CA1304369C - Azoniaspironortropanol esters and processes for the preparation thereof - Google Patents

Abstract

ABSTRACT
The present invention provides a process for the preparation of azoniaspironortropanol esters of the general formula:- (I) wherein R signifies one of the following radicals:
a) an alkylene radical of the general formula:--(CH2)n-CH-(CH2)n-in which R3 is a hydrogen atom or an alkyl, benzyl, aryl or alkoxy radical and n is a whole number of from 1 to 4, b) an alkenylene radical of the general formula:- in which R4 and R5, which can be the same or different, are hydrogen atoms or alkyl or alkenyl radicals and n is a whole number of from 1 to 4, c) an azaalkylene radical of the general formula:--(CH2)n-N-(CH2)n-in which R6 is a hydrogen atom or an alkyl, alkoxy-carbonyl or acyl radical and n is a whole number of from 2 to 4, d) an oxaalkylene radical of the general formula:--(CH2)n-O-(CH2)n-in which n is a whole number of from 2 to 4, e) an epoxyalkylene radical of the formula:- f) an o-phenylene radical of the general formula:- g) a peri-naphthylene radical of the general formula:- h) a 2,3-quinoxalinene radical of the general formula:- in which in formulae f) to h), the symbols X and Y, which can be the same or different, are hydrogen atoms or alkyl or alkoxy radicals;
and wherein R1 and R2, which can be the same or different, are hydrogen or halogen atoms or alkyl, alkoxy, alkoyl, cyclohexyl, phenyl, alkylphenyl, alkoxyphenyl, halo-phenyl, thienyl or furyl radicals, the alkyl moieties in the said radicals containing up to 6 carbon atoms and being straight-chained or branched, and A ? is the anion of a mono- to tribasic mineral acid, by a) demethylation of tropine to give nortropine, b) reaction of nortropine with a dihalide to give a corresponding azonia compound, and c) esterification of the azonia compound, wherein A) the demethylation of tropine of the formula:
(II) is carried out either by working in a C1-C3-chloro-alkane which contains at least one trichloromethyl radical in the presence of an oxidation agent in basic aqueous solution or the tropine is reacted with a chloroformic acid ester in an inert solvent in the presence of an acid-binding agent to give an 8-alkoxy-carbonylnortropine and this is hydrolysed with a base in aqueous solution, B) the nortropine thus obtained of the formula:- (III) is reacted at ambient temperature for 1 or more days in a dipolar aprotic solvent with a compound of the general formula:-A - R - A

in which A and R have the above-given meanings, in the presence of a secondary or tertiary amine and C) the compound thus obtained of the general formula:- (IV) in which R and A ? have the above-given meanings, is esterified in an anhydrous, dipolar, aprotic solvent with an imidazolide of the general formula:- (V) in which R1 and R2 have the above-given meanings, in the presence of a catalyst, and D) when the radical R contains one or more olefinic double bonds in the azonium ring after passing through steps B and/or C, this unsaturated compound is option-ally hydrogenated in a polar solvent with the help of a noble metal catalyst to give the corresponding saturated compound of general formula (I) in which R
is a radical a) as defined hereinbefore.

Description

The present invention is concerned with a process for the preparation of azoniaspironortropanol esters, as well as new azoniaspironortropanol esters and pharmaceutical compositions which contain these compounds. The present invention is also concerned with the use of azoniaspironortropanol esters as therapeutics for the treatment of asthma and as broncholytis.
Because of their excellent spasmolytic properties, azoniaspironortropane derivatives are frequently used pharmaceutically. These compounds are prepared from the naturally occurring tropine but the known processes are laborious and time-consuming and, because of the low yields obtained, are also expensive.
Usually, the preparation of azoniaspironortropane derivatives takes place according to the following reaction scheme:

~304369 H3C\ ~tep a \ A\
N ) N N

\~OH ~OH \~OH
tropine nortropine / step b ~tep b' / alkylation ecterif-ication Hal ~ A

OH ~ O-C-R' O

step c esteri-ication , Hal ~ - H
step c;

~ O-C-R' O O

In the above scheme, R' signifie~ the residue of a carboxylic acid and A is an amino protective group.
The oxidative demethylation of tropine to give nortropine (~tep a) is described by S.P. Findley in J.A.C.S., 75, 3204/1953. However, this process, which take~ place with a super~aturated tropine solution at 15C. and with a reaction time of f rom 4 to 7 days, cannot be carried out on a technical scale since, under these reaction conditions, the tropine concentration needed for the reaction cannot be kept stable because the tropine precipitates out spontaneously and is thus removed from the further reaction. A homogenisation of the precipitated tropine, for example by an in-line homogeniser, also did not produce any noticeable improvement.
- It i9 also known to carry out the demathylation by exchange of the methyl radical for an ~-alkoxy-carbonyl radical and subsequent hydrolysi B of the alkoxycarbamate (see J.C. Kirn, Org. Prep. Proc. Int., 9, 1-4/1977). In the case of 8-ethoxycarbonylnortropine, the best yield of nortropine to be found in the liter-ature is 1~%, referred to tropine (see G. Kraiss and K. Nador, Tetrahedron Letters, 1971, pp. 7-8). Later, it was even reported that an acidic or alkaline splitting of 8-ethoxycarbonylnortropine i-~ not possible (see T.A. Monzka, J.D. Matiskella and ~.A. Partyka, Tetrahedron Letters, 1974, pp. 1325-1327).
The preparation of azonia-qpironortropane deriv-atives by quaterniqation and esterification or by the reverse reaction ~equence is known from Federal Republic of ~ermany Patent Specification No. 1,194,422 and from Arzneimittelforschung, 17, 714-719/1967 (steps b and c or steps h' and c'). The hydroxyl group of the nor-tropine or of the corre~ponding azoniaqpiro compound is thereby esterified by reaction with the appropriate acid ch~orides, the hydroxyl group of hydroxycarboxylic acids and possibly the NH group of the nortropine thereby having to be protected. A diqadvantage of the processes de~cribed in these publications iq the poor yield, the esterification of the nortropine (step b') and the ~ubseque~t reaction with a dihalide (step c') thereby also requiring two further reaction steps. It has long been known to use acid imidazolides as reagent-q for the esterification of alcohols (see Chem. Ber., 95, 1284-1297/1962). In particular, ~ederal Republic of 20 Germany Patent Specification No. 2,003,680 describes the reaction of benzilic acid imidazolide with alcohols or thioalcohol~ which contain a tertiary amino group.

On the other hand, in principle, there are three possibilities for the treatment of diseases due to asthma and for bronchial diseases: cortisone or cortico-steroids, sympathomimetics and parasympatholytics.
As is known, corticosteroids involve serious side 1;~04369 -4a-effects, for example susceptibility to infections.
Sympathomimetics also have considerable symptomatic side effects, for example tachycardia. Parasym-patholytics, on the other hand, are characterised by a good measure of success, especially in the case of local administration, by the absence of or only small side effects but, on the other hand, the therapeutic results are not uniform and not certain because of differing response of the symptoms of the disease.
In this regard, reference is made to J.F. Keighley, Iatrogenic asthma associated with adrenergic aerosols, Ann. intern. Med., 65, 985/1966 and F.E. Speizer et al., Observations on recent increase in mortality from asthma, B.M.J., 1, 335/1968.
It is known that some azoniaspironortropane derivatives possess spasmolytic properties ~see Federal Republic of Germany Patent Specification No. 11 94 422 and Arzneimittelforschung, 17, 714-719/1967). However, these compounds have hitherto only been used in the urogenital region.
There is a need for new asthma therapeutics and broncholytics with a parasympatholytic character of action but without a systemic accompanying action, i.e.
without effect on the circulatory regulation, and with a dependable action.
It is an object of the present invention to pro-vide a process for the preparation of azoniaspironor-tropanol esters which can be carried out on a technical ~304369 -4b-scale and which permits these compounds to be prepared in a simple manner in good yield.
It is also an object of the present invention to improve the treatment of asthmatic diseases and of diseases of the bronchial region.

Surpri~ingly, we have now found that azoniaspiro-nortropanol esters can be prepared in good yield when the demethylation of tropine i~ carried out in the pre~ence of a Cl-C3-chloroalkane which contains a trichloromethyl radical. The nortropine thus obtained is alkylated with a dihalide in the presence of an amine and the corresponding azoniaspiro compound i~ esterified by reaction with an acid imidazolide in the pre~ence of a catalyst.
T~us, according to the present invention, there i8 provided a proce~ for the preparation of azonia-spironortropanol esters of the general formula:-: R ~ A ~

Rl wherein R ~ignifie~ one of the follownng radicals:

a) an alkylene xadical of the general formula:--(CH2)n-CH-(CH2)n in which R3 i~ a hydrogen atom or an alkyl, benzyl, aryl or alkoxy radical and n i8 a whole number of from 1 to 4, b) an alkenylene radical of the general formula:-~304369 --6~

C = C /
(C 2)n (CH2)n~

in which R4 and R5, which can be the ~ame or different,are hydrogen atoms or alkyl or alkenyl radical~ and n iq a whole number of from 1 to 4;
c) an azaalkylene radical of the general formula:-: l6 -(CH2)n~N-(CH2)n in which R6 i~ a hydrogen atom or an alkyl, alkoxy-carbonyl or acyl radical and n i8 a whole number of from 2 to 4;
`10 d) an oxaalkylene radical of the general formula:--(CH23n-0-(CH2)n in which n i8 a whole number of from 2 to 4;
e) an epoxyalkylene radical of the fonmula:--CH2- CH - C~- CH2 f) an o-phenylene radical of the general formula:~
X~,Y

g) a peri-naphthylene radical of the general formula:-X~Y

. h) a 2~3-quinoxalinene radical of the general formula:-X~Y
~. ' N ~

in which, in formulae f) to h~, the symbols X and Y, which can be the same or different, are hydrogen atoms or alkyl or alkoxy radicals, and wherein Rl and R2, which can be the same or different, are hydrogen or halogen atoms or alkyl, alkoxy, alkoyl, cyclohexyl, phenyl, alkylphenyl, alkoxyphenyl, halo-phenyl, thienyl or furyl radicals, the alkyl moieties in the said radicals containing up to 6 carbon atom~
and being straight-chained or branched, and A ~ is the - anion of a mono- to tribasic mineral acid, by a) demethylation of tropine to give nortropine, ~304369 b) reaction of nortropine with a dihalide to give ` the corre~ponding azonia compound and `. c~ e~terification of the azonia compound, wherein S A) the demethylation of tropine of the formula:

~ H3C\
~` \\
' ~ (II) ' ~ OH

is carried out either by working in a Cl-C3-chloro- -: alkane which contain~ at lea~t one trichloromethyl radical in the presence of an oxidation agent in ba~ic 10 aqueou~ solution or the tropine i9 reacted wqth a !. chlorofonmic acid e~ter in an inert ~olvent in the pre~ence of an acid-binding agent to give an 8-alkoxy-carbonylnortropine and thi~ i8 hydroly-~ed with a ba~e in aqueous ~olution, 15 B) the nortropine thu~ obtained of the formula:-H~
s ~\

OH

i~ reacted at ambient temperature for 1 or more day~
in a dipolar aprotic ~olvent with a compound of the general formula:-~304369 A - R - A

in which A and R have the above-given meaning-~, in the presence of a secondary or tertiary amine and C) the compound thus obtained of the general formula:-R -~ A
~ N ~

: 5 I ~IV) H

OH

in which R and A ~ have the above-given meaning~, i5 e~terified in an anhydrou~, dipolar, aprotic solvent with an imidazolide of the general formula:-~ 0~
j N - C - C - R2 (V) ~/ 11 1 O Rl in which Rl and R~ have the above-given meanings, in the pr~sence of a catalyst.

