SK452390A3 - Esters of thienyl carboxylic acids and amino alcohols, process for their preparation, intermediate products, pharmaceutical compositions containing same and their use - Google Patents

Abstract

The new compounds of formula (I) (where A, R1, Ra and R2 are defined in the description) can be manufactured by processes known per se and used as the active ingredients of drugs.

Description

Esters of thienylcarboxylic acids and aminoalcohols, process for their preparation, intermediates, pharmaceutical compositions containing them and their use

Technical field

The invention relates to thienylcarboxylic acid esters and aminoalcohols, to a process for their preparation, to pharmaceutical compositions containing them and to their use.

BACKGROUND OF THE INVENTION

Parasympathetic nerves provide the dominant bronchoconstrictive neural control of airway smooth muscle in humans. Cholinergic neural tone is a major reversible component of chronic obstructive pulmonary disease (COPD) where it also contributes to nocturnal asthma attacks through daytime irritation of tonus vagus. The duration of action of current anticholinergic drugs is sometimes insufficient to provide satisfactory maintenance of therapy in patients or to control nocturnal asthma. Therefore, there is a clinical need for the development of a new anticholinergic active substance which has a longer duration than the known drugs.

It is an object of the present invention to provide quaternary ammonium compounds which are long-acting anticholinergic bronchodilators for the treatment of patients with reversible obstructive airway disease. These compounds inhibit exogenous acetylcholine (Ach) -induced bronchospasm three times more efficiently than, for example, ipratropium bromide known in the art and exhibit a considerably longer duration of action than the same dose of ipratropium bromide. The duration of protection against cholinergic neural bronchoconstriction is the most significant therapeutic effect of these substances.

SUMMARY OF THE INVENTION

The present invention provides esters of thienylcarboxylic acids and aminoalcohols of formula (I)

2 (i)

_R 1 -C-CO-OA i

where

A is a group of formula II

where

Q represents one of the divalent groups -CH ₂ -CH 2, -CH ₂ -CH ₂ -CH 2 -, -CH = CH-,

-CH-CHa

R is C 1 -C 4 alkyl optionally substituted by halogen or hydroxy,

R 'is C 1 -C 4 alkyl, and R and R' can be taken together to form a C 4 -C 6 alkylene moiety, whereby the positive charge of the nitrogen atom is offset by the anion equivalent of X ⁽ ''

R ¹ is thienyl, phenyl, furyl, cyclopentyl or cyclohexyl, each of these radicals to be substituted by methyl radicals, phenyl and thienyl also chlorine or fluorine

R2 represents a hydrogen atom, a hydroxy group, an alkoxy group or an alkyl group, both having 1 to 4 hydrogen atoms

-3R ^a is a hydrogen atom, fluorine atom, chlorine atom or methyl.

Preferred compounds of the invention are those wherein R ¹ is 2-thienyl. Preferred compounds are those wherein R ² is hydroxy.

Other preferred compounds of the invention include those wherein A is

R and X ⁽⁾ are as defined in claim 1 and R 'is as defined in claim 1, except for a hydrogen atom.

Particularly preferred are compounds wherein R1 is 2-thienyl and A is or

In the form of 3α-, wherein X ^w represents an anion equivalent, preferably Br or CH 3 SO 3.

in the form of 3α-, such as metobromides or methanesulfonates.

The compounds of the invention are prepared by the ester of the formula IVa

R ' _r 1_C_C0-0R

I

R ² (IV) wherein R is C 1 -C 4 alkyl and R 1, R ² and R 3 are as defined above, is subjected to the transesterification with the amino alcohol of formula V

CH.

CH kde

HO-CH

CH.

Q Q

CH

And Q is = NR or = NH, in an inert organic solvent or melt, in the presence of an ester exchange catalyst, and the compound of formula VI obtained is

(a) when Q is = NR, quaternize by treatment with a reactive mono derivative of an alkane of the formula Z- (C 1 -C 4 alkyl), wherein Z is an easily cleavable group, or

b) when Q is = NH, quaternize with a disubstituted alkane of formula Z- (C 4 -C 6 alkylene) -Z without isolation of the intermediates.

