IE903342A1 - Novel thienylcarboxylates of amino alcohols, their quaternary products and the preparation and use of these compounds - Google Patents

Novel thienylcarboxylates of amino alcohols, their quaternary products and the preparation and use of these compounds

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IE903342A1
IE903342A1 IE334290A IE334290A IE903342A1 IE 903342 A1 IE903342 A1 IE 903342A1 IE 334290 A IE334290 A IE 334290A IE 334290 A IE334290 A IE 334290A IE 903342 A1 IE903342 A1 IE 903342A1
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thienyl
compounds
tropanyl
methobromide
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IE65528B1 (en
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Rolf Dr Banholzer
Rudolf Dr Bauer
Richard Dr Reichl
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Boehringer Ingelheim Int
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

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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

The present invention relates to novel 5 thienylcarboxylates of amino alcohols and their guaternised derivatives, the preparation thereof and their use as active ingredients in medicaments.
According to one aspect of the invention, we provide 10 compounds of the formula (I) (I)/ in which A represents the group (II) 25 wherein m and n independently of one another denote l or 2; - 2 Q represents one of the double-bonding groups -CH2-CH2-, -CH2-CH2-CHz-, -CH=CH-, and -CH-CH- ; XOX Q’ represents the group =NR or the group =NRR', wherein R denotes a hydrogen atom or an optionally halogen-substituted or hydroxy-substituted C.,_4-alkyI radical and R* denotes a C1.4-alkyl radical; or R and R' together form a C4.6-alkylene radical; R1 represents an optionally methyl-substituted thienyl, phenyl, furyl, cyclopentyl or cyclohexyl radical, the groups thienyl and phenyl optionally being fluoro- or chloro-substituted; Rj represents a hydrogen atom, or an OH, CV4-alkoxy or CV4-alkyl group; Ra represents hydrogen, fluorine, chlorine or CH3; and quaternary derivatives thereof, wherein one equivalent of an anion (Xs) opposes the positive charge of the N atom in the group Q1; and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof; and/or, where appropriate, acid-addition salts thereof.
Compounds of the present invention which are preferred include compounds of formula I as defined above wherein R1 represents thienyl; and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof; and/or, where appropriate, acid-addition salts thereof. - 3 Compounds of the present invention which are particularly preferred include compounds of formula I as defined above wherein R2 represents OH; and all diastereoisomeric, enantiomeric and racemic forms 5 thereof or mixtures thereof; and/or, where appropriate, acid-addition salts thereof.
The group -OA preferably has the α-configuration and is derived from, for example, scopine, tropine, granatoline or 6,7-dehydrotropine or the corresponding norcompounds; however, -OA may also have the 0-configuration, as in pseudotropine or pseudoscopine.
Compounds of the present invention which are especially preferred include compounds of formula I as defined above wherein A represents a group selected from; - 4 and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof? and/or, where appropriate, acid-addition salts thereof.
The substituent R is preferably a lower alkyl radical, for example, CH3, C2H5, n-C3H7, i-C3H7; R· is preferably CHj. R and R' together may represent, for example -(CH2)5~. As halogen substituents for R, fluorine or chlorine are preferred. If R denotes a halogen-substituted or hydroxy-substituted alkyl radical, it is preferably -CH2-CH2F or -CH2-CH2OH. Accordingly, the group A represents, for example, the radicals of scopine, N-ethylnorscopine, N-isopropylnorscopine, tropine, N-isopropylnortropine, 6,7-dehydrotropine, N-0-fluoroethylnortropine, N-isopropyl-6,7-dehydronortropine, N-methylgranatoline or the corresponding quaternary derivatives, wherein the anion X® is preferably Br® or CH3SO3®.
For the acyl radical (III) R1-C-CO(III) R, particular mention must be made of the following groups: The compounds of the present invention may be prepared by the following process, which process constitutes a further feature of the present invention: wherein R" represents a CV4-alkyl radical, preferably a methyl or ethyl radical, and Rv R2 and Ra have the above meanings, is preferably transesterified using an amino alcohol of the formula V HO —CH (CH.,)—CH \ / Q (V) wherein m, n and Q have the above meanings, Q" represents =NR or =NH and the OH group is in the a- or -position, in the presence of a conventional transesterification catalyst, and the compound thereby obtained is either a) if Q denotes =NR (R * H) optionally quaternised, using a reactive monofunctionalised derivative Z-(C1-C4-alkyl) of a corresponding alkane (Z = leaving group) or b) if Q denotes =NH, is optionally quaternised using a terminally disubstituted alkane Z-(C4-C6-alkylene)-Z, without isolation of intermediates.
