AU604677B2 - Esters of N-alkyl-nortropines and their quaternary derivatives having anti-bronchospastic activity, process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

COMMONWEALTH OF AUSTRALIA 6 Form PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

69-702 r7 Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: This document contins the ameindmets made under and is correct for J~rin Liiic' Related Art: Name of Applicant: LABORATORI GUIDOTTI Spa Address of Applicant: Actual Inventor: Address for Service: Via Trieste, 40, 56100 Pisa, Italy LUIGI TURBANTI and GUIDO CERBAI EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: ESTERS OF N-ALKYL-NORTROPINES AND THEIR QUATERNARY DERIVATIVES HAVING ANTI-BRONCHOSPASTIC ACTIVITY, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM The following statement is a full description of this invention, including the best method of performing it known to us L

I

~lll-- -2-

SPECIFICATION

The present invention relates to a series of novel esters of N-alkyl-nortropines with phenyl-cyclohexen-carboxylic and phenyl-cyclohexen-acetic acids and their quaternary ammonium derivatives with alkyl halides and alkyl sulphates having anti-bronchospastic activity, to processes for their preparation and to pharmaceutical compositions containing them.

The products of the present invention correspond to the following general formula: IRR X

R

C(C x I c-(cII 2 2 n 6 4 0 6 4 5 r wherein n= 0,1 (and when n:-O the double bond is in the position 2-3 and 0 when n=l the double bond is in the position R= -CH 3 -CH2-CH 3 -Cll2--Cl2-Cl1,

-CH(CH

3 -CH3, -CH 2 -C 3,-CH 2 -CH-CH3, -CH(CH 3 2

,-CH

2

-CH

2 -CH2-CH 3 S\ -CH2-CH -(CH X Cl, Br, CH SO '3 4 R being -CH only if n=l More precisely the compounds of the present invention comprise a series of esters of N-ethyl, N-isopropyl-, N-propyl-nortropine with 2-phenyl-2- -cyclohexen-l-carboxylic and 2-phenyl-l-cyclohexen-l-acetic acid, also -the ester of the latter with tropine being included, and the related quaternary ammonium derivatives with alkyl halides and alkyl sulphates, as it results from the general formula I.

The compounds of the invention, particularly the quaternary ammonium derivatives, are endowed with a remarkable anti-bronchospastic action which is revealed both in the in vitro tests and in the animal in vivo after admnistration by venous and inhalatory route, mainly with respect r? to the spasms induced by muscarinic agonists.

R, W AWWWWW -3- By combining these properties with the fact that this quaternary ammonium derivatives are very poorly absorbed by the gastroenteric tract and by the bronchopulmonary one and that they are not capable of passing the hemato-encephalic barrier, the compounds of the invention are consequently efficacious pharmacologic agents used in the therapy of the broncho-obstructive forms, particularly suitable for the administration by inhalatory route, and practically devoid of side effects of atropinic type or of secondary pllarmacological actions.

The interest of the compounds of the invention in the aforesaid therapy is nowadays enhanced by the almost unanimous acknowledgment of the prevailing r8le plaid by the vagous nerve in the bronchial hyperactivity o"o X (Gross and Skorodin, Am. Rev. Resp. Dis, 129, 856, 1984).

O 0 oo000 The use of atropinic derivatives as anti-bronchospastic drugs has been 0000 o0 discovered again in the latter years also owing to a renewed interest for o o 0 Oft cld' the whole class of antimuscarinic compounds which lead to introduce other 0 03 chepnmic.n modificntions in the structure of the natural alkaloids, atropine and scopolamine: thus novel N-alkyl-nortropines and N-alkyl-nor- -scopolamines have been developed as well as the related quaternary ammonium derivatives, among which some compounds have been selected and developed as anti-bronchospastic agents, such as ipratropium bromide (Arzneim. Forsch., 23, 468, 1973; Postgrad. Medic. 51, Suppl. 7, 82-4, 1975) and oxitropium bromide (Arzneim. Forsch., 35, 217, 1985: ibidem, 435), both having been firstly studied as gastric anti-secretion compounds (Arzneim. Forsch., 23, 1334; ibidem 26, 960; ididem 26, 974) and described in two respective patents although being not claimed (U.S.P 3,505,337 and 2,472,861).

The compounds of the present invention are distinguished with respect to the aforesaid compounds firstly under the chemical point of view, since esters of phenyl-cyclohexen-carboxylic or phenyl-cyclohexen-acetic acids are involved, namely compounds which are chemically different from the structure of the natural alkaloids.

The esterification of these acids with N-alkyl-nortropines and the sub- L i n sequent quaternarization of the tertiary bases with several alkyl halides or alkyl sulphates permitted a wide class of compounds to be provided, having remarkable spasmolytic properties with respect to the tracheobronchial tract. These pharmacological properties had not been revealed in a series of basic esters of 2-phenyl-2-cyclohexen-l-carboxylic acid previously disclosed as spasmolytic agents for the gastro-intestinal apparatus Patent 1194280 and U.S. Patent 3,699,109).

From the pharmacological point of view the compounds of the invention show an inhibitory action against the spasms of the smooth tracheo-bronchial muscles as induced by muscarinic agents, which is particularly powerful and long lasting in some of them. Moreover some compounds are characterized with respect to the anti bronchospastic agents of anti- -muscarinic type by being active even against the bronchospams as induced by PAF-acether, which is a powerful mediator of the bronchial asthma recently identified, and the importance of which being more and more evidenced (Page et al., TIPS, 5, 239, 1984; Morely et al., Lancet ii, 1142, 1984). By this action they are qualitatively distinguished over the standard anti-muscarinic compounds, which have no activity with respect to the PAF-acether induced bronchospasm.

Object of the present invention are also the processes for the preparation of this class of compounds consisting in reacting, as shown in the scheme 1, the derivative of an acid selected among 2-phenyl-2-cyclohexen- -1-carboxylic and 2-phenyl-l-cyclohexen-l-acetic acid, suitable to promote a reaction of nucleophylic substitution at the acyl carbon atom, such as an acid chloride or an alkyl ester, with a basic alcohol selected in the group comprising tropine, N-ethyl-nortropine, N-isopropyl- -nortropine, N-propyl-nortropine, having in the alcoholic hydroxyl the nucleophylic group capable of bonding the acyl carbon atom. Such a reaction is carried out in an aprotic solvent, either in the presence or not of an acid acceptor, by isolating from the reaction solvent by means of the standard proceedings, the tertiary aminoesters 5, by purifing them as bases through fractionated distillation under vacuum or as salts with hydrogen halides by crystallization, and lastly by converting these basic esters by treatment with the suitable alkyl halides or alkyl sulphates to the corresponding quaternary ammonium derivatives which are obtained as chrystalline products by isolating them from the reaction mixture after separation by cooling or by adding suitable solvent.

In the scheme 1 there is illustrated the case in which in formula 1 n=O, but the reaction scheme remains unchanged even for n=l, namely starting from the compound 3a: 0 I I

-C-B

a t a a o a c £0 a 0 0 0004 (3a) SCHEME I 0 1I Pa ao 4 0 4 a o 01 i ,-0 C i3

R

N

-C

0 0

R

C

OQ

1 9 -Ir -6wherein Q= -Cl, -OCH e R, R' and X have the above indicated meanings.