The present invention also relates to compounds of formula VI wherein Q, Q ', Q, R ^a , R 1 and R 6 are as defined above, as well as acid addition salts thereof with the exception of phenyl-2-thienylglycol, 2,2- dithienylglycolic acid and 3,3'-dithienylglycolic acid.

Furthermore, The present invention also compounds of formula VI, such as: _ _{_}

-----WITH

\

A pharmaceutical composition with anticholinergic effects, for the treatment of respiratory diseases and sinus bradycardia, comprising a compound of the invention together with adjuvants and / or carriers.

The compounds of the invention are used for the preparation of pharmaceutical compositions with anticholinergic activity, further for the treatment of respiratory diseases and sinus bradycardia.

Quaternary derivatives are particularly suitable for therapeutic use, while tertiary compounds are also useful as intermediates.

The compounds of the invention are cholinergic substances with a strong and long-lasting effect. When doses of the order of pg are administered by inhalation, an effect time of up to 24 hours can be achieved. The toxicity is approximately the same as that of the commercially available Ipratropium bromide product, but the therapeutic effect is stronger.

The compounds of the invention may be used as anticholinergic agents for the treatment of chronic obstructive bronchitis and mild to moderate asthma, and for the treatment of sinus bradycardia caused by vagal irritation.

In respiratory diseases, the inhalation use of the compounds according to the invention, in particular the quaternary compounds, is in particular possible, so that any side effects can be largely avoided. In bradycardia, the agents are preferably administered intravenously or orally. In this case, it is preferred that the compounds of the invention are not affected by gastric and bowel movements.

When processing the dosage form, known excipients and / or carriers are added to the active ingredients. For administration by inhalation, for example, suspensions in liquefied propellants, liposome or proliposome formulations, injectable solutions, tablets, dragees, capsules or powders for use in conventional inhaler devices are provided.

Examples of the formulation of the dosage forms will be given below. Data are in% by weight.

1. Aerosol in a dosage package active ingredient according to the invention 0.005 sorbitan trioleate 0.1 monofluorotrichloromethane and difluorodichloromethane in a ratio of 2: 3 to 100

The suspension is filled into a container fitted with a metering valve. One actuation of the valve preferably releases 50 μΙ of the suspension, the solution may also contain a higher dose of the active ingredient, for example 0.02% by weight.

2. Tablets Active ingredient according to the invention 0.05 Colloidal silicic acid 0.95 Milk sugar 65.00 Potato starch 28.00 Polyvinylpyrrolidone 3.00 Sodium cellulose glycolate 2.00 Magnesium stearate 1.00

The mixture is processed to 200 mg tablets in a conventional manner. Advantageous properties of the compounds of the invention can be demonstrated, for example, in inhibiting broncholysis in a rabbit in which convulsions have been induced by intravenous administration of acetylcholine. Following intravenous administration of the compounds of the invention at 3 µg / kg intravenously, the maximal effect was 10 to 40 minutes. Even after 5 hours, the effect has not yet decreased by half, i.e. the decrease in effect in half lasts considerably longer than 5 hours, as can be shown by the percent action of the individual doses after 5 hours.

..8 compound residual effect in%

A

B

C

D

E

F

G

-9Compound of formula

HO-C-CO-A

R

Compound A

R ¹

3-thienyl

2-thienyl

3-thienyl

2-thienyl

Br®

-about

CH ₃ -? - CH (CH ₃ ) 2 cyclopentyl

Br®

-about

CH ₃ -? - CH ₂ -CH ₂ F cyclopentyl

-10Compound C

notes:

1) Compounds in which R ¹ is different from the 2-thienyl radical are racemates.

2) These are always 3a-compounds.

