SI9011744A - New esters of carboxylic acid with amino-alcohols, their quaternary products and the preparation and application of these compounds - 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

BOEHRINGER INGELHEIM KG

New thienyl carboxylic acid esters with amino alcohols, their quaternary products, and the preparation and use of these compounds

The invention relates to novel thienyl carboxylic acid esters of amino alcohols and their quatemime products, as well as to the preparation of new compounds and to their use as active ingredients in pharmaceuticals.

The new compounds correspond to the formula (I) / in which

A stands for the group

(II) in which m and n independently of one another are 1 or 2,

Q one of the two-link groups

-CH ₂ -CH ₂ - / -CH ₂ -CH ₂ -CH ₂ -, -CH = CH-, -CH-CHin

Q 'represents a group = NR or a group = NRR', wherein R is H or optionally halogen or hydroxy substituted C _x -C ₄ alkyl radical and R 'is a C _x -C ₄ alkyl radical and R and R' together they may also form a C ₄ -C ₆ alkylene residue and, with the quaternary compounds, opposite to the positive charge of the N atom, is the equivalent of the anion (X ⁹ ),

R _x stands for a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl moiety, these moieties may also be substituted by methyl, thienyl and phenyl as well as fluorine or chlorine,

R2 is hydrogen, OH, C _x -C ₄ alkoxy or C _x -C ₄ alkyl,

R _a for H, F, Cl or CH ₃ , and if = NR represents a secondary or tertiary amino group, including their acid addition salts.

In the compounds of formula I, R _{x is} preferably thienyl and R 2 is preferably OH. Group - OA has a preferred "-configuration and is implemented e.g. from clusters, marc, granatoline or 6,7-dehydrotropin or the corresponding nor-compounds; -OA may also have a β configuration, as in pseudotropin and pseudoscopin.

The corresponding residues are e.g.

-O

R-N ^ -R '

R-N-R

-ο

-Ο- <R-N®-R 'Χθ

-0- <R-N-R '/ X

-Ο

Mr Rücker \ _

The substituent R is preferably a lower alkyl residue than CH ₃ , C ₂ H ₅ , n-CgHp i-CgH ,, R'a preferably CH _y R and R 'are, for example, - (CH) ^ -. As halogen substituent for R, fluorine and chlorine are second to none. If R is a halogen or hydroxy substituted alkyl residue, it is preferably -CH ₂ -CH ₂ F or -CH ₂ -CH ₂ OH. Group A stands for example. for the residues of scopin, N-ethylnorscopin, N-isopropylnorscopin, tropin, N-isopropylnortropine, 6,7-dehydrotropin, N- / 3fluoroethylnortropin, N-isopropyl-6,7-dehydronortropine, N-methylgranatoline, or the corresponding quartem compounds anion preferably of Bi®oziro CH ₃ -SO®. Like an acid residue

Rj-C-CO (III) is particularly relevant:

= / s

= y

I

HO-C-CO

HO-C-CO-

Quaternary compounds are particularly suitable for therapeutic use, while tertiary compounds are important as active ingredients and also as intermediates.

The compounds of the invention are potent and long-acting anticholinergics. At doses, an inhalation duration of at least 24 hours is achieved in the microgram range. However, the toxicity is in the same range as the marketed product ipratropium bromide, while at the same time the therapeutic effect is stronger.

The novel compounds are suitable for their nature as anticholinergics, e.g. for the treatment of chronic obstructive bronchitis and (mild to moderate) asthma, further for the treatment of vagally conditioned sinusbradycardia.

While in the respiratory tract diseases it is generally advisable to use inhalation of new active substances (especially quartem compounds), largely eliminating side effects, preferably in the sinus bradycardia, preferably intravenously or orally. In doing so, it is appropriate that the new compounds generally do not affect gastric / intestinal motility.

