DD297647A5 - NEW THIENYCARBONIC ACID ESTERS OF AMINO ALCOHOLIC PRODUCTS, THEIR QUATERNATION PRODUCTS AND THE PREPARATION AND USE 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

hydroxy-substituted CH ^ alkyl radical, R 'is a C ₄ -C _e -alkylene radical and R and R' together can also form a C ₄ -C 6 -alkylene radical, and wherein in the case of the quaternary compounds of the positive charge of the N atom, one equivalent of a Facing Anions (X ⁰ ),

for a thionyl, phenyl, fury I, cyclopentyl or cyclohexyl radical, where these radicals may also be methyl-substituted, thionyl and phenyl may also be fluorine- or chlorine-substituted, for hydrogen, OH, C, -C ₄ -alkoxy or C, - C ₄ alkyl, R _{a is} H, F, Cl or CH ₃ and, if = NR represents a secondary or tertiary amino group, and the acid addition salts. In the compounds of the formula I, R _{1 is} preferably thionyl, R _{2 is} preferably OH. The group -OA preferably has a configuration and is derived, for example, from From scopine, tropine, garnetolin or 6,7-dehydrotropin or corresponding Nor compounds; However, OA may also have β configuration as in pseudotropin, pseudoscopin. Corresponding radicals are z. B.

R-N

-0-

RN ^ -R ¹

R-N

O, -O- / R-N®-R ·

R-N

R-N

-O

The substituent R is preferably a lower alkyl radical CH ₃ , C ₂ He, "-CaH ₇ , 1-C ₃ H ₇ , R 'are preferably CH ₃ , R and R' in common

z. B. - (CH ₂ Is-. As a halogen substituent for R is F or secondarily Cl in question.

If R is a halogen- or hydroxy-substituted alkyl radical, it is preferably -CH ₂ -CH ₂ F or -CH ₂ -CH ₂ OH.

Accordingly, the group Az. B. represents the residues of scopine, of N-ethylnorcopine, of N-isopropylnorcopine, of tropine, of N-isopropylnortropine, of 6,7-dehydrotropin, of N-β-fluoroethylnortropine, of N-isopropyl -6,7-Dehydronotropin, des

N-Methylgranatolins or the corresponding Quatärverbindungen, wherein the anion is preferably Br ⁶ or CH ₃ SOf.

As an acid residue

R ₁ -C-CO-

are especially considered:

HO-C-CO-

HO-C-CO-

H ₃ CC-CO-

HO-C-CO-

HO-C-CO-

Particularly suitable for the therapeutic application are the quaternary compounds, while the tertiary compounds are also important as intermediates except as active ingredients.

The compounds according to the invention are strong and long-acting anticholinergics. At dosages in the μg range, inhalation periods of at least 24 hours are achieved by inhalation. The toxicity is also in the same range as the commercial product ipratropium bromide, while at the same time the therapeutic effect is stronger.

The new compounds are suitable, according to their nature as anticholinergics, eg. B. for the treatment of chronic obstructive bronchitis and (mild to moderate) asthma, further for the treatment of vagally induced sinus bradycardia.

While in respiratory diseases mainly the ir.halative use of the nouen active ingredients (in particular the quaternary compounds) is recommended, whereby side effects are largely eliminated, the application in sinus bradycardia is preferably intravenous or oral. It proves to be advantageous that the new compounds leave the lean / bowel motility largely unaffected.

For the application, the compounds of the invention with known excipients and / or carriers are processed into conventional pharmaceutical preparations, for. As to inhalation solutions, suspensions in liquefied propellants, liposomes or proliposomes containing preparations, injection solutions, tablets, dragees, capsules, inhalation powders for use in conventional inhalers.

Formulation Examples (in% by weight):

1. Metered dose inhalant Active ingredient according to the invention Sorbitan trioleate Monofluorotrichloromethane and difluorodichloromethane 2: 3

0.005 0.1

ad 100

The suspension is filled in a conventional aerosol container with metering valve. Per actuation preferably 50μΙ suspension are delivered. If desired, the active ingredient can also be metered in higher (for example 0.02% by weight).

2. tablets 0.05 Active ingredient according to the invention 0.95 Colloidal silica 55,00 lactose 28,00 potato starch 3.00 polyvinylpyrrolidone 2.00 Na-cellulose glycolate 1.00 magnesium stearate

Dia ingredients are processed in the usual way to tablets of 200mg.