The transesterification is advantageously carried out with heat in an organic solvent, for example toluene, xylene, heptane, or in a melt; strong bases such as sodium methylate, sodium ethylate, sodium hydride or metallic sodium are preferably used as catalyst. Reduced pressure may be used to remove the released lower alcohol from the equilibrium; the alcohol may optionally be distilled off azeotropically. The transesterification in general takes place at temperatures which do not exceed 95°C. Transesterification often proceeds more favourably in a melt.
If required, the free bases may be obtained by conventional techniques from the acid addition salts of the tertiary amines using suitable basic compounds.
Quaternisation may be carried out in suitable solvents, - Ί for example acetonitrile or acetonitrile/methylene chloride, preferably at room temperature; a corresponding alkyl halide, for example alkyl bromide, is preferably used in the process as a quaternising agent. Transesterification products wherein Q* represents NH are used as starting materials for those compounds in which R and R' together represent a C4.6alkylene group. Conversion into the tertiary and then quaternary compound then takes place with the aid of suitable 1,4-dihaloalkanes, 1,5-dihaloalkanes or 1,6-dihaloalkanes without isolation of intermediates.
The starting materials may be obtained by methods known per se.
Examples of preparations of starting materials methyl di-(2-thienyl)glycolate from dimethyl oxalate and 2-thienyl magnesium bromide; ethyl di-(2-thienyl)glycolate from (2-thienyl)glyoxylic 20 acid and 2-thienyl lithium; ethyl hydroxy-phenyl-(2-thienyl)acetate from methyl phenylglyoxylate and 2-thienyl magnesium bromide or from methyl (2-thienyl)glyoxylate and phenyl magnesium bromide.
Methyl 2-thienylglyoxylate and cyclohexyl or cyclopentyl magnesium bromide may be reacted in a similar manner.
Several processes are also available for the preparation of the amino alcohols.
Pseudoscopine may be obtained in accordance with M.Polonovski et al., Bull. soc. chim. 43., 79 (1928). Pseudotropenol may be removed from the mixture (fractional crystallisation or distillation) which is obtained, for example in accordance with V. Hayakawa et al., J. Amer. Chem. Soc. 1978. 100(6), 1786 or R. Noyori et al., J. Amer. Chem. Soc. 1974, 96(10), 3336. - 8 The corresponding methyl esters may be prepared in a conventional manner starting from 2-furylglyoxylnitrile or 3-furylglyoxylnitrile via the 2-furylglyoxylic acid or 3-furylglyoxylic acid which can be obtained therefrom. The corresponding glycolates are obtained from these as described using the organometallic derivatives of 2-bromothiophene or 3-bromothiophene. The organometallic compounds which can be obtained from 2-, 3- or 4-halopyridine can be reacted with methyl 2-thienylglyoxylate or 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 starting from 2-fluorothiophene or 3-fluorothiophene (bromination to give 2bromo-3-fluorothiophene or 2-bromo-5-fluorothiophene), and after conversion to the corresponding organometallic compounds, reaction with suitable glyoxylates to give the glycolates. 2-Fluorothiophene and 3-fluorothiophene can be reacted analogously to give 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 give glycolates. Symmetrically substituted di-thienylglycolates can be prepared analogously by selecting suitable components.
A further route is available via a process analogous to the benzoin condensation and benzilic acid rearrangement.
The guaternary derivatives are particularly suitable for therapeutic application, whereas the tertiary compounds are important not only as active ingredients but also as intermediate products. - 9 The compounds of the present invention have strong anti-cholinergic activity and have a prolonged action. Action lasting at least 24 hours is achieved at inhaled dosages in the pg range. In addition, the toxicity is in the same range as the commercial product Ipratropium bromide, while at the same time the therapeutic effect is stronger.