In the above-defined radical~, n can be the same or different, the radicals n preferably being ~o ~elected that there is a 5- or 6-membered ring.
The anion A ~ iq preferably a halide ion, such aq a chloride, bromide or iodide ion, or a phosphate, sulphate or nitrate ion.

~304369 Preferred examples of the radical R include the following:

2 4 (CH2)2 CH-(CH2)2- , -CH2-CH=CH-CH2 , 2 , H2 ~ (CH2)2-N-(cH2)2- and -(cH2)2-o-(cH ) -CH H or -COCH3 Within the ~cope of the present invention, the alkyl radical~, including those present in alkoxy, acyl, alkyl~mino and the like radicals, can be straight-chained or branched and contain up to 18 carbon atom~
and preferably up to 6 and more preferably up to 4 carbon atoms. Specific examples of 3uch radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, hexyl, lauryl and stearyl radicals.
Preferred acyl radicals include the acetyl and benzoyl radicals.
D) When the radical R contains one or more olefinic double bond~ in the azonium ring after passing through steps B and/or C, these unsaturated compounds can be hydrogenated in a polar ~olvent with the help of a noble metal catalyst to give the corresponding saturated compounds, compounds of general formula ~I) then being obtained in which R i8 a radical a) as defined above.

Step A.
mis process ~tep makes possible the demethyl-ation even on a technical scale and gives nortropine in considerably higher yield~ in com~arison with the prior art. Two proces~ variant~ can thereby be used, namely, oxidative demethylation or the carbamate method.
The advantages of the oxidative method depend upon the use of a Cl-C3-chloroalkane containing at least one trichloromethyl radical which i~ finely dispersed in the aquéou~ phase. Examples of chloroalkane,s which can be u~ed include, for example, 1,1,1-trichloroethane, l,l,l-trichloropropane and preferably chloroform. The amount of chloroalkane used is in the range of from 1 - 10% by volume, preferably from 1 to 5% by volume and mo~t preferably from 2 to 4% by volume.
For the demethylation, there can be employed any oxidation agent normally u3ed for thi~ purpose, pota~sium ferricyanide being preferred.
The proce~ can be carried out in a wide temper-20 ature range, for example of from 0 to 100C. but it i8 preferred to work at a temperature of from 20 to 30 C.
When the reaction is finished, the product is extracted in counter-current, preferably with the ~olvent used for the demethylation.
The oxidative method result~ in a con-~iderable saving of time in comparison with the known methods, which additionally improves the economy of the process `` 1304369 according to the present invention.
However, it i~ preferred to use the carbamate method. For this pu~pose, tropine is reacted in an inert solvent with a 4 to 6 fold excess of a chloro-S formic acid ester and generally with ethyl chloro-formate. As solvent, there is thereby preferably used a chlorinated hydrocarbon, especially chloroform. The reaction i8 carried out in the presence of an acid-binding agent, preferably of an alkali metal carbonate or bica~bonate. Working is carried out at an elevated temperature, preferably in the range of from 40 to 80C.
After sub~tantial di~tilling off of the solvent, the 8-alkoxycarbonylnortropine thus obtained i8 hydrolysed with a base in aqueous ~olution. As ba~e, there ~ preferably used potas~ium or sodium hydroxide, preferably in 16 to 20 fold exces~.
The nortropine i8 extracted from the aqueou~
reaction mixture in the manner described above for the oxidation demethylation.
According to step A, nortropine can be obtained in almost quantitative yield, especially according to the carbamate method.
Step B.
The crude nortropine obtained in step A can be u~ed in step B without further purification, in contra-distinction to the prior art which requires 48 hours of continuous extraction and crystallisation from diethyl `-` 130436~

-13~

ether. We have, surpri~ingly, found that the tropine ~till present in the crude nortropine as impurity i 9 not quaterni~ed under the reaction condition~ of step B.
Solvents which can be used for quaternising the nortropine include, for example, ~,N-dimethylformamide, chloroform or chloroform/acetonitrile. With dihalides in the pre~ence of secondary or tertiary amine~, after a reaction period of one or more day~ at ambient temp-erature,. the corresponding azonia~piro compound~ are obtained in pure form and with high yields. It i8 preferred to work in anhydrou~ solution, u~ing nor-tropine, amine and dihalide in a mole ratio of 1:2:4.
AA already mentioned, the product obtained in good yield iB of high purity 80 that a further purification is not necessary.
Secondary amines which can be used for this reaction include, for example, dimethylamine, diethyl-amine, diisopropylamine, dicyclohexylamine and the like.
Examples of tertiary amines which can be used include trimethyl~ine, triethylamine, pyridine, quinoline and the like. The use of diethylamine iR preferred.
Ste~ C.
Not only the azonia~piro compounds obtained from step B but also the carboxylic acid imidazolides are generally of low solubility in the anhydrous, dipolar, aprotic ~olvent~ usually employed for such a reaction, for example acetone, acetonitrile, dimethylformamide, tetrahydrofuran and the like. If it is endeavoured to overcome the problems therewith involved by increasing the reaction temperature, then the products resulting therefrom are contaminated with a high proportion of by-products. In particular, carboxylic acid imidazol-ides which have an unprotected hydroxyl group react with themselves at an elevated temperature.
Surprisingly, we have now found that the reaction of a co~pound of general formula (I~) with a carboxylic acid imidazolide of general formula (V) can be carried out in the presence of an appropriate catalyst even in the above-mentioned anhydrous, dipolar, aprotic solvents by reacting the reaction components in suspension. The advantage of thic proces~ i~ that the free hydroxyl group~ of the carboxylic acid imidazolides do not have to be protected and that the reaction product precipit-ates from the above-mentioned solvents and, therefore, can be isolated in a simple manner. The reaction product is not, as was to have been expected, contaminated by a reactant introduced into the reaction in solid form.
Furthermore, the reaction takes place under such mild conditions that no fragmentation and elimination reactions attributable to the pre~ence of the quaternary ammonium group take place. Consequently, no corre~pond-ing by-products can be formed.

1~04369 4-(Dimethylamino)-pyridine has proved to be the moAt advantageous catalyst for this process. This compound can be u~ed in amounts of from 1 to 30 mole %
and preferably of from 5 to 10 mole %~ referred to the benzilic acid imidazolide.
A~ solvents, there can be used the above-mentioned anhydrous, dipolar, aprotic solvent~. me - reaction is carried out at an elevated temperature and preferably at a temperature of from 60 to 80C.
T~e preparation of the carboxylic acid imidazolides used in this reaction takes place in known manner by reacting N,N-carbonyldiimidazole with the appropriate carboxylic acids in dry dichlorometh~ne.
Step D.
Since, in the case of the quaterni-~ation accord-ing to ~tep B) with the dihalides ~ubstituted on the double bond, for example with cis-1,4-dichlorobutene, - a much greater speed of reaction i~ achieved, for example from 18 days to 1 hour, it can be advantageous for the preparation of compounds of general formula (I~, in which R has the meaning of a radical ~uch as a), for example a benziloyloxynortropane-8-spiro-1'-pyrrolidinium salt, to choose the route via the corres-ponding unsaturated compounds with subsequent catalytic hydrogenation either after pa~sing through step B) or steps B~ and C).

~304369 The hydrogenation of the un~aturated compounds ; i9 carried out in a polar solvent, ~uch as water or an alcohol containing up to 4 carbon atoms, preferably methanol, in the presence of a noble metal catalyst, s-~ch as platinium dioxide or palladium on active charcoal.
In the case of using an unsaturated halide, in carrying out the quaternisation there is used a con-siderably smaller excess of dihalide. The mole ratio of nortropine, amine and dihalide previously stated to be preferably 1:2:4 in step B) can then be changed to 1:2:2.
m e present invention also provides new azonia-spironortropanol esters of the general formula:

R
~A ~

~ ~ (I) O
~I 1 2 Rl wherein R, Rl, R2 and A ~ have the same meanings as indicated above, but excluding the following compounds:
azoniaspiro-[3-phenylglycoloyloxynortropan-8,1'-pyrrolidine] chloride, 13~4369 azoniaspiro-[3~-diphenylglycoloyloxynortropan-8 pyrrolidine] chloride, 3-phenylglycoloyloxynortropan-8 spiroi 80i ndolinium chloride, 3-diphenylglycoloyloxynortropan-8-spiroi~oindolinium chloride, 3-phenylglycoloyloxynortropan-8-spiro-4'-morpholinium chloride, 3a-diphenylglycoloyloxynortropan-8-spiro-4'-morpholi'nium chloride,azoniaspiro-[3a-cyclohexylphenylglycoloylnortropan-8,1'-pyrrolidine] chloride, azoniaspiro-[3a-phenylglycoloyloxynortropan-8,1'-piperidine] chloride and azoniaspiro-[3a-diphenylglycoloyloxynortropan-8,1'-piperidine~ chloride.
These compounds possess outstanding spasmolytic properties.
In addition, the present invention provides pharmaceutical compositions containing at least one of the compounds according to the present invention, optionally in admixture with pharmaceutically-acceptable carriers and/or adjuvants.
According to the present invention, there is also provided the use of the azoniaspironortropanol esters defined above, including those which are known as asthma, asthma therapeutics or broncholytics.

-17a-The following Examples are given for the purpose of illustrating the present invention:-Example 1.
3-Benziloyloxynortropane-8-spiro-1'-pyrrolidinium chloride.

~04~69 Ste~ A:
Demethvlation of tropine to nortroPine.
In a 300 litre stirrer vessel equipped with a reflux condenser, 1.9 kg. tropine (97%, corresponding to 1.843 kg. of pure compound, equal to 13 mole) are dissolved in 240 litres chloroform and 5.7 kg. sodium hydrogen carbonate powder and 5.3 litres ethyl chloro-formate (98%, corresponding to 6.0 kg. and to 55.7 mole) are stirred in. The reaction mixture is heated to the boil and then heated under reflux for a further 2 hour~.
The progress of the reaction is monitored by means of thin layer chromatography (Yilica gel 60, dimethyl- - -formamide/diethylamine/ethanol/ethyl acetate 5:10:30:60 v/v/v/v). The reaction mixture is filtered while hot and the chloroform is di~tilled off. A solution of 18 kg. 8~% potassium hydroxide in 90 litre3 water is added to the residue. The reaction mixture is heated to the boil and then heated under reflux for a further 9 hours. The cooled solution i~ then extracted with chloroform using a Xarr column. Extraction conditions:
the "stationary~ phase i9 the light phase (aqueous potassium hydroxide solution) which is conveyed at a rate of about 14 litres/hour. The dispersed phase is the heavy chloroform phase which is conveyed at a rate of about 35 to 50 litres/hour. Shaking frequency:
200 stroke3/minute, temperature 26 to 28C.

