FI114395B - Process for Preparation of Esters and Intermediate Pharmacologically Efficient Thienyl Carboxylic Acids and Amino Alcohols - 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

114395

A process for the preparation of pharmacologically active esters of thienylcarboxylic acids and aminoalcohols and an intermediate - Förfarande för framställning av pharma- logologic verksamma thienylcarboxylsyrors and aminoalkoholers estrar och mel-lanprodukt

The present invention relates to a process for the preparation of pharmacologically active esters of thienylcarboxylic acids and amino alcohols of formula I

[= \ 10 aΊΞ (= / m

R ^ C-CO-OA

wherein 15 A is a group

ru CH

/ l® \ -CH R-N-R 'Q {m

IX

20 CH 2 -CH

• '· where:; Q is one of the following bivalent radicals '-CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH = CH-, O': -CH-CH-? is an optionally halogen-substituted or hydroxy-substituted C 1 -C 4 -alkyl radical, R 'is a C 1 -C 4 -alkyl radical and R and R' may also be taken together to form a C 1 -C 6 alkylene radical, and wherein sets anion (XB), 2 114395

R1 is a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl radical, whereby these radicals may also be methyl-substituted, thienyl and phenyl may also be fluoro-substituted or chloro-substituted, R2 is hydrogen, OH, C1-C4-alkoxy or C1-C4-alkyl ,

Ra is H, F, Cl or CH3.

In the compounds of formula I obtained by the process of the invention, R 1 is preferably thienyl, R 2 is preferably OH. The -OA group preferably has the α configuration and is derived, for example, from scopine, tropine, granatoline or 6,7-dehydrotropin or similar nor compounds; However, -OA may also have the β-configuration as in pseudotropin, pseudoscopin.

15 Corresponding radicals are, for example, / Π / “Tl.

\ _1_ λ _! _ / I | \ / Γ, | \.

·; · Λ. I / '· —l — 1 / "· / n / -1 — il

\ --- 1 - XlL

: -o- ^ R-N ^, -ο <; κ | -Γ> x® * ::: -o ^ ®n x® \ Is— • * · * ·: · '20 * * · 114395

The substituent R is preferably a lower alkyl radical such as CH 2, C 2 H 5, n-C 3 H 7, i-C 3 H 7, R 'is preferably CH 3. For example, R and R 'together are - (ChWs' · R as halogen substituents is a suitable F, or Cl is in the second position).

When R is a halogen substituted or hydroxy substituted alkyl radical, it is preferably -CH 2 -CH 2 F or -CH 2 -CH 2 OH. Thus, for example, Group A is a radical of the compounds scopine, N-ethylnorscopine, N-isopropylnorcopine, tropine, N-isopropylnortropine, 6,7-dehydrotropine, Ν-β-fluoroethylnortropine, N-isopropyl-6,7-dehydronorthropine, -methylgranatoline or the like quaternary compounds, wherein the anion is preferably Br 'or CH 3 SO 3' ·

As the acidic radical of formula III, the following compounds are particularly suitable: F = \ F = \ \ = / LL / L / 5 HO -C-CO- to3-co- HO-i-CO-

D O D

P b p HO-C-CO-HC-CO-H-C-C-CO-

, 1/3 I

6- 6- O

15 p> r ^ s ΠΡ = / kb HO-C-CO-HO-C-CO-HO-C-CO-

, '<P b <P

The quaternary compounds obtained by the process of the invention are particularly suitable for therapeutic use, while the tertiary compounds are important as intermediates.

The novel compounds of the process of the invention are potent anticholinergic agents. And have a longer lasting effect. The effect is maintained for at least 24 hours with:,,, inhaled doses in the pg range. In addition, the toxicity is of the same class: \ # 30 as the commercial product ipratropium bromide, while having a therapeutic effect; 1 "; is stronger. The novel compounds obtained by the process of the invention are suitable for anti-. according to its cholinergic nature, for example, chronic obstructive bronchodilation. for the treatment of inflammation of the field and asthma (mild to moderate), including for the treatment of vagal induced sinus bradycardia.