The compounds of the present invention are, therefore, suitable, in accordance with their anti-cholinergic nature, for the treatment of, for example, chronic obstructive bronchitis and (slight to moderately severe) asthma, and also for the treatment of vagally induced sinus bradycardia.
According to a further feature of the present invention there is provided a method of treatment of diseases or disorders in a subject for which anticholinergic treatment is required which comprises administering to said subject an effective amount of a compound of formula I as hereinbefore defined or a physiologically acceptable acid addition thereof.
Whereas application of the compounds of the present invention (in particular the quaternary derivatives) by inhalation is mainly recommended for respiratory tract diseases, as a result of which side-effects are largely eliminated, the application for sinus bradycardia is preferably carried out intravenously or orally. It has thus proved to be advantageous that the compounds leave the gastro/intestinal motility largely unaffected.
For administration the compounds of the present invention are processed using known auxiliaries and/or excipients to give conventional galenic preparations, for example inhalation solutions, suspensions in liquified propellants, preparations containing liposomes - 10 or proliposomes, injection solutions, tablets, coated tablets, capsules, inhalation powders for use in conventional inhalation apparatus.
Thus, according to a yet further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula I or a quaternised derivative thereof, as hereinbefore defined, in the form of a single enantiomer or diastereoisomer or mixtures thereof and/or a physiologically acceptable acid-addition salt thereof in association with one or more pharmaceutically acceptable carriers, diluents or excipients. - 11 Pharmacological characteristics The advantageous properties of the compounds of the present invention are shown, for example, in the inhibition of broncholysis in the rabbit (acetylcholine spasms intravenously).
After intravenous administration of the novel active ingredients (dosage 3 Mg/kg intravenously), the maximum effect occurred after 10 to 40 minutes. After 5 hours the inhibiting effect had still not been reduced to half; the half effect time is more, in some cases considerably more, than 5 hours, as shown by the residual effects after 5 hours listed below: Compound Residual effect in % A B C D E F G The data above relate to the following compounds of formula I: - 12 10 Compounds of the formula Γ HO- R, Compound -O / CH3-rf&-CH3 Bi® 2-thienyl B D E 3-thienyl 2-thienyl 3-thienyl F Br® -O_/ CH3 -ίΦ-CH ( CH3 ) 2 __,_. Bl® -0—/ CH3-ri$-CH2-CH2F cyclopentyl cyclopentyl - 13 Compound C Br .© For the compounds A to G above:i) the compounds in which R1 does not represent 2-thienyl are racemates. ii) the compounds are 3a-compounds in each case.
The following examples serve to illustrate the present invention without limiting it.
Example 1 Scopine di-(2-thienyl)glycolate 50.87 g (0.2 mole) of methyl di-(2-thienyl)glycolate and 31.04 g (0.2 mole) of scopine are dissolved in 100 ml of absolute toluene and reacted at a bath temperature of 90°C with addition of 1.65 g (0.071 gram atom) of sodium in several portions. The resulting methanol is distilled off at a reaction mixture temperature of 78 - 90°C under a pressure of 500 mbar. After a reaction time of about 5 hours, the reaction mixture is stirred into a mixture of - 14 ice and hydrochloric acid. The acid phase is separated off, rendered alkaline using sodium carbonate and the free base is extracted using methylene chloride. After drying over sodium sulphate, the methylene chloride is distilled off under reduced pressure and the residue is recrystallised from acetonitrile; beige-coloured crystals (from acetonitrile), m.p. 149 - 50°C, Yield: 33.79 g (44.7 % of theoretical).
Example 2 Scopine di-(2-thienyl)glycolate 12.72 g (0.05 mole) of methyl di-(2-thienyl)glycolate and 7.76 g (0.05 mole) of scopine are melted in a heating bath at 70°C under a water jet vacuum. 2.70 g (0.05 mole) of sodium methylate are introduced into this melt and heated for 1 hour in a heating bath at 70°C under a water jet vacuum and subsequently for a further hour in a heating bath at 90°C. The solidified melt is taken up in a mixture of 100 ml of water and 100 ml of methylene chloride while monitoring the temperature, and the methylene chloride phase is extracted several times using water. The methylene chloride phase is extracted using the corresponding amount of dilute hydrochloric acid. The scopine di-(2-thienyl)glycolate is extracted from the combined aqueous phases using methylene chloride after adding the corresponding amount of sodium carbonate and dried over sodium sulphate. The hydrochloride is prepared from the dried methylene chloride solution in a conventional manner. The crystals are filtered off under suction, washed using acetone and dried under reduced pressure at 35°C. Pale yellow crystals (from methanol), m.p. 238 - 41°C (decomposition); Yield: 10.99 g (53.1 % of theoretical). - 15 The hydrochloride may be converted to the base in a conventional manner.