3 The intermediate N-alkyl-nortropines prepared according to known processes have the endo configuration indicated by the formula 4 and are chemically defined as endo-8-alkyl-8-azabicyclo- 3.2.11-octane-3-ols.

The esterification of these azabicyclo octaneols under the experimental conditions detailedly described in the examples 2, 5, 6 and 7 lead to the formation of the basic esters of formula 5 having to endo configuration.

If, on the contrary, the esterification is carried out by previously treating the N-alkyl-nortropines with metal potassium and in suitable solvents, according to the conditions described in the example 3, a mixture of the tropinic and pseudotropinic esters is obtained, namely of the endo and eso forms, from which the eso isomer of formula 6 has been obtained.

The quaternarization of the tertiary N of the esters of formula 5 and also of those of formula 6 leads to the formation of the quaternary ammonium derivatives of formula 2 and 2a indicating that the attack of the alkyl group at the nitrogen atom takes place in stereospecific manner in equatorial position.

The configuration of the tertiary basic esters (5 and 6) and of their S. quaternary ammonium derivatives (1 and 2a) have been demonstrated by spectrum analysis: they correspond, according to what has been reported in the literature about the synthesis of like compounds, to the indicated steric formulae.

The 2-phenyl-2-cyclohexen-l-carboxylic acid has been prepared according to the process of the US Patent 3,699,109 whereas the 2-phenyl-l-cyclohexen-l-acetic acid disclosed in J. Chem. Soc. 1936, 71, has been prepared by synthesis according to the known method. Also the N-alkyl- -nortropines have been prepared by synthesis according to the method described in the literature (Le Roy, Keagle, Hartung; J. Am. Chem. Soc., 68, 1608-10, 1946).

The compounds of the invention have been pharmacologically studied by 15 c s means of in vitro and in vivo tests, suitable to evidence the anti-bronchospastic properties of the compounds. It has been found that the quaternary ammonium derivatives show in vitro a powerful action relaxing the spasm of the trachea as induced by methacolin, which action is generally more intense by several magnetude orders with respect to the tertiary basic amminoesters. To this action a remarkable anti-bronchospastic action in the tests in vivo corresponded after administration by i.v. and inhalatory route. Moreover, differently from the available anti-muscarinic anti-bronchospastic compounds, some compounds as above indicated namely the more active in the two indicated tests, demonstrated also an intense activity in inhibiting the bronchospams as induced by PAF-acether and other biological actions of PAF-acether possibly related to the r8le of this asthma mediator.

The power of some terms of the series may be expressed by the comparison values of some experimental parameters reported in the following table 1; (see Eur. Journal of Pharm. 126, 81, 1986) for the most active compound the activity of relaxing the contraction of the isolated trachea of guinea pig, as induced by methacoline, expressed as IC50 is comprised -9 -11 between values of the order of between 1,1 x 10 M and 3.0 x 10 M in comparison with the IC50 of .9 x 9 and 2.0 x -9 M: of atropine and comparison with the IC50 of 6.9 x 10 and 2.0 x 10 M: of atropine and ipratropium bromide.

The experimental values of activity inhibiting the bronchospasm as induced by acethyl choline aerosol in the awake guinea pig expressed as are reported in table 2 (see Eur.Journal of Pharm. 126, 81, 1986) -1 and are of between 8 and 57 nmol kg i.v. in comparison with a -1 values of 68 and 12 nmol kg respectively of atropine and ipratropium bromide.

Moreover the property by which the compounds of the present invention are definitely distinguished over the antibronchospastic compounds already known of antimuscarinic type, is their inhibiting action against the bronchospasm as induced by PAF-acether. The experimental values of the inhibiting action of some compounds of the invention is shown in table 3.(see Agent and Action 19, page 24G0, 1986, Subissi A., The most powerful compou~nd ill this sense, the compound of example 21, in fact inhibits the bronchospasm induced by PAF-acether in the anestetized guinea pig with a ED 50of 0.8 /u1mol.k-g- whereas atropine and ipratropium bromide are fully inactive up to 3 umol/kg.

Table 4, inturn, shows the acute toxicity of the compounds of table 3.

00 -0 .9 If.- ted trachea of guire3. pig precontracted with 5ehao0n MI SFormula R R -CH R'=CR -CH P'=-CH -CR R'=-CH -CR -CH R'=-CR -CH-CR- R'=-CH -(CH )-CH 3 2 3 1 3 2 2 3 212 2 2 3 CR CH r3 3

-CO

J

-CR 2--CR 2 3 3 -CH -CH -CR 2 23

-CR

3

-CR-CR

1 3 -7 2.8x10 -7 3. 5x10 1.7l-6 4.2x10- -5 3. OxlO -10 9. 5x10 -10 6.7x10 3. 3x10- -9 1. 1X10 2.7x10- -1i 3. 0x10 5.Ol-10 -8 3. 2x10 -6 9. OxlO -7 6.3x10 -8 4.6 x10 -7 4. 9x10 -8 4. 5 xlO -5 6. 7xl0 7.OxlO -85.4x10 6.9xl0 8.7X108 8.OxlO -84.5xl10- 3.8xl1 1.2x10 1.9X107 -7 2.4x10 -6 8. 5x10 Atropine sulphate lore tropim bromide 6.9xl1- 2. OxlO9 a 90 0 00f AD 0 0 Q 0 0 0 0 0 0 a a 0 0 LE.2* inhibition of bronchospasm induced by acethyl choline aerosol in guinea pig (ED 50nmol kg i.v.) General Formula R R -CH 3 R'0CH 9-CH R'=-CH -CH R'=-CH -CH -CH R'=-CH -OH-CH 3 3 2 2 3 2 1 3 OH 3CH~ R'=-CH 2-(OH 2 u ©0 0-c x= j -CH -OH 6120 2 3 -CH-CH 1500

CH

3 -O-OH-4i--OH -77700 2 2 5900 ''2000 -~5700 2500 1500 1080 990 -7 5700 2400 5600 ,5600 -:>600 ,600 -75600 5600

-OH

3

-OH-OH

1 3 3 15000 *7400 ''400 -~5700 Atropine sulphate 68 Ipratropime bromide 12 4 CI PCC P a o a

II

PO CI RI~ r, n P ps) IEC RCIR CD r a n Daol

OPCI~O

r) TABLE 3 Inhibition of PAF-acether induced bronchospasm Compounds Example No.

PAF-acether induced bronchospasm in guinea pig i.v. administration at the dose of -1 -1 0.3 umol kg 3 umol kg inhibition Platelet aggregation PAF collagen acether (rabbit prp) from arachidonic acid IC50 /uM 50 0 0 3 11 43 16 28 13 42 14 36 17 64 16 39.1 29.9 7.7 2.4 S100 >100 >>100 >'100 100 >>100 8 atropine sulphate ipratropime bromide 0 7 10 1000 1000 1000 1000 1000 r r r -I -12- TABLE 4 Compounds example n.