For application, the compounds of the invention are processed with known excipients and / or carriers into conventional galenic preparations, e.g. in inhalation solutions, suspensions in liquefied propellants, preparations containing liposomes or proliposomes, injectable solutions, tablets, dragees, capsules and inhalation powders for use in conventional inhalation preparations.

Examples of formulations (percentages by mass):

1. Dosing aerosol

the active ingredient of the invention 0,005 sorbitan trioleate 0.1 monofluorotrichloromethane and difluorodichloromethane 2: 3 adlOO

The suspension is filled into a conventional aerosol container with a metering valve. Once activated, 50 μ 50 of the suspension is preferably dispensed. However, the active ingredient can also be dosed higher if desired (eg 0.02% by weight).

2. Tablets

The active ingredient of the invention 0.05 Colloidal flint 0.95 Milk sugar 65,00 Potato starch 28,00 Polyvinylpyrrolidone 3.00 Na-cellulose glycolate 2.00 magnesium sterate 1.00

Ingredients are normally incorporated into 200 mg tablets.

Suitable properties of new compounds are demonstrated e.g. by inhibiting rabbit broncholysis (acetylcholine spasm i.v.). After intravenous administration of new active substances (dose 3 / xg / kg

i.v.) maximal effect occurred after 10 to 40 minutes. After 5 hours the inhibitory effect has not yet fallen in half, that is, the time in which the effect falls in half is more, in part, even substantially more than 5 hours, as can be clearly seen from the following remaining effects after 5 hours:

Compound

A

B

C

D

E

F

Mr

Residual impact in%

Compounds of Formula:

Compound

-O

CH ₃ -1 $ -CH ₃

Br®

2-thienyl

3-thienyl

2-thienyl

3-thienyl

-O ____ Br® c

CH ₃ -ri $ -CH <CH ₃ ) 2 cyclopentyl

CH ₃ -lU-CH ₂ -CH ₂ F

Br® cyclopentyl

Compound C

COMMENTS:

1. Compounds in which R _x is not 2-thienyl are racemates.

2. These are each 3a-compounds.

Known methods are known for the preparation of new compounds. Preferably the formula ester

(iv) in which R 'is a C 1 -C 6 alkyl residue, preferably a methyl or ethyl residue (R _p R ₂ and R _a have the above meaning), is esterified with an amino alcohol of formula

in which m, n and Q have the upper meanings, Q 'stands for = NR or for = NH and the OH group is in position a or β, in the presence of a conventional diverting catalyst, and the compound obtained in the present case

a) if Q 'is = NR (wherein R is other than hydrogen), quaternary with the mono derivative of Z 1 -C 1 -C 6 -alkyl) of the corresponding alkane capable of reaction (Z = cleavable group),

b) if Q 'is = NH, quaternized with the terminal disubstituted alkane Z- (C ₄ -C ₆ -alkylene) -Z, without intermediate isolation.

The diversion is carried out in a warm organic solvent, e.g. toluene, xylene, heptane, or melt, using as strong catalysts strong bases as sodium methylate, sodium ethylate, sodium hydride, and metallic sodium. To remove the released lower alcohol from the equilibrium, a reduced pressure is used, in which case the alcohol is azeotropically distilled off. Transesterification takes place at temperatures not generally exceeding 95 ° C. Often, diversion is more favorable in the melt.

From the acid addition salts of tertiary amines, free bases can be obtained in a very known manner, if desired, with suitable basic compounds. The quaternization is carried out in suitable solvents such as acetonitrile or acetonitrile / methylene chloride, preferably at room temperature; preferably a suitable alkyl halide, e.g. alkyl bromide. The di-esterification products of Q 'in the sense of NH are used as starting materials for those compounds in which R and R' together represent (a C ₄ -C ₆ alkylene group). Conversion to the tertiary and then quartile compounds is then carried out using suitable 1,4-, 1,5- and 1,6-dihalogenalkanes, without intermediate isolation.

The starting materials can - if not already described - be obtained in analogy to known compounds.