5, 114395

Where the use of new active ingredients (particularly quaternary compounds) by inhalation is recommended for respiratory diseases, which results in the avoidance of side effects to a large extent, administration to the sinus bradycardia is preferably performed intravenously or orally. Thus, it has proven to be advantageous that the new compounds do not largely affect the gastrointestinal tract.

The compounds of the invention are processed for administration using conventional excipients and / or excipients to provide conventional galenical formulations, for example, inhalation solutions, suspensions in liquefied propellants, formulations containing liposomes or proliposomes, injection solutions, tablets, inhaled capsules, for use in tea.

EXAMPLES OF FORMULATION (DIMENSIONS UNIT BY WEIGHT BY WEIGHT): 15 1. Controlled Dose Aerosol Active Ingredient of the Invention 0.005 Sorbitan Trioleate 0.1 20 Monofluorotrichloromethane and '· Difluorochlorochloromethane 2: 3 to 100: ,,, ·' The suspension is poured into a conventional aerosol container .

1 "'Preferably 50 µl of suspension / start is dispensed. The active ingredient can also be: ': if necessary, a larger amount (e.g., 0.02% by weight) may also be measured.

2. Tablets

Active ingredient according to the invention 0.05 30 colloidal silica 0.95 lactose 65.00 potato starch 28.00 · * ·:, polyvinylpyrrolidone 3.00

Na-Cellulose Glycolate 2.00 35 Magnesium Stearate 1.00 6 114395

The ingredients are processed in a conventional manner to give 200 mg tablets.

The beneficial properties of the novel compounds are demonstrated, for example, by the inhibition of bronchodilation in the rabbit (intravenous acetylcholine seizures). Following intravenous administration of the new 5 active ingredients (3 pg / kg i.v.), the maximal effect was obtained after 10-40 min. After 5 hours, the inhibitory effect had not yet halved, i.e., the half-life is greater than, in some cases, significantly more than 5 hours, as explained by the residual effects listed below after 5 hours: 10 compound residual activity% A 76 B 76 15 C 81 D 61 E 68 F 73 G 69 II t> · I · »I» »t

Compounds of Formula 7 114395 F = \ L> i

HO-C-CO-A

R 1 Compound A R 5 - -, - K Br &lt; + &gt; L-2-thienyl-o-ch 3-iP-ch 3 10. Br © 15 D-o - / ch 3 - ^ - ch 3 2-thienyl: V: E / j Br ° -o - / CH 3 -? - CH 3 3-thienyl; o_V ch3 -10-ch (ch3) 2 cyclopentyl C> 25, -, -, ΒΛ G / c

· -O— / CH2-I © -CH2-CH2F

'' \ cyclopentyl> 1

Compound C

8 114395 [= Ν

S

- / t_ Br® HO-C-CO-O - <^ CH3- | 1-CH3 'y

Notes: 1. Compounds where R 1 is not 2-thienyl are racemates.

2. In each case, the compounds are 3a compounds.

Methods known per se can be used in the preparation of the compounds of the process of the invention.

The process of the invention is characterized in that the ester of formula IV is esterified by transesterification; · 15 [= \ vv Ra L - ^ - vS (iv): · 'Rj-C-CO-OR ";: r2 i 1 I> 1 1 20

* 1 I

wherein R "is a C 1 -C 4 alkyl radical and R 1, R 2 and R a are as defined above, using: - an amino alcohol of formula V

I I

·; · F-u-CH

/ 2 1 \ 25 ho-ch q "q (v) \ h2-ch> 9114595 wherein Q is as defined above and Q" is = NR or = NH, in an inert organic solvent or melt, in the presence of a transesterification catalyst, and the compound of formula (VI) 5 obtained

R - S CH -, - CH

Τ '/ i \ R ^ C-CO-O-CH Q "Q (VI)

R> \ IX

10 CH 2 - CH

wherein Q "is = NR, is quaternized using an alkane reactive monofunctionalized derivative Z- (C 1 -C 4 alkyl) where Z is a leaving group.