13 14 Acute -toxicity approximate value i.p.

123 91 126 107 of LD 5 (mg 1kg )1 in 500 350 800 the mouse os/i.p.

4.1 3.3 2.8 8 atroprine sulphaLe Ipratropime bromide 800 500 600 4.8 18.0 2.4 7.1 -13- Such a compound furthermore inhibits some other biological actions of PAF-acether possibly related with the r81e of this asthma mediator. These pharmacological results, in combination with the poor absorption of the quaternary ammonium derivatives in the gastrointestinal and broncho-pulmonary tracts give place for the compounds of the invention to a very advantageous pharmaco-toxicologic and pharmacokinetic profile by which they are proposed as useful agent in the therapy of the broncho-obstructive form, suitable for the administration by inhalatory route and practically devoid of side effects.

The compounds of the present invention, the processes for their preparation and the pharmaceutical formulations for their therapeutical use are described in the following examples having illustrating but non limiting title.

EXAMPLE 1 Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-isopropyl-8-azabicyclof_3.2.1 -octane (formula 5 with R= -CH(CH3) A solution of 6.5 g (0.038 moles) of endo-8-isopropyl-8-azabyciclo- -13.2.1l-octan-3-ol and 3.87 g (0.038 moles) of triethylamine in 77 ml of 1,2-dichloroethane heated at 350C is added dropwise under stirring with a solution of 8.37 g (0.038 moles) of 2-phenyl-2-cyclohexen-carboxylic acid chloride.

Upon the chloride addition is completed, the temperature of the external bath is brought to 90 0 C and the heating of the reaction mixture is continued under stirring for 20 hours. The reaction mixture is left to cool to room temperature, then maintained at rest in refrigerator at 0 0 C for about 12 hours. By filtration under vacuum a crystalline precipitate is collected, which is washed on the filter with ether and dried. The residue consists of about 80% of the theoretical weight of trietilamine hydrochloride formed during the reaction. The filtrate is then evaporated to dryness under vacuum and the oily residue is treated with 80 ml of ether.

The ether suspension obtained is extracted with 50 ml of 10% diluted HC1 -e -14and the acidic aqueous solution is treated under stirring with portions of NaHCO 3 up to complete neutralization. The resulting suspension is extracted with several portions of ether and the ether extracts are combined, dehydrated over anhydrous Na2SO and evaporated under vacuum.

The oily residue (8.9 g) is distilled under vacuum by collecting the fraction boiling at 171°C at 0.2 mm Hg. There are obtained 8.22 g (yield 60.6%) of unitary aminoester having purity degree of 98% (GLC, CSS).

The structure is confirmed through elemental analysis and NMR spectrum, demonstrating the presence of only the isomer with endo configuration.

The hydrochloride salt (as prepared by precipitation of the ether solution of the base treated with gaseous HC1) melts at 196 0 C (from isopropanol).

EXAMPLE 2 Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-isopropyl-8-azabicyclo- '3.2.1 1-octane (Formula 5 with R= -CH-(CH 3 2 A reaction vessel, having mechanical stirrer and connected to a diso 0 C So tillator, is charged, in the order, with 7 g (0.032 moles) of methyl 2-phenyl-2-cyclohexen-l-carboxylate, 22 mg of CH ONa (0.4 mmoles) as freshly prepared and 4 g (0.0236 moles) of N-isopropyl-nortropine. Under .s continous stirring, the reaction mixture, in form of a homogeneous susa 0t °'00 pension is gradually heated to 140°C it being maintained at a pressure of 35-40 mm Hg. After 10 hours heating, the reaction mixture is taken with ml toluene and the resulting suspension is filtered under vacuum to recover the unreacted N-isopropyl-nortropine The toluene filtrate is extracted with 25 ml of 10% IIC1 and the acid aqueous extract is neutralized with a saturated NaICO solution and extracted with 20 ml 3 dichloromethane. After dehydratation and evaporation under vacuum of the organic solution the desired aminoester is obtained with a purity greater then 98%.

EXAMPLE 3 Eso-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-isopropyl-8-azabicyclo- -octane.

(Formula 6 with R= -CH(CH3) 2 A suspension of 1.15 g (0.0068 moles) of endo-8-isopropyl-8-azabicyclo-r3.2.1.1-octan-3-ol and 0.27 g (0.0069 g.atoms) of metal potassium in 18 ml toluene is maintained under stirring at 110 0 C for 8 hours under nitrogen atmosphere, up to the formation of the potassium salt of the aminoalcohol is completed. At that point the reaction mixture is cooled to room temperature and the suspension, externally cooled with ice and under stirring, is added with a solution of 1.49 g of 2-phenyl-2-cyclohexen-l- -carboxylic acid chloride in 5 ml toluene.

The suspension is refluxed at 120 0 C under stirring for 5 hours. The inorganic precipitate is removed by filtration and the toluene filtrate is vacuum evaporated so as to obtain an oily residue which is purified by dissolving in ether, extracting with 10% diluted HC1, neutralizing of the 00 4 co aqueous solution with NaHCO and extracting again with ether of the ob- 3 000E o0o*, tained dense oil.

1.1 g (yield 45%) of unitary aminoester are obtained in form of dense oil 44 (analysis GLC and CSS), which is identified through elemental and C.el chemico-physical analysis (IR and NMR spectra) as the eso form of the desired aminoester.

•EXAMPLE 4 4 t 4C t Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-ethyl-8-azabicyclo- S3.2.1 ]-octane.

(Formula 5 with R= -CH2-CI- 3 This compound has been prepared starting from 1.5 g (0.01 moles) of endo-8-ethyl-8-azabicyclo-[3.2.1-~-octan-3-ol, 1.01 g (0.01 moles) of triethylamine and 2.25 g (0.01 moles) of 2-phenyl-2-cyclohexen-l-carboxylic acid chloride in 25 ml of 1,2-dichloroethane, according to the process described in the example 1. The product obtained by evaporation of the ether extract can not be vacuum distilled, differently from the example 1, owing to the decomposition and is thus purified by repeated conversion into the hydrochloride salt, a glassy solid, and subsequent i C 00 a o 00 0 O 0 0 0 0 0 0 o 4 00 o0 S0 00 o o ar a C S -16return to the base with NaHCO until the aminoester, which is a dense 3 oil, is not analytically pure (GLC, CSS). The structure and configuration have been confirmed through elemental analysis and NMR spectrum. The ield of pure final product (title 98%) is 58.7%. (hydrochloride):161-162 0

C

from isopropanol) EXAMPLE Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-propyl-8-azabicyclo- F3.2.11.-octane (Formula 5 with R= -CH 2

-CH

2

-CH

3 It is prepared, according to the process described in the example 1, from 4.3 g (0.25 moles) of endo-8-propyl-8-azabicyclo-|3.2.1.]-octan-3-ol, 2.52 g (0.025 moles) of triethylamine and 5.50 g (0.025 moles) of 2-phenyl-2-cyclohexen-l-carboxylic acid chloride in 65 ml of 1.2-dichloroethane.