Examples:

Di- (2-thienyl) glycolic acid methyl ester of oxalic acid dimethyl ester and 2-thienyl magnesium bromide;

Di- (2-thienyl) glycolic acid ethyl ester from (2-thienyl) glyoxylic acid and 2-thienyl lithium; Hydroxy-phenyl- (2-thienyl) acetic acid ethyl ester of methyl ester-phenyl glyoxylic acid and

2- thienyl magnesium bromide or (2-thienyl) glyoxylic acid methyl ester and phenyl magnesium bromide.

Similarly, 2-thienyl glyoxylic acid methyl ester and cyclohexyl or cyclopentyl magnesium bromide can be converted.

Several procedures are also available for the preparation of amino alcohols.

The pseudoscopin can be obtained from M. Polonovski et al., Buli. Soc. Chim. 43.79 (1928).

Pseudotropenol can be isolated from mixtures (fractionation crystallization or distillation) obtained, for example, according to V. Hayakawa et al., J. Amer.Chem.Soc. 1987,100 (6), 1786 oz. R. Noyori et al., J.Amer.Chem.Soc. 1974, 96 (10), 3336.

Starting from 2-oz. 3-furylglyoxylnitrile, 2-oz.

3- furylglyoxyl acids prepare the corresponding methyl esters in the usual way. From these, 2-oz. 3-Bromothiophene of the corresponding glycolic acid ester. The metal-organic compounds obtained from 2-, 3- or 4-halogenpyridine can be converted with methyl 2-oz. Of 3-thienylgboxylic acid to the corresponding glycolic acid esters.

Thienylglycolic acid esters in which the thiophene ring contains fluorine in position 2 or 3, for example, is prepared from 2-fluoro- or 3-fluorothiophene (bromination in

2-bromo-3-fluoro-or 2-bromo-5-fluorothiophene, and after conversion to the corresponding metal-organic compounds, by conversion with suitable glyoxylic acid esters into glycolic acid esters.

2-fluorothiophene and 3-fluorothiophene can be converted analogously to Unterhalt, Arch.Pharm. 322, 839 (1989) to the corresponding glyoxylic acid esters, which can be described in the manner already described, e.g. with 2 or 3-thienyl derivatives, is converted into glycolic acid esters. With an appropriate selection of components, analogically symmetrically substituted dithienyl glycolic acid esters can be prepared.

The further route is offered analogously to benzoic condensation and benzyl acid displacement.

The following examples illustrate the invention without limiting it.

Example 1

Skopinester di- (2-thienyl) glycolic acid.

50.87 g (0.2 mol) of di- (2-thienyl) glycolic acid methyl ester and 31.04 g (0.2 mol) of the group are dissolved in 100 ml of absolute toluene and 1.65 g (0.071 g of atoms) are added sodium is allowed to react in several portions at a bath temperature of 90 ° C. At a temperature of 78 to 90 ° C, the reaction mixture was distilled off at a pressure of 500 mbar, the resulting methanol. After a reaction time of 5 hours, the reaction mixture was stirred into a mixture of ice and hydrochloric acid. The acidic phase is decided, basified with sodium carbonate and the free base 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; beige colored crystals (from acetonitrile), mp 149-150 ° C, yield: 33.79 g (44.7% of theory).