According to the process of the invention, the transesterification is carried out by heating in an organic solvent, for example toluene, xylene, heptane, or in a melt, using strong bases such as sodium methylate, sodium ethylate, sodium hydride, metallic sodium as catalyst. To reduce the released lower alcohol from equilibrium, a reduced pressure is used, possibly distilling off the alcohol azeotropically. The transesterification takes place at temperatures not generally above 95 ° C. Often, transesterification proceeds more favorably in the melt. When required, the free: bases may be obtained in a manner known per se from the acid addition salts of the tertiary amines using appropriate basic compounds. The quaternization is carried out in suitable solvents, for example acetonitrile or acetonitrile / methylene chloride, preferably at room temperature; the method is preferably used as a quaternization reagent; ; : a corresponding alkyl halide, for example alkyl bromide. Exchange esterification products wherein Q 'is NH are used as starting materials for those compounds wherein R and R' together are a C 4 -C 6 alkylene group.

I t »·; - | Conversion to a tertiary and then quaternary compound is accomplished by the use of appropriate I · ', ···, 1,4-dihaloalkanes, 1,5-dihaloalkanes or 1,6-dihaloalkanes, without isolation of intermediates.

114395 Starting materials may be obtained analogously to known compounds insofar as they have not already been described.

Examples: 5 methyl di- (2-thienyl) glycolate of dimethyl oxalate and 2-thienyl magnesium bromide; ethyl di (2-thienyl) glycolate (2-thienyl) glyoxalic acid and 2-thienyl lithium; ethyl hydroxyphenyl (2-thienyl) acetate from methyl phenylglyoxylate and 2-thienylmagnesium bromide or methyl (2-thienyl) glyoxylate and phenylmagnesium 10 bromide.

Methyl 2-thienylglyoxylate and cyclohexyl or cyclopentylmagnesium bromide can be reacted similarly.

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

15

Pseudoscopin can be obtained in the manner described by M.Polonovski et al .; Buli. soc. chim. 43 (1928) 79. The pseudotropenol may be removed from the resulting mixture (fractional crystallization or distillation), for example, as described in V. Hayakawa et al., J. Amer. Chem. Soc. 100 (6): 1786 (1978); or R. Noyori et al., J.

20 Amer. Chem. Soc. 96 (10) 3336 (1974).

The corresponding methyl esters may be prepared in a conventional manner starting from 2-furyl-glycyl nitrile or 3-furylglyoxylnitrile via 2-furylglyoxalic acid or 3-furyl-*: liglyoxalic acid which can be obtained therefrom. The corresponding glycolates are obtained: 25 of these as described using organometallic derivatives of 2-bromothiophene or 3-bromothiophene. Organometallic compounds which may be obtained from 2-, 3- or 4-halo-pyridine may be reacted with methyl 2-thienylglyoxylate or n-methyl 3-thienylglyoxylate to give the corresponding glycolates.

: *. Thienylglycolates in which the thiophene ring contains fluorine in the 2- or 3-position are prepared, for example, by starting from 2-fluorothiophene or 3-fluorothiophene (bromination to give 2-bromo-3-fluorothiophene or 2-bromo-5-fluorothiophene) and the like. ....: After conversion to organometallic compounds, reaction with appropriate glyoxylates to yield glycolates.

11434395 2-Fluorothiophene and 3-Fluorothiophene can be reacted analogously to afford the corresponding glyoxylates, Unterhalt, Arch. Pharm. 322, 839 (1989), which in turn, as already described, may be reacted with, for example, 2-thienyl or 3-thienyl derivatives to yield glycolates. Symmetrically, sub-5-substituted dithienyl glycolates can be prepared analogously by selecting appropriate components.

An additional route is available by a process analogous to benzoic condensation and benzylic acid rearrangement.

10

The following examples illustrate the invention without limiting it.

Example 1 Scopine di (2-thienyl) glycolate 50.87 g (0.2 mol) of methyl di (2-thienyl) glycolate and 31.04 g (0.2 mol) of scopine are dissolved in 100 ml of absolute toluene and reaction at a bath temperature of 90 ° C by adding 1.65 g (0.071 grams) of sodium in several portions.