Example 3 5 Scopine di-(2-thienyl)alveolate 38.15 g (0.15 mole) of methyl di-(2-thienyl)glycolate and 23.28 g (0.15 mole) of scopine are mixed, 0.34 g (0.015 gram atom) of sodium is added and the mixture is melted in a heating bath at 90°C under a water jet vacuum. The reaction lasts 2.5 hours. 100 ml of absolute toluene are then added and the mixture is stirred at a heating bath temperature of 90°C until a solution is produced. The reaction solution is cooled to room temperature and stirred into a mixture of ice and hydrochloric acid cooled using ice. The hydrochloride of the basic ester crystallising out is filtered off under suction and washed using 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 filtered off under suction is suspended in the (acid) aqueous phase and converted to the base while monitoring the temperature and adding the corresponding amount of sodium carbonate; the base is extracted using methylene chloride. The combined methylene chloride phases are dried over sodium sulphate. After distilling off the methylene chloride, crystals remain which are purified over active charcoal and recrystallised from acetonitrile. Pale yellow crystals (from acetonitrile), m.p. 148 - 49°C; Yield: 39.71 g (70.1 % of theoretical). - 16 Example 4 Scopine di-(2-thienyl)glycolate methobromide .0 g (0.0265 mole) of scopine di-(2-thienyl)glycolate are dissolved in a mixture comprising 20 ml of anhydrous methylene chloride and 30 ml of anhydrous acetonitrile and treated with 12.8 g (0.1325 mole) of methyl bromide (as 50 % strength solution in anhydrous acetonitrile), and the reaction mixture is allowed to stand for 24 hours at room temperature in a tightly sealed reaction vessel. Crystals are precipitated during this time. They are filtered off under suction, washed using methylene chloride and dried at 35°C under reduced pressure.
White crystals (from methanol/acetone), m.p. 217 - 8°C (decomposition) after drying at 111°C under reduced pressure.
According to the invention, the compounds listed in the following Tables may also be obtained.
Compounds of the formula - 17 Table I HO-C-CO-OA M.p.[*C] No AR1 Base Hydro- chloride 1 3a-(6β,7β-epoxy)-tropanyl 2-thienyl 149-50 238-41 20 2 3a-tropanyl 2-thienyl 167-8 253 3 3a-(6,7-dehydro)-tropanyl 2-thienyl 164-5 4 3a- (N-/3-fluoroethyl) - 2-thienyl nortropanyl 236 25 5 3a-(N-isopropyl)granatanyl 2-thienyl 232 6 3a-(N-isopropyl)nortropanyl 2-thienyl 256 7 3a-(6/3,70-epoxy) -N- 30 isopropyl-nortropanyl 2-thienyl 206 8 3a- (6β, 7/3—epoxy) -N-ethyl- nortropanyl 2-thienyl 212-3 9 3a-(N-ethyl)-nortropanyl 2-thienyl 256-7 35 10 3a-(N-N-methyl)-granatanyl 2-thienyl 241 11 3a- (6β, 7/3-epoxy) -N-/3- 2-thienyl fluoroethylnortropanyl 188-90 c No. A R1 Base M.p.