The advantageous properties of the new compounds are shown, for example, in the inhibition of broncholysis in rabbits (acetylcholine spasm i.V.). After intravenous administration of the new drugs (dose 3pg / kg i.v.), the maximum effect occurred after 10 to 40 minutes. After 5 hours, the inhibitory effect had not yet halved, d. H. the half-action time is more, z.T. significantly more than 5 hours, as the following residual effects after 5 hours make clear:

Compound residual effect in%

A 76 B 76 C 81 D 61 e 68 F 73 G 69

Compounds of the formula

HO-C-CO-A R-,

connection

^{A is} -O / CH ₃ -N ^ -CH ₃

R1

2-thienyl

B is -O- / CH ₃ -N ^ -CH ₃

3-thienyl

D -O- / CII ₃ -N ^ -CH ₃

2-thienyl

E -O / CH ₃ -NaB-CH ₃

F is -Ο- / CH ₃ -N ^ -CH (CH ₃ ) 2

3-thienyl

cyclopentyl

G -O_ / CH ₃ -Kr ^ -CH ₂ -CH ₂ F

br ©

cyclopentyl

Compound C

HO-C-CO-O

Remarks:

1. Compounds in which Ri is not 2-thlenyl are racemates.

2. Each is 3a compound.

To Hersteilung the new compounds are known methods used. Preference is given to an ester of the formula

(IV),

R ₁ -C-CO-OR "

^R 2

wherein R "is a C ₁ -C ₄ -AIkVIrBSt, preferably a methyl or ethyl radical (R ₁ , R ₂ and R, have the above meaning), with an aminoalcohol of the formula

HIGH

(V)

< ^CH 2> n

wherein m, η and Q have the above meaning, Q "is = NR or for = NR and the OH group is in α or ß-position, transesterified in the presence of a conventional transesterification catalyst and the resulting compound optionally

a) when Q "= NR (R Φ H), quaternized with a reactive Monodeiivat Z- (C, -C ₄ alkyl) of a corresponding alkane (Z = leaving group) or

b) when Q "= NH, quaternized with a terminally disubstituted alkane Z- (C ₄ -C ₆ -alkylene) -Z without intermediate isolation.

The transesterification is carried out in the heat in an organic solvent, for. As toluene, xylene, heptane, or carried out in the melt, with strong bases such as sodium, sodium, sodium hydride, metallic sodium, serve as a catalyst. To remove the liberated lower alcohol from the equilibrium, reduced pressure is used, if necessary distilling off the alcohol azeotropically. The transesterification takes place at temperatures which generally do not exceed 95 ^° C. Often the transesterification in the melt proceeds more favorably.

From acid addition salts of the tertiary amines, if desired, the free bases can be obtained in a manner known per se with suitable basic compounds. The quaternization is carried out in suitable solvents, such as acetonitrile or acetonitrile / methylene chloride, preferably at room temperature; In this case, as a quaternizing preferably a corresponding Alkylhalogenia, z. As alkyl bromide used. Transesterification with Q 'in the meaning NH serve as starting materials for those compounds in which R and R' together represent a C4-C _e alkylene group. The conversion into the tertiary and then quaternary compound is then carried out with the aid of suitable 1,4-, 1,5- or 1,6-dihaloalkanes without intermediate isolation

 The starting materials can-as they have not already been described-are obtained analogously to known compounds.

Examples

Di (2-thienyl) glycolic acid methyl ester of oxalic acid dimethyl ester and 2-thienylmagnesium bromide; Di- (2-thienylglycolic acid ethyl ester of (2-thienyl) glyoxylic acid and 2-thienyllithium; hydroxy-phenyl- (2-thienyl) -acetic acid ethyl ester of methyl phenylglyoxylate and 2-thienylmagnesium bromide or of methyl (2-thienylglyoxylate and phenylmagnesium bromide.

Similarly, methyl 2-thienylglyoxylate and cyclohexyl or cyclopentylmagnesium bromide can be reacted.

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

Pseudoscopin may be described by M. Polonovski et al., Bull. Soc. chim. 43.79 (1928).

Pseudotropenol can be isolated from the mixture (fractional crystallization or distillation), the z. 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.