The purification of the final compound is carried out through the precipitation from the ether solution of the basic aminoester by treatment with gaseous HC1 of the hydrochloride which is crystallized from isopropanol. By displacement in aqueous solution with NaHCO and extraction with ether the desired pure aminoester ,(elemental analysis, GLC and CSS), is obtained in form of a resinous oil, with a yield of 47%, 'ie configuration has been demonstrated through IR and NMR spectra. The crystalline hydrochloride (from isopropanol) melts at 1580C.

EXAMPLE 6 Endo-3-(2-phenyl--cyclohexen-l-acetoxy)-8-sin-methyl-8-azabicyclo- f3.2.1.

-octane (Formula 1 with n= 1, R= -CH 3 X= It is prepared, according to the process described in the example 1, from g (0.039 moles) of endo-8-methyl-8-azabicyclo-[3.2.1.]-octan-3-ole, 3.95 g (0.039 moles) of triethylamine and 13.8 g (0.039 moles) of 2-phenyl-l-cyclohexen-l-acetic acid chloride in 100 ml of 1.2-dichloroethane. The reaction raw product is purified by distillation collecting the fraction boiling at 176-178°C at 0.1 mmHg. 9g of oil (yield 68%) have been obtained corresponding to the desired compound (GLC, CSS and -17elemental analysis); the configuration has been confirmed through the NMR spectrum.

EXAMPLE 7 Endo-3-(2-phenyl-l-cyclohexen-l-acetoxy)-8-sin-isoproyl-8-azabicyclo- S3.2.1. -octane.

(Formula 1 with n=l, R= -CH(CH3 X= It is prepared, according to the process described in the example 1, from g (0.015 moles) of endo-8-isopropyl-8-azabicyclo 3.2.1.-octan- -3-ol, 1.52 g (0.015 moles) of triethylamine and 5.3 g (0.015 moles) of 2-phenyl-l-cyclohexen-l-acetic acid chloride in 25 ml of 1,2-dichloroethano. The desired aminoester is obtained in form of a crystalline solid product melting at 84 0 C (from hexane), with a yield of 54%. Purity, structure and configuration have been confirmed through GLC, CSS, elemental analysis and IR and NRM spectra. The hydrochloride, precipitating o t I' from the ether solution of the base treated with anhydrous gaseous HC1 0 4C melts at 2050C (from isopropanol).

EXAMPLE 8 Endo-3-(2-phenyl-l-cyclohexen-l-acetoxy)-8,8-dimethyl-8-azoniabicyclo- K3.2.1.]-octane iodide.

(Formula 1 with n=l, -CH 3

X=J)

i 4 S 4 g (11.78 mmoles) of endo-3-2-phenyl-l-cyclohexen-l-acetoxy-8-sin-me- CC' thyl-8-azabicyclo-_3.2.1.-octane, (example 6) are dissolved in 20 ml acetonitrile, treated with 9.2 g (4 ml) of methyl iodide (64.2 mmoles) and the resulting solution is heated to 500C in a closed vessel for hours. By cooling a crystalline solid is spontaneously precipitated and is collected by filtration, washed on the filter with ether and purified by crystallization from methanol up to a constant melting point of 253 0

C.

The desired product, pure, is obtained with a yield of 76%. The structure has been confirmed by elemental analysis and IR and NMR spectra.

EXAMPLE 9 Endo-3-(2-phenyl-l-cyclohexen-l-acetoxy)-8-sin-methyl-8-ethyl-8-azoniabicyclo-i[3.2.1. -octane iodide.

1 ULoL vauuiu or as salts with aa 4 al a aa a~ a a4 -18- (Formula 1 with n= 1, R= CH -C2H X=J).

It is prepared according to example 8 from endo-3-(2-phenyl-l-cyclohexen-l-acetoxy)-8-sin-methyl-8-azabicyclo-[(3.2.1.-octane and ethyliodide, giving place to a crystalline product melting at 196 0 C (from ethanol).

The structure has been confirmed by elemental analysis and by IR and NMR spectra.

EXAMPLE Endo-3-(2-phenyl-l-cyclohexen-l-acetoxy)-8-sin-methyl-8-propyl-8-azoniabicyclo-13.2.f -octane iodide (Formula 1 with n=l, R= -CH3, -CH2-CH 3, X=J).

It is prepared according to example 8 from endo-3-(2-phenyl-l-cyclohexen-l-acetoxy)-8-sin-methyl-8-azabicyclo-F3.2.1.T-octane and ethyl iodide, giving place to a crystalline product melting at 194 OC (from isopropanol). The structure is confirmed by the elemental analysis and by the IR and NMR spectra.

EXAMPLE 11 Endo-3-(2-phenyl-l-cyclohexen-l-acetoxy)-8-sin-methyl-8-isopropyl-8-azoniabicyclo-1_3.2.1.-octane iodide.

(Formula 1 with n= 1, R= -CH3, R'=-CH(CH3) 2, X=J).

It is prepared according to example 8 from endo-3-(2-phenyl-l-cyclohexen-l-acetoxy)-8-sin-methyl-8-azabicyclo-f 3.2.1 7-octane and isopropyl iodide, giving place to a crystalline product melting at 228 OC (from isopropanol).

The structure is confirmed by elemental analysis and IR and NRM spectra.

EXAMPLE 12 Eso-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-isopropyl-8-methyl-8-azoniabicyclo-[73.2. 1.-octane iodide.

(Formula 2a; R= -CH(CH 3 2

-CH

3

X=J)

It is prepared according to example 8 from eso-3-(2-phenyl-l-cyclohexen-l-carbonyloxy)-8-sin-isopropyl-8-azabicyclo- 3.2.12.-octane and methyl iodide, giving place to a crystalline solid melting at 213 OC (from isopropanol). The structure is confirmed by elemental analysis and IR and -19- NMR spectra.

EXAMPLE 13 Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-isopropyl-8-methyl-8azoniabicyclo-[_3.2.1. -octane iodide.

(Formula 2 with: R= -CH(CH3) 2, -CH3, X=J).

It is prepared according to example 8 from endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-isopropyl-8-azabicyclo-[_3.2.17 -octane and methyl iodide, giving place to a crystalline solid melting at 237 OC (from isopropanol). The structure is confirmed by the elemental analysis and the IR and NRM spectra.

EXAMPLE 14 Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-isopropyl-8-ethyl-8-azoniabicylo-i_3.2.1.j-octane iodide.

(Formula 2 with: R= -CH(CH3) 2 -CH2-CH3, X=J) It is prepared according to example 8 from endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-isopropyl-8-azabicyclo-r_3.2.1 -octane and ethyl iodide giving place to a crystalline solid melting at 232-232,50C (from absolute ethanol). The structure is confirmed by elemental analysis and IR and NMR spectra.

EXAMPLE Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-isopropyl-8-propyl-8azoniabicyclo-f_3.2.1 ]-octane iodide.

(Formula 2 with: R= -CH(CH -CH -CH -CH X=J).