In this way, the nortropine formed is extracted from the aqueous potassium hydroxide solution in almost quantitative yield. After stripping off the solvent, the crude product obtained is used in the 5 following step B) without further purification. There B is obtained 1.876 kg. nortropine with a content of 87%
(high pressure liquid chromatography: ~-Bondapack C18-column, elution agent: methanol/water 1:9 v/v with PIC-B7). This corresponds to 1.632 kg. of pure tropine 10 and to a yield of 9~%.
Ste~ B.
3a-Hvdroxynortropane-8-spiro-1'-pyrrolidinium chloride.
The composition of the reaction mixture must be referred to pure nortropine and the mole ratio of 15 nortropine:diethylamine:l,4-dichlorobutane must be exactly 1:2:4.
The crude nortropine obtained in step A) (1.186 kg., corresponding to 1.632 kg. of pure substance and to 12.85 mole) is dissolved in 52 litres N,~-dimethyl-fonmamide and 2.665 litres (1.876 kg., 25.7 mole) diethylamine and 5.736 litres ~6.528 kg., 5.14 mole) 1,4-dichlorobutane added thereto. The reaction mixture is left to stand for 18 days at ambient temperature.
The cr~stals which qeparate out are filtered off with suction, washed with a little dry acetonitrile and dried at 50C. in a vacuum drying cabinet. There are obtained 2.25 kg. (80%, referred to the amount of l rad~ ~qr/~

tropine used in the first step) of pure product, m.p. 250C.
Ste~ C.
3-Benzilovloxvnortropane-8-spiro-1'-pyrrolidinium chloride (trospium chloride~.
a) Benzilic acid imidazolide.
1.944 kg. (12 mole) ~,~-carbonyldiimidazole are dissolved in 19.2 litres dry dichloromethane with the exclusion of moisture. 2.736 kg. (12 mole) dry benzilic acid are added thereto, while stirring, at 15 to 20C.
in the course of 6 minute3, whereafter the reaction mixture i8 stirre~ for 1 hour at ambient temperature.
The benzilic acid thereby first goes into ~olution but soon afterwards the benzilic acid imidazolide begins lS to separate out in solid form. It i~ filtered off with suction and washed with 0.8 litre~ dry dichloromethane.
There are obtained 2.4 kg. benzilic acid imidazolide.
b) PreDaration of the title compound.
In a 300 litre stirrer vessel, 1.3 kg. of the compound obtained in step B) are suspended in 230 litres anhydrouR acetonitrile and heated to 78C. A ~olution of 74.0 g. 4-(dimethylamino)-pyridine in 2 litres anhydrous acetonitrile is added thereto. A suspension of 2.086 kg. benzilic acid imidazolide in 9.0 litres anhydrou~ acetonitrile is then added thereto in three portions at intervals of 30 minutes at 78 C. The reaction mixture is sub~equently stirred at 78CC. until there is achieved a total reaction time of 4 hour~
after the first addition of benzilic acid imidazolide.
The reaction mixture i~ then cooled to 20C. and further stirred overnight. The qu~pen~ion formed i8 filtered off with suction and washed with some aceto-nitrile. The residue, a~ well a~ further product obtained by concentration of the mother liquor (total 2.14 kg.), are recrystalli~ed from i~opropanol. There i~ obtained 1.78 kg. ~70%) of pure product, m.p.
258 - 263C. (decomp.).
FD-MS: m/e = 392 (molecule cation~
IR ~KBr): r = 3150, 1735, 1498, 1452, 747.
Example 2.
3a-BenzilovloxYnortropane-8-~piro-1'-(3'-Pvrrolidinium).
Ste~ B.
3-Kydroxynortropane-8-s~iro~ 3'-pyrrolidinium~
chloride.
1.05 ml. (10 mMole) diethylamine and 1.05 ml.
(10 mMole) cis-1,4-dichlorobut-2-ene are stirred into a solution of 635 mg. (5 mMole) nortropine in 9.5 ml. ~,N-dimethylformamide. After 1 hour, the pure cry~talline product i8 filtered off with suction. The mother liquor is mixed with ethyl acetate until the commencement of turbidity in order to obtain further product. The crystal~ are filtered off with suction and washed with a little acetone. Yield 984 mg. (91% of theory), m.p. 204C, FD-MS: m/e = 180 (molecule cation) IR (KBr): Y = 3250, 1621 cm H-~MR (90 MHz, D20, ~-values referred to TSP-0):
~ = 1,7-2.7 (8H H-2, H-4, H-6, H-7) 3.92 (2H;
H-l, H-5): 4.05 (lH; H-3); 4~14 and 4.31 ~each 2H; H-2' and H-5') 5.90 (2H; J-3', H-4').
Ste~ C.
3-Benziloyloxvnortropane-8-spiro-1'-(3'-pyrrolinium) chloride.
530 mg. (2.4 mMole) 3a-hydroxynortropane-8-spiro-1'-(3'-pyrrolinium) chloride are ~uspended in 353 ml.
anhydrous acetone and stirred in an autoclave for 23 hour~ at 70C. with 14 mg. (0.12 mMole) 4-dimethylamino-pyridine and 678 mg. (2.4 mMole~ benzilic acid imidazolide. Upon cooling to ambient temperature, the product crystallises out of the reaction mixture. It is filtered off with suctlon and wa~hed wlth a little acetone. Yield 650 mg. (6~ of theory), m.p. 267C.
FD-MS: m/e = 390 (molecule cation) 20 IR (KBr): r = 1722, 1595, 1490, 1445, 741 cm H-NMR (90 MHz, D20, ~-values referred to TSP=0):
~= 1.3-2.8 (8H; H-2, H-4, H-6, H-7) 3.85 (2H, H-l, H-5), 4.09 and 4.37 (each 2H; H-2' and H-5'), 5.24 (lH; H-3); 5.95 (2H; H-3', H-4');
7.44 (lOH aromatic protons of the benzilic acid).

`~ 130~369 Step D.
Conversion of 3a-benziloyloxynortropane-8-spiro-1'-(3'-pyrrolinium) chloride into 3a-be_ziloyloxYnor-tropane-8-~piro-1'-pyrrolidinium chlo ide.
500 mg. 3a-benziloyloxynortropane-8-spiro-1'-(3'-pyrrolinium~ chloride are dissolved in 15 ml. methanol and, after the addition of a spatula tip of platinum dioxide, hydrogenated at normal pressure and at a temperature of 25C. up to the end of the hydrogen take-up. Thé hydrogenation i carried out in a standard apparatus, such as is illustrated, for example, in Houben-Weyl, Methoden der organischen Chemie, 4th edition, Vol. IV/lc, pub. Georg Thieme Verlag, Stuttgart, ~ew York, 1980, pp. 33-39. After filtering off the cataly~t, the filtrate i~ evaporated to dryness in a vacuum~ According to H-~MR ~pectroscopy, the reaction is quantitative. Crystalli~ation i~ carried out a~
described in Example 1, Step C.
Example 3.
3-Benziloyloxynortropane-8-spiro-2~-isoindolinium chloride.
1) 3a-H~drox~nortro~ane-8-sPiro-2'-isoindolinium chloride.
1.27 g. (10 mMole3 nortropine are di~solved in 25 7 ml. chloroform and mixed with 1.46 g. (20 mMole) diethylamine and 4 g. (40 mMole) 1,2-bi~-(chloromethyl)-benzene. The clear reaction ~olution is left to ~tand for 24 hours at ambient temperature in a closed vessel.
It is then concentrated to one half and mixed with ethyl acetate in order to initiate crystallisation.
The cry~tals are filtered off with ~uction and re-crystallised fr~m i~opropanol/ethyl acetate. Yield1 g. (3~% of theory); m.p. 245 - 247C.
FD-MS: m/e = 230 (molecule cation) IR (~Br): r = 3168, 757, 742 cm 1, ~-NMR (250 MHz, D20, ~ -values referred to TSP=0):
~ = 2.09 (2H, H-6a, H~7a), 2.40-2.67 (4H; H-2, H-4), 2.59 (2H; H-6b, H-7b); 4.03 (2H; H-l, H-5);

4.24 (lH, H-3); 4.82 and 4.99 (4H; H-l' and H-3'), 7.47 (4H: H-4' to H-7').
2) 3a-Benziloyloxynortropane-8-~iro-2'-i~oindolinium chlori_ .
1.33 g. (5 mMole) 3-hydroxynortropane-8-spiro-l'-i~oindolinium chloride i8 suspended in 210 ml.
anhydrou~ acetonitrile and heated to 78C. While ~tirring, there are first introduced 62 mg. (0.5 mMole) 4-dimethylaminopyridine and then, wnthin the course of 2.5 hours, portionwise 3.2 g. (11.5 mMole) benzilic acid imidazolide. The reaction mixture is further ~tirred for 5.5 hours at 78C., then cooled to 22~.
and further stirred overnight. The ~olution is con-centrated to one quarter of its volume and the productcaused to cry~talli~e by the addition of ethyl acetate.
Yield 1.3 g. (54% of theory), m.p. 263 - 265C.

FD-MS: m/e = 440 (molecule cation).
IR (KBr): y = 1740, 757, 745, 703 cm H-NM~ (250 MHz, D20, ~-values referred to TSP=0):
~ = 1,57 (2H; H-6a, H-7a); 2.03 (2H, H-2a, H-4a);
2.07 (2H; H-6b, H-7b), 2.70 (2H, H-2b, H-4b), 3.86 (2H; H-l, H-5); 4.69 amd 4.96 (4H; H-l'-and H-3'); 5.32 (lH; H~3), 7.40 - 7.51 (14H;
H-4' to H-7' and aromatic protons of the benzilic acid).
Example 4.
3-Benzilo~y~ynortro~ane-8-splro-4'-morpholinium chloride.
1) 3a-Hydroxynortropane-8-sPiro-4'-morpholinium chloride.
11.8 ml. (113.2 mMole) diethylamine and 26.6 ml.
(226.5 mMole) 2,2'-d-chlorodiethyl ether are stirred into a solution of 7.2 g. (56.6 mMole) nortropine and 70 ml. chloroform. The clear reaction solution is left to stand for 3 days at am~ient temperature in a closed vessel. The oil-cr,vstal mixture which separates out is homogenised and crystalli~ed through overnight at 0 C.
The crystals are filtered off with suction, washed with a little chloroform and dried under a vacuum at 40C.
for 2 hours. Additional ~ubstance is obtained by evaporating the mother liquor and treating with ethyl acetate. Yield 12.5 g. (95% of theory); m.p. 274 -276C. (decomp.).

FD-MS: m/e = 198 (molecule cation).
I~ (XBr): y = 3320, 892 cm N-~MR (250 MHz, D20, a~ -values referred to TSP=0):
~ = 2.00 (2H H-6a, H-7a) 2.22-2.62 (6H H-2, H-4, H-6b, H-7b), 3.50 and 3.65 (4H, H-2' and H-6'), 4,01 and 4.08 (4H, H-2' and H-6') 4.18 (lH:
H03) 4.22 (2H, H-l and H-5).
2) 3~-BenziloxvloxynortroRane-8-spiro-4-morpholinium chloride.
7:5 g. (32 mMole) 3-hydroxynortropane-B-spiro-4'-morpholinium chloride are su~pended in 650 ml.
anhydrous acetonitrile and mixed with 0.587 g. (4.8 mMole) 4-(dimethylamino)-pyridine. 26 g. (92.8 mMole) benzilic acid imidazolide are added portionwq~e at 79C.
within the course of 3 hours. The reaction mixture i9 left to ~tand for 7 days at ambient temperature and the pure cry~talline product i8 then filtered off with suction. The cry~tals obtained are dried under vacuum for 2 hours at 40C.; yield 8.4 g. (60% of theory), m.p. 225C. (decomp.).
FD-MS: m/e = 408 (molecule cation).
IR (KBr): y = 3410, 3183, 1731, 1492, 703 cm H-NMR (250 MHz, D20, ~- value~ referred to TSP=0):
~ = 1.51 (2H H-6a, H-7a) 2.00 (4H H-2a, H-4a, H-6b, H-7b) 2.63 (2H H-2b, H-4b), 3.38 and 3064 (4H H-2' and H-6'), 3.99 and 4.04 (4H
H-3' and H-S') 4.09 (2H H-l, H-5), 5.30 tlH, H-3~; 7.46 (lOH, aromatic protons of the benzilic acid).
Example 5.
3a-Benziloxyoxynortropane-8-spiro-l~-pyrrolidin r 3',4'-blquinoxalinium bromide.
1) 3a-HvdroxynortroPan-8-sPiro~ ~yrrolidino-r 3',4'-bl~uinoxalinium bromide.
- 4.58 g. (43.6 mMole) diethylamine and 13.85 g.
~43.6 mMole~ 2,3-bis-(bromoethyl)-quinoxaline are stirred.into a solution of 5.57 g. (43.6 ~Mole~ nor-tropine and 100 ml. chloroform. The reaction mixture, which has become warm, is cooled to 20C., the product thereby precipitating out in crystalline form. It is filtered off with suction, washed with chloroform and dried in a vacuum for 22 hours at 55C. Yield 11.1 g.
(71% of theory); m.p. 283C. (decomp.).
FD-MS: m/e = 282 (molecule cation).
IR (KB~): r = 3345, 1504, 773 cm 1, lH-~MR (250 MHz, D20, ~-value~ referred to TS~=0):
~ = 2.21; (2~,H-6a, H-7a), 2.53 - 2.89 (6H; H-2, H-4, H-6b, H-7b); 4.29 (2H, H-l and H-5); 4.31 (lH;
H-3); 5.21 and 5.41 (each 2~; H-2' and H-5');
7.94 - 8.05 (2H; quinoxaline o-protons); 8.11 -8.22 ~2H; quinoxaline m-protonq).
2~ 3a-Benzilovloxvnortropane-8-spiro-l'-~yrrolidin - r 3',4'-blquinoxalinium bromide.