Example 2

Di- (2-thienfl) glycolic acid Skopin ester

12.72 g (0.05 mol) of di- (2-thienyl) glycolic acid methyl ester and 7.76 g (0.05 mol) of the cluster were melted in a heating bath at 70 ° C under a water jet vacuum. 2.70 g (0.05 mol) of sodium methylate are introduced into this melt and heated in a water-jet vacuum at 70 ° C for one hour in a water-jet vacuum, and for another hour in a 90 ° C heating bath to continue the reaction. The solidified melt was taken up in a mixture of 100 ml of water and 100 ml of methylene chloride while controlling the temperature, and the methylene chloride phase was repeatedly extracted with water. The methylene chloride phase is extracted with an appropriate amount of dilute hydrochloric acid. Extract from the collected aqueous phases after addition of an appropriate amount of sodium carbonate of scopinester Di (2-thienyl) glycolic acid with methylene chloride and dry over sodium sulfate. Hydrochloride is prepared in the usual way from the dried methylene chloride solution. The crystals were aspirated, washed with acetone and dried at 35 ° C under reduced pressure. Light yellow crystals (from methanol), mp 238 - 241 ° C (decomposition) are obtained; yield: 10.99 g (53.1% of theory).

The hydrochloride can be conveniently converted to the base.

Example 3

Di- (2-thienyl) glycolic acid Skopin ester

38.15 g (0.15 mol) of di- (2-thienyl) glycolic acid methyl ester and 23.28 g (0.15 mol) of the cluster are mixed, 0.34 g (0.015 g of atoms) of sodium are added and the water jet is vacuum melt on a 90 ° C heating bath. The conversion takes 2.5 hours. Then add 100 ml of absolute toluene and stir for 90 minutes at a heating bath until a solution is formed. The reaction solution was cooled to room temperature and stirred in a mixture of ice and hydrochloric acid cooled with ice. The crystallized hydrochloride of the basic ester is filtered off with suction, washed with a little water and exhaustively with diethyl ether. The filtrate phases are separated and the aqueous phase is extracted with diethyl ether. The recovered hydrochloride is suspended in the (acidic) aqueous phase and, under temperature control and with the addition of an appropriate amount of sodium carbonate, transferred to a base which is extracted with methylene chloride. The combined methylene chloride phases were dried with sodium sulphate. After distillation of the methylene chloride, the crystallizate which is purified via activated carbon is recrystallized from acetonitrile. Light yellow crystals (from acetonitrile), mp 148-149 ° C are obtained;

yield: 39.71 g (70.1% of theory).

Table I

Compounds of Formula

HO-C-CO-OA ^R 1

Mp (° C)

no A Rl Base hydrochloride 1 3α- (6,3,7,8-epoxy) -tropanyl 2-thienyl 149-50 238-41 2 3a-Tropanyl 2-thienyl 167-8 253 3 3a- (6,7-dehydro) tropanyl 2-thienyl 164-5 4 3- (N-S-Fluoroethyl) -nortropanyl 2-thienyl 236 5 3- (N-isopropyl) -granatanyl 2-thienyl 232 6 3- (N-isopropyl) -nortropanil 2-thienyl 250 7 3- (6j3,7 / 3-epoxy) -N- isopropylnortropanil 2-thienyl 206 8 3- (6 / 3,7S-epoxy) -N-ethyl- nortropanil 2-thienyl 212-3 9 3- (N-ethyl) -nortropanil 2-thienyl 256-7 10 3- (N-N-methyl) -granatanyl 2-thienyl 241 11 3- (6 / 3,7j-epoxy) -N- / 3- fluoroethylnortropanil 2-thienyl 188-90 12 3a - (^ 3,7j3-epoxy) -N-n-