In principle, known methods can be used to produce the compounds of the invention.

The ester group is exchanged at a higher temperature in an organic solvent such as toluene, xylene, heptane or melt, and a strong base such as sodium methoxide, sodium ethoxide, sodium hydride or sodium metal may be used as the catalyst. A reduced pressure or azeotropic distillation of the alcohol is used to remove the released lower alcohol from the mixture. The reaction is usually carried out at a temperature not exceeding 95 ° C. Often, the reaction is preferably carried out in the melt.

If desired, free bases can be obtained from the tertiary amine addition salts with acids by treatment with suitable bases in a known manner. The quaternization is carried out in a suitable solvent, for example acetonitrile or in a mixture of acetonitrile and methylene chloride, preferably at room temperature. The quaternizing agent is preferably a corresponding alkyl halide such as an alkyl bromide. The products in which Q 'has the meaning of NH serve as starting materials for those compounds in which R and R' together form an alkylene radical having 4 to 6 carbon atoms. Conversion to a tertiary and then quaternary compound can then be accomplished by treatment with 1,4-, 1,5- or 1,6-dihaloalkane without isolation of the intermediate.

The starting materials may, if not already described, be obtained by analogous methods to known compounds.

For example, you can get:

methyl di- (2-thienyl) glycolic acid from dimethyl oxalic acid and 2-thienylmagnesium bromide; from methylglycylic acid methyl ester and 2-thienylmagnesium bromide; or (2-thienyl) glyoxylate and phenylmagnesium bromide methyl ester.

In a similar manner, the methyl ester can also be reacted

2-thienylglyoxyl and cyclohexyl- or cyclopentylmagnesium bromide.

Such aminoalcohols can be prepared in various ways.

The production of pseudoscopy has been described by M. Polonovski et al., Bull, Soc. Chim. 43, 79 (1928).

Pseudotropenol can be obtained by traction crystallization from the mixture described by V. Hayakawa et al., J. Amer. Chem. Soc. 1978, 100 (6), 1786 and R. Noyori et al., J. Amer. Chem. Soc. 1974, 96 (10), 3336, it is also possible to distill these mixtures.

When 2- or 3-furylglyoxylnitrile is used, it is possible, in addition to 2- or 3-acid

3-furylglyoxyl can also be obtained in the usual manner by the corresponding methyl esters. The corresponding glycolic esters can then also be obtained from these materials using the organic metal derivatives of 2- or 3-bromothiophene as described above. The organic metal compounds obtained from 2-, 3- or 4-halopyridine can be reacted with 2- or 3-thienylglyoxylic acid methyl ester to give the corresponding glycolic acid esters.

Thienylglycolic acid esters in which the thiophene ring contains a fluorine atom in the 2 or 3 position can be prepared, for example, from 2- or 3-fluorothiophene

By bromination to 2-bromo-3-fluoro- or 2-bromo-5-fluorothiophene followed by conversion to an organic metal compound and reaction with an appropriate glyoxylic ester to give the desired glycolic ester.

2-Fluorothiophene and 3-Fluorothiophene can be converted to glyoxylic esters according to Unterhalt, Ar. Pharm. 322, 839 (1989) and the esters obtained can be reacted as described above with 2- or 3-thienyl derivatives to give glycolic acid esters. Symmetrically substituted dithienylglycolic esters can be obtained by suitable choice of components.

A further procedure leads analogously to the condensation of benzoin and an analogous reaction with benzylic acid.