5 g. (1.3g mMole) 3-hydroxynortropane-8-spiro-\
~304369 l'-pyrrolidino[3',4'-b]-quinoxalinium bromide are sus-pended in 130 ml. dried dimethyl -qulphoxide and 100 ml.
dry acetonitrile. After the addition of 0.26 g. (2.09 mMole) 4-dimethylaminopyridine, the reaction mixture S is heated to 78 C. While stirring vigorously, 7.74 g.
(27.8 mMole) benzilic acid imidazolide are added in 3 portions at intervals of 30 minutes. The reaction mixture i~ further stirred for 2.5 hour~ at 78C. and is then cooled to 20C. and filtered. The filter residue is discarded. The filtrate is evaporated to dryness at about 0.2 mbar pressure. The residue is extracted with 500 ml. boiling isopropanol and filtered hot. The filter re~idue is discarded. The filtrate is concentrated to 200 ml. The product crystallises out after standing overnight at ambient temperature. It i3 filtered off with suction, wa~hed with cold iso-propanol and dried in a vacuum for 2 hour~ at 55 C.
Yield 3.5 g. (44% of theory), m.p. 205C. (decomp.).
FD-MS: m/e = 492 (molecule cat~on).
IR (KBr): Y = 3375, 1730, 1504, 763 cm H-NMR (250 MHz, CDC13/CD30D = 3:1 v/v, ~-values referred to TMS=0):
= 1.78 (2H H-6a, H-7a), 2.08 (2H, H-2a, H-4a), 2.20 (2H, H-6b, H-7b), 2.85 (2H, H~2b, H-4b), 4.23 (2H; H-l, H-5), 4.62 (4H, H-2', H-5'), 5.35 (lH H-3); 7.30-7.48 (lOH, benzilic acid protons) 7.84-7.97 (2H, quinoxaline o-protons), ;

8.07-8.22 (2H quinoxaline m-protons).
ExamE~le 6.
3a-Benzilovloxynortropane-8-spiro-2'-(2'-aza-3H-phenolenium~ b omide.
1) 1.33 ml. (12.7 mMole) diethylamine and 4 g.
(12.7 mMole~ 1,8-bis-(bromoethyl)-naphthalene are stirred into a solution of 1.62 y. (12.7 mMole) nor-tropine and 75 ml. N,N-dimethylformamide. From the reaction mixture, which has become ~lightly warm, the product'cry~tallises out within 2 hour~. It is filtered off with ~uction, washed with a little N,~-diemthylformamide and dried in a vacuum at 55C. for 2 hours. Yield 3.5 g. (76% of theory); m.p. 330C.
(decomp.).
FD-MS: m/e = 280 (molecule cation):
IR (KBr): y = 3410, 1604, 1512 cm H-NMR (250 MHz, CDC13/CD30D = 3:1 v/v, ~-values referred to TMS=0):
~ = 2.02 (2H: H-6a, H-7a), 2.39-2.85 t6H, H-2, H-4, H-6b, H-7b); 3.92 (2H, H-l, H-5), 4.28 (lH, H-3);
S.01 and 5.16 (4H; H-l' and H-3'), 7.51-7.64 (4H; H-5', H-6', H-7', H-8'), 7.93 (2H, H-4', H-9')-2) 3-BenziloxyoxYnortropane-8-~piro-2'-(2'-aza-3H-phenolenium)-bromide .

2.95 g. (8.2 mMole) 3a-hydroxynortropane-8-spiro-2'-(2'-aza-3H-phenolenium) bromide are suspended in 1660 ml. dry acetonitrile and 160 ml. dry N,N-dimethyl-formamide. After the addition of 152 mg. ~1.2 mMole) 4-dimethylaminopyridine, the reaction mixture i~
heated to 78C. 4.56 g. 116.4 mMole) benzilic acid imidazolide are added in three portions with vigorou~
stirring at intervals of 30 minutes. The reaction mixture is then stirred for 2.5 hours at 78C. and the - reaction mixture thereafter evaporated to one half.
The precipitated crude product i~ filtered off wnth suction'at 20C. and susp~nded in methanol. ~he material which is insoluble in methanol is filtered off and di~carded. The filtrate is concentrated until the cry~tallisation of the product commence~. After crystalli~ation overnight at ambient temperature, the product i~ filtered off with suction and dried in a vacuum for 2 hours at 55C. Yield 2.1 g. (42~ of theory); m.p. 322C. ~decomp.).
FD-MS: m/e 490 (molecule cation).
IR (KBr3: y = 3428, 3240, 1738, 1603, 1497 cm H-NMR (250 MHz, C~C13/CD30D = 3:1 v/v. ~-value~
referred to TMS=O):
~ = 1.75 (2H; H-6a, H-7a); 1.94 (2H; H-2a, H-4a), ; 2.20 (2H H-6b, H-7b) 2.80 (2H H-2D, H-4b), 3.85 (2H H-l, H 5), 4.93 and 5 19 (each 2H:
H-l' and H-3'); 5.45 (lH, H-3): 7.31-7.46 (lOH;
benzilic acid proton) 7.47-7.67 (4H H-5', H-6', H-7', H-8'), 7.93 (2H, H.4', H-9').

~304369 Example 7.
3-Benziloyloxvnortropane-8-qpiro-1'-(4'-methvl)-piperidinium chloride.
1~ 3a-HYdro~ynortroPane-8-~piro-1'-~4'-methYl)-piperidinium chloride.
7.62 g. (0.06 mole) Nortropine are dis~olved in 200 ml. anhydrous N,~-dimethylfcrmamide. After stirring in 8.76 g. (0.12 mole) diethylamine and 37.18 ~. (0.24 mole) 1,5-dichloro-3-methylpentane, the reaction mixture i~ left to Atand for 18 day~ at ambient temperature in a clo~ed ve~el. The cry~tal~ which separate out are filtered off with suction, washed with a little dry acetonitrile and dried in a vacuum drying cabinet at 50C. There are obtained 7.84 g. (53% of theory) of pure product, m.p. 290C. (decomp.).
FD-MS: m/e = 210 (molecule cation).
IR (KBr): y = 3190 cm H-NMR (250 MHz, D20, ~'-value~ in ppm, referred to TSP=O):
~ = 1.01 (m, 3H; CH3); 1.37-2.02 tm; 7H H-6a, H-7a, H-3', H-4', H-5'); 2.20-2.52 (m; 5H H-2a, H-4a, H-6b, H-7b, OH~, 2.60 and 2.67 (2 x t, 2H H-2b and H-4b); 3.10, 3.20, 3.63 and 3.74 (4 x m;
4H; H-2' and H-6') 3.76 and 4.24 (2 x m; 2H;
H-l and H-5), 4.19 (t; lH; H-3).
2) 3-benziloyloxynortropane-8-spiro-1'-(4'-methyl)-piperidinium chloride.

7.37 g. (30 mMole) 3a-Hydroxynortropane-8-spiro-1'-(4'-methyl)-piperidinium chloride are suspended in 650 ml. anhydrous acetonitrile and heated to 78C., while stirring. At this temperature, there are fir~t stirred in 587 mg. (4~8 mMole) 4-(dimethylamino)-pyridine and then, in the cour~e of 2 hours, 13.35 g.
(48 mMole) benzilic acid imidazolide in 4 approximately equal portions. Stirring is continued for 1.5 hours at 78C. and then the reaction mixture i~ allowed to cool overnight at ambient temperature, without ~tirring.
The crystalline product is filtered off with suction and washed with a little acetone. The crude crystallis-ate is recrystallised from dry isopropanol. The pure cry~tals are dried in a vacuum for 2 hours at 40C.
15 Yield 9.56 g. (70% of theory) as a 1:1 mixed crystallis-ate with isopropanol; m.p. 256 - 259C.
FD-MS: m/e = 420 (molecule cation).
s~ ~Br~ 135 crl~ I
H-NMR (250 MHz, D20, ~-values in ppm, referred to TSP=0):
~= 0.98 (m; 3H: CH3), 1.30-1.65 (m; 4H; H-6a, H-7a, H-3'a, H-5'a); 1.65-2.03 (m: 7H; H-2a, H-4a, H-6b, H-7b, H-3'b, H-4', H-5'b), 2.52 and 2.72 (m 2H;
H-2b, H-4b): 3.02, 3.19, 3.47, 3.72 (t, t; d; 4H;
H-2' and H-6'); 3.62 and 4.10 (m, m; 2H, H-l and H-5), 5.30 (t; lH; H-3); 7.40-7.40 (m; lOH, aromatic protons).