['C] Hydrochloride □ 12 3a-(6)3,7^-epoxy)-N-n- 2-thienyl 104-6 propylnortropanyl 13 3a-(6)3,7/J-epoxy) -N-n- 2-thienyl butylnortropanyl 225-7 10 14 3a-(6£,7/J-epoxy)-tropanyl phenyl 246-7 15 3a-tropanyl phenyl 243-4 16 3a-(N-)9-fluoroethyl) - phenyl nortropanyl 219-20 17 3a-(6,7-dehydro)-tropanyl phenyl 181-3 15 18 3a-(N-ethyl)-nortropanyl phenyl 231-2 19 3a-(N-isopropyl)- nortropanyl phenyl 246-7 20 3a-tropanyl cyclohexyl 260 21 3a-(N-0-fluoroethyl)- cyclohexyl 20 nortropanyl 203-4 22 3a- (6j9,70-epoxy) -tropanyl cyclopentyl 237 23 3a-tropanyl cyclopentyl 260 24 3a-(N-/?-fluoroethyl) - cyclopentyl nortropanyl 182-3 25 25 3a-(N-ethyl)-nortropanyl cyclopentyl 227-8 26 3a-(N-isopropyl)- nortropanyl cyclopentyl 174-5 27 3)3-(6)8,70-epoxy)-tropanyl 2-thienyl 240-2 28 3j3-tropanyl 2-thienyl 217-9 30 29 3)8-(6,7-dehydro)-tropanyl 2-thienyl 233-5 30 3a-(6,7-dehydro)-tropanyl 3-thienyl 247-8 31 3α-(6)8,7β-epoxy)-tropanyl 3-thienyl 242-3 32 3a- (6)8,7/3-epoxy) -tropanyl 2-furyl 33 3a-(6,7-dehydro)-tropanyl 2-furyl 35 34 3a-tropanyl 2-furyl 35 3a-tropanyl 2-pyridyl 3 6 3a-(6)3,7)8-epoxy)-tropanyl 2-pyridyl - 19 10 No. A M.p.[°C] R1 Base Hydrochloride 37 3a-(6,7-dehydro)-tropanyl 2-pyridyl 38 3a-tropanyl 3-thienyl 39 3a-(6,7-dehydro)-tropanyl cyclopentyl 40 3 a- (60,7)3-epoxy) -tropanyl cyclohexyl 41 3a-(6,7-dehydro)-tropanyl cyclohexyl Note: All hydrochlorides melt with decomposition.
Quaternary compounds of the formula - 20 Table II No. A R1 M.p. [°C] -------------------------------------------------------- 1 3a- (6β, 7/?-epoxy) -tropanyl methobromide 2-thienyl 217-18 2 3a-tropanyl methobromide 2-thienyl 263-64 20 3 3a-(6,7-dehydro)-tropanyl methobromide 2-thienyl 191-92 4 3α-(N-0-fluoroethyl)- nortropanylmethobromide 2-thienyl 242-43 5 3a-tropanyl-)3- 25 fluoroethobromide 2-thienyl 214-15 6 3a-(N-isopropyl)granatanyl methobromide 2-thienyl 229-30 7 3a-(N-isopropyl) nortropanylmethobromide 2-thienyl 245-46 30 8 3a-(6β,70-epoxy)-Nisopropyl-nortropanyl methobromide 2-thienyl 223-24 9 3a-(6β,7/?-epoxy)-N- ethylnortropanyl 35 methobromide 2-thienyl 215-16 10 3a-(N-ethyl)-nortropanyl methobromide 2-thienyl 260-61 No. AR1 M.p.(°C) 5 11 3a-(N-methyl)-granatanyl- methobromide 2-thienyl 246-47 12 3a- (6β, 7)3-epoxy) -N- -fluoroethyl- nortropanyl methobromide 2-thienyl 182-83 10 13 3a- (6)3, Ίβ-epoxy) -N-n- propylnortropanyl methobromide 2-thienyl 209-10 14 3a-tropanyl-)3- hydroxyethobromide 2-thienyl 231-32 15 15 3a- (6β, 70-epoxy) -tropanyl methobromide phenyl 217-18 16 3a-tropanyl methobromide phenyl 273-74 17 3a-(N-/3-fluoroethyl) nortropanylmethobromide phenyl 215 20 18 3a-(6,7-dehydro)-tropanyl methobromide phenyl 170-71 19 3a-(N-ethyl)-nortropanyl me thobrom ide phenyl 