9° (doc). The analysis was calculated for C21H25N20Q:1- Calculated : N 7.86$ Pound t N 8.07$ Step 2, 6.7 6,7 _ 10 g of •er9-dibenzyie79-diaza- 3,2,3/~bicyclononan-3-one are reduced with Raney Nickel in ethanol bjr a procedure similar to that described in Example 2, to yield lO'g of 8,9-dibenzyl-8,9-diaza-/3,2,27-bicyclononan-3o-ol which is converted to its hydrochloride and used in the next step.

Step 3. 6,7 6,7 10 g of-e79-dibenzyl-679-diaza-^3*,2,27-nonan-3a-ol hydrochloride are converted to its tropoyl ester by a procedure similar to that described in Example 5 to yield 4 g of 8,9-dibenzyl-8,9-diaza-/3,2,27-bicyclononan-3oc-yl tropate which can be purified by chromatography.

NMB (CD5Q3) 2.92 (ιη,Ι^,Ι^), 3.6-4.30 (ABC, CH-CH20, 3H) , 3.80 (S,CH2, 4H), 5.38 (quin., J = 6.0, H3), 7.0-7.3 (m,Ph, 10H).

Example 13 Step 1. 6,7 6,7 ■87-9—dibenzyl-*f9—diaza-/3, 2, 2/ -bicyclononan-3-one are reduced with lithium alumium hydride in a similar manner as described in Example 4 to yield a mixture of ~8v9-dibenzyl-¾ 9-diaza/3,2,2 -bicyclononan-3o/p-ol in approximately 1:1 ratios*,.

The mixture of alcohols obtained in Step 1 is converted to a mixture of benzoate esters by a procedure similar to that described in Example 9. On crystallization from isopropanol the two isomeric 6,7 6,7 • -- - 44765/2 MR (CDC13) 3.04 (m,^, H5), 3.91 (e,CH2,4H), 5.67 (quintet-like J = 6.0,H3) 7.1-7.55 (m,Ph,3H), 7.1-7.55 (m,Ph,10H), 7 eye1ononan-3β-yl-benzoate; m.p. 80-2°.

NMR (CDC13), 3.05 3.91 (s,CH2,4H), 5.46 (quin.f J » 10.0 H3), 7.1-7.6 (m,Ph,3H), 7.1-7.6 (m,Ph,10H), 7.9-8.16 (m,Ph,2H).

Example 14 1,2-Diisopropylhydrazine monohydrochlorlde was reacted vith cyclohepta-2, 6-dien-l-one in a similar manner as des- 6,7 6,7 cribed in Example 7 to yield -e-?-9-diiaopropyl-ey9»diaza- 5,2,27bicyclononan-3-one| m.p. 64-5° (recrystallized from petroleum ether). The analysis was calculated for Calculated t C 69.60#| H 10.78#j N 12.49$ Found I C 69.65$ H 10.52$; N 13.34 Example 15 l-Methyl-2-all ylhydrazine was reacted with cyclohepta-2, 6-dien-l-one in a similar manner as described in Example 1 to yield a mixture of 6-methyl-7-al)lyl~and 7-all l-6-methyl-6,7diaza- 3*,2, 27bicyclononan-3-one. The product was characterized as the picrate. m.p. 156-60° (recrystallized from acetone-methanol 1:1). The analysis of the picrate was calculated for ^i2¾1^5^8* Calculated t C 48.22$; H 5.00$; N 16.54$ Found t C 49.23%} H 4.85$; N 16.71$ Example 16 The product vas characterized as the picrate, in.p. 145-7° (recrystallized from methanol)* The analysis of the picrate vas calculated for ^19^23^5^8* Calculated 1 C 50.78%; H 5.16%; N 15.58% Pound : C 50.83%; H 4.85%; N 15.77% Example 17 3-(2-Methylhydrazino)-3-phenylpropionic acid vas reacted vith cycldhepta-2,6-dien-l-one in a similar manner as described in Example 1. The solvent vas evaporated and the residue vas reacted vith an ethereal solution of diazo-methane. Owing to the presence of tvo asymmetric centers in the molecule, tvo diasteromers of 6,7(7,6)- 7(6) (7)£a-(methylcarbonyl methyl)-benzy]Jfmethyl-6,7-diaza 3",2,27 bicyclononan-3-one could be isolated, named A and B. The diasteromers were separated by chromatography on alumina* A. M.g. 89-91°. The analysis vas calculated for ci8H24N2°3 Calculated : C 68.33%; H 7.65%; N 8.86% Pound : C 68.38$; H 7.41%; N 8.93% B. M.p. 115-7°. The analysis vas calculated for CigH24N2°3 Calculated : C 68.33 ; H 7.65%; N 8.86% .74 Pound » C 68.52%» H 7.54%; N 2.00%

Claims (1)