1~04369 Example 8.
3a-(4,4'-Difluorobenziloyloxy)-nortropane-8-spiro-l'-pYrrolidinium chloride.
2.17 g. (0.01 mole) 3a-hydroxynortropane-8-~piro-l-pyrrolidinium chloride are dissolved with 2.02 g.
(0.01 mole) sodium heptane-l-sulphonate, with warming, in 500 ml. anhydrous acetonitrile. After cooling to 25 to 27C., the sodium chloride precipitate is filtered off with suction with the exclusion of moi~ture. The solutio~ is mixed with 0.125 g. 4-(dimethylamino)-pyridine and tran~ferred to a reaction vessel which is connected to a stirrer vessel in which 4,4'-difluoro-benzilic acid imidazolide is prepared~ This stirrer vesqel i~ equipped with two dropping funnels. In one dropping funnel, there are placed 2.64 g. (0.01 mole) 4,4'-difluorobenzilic acid (preparation analogous to the de~cription in Federal Republic of Germany Patent Specification ~o. 20 34 943), dissolved in 100 ml.
anhydrous acetonitrile. In the other dropping funnel there is placed a solution of 2.43 g. (0.015 mole) N,N-carbonyldiimidazole in 150 ml. anhydrou~ acetonitrile.
From each of the two ~olutions, about one quarter of the volume is run in simultaneously, while stirring, into the stirrer vessel, the mixture is then ~tirred for 15 minutes and the resultant imidazolide ~olution tran ferred, with the strict exclusion of moisture, into the reaction vessel in which the solution of 3-hydroxynortropane-8-~piro-1'-pyrrolidinium heptane-sulphonate iq stirred at ambient temperature. This procedure is repeated three time~ until all the reactants have been combined. The reaction mixture is then boiled under reflux for 2 hourq and subsequently cooled overnight to ambient temperature. The reaction mixture is then evaporated to dryness in a rotary evaporator under vacuum. The residue is purified chromatographically over a silica gel column (silica gel 60,'0.063 - 0.200 mm., Merck ~o. 7734), the mobile phase being 1,2-dichloroethane:acetic acid:methanol:
water 57:23:13:7 v/v~v/v). Yield 870 mg. (14% of theory) 3a-(4,4'-difluorobenziloyloxy)-nortropane-8-spiro-l'-pyrrolidinium heptanesulphonate. After passage over a column packed with a strongly basic ion exchanger in the chloride form ~Lewatit MP 500), there i~ obtained the title compound. The crude product i-q recrystallised from isopropanol, washed with ethyl acetate and dried in a vacuum under vacuum at 40 C. to constant weight. Yield 470 mg. as 1:1 mixed crystallisate with isopropanol m.p. 242 - 245C.
FD-MS: m/e = 428 (molecule cation) IR (~Br): r = 1508, 1603, 1733 cm lH-NMR ~250 MHz, D20, ~-values in ppm, referred to TSP= 0):
~`= 1.44-1.67 (m 2H, H-6a, H-7a): 2.00-2.20 (m, 8H, H-2a, H-4a, H-6b, H-7b, H-3', H-4'), 2.57 and ~304~69 2.64 (2 x m; 2H, H-2b and H-4b); 3.38 and 3.60 (2 x m 4H; H-2', H-5'): 3.73 (m; 2H, H-l, H-5):
5.27 (t lH, H-3) 7.19 and 7.42 (2 x m 8H
aromatic protons).
Example 9.
3a-(4,4'-DimethYlbenziloyloxY~-nor trole~ne-8-~piro-1 ' -Pvrrolidinium chloride.
The procedure i~ as in Example 8 but instead of 4,4'-difluorobenzilic acid there is u~ed 4,4'-dimethyl-benzilic' acid a~ ~tarting material (preparation analogou~ to J.G. Cannon, J. Org. Chem., 25, 959-962/
1960~. Yield 1.68 g.: m.p. 175C.
FD-MS: m/e = 420 (molecule cation) IR (KBr): y = 1508, 1612 (weak), 1718 cm lH-~MR (250 MHz, D20, ~-values in ppm, referred to TSPs 0) = 1.47-1.51 (m; 2H, H-6a, H-7a); 1.79-2.21 (m; 8H;
H-2a, H-4a, H-6b, H-7b, H-3', H-4'): 2.33 (~: 6~:
2 x CH3) 2.48-2.66 (m; 2H: H-2b, H-4b) 3.34 and 3.58 (2 x m: 4H, H-2' and H-5'); 3.67 (m: 2H, H-l, H-5) 5.23 (t; lH, H-3); 7.20-7.31 (m; 8H;
aromatic protons).
Example 10.
3a-(4,4'-Di-n-butyloxvbenzilovloxy)-nortropane-8-spiro-l'-pYrrolidinium chloride~
The procedure is a~ in Example 8 but in~tead of 4,4'-difluorobenzilic acid there i~ used 4,4-di-n--~6-butyloxybenzilic acid a~ qtarting material (preparation analogou~ to J.G. Cannon, J. Org. Chem., 25, 959-962/
1960), Yield 240 mg. of cry~tal~ which deliquesce at ambient temperature.
S FD-MS: m/e = 536 (molecule cation) IR (KBr): y = 1508, 1580 (weak), 1608, 1734 cm H-NMR (250 MHz, CDC13, ~-values in ppm, referred to TSP= O):
; , ~ = 0.96 (t; 6H; 2 x CH3 of n-butyloxy); 1.47 (t; q:
4~; 2 x CH3 of n-butyloxy); 1.53-1.63 (m; 2H, H-6a, H-7a); 1.76 (t, t: 4H; 2 x CH3 of n-butyloxy); 1,80-2.30 (m, 8H; H-2a, H-4a, H-6b, H-7b, H-3', H-4'), 2.62-2.77 (m 2H; H-2b, H-4b), 3.65 and 3.99 (2 x m: 4H: H-2' and H-5'); 3.94 (t, 4H, 2 x CH3 of n-butyloxy) 4.16 (m 2H, H-l, H-5): 5.28 (t, lH; H-3), 6.84 and 7.25 (2 x d, 8H; aromatic proton~).
Example 11 3a-(4-n-butYloxybenzilovloxv3-nortroDane-8- 9pi ro-l~-pvrrolidinium chloride.
The procedure is a~ in kxample 8 but instead of 4,4'-difluoro~enzilic acid there i8 used 4-n-butyloxy-benzilic acid as starting material (preparation analogous to C.D. Shacklett and H.A. 5mith, J.A.C.S., 75, 2654-2657/1953). Yield 250 mg., m.p. 206C.
FD-MS: m/e = 464 (molecule cation~
IR (KBr): y = 1512, 1609, 1742 cm H-NMR (250 MHz, CDC13, ~-values in ppm, referred to TMS= 0):
S = 0.97 (t, 3H: CH3 of n-butyloxy), 1.50 (t, q; 2H;
CH2 of n-butyloxy), 1.56-1.64 (m, 2H, H-6a, H-7a), 1.77 (t,t: 2H; CH2 of n-butyloxy), 1~84-2.45 (m, 8H H-2a, H-4a, H-6b, H-7b, H-3', H-4'): 2.65-2.85 (m 2H: H-2b, H-4b): 3.58 and 3.95 (2 x m, 4H:
H-2' and H-5'); 3.95 (t, 2H: CH2 of n-butyloxy) 4.08 (m, 2H: H-l and ~-5) 5.30 (t: lH 6.84 (d) a~d 7.26-7.37 (m, 9H: aromatic protons).
Ga ~ , 1. Tablets .
40 mg. azoniaspironortropanol ester according to one of the chemical Examples 20 mg. lacto~e 30 mg. qtarch 0.5 mg. magnesium ~tearate 74.5 mg. microcry~talline cellulose 2. Su~o~itories.
0 120 mg. azoniaqpironortropanol ester according to one of the chemical Examples 2 mg. "~ero~il n 200 (silicic acid) 2278 mg. Witepsol (modified triglyceride~ of ~aturated plant fatty acids) 3. Solution for intravenous injection.
20 mg. azoniaspironortropanol e~ter according to one of the chemical Example q ~racl~ mar k 4.6 mg. citric acid monohydrate 14.8 mg. sodium citrate dihydrate ad 2 ml.
4. Solution for intravenous infusion.
500 mg. azoniaspironortropanol ester according to one of the chemical Examples 130 mg. citric acid monohydrate 370 mg. sodium citrate dihydrate ad 50 ml.
10 5 Reta~d form.~ diffusion pellets.
Per hard gelatine capsule:

Without With initial initial dose dose ~ugar spheroids 150 mg. 150 mg.

15 azoniaspironortropanol ester according to one of the 80 mg. WS 60 mg.
B chemical Examples hydroxypropylcellulose (Klucel) 10 mg. 8 mg.
acrylic or methacrylic esters:
20 Endragit RL 2 mg. 2 mg.
Endragit RS 8 mg. 8 mg.
polyethyleneglycol (8000)1 mg. 1 mg.
talc 5 mg. 5 mg.
~ WS 20 mg.
Klucel 2 mg.

6. Retard form: matrix tablet.
-- -- . . .~
80 mg. azoniaspironortropanol ester according to one of the chemical Examples Trade ~ r ~

120 mg. lactoYe 15 mg. ethyl cellulose 20 mg. starch 2 mg. magne~ium stearate 3 mg. polyethylene glycol (8000) 7. Retard form: two-laYer tablet with initial dose.
1st layer 2nd layer retard retard tablet tablet 10 azonia~pironortropanol ester 60 mg. 20 mg.
lactose 90 mg. 10 mg.
ethyl cellulose 12 mg.
qtarch 15 mg. 15 mg.
magnesium stearate 1.5 mg. 0.3 mg.
15 polyethylene glycol (8000~ 2 mg.
microcrystalline cellulose - 37.2 mg.

8. Dosed aerosol for inhalation.
Formulation per dosage/3pray impulse:
0.1 mg. azonia~pironortropanol ester according to one of the chemical Examples B o. 02 mg. Span~85 (sorbitan mono- and trifatty acid residue based on oleic acid) 10 ~1. Frigen 11 (trichlorofluoromethane) 40 ~1. Frigen 12 (dichlorodifluoromethane).
25 9. Dosed spra~ for nasal use.
Formulation per dosage/spray i~pu182:
2 mg. azoniaspironortropanol e~ter according to one of the chemical Examples 90 ~1. physiological saline ~a~ ~ Q~l~

1~04369 ;

The following compound~ according to the pre~ent invention have been tested for spasmolytic effective-ne~Q:
3a-benziloyloxynortropane-8-spiro-1'-(3'-pyrrolinium) chloride (Example 2) 3-benziloyloxynortropane-8-~piro-2'-isoindolinium chloride (Example 3) 3~-benziloyloxynortropane-8-spiro-4'-morpholinium chloride (Example 4) 3-benzi'loyloxynortropane-8-spiro-1'-pyrrolidino-[3',4'-b~quinoxalinium bromide (Example 5) 3-benziloyloxynortropane-8-~piro-2'-(2'-aza-3H-phenolenium) bromide (Example 6).
Ac known comparison compound, there was used tro~pium chloride ~Example 1).
The experiment~ were carried out on i~olated rat intestine.
Animal material:
Male and female Wistar rat~ with a body weight of 20 150 to 250 g. The animal3 were acclimati~ed for 1 week at 20 + 2C. and at a relative humidity of 50 1 10%.
The room illumination wa~ daylight with additional neon tubes with a day/night illumination r~ythm of 7.00 to 18.00 hours. The animalq were kept in Makrolon cage~
type 4, each being occupied by 10 rat~. The cage~ had a ~awdu~t bedding. The feed was "~niff" ~tandard feed (Ver~uch3tierdiaten GmbH, 4770 Soe~t, Genmany) available ad libitum and the drinking water, which was tap water from synthetic re~in flasks with stainless steel drinXing tubes, was available ad libitum.
Substance~, do~aae~:
test substances: compounds of Examples 1 - 6.
~olvent: demineralised water concentration: 1.185 x 10 g./ml. bath ve~el content~
(again~t Carbachol) volume administered: 0.25 ml.

time of~action before admini~tration of spasmodic:
3 minutes further substances-used: carbamoylcholine (Carbochol) hydrochloride, Merck, Darmstadt (Art No.
q 500 940) sum fonmula: C6H15ClN202 concentrations: 4 x 10 9 g./ml. bath vessel content 2 x 10-8 g /ml u 1 x 10 7 g./ml.
S x 10-7 g./ml. ~
2.5 x 10-6 g./ml. "
1.25 x 10 5 g./ml.
6.25 x 10 5 g./ml.
volume administered: 0.25 ml.
time of action: 5 minutes Ringer's nutrient solution with the following compo~ition:

sodium chloride = 9.000 y. (E. Merck, Darmstadt) potas~ium chloride = 0.210 g. "
~odium bicarbonate = 0.500 g. n glucose monohydrate = 0.500 g.
5 calcium chloride monohydrate= 0.318 g. n Carryinq out of the experiments.
The rats were sacrificed by a neck blow. The abdomen was opened along the median line, an approximately , lo cm. long piece of ileum was removed, im~ediately transfer~ed to a physiological tempered nutrient ~olution and then completely and carefully rinsed through twice in toto with the help of a 10 ml. yringe with nutrient solution for the removal of the inte~tinal contents.
For the subsequent experiments, two pieces of intestine of 2 cm. length were separated off and the remaining piece of intestine kept in a refrigerator. me two pieces of inte~tine were freed in nutrient solution from ti~sue pos~ibly still attached thereto. Around one end there wa~ applied a sling of silk thread for fixing the piece of intestine in an organ bath, while around the other end wa~ applied a longer thread with a connecting clamp for fixing to a recording layer.
The piece of organ wa~ thereafter filled with nutrient solution and suspended in a bath vessel with Carbogen bubbling therethrough and loaded with 0.5 g. After a resting period of 30 minutes, the experiment can commence.