propylnortropanil 2-thienyl 104-6 13 3a (6 / 3,7 / 3-epoxy) -N-n- butylnortropanil 2-thienyl 225-7 14 3- (6 / 3,7,8-epoxy) -tropanyl phenyl 246-7 15 3a-Tropanyl phenyl 243-4 16 3- (N- / 3-fluoroethyl) -nortropanyl phenyl 219-20 17 3- (6,7-dehydro) -tropanyl phenyl 181-3 18 3- (N-ethyl) -nortopanil phenyl 231-2 19 3- (N-isopropyl) -nortropanyl phenyl 246-7 20 3a-Tropanyl cyclohexyl 260 21 3- (N- / 3-fluoroethyl) -nortropanyl cyclohexyl 203-4 22 3- (6 / 3,7 / 3-epoxy) -tropanyl cyclopentyl 237 23 3a-Tropanyl cyclopentyl 260 24 3- (N- / 3-fluoroethyl) -nortropanil 182-3 25 3- (N-ethyl) -nortropanil cyclopentyl 227-8 26 3- (N-isopropyl) -nortropanil cyclopentyl 174-5 27 3 / 3- (6 / 3,70-epoxy) -tropanyl 2-thienyl 240-2 28 3/3-Tropanyl 2-thienyl 217-9 29 3 / 3- (6,7-dehydro) -tropanyl 2-thienyl 233-5 30 3- (6,7-dehydro) -tropanyl 3-thienyl 247-8 31 3- (6 / 3,7 / S-epoxy) -tropanyl 3-thienyl 242-3 32 3- (6 / 3,7 / 3-epoxy) -tropanyl 2-furyl 33 3- (6,7-dehydro) -tropanyl 2-furyl 34 3a-Tropanyl 2-furyl 35 3a-Tropanyl 2-Pyridyl 36 3- (6 / 3,7 / 3-epoxy) -tropanyl 2-Pyridyl 37 3- (6,7-dehydro) -tropanyl 2-Pyridyl 38 3a-Tropanyl 3-thienyl 39 3- (6,7-dehydro) -tropanyl cyclopentyl 40 3- (6 / 3,7 / 3-epoxy) -tropanyl cyclohexyl 41 3- (6,7-dehydro) -tropanyl cyclohexyl

Footnote:

All hydrochlorides melt upon decomposition.

Example 4

Skopinester - di- (2-thienyl) glycolic acid metobromide

10.0 g (0.0265 mol) of di- (2-thienyl) glycolic acid scopinester dissolved in a mixture of 20 ml of anhydrous methylene chloride and 30 ml of anhydrous acetonitrile, 12.8 g (0.1325 moles) of methyl bromide (as 50%) were added solution in anhydrous acetonitrile) and the reaction mixture was allowed to stand in the reaction vessel tightly closed at room temperature for 24 hours. During this time, crystals precipitate. They are aspirated, washed with methylene chloride and dried at 35 ° C under reduced pressure.

White crystals (from methanol / acetone) are obtained, mp 217-218 ° C (decomposition) after drying at lirC under reduced pressure.

Table II

Quarteme compounds of formula

HO-C-CO-OA k

No A Tal. ra 1 3- (6,3,7 / 3-epoxy) -tropanyl metobromide 2-thienyl 217-18 2 3a-Tropanyl-metobromide 2-thienyl 263-64 3 3- (6,7-dehydro) -tropanyl metobromide 2-thienyl 191-92 4 3u- (N- / 3-fluoroethyl) -nortropanil- metobromide 2-thienyl 242-43 5 3α-Tropanyl-β 3-fluoroethobromide 2-thienyl 214-15 6 3- (N-isopropyl) -granatanyl- metobromide 2-thienyl 229-30 7 3- (N-isopropyl) -nortropanil-