The resulting methanol is distilled at a temperature of the reaction mixture between 78 ° C and 90 ° C under a pressure of 50 kPa. After a reaction time of about 5 hours, the reaction mixture is stirred into a mixture of ice and hydrochloric acid. The acid phase is separated off, adjusted to an alkaline pH '...; sodium carbonate, and the free base is extracted with methylene chloride. After drying over sodium sulfate, methylene chloride is distilled off. 1: 25 under pressure and the residue was recrystallized from acetonitrile; beige crystals v: (from acetonitrile), m.p. 149-50 ° C, yield: 33.79 g (44.7% of theory).

t: · ·: ...: Example 2 30: '']: Scopinide (2-thienyl) glycolate 1 :. 12.72 g (0.05 mol) of methyl di (2-thienyl) glycolate and 7.76 g (0.05 mol) of scopine

Ml · is thawed in a heat bath at 70 ° C under vacuum of a water jet pump. To this melt is added 2.70 g (0.05 mol) of sodium methylate and heated for 12 hours in a 12114395 heat bath at 70 ° C under a vacuum of a water jet pump and then for an additional 1 hour in a heat bath at 90 ° C. The solidified melt is taken up in a mixture of 100 ml of water and 100 ml of methylene chloride, monitoring the temperature, and the methylene chloride phase is extracted several times with water. The methylene chloride phase is extracted using 5 equal volumes of dilute hydrochloric acid. The scopinide (2-thienyl) glycolate is extracted from the combined aqueous phases using methylene chloride after addition of the corresponding amount of sodium carbonate, and dried over sodium sulfate. From the dried methylene chloride solution, the hydrochloride is prepared in the usual manner. The crystals are suction filtered, washed with acetone and dried under reduced pressure at 35 ° C. Light yellow crystals (from methanol), m.p. 238-41 ° C (dec.); yield: 10.99 g (53.1% of theory).

The hydrochloride can be converted to the base in a conventional manner.

Example 3 15

Skopiinidi (2-thienyl) glycolate

38.15 g (0.15 mol) of methyl di (2-thienyl) glycolate and 23.28 g (0.15 mol) of scopine are mixed, 0.34 g (0.015 gram atom) of sodium are added and the mixture is melted. 20 is heated in a heat bath at 90 ° C under vacuum of a water jet pump. The reaction takes 2.5 hours.

100 ml of absolute toluene are then added and the mixture is stirred in a heat bath at 90 ° C until a solution is formed. The reaction solution is cooled to room temperature and stirred in an ice / ice-cooled hydrochloric acid mixture. Exit '' ': the precipitating basic ester hydrochloride is filtered off with suction and washed with a small amount of water and a large amount of diethyl ether. The filtrate phases are separated off and the aqueous phase is extracted using diethyl ether. The hydrochloride is filtered off with suction. aqueous phase and basified with monitoring of temperature and addition of an appropriate amount of sodium carbonate, the base is extracted using methylene chloride. Light yellow crystals (from acetonitrile), mp 148-49 ° C; ** ". Yield: 39.71 g (70.1% of theory).

Compounds of formula 13114395

Table I

5 (^ s ho-c-co-oa R1 10 sp [° c]

Well. A 1 Base Hydrochloride 15 1 3a- (6B, 7B-Epoxy) -tropanyl 2-thienyl 149-50 238-41 2 3oc-tropanyl 2-thienyl 167-8 253 3 3a- (6,7-dehydro) - tropanyl 2-thienyl 164-5,43a- (N-8-fluoroethyl) -2-thienyl nortropanyl 236 20 5 3a- (N-isopropyl) -granatanyl 2-thienyl 232: 6 3α- (N-isopropyl) - ' : nortropanyl 2-thienyl 256 7 3α- (6β, 76-epoxy) -N-25 isopropylnortropanyl 2-thienyl 206: 8 3α- (66.76-epoxy) -N-ethyl-2-thienyl nortropanyl 212-3 9 3oc - (N-ethyl) -nortropanyl 2-thienyl 256-7103a- (NN-methyl) granatanyl 2-thienyl 241 30 11 3a- (66.76-epoxy) -N-8- 2-thienyl; 188-9012 3a- (6B, 7B-Epoxy) -Nn-2-thienyl 104-6 '. propyylinortropanyyli