~304369 There was first plotted a dosage action relation-ship of the spasmodic. The solution to be tested was injected by means of a tuberculin syringe with applied single-use canule into the bath liquid. Depending upon the volume to be injected, for the precise maintenance of the bath content there was previously always removed an equal volume of nutrient solution. Concentrations ~ were selected which, in geometric steps of a factor of 5, displayed spasmodic effects of > lOyo to lOOyo~ the 10~% effect being taken as being the limiting concen-tration, exceeding of which brought about no greater effect. The limiting concentration is taken as refer-ence value and the effect~ of the lower concentrations were calculated to refer to this 10~/o value. A complete concentration activity curve was plotted using a piece of intestine.
The period of action of the spa~modic on the organ was 5 minutes. Thereafter, the content of the bath ve~el was changed three times by rinsing and followed by a resting phase (no addition of substance) of 30 minute~.
After plotting of the concentration-activity relation~hip of the ~pasmodic, the antagonistic strength of action of the substance to be tested wa~ tested. For this purpose, the te~t substance was injected in a constant concentration into the bath ve~sel content 3 minutes before application of the spa~modic. The qubsequent cour~e of the experiment corresponded to that already de~cribed: addition of spasmodic in increaqing concentrations, rinsing three timeq, 30 minute resting phase. Depending upon the effect, the concentrations of the test substance were varied, ten experiments being carried out per concentration.
Analvsis and apparatu~.
The experimental apparatus consisted of a horizontally fixed, about 66 cm. long cylinder-shaped glass surround with inlet and outlet taps in which were melt-sealed two pre-heating spirals which were provided on the outside with inlet pipes and each of which open downwardly into a bath veqsel of 25 ml. volume clo~able below by ~topcocks. Demineralised water warmed to 34C.
was circulated by an ultrathermostat of the firm ~Colora n through the glass ~urround ~o that the nutrient solution present in the pre-heating spirals and bath vessels was always uniformly wanmed. In case of need, it was pa~sed from a higher-standing supply vessel via a tube system into the pre-heating spirals. On the bottom of the bath vessel, for the continuou3 bubbling through of the nutrient solution with Carbogen ~95%
oxygen and 5% carbon dioxide), there were provided gassing tubes, on the limbs of which, in the lower third thereof, were melt-sealed gla~s hooks on to which were -quspended on one end the previously prepared piece of inte-qtine, whereas the other end waq attached with its long thread with a metal recorder lever for MP
recordal. Finally, the loading was adjusted on the recorder lever and the star recorder of the lever applied to the MP paper on the recorder drum (diameter 200 mm.) of a kymograph. During the experiment, the MP paper was rolled from the table unrolling device on to the drum. The paper movement was 2.62 mm. x min 1. The recording breadth could be regulated via an MP generator with incoryorated potentiometer. For a better'current flow, a contact roller was addition-ally applied to the MP paper which was connected with the earthing box of the MP gënerator.
After ending of the experiment, the recordings on the MP paper were fixed with a special fixing spray.
All apparatus necessary ~or the recordings were obtained from the firm Braun, Melsungen, Germany.
Evaluation.
For each concentration in g./ml. there was obtained the arithmetic average values and their standard deviations (x~ + g) of the spasmodic effect.
Re~ult~.
A 50% spasm was obtained with Carbachol alone (blank experiment) at a concentration of 4.3 x 10 g./ml.
In the case of the use of the a~ove-mentioned spasmolytically-acting test substances in a concent-ration of 1.18 x 10 8 g./ml., for the initiation of a 50% spasm, carbachol concentrations of the order of 10 6 g./ml. were needed.

The compounds used according to the present invention as asthma therapeutics and broncholytics can be applied in the form of, for example, aerosols, solutions and the like, the routes of administration being, for example, by inhalation, orally, intra-venously or the like.
The following Examples are given for the purpose of illustrating the present invention:
Example 12.
Inhalation solution.
. .
trospium chloride 0.100 g.
citric acid monohydrate 0.470 g.
trisodium citrate dihydrate 0.530 g.
sodium chloride 0.645 g.
The solution is prepared by successively dissolving the components in water, followed by sterilising filtration and placing into light-protected containers. The pH value of the solution is - about 4.2.

~304369 ExamDle i3 Dosed aerosol.
trospium chloride 0.030 g.
- trichlorofluoromethane/dichloro- ad 15,0 ml.
difluoromethane The aerosol i 3 prepared by grinding the trospium chloride to a particle qize of less than 5 ~m., qu~-pending it in cooled and liquefied propellant ga3 and placing into conventional aerosol containers at about 45 to 50C. The valve on the container is so chosen that, per spray impulse, 0.1 mg. trospium chloride is applied.
ExamPle 14 Dosed aerosol for inhalation.
Formulation per dosage/spray impulse:
0,1 mg. azoniaspironortropanol ester according to one of the chemical Examples 0.02 mg. Span 85 (~orbitan mono- and trifatty acid re~idue ba~ed on oleic acid) 10 ~1. Frigen 11 (trichlorofluoromethane) 20 40 ~1. Frigen 12 (dichlorodifluoromethane).
ExA~le l5 Dosed s~rav for nasal use.
Formulation per dosage/~pray impulse:
2 mg. azoniaspironortropanol e~ter according to one of the chemical Examples 90 ~1. physiological qaline ~304369 In order to confirm the effectivenesq of the active materials according to the present invention, inhalative provocation~ were carried out on awake guinea pig9 with a cholinergically-effective aerosol.
3 x 10 7 mole kg 1 of active material thereby antagonise an asthmatoid respiratory difficulty brought about by an acetyl-~-methylcholine aero~cl 15 minute~ after intra-peritoneal administration. The therapeutic effective-ness of the active materials according to the present inventio~ is markedly ~tronger than that of equimolar dosages of reference substances, such as atropine and isoproterenol.
Method.
Animal material.
animal type: guinea pigs animal strain: Pirbright white origin: Lippische Versuch~tierzucht Hagemann Gmb~ & Co., 4923 Extertal l, Germany ~ex: male 20 body weight: about 500 - 700 g.
acclimatisation time: > 8 days Animal maintenance.
living ~pace: maq~ive con~truction, conventional maintenance room temperature: 22 + 2C.
atmospheric humidity: S0 - 60% relative humidity room illumination: artificial 12 hour rhythm cage~: Macrolon lower part and wire mesh covering with feed and water containers, bedding U3sniff'' from "ssniff Versuchstierdiaten GmbH, 4770 Soe~t, Germany feed: Altromin-MS from Altrogge Spezialfutterwerk, Lage/Lippe, Germany, "ssniff"-MS diet and hay drinking water: tap water ad libitum Trospium chloride = MP 194 = 3-benziloyloxynortropane-8-spiro-1'-pyrrolidinium chloride 0 dehydrotrospium chloride + WG 71 = 3a-benziloyloxynor-tropane-8-spiro-1'-(3'-pyrrolinium~ chloride Substances~ do~aae~ and mode of administration.
test substance: trospium chloride (MP 194) (M.W. 428) dosage: 3 x 10 7 mole ml 1 kg 1 mode of administration: intraperitoneally test sub3tance: dehydrotrospium chloride ~WG 71) (M.W. 426) do~age: 3 x 10-7 1 ml-l k -1 mode of administration: intraperitoneally 0 reference substance: atropine hydrochloride (Serva, M.W. 325.8) do~age 3 x 10-7 1 ml-l k -1 mode of administration: intra~eritoneally reference substance: isoproterenol (Fluka, M.W. 247.723 dosage: 3 x 10 mole ml kg mode of administration: intraperitoneally control substance: physiological saline dosage: 1 ml. kg 1 mode of admini~tration: intraperitoneally further substances: acetyl-~-methylcholine chloride (Sigma, M.W. 195.7) concentrations: 0.0316 g. x 100 ml double distilled water 0.0562 g. x 100 ml "
0.1 g. x 100 ml 1 "
0.178 g. x 100 ml~l 0.316 g. x 100 ml-l "
0.562 g. x 100 ml-l "
mode of administration: 0.5 ml. min by inhalation.
Groupinq.
distribution to the groups: random animals per group: 10 5 group division: as far as possible, on one day, animals of the experimental and control groups are taken into the experiment.
Carryina out of the experiments.
The guinea pigs intended for an experiment are, after an acclimatisation time of at least 8 days, sub-jected twice to an aerosol of 0.1% acetyl-~-methylcholine chloride ~olution ~ince, as is known from experience, during the first two inhalative provocations, the animals react wnth more distinct respiratory disturbances than in the case of the qubsequent provocations (adaptation3.
If, in the ca~e of the two inhalation pha~es, a non-sen~itivity (absence of respiratory disturbances) is observed towards the exposure, these animals are excluded f rom the actual experiment.
For the purpose of aero-~ol provocation, the guinea pigs are placed individually in an inhalation chamber (see Section 3.6 hereinafter) in which 0.5 ml. of solution per minute are atomised as droplet aerosol by means of a special nozzle (Rhema, Hofheim, Germany).
Dependent upon the active material concentration, as well as of a pre-treatment possibly carried out, the lo aerosol exposure leads to a more or less marked dyspnoea, to attacks of coughing and finally to asphyxia and lo~s of consciousness following a tonic-clonic cramp of differing strength. With the help of a ~topwatch, there i9 recorded the time from the commencement of inhalation to the appearance of the asphyctic state:
the animals are immediately removed from the inhalation chamber and, as a rule, recover in a very short period of time (recovery of consciou~ness and normalisation of breathing). If, within 180 ~econds, no dy~pnoea occurs, the inhalation is discontinued.
In order to demonstrate the protective action of the teRt and reference substances, the animal~ in the experiment, 15 minutes before the commencement of the inhalation, are pre-treated with these substances accord-ing to their body weight (control animals correspond-ingly with isotonic sodium chloride solution) and subjected to logarithmically graduated concentrations i304369 of acetyl-~-methylcholine aerosol. One aerosol con-centration is tested per test day the time between the individual aerosol provocations is at least 1 week.
Analvses and a~paratus.
The inhalation chamber is a Plexiglass container specially made for this purpose, the lid of which can be closed in an air-tight manner by means of rubber sealing and grip closure means. The internal measure-ments of the chamber are 285 x 190 x 180 mm., which corresponds to a volume of about 9.75 litreq. The special nozzl~ (Rhema, Hofheim, ~ermany, order No.
504104) i~ fixed to a recess on the lid and ensures a unifonm ~upply of the available chamber space with the aerosol. The provocation solution is ~upplied to the nozzle via an infu~ion pump (Braun, Melsungen, Germany) (0.5 ml./minute) and there atomised with a ~uperpressure of 180 kPa from an attached pre~sure gas bottle (artificial air, KW-free). For reasons of qafety, the aerosol provocation is carried out under a ventilator.
Evaluation.
For each of the tested substances (test, reference and control substance~) there i 8 taXen, in the ca~e of - each investigated active material concentration, the percentage proportion of the animals reactiny with dyspnoea for the calculation of the EC50.
The EC50, as well as the related confidence interval (p >95%), are determined from the probit ~304369 regression lines of the percentage value~ (v. supra) provided with weight coefficientq after line adaptation by the "maximum likelihood" method ~10 iteration~).
Furthermore, there i9 examined the adaptation of the lines to the observed data by means of the chiquadrat test. For the evaluation, a calculation programme is commercially available (Olivetti).
Results.
The tested substance~, trospium chloride a~ well lo a-~ dehydrotrospium chloride, ~how, after intraperitoneal administration, an outstanding broncholytic effect in the case of cholinergically-induced bronchial cramps on - the awake guinea pig. The average effective concen-tration (EC50) of acetyl-~-methylcholine chloride in the solution to be atomised i3, in the case of the control animals, w = 0.00054 (see the following Table 1).
After pre-treatment with trospium chloride or dehydro-trospium chloride, the corresponding EC50 values are w = 0.00286 and w = 0.00173, respectively (see the following Tables 2 and 3).
Atropine and isoproterenol were used as reference substances. For stropine and isoproterenol, there were determined average effective concentration~ of the provocation ~ubstances of w = 0.00138 and w = 0.00145, ; 25 respectively (see the following Tables 4 and 5).
Furthermore, the average effective concentrations EC50 of the provocation ~ubstances 15 minute~ after ~304369 intraperitoneal admini~tration of MP 194, WG 71, atropine and i~oproterenol are illu~trated ~chematic-ally in Fig. 1 of the accompanying drawing~.