Starting from 2- or 3-Furylglyoxylnitril the corresponding methyl esters can be prepared in a conventional manner on the available 2- or 3-Furylglyoxylsäure. From these, as described with the organometallic derivatives of 2- or 3-bromothiophene, the corresponding glycolic acid esters are obtained. The organometallic compounds obtainable from 2-, 3- or 4-halopyridine can be reacted with 2- or 3-thienylglyoxylic acid methyl esters to give the corresponding glycolic acid esters.

Thienylglykolsäureester in which the thiophene ring in the 2- or 3-position fluorine, z. B. starting from 2-fluoro or

3-fluorothiophene prepared (bromination to 2-bromo-3-fluoro or 2-bromo-5-fluorothiophene and, after conversion into corresponding organometallic compounds, reaction with suitable Glyoxylsäureestern to the glycolic acid esters.

2-Fluoro-thiophene and 3-fluorothiophene can be analogously maintained, Arch. Pharm. 322, 839 (1989) to the corresponding glyoxylic acid esters, which in turn, as already described, with e.g. 2- or 3-thienyl derivatives, can be converted to glycolic acid esters. By suitable selection of the components can be prepared analogously symmetrically substituted Dithienylglykolsäureester.

Another way is analogous to Benzoinkondensation and Benzilsäureumlagerung.

The following examples illustrate the invention without limiting it.

example 1

Di- (2-thlenyl) glykols§urescopinester

50.87 g (0.2 mol) of di- (2-thienyl) glycolic acid methyl ester and 31.04 g (0.2 mol) of scopine are dissolved in 100 ml of abs. Toluene dissolved and reacted with the addition of 1.65 g (0.071 gram atoms) of sodium in several portions at a bath temperature of 90 ° C. At a temperature of 78-90 ° C of the reaction mixture, the resulting methanol is distilled off under a pressure of 500 mbar. After a reaction time of about 5 hours, the reaction mixture is stirred in a mixture of ice and hydrochloric acid. The acid phase is separated, made alkaline 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 crystals (from acetonitrile), mp 149-15O ⁰ C, yield: 33.79 g (44.7% of theory).

Example 2

Di- (2-thlenyl) glycolate

12.72 g (0.05 mol) of di (2-thienyl) glycolic acid methyl ester and 7.76 g (0.05 mol) of scopin are melted in a heating bath of 7O ⁰ C under water jet vacuum. In this melt 2.70 g (0.05 mol) of sodium methylate are added and heated under aspirator vacuum for 1 hour in a heating bath at 7O ⁰ C and an additional hour for secondary reaction in a heating bath at 90 ⁰ C. The solidified melt is taken up in a mixture of 100 ml of water and 100 ml of methylene chloride under temperature control and extracted the methylene chloride phase several times with water. The methylene chloride phase is extracted with the appropriate amount of dilute hydrochloric acid. From the collected water phases, after addition of the appropriate amount of sodium carbonate, the di (2-thienyl) glycolic acid copoester is extracted with methylene chloride and dried over sodium sulfate. From the dried methylene chloride solution, the hydrochloride is prepared in the usual manner. The crystals are filtered off, washed with acetone and dried at 35 ° C under reduced pressure. Light yellow crystals (from methanol), m.p. 238-241 ⁰ C (dec.). Yield: 10.99 g (53.1% of theory). The hydrochloride can be converted to the base in the usual way.

Example 3

Di- (2-thienyl) glykolsSurescopinestnr

38.15g (0.15mol) of di- (2-thienyl) glycolic acid methyl ester and 23.28g (0.15mol) of scopine are mixed, 0.34g (0.015 gram) of sodium added and melted under aspirator vacuum in a 90 ° C heating bath. the reaction time is 2.5 hours. Then, 100 ml of abs. toluene are added and stirred at a heating bath temperature of 9O ⁰ C until a solution forms. the reaction solution is cooled to room temperature and stirred in an ice-cooled mixture of ice and hydrochloric acid The crystallizing hydrochloride of the basic ester is filtered off with suction, washed with a little water and extensively with diethyl ether, the phases of the filtrate are separated off and the aqueous phase is extracted with diethyl ether The aspirated hydrochloride is suspended in the (acidic) water phase under temperature control and with addition the corresponding amount of sodium carbonate is converted into the base, which is extracted with methylene chloride The collected Methylenchloridp bunches are dried over sodium sulphate. After distilling off the methylene chloride remains behind a crystallizate, which is purified over charcoal and recrystallized from acetonitrile. Slightly yellow crystals (from acetonitrile), mp 148-149 ⁰ C; Yield: 39.71 g (70.1% of theory).