Sp. [° C] 14114395

Well. A 1 Basic Hydrochloride 5 13 3α- (66.76-epoxy) -Nn-2-thienyl butylnortropanyl 225-7 14 3α- (66.76-epoxy) -tropanyl phenyl 246-7 15 3α-tropanyl phenyl 243- 4 16 3a- (N-6-fluoroethyl) phenyl 10 nortropanyl 219-20 17 3a- (6,7-dehydro) tropanyl phenyl 181-3 18 3a- (N-ethyl) -nortropanyl phenyl 231-2 19 3a (N-Isopropyl) -Nortropanyl Phenyl 246-7 15 20 3a-Tropanyl Cyclohexyl 260 213a- (N-6-Fluoroethyl) Cyclohexyl Nortropanyl 203-4 22 3a- (68,78-Epoxy) Tropanyl Cyclopentyl 237 23 3a -tropanyl cyclopentyl 260 20 24 3- (N-8-fluoroethyl) cyclopentyl; nortropanyl 182-3 25 3a- (N-ethyl) -nortropanyl cyclopentyl 227-8: ...: 26 3a- (N-isopropyl) nortropanyl cyclopentyl 174-5 25 27 38- (66,78-epoxy) -tropanyl 2-thienyl 240-2 v ′ 28 36-tropanyl 2-thienyl 217-9 29 36- (6,7-dehydro) tropanyl 2-thienyl 233-5.1: 30 3α- (6,7-dehydro) -tropanyl 3-thienyl 247-8 31 3a- (66.76-epoxy) -tropanyl 3-thienyl 242-3: 30 32 3a- (66.76-epoxy) -tropanyl 2-furyl 33 3a- (6.7 -dehydro) -tropanyl 2-furyl 34 3a-tropanyl 2-furyl ....: 35 3a-tropanyl 2-pyridyl 36 3- (66.76-epoxy) -tropanyl 2-pyridyl

Sp. [° C] 15114395

Well. A 1 Basic Hydrochloride 5 37 3α- (6,7-Dehydro) Tropanyl 2-Pyridyl 38 3α-Tropanyl 3-Thienyl 39 3α- (6,7-Dehydro) Tropanyl Cyclopentyl 40 3α- (66.78- epoxy) -tropanyl cyclohexyl 41 3- (6,7-dehydro) -tropanyl cyclohexyl 10

Note: All hydrochlorides will melt with decomposition.

Example 4 Scopinide (2-thienyl) glycolate metobromide 10.0 g (0.0265 mol) of scopine di (2-thienyl) glycolate are dissolved in a mixture of 20 ml of anhydrous methylene chloride and 30 ml of anhydrous acetonitrile and treated with 12.8 g : Ha (0.1255 mol) methyl bromide (50% solution in anhydrous acetonitrile-20) and the reaction mixture is allowed to stand for 24 hours at room temperature in an airtight container. During this time crystals precipitate. They are suction filtered, washed with methylene chloride; :; lene chloride and dried at 35 ° C under reduced pressure. White crystals (from methanol / acetone), m.p. 217-8 ° C (decomposes) after drying at 111 ° C under reduced pressure.

. ··; 25

Quaternary compounds of the formula ie 114395

Table II

5 r ^ s * == <

HO-C-CO-OA

R1 10 No. Rl Sp. [° C] 13a - (68.7B-epoxy) -tropanyl-methobromide 2-thienyl 217-18-23a-tropanyl-methyl-bromide 2-thienyl 263-64153- 3 - (6,7-dehydro) -tropanyl-methobromide 2 -thienyl 191-92 4- 3a- (N-6-fluoroethyl) -nortropanylmethobromide 2-thienyl 242-43,53a-tropanyl-6-fluoroethobromide 2-thienyl 214-1520 6 3a- (N-isopropyl) - • granatanylmetobromide 2-thienyl 229-30 7c- (N-isopropyl) -nortropanylmethobromide 2-thienyl 245-46-8 3a- (66.76-epoxy) -N-isopropyl-: 25-nortropanyl-methobromide 2-thienyl 223- 24th 9α- (6,6,78-epoxy) -N-ethylnortropanylmetobromide 2-thienyl 215-16: 10β- (N-ethyl) -nortropanyl; metobromide 2-thienyl 260-61: ·. 30 11 3a- (N-Methyl) -Granatanyl · · *. metobromide 2-thienyl 246-47 '. - 12 3a- (6,6,78-epoxy) -N-fluoroethyl orthropanylmethobromide 2-thienyl 182-83 »·