1. 44765/2 15 aims 6,7-Diaza- 3, 2, 27-bicyclononane derivatives of general formula I in which Γϊχ stands eithe for = 0 or for H,OR» in which R' stands either for hydrogen atom or for a radical selected among the group consisting of tropoyl, acetyl-tropoyl , atropoyl and benzoyl, radicals; and g and ^ stand for hydrogen or for iifferent or identical alkyl (having up to 7 carbon atoms), cycloalkyl (having 3-7 carbon atoms), 5.V.74 5.V.74 benzyl, phenethyl, lower alkoxy carbonyl (phenyl) alkyl and lower alkenyl groups; their steroisomers and the mixtures thereof and the optical antipodes and the racemates} and the phyeiologically active and pharmaceutically acceptable acid addition salts. 6,7-Diaza-/3,2,27-bicyclononane-derivative8 according to Claim 1, wherein the addition salts are selected among the group consisting of the hydroualides, sulfates, nitrates, tartrates and the alkyl-halide or alkylsulfonate addition salts such as methiodidis, methobromides, methochlorldes, methonitrates and methyl-methane-sulfonates. - 16 - 44765/2 j? 3. 6,7-Dimethyl-6,7-diaza- 3\2,2 -bicyclononan-3-one. 4. 6,7-Dicyclopentyl-6,7-diaza-.3,2,27-blcyclononanr.3Tone. 5. A racemic mixture of 6-benzyl-7-methyl and 7-benzyl-6-methyl- 6 ,7-eiaza-.3*, 2 , 27-bicyclononan-3-one . 6. 6,7-Dibenzyl-6,7-dlaza-5,2,27-bicyclononan-3-one. 7. 6,7-Diieopropyl-6,7-diaza-5,2,27-bicyolononan-3-one. 1 1 8. A vacemic mixture of 6-methyl-7-aHtyl and 6-alkyl-7-methyl- 6, 7-diaza- 3 , 2, 27-bicyclononan-3-one . 9. 6 , 7-Diallyl-6 » 7-diaza- 3 , 2 , 27-bicyclononan-3-one . 10. 6,7-.a-(methylcarbonyl methyl)-benzyl/methyl-6,7-diaza- .3,2, 27-bicyclononan-3-one, diasteromer A. 11. 7»6-^o-(methoxycarbonyl-methyl-benzyl/tmethyl-6,7-diaza- 5,2, 27-bicyclononan-3-one, diasteromer B. 12. 6,.7-Dimethyl-6,7-diaza-.3"f 2,27-bicyclononan-3o-ol. 13. 6,7-J)imethyl-6,7-diaza-5,2,27-bicyclohonan-3p-ol. 14. 6,7-Dimethyl-6,7-diaza-5,2,27-bioyclononan-3a/ -ol. 15. 6,7-Dicyclopentyl-6,7-diaza-5,2,27-bicyclononan-3o-ol. 16. 6,7-Dicyclopentyl-6,7-diaza-^>3,2,27-bicyclononan-3 -ol . 17. 6-benzyl-7-methyl-6,7-diaza- 3*,2,27-b'icyclonona'n-3o-ol . 18. 6-methyl-7-benzyl-6f 7-diaza-.5,2, 27-bicyclonona'n-3 -ol . 19. 6,7-Dibenzyl-6,7-diaza-/5,2,27-bicyclononan-3a-ol. 20. e^-Dibenzyl-e^-diaza-^^j^-bicyclononan-Sa ^-ol . 21. 6,7-Dimethyl-6,7-diaza- 3,2,27-bicyclononan-3a-yl tropate. 22. 6,7-Dimethyl-6,7-diaza- 3*|2,^7-bicyclononan-3a-yl acetyltropate . 23. 6t7-Dicyclopentyl-6,7-diaza- 3,2, 27-bicyclononan-3o-yl tropate. 24. 6 , 7-Dicyclopentyl-6 , 7-diaza-.5 , 2 , 27-bicyclononan-3 -yl tropate · 25. 6 , 7-Dicyolopentyl-6 , 7-diaza-5, 2 , 27-bicyclononan-3 -yl benzoate . 26. 6-Benzyl-7.methyl-6,7-diaza-5,2,27-bicyclononan-3o-yl tropate. 30. A process for the preparation of the compounds of general formula I as defined in Claim 1, wherein R^ stands for H,0R', R' having the same meaning as above wherein a compound of general formula II in which and ^ have the same meaning as above is reduced to yield a compound of general formula I, in which R^ stands for Η,ΟΗ, having 3a- or 3p-form or being a mixture thereof, and said compound if desired, is esteri- fyed to yield a compound of general formula I in which Rj stands for H,0R' , R' standing for any of the radicals indicated above, having the 3a- or 3β- form or being a mixture thereof. 31. A process according to Claim 30, wherein the ketone of general formula II is prepared by the reaction of a 1,2- disubstituted hydrazine of general formula III, R2NH-NHR3 in which Rg and R^ have the same meaning as in general formula I or one of its salts with cyclohepta-2,6-dien-l-one. 32. A process according to Claim 30, wherein the ketone of general formula II is prepared by reacting a 1 , 2-disubstituted t . 31 hydrazine of general formula III as defined in Claim "2