0.6 g (1.7 mmoles) of endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin- -isopropyl-8-azabicyclo-| 3.2.1._-octane (example 1) are dissolved in 3 ml of propyl alcohol and treated with 0.58 g (3.4 mmoles) of n-propyl iodide. The resulting solution is heated in closed vessel to 800C for hours. After cooling to room temperature, the reaction mixture is maintained at rest at 0°C for 12 hours, during which a crystalline precipitate is formed which is collected by vacuum filtration. The filtrate is evaporated to dryness under vacuum and the oily residue (0.3 g; 0.85 mmoles) is dissolved in 2 ml of propanol treated with 0.29 g (1.7 -e *1* mmoles) of n-propyl iodide and heated as above for 24 hours. After cooling and keeping at rest at 0 0 C for 24 hours, a second portion of a precipitate is obtained which is collected and combined with the first one. The thus obtained product is recrystallized from n-propyl alcohol and 0.42 g of crystalline product are obtained melting at 177 0

C.

The elemental and chemical-physical analysis (CSS and NMR spectra) confirmed the structure and the configuration of the product.

EXAMPLE 16 Endo-3- 2-phenyl-2-cyclohexen-l-carbonloxy)-8,8-di-isopropyl-8-azoniabicyclo- _3.2.11l-octane iodide.

(Formula 2 with: R=Rl= -CH(CH3 2, X=J) It is prepared according to example 8 from endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-isoproyl-8-azobicyclo-F3.2.1 j-octane and isopropyl iodide, giving place to a crystalline solid .ilting at 175-177,5 0

C

(from isopropanol). The structure is confirmed by elemental analysis and by IR and NMR spectra.

EXAMPLE 17 Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-isopropyl-8-n butyl-8azoniabicyclo- F3.2.1 -octane iodide.

(Formula 2 with: R= -CH(CH3 2, -CH -CH -CH2-CH X=J) 3 2' 2 2 2 3 =J It is prepared according to example 8 from endo-3-(2-phenyl-2-cyclohexen-1-carbonyloxy)-8-sin-isopropyl-8-azabicyclo- 3.2.17 -octane and n.butyl iodide, giving place to a crystalline solid melting at 184 0 C (from acetonitrile). The structure is confirmed by elemental analysis and IR and NMR spectra.

EXAMPLE 18 Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-isopropyl-8-iso-butyl- 8-azoniabicyclo- F3.2.1.]-octane iodide.

(Formula 2 with R= -CH(CH -CH -CH(CH X=J) 322 3 2 It is prepared according to example 8 from endo-3-(2-phenyl-2-cyclohexen-1-carbonyloxy)-8-sin-isopropyl-8-azabicyclo- 3.2.1 -octane and isobutyl iodide, giving place to a crystalline solid melting at 166 0 C (from -21acetonitrile). The structure is confirmed by elemental analysis and IR and NMR spectra.

EXAMPLE 19 Endo-3-( 2-phenyl-2-cycloh exen-l--carbonyloxy sin-isopropyl-8-cyclopropyl-8-azonibicyclo- 13.2.1 .3-octane bromide.

(Formula 2 with: R= -CH(CH 3 2, R, X= Br) It is prepared according to example 8 from endo-3-(2--phenyl-2-cyclohexen-l-carbonyloxy)--8-sin-isopropyl-8-azabicyclo-.r_3.2.1. octane and cyclopropyl bromide, giving a crystalline solid melting at 193-195 0 C (from acetonitrile/ether The structure is confirmed by elemental analysis and IR and NMR spectra.

EXAMPLE Enido-3- (2-ph enyl-2-cyclohexen--l-carbonyloxy )-8-sin-ethyl-8-methyl-8-azoniabicyclo-f3.2..f-octane iodide.

(Formula 2 with: R= -CII -CII3 l' -CHII X=J) It is prepared according to example 8 from endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-.ethiyl-8-azabicyclo.[_3.2.lfl-octane and methyl iodide, giving a crystalline solid melting at 2191C (from acetonitrile).

The structure is confirmed by cmental anolyoire and 1.11 and NMI1 spct~ra.

EXAMPLE 21 Endo-3- (2-phienyl-2-cycloh exeni-l-carbonyloxy 8-di-ethyl-8-ethyl-8-azoiiiabicyclo-13.2.lj2-octanie iodide.

(Formula 2 with R= -CH CH -CH -CH X=J) 2 3 2 3 It is prepared according to example 8 from endo-3-(2-phenyl-2-cyclohexenlcroyoy--i-til--zbcco1321 otn and ethyl iodide, giving a crystalline solid melting at 238 0 C (from acetonitrile).

The structure is confirmed by elemental analysis and IR and NMR spectra.

EXAMPLE 22 Endo-3- 2 -phenyl-2-cyclohexen-l-carbonyloxy )-8-sin-ethyl-8-n. propyl-8-azoniabicyclo- 13.2.1. -octane iodide.

(Formula 2 with: R= -CII 2_C11I -CHLI -CH I -CHLI X=J) It is prepared according to example 15 from endo-3-(2-phenyl-2-cyclohex- -22en-l-carbonyloxy)-8-sin-ethyl-azabicyclo-]3.2.l].-octane and n-propyl iodide, giving a crystalline solid melting at 1781C (from n.propanol). The structure is confirmed by elemental analysis and IR and NMR spectra.

EXAMPLE 23 Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy )-8-sin-ethyl-8-isopropyl-8-azoniabicyclo- 3.2.1.[-octane iodide (Formula 2 with: R1= -CH -CH -CH-(CH 2 3 3 2 It is prepared according to example 8 from endc-3--(2-phenyl-2-cyclohexeni-l-c arboniyloxy) -8-s in-etLhyl-8-azab icyc lo-rV3 .2.1 j -oc-tanie and isopropyl iodide, giving a solid melting at 183-1850C (from isopropanol). The structure is confirmed by elemental analysis and IR and NMR spectra.

EXAMPLE 24 Endo-3-( 2-phenyl-2-cyclohiexen-l-carbonyloxy )-8-sin-etLhyl-8-isopropyl-8-azoniabicyclo-[3~.2.1.]-octane iodide (Formula 2 with: R= -CHI -CH -CHi 2-(CH3 2, X=J) It is prepared according to example 8 from endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin--ethyl-8-azabicyclo-1_3.2.1 .J-octane and isopropyl iodide, giving a crystalline solid melting at 184-1860C (from isopropanol). The structure is confirmed by elemental analysis and IR and NMR spectra.

EXAMPLE Endo-3-( 2-pheniyl-2-cyclohexen-l-carbonyloxy)-8-sin-propyl-8-methyl-8-azoniabicyclo-[.3.2.1.] -octane iodide (Formula 2 with: R= -CH -CH -CH R XJ 2 2 3) -C 3 1 It is prepared according to example 8 from endo-3-(2-phenyl-2-cyclohexeni-1-carbonyloxy )-8-sin-propyl-8-azabicyclo- F 3.2.1] -octane and methyl iodide, giving a solid melting at 22700 (from isopropanol). The structure is confirmed by elemental analysis and IR and lIMR spectra.