Well. Ri Sp. [° C] 17114395 13a- (66.78-epoxy) -Nn-propyl-orthropanyl-methobromide 2-thienyl 209-105143-a-tropanyl-6-hydroxy-ethobromide 2-thienyl 231-32153- (66.76 -epoxy) -tropanyl-methobromide phenyl 217-18 16 3a-tropanyl-methobromide phenyl 273-74 17 3α- (N-8-fluoroethyl) -nortropanyl-methobromide phenyl 215 18 3α- (6,7-dehydro) -tropanyl-methobromide phenyl 170-71 19 3a- (N-ethyl) -nortropanyl-methobromide phenyl 249-50 15 20 3a- (N-isopropyl) -nortropanyl-methobromide phenyl 259-60 21 3a-tropanyl-ethobromide phenyl 248-49 22 3a- (N -ethyl) -nortropanyl-ethobromide phenyl 244-45 20 23 3α- (6β, 76-epoxy) -tropanyl-ethobromide phenyl 226v ,: 24 3α-tropanyl-6-fluoro-ethobromide phenyl 241 25 3α-tropanyl-methobromide cyclohexyl 278: 26 3α- (N-6-fluoroethyl) nortropanylmethobromide cyclohexyl 198v: 27 3α-tropanyl-6-fluoroethobromide cyclohexyl 233-34 28 3α-tropanylmethobromide cyclopentyl 260 29 3a-tropanyl ethobromide cyclopentyl 235-36) »(30 3a- (N-ethyl) -nortropanyl-30-methobromide cyclopentyl 251-52 31 3a- (N-isopropyl) -nortropanyl methobromide cyclopentyl 244-45 ...,: 32 3a-tropanyl-6-fluoroethobromide cyclopentyl 189-90 • *

Well. Ri Sp. [° C] 18114395 33 3c- (N-8-Fluoroethyl) nortropanylmethobromide cyclopentyl 226-27-534 3a- (6,7-dehydro) tropanylmethane sulfonate 2-thienyl 225-6 35 3a- (68.76 -epoxy) -tropanyl-methobromide 2-thienyl 218-20 36 3a-tropanyl-methobromide 2-thienyl 243-4 10 37 3a- (6,7-dehydro) -tropanyl-methobromide 2-thienyl 211-4 38 3a- (6, 7-Dehydro) -tropanyl-methobromide 3-thienyl 182-3 * 39 3a- (6B, 76-epoxy) -tropanyl-methobromide 3-thienyl 217-8 Γ.η (-t -) - Enantiomer 41 1 - (-) - Enantiomer 42 3a- (6,6,76-epoxy) -tropanyl-methobromide 2-furyl 20 43 3a- (6,7-dehydro) -tropanyl-4'-metobromide 2-furyl 44 3a-tropanyl-methobromide 2-furyl:,,: 45 3c- (68.78-epoxy) tropanyl ':: methobromide 2-pyridyl: 25 46 3α- (6,7-dehydro) -tropanyl :,: metobromide 2-pyridyl 47 3a-Tropanylmethobromide 2-Pyridyl 48 3a-Tropanylmethobromide 3-Thienyl 49 3a- (6,7-Dehydro) -tropanyl-Metobromide Cyclopentyl 50 3a- (66.76-Epoxy) -tropanyl ', Metobromide Cyclohexyl 19 Π4395

Well. Ri Sp. [° C] 51 3a- (6,7-Dehydro) -tropanyl-methobromide cyclohexyl-5 52 3a- (66.76-epoxy) -tropanyl-methobromide cyclopentyl * contains crystal methanol 10 Note: All compounds in the table decompose.