TABLE
Control substance: NaCl (W = 0.009) mode of administration: intraperitoneal doqage: 1 ml kg active material: acetyl-~-methylcholine chloride mode of admini-~tration: by aerosol inhalation concentration: see below ~ , active number of animals probit reaction %
material _ analysi~ calculated concentrat~on tested reacting observed 0.000316 10 2 20.00 22.79 0.000562 10 5 S0.00 52.35 0.000750 10 7 70.00 67.81 0.001000 10 9 90.00 80.64 15 0 001780 10 . _ 90.00 95.26 Test for linearity: x = 1.2629 (FG = 3) linearity can be assumed ( ~ 0.05) Result of the Drobit analYsis Average effective concentration of the active material:
; 20 EC50: w = 0.000539 confidence interval (P = 0.95) : 0.000339 - 0.000855 test substance: trospium chloride mode of administration: intraperitoneal dosage: 3 x 10 mol ml 1 kg 1 5 active material: acetyl-~-methylcholine chloride mode of administration: by aerosol inhalation concentration: see below ~ . .
active number of animals probit reaction %
material .._ analysis calculated concentration tested reacting observed .. .7_ , , , _ .... ~
0.000562 10 0 2.50~5.46 0.001000 10 1 lo.oo15.03 0.001780 10 5 50.0032.00 0.003160 10 5 50.0053.87 lS 0.005620 10 ~_ 70.0074.66 ~ correction according to Bli ~9 test for linearity: x = 2.0313 (FG = 3) linearity can be assumed ( ~ 0.05) Result of the probit analvsis 0 average effective concentration of the active material EC50: w = 0.00286 confidence interval (P = 0.95): 0.00147 - 0.00557 test substance: dehydrotrospium chloride mode of administration: intraperitoneal dosage: 3 x 10 mol ml 1 kg 1 S active material: acetyl-~-methylcholine chloride mode of administration: by aerosol inhalation concentration: see below ~ . _ . , active number of animals probit reaction %
material ~_ analysis calculated 10 concentration tested reacting obaerved 0.001000 10 3 30.00 38.74 0.001780 9 6 66.67 50.60 .
0.003160 10 6 60.00 62.35 0.005620 10 7 70.00 73.08 test for linearity: x = 1.3234 (FG = 2) linearity can be assumed (a >O.05) Result of the probit anal~sis average effective concentration of the active material EC50: w = 0.00173 confidence interval (P = 0.95): 0.00031 - 0.00972 reference sub~tance: atropine chloride mode of administration: intraperitoneal do~age: 3 x 10 mol ml 1 kg 1 active material: acetyl-~-methylcholine chloride ~ode of admini~tration: by aero~ol inhalation concentration: see below ..
active number of animals probit reaction %
material . analy~i calculated 10 concentration tested reacting observed 0.000562 . 10 3 30.00 38.93 O.OOlOQ0 10 6 60.00 45.98 .
0.001780 9 5 55.56 53.16 0.003160 10 5 50.00 60.20 0.005620 10 7 70.00 66.95 teRt for linearity: x = 1,6245 (FG = 3) linearity can be aq~umed (a > 0.05) Result of the probit analy~is average effective concentration of the active material EC50 w = 0.00138 confidence interval ~P = O.95): 0.00022 - 0.00888 reference ~ubstance: isoproterenol ~ode of administration: intraperitoneal dosage: 3 x 10 mol ml 1 kg 1 active material: acetyl-~-methylcholine chloride mode of administration: by aeroqol inhalation concentration: see below active number of animals probit reaction %
material -_ analy~is calculated concentration tested reacting observed . _ _ 0.001000 9 3 33.33 36.21 0.001780 8 5 62.50 57.88 0.003160 9 7 77.78 77.28 0.005620 8 88.89 90.30 test for linearity: x2 = 0.1240 (~G - 2) linearity can be assumed (a > 0.05) Result of the p ~
average effective concentration of the active material EC50: w = 0.00145 confidence interval (P = 0.95): 0.00050 - 0.00426 ~304369 Assessment.
The test substances trospium chloride and dehydro-trospium chloride are, lS minutes after intraperitoneal administration, comparable with or Ruperior to the well known parasympatholytics atropine and the ~-sympathomimetic i oproterenol with regard to their broncholytic effectiveness (see Fig.l of the accompany-ing drawings). From the calculations of the concent-rations of acetyl-~-methylcholine chloride which, in each casé, are on average effective, which is necessary for the initiation of a dyspnoea, there can be ascert-ained a greater effectiveness of the test substances, especially of trospium chloride, in comparison with the reference substances.
In order to test the receptor specificity of the compounds according to the pre~ent invention, the specificity of the cholinergic antagonisation must be demonstrated. A model for this is the mea~urement of the anticholinergic effectiveness on isolated tracheal spirals of the guinea pig.
The test substance used was 3-benziloyloxynor-tropane-8-spiro-1'-pyrrolidinium chloride (trospium chloride, MP 194), ipratropium bromide being used as comparison substance.
1. SummarY.
MP 194 is competitively antagonistically effective on the i~olated tracheal spirals of the guinea pig in comparison with acetyl-~-methylcholine chloride. Its strength of activity is thereby equivalent to the reference substance ipratropium bromide.
2. Interro~atory There is to be determined the anticholinergic effectiveness of MP 194 in comparison with the reference substance ipratropium bromide on the isolated tracheal spiral~ of the guinea pig.
3. Method.
3.1. Animal material 3.1,1. animal species: guinea pig 3.1.2. animal ~train~ Pirbright white 3,1,3, origin: Hagemann GmbH & Co., 4923 Extertal 1, Germany 3.1.4. sex: male 3,1.5. body weight: about 500 g.
3.1.6. acclimati~ation time: ~ 8 days 3.2. Animal maintenance 3.2.1. living space: massive construction, conventional maintenance 3.2.2. room temperature: 22 + 2C.
3.2.3. relative atmospheric humidity: 50 + 15%
3.2.4. room illumination: artificial dark/light rhythm in 12 hour intervals 5 3.2.5. animal cages: Makrolon lower part and wire mesh covering with feed and water containers bedding "ssniff" (Versuchstierdiaten GmbH, 4770 Soe~t, Germany) ~304369 3.2.6. feed: "ssniff" guinea pig diet 3.2.7. drinking water: tap water ad libitum 3.3. Substances, dosaging and mode of administration 3.3.1. test substance (test antagoni t) trospium chloride (MP 194) (M.W. 428) solvent: tyrode solution bath concentrations: 1 x 10 9 M/ml. bath solution 3.16 x 10 9 M/ml. bath solution 1 x 10 8 M/ml. bath solution 1 x 10 M/ml. bath solution administration volume: 50 ~1./28 ml. bath solution 3.3.2. reference substance (reference antagonist) ipratropium bromide (Atrovent) (M.W. 412.4) solvent: tyrode solution bath concentrations: 1 x 10 9 M/ml. bath solution 3.16 x 10 9 M/ml. bath solution 1 x 10 8 M/ml. bath solution 1 x lG 7 M/ml. bath solution administration volume: 50 ~1./28 ml. bath solution.
3.3.3. further substances (reference antagonists) 3.3.3.1. acetyl-~-methylcholine chloride (Sigma) (M.W. 195.7) solvent: tyrode solution bath concentrations: 1 x 10 7 M/ml. bath solution 1 x 10 M/ml. bath ~olution 1 x 10-5 M/ml. bath solution 1 x 10 4 M/ml. bath solution 1 x 10 3 M/ml. bath solution 1 x 10 2 M/ml. bath solution 3.16 x 10 2 M/ml. bath solution administration volume: 50 ~1./28 ml. bath ~olution, cumulative 3.3.3.2. tyrode solution as nutrient medium ., . __ component mMole/1. ~tock solution ml. stock solution/
litre tyrode ~olution _ ~. ._ .
~aCl 139.2 58.00 g/l (1 M) 139.2 ml.
10 KCl 2.7 74.56 g/l (1 M) 2.7 ml.
CaC12'2H21.8147.00 g/l (1 M) 1.8 ml.
g 2.6H200.24599.62 g/l (0.49 M) 0.49 ml.
~aHC03 11.9s ' g/l ~0.25 M) 47.6 ml.
~aH2P04.H20 0.4 4.00 g/l (O.03 M) 15,6 ml.
6 126 5.5 _ 1.0 g.