metobromide 2-thienyl 245-46 8 3 "- (60,7j3-epoxy) -N-isopropyl- nortropanil-metobromide 2-thienyl 223-24 9 3- (6 ^ 3,7) 3-epoxy) -N-ethylnor- tropanyl metobromide 2-thienyl 215-16 10 3 "- (N-ethyl) -nortropanil- metobromide 2-thienyl 260-61 11 3- (N-methyl) -granatanyl- metobromide 2-thienyl 246-47 12 3- (6 / 3,7 / 3-epoxy) -N- / 3-fluoro-ethyl- nortropanil-metobromide 2-thienyl 182-83 13 3a- (0) 8,73-epoxy) -N-n-propyl- nortropanil-metobromide 2-thienyl 209-10 14 3a-Tropanyl- / 3-hydroxyetobromide 2-thienyl 231-32 15 3 «- (6 & 7 / J-epoxy) -tropanyl- metobromide phenyl 217-18 16 3a-Tropanyl-metobromide phenyl 273-74 17 3- (N- / 3-fluoroethyl) -nortropanil- metobromide phenyl 215 18 3- (6,7-dehydro) -tropanyl- metobromide phenyl 170-71 19 3- (N-ethyl) -nortropanil- metobromide phenyl 249-50 20 3- (N-isopropyl) -nortropanil- metobromide phenyl 259-60 21 3a-Tropanyl-ethobromide phenyl 248-49 22 3- (N-ethyl) -nortropanil- ethobromide phenyl 244-45 23 3- (6 / 3,7 / 3-epoxy) -tropanyl- ethobromide phenyl 226 24 3a-Tropamyl- / 3-fluoro-bromide phenyl 241 25 3a-Tropanyl-metobromide cyclohexyl 278 26 3- (N- / 3-fluoroethyl) -nortropanil- metobromide cyclohexyl 198 27 3-Tropanyl- / 3-fluoro-bromide cyclohexyl 233-34

28 3a-Tropanyl-metobromide cyclopentyl 260 29 3a-Tropanyl-ethobromide cyclopentyl 235-36 30 3- (N-ethyl) -nortropanil- metobromide cyclopentyl 251-52 31 3- (N-isopropyl) -nortropanil- metobromide cyclopentyl 244-45 32 3a-tropanyl-1S-fluoroethobromide cyclopentyl 189-90 33 3- (N- / 3-fluoroethyl) -nortropanil- metobromide cyclopentyl 226-27 34 3a (6,7-dehydro) -tropanyl- metho-methanesulfonate 2-thienyl 225-6 35 3 / 3- (6 / 3,7 / 3-epoxy) -tropanylmetobromide 2-thienyl 218-20 36 3,8-Tropanyl-metobromide 2-thienyl 243-4 37 3 / 3- (6,7-dehydro) -tropanylmetobromide 2-thienyl 211-4 38 3a (6,7-dehydro) -tropanyl- metobromide 3-thienyl 182-3 * 39 3- (6 / 3,7 / 3-epoxy) -tropanyl- metobromide 3-thienyl 217-8 40 (+) - enantiomer no. 1 41 (-) - enantiomer no 42 3- (6 / 3,7 / 3-epoxy) -tropanyl- metobromide 2-furyl 43 3- (6,7-dehydro) -tropanyl- metobromide 2-furyl 44 3a-Tropanyl-metobromide 2-furyl 45 3- (6 / 3,70-epoxy) -tropanyl metobromide 2-Pyridyl 46 3- (6,7-dehydro) -tropanyl metobromide 2-Pyridyl 47 3atropanyl-metobromide 2-Pyridyl 48 3a-Tropanyl-metobromide 3-thienyl

* contains crystalline methanol

49 3- (6,7-dehydro) -tropanyl metobromide cyclopentyl 50 3- (6 £, 70-epoxy) -tropanyl metobromide cyclohexyl 51 3- (6,7-dehydro) -tropanyl metobromide cyclohexyl 52 3- (6 / 3,7 / 3-epoxy) -tropanyl metobromide cyclopentyl

Comment:

All compounds in the table melt upon decomposition

Table III

Compounds of Formula

No. A Rl M.p. (° C) Hydrochloride 1 3- (6 / 3,7 / 3-epoxy) -tropanyl phenyl 246-7 2 3- (6,7-dehydro) -tropanyl phenyl 261-2 3 3- (6 / 3,70-epoxy) -tropanyl 3-thienyl 4 3- (6,7-dehydro) -tropanyl 3-thienyl 5 3a-Tropanyl 3-thienyl 6 3a- (N-methyl) granatanyl 3-thienyl