EXAMPLE 26 Endo-3- (2-phenyl-2-cycl ohexen-l-carbonyloxy )-8-sin-propyl-8-ethyl-8-azoniabicyclo- L3.2.1 7j -octane iodide (Formula 2 with: R= -CH1 2 -CH 2 -CM 3 -CH 2 -CH 3

X=J)

-23- It is prepared according to example 8 from endo-3-(2-phenyl--2-cyclohexen-l-carboniyloxy )-8-sini-propyl-8-azabicyclo- 13.2.1 -octane and ethyl iodide, giving a solid melting at 172-1741C (from acetonitrile). The structure is confirmed by elemental analysis and IR and 1NMR spectra.

EXAMPLE 27 Endo-3-(2-phenyl-2-cyclohiexen-l-carbonyloxy 8-di-propyl-8, 8-azoniabicyclo-[3.2.lJ.-octane iodide (Formula 2 with: R= -CH 2-CH 2-CH 3YR'= -CH 2-CH 2-CH 3X..J) It is prepared according to example 8 from endo-3-(2-phenyl-2-cyclohexeni-l-carbonyloxy)--8-sin-propyl-8-azabicyclo-F_3.2.1.1-octane and n.-propyl iodide, giving a crystalline solid melting at 165-1661C (from acetonitrile). The structure is confirmed by elemental analysis and IR and NMR spectra.

EXAMPLE 28 Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy )-8-sin-propyl-8-isopropyl-8azoniabicyclo- 3.2.l -octane iodide (Formula 2 with: R -CHI -C11 -CHII -CH(CH 2 2 3 3 2 It is prepared according to example 8 from endo-3-(2-plienyl-2-cyclohexen-l-carbonyloxy)-8-sin-propyl-8-azabicyclo-1 3.2.1 ]-octane and isopropyl iodide, giving a crystalline solid melting at 168-170 0 C (from acetonitrile). The structure is confirmed by elemental analysis and IR and NRM spectra.

EXAMPLE 29 Endo-3- (2-phenyl-2-cyclohexen-l-carbonyloxy )-8-sin-propyl-8-n .butyl-8-azoniabicyclo-F 3.2.l-.j-octane iodide.

(Formula 2 with: R= -CH1 2 -CII 2 -C11 3 Y -CH 2 -CH 2 -C-1 2 -CH1 3

X=J)

It is prepared according to example 8 from endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-propyl-8-azabicycle- F 3.2.1l.i-octane and n.butyl iodide, giving a solid melting at 187 0 C (from acetonitrile). The structure is confirmed by elemental analysis and IR and NRM spectra.

EXAMPLE Endo-3- (2-phenyl-2-cyclohexen-l-carbonyloxy )-8-sin-propyl-8-isobuty1-8-a- -24zoniabicyclo-13.2.1 a -octane iodide.

(Formula 2 with: R= -CH1 2 -CH 2 -CH 3 -CHi -CH(C-3 21 X=J) It is prepared according to example 8 from endo-3--(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-sin-propyl-8-azabicyclo- F_3.2. l.j.-octane and isobutyl iodide, giving a solid melting at 153-155'C (from isopropanol). The structure is confirmed by elemental analysis and IR and NMR spectra.

EXAMPLE 31 Endo-3- (2-phenyl-l-cycloh exen-l-acetoxy )-8-sin-isopropyl-8-methyl-8-azoniabicyclo-7-3.2.lTI -octane iodide.

(Formula 1 with: n= 1, R= -CH(CH 3 2f -CH 3

X=J)

It is prepared according to example 8 from endo-3-(2-phenyl-l-cycloilexen-l-ace-toxy)-8-sin-isopropyl-8-azabicyclo-F3.2.lj]-octane and methyl iodide, giving a crystalline solid melting at 248-250 0 C (from methanol).

The structure is confirmed by elemental analysis and IR and NMR spectra.

EXAMPLE 32 Endo-3- (2-phenyl-l-cyclohiexen-l-,cctoxy )-8-sin-isopropyl-8-ethyl-8-azoniabicyclo-13.2.l17-octane iodide.

(Formula 1 with n= 1, R= -CI-(CH 3)2' -CH- 2CH3 X=J) It is prepared according to example 8 from endo-3-(2-phenyl-l-cyclohexen-l-acetoxy)-B-sin-isopropyl-8-azabicyclo-[73.2.ll..octane and ethyl iodide, giving a crystalline solid melting at 256-2591C (from ethanol). The structure is confirmed by elemental analysis and Ill and NMR spectra.

EXAMPLE 33 Endo-3- (2-phenyl-l-cyclohexen-l-acetoxy )-8-sin-isopropyl-8-propyl-8-azoniabicyclo- Fi 3.2.4j -octane iodide (Formula 1 with n= 1, R= -CH(CH 3 -CH 2 -CH 2 -CH 3 P X=J) It is prepared according to example 15 starting from endo-3-(2-phenyl-lcylhxnlaeoy--i-spopl8aaiyl-F3211otn and n-propyl iodide, giving a crystalline solid melting at 249 0 C (from n-propanol). The structure is confirmed by elemental analysis and lB and NMR spectra.

EXAMPLE 34 -0 a q b' W 0 01 ce) "rY 0 H LO 00 *R o H, 0. N C'J C\J Co a r 4 jEndo-3-( 2 -phenyl--l-cyclohexen-1-acetoxy 8-di-isopropyl--8-azoniabicyclo- 13.2.1 .7-octane iodide.

(Formula 1 with n= 1, R= -CH(CH -CH(CH 3 2 3 2 it is prepared according to example 8 from endo-3-(2-phenyl-l-cyclohexen-l-ace-toxy)-8-sin-isopropyl-8-azabicyclo-r_3.2.1 7 -octane and isopropyl iodide, giving a crystalline solid melting at 248 0 C (from isopropanol).

The structure is confirmed by elemental analysis and IR and NMR spectra.

EXAMPLE Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy )-8-sin-ethyl-8-methyl-8-azonibicyclo-1 -3 .2.1.1 -octane methylsulphate.

(Formula 2 with R1= -CH 2-CH 3 R'=-CH 3, X= -CH 3SO4 A solution of 0.72 g (2.12 mmoles) of the basic aminoester of example 4 in 2 ml benzene is treated at room temperature with 0.504 g (0.38 ml) of dimethyl sulphate (4 mmoles). The mixture is maintained at rest at room temperature for 12 hours, during which, starting from the second hour, a crystalline product precipitates, which, upon being collected and purified by crystallization from benzene, is in form of colorless crystals, with melting point of 12900 (with decomposition). The structure is con- Olt* firmed by elemental analysis and IR and NMR spectra.

gnde 3 (2 phenyl-2 syG!91hcxen I caarbonyley) 8,8 S znaly! 1 :l-octane methylsulphate (Formula 2 with: R= -CH -CH X=-CHi so It is prepared according to example 35, s ing from endo-3-(2-phenyl-2- -cyclohexen-l-carbonyloxy)-8-si ethyl-8-azabicyclo-1 _3.2.1J -octane and dimethylsulphate, givI a crystalline, straw-yellow solid, melting at 22000 (fro enzene). The structure is confirmed by elemental analysis EXAMPLE 3b Endo-3-(2-phenyl-2-cyclohiexen4-lcarbonyloxy )-8-sin-isopropyl-8-methyl..azoniabicyclo- FI3.2.1 .J-octane methylsulphate

~&AL,

44 (Formula 2 with: R= -CH ,X -CH SO ks 3'2' 3 3 4 -26- It is prepared according to example 35, starting from endo-3-(2-phenyl-cyclohexen-1--carbonyloxy)-8-sin-isopropyl -8-azabicyclo-i3.2.1. ]-octane and dimethylsulphate. It is a solid melting at 132 0 C from benzene. The elemental analysis corresponds to the structure looked for.