The following examples illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

Di- (2-thienyl) glycolic acid scopine ester

50.87 g, 0.2 mol of methyl di- (2-thienyl) glycolic acid ester and 31.04 g, 0.2 mol of scopine are dissolved in 100 ml of absolute toluene and then 1.65 g, 0.071 are added in several portions. of sodium gramamatome at a bath temperature of 90 ° C. At a temperature of 78-90 DEG C. and a pressure of 0.5.10 ⁵ Pa (500 mbar), the reaction mixture was distilled off formed methanol. After a reaction time of 5 hours, the reaction mixture is stirred into a mixture of ice and hydrochloric acid. The acid phase was separated, basified with sodium carbonate and the free base was extracted with methylene chloride. After drying over sodium sulfate, the methylene chloride is distilled off under reduced pressure and the residue is recrystallized from acetonitrile. Yield: 33.79 g of a beige crystalline product (44.7% of theory); m.p. 149 DEG-150 DEG C. (acetonitrile).

Example 2

Di- (2-thienyl) glycolic acid scopine ester

1312.72 g, 0.05 mol of di- (2-thienyl) glycolic acid methyl ester and 7.76 g, 0.05 mol of scopine are heated in a 70 ° C bath using a water pump until melting. Sodium methoxide (2.70 g, 0.05 mol) was added to the melt and the mixture was heated using a water pump for 1 hour in a 70 ° C bath and then for an additional hour in a 90 ° C bath. The solidified melt is mixed with a mixture of 100 ml of water and 100 ml of methylene chloride at a controlled temperature, and the methylene chloride phase is repeatedly extracted with water and then with an appropriate amount of dilute hydrochloric acid. The aqueous phases are decanted, after addition of the appropriate amount of sodium carbonate, the di- (2-thienyl) glycolic acid scopine ester is extracted with methylene chloride and the methylene chloride solution is dried over sodium sulphate and the hydrochloride is prepared in a conventional manner. The crystals were filtered off with suction, washed with acetone and dried under reduced pressure at 35 ° C. In a yield of 53.1%, after recrystallization from methanol, 10.99 g of pale beige crystals with a melting point of 238 DEG-241 DEG C. are obtained with decomposition. The free material can be obtained from the hydrochloride in a conventional manner.

Example 3

Di- (2-thienyl) glycolic acid scopine ester

38.15 g (0.15 mol) of di- (2-thienyl) -glycolic acid methyl ester and 23.28 g (0.15 mol) of scopine are mixed, 0.34 g (0.015 gram) of sodium are added and the mixture melted. using a water pump on a 90 ° C bath. The reaction takes 2.5 hours. 100 ml of absolute ethanol are then added and the mixture is stirred at a bath temperature of 90 ° C until a solution is formed, which solution is then cooled to room temperature and a mixture of ice-cooled ice-hydrochloric acid is added. The crystallized basic ester hydrochloride is filtered off with suction and washed with a little water and a sufficient amount of diethyl ether. The filtrate phase is separated and the aqueous phase is extracted with diethyl ether. The filtered hydrochloride is suspended in the acidic aqueous phase and converted to the free material by addition of sodium carbonate under temperature control, which is extracted with methylene chloride. The methylene chloride phases are dried over sodium sulphate and distilled off, the crystalline material obtained is purified with activated carbon and recrystallized

-14acetonitrilu. 39.71 g of pale yellow crystals with a melting point of 148-149 ° C are obtained in a yield of 70.1%.

Table I

Compounds of general formula

HO-C-CO-OA

I

R ¹

no. A R1 base mp ° C hydrochloride 1 3a- (6?, 7? Epoxy) tropanyl 2-thienyl 149-150 238-241 2 3-tropanyl 2-thienyl 167-168 253 3 3a- (6,7-dehydro) tropanyl 2-thienyl 164-165 4 3a- (N-p-fluoro-ethyl) nortropanyl 2-thienyl 236 5 3a- (N-isopropyl) granatanyl 2-thienyl 232 6 3a - (N-Isopropyl) nortropanyl 2-thienyl 250 7 3a- (6?, 7? Epoxy) -N-izopropylnor- tropanyl 2-thienyl 206 8 3a- (6?, 7? Epoxy) -N-ethyl- nortropanyl 2-thienyl 212-213 9 3a- (S-ethyl) nortropanyl 2-thienyl 256-7 10 3a- (N, N-methyl) granatanyl 2-thienyl 241 11 3a- (6?, 7? Epoxy) -N-p-fluoro- etylnortropanyl 2-thienyl 188-190 12 3a- (6?, 7? * Epoxy) -N-n- propylnortropanyl 2-thienyl 104-106