Table IV

Compounds of Formula

No. A R2 1 3- (6 / 3,7 / 3-epoxy) -tropanyl H 2 3- (6,7-dehydro) -tropanyl H 3 3- (60,7j8-epoxy) -tropanyl methyl 4 3- (6,7-dehydro) -tropanyl methyl 5 3- (6 £, 7 / J-epoxy) -tropanyl methoxy 6 3- (6,7-dehydro) -tropanyl methoxy

M.p. (° C)

Hydrochloride

210-2,5

Table V

Compounds of Formula

~ HO-C-CO-OA

no A R2 R Tal.PC) 1 3- (6 | S, 7/3-epoxy) -tropanyl 2-thienyl 5-methyl 2 3- (6,7-dehydro) -tropanyl 2-thienyl 5-methyl 3 3a-Tropanyl 2-thienyl 5-methyl 4 3- (6 / 3,7 / 3-epoxy) -tropanyl 2- (5-methyl) -thienyl 5-methyl 5 3- (6,7-dehydro) -tropanyl 2- (5-methyl) -thienyl 5-methyl 6 3a-Tropanyl 2- (5-methyl) -thienyl 5-methyl 7 3a- (6ft7j3-epoxy) -tropanyl 2-thienyl 5-fluorine 8 3- (6,7-dehydro) -tropanyl 2-thienyl 5-fluorine 9 3a-Tropanyl 2-thienyl 5-fluorine 10 3- (6 / 3,7 / 3-epoxy) -tropanyl 2- (5-flour) -thienyl 5-fluorine 11 3- (6,7-dehydro) -tropanyl 2- (5-Fluoro) -thienyl 5-fluorine 12 3a-Tropanyl 2- (5-Fluoro) -thienyl 5-fluorine

Table VI

Quaternary compounds of formula

no A Rl R _a Tal. (' 1 3a- (6 / 3,7 /? - epoxy) -tropanyl- metobromide 2-thienyl 5-methyl 2 3- (6,7-dehydro) -tropanyl- metobromide 2-thienyl 5-methyl 3 3a-Tropanyl-metobromide 2-thienyl 5-methyl 4 3- (60,7j3-epoxy) -tropanyl- 2- (5-methyl) - metobromide thienyl 5-methyl 5 3- (6,7-dehydro) -tropanyl 2- (5-methyl) - metobromide thienyl 5-methyl 6 3a-Tropanyl-metobromide 2- (5-methyl) - thienyl 5-methyl 7 3- (6 / 3,7 / 3-epoxy) -tropanyl- metobromide 2-thienyl 5-fluorine 8 3- (6,7-dehydro) -tropanyl- metobromide 2-thienyl 5-fluorine

9 3a-Tropanyl-metobromide 2-thienyl 5-fluorine 10 3- (60,7 / 3-epoxy) -tropanyl-2- (5-fluoro) - metobromide thienyl 5-fluorine 11 3- (6,7-dehydro) -tropanyl- 2- (5-fluoro) - metobromide thienyl 5-fluorine 12 3a-Tropanyl-metobromide 2- (5-fluoro) - thienyl 5-fluorine

Table ΥΠ

Compounds of Formula

No A Rj Tal. (°)

3- (6 / 3,7 / 3-epoxy) -tropanyl metobromide phenyl 211-2 3- (6,7-dehydro) -tropanyl metobromide 3- (6 / 3,7 / 3-epoxy) -tropanyl phenyl 158-60 *

metobromide 3-thienyl 4 3- (6,7-dehydro) -tropanyl metobromide 3-thienyl 5 3a-Tropanyl metobromide 3-thienyl 6 3- (N-methyl) -granatanyl metobromide 3-thienyl

* with crystalline methanol

Table Vin

Quarteme compounds of formula

No A

3- (6 & 7j-epoxy) -tropanyl metobromide H

3- (6,7-dehydro) -tropanyl metobromide H

3a - (^ 3,7,8-epoxy) -tropanyl

M.p. metobromide methyl

3- (6,7-dehydro) -tropanyl methyl metobromide

3a-Tropanyl metobromide methoxy

3- (N-methyl) -tropanyl metobromide methoxy

Claims (8)