double distilled water ad 1000 ml.
Calcium chloride is hygroscopic. Therefore, the stock solution must be titrated with the help of a Bl rrlarius-(oulter-o-cot~
Chlor-o-Counter ~ , Kipp and Zonen, 6242 Schonberg/Taunus, Germany).
In the mixing of the various ~tock ~olutions, it is to be noted that calcium precipitates out with bicarbonate and phosphate when the solution~ are mixed together in high concentration~ This i~ avoided by ~, ~304369 -6~-first diluting the 1.8 ml. of calcium chloride parent solution with about 100 ml. of double distilled water, the other stock solutions in a measurement flask already having been qubstantially made up with double distilled water and only then adding the calcium solution.
3.4. Grou~inq.
3.4,1. division into group~: random 3.4.2. number of preparations:
of the test substance group: n = 4 (1 x 10 9M) n = 2 (3.16 x 10 M) n = 2 (1 x 10 M) n = 4 (1 x 10 M) of the reference substance 9 group: n = 4 (1 x 10 ~) n = 2 (3.16 x 10 9M) n = 2 (1 x 10 M) n = 4 (1 x 10 M).
3.5. Carrvin~ out of the experiments The guinea pig is stunned by a blow on the neck.
Subsequently, the whole of the trachea is roughly freed beginning from the larynx up to the tracheal bifurcation, removed and transferred to tempered (37C.) and carbo-genised tyrode solution. After ~urrounding connective tissue has been removed as far as possible, the prepar-ation i8 cut up spirally by means of fine scissors at an angle of about 45 and separated into two equal sized " 1304369 sections. After weighing, both preparations are provided proximally and distally with a silk thread.
One thread serves for fixing the preparation by means of a loop to the bottom of the bath and the other is connected via a hook with the transducer above the bath vessel.
Subsequently, the preparations, corresponding to the calibration, are prestreqsed with about 80 mN and equilibrated from 50 - 100 minutes. During the equilib-ration phase, the nutrient solution in the bath vesselsis renewed in 15 minute intervals. As ~oon as the resting mu~cle tonus of the prepar~tion has stabilised, there takes place the cumulative addition of the agoniqt, whereby the addition of the next highest concentration first take~ place when no further increase of contraction is recognisable (plateau). When the maximum contraction height of the preparation is achieved, the cumulative agonist addition is ended and the preparation i8 rinsed.
After a further equilibration phase (v. supra), the cumulative addition of the agonist is repeated but this time in the presence of the test or reference antagonist.
3.6. Analvses and apparatus.
3.6.1. The perfusion part consists of an L-shaped organ bath in the hollow space of which (longer limb) runs a double glas~ spiral through which the nutrient solution is passed into the actual bath vessel (28 ml.
content~ shorter lir~). ~is bath ~essel is divided into two chambers which are, however, connected together by two transverse connection~. Thus, the supply of the organ with Carbogen (95% oxygen and 5%
carbon dioxide) can take place indirectly from the smaller rearmost of the two chambers, whereby the organ does not hang directly in the Carbogen inflow which, inter alia, makes possible a more precise recordal of the organ reactions. The inlet chambers as well as the feeding glas~ spirals are tempered from the outside to 37C. by a separate liquid circulation. This tempering takes place with the help of a "Colora" ultra-thermostat type K (Colora Messtechnik Gm~H, Du~seldorf, Germany) which serves as ther~ostat and pump. In order, in case of need, always to have available ready-for-use nutrient solution, above the organ bath is provided a double-walled storage container in which the nutrient solution is also tempered and carbogenised. This i8 connected via a glass stopcock and a polypropylene tube with double glass spiral in the interior of the organ bath.
3.6.2. The measurement and recording part includes a transducer (Statham-Univer~al-Zelle UC-2, Hugo Sachs Elektronic KG, Hugstetten, Germany). By means of a hanging-in weight, a force of 40 mN is produced on the transducer which pa~ses as electrical signal via a connecting cable to a bridge amplifier. The amplific-ation ls smoothly ~o regulated that the force provided ~304369 ~67-corresponds to a constant value on the scale or an analogou~ value on the millimeter paper of the recorder (dependent upon the ampli~ication, see below).
After fixing the organ, the preparation is prestressed to the doubled mark, corresponding to 80 m~. The recorder connected with the amplifier (Hellige, Freiburg/Breisgau, Genmany) records all analogue signals on thermosensitive paper with millimeter divisions.
The recorder amplification is thereby so regulated that the pulllng force of the weight t40 mN) on the trans-ducer corresponds to an indicator stroke of 4 cm.
(calibration: force produced by means of the weight - 4 cm. on the analogue protocol).
3.7. Evaluation.
The cumulative addition of the agonist leads on the isolated tracheal spiral to a dosage-dependent contraction force increase which is recorded proportion-ally on the analogue recorder (see calibration). From these analogue protocols is carried out the quantitative evaluation of the cumulative dosage action curves according to the method of van Rossum (1963), For this purpose, the absolute measurement data (in [mm]~ is first converted on the basis of the maximum effect (EAm or EAmB), which is taken as being l00oh, into percentage values. By means of non-linear regression, from these data there is determined for each individual preparation the ratio of the molar concentrations of the agonists (quotient = x) which are necessary in order precisely to achieve half of the maximum effect in the pre~ence and absence of the test or reference antagonists of the molar concentration [B] (-log [B] =
5 pAx). On the basis of the fonmula PA2 = PAX + log (x-l) (Ariens and Schild, 1957), there is determined the negative decadic logarithm of the molar antagoni~t concentration (PA2) in the case of which x corresponds r to the value of 2, i.e. in the case of the presence of 10 antagonists in the appropriate molar concentration, th~e molar agonist concentration must be doubled in order to achieve the same effect as without the action of the antagonists. The quality of the antagonism (competitive/non-competitive) i~ tested Rtatis ically 15 on the ba~is of the comparison of the maximum effect in the ab-~ence (EAm) and presence (EAmB) of the ~est or reference antagonists. (t-test with paired arrange-ment). Finally, the difference of the PA2 + 9 between test and reference antagonist is examined for signif-20 icance (t-te~t of two independent ~amples).
4. Result~.
, MP 194 and ipratropium bromide (Atrovent) show on isolated tracheal spirals from the guinea pig a comparable, do~age-dependent antagonism again~t the 25 cholinergic agonist acetyl-~-methylcholine chloride (see Fig. 2 of the accompanying drawings). The PA2 + s determined for MP 194 of 9.26 ~ 0.29 doe~ not differ ~3(~4369 significantly from the PA2 + s for ipratropium bromide of 9.31 + 0.39 (see Table 1).
The quality of the antagonism is competitive not only in the case of MP 194 but also in the case of S ipratropium bromide, on the basis of the comparison between the maximum effects in the case of the absence and presence of the antagonist in question (see the following Table 6).
5. Asse.qsment.
10Thé investigation demonstrates the clear anti-cholinergic effectivene~s of MP 194 on isolated tracheal spirals from the guinea pig and thus supplements the earlier investigations of effectiveness on the awake - animal. The better quantification of the results of the in vitro models also permits the conclusion that MP 194 is, with regard to the strength of action, equal to the reference substance ipratropium bromide (~ee the PA2 value~). Furthermore, on the basis of the investig-ation, a competitive antagoniqm of both substances can be assumed (~ee EAmB/EAm) Table 6.

.__ _ MP 194 ipratropium bromide . . . .
PA2 + s 9.26 + 0.29 9.31 + 0.39 EAmB/EAm + s 1.09 + 0.22 1.10 + 0.24

Claims (14)

1. Process for the preparation of azoniaspironor-tropanol esters of the general formula:- (I) wherein R signifies one of the following radicals:
a) an alkylene radical of the general formula:- in which R3 is a hydrogen atom or an alkyl, benzyl, aryl or alkoxy radical and n i 9 a whole number of from 1 to 4, b) an alkenylene radical of the general formula:- in which R4 and R5, which can be the same or different, are hydrogen atoms or alkyl or alkenyl radicals and n is a whole number of from 1 to 4, c) an azaalkylene radical of the general formula:- in which R6 is a hydrogen atom or an alkyl, alkoxy-carbonyl or acyl radical and n is a whole number of from 2 to 4, d) an oxaalkylene radical of the general formula:--(CH2)n-O-(CH2)n-in which n is a whole number of from 2 to 4, e) an epoxyalkylene radical of the formula:- f) an o-phenylene radical of the general formula:- g) a peri-naphthylene radical of the general formula:- or h) a 2,3-quinoxalinene radical of the general formula:- in which in formulae f) to h), the symbols X and Y, which can be the same or different, are hydrogen atoms or alkyl or alkoxy radicals, and wherein R1 and R2, which can be the same or different, are hydrogen or halogen atoms or alkyl, alkoxy, alkoyl, cyclohexyl, phenyl, alkylphenyl, alkoxyphenyl, halo-phenyl, thienyl or furyl radicals, the alkyl moieties in the said radicals containing up to 6 carbon atoms and being straight-chained or branched, and A ? is the anion of a mono- to tribasic mineral acid, by a) demethylation of tropine to give nortropine, b) reaction of nortropine with a dihalide to give a corresponding azonia compound, and c) esterification of the azonia compound, wherein A) the demethylation of tropine of the formula:

(II) is carried out either by working in a C1-C3-chloro-alkane which contains at least one trichloromethyl radical in the presence of an oxidation agent in basic aqueous solution or the tropine is reacted with a chloroformic acid ester in an inert solvent in the presence of an acid-binding agent to give an 8-alkoxy-carbonylnortropine and this is hydrolysed with a base in aqueous solution, B) the nortropine thus obtained of the formula:- (III) is reacted at ambient temperature for 1 or more days in a dipolar aprotic solvent with a compound of the general formula:-A - R - A
in which A and R have the above-given meanings, in the presence of a secondary or tertiary amine and C) the compound thus obtained of the general formula:- (IV) in which R and A ? have the above-given meanings, is esterified in an anhydrous, dipolar, aprotic solvent with an imidazolide of the general formula:- (V) in which R1 and R2 have the above-given meanings, in the presence of a catalyst, and D) when the radical R contains one or more olefinic double bonds in the azonium ring after passing through steps B and/or C, this unsaturated compound is option-ally hydrogenated in a polar solvent with the help of a noble metal catalyst to give the corresponding saturated compound of general formula (I) in which R
is a radical a) as defined hereinbefore.

2. Process according to claim 1, wherein in the first variant of step A, the demethylation is carried out with potassium ferricyanide, chloroform and sodium hydroxide.

3. Process according to claim 1 or 2, wherein in the first variant of step A, there is used a 1 to 5 fold molar amount of chloroalkane, referred to the tropine.

4. Process according to claim 1 or 2, wherein the reaction temperature in the first variant of step A
is from 20 to 30°C.

5. Process according to claim 1, wherein, in the second variant of step A, the reaction is carried out in chloroform in the presence of an alkali metal hydrogen carbonate.

6. Process according to claim 1, 2 or 5, wherein in step B the ratio of nortropine: amine: dihalide is 1:2:4.

7. Process according to claim 1, 2 or 5, wherein the amine used in step B is diethylamine.

8. Process according to claim 1, 2 or 5, wherein the catalyst used in step C is 4-(N,N-dimethylamino)-pyridine.

9. Process according to claim 1, 2 or 5, wherein the dipolar aprotic solvent used in step C is acetonitrile.

10. Process according to claim 1, 2 or 5, wherein the dipolar aprotic solvent used in step B is dimethylformamide and/or acetonitrile and/or chloroform.

11. Process according to claim 1, wherein in step D
the hydrogenation is carried out in water or in an alcohol containing up to 4 carbon atoms in the presence of platinum dioxide or palladium on active charcoal.

12. Process according to claim 11, wherein the alchol used is methanol.

13. Azoniaspironortropanol esters of the general formula:- (I) wherein R, R1, R2 and A ? have the same meanings as in claim 1, but excluding the following compounds:
azoniaspiro-[3.alpha.-phenylgycoloyloxynortropan-8,1'-pyrrolidine] chloride, azoniaspiro-[3.alpha.-diphenylglycoloyloxynortropan-8,1'-pyrrolidine] chloride, 3.alpha.-phenylglycoloyloxynortropan-8-spiroisoindolinium chloride, 3.alpha.-diphenylglycoloyloxynortropan-8-spiroisoindolinium chloride, 3.alpha.-phenylglycoloyloxynortropan-8-spiro-4'-morpholinium chloride, 3.alpha.-diphenylglycoloyloxynortropan-8-spiro-4'-morpholinium chloride, azoniaspiro-[3.alpha.-cyclohexylphenylglycoloylnortropan-8,1'-pyrrolidine] chloride, azoniaspiro-[3.alpha.-phenylglycoloyloxynortropan-8,1'-piperidine] chloride and azoniaspiro-[3.alpha.-diphenylglycoloyloxynortropan-8,1'-piperidine] chloride.

14. Pharmaceutical compositions containing at least one of the following compounds:
azoniaspiro-[3.alpha.-phenylglycoloyloxynortropan-8,1'-pyrrolidine] chloride, azoniaspiro-[3.alpha.-diphenylglycoloyloxynortropan-8,1'-pyrrolidine] chloride, 3.alpha.-phenylglycoloyloxynortropan-8-spiroisoindolinium chloride, 3.alpha.-diphenylglycoloyloxynortropan-8-spiroisoindolinium chloride, 3.alpha.-phenylglycoloyloxynortropan-8-spiro-4'-morpholinium chloride, 3.alpha.-diphenylglycoloyloxynortropan-8-spiro-4'-morpholinium chloride, azoniaspiro-[3.alpha.-cylcohexylphenylglycoloylnortropan-8,1'-pyrrolidine] chloride, azoniaspiro-[3.alpha.-phenylglycoloyloxynortropan-8,1'-piperidine] chloride and azoniaspiro-[3.alpha.-diphenylglycoloyloxynortropan-8,1'-piperidine] chloride, in association with a pharmaceutically acceptable carrier.