-15R ¹ base melting point ° C hydrochloride

3a- (6?, 7? Epoxy) -N-n-butyl

nortropanyl 2-thienyl 225-227 3a (6a, 7p-epoxy) tropanyl phenyl 246-247 3-tropanyi phenyl 243-244 3a- (N-p-fluoro-ethyl) nortropanyl phenyl 219-220 3a- (6,7-dehydro) tropanyl phenyl 181-183 3a- (N-ethyl) nortropanyl phenyl 231-232 3a- (N-isopropyl) nortropanyl phenyl 246-247 3-tropanyl cyclohexyl 260 3a- (N-p-fluoro-ethyl) nortropanyl cyclohexyl 203-204 3a- (6?, 7? Epoxy) tropanyl cyclopentyl 237 3-tropanyl cyclopentyl 260 3oc- (N-p-fluoro-ethyl) nortropanyl cyclopentyl 182-183 3a- (N-ethyl) nortropanyl cyclopentyl 227-228 3a- (N-isopropyl) nortropanyl cyclopentyl 174-175 3a- (6?, 7? Epoxy) tropanyl 2-thienyl 240-242 3-tropanyl 2-thienyl 217-219 3a- (6,7-dehydro) tropanyl 2-thienyl 233-235 3a- (6,7-dehydro) tropanyl 3-thienyl 247-248 3a- (6?, 7? Epoxy) tropanyl 3-thienyl 242-243 3a- (6?, 7? Epoxy) tropanyl 2-furyl 3a- (6,7-dehydro) tropanyl 2-furyl 3-tropanyl 2-furyl 3-tropanyl 2-pyridyl 3a (6p7p-epoxy) tropanyl 2-pyridyl 3a- (6,7-dehydro) tropanyí 2-pyridyl 3-tropanyl 3-thienyl

No. A base mp ° C hydrochloride 39 3a- (6,7-dehydro) tropanyl cyclopentyl 40 3a- (6?, 7? Epoxy) tropanyl cyclohexyl 41 3a- (6,7-dehydro) tropanyl cyclohexyl

Note: all hydrochloride melts with decomposition.

Example 4

Di- (2-thienyl) glycolic acid scopine ester metobromide

Di- (2-thienyl) glycolic acid scopine ester (10.0 g, 0.0265 mol) is dissolved in a mixture of 20 ml of anhydrous methylene chloride and 30 ml of anhydrous acetonitrile, and 12.8 g of 0.1325 mol of methyl bromide is added as 50% - The reaction mixture was sealed into anhydrous acetonitrile and the reaction mixture was sealed firmly in the reaction vessel and allowed to stand at room temperature for 24 hours. During this time, a crystalline precipitate forms. The precipitate was filtered off with suction, washed with methylene chloride and then dried under reduced pressure at 35 ° C. After drying at 111 ° C and recrystallization from methanol-acetone, a white crystalline product is obtained with a melting point of 217-218 ° C.

Table II

Quaternary compounds of formula

HO-C-CO-OA

I.

R ¹

-17C.