»» * »114395 5

Compounds of Formula 20

Table III

HO-C-CO-OA

^ R1 10 No. Rl Sp. [° C] Hydrochloride 13α- (66.76-epoxy) -tropanyl phenyl 246-7 15α-3α- (6,7-dehydro) -tropanyl phenyl 261-23β- (6β, 76-epoxy) tropanyl 3-thienyl 4 -3a- (6,7-dehydro) -tropanyl 3-thienyl 5 3c-tropanyl 3-thienyl 6 3a- (N-methyl) -grananyl 3-thienyl * · 1 «»

Table IV

21, 114395

Compounds of Formula 5

Ur / R.-c-co-o-a

Hn 10

Well. R2 Sp. [° C] hydrochloride 15

13? - (6B, 7B-Epoxy) -tropanyl H

2 3a- (6,7-dehydro) -tropanyl H

3α- (6β, 7β-epoxy) -tropanylmethyl 4α- (6β, 7β-dehydro) -tropanylmethyl 210-2.5 20 5α- (6β, 7β-epoxy) -tropanyl methoxy 6α- , 7-Dehydro) -tropanyl Methoxy • · * • * * t * •> • • • • • I * • * »I '» * * · I ·> »· tt *» (»•»}

»I

Table V

Compounds of formula 22 1 14395

5 Ra-P

HO-C-CO-OA

R1 10 No. A Ri Ra Sp. [° C] 13α- (66.76-epoxy) tropanyl 2-thienyl 5-methyl-2,3α- (6,7-dehydro) -tropanyl 2-thienyl 5-methyl-3α-tropanyl 2-thienyl 5-methyl 4α- (68.78-epoxy) -tropanyl 2- (5-methyl) -thienyl 5-methyl-5α- (6,7-dehydro) -tropanyl 2- (5-methyl) -thienyl 5-methyl-6α -tropanyl 2- (5-methyl) -20-thienyl 5-methyl-7α- (68.76-epoxy) -tropanyl 2-thienyl 5-fluoro-β- (6,7-dehydro) -tropanyl 2-thienyl -fluorine; 9α-tropanyl 2-thienyl 5-fluoro: 10α- (6β, 76-epoxy) -tropanyl 2- (5-fluoro) -; ': Thienyl 5-fluoro; 11a - (6,7-dehydro) -tropanyl 2- (5-fluoro) -thienyl 5-fluoro. '12 3a-Tropanyl 2- (5-fluoro) -1] thienyl 5-fluoro t

* I

! t »t * ϊ ί» S! I »

Table VI

23 114395

Compounds of Formula 5 f = \

HO- <p ~ CO-OA

R1 10

Well. A Ri Ra Sp. [° C] 13? - (66.76-epoxy) tropanyl-2-thienyl 5-methyl methobromide 15? 3? - (6,7-dehydro) tropanyl-2-thienyl 5-methyl methobromide 3? 5-methyl-4 - [(6,7,7-epoxy) tropanyl-2- (5-methyl) -metobromide thienyl] -5-methyl-5 - [(6,7-dehydro) tropanyl-2- (5-methyl) -, ·· Metobromide thienyl 5-methyl 6 3α-tropanylmethobromide 2- (5-methyl) -: thienyl 5-methyl 7β- (6,6,70-epoxy) tropanyl-2-thienyl 5-fluoro :: 25 methobromide 8 3α- ( 6,7-dehydro) tropanyl-2-thienyl 5-fluoro-methobromide 9a-tropanyl-methobromide 2-thienyl-5-fluoro · 10 3α- (66.76-epoxy) tropanyl-2- (5-fluoro)-- 30 Metobromide Thienyl 5-Fluoro; 11c- (6,7-Dehydro) tropanyl-2- (5-fluoro) -metobromide thienyl 5-fluoro 12 3a-tropanyl-methobromide 2- (5-fluoro) thienyl 5-fluoro