Table I

Compounds of the formula

HO-C-CO-OA

A Ri base Fp-I ⁰ C] No. hydro- 3a- (6β, 7β-epoxy) -tropanyl 2-thienyl 149-150 chloride 1 3a-tropanyl 2-thienyl 167-168 238-241 2 3a- (6,7-dehydro) tropanyl 2-thienyl 164-165 253 3 3a- (N-.beta.-Fluoroethyl) -nortropanyl 2-thienyl 4 3a- (N-isopropyl) -granatanyl 2-thienyl 236 5 3a- (N-isopropyl) -nortropanyl 2-thienyl 232 6 3a- (6ss, 7.beta.-Epoxy) -N-isopropylnortropanyl 2-thienyl 250 7 3a- (6ss, 7.beta.-Epoxy) -N-ethylnortropanyl 2-thienyl 206 8th 3a- (N-ethyl) -nortropanyl 2-thienyl 212-213 9 3a- (N-N-methyl) -granatanyl 2-thienyl 256-257 10 3a- (6ss, 7.beta.-Epoxy) -N-.beta.-fluorethylnortropanyl 2-thienyl 241 11 3a- (6ss, 7.beta.-Epoxy) -N-n-propylnortropanyl 2-thienyl 104-106 188-190 12 3 a- (6β, 7β-epoxy) -N-n-butyl inortropanyl 2-thienyl 13 3 a- (6β, 7β-epoxy) -tropany I phenyl 225-227 14 3a-tropanyl phenyl 246-247 15 3 a- (N-.beta.-fluoroethyl) -nortropanyl phenyl 243-244 16 3a- (6,7-dehydro) tropanyl phenyl 181-183 219-220 17 3a- (N-ethyl) -nortropanyl phenyl 18 3a- (N-isopropyl) -nortropanyl phenyl 231-232 19 3a-tropanyl cyclohexyl 246-247 20 3 a- (N-.beta.-fluoroethyl) -nortropanyl cyclohexyl 260 21 3a- (6a, 7.beta.-Epoxy) tropanyl cyclopentyl 203-204 22 3a-tropanyl cyclopentyl 237 23 3a (N-f! Fluoroethyl) -nortropanyl cyclopentyl 260 24 3a- (N-Eihyl) -nortropanyl cyclopentyl 182-183 25 3a- (N-isopropyl) -nortropanyl cyclopentyl 227-228 26 3ß- (6ss, 7.beta.-Epoxy) tropanyl 2-thienyl 174-175 27 3.beta.-tropanyl 2-thienyl 240-242 28 3β- (6,7-dehydro) -tropanyl 2-thienyl 217-219 29 3a- (6,7-dehydro) tropanyl 3-thienyl 233-235 30 3a- (6ss, 7.beta.-Epoxy) tropanyl 3-thienyl 247-248 31 3 α · (6β, 7β-epoxy) -tropanyl 2-furyl 242-243 32 3a- (6,7-dehydro) tropanyl 2-furyl 33 3a-tropanyl 2-furyl 34 3a-tropanyl 2-pyridyl 35 3 a- (6β, 7β-epoxy) -tropanyl 2-pyridyl 36 3a- (6,7-dehydro) tropanyl 2-pyridyl 37 3a-tropanyl 3-thienyl 38 3a- (6,7-dehydro) tropanyl cyclopentyl 39 ' 3a (6β, 7β-epoxy) -tropanyl cyclohexyl 40 3a- (6,7-dehydro) tropanyl cyclohexyl 41

Note: All hydrochlorides melt with decomposition.

Example 4

Di (2-thienyl) glycolic acid copoester methobromo d 10.0g (0.0265mol) of di- (2-thienyl) glycolic acid copo pter are dissolved in a mixture consisting of 20ml of anhydrous methylene chloride and 30ml of anhydrous acetonitrile and charged with 12.8g (0 , 1325 mol) of methyl bromide (as a 50% solution in anhydrous acetonitrile) and the reaction mixture was allowed to stand in a reaction vessel tightly closed at room temperature for 24 hours. During this time crystals fall out. These are filtered off, washed with methylene chloride and dried at 35 ° C under reduced pressure.

White crystals (from methanol / acetone), mp 217-218 ⁰ C (dec.) After drying at 111 ⁰ C under reduced pressure.