R ¹ temp. top. ° C

1 3a (6p7p-epoxy) tropanylmetobromid 2-thienyl 217-218 2 3-tropanyl-methobromide 2-thienyl 263-264 3 3a- (67-dehydro) tropanyl-methobromide 2-thienyl 191-192 4 3a- (N-p-fluoro-ethyl) nortropanylmetobromid 2-thienyl 242-243 5 3-tropanyl-P-fluórmetobromid 2-thienyl 214-215 6 3a- (N-isopropyl) granatanyl-methobromide 2-thienyl 242-243 7 3a- (N-isopropyl) nortropanyl-methobromide 2-thienyl 229-230 8 3a- (6?, 7? Epoxy) -N-izopropylnortropanyl- methobromide 2-thienyl 223-224 9 3a- (6?, 7? Epoxy) -ethyl nortropanylmetobromid 2-thienyl 215-216 10 3a- (N-ethyl) nortropanyl-methobromide 2-thienyl 260-261 11 3a- (N-methyl) granatanyl-methobromide 2-thienyl 246-247 12 3a- (6?, 7? Epoxy) -N-p-fluoro-etylnortropanyl- methobromide 2-thienyl 182-183 13 3a- (6?, 7? Epoxy) -N-n-propyl-nortropanyl- methobromide 2-thienyl 209-210 14 3-tropanyl-p-hydroxyetylbromid 2-thienyl 231-232 15 3a- (6?, 7? Epoxy) tropanylmetobromid phenyl 217-218 16 3-tropanylmetobromid phenyl 273-274 17 3a- (N-p-fluoro-ethyl) nortropanylmetobromid phenyl 215 18 3a- (6,7-dehydro) tropanyl-methobromide phenyl 170-171 19 3a- (N-ethyl) nortropanyl-methobromide phenyl 249-250 20 3a- (N-isopropyl) nortropanyl-methobromide phenyl 259-260 21 3-tropanyletylbromid phenyl 248-249 22 3a- (N-ethyl) nortropanyl-ethyl bromide phenyl 244-245 23 3a- (6?, 7? Epoxy) tropanyl-ethyl bromide phenyl 226 24 3-tropanyl-P-fluórbromid phenyl 241 25 3-tropanylmetobromid cyclohexyl 278

A R1 temp. top. 3a- (N-p-fluoro-ethyl) nortropanyl-methobromide cyclohexyl 260 3-tropanyl-p-fluoroethyl bromide cyclohexyl 233-234 3-tropanylmetobromid cyclopentyl 260 3-tropanyletylbromid cyclopentyl 235-236 3a- (N-ethyl) nortropanyl-methobromide cyclopentyl 251-252 3a- (N-isopropyl) nortropanyl-methobromide cyclopentyl 244-245 3-tropanyl-p-fluoro-ethyl-bromide cyclopentyl 189-190 3a- (N-p-fluoro-ethyl) nortropanyl-methobromide cyclopentyl 266-267 3a- (6,7-dehydro) nortropanyl-metometáň sulfonate 2-thienyl 225-226 3? (6?, 7? Epoxy) tropanyl-methobromide 2-thienyl 218-220 3p-tropanylmetobromid 2-thienyl 243-244 3? (6,7-dehydro) tropanyl-methobromide 2-thienyl 211-214 3a- (6,7-dehydro) tropanyl-methobromide 3-thienyl 182-183 * 3a- (6?, 7? Epoxy) tropanyl-methobromide 3-thienyl 217-218 (+) - enantiomer no. 1 (-) - enantiomer no. 1 3a- (6?, 7? Epoxy) tropanyl-methobromide 2-furyl 3a- (6,7-dehydro) tropanyl-methobromide 2-furyl 3-tropanylmetobromid 2-furyl 3a- (6?, 7? Epoxy) tropanyl-methobromide 2-pyridyl 3a- (6,7-dehydro) tropanyl-methobromide 2-pyridyl 3-tropanylmetobromid 2-pyridyl 3-tropanylmetobromid 3-thienyl 3a- (6,7-dehydro) tropanyl-methobromide cyclopentyl 3a- (6?, 7? Epoxy) tropanyl-methobromide cyclohexyl 3a- (6,7-dehydro) tropanyl-methobromide cyclohexyl 3a- (6?, 7? Epoxy) tropanyl-methobromide cyclopentyl

- 19 * contains crystalline methanol

Note: all compounds of this table melt with decomposition.