EXAMPLE 3-*l Endo-3- (2-phenyl-2-cyclohexen-1-carbonyloxy )-sin-propyl- -8-methyl-8-azoniabicyclo-[3.2.1. 3-octane methylsuiphate.

(Formula 2 with: R= -CH 2

CH

2

CHR

3 -H X= -CH 3 SO 4 It is prepared according to example 35, starting from endo-3- (2-phenyl-2-cyciohexen-1--carbonyloxy) -8-sin-propyl- -8-azabicyclo-[3.2.1. ]-octane and dimethylsulphate. it is a crystalline solid, melting (with decomposition) at 121 0 -123 0 C (from benzene). The elemental analysis corresponds to the structure foreseen.

EXAMPLE 312 Endo-3- (2-phenyl-2-cyclohexene-1-carbonyloxy )-8-sin- -isopropyl-8-methyl-8-azoniabicyclo-[3.2.1. ]-octane bromide.

(Formula 2 with: R= -CH(CH 3 2 R'=CH 3 X=Br) It is prepared according to example 8 from endo-3--(2- -phenyl- 2 -cyclohexen-l-carbonyloxy)8-sinisopropyl8azabicyclo-[3.2.1.]-octane and methyl bromide; a crystal- <line solid is obtained melting at 262 CG (from ethanol).

The structure is confirmed by the elemental analysis and 4 by the IR and NMR spectra.

EXAMPLE 23$9 Endo-3-( 2 -phenyl- 2 -cyclohexen-1-carbonyloxy-8sin- -isopropyl-8-ethyl-8-azoniabicyclo-[3.2.1. 1-octane bromide.

(Formula 2 with: R= -GI-(GH 3 2 3 -GH 2 -CH 3 X=Br) It is prepared according to example 8 from endo-3-(2- -phenyl-2-cyclohexen-l-carbonyloxy 8 -sin-isopropyl-8- -azabicyclo-[3.2.11-octane and ethyl bromide; a crystalline solid is obtained melting at 182-183 0 C (from absolute ethanol). The structure is confirmed through elemental analysis and IR and NMR spectra.

EXAMPLE 4Q \U4' Eno3(-hnl2ccoee--abnlx)8snehl8 -methyl-8-azoniabicylo-[3.2.1. 1-octane bromide.

-27-

I

(Formula 2 with: R= -CH 2

-CH

3

CH

3 X=Br) 1 It is prepared according to example 8 from endo-3-(2-phenyl S-2-cyclohexen-l-carbonyloxy)-8-sin-ethyl-8-azabicyclo- [3.2.1.]-octane and methyl bromide; a crystalline solid is obtain)d m:lting at 226-228 0 C (from ethanol). The structure s confirmed through elemental analysis.

EXAMPLE 4.1 Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8,8-diethyl-8azoniabicyclo-[3.2.1.-octane bromide.

(Formual 2 with: R= -CH 2

-CH

3

-CH

2

-CH

3 X=Br) It is prepared according to example 8 from endo-3-(2-phenyl -2-cyclohexen-l-carbonyloxy)-8-sin-ethyl-8-azabicyclo- [3.2.1.]-octane and ethyl bromide; a crystalline solid is obtained melting at 198 0 C (from ethanol). The structure is confirmed through elemental analysis and the IR and NMR spectra.

EXAMPLE 42, Example of a pharmaceutical composition suitable for the administration by inhalatory route of advisable doses of the compounds of the invention.

Compound of the example 21 mg 12 sorbitantrioleate (Arlacel 85) mg 3 Freon 11 mg 5235 Freon 12 mg 15750 Total mg 21000 Such a pharmaceutical preparation, contained in anatomizing device provided with dosing valve, permits the administration of single measured doses from 20 to ug of active ingredient.

Like pharmaceutical compositions can be prepared with the other compounds of the invention.

The daily posology for the therapeutical use is of 2 to 3 sprays, each of an unitary dose, 3 to 4 times a day.

L h

Claims (5)

1. N-alkyl-nortropine esters with phenyl-cyclohexen- carbonylic and phenyl-cyclohexen-acetic acids and their quaternary ammonium derivatives, having general formula: 2 wherein n= 0,1 (and when n=O the double bond is in the 2-3 position, and when n=l the double bond is in the 1-2 position) CR= -CH 3 CH 2 CH 3 -CH 2 CH 2 CH 3 -CH(CH 3 )21 -CH 2 -CH(CH 3 2 R' is absent or represents H, -CH 3 ,-CH 2 -CH 3 -CH 2 -CH 2 CH 3 -CH(CH 3 2 CH 2 -CH 2 CH 2 -CH 3 CH 2 -CH(CH 3 2 X =Cl, Br, I, CH S04 with the proviso that when R= -CH 3 n=l.

2. Esters according to claim 1, characterized by being: Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-syn- isopropyl-8-azabicyclo-13.2.l. ]-octane Exo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)8-syn-isopropyl- N 8-azabicyclo-[3.2.1. 1-octane Endlo-3-( 2-phenyl-2-cyclohexen-l-carbonyloxy)-8-syn-ethyl-8- azabicyclo-t3.2.l. I-octane Endo-3-( 2-phenyl-2-cyclohexen-l-carbonyloxy)-8-syn-propyl-8- azabicyclo-II3.2.l. ]-octane Endo-3-( 2-phenyl-l-cyclohexen-l-acetoxy)-8-syn-methyl-8- azabicyclo-[3.2.l. 1-octane I0 29 Endo-3-(2-phenyl-1-cyclohexel)-l-acetoxy)-8-syfl-isopropy2-8- azabicyclo-[3.2.1. ]-octane Endo-3- (2-phenyl-l-cyclohexen-1-acetoxy)