Tables Quaternary compounds of the formula

HO-C-CO-OA

JL

Mp I ⁰ C]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52

3a- (6β, 7β-epoxy) -tropanyl-methobromide 3a-tropanyl-methobromide 3α- (6,7-dehydro) -tropanyl-methobromide 3α- (N-β-fluoroethyl) -nortropanyl-methobromide 3a-tropanyl-β- fluorocthobromide 3a (N isopropyld-garnetanylmethobromide 3a (N-isopropyl) -nortropanylmethobromide 3a (6β, 7β-epoxy) -N-isopropylnortropanylmethobromide 3a (6β, 7β-epoxy) -N- ethylnortropanyl-methobromide 3α- (N-ethyl) -nortropanyl-methobromide 3α- (N-methyl) -granatanyl-methobromide 3α- (6β, 7β-epoxy) -N-β-fluoro-ethyl-nortropanyl-methobromide 3a (6β , 7β-epoxy) -n-propylnortropanyl-methobromide 3a-tropanyl-β-hydroxyethobromide 3α- (6β, 7β-epoxy) -tropanyl-methobromide 3α-tropanyl-methobromide 3α- (N-β-fluoroethyl) -nortropanyl-methobromide 3a- (6,7-dehydro) -tropanyl-methobromide 3α- (N-ethyl) -nortropanyl-methobromide 3α- (N-isopropyl) -nortropanyl-methobromide 3β-tropanyl-ethobromide 3α- (N-ethyl) -nortropanyl- ethobromide 3a (6β, 7β-epoxy) -tropanyl-ethobromide 3a-tropanyl-β-fluoroethobromide 3α-tropanyl-methobromide 3a (Np-fluoroethyl) -nortropanyl-meth obromide 3a-tropanyl-beta-fluoroethobromide 3 a-tropanyl-methobromide 3 a-tropanyl-ethobromide 3a (N-ethyl) -nortropanyl-methobromide 3a (N-isopropyl) -nortropanyl-methobromide 3 a-tropanyl-beta-fluoroethobromide 3α- (N-β-fluoroethyl) -nortropanyl-methobromide 3α- (6,7-dehydro) -tropanyl-meth-methanesulfonate 3β- (6β, 7β-epoxy) -tropanyl-methobromide 3β-tropanyl-methobromide 3β- (6,7-dehydro) -tropanyl-methobromide 3α- (6,7-dehydro) -tropanyl-methobromide 3a (6β, 7β-epoxy) -tropanyl-methobromide (+) - enantiomer of No.

(-) - Enantiomer of No.

3a- (6β, 7β-epoxy) -tropanyl-methobromide 3α- (6,7-dehydro) -tropanyl-methobromide 3α-tropanyl-methobromide 3α- (6β, 7β-epoxy) -tropanyl-methobromide 3a (6,7-Dehydro) -tropanyl-methobromide 3a-tropanyl-methobromide 3a-tropanyl-methobromide 3a - (6,7-dehydro) -tropanyl-methobromide 3a (6β, 7β-epoxy) -tropanyl-methobromide 3a ( 6,7-dehydro) -tropanyl-methobromide 3α-! 6β, 7β-epoxy) -tropanyl-methobromide

2-thienyl 217-218 2-thienyl 263-264 2-thienyl 191-192 2-thienyl 242-243 2-thienyl 214-215 2-thienyl 229-230 2-thienyl 245-246 2-thienyl 223-224 2-thienyl 215-216 2-thienyl 260-261 2-thienyl 246-247 2-thienyl 182-183 2-thienyl 209-210 2-thienyl 231-232 phenyl 217-218 phenyl 273-274 phenyl 215 phenyl 170-171 phenyl 249-250 phenyl 259-260 phenyl 248-249 phenyl 244-245 phenyl 226 phenyl 241 cyclohexyl 278 cyclohexyl 198 cyclohexyl 233-234 cyclopentyl 260 cyclopentyl 235-236 cyclopentyl 251-252 cyclopentyl 244-245 cyclopentyl 189-190 cyclopentyl 226-227 2-thienyl 225-226 2-thienyl 218-220 2-thienyl 243-244 2-thienyl 211-214 3-thienyl 182-183 * 3-thienyl 217-218 2-furyl 2-furyl 2-furyl 2-pyridyl 2-pyridyl 2-pyridyl 3-thienyl cyclopentyl cyclohexyl cyclohexyl cyclopentyl

> contains crystal methanol

Note: All compounds of the table melt under decomposition.