Compounds (I) / in which A stands for the group -CH (II) in which m and n independently of one another represent 1 or 2, Q is one of the two-link groups -CH ₂ -ch ₂ -, -ch ₂ -ch ₂ -ch ₂ -, -CH = CH-, and Q 'represents a group = NR or a group = NRR', wherein R is H or optionally halogen or hydroxy substituted C _x -C ₄ alkyl radical and R 'is a C _x -C ₄ alkyl radical and R and R' together they may also form a C ₄ -C ₆ alkylene residue and, in quartem compounds, opposite to the positive charge of the N-atom, is the equivalent of the anion (X®), Rj stands for a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl moiety, these moieties may also be substituted by methyl, thienyl and phenyl as well as fluorine or chlorine, R is hydrogen, OH, C-C ₄ - alkoxy or C _x -C ₄ - alkyl, R _a stands for H, F, Cl or CH ₃ , and to the extent that = NR represents a secondary or tertiary amino group, including their acid addition salts. 2. Compounds according to claim 1, wherein R1 stands for 2-thienyl. Compounds according to claim 1 or 2, wherein R2 is OH. Compounds according to claim 1,2 or 3, wherein A is RNR'® where R and X ^{0 are of the} above meaning and R 'is of the above meaning with the exception of hydrogen. Compounds according to claim 1-4, wherein R ₃ is 2-thienyl and A stands for a residue in the form 3a, where X® is the equivalent of an anion, preferably Brcali CH 2 SO 4 A process for the preparation of compounds according to claims 1 to 5 or 7, characterized in that the ester of formula (IV) in which R 'is a C 1 -C ₄ -alkyl radical, and R _p R 2 and R _{a have the} above meaning, is esterified with an amino alcohol of the formula m, n and Q is the above meaning and Q 'stands for = NR or za = NH, in an inert organic solvent or in a melt in the presence of a diverting catalyst and the compound obtained, where appropriate' a) if Q 'is = NR (wherein R is other than hydrogen), quaternized with the mono derivative of Z- (C 1 -C ₄ -alkyl) of the corresponding alkane capable of reaction (Z = cleavable group), b) if Q 'is = NH, substituted and quaternized with terminal alkane Z- (C ₄ -C ₆ alkylene) -Z, without intermediate isolation. Ί. Compounds of formula 3a and their acid addition salts as well as their metobromides or metomethanesulfonates. Use of compounds of formula I wherein Q '= NR and their salts as intermediates for the preparation of the corresponding quaternary compounds of formula I. For: BOERINGER INGELHEIM KG 21333-I-92 / KM SUMMARY The new thienyl carboxylic acid esters of amino alcohols, their quatum products as well as the preparation and use of these compounds. New compounds of formula I are described R.-C-CO-OA (I), R. in which A stands for a group in which m and n independently of one another are 1 or 2, Q one of the two-link groups -C ^ -C ^ -, -CH ₂ -CH ₂ -CH ₂ -, -ch = ch-, -CH-CH - in Q 'represents a group = NR or a group = NRR', wherein R is H or optionally halogen or hydroxy substituted C 1 -C ₄ alkyl residue and R 'is a C 1 -C 4 -alkyl radical and R and R' may be taken together they also form a C ₄ -C ₆ alkylene residue, and in quartem compounds, opposite to the positive charge of the N atom, is the equivalent of an anion (X? ³ ), R _x stands for a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl moiety, these moieties may also be substituted by methyl, thienyl and phenyl as well as fluorine or chlorine, R ₂ stands for hydrogen, OH, C 1 -C ₄ alkoxy or C 1 -C ₄ alkyl, R _a stands for H, F, Cl or CH ₃ , and to the extent that = NR represents a secondary or tertiary amino group, including their acid addition salts, which may be prepared by methods known per se and useful as drug agents.