Table III

Compounds of formula _ \

HO-C-CO-OA

no. A R ¹ melting point hydrochloride 1 3a- (6?, 7? Epoxy) tropanyl phenyl 246-247 2 3a- (6,7-dehydro) tropanyl phenyl 261-262 3 3ct- (6?, 7? Epoxy) tropanyl 3-thienyl 4 3a- (6,7-dehydro) tropanyl 3-thienyl 5 3-tropanyl 3-thienyl 6 3cc- (N-methyl) granatanyl 3-thienyl

Table IV

Compounds of formula

no. A R ² mp ° C hydrochloride 1 3a- (6?, 7? Epoxy) tropanyl H 2 3α- (6,7-dehydro) tropanyl H 3 3a- (6?, 7? Epoxy) tropanyl methyl 4 3a- (6,7-dehydro) tropanyl methyl 210 to 212.5 5 3a- (6?, 7? Epoxy) tropanyl methoxy 4 3a- (6,7-dehydro) tropanyl methoxy

Table V

Compounds of formula

HO-C-CO-OA

R ¹

no. A R ¹ R ^a 1 3a- (6?, 7? Epoxy) tropanyl 2-thienyl 5-methyl 2 3a- (6,7-dehydro) tropanyl 2-thienyl 5-methyl 3 3-tropanyl 2-thienyl 5-methyl 4 3a- (6?, 7? Epoxy) tropanyl 2- (5-methyl) thienyl 5-methyl 5 3a- (6,7-dehydro) tropanyl 2- (5-methyl) thienyl 5-methyl 6 3-tropanyl 2- (5-methyl) thienyl 5-methyl 7 3a (63,73-epoxy) tropanyl 2-thienyl 5-fluoro 8 3oc- (6,7-dehydro) tropanyl 2-thienyl 5-fluoro 9 3CC-tropanyl 2-thienyl 5-fluoro

no. A R ¹ R ^a 10 3a- (6?, 7? Epoxy) tropanyl 2- (5-fluoro-thienyl) 5-fluoro 11 3a- (6,7-dehydro) tropanyl 2- (5-fluoro-thienyl) 5-fluoro 12 3-tropanyl 2- (5-fluoro-thienyl) 5-fluoro

Table VI

Quaternary compounds of formula

R ¹

no. A R ¹ R ^a 1 3a- (6?, 73-epoxy) tropanyl-methobromide ' 2-thienyl 5-methyl 2 3a- (6,7-dehydro) tropanyl-methobromide 2-thienyl 5-methyl 3 3CC-tropanylmetobromid 2-thienyl 5-methyl 4 3a- (6?, 7? Epoxy) tropanyl-methobromide 2- (5-methyl) thienyl 5-methyl 5 3a- (6,7-dehydro) tropanyl-methobromide 2- (5-methyl) thienyl 5-methyl 6 3-tropanylmetobromid 2- (5-methyl) thienyl 5-methyl 7 3a- (6?, 7? Epoxy) tropanyl-methobromide 2-thienyl 5-fluoro 8 3a- (6,7-dehydro) tropanyl-methobromide 2-thienyl 5-fluoro 9 3-tropanylmetobromid 2-thienyl 5-fluoro 10 3a- (6?, 7? Epoxy) tropanyl-methobromide 2- (5-fluoro) thienyl 5-fluoro 11 3a- (6,7-dehydro) tropanyl-methobromide 2- (5-fluoro) thienyl 5-fluoro 12 3-tropanylmetobromid 2- (5-fluoro) thienyl 5-fluoro

-22Table VII

Compounds of formula

HO-C-CO-OA

R ¹

no. A R ¹ tepl.top. ° C 1 3a- (6?, 7? Epoxy) tropanyl-methobromide phenyl 211-212 2 3a- (6,7-dehydro) tropanyl-methobromide phenyl 158-160 * 3 3a- (6?, 7? Epoxy) tropanyl-methobromide 3-thienyl 4 3a- (6,7-dehydro) tropanyl-methobromide 3-thienyl 5 3CC-tropanylmetobromid 3-thienyl 6 3a- (N-methyl) granatanyl-methobromide 3-thienyl