Table III Compounds of the formula

Fp-IX] (Hydrochloric))

3α- (6β, 7β-epoxy) -tropanyl

3a- (6,7-dehydro) tropanyl

3a- (6ss, 7.beta.-Epoxy) tropanyl

3a- (8,7-dehydro) tropanyl

3a-tropanyl

3a- (N-methyl) -granatanyl

phenyl

phenyl

3-thienyl

3-thienyl

3-thienyl

3-thienyl

246-247 261-262

Table IV Compounds of the formula

R ₂ -C-CO-OA

Mp [ ⁰ Cl (hydrochloride)

3α- (6β, 7β-epoxy) -tropanyl 3a - (6,7-dehydro) -tropanyl 3a (6β, 7β-epoxy) -tropanyl 3a (6,7-dehydro) -tropanyl 3a (6β, 7β-epoxy) - tropanyl 3α- (6,7-dehydro) -tropanyl

methyl

methyl

methoxy

methoxy

210 to 212.5

Table V Compounds of the formula

HO-C-CO-OA I A rj R.Fp. [° C] ^R l 3a- (6β, 7β-epoxy) -tropanyl 2-thienyl 5-Methyl No. 3α- (6,7-dehydro) -tropanyl 2-thienyl 5-Methyl 1 3a-tropanyl 2-thienyl 5-Methyl 2 3a- (6ss, 7.beta.-Epoxy) tropanyl 2- (5-methyl) thienyl 5-Methyl 3 3a- (6,7-dehydro) tropanyl 2- (5-methyl) thienyl 5-Methyl 4 3a-Tro "> Anyl 2- (5-methyl) thienyl 5-Methyl 5 3a- (6p, 7.beta.-Epoxy) tropanyl 2-thienyl 5-fluoro 6 3a- (6,7-dehydro) -tiopanyl 2-thienyl 5-fluoro 7 3a-tropanyl 2-thienyl 5-fluoro 8th 3 a- (6β, 7β-epoxy) -tropanyl 2- (5-fluoro) thienyl 5-fluoro 9 3a- (6,7-dehydro) tropanyl 2- (5-fluoro) thienyl 5-fluoro 10 3a-tropanyl 2- (5-fluoro) thienyl 5-fluoro 11 12

Table VI Quaternary compounds of the formula

HO-C-CO-OA R,

R. Fp. [ ⁰ C]

3α- (6β, 7β-Epoxy) -tropanyl-methobromide 3a (6,7-dehydro) -tropanyl-methobromide 3α-tropanyl-methobromide 3a (6β, 7β-epoxy) -tropanyl-methobromide 3a (6,7-dehydro) tropanyl-methobromid3a-tropanyl-methobromid3a- (6ss, 7.beta.-epoxy) tropanyl-methobromid3a- (6,7-dehydro) tropanyl-methobromid3a-tropanyl-methobromid3a- (6ss, 7.beta.-epoxy) tropanyl-methobromid3a- ( 6,7-dehydro; -tropanyl-methobromide 3 a-tropanyl-methobromide-2-thienyl

2-thienyl

2-thienyl

2- (5-methyl) thienyl

2- (5-methyl) thienyl

2- (5-methyl) thienyl

2-thienyl

2-thienyl

2-thienyl

2- (5-fluoro) thienyl

2- (5-fluoro) thienyl

2- (5-fluoro) thienyl

5-Methyl

5-Methyl

5-Methyl

5-Methyl

5-Methyl

5-Methyl

5-Fliior

5-fluoro

5-fluoro

5-fluoro

5-fluoro

5-fluoro

Table VII Compounds of the formula

HO-C-CO-OA

Fp.CCl

3 a- (6β, 7β-epoxy) -tropanyl-methobromide 3a (6,7-dehydro) -tropanyl-methobromide 3α · {6β, 7β-epoxy) -tropanyl-methobromido-3a (6,7-dehydro ) tropanyl-methobromid3a-tropanyl-methobromid3a- (N-methyl) -granatanyl methobromide

phenyl 211-212 phenyl 158-160 * 3-thienyl 3-thienyl 3-thienyl 3-thienyl "