249-50 20 3a-(N-isopropyl) - 25 nortropanyl methobromide phenyl 259-60 21 3a-tropanyl ethobromide phenyl 248-49 22 3a-(N-ethyl)-nortropanyl ethobromide phenyl 244-45 23 3a- (6)3,7)3-epoxy) -tropanyl 30 ethobromide phenyl 226 24 3a-tropanyl-)3- fluoroethobromide phenyl 241 25 3a-tropanyl methobromide cyclohexyl 278 26 3 a-(N-)3-fluoroethyl) - 35 27 nortropanyl methobromide 3a-tropany 1-/3- cyclohexyl 198 fluoroethobromide cyclohexyl 233-34 - 22 10 No. AR1 M.p.[°C] 28 3a-tropanyl methobromide cyclopentyl 260 29 3a-tropanyl ethobromide cyclopentyl 235-36 30 3a-(N-ethyl)-nortropanyl methobromide cyclopentyl 251-52 31 3a-(N-isopropyl)nortropanyl-methobromide cyclopentyl 244-45 32 3a-tropanyl-0- fluoroethobromide cyclopentyl 189-90 33 3a- (N-0-fluoroethyl) nortropanyl-methobromide cyclopentyl 226-27 34 3a-(6,7-dehydro)-tropanyl metho-methanesulphonate 2-thienyl 225-6 35 30-(60,70-epoxy) -tropanyl methobromide 2-thienyl 218-20 36 30-tropanyl methobromide 2-thienyl 243-4 37 30-(6,7-dehydro)-tropanyl methobromide 2-thienyl 211-4 38 3a-(6,7-dehydro)-tropanyl methobromide 3-thienyl 182-3* 39 3a-(60,70-epoxy)-tropanyl methobromide 3-thienyl 217-8 40 (+) enantiomer of No. 1 41 (-) enantiomer of No. 1 42 3a-(60,70-epoxy)-tropanyl methobrom ide 2-furyl 43 3a-(6,7-dehydro)-tropanyl methobromide 2-furyl 44 3a-tropanyl methobromide 2-furyl 45 3a-(60,70-epoxy)-tropanyl methobromide 2-pyridyl 46 3a-(6,7-dehydro)-tropanyl methobromide 2-pyridyl 47 3a-tropanyl methobromide 2-pyridyl 48 3a-tropanyl methobromide 3-thienyl No. AR1 49 3a-(6,7-dehydro)-tropanyl 5 methobromide cyclopentyl 50 3a- (6/3,7/3-epoxy) -tropanyl methobromide cyclohexyl 51 3a-(6,7-dehydro)-tropanyl methobromide cyclohexyl 10 52 3a- (6/8,7/3-epoxy) -tropanyl methobromide cyclopentyl •p.[°C] * contains crystalline methanol Note: All compounds in the table melt with decomposition. - 24 Table III Compounds of the formula No. A R., M.p. [°C] Hydrochloride 3a-(6β,7β-epoxy)-tropanyl 3a-(6,7-dehydro)-tropanyl 3a-(60,7j3-epoxy) -tropanyl 3a-(6,7-dehydro)-tropanyl 3a-tropanyl 3a-(N-methyl)-granatanyl phenyl phenyl 3-thienyl 3-thienyl 3-thienyl 3-thienyl 246-7 261-2 Compounds of the formula - 25 Table IV M.p.[°C] Hydrochloride 3a-(6/3,7/3-epoxy)-tropanyl H 3a-(6,7-dehydro)-tropanyl H 3a-(6/3,7/3-epoxy)-tropanyl methyl 3a-(6,7-dehydro)-tropanyl methyl 3a-(6/3,7/3-epoxy)-tropanyl methoxy 3a-(6,7-dehydro)-tropanyl methoxy 210-2.5 Compounds of the formula - 26 Table V HO-C-CO-OA I No. AR1Ra 20 1 3a- (6)3,7)3-epoxy) -tropanyl 2-thienyl 5-methyl 2 3a-(6,7-dehydro)-tropanyl 2-thienyl 5-methyl 3 3a-tropanyl 2-thienyl 5-methyl 4 3a-(6)3,7)3-epoxy) -tropanyl 2-(5-methyl)- thienyl 5-methyl 25 5 3a-(6,7-dehydro)-tropanyl 2-(5-methyl)thienyl 5-methyl 6 