Compounds of formula 24 114395

Table VII

5 ρ = \ *

HO-C-CO-OA

10

Well. Ri Sp. [° C] 13a - (6B, 7B-epoxy) tropanyl-phenyl 211-2 methobromide 15-23a- (6,7-dehydro) tropanyl-phenyl 158-60 * metobromide 3a-3a (6B, 7B-epoxy) tropanyl-3-thienyl methobromide 4 3a- (6,7-dehydro) tropanyl-3-thienyl 20 methobromide • 5 3 C -tropanylmethobromide 3-thienyl:? : 25 * (with crystal methanol) 25 114395

Table VIII

Quaternary compounds of formula 5 f == r \

S

R - C-CO-OA

r1-, io ------

Well. R2 Sp. [° C]

13α- (66.76-epoxy) -tropanyl-H

15 Metobromide

2 3a- (6,7-dehydro) -tropanyl-H

methobromide 3α- (6,6,73-epoxy) -tropanylmethyl methobromide 20β-3- (6,7-dehydro) -tropanylmethyl 206-8; · Methobromide v: 5 3a-tropanylmethobromide methoxy * ... · 6 3a- (N-methyl) -tropanylmethobromide methoxy 25

Claims (5)

26 114395 1. A process for preparing pharmacologically active esters of thienylcarboxylic acids and amino alcohols of the formula I 5 F = R - S a 1 = ^ / (i) R 1 -C-CO-OA 2 R 2 wherein A is CH 2 -CH / O RNR 'Q (n) 15 \ CH;, -CH where Q is one of the following bivalent groups 20 -ch2-ch2-, -ch2-ch2-ch2-, -ch = ch-, -CH-CH- / \ ???????? and R is optionally halogen substituted or hydroxy substituted C 1 -C 6 alkyl radical; i * calix, R 'is a C 1 -C 4 alkyl radical and R and R' may also be taken together to form a C 1 -C 6 alkylene radical, and in which the anion (Χθ), is a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl radical, wherein these are ""; the radicals may also be methyl-substituted, thienyl and phenyl may also be fluoro-substituted or chloro-substituted; R 11 is hydrogen, OH, C 1 -C 4 -alkoxy or C 1 -C 4 -alkyl, R a is H, F, Cl or CH 3, characterized in that the ester 5 F = 1 R - S a (IV) R 1 -C-CO-OR "r 2 10 wherein R" is a C 1 -C 4 alkyl radical and R 1, R 2 and R a are as defined above, aminoalcohol HO-CH Q "Q (V) ΧΧχ0Η2— wherein Q is as defined above and Q" is = NR or = NH, in an inert organic solvent or melt, in the presence of a transesterification catalyst, and the compound of formula ( VI) II * - \ .. · n - C ru-CH! ΚΠΞ | ζ = ι / ^ Γ2 | X ;; i 25 RrC-C0-0-CH Q "Q (VI) \ 1 / ^ CH2-. - - CH: where Q "is = NR is quaternized using an alkane reactive monofunctional derivative Z- (C 1 -C 4 alkyl) where Z is a leaving group. A process according to claim 1 for the preparation of a compound of formula I wherein R 1 is 2-thienyl, characterized in that the corresponding starting materials are used. 28, 114395 A process for the preparation of a compound of formula I according to claim 1 or 2, wherein Rx is 2-thienyl and A is CH3-®N-CH3 ^ O -p or _ ^ _ - ^ CH3®N-CH3 xG10 in its 3a form, wherein X9 is the anion equivalent of Br9 or CH3SO39, characterized in that the corresponding starting materials are used. A process according to claim 1 for the preparation of a compound of the formula 15 [= Λ -SH0-C3-C0-0Br ° or CH3Sof20 [= ^ S -— /:; it - \ _ S 25 H0 - (^ - CO-0 - <(CH3l | ^ H3 Br ° or CH3SC> f S 30 in its 3cx form, characterized in that the corresponding starting materials are used.) »· * 11 · t · 29 114395 5. Chemical compound used as starting material, characterized in that it has the formula _S5 (/ ~ 1N H0- (j: -C0-0 fjjCH3 OS - / or 10 \ H / Ί-HO- (j> CO-C ) lj! CH3 s - / 15 tf · t 30 11439 5