with crystal methanol

Table VIII Quaternary compound of the formula

R ₂ -C-CO-OA

Mp [ ⁰ Cl

3 a- (6β, 7β-epoxy) -tropanylmethobromide H

3α- (6,7-dehydro) -tropanyl-methobromide H

3a- (6β, 7β-epoxy) -tropanyl-molo-bromide methyl

3 a- (6,7-dehydro) -tropanyl-methobromide methyl

3 a-tropanyl-methobromide methoxy

3α- (N-methyl) -tropanylmethobromide methoxy

206-208

Claims (11)

claims:
1. Compounds of the formula (D, in the A for the group , <CH ₂ ) _m -CH -CH (CH ₂ ) _n -CH , in which m and η are independently from each other 1 or 2, Q einederzweibindigenGmPPOn-CH ₂ -CH ₂ -, - CH ₂ -CH ₂ -CH _2, -CH = CH-, -CH CH- (II) and Q 'is the group = NR or the group = NRR', where R is H or an optionally halogen- or hydroxy-substituted C ₁ -C ₄ -alkyl radical, R 'is a C ₄ -C ₆ -alkylene radical and R and R' together can also form a C ₄ -C ₆ -alkylene radical, and wherein in the case of the quaternary compounds the positive charge of the N atom is opposed to one equivalent of an anion (Χ ^θ ),
R _{1 is} a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl radical, these radicals also methyl-substituted, thienyl and phenyl may also be fluoro-substituted or chloro, R ₂ is hydrogen, OH or C ₁ C ₄ -AIkOKy C ₁ -C ₄ -alkyl, R _{a is} H, F, Cl or CH ₃ and, if = NR represents a secondary or tertiary amino group, the acid addition salts. 2. Compounds according to claim 1, wherein R ₁ I is 2-thienyl. 3. Compounds according to claim 1 or 2, wherein R _{2 is} OH. 4. Compounds according to claim 1, 2 or 3, wherein A is RNR " VJ RNR ¹ O X ' VJ RNR ¹ wherein R and Χ ^θ and have the above meaning and R 'has the above meaning except hydrogen.
5. Compounds according to claim 1 to 4, in which R _{1 is} 2-thienyl and A is the radical or CH ₃ -N- ^ CH ₃ is in der3a form wherein X® is an equivalent of an anion, preferably Br® or CH ₃ SOF. 6. Medicaments, characterized by a content of a compound according to claim 1 to 5 or 11, in addition to customary excipients and / or carriers. 7. Use of compounds according to claim 1 to 5 or 11 in the treatment of diseases. 8. Use of compounds according to claim 1 to 5 or 11 in the preparation of anticholinergic Arnzeimitteln. 9. Use of compounds according to claim 1 to 5 or 11 in the manufacture of medicaments for the treatment of respiratory diseases and sinus bradycardia. 10. A process for the preparation of the compounds according to claim 1 to 5 or 11, characterized in that an ester of the formula U = / R ₁ -C-CO-OR " (IV), wherein R "is a CH ^ t-alkyl radical and R ₁ , R ₂ and R _{a have} the above meaning, with an aminoalcohol of the formula (CH ₂ ) _m -CH- HIGH Q " (CH ₂ J _n -CH (V) wherein m, η and Q have the above meaning and Q "is = NR or for = NH, transesterified in an inert organic solvent or in the melt in the presence of a transesterification catalyst and the compound obtained optionally a) when Q "= NR (R Φ H), quaternized with a reactive monoderivative Z- (C ₁ -C ₄ alkyl) of an alkane (Z-leaving group) or b) when Q "= NH substituted with a terminally disubstituted alkane Z- (C ₄ -C ₆ alkylene) -Zeine intermediate isolation and quaternized. 11. Compounds of the formula HO-C-CO-O- / NCH, or. in the 3a-form and their acid addition salts and their methobromides or Methomethansulfonate. 12. Use of compounds of the formula I in which Q '= NR, and their salts as intermediates for the preparation of the corresponding quaternary compounds of the formula I. The invention relates to new Theinylcarbonsäureester of amino alcohols and their Quaternierungsprodukte and the preparation of the novel compounds and their use as active ingredients in medicaments. The new compounds correspond to the formula R ₁ -C-CO-OA in the A for the group -CH (CH ₂ ) _n -CH (II) where m and η independently of one another are 1 or 2, Q is one of the two-chain groups -CH ₁ CH ₂ -, - CH ₂ -CH ₂ -CH ₂ , -CH = CH- -CH CH-