8-dime thyl-8- azoniabicyclo-[3.2.1. 1-octane iodide Endo-3-( 2-phenyl-l-cyclohexel--acetoxy)-8-syfl-methyl-8- ethyl-8-azoniabicyclo-[3.2.1. ]-octane iodide Endo-3-( 2-phenyl-l-cyclohexen-1-acetoxy)-8-syl-methyl-8- propyl-8-azoniabicyclo-[3. 2 1-octane iodide Exo-3-( 2-phenyl-2-cyclohexen-1-carbonyloxy)-8-syl-isopropyl- 8-methyl-8-azoniabicyc-o-13. 2 1-octane iodine Endo-3-( 2-phenyl-2-cyclohexen-1-carbonyloxy)-8-syn- isopropyl-8-methyl-8-azoniabicyclo-[3. 2 1-octane iodide Endo-3-( 2-phenyl-2-cyclohexen-l-carbonyloxy)-8-syn- isopropyl-8-ethyl-8-azoniabicyclo-[3, 2 1-octane iodide Endo-3-( 2-phenyl-l-cyclohexen-l-carbonyloxy)-8-syn- isopropyl-8-propyl-8-azoniabicyclo-[3. 2 1-octane iodide Endo-3-(2-phenyl-2-cyclohexenl-carbonyloxy)-8,8- di isopropyl-8-azoniabicyclo-[3.2.1.1-octane iodide Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-syn- isopropyl-8-n.butyl-8-azoniabicyclo-[3.2.1. 1-octane iodide Endo-3-(2-phenyl-2-cycJlohexen-l-carbornyloxy)-8-syn- isopropyl-8-iso-butyl-8-azoniabicyclo-13.2.1. 1-octane iodide Endo-3-( 2-phenyl-2-cyclohexen-l-carbonyloxy)-8-syn- isopropyl-8-cyclopropyl-8-azoniabicyclo-[3. 2 1-octane bromide Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-syn-ethyl-8 methyl-8-azoniabicyc-o-[3.2.1. 1-octane iodide Endo-3- (2-phenyl-2-cyclohexen-1-carbonyloxy ,8-diethyl-8- azoniabicyclo-[3.2.l. 1-octane iodide Endo-3-( 2-phenyl-2-cyclohexen-l-carbonyloxy)-8-syn-ethyl-8- n-propyl-8-azoniabicyclo-E 3.2.1. 1-octane iodide Endo-3-( 2-phenyl-2-cyclohexen-1-carbonyloxy)-8-syn-ethyl-8- isopropyl-8-azoniabicyclo-[3. 2 1-octane iodide Endo-3-( 2-phenyl-2-cyclohexen-l-carbonyloxy)-8-syn-ethyl-8- isobutyl-8-azoniabicyclo-[3. 2 1-octane iodide Endo-3-( 2-phenyl-2-cyclohexen-l-carbonyloxy)-8-syn-propyl-8- -~~methyl-8-azoniabicyclo-13. 2 1-octane iodide 30 Endo-3- (2-phenyl-2-cyclohexen-l-carbonyloxy) -8-syn-propyl-8- ethyl-8--azoniabicycle-[3.2.1. 1-octane iodide Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8,8-dipropyl-8- azoniabicyclo-[3.2.1. 1-octane iodide Endo-3-( 2-phenyl-2--cyclohexen-l--carbonyloxy)-8-syn-propyl- 8-isopropyl--8-azoniabicyclo-[3.2.1. ]-octane iodide Endo-3-( 2-phenyl-2-cyclohexen-1-carbonyloxy)-8-syn-propyl- 8-n.butyl-8-8-azoniabicyclo-[3.2.1. 1-octane iodide Endo-3-(2-phenyl-2-cyclohexen-l-carbonyloxy)-8-syn-propyl- -isobutyl-8-azoniabicyclo-[3.2.1. ]-octane iodide Endo-3-( 2 -phenyl-l-cyclohexen-1-acetoxy)-8-syn-iospropyl- 8-methyl-8-azoniabicyclo-[3.2.1. ]-octane iodide Endo-3-( 2 -phenyl-l-cyclohexen-1-acetoxy)-8-syn-isopropyl- 8-ethyl--8-anzoniabicyclo-[3.2.1. 1-octane iodide Endo-3-(C2-phenyl-l--cyclohexen-i--acetoxy )-8-syn-i sopropyl- 8-propyl-8-azoniabicyclo-j3.2.1. 1-octane iodide Endo-3-( 2-phenyl-1-cylohexen-1-acetoxy)-8,8-diisopropyl-8- azoniabicyclo-[3.2.1.]-octane iodide Endo-3-( 2 -phenyl- 2 -cyclohexen-1-carbonyloxy)-8-syn-methyl- 8-ethyl-8-azoniabicyclo-[3.2.1. ]-octane methylsuiphate Endo-3-( 2-phenyl-2-cyclohexen-1-carbonyloxy)-8-syn- isopropyl-8-methyl-8-azoniabicyclo-[3.2.1. 1-octane methylsuiphate Endo-3-( 2 -phenyl- 2 -cyclohexen-1-carbonyloxy)-8-syn-propyl- 8-methyl-8-azoniabicyclo-[3.2.1. 1-octane methylsuiphate Endo-3-( 2-phenyl-2-cyclohexen-1-carbonyloxy)-8-syn- isopropyl-8-methyl-8-azoniabicyclo-[3.2.1. 1-octane bromide Endo-3-( 2-phenyl-2-cyclohexen-1-carbonyloxy)-8-syn- isopropyl-8-ethyl-8-azoniabicyclo-[3.2.1. 1-octane bromide Endo-3-( 2-phenyl-2-cyclohexen-l-carbonyloxy)-8-syn-ethyl-8- methyl-8-azoniabicyclo-[3.2.1. 1-octane bromide Endo-3-(2-phenyl-2-cyclohexen--carbonyloxy)-8,8-diethyl8 azoniabicyclo-[3.2.1. 1-octane bromide 41it jK 31 3. A process for the preparation of the esters according to claim 1, characterized in that a derivative of an acid selected among 2-phenyl-2-cyclohexen- 1-carboxylic acid and 2-phenyl-cyclohexen-l-acetic acid, adapted to promote a reaction of nucleophilic substitution at the acylic carbon atom, is reacted with a basic alcohol, selected in the group comprising tropine, N-ethyl- nortropine, N-isopropyl-nortropine, N-propyl-nortropine, the reaction being carried out in an aprotic solvent; the resulting tertiary aminoester is isolated from the reaction solvent; said tertiary aminoester is purified and (d) possible converted into a quaternary ammonium derivative with an alkylhalide or an alkyl sulphate. 4. A process according to claim 3, characterized in that the step is carried out in the presence of an acid acceptor. A process according to claim 4, characterized in that said acid acceptor is triethylamine. 6. A process according to claim 3, characterized in that said derivative of 2-phenyl-2-cyclohexen-l-carboxylic acid or of 2-phenyl-2-cyclohexen-l-acetic acid is selected among an acid chloride and an alkyl ester. 7. A process according to claim 3, characterized in that said purification of said tertiary aminoester is carried out as the base by fractionated distillation under vacuum. 8. A process according to claim 3, characterized in that said purification of said tertiary aminoester is carried out as the salt with halogen hydride acids by crystallization. 32

9. A process according to claim 3, characterized in that said quaternary ammonium derivative is isolated from the reaction mixture after separation by cooling or by solvent addition. Pharmaceutical composition comprising as the active ingredient a compound according to claim 1, together with pharmaceutically acceptable excipients.

11. Pharmaceutical composition according to claim in a form suitable for administration by the inhalatory route. DATED this 21st day of February, 1990 LABORATORI GUIDOTTI S.p.A. WATERMARK PATENT TRADEMARK ATTORNEYS, 2nd Floor, "The Atrium", 290 Burwood Road, Hawthorn, Victoria, 3122, AUSTRALIA. LCG:EK(12:7) W, A 0*