* with crystalline methanol

Table VIII

Compounds of formula

r ₂ -C-co-oa \

no. A R ² temp. top. ° C 1 3a- (6?, 7? Epoxy) tropanyl-methobromide H 2 3α- (6,7-dehydro) tropanyl-metobromide H 3 3a- (6?, 7? Epoxy) tropanyl-methobromide methyl 4 3a- (6,7-dehydro) tropanyl-methobromide methyl 206-208 5 3α-tropanylmetobromide methoxy 6 3a- (N-methyl) tropanyl-methobromide methoxy

Claims (12)

PATENT CLAIMS Compounds of formula I R ^a _r 1 -C-CO-OA i R ² (d) where A represents a group of formula II wherein Q represents one of the divalent groups -CH ₂ -CH ₂ , -CH ₂ -CH ₂ -CH ₂ -, -CH = CH-, -CH-CHa R is C 1 -C 4 alkyl optionally substituted by halogen or hydroxy, R 'is C 1 -C 4 alkyl and R and R' can be taken together to form a C 4 -C 6 alkylene moiety, whereby the positive charge of the nitrogen atom is offset by the anion X equivalent ^(_) R ¹ is thienyl, phenyl, furyl, cyclopentyl or cyclohexyl, each of these radicals to be substituted by methyl radicals, phenyl and thienyl also chlorine or fluorine -25R ² represents a hydrogen atom, a hydroxy group, an alkoxy group or an alkyl group, both having 1 to 4 carbon atoms Ŕ ^a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group. Compounds according to claim 1, wherein R ¹ is 2-thienyl. Compounds according to claim 1 or 2, wherein R ² is hydroxy. Compounds according to claim 1, 2 or 3, wherein A represents X and R ^w is as defined in claim 1 and R is as defined in claim 1, except hydrogen. Compounds according to claims 1 to 4, wherein R * represents 2-thienyl and A represents a group 26 or in the form of 3α-, wherein X ¹⁾ is an anion equivalent, preferably Bi ⁰ or CH ₃ Sof Compounds of formula I according to claim 1, in the form of 3α-, such as metobromides or methanesulfonates. A process for the preparation of the compounds according to claims 1 to 6, characterized in that the ester of the general formula (IV): (IV) -27 where R is C 1 -C 4 alkyl and R ¹ , R ² and R ³ are as defined in claim 1, undergoes ester exchange with an amino alcohol of formula V wherein: Q is as defined in claim 1 and Q is = NR or = NH, in an inert organic solvent or in the melt, in the presence of an ester exchange catalyst and the compound of formula (VI) obtained (VI) (a) when Q is = NR, quaternize by treatment with a reactive mono-derivative of an alkane of the formula Z- (alkyl of 1 to 4 carbon atoms), where Z is a readily cleavable group, or b) when Q is = NH, quaternize with a disubstituted alkane of formula Z- (C 4 -C 6 alkylene) -Z without isolation of the intermediates. Intermediate of formula VI, wherein Q, Q, R ^a , R 1 and R ² are as defined in claim 1, as well as acid addition salts thereof with the exception of phenyl-2-thienylgiylcolic, 2,2'-dithienylglycolic tropinesters and 3,3'-28-dithienylglycolic acid for the preparation of a compound of formula I according to claim 1. 9. An intermediate according to claim 8, which is WITH \ Pharmaceutical composition with anticholinergic effects, for the treatment of respiratory diseases and sinus bradycardia, characterized in that it contains the compounds according to claims 1 to 6 together with adjuvants and / or carriers. Use of the compounds according to claims 1 to 6 for the preparation of pharmaceutical compositions having anticholinergic activity. Use of the compounds according to 1 to 6 for the preparation of pharmaceutical compositions for the treatment of respiratory diseases and sinus bradycardia.