3a-tropanyl 2-(5-methyl)thienyl 5-methyl 7 3a- (6)3,Ίβ-epoxy) -tropanyl 2-thienyl 5-fluoro 30 8 3a-(6,7-dehydro)-tropanyl 2-thienyl 5-fluoro 9 3a-tropanyl 2-thienyl 5-fluoro 10 3a- (6)3,7)3-epoxy) -tropanyl 2-(5-fluoro)- thienyl 5-fluoro 11 3a-(6,7-dehydro)-tropanyl 2-(5-fluoro)- 35 thienyl 5-fluoro 12 3a-tropanyl 2-(5-fluoro)- thienyl 5-fluoro Compounds of the formula - 27 Table VI No. AR1Ra 15 1 3a-(60,70-epoxy)-tropanyl methobromide 2-thienyl 5-methyl 2 3a-(6,7-dehydro)-tropanyl methobromide 2-thienyl 5-methyl 3 3a-tropanyl-methobromide 2-thienyl 5-methyl 20 4 3a-(60,70-epoxy)-tropanyl 2-(5-methyl)- methobromide thienyl 5-methyl 5 3a-(6,7-dehydro)-tropanyl 2-(5-methyl)- methobromide thienyl 5-methyl 25 6 3a-tropanyl methobromide 2-(5-methyl)thienyl 5-methyl 7 3a-(60,70-epoxy)-tropanyl methobromide 2-thienyl 5-fluoro 8 3a-(6,7-dehydro)-tropanyl 2-thienyl 5-fluoro 30 methobromide 9 3a-tropanyl methobromide 2-thienyl 5-fluoro 10 3a-(60,70-epoxy)-tropanyl 2-(5-fluoro)- methobromide thienyl 5-fluoro 11 3a-(6,7-dehydro)-tropanyl 2-(5-fluoro)- 35 methobromide thienyl 5-fluoro 12 3a-tropanyl methobromide 2-(5-fluoro)thienyl 5-fluoro Compounds of the formula - 28 Table VII No. AR1 M.p.[-C) 1 3 a- (6/0,7/3-epoxy) -tropanyl methobromide phenyl 211-2 2 3a-(6,7-dehydro)-tropanyl methobromide phenyl 158-60* 3 3a- (6/0,7/0-epoxy) -tropanyl methobromide 3-thienyl 4 3a-(6,7-dehydro)-tropanyl methobromide 3-thienyl 5 3a-tropanyl methobromide 3-thienyl 6 3a-(N-methyl)-granatanyl 3-thienyl methobromide * (with crystalline methanol) Quaternary compounds of the formula - 29 Table VIII No. A R, M.p.(-C) 3a-(60,70-epoxy)-tropanyl methobromide 3a-(6,7-dehydro)-tropanyl methobromide 3a-(60,70-epoxy)-tropanyl methobromide 3a-(6,7-dehydro)-tropanyl methobromide 3a-tropanyl methobromide 3a-(N-methyl)-tropanyl methobromide H H methyl methyl 206-8 methoxy methoxy - 30 The following preparation examples serve to further illustrate the present invention without, however, limiting it (measures are given in weight per cent):5 1. Controlled dosage aerosol Active ingredient according to the invention 0.005 Sorbitan trioleate 0.1 Monofluorotrichloromethane and Difluorodichloromethane 2 : 3 to 100 The suspension is poured into a conventional aerosol container with a dosage valve. 50 μΐ of suspension are preferably dispensed per actuation. The active ingredient may also be metered in a higher amount if required (for example 0.02 wt.%). 2. Tablets Active ingredient according to the invention 0.05 Colloidal silicic acid 0.95 Lactose 65.00 Potato starch 28.00 Polyvinylpyrrolidone 3.00 Na cellulose glycolate 2.00 Magnesium stearate 1.00 The constituents are processed in conventional manner to give tablets of 200 mg.

Claims (17)

1. 1. Patent Claims (I), 15 in which A represents the group (II) (II) wherein 30 m and n independently of one another denote 1 or 2; Q represents one of the double-bonding groups -ch 2 -ch 2 - , -ch 2 -ch 2 -ch 2 - , -CH-CH- ; -CH=CH-, and - 32 Q’ represents the group =NR or the group =NRR·, wherein R denotes a hydrogen atom or an optionally halogen-substituted or hydroxy-substituted C^-alkyl radical and R’ denotes a C 1 . 4 -alkyl 5 radical; or R and R’ together form a C 4 . 6 -alkylene radical; R, represents an optionally methyl-substituted thienyl, phenyl, furyl, cyclopentyl or cyclohexyl radical, the 10 groups thienyl and phenyl optionally being fluoro- or chloro-substituted; Rj represents a hydrogen atom, or an OH, C 14 ~alkoxy or C 1 . 4 -alkyl group; R a represents hydrogen, fluorine, chlorine or CH 3 ; and quaternary derivatives thereof, wherein one equivalent of an anion (X e ) opposes the positive charge 20 of the N atom in the group Q'; and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof; and/or, where appropriate, acid-addition salts thereof.
2. Compounds as claimed in claim 1, wherein R 1 represents a 2-thienyl group.
3. Compounds as claimed in claim 1 or claim 2, wherein R 2 30 represents OH.
4. Compounds as claimed in any one of claims 1, 2 or 3, wherein A represents a group selected from wherein R and X® are as defined in claim 1 with defined in claim 1 and R' is the exception of hydrogen. as
5. Compounds as claimed in any one of claims 1 to 4, 25 wherein R, represents 2-thienyl and A represents the radical or in the 3a-form, wherein X® is one equivalent of an anion
6. Compounds as claimed in claim 5 wherein X® represents Br® or CH 3 SO 3 ®.
7. Compounds as claimed in any one of claims 1 to 6 15 selected from: S or in the 3a form and their acid addition salts and their methobromides or methomethanesulphonates.
8. Compounds as claimed in claim 1 as herein specifically disclosed in any of the Examples. - 35
9. A process for the preparation of compounds as claimed in claim 1 wherein an ester of the formula IV (IV), wherein R” represents a C V4 -alkyl radical and R v R 2 and R a are as defined in claim 1, is transesterified using an amino alcohol of the formula V wherein m, n and Q are as defined in claim 1 and Q represents =NR or =NH, in an inert organic solvent or in 25 a melt, in the presence of a transesterification catalyst; the compound thereby obtained is either a) if Q denotes =NR (R * H) optionally quaternised, using a reactive mono-functionalised derivative Z-(C 1 . 4 -alkyl) of an alkane (Z = leaving group) 30 or b) if Q denotes =NH is optionally substituted and quaternised, using a terminally disubstituted alkane Z-(C 4 . 6 -alkylene)-Z, without isolation of intermediates; and, if desired, the compounds thereby obtained are 35 converted into acid-addition salts thereof using conventional techniques. - 36 10. A process as claimed in claim 9 substantially as hereinbefore described and with reference to any of the Examples. 5 11. Compounds as claimed in claim 1 whenever prepared by a process as claimed in claim 9 or claim 10. 12. Pharmaceutical compositions comprising as active ingredient at least one compound of formula I or a
10. Quaternised derivative thereof, as defined in claim 1, in the form of a single enantiomer or diastereoisomer or mixtures thereof and/or a physiologically acceptable acid-addition salt thereof in association with one or more pharmaceutically acceptable carriers, diluents or 15 excipients.
11. 13. Compositions as claimed in claim 12 substantially as herein described. 20
12. 14. Compounds of general formula I as claimed in claim 1 and physiologically acceptable acid addition salts for use in therapy.
13. 15. The use of a compound as claimed in any one of 25 claims 1 to 8 or 11 or a physiologically acceptable acid addition salt thereof for the preparation of a medicament for use in the treatment of diseases or disorders in which anti-cholinergic therapy is required. 30
14. 16. The use as claimed in claim 15 for the treatment of chronic obstructive bronchitis, slight to moderately severe asthma and vagally induced sinus bradycardia.
15. 17. A method of treatment of diseases or disorders in a 35 subject for which anticholinergic treatment is required which comprises administering to said subject an effective amount of a compound of formula I as defined in claim 1 or a physiologically acceptable acid addition salt thereof.
16. 18. A method as claimed in claim 17 for the treatment 5 of chronic obstructive bronchitis, slight to moderately severe asthma and vagally induced sinus bradycardia.
17. 19. Each and every novel compound, process, method, composition and use herein disclosed.
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