NZ235306A

NZ235306A - Thienylacetic acid esters and pharmaceutical compositions

Info

Publication number: NZ235306A
Application number: NZ235306A
Authority: NZ
Inventors: Rolf Banholzer; Rudolf Bauer; Richard Reichl
Original assignee: Boehringer Ingelheim Int
Priority date: 1989-09-16
Filing date: 1990-09-14
Publication date: 1997-06-24
Also published as: DE10299026I1; DE10299026I2; ES2052125T3; DK0418716T3; NL300084I1; USRE39820E1; ZA907338B; IE903342A1; PL286900A1; NO301478B1; CZ284589B6; CZ452390A3; DE3931041A1; PT95312B; NO921002L; IL95691A; NO921002D0; DE59005250D1; WO1991004252A1; IL95691A0

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

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £35306 New Zealand No. 235306 International No. PCT/ TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 16.09.1989; Complete Specification Filed: 14.09.1990 Classification:^) C07D451/10,14; C07D471/08,18; C07D487/08,18; C07D491/18; A61K31 /40,445,46,55 Publication date: 24 June 1997 Journal No.: 1417 NO DRAWINGS NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: THIENYLCARBOXYLATES OF AMINO-ALCOHOLS Name, address and nationality of applicant(s) as in international application form: BOEHRINGER INGELHEIM INTERNATIONAL GMBH, a German body corporate of D-6507 Ingelheim am Rhein, Federal Republic of Germany 235306 WE, BOEHRINGER INGELHEIM INTERNATIONAL GMBH.,D-6507 Ingelheim am Rhein, West Germany, a body corporate organised under the laws of the Federal Republic of Germany, hereby declare the invention, for which We pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement! - 1 - (followed by page la) - la "THIENYLCARBOXYLATES OF AMINO ALCOHOLS" The present invention relates to novel thienylcarboxylates of amino alcohols and their quaternised derivatives, the preparation thereof and their use as active ingredients in medicaments. A divisional specification NZ 314677 has been filed out of this specification and relates to methods of treating patients requiring anticholinergic therapy, by employing thienylcarboxylates of amino alcohols. According to one aspect of the invention, we provide compounds of the formula (I) a % R,-C-CO-OA A 2 (i), in which A represents the group (II) (CH)-CH ' z m i -CH <CH2)n-CH (ii) wherein m and n independently of one another denote 1 or 2; (followed by page 2) 20 235306 Q represents one of the double-bonding groups -ch2-ch2-, -ch2-ch2-ch2-, -ch=ch-, or -ch ch- ; 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-alkyl radical and R' denotes a C^-alkyl 10 radical; or R and R1 together form a C^-alkylene radical; R1 represents an optionally methyl-substituted thienyl, phenyl, furyl, cyclopentyl or cyclohexyl radical, the 15 groups thienyl and phenyl optionally being fluoro- or chloro-substituted; Rj represents a hydrogen atom, or an OH, ct.4-alkoxy or C^-alkyl group; Ra represents hydrogen, fluorine, chlorine or CH3; and quaternary derivatives thereof, wherein one equivalent of an anion (X®) opposes the positive charge 25 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; 30 ■ with the exception of 3-tropanyl di(2-thienyl)glycolate and 3-tropanyl di(3-thienyl)glycolate, which were disclosed in Acta Chemica Scandinavia 2A (1970) pp.1590-1596. 35 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 appmpriafo salts 40 thereof. [ N-Z. PATSMT OFFKffL -9 FEB 1993 nccs!v3;" i 235300 - 3 - Compounds of the present invention which are particularly preferred include compounds of formula I as defined above wherein Rj 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 a-configuration and is derived from, for example, scopine, tropine, granatoline 10 or 6,7-dehydrotropine or the corresponding nor-compounds; however, -OA may also have the {3-configuration, as in pseudotropine or pseudoscopine. Compounds of the present invention which are especially 15 preferred include compounds of formula I as defined above wherein -OA represents a group selected from: 20 25 30 35 -O- -O V R-N / I [\ R-N -O- -0-. R-N^-R* I R-N®-R* \ / .0 Xs -0- -0- R-N -O- R-N®-R * R-N l> and -0-C R-Ne-R • XM 9 N Is ' ! N-Z. PATSMT OFF*** -8 FEB 199-5 20 25 235 306 - 4 - and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof; and/or, where appropriate, acid-addition salts thereof. 5 The substituent R is preferably a lover alkyl radical, for example, CHj, C^, n-CjH^, i-C^fy; 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 10 halogen-substituted or hydroxy-substituted alkyl radical, it is preferably -CH2-CH2F or -CHj-CHjOH. Accordingly, the group A represents, for example, the radicals of scopine, N-ethylnorscopine, N-isopropylnorscopine, tropine, N-isopropylnortropine, 15 6,7-dehydrotropine, N-/9-fluoroethylnortropine, N-isopropyl-6,7-dehydronortropine, N-methylgranatoline or the corresponding quaternary derivatives, wherein the anion X® is preferably Br® or CHjSOj®. For the acyl radical (III) % 4=/ •> rj-c-co- R, (III) particular mention must be made of the following groups: 30 35 A S \ s HO-C-CO- 'HO-d-CO- HO-C-CO- "A > % =/ - 5 - 235 306 HO-C-CO- HC-CO- =N s HgC-C-CO- 10 15 HO-C-CO- s HO-C-CO- :x S =/ HO-C-CO- / \ 20 The compounds of the present invention may be prepared by the following process, which process constitutes a further feature of the present invention: 25 30 an ester of formula IV R^-C—CO-OR' (IV), 35 wherein R" represents a C^-alkyl radical, preferably a methyl or ethyl radical, and R1, Rg and Ra have the above meanings, is preferably transesterified using an amino alcohol of the formula V 235306 6 <CH2>m— C" HO —CH Q" Q (V) \ (CH2)n—e.. wherein in, n and Q have the above meanings, Qn represents «NR or =NH athe OH group is in the a- or 0-position, in the presence of a conventional transesterificatlon catalyst, and the compound thereby obtained is either a) if Qn denotes =NR (R # H) optionally quaternised, using a reactive mono-functionalised derivative Z-fCj-C^-alkyl) of a corresponding alkane (Z » leaving group) or b) if Q" denotes «NH, is optionally quatemised using a terminally disubstituted alkane Z- (C4-C6-alJcylene) -Z, without isolation of Intermediates. The transesterificatlon 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 transesterificatlon in general takes place at temperatures which do not exceed 95°C. Transesterificatlon 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, 235306 30 for example acetonitrile or acetonitrile/methylene chloride, preferably at room temperature; a corresponding alley 1 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 C4.6-alkylene group. Conversion into the tertiary and then quaternary compound then takes place with the aid o£ suitable 1,4-dihaloalkanes, 1,5-dihaloalkanes or 1,6-dihaloalkanes without isolation of intermediates. The starting materials may be obtained by methods known BSE S£. 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 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) (copy available on request). 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. .. •• v.. 23 5306 - 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 2-bromo-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 cam be reacted analogously to give the corresponding glyoxylates Untarhalt, Arch. Pharm. 322, 839 (1989) (copy available on request) 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 cam 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 quaternary derivatives are particularly suitable for therapeutic application, whereas the tertiary compounds are important not only as active ingredients but also as intermediate products. - 9 - £35306 The compounds of the present invention and 3-tropanyl di(2-or 3-thienyl)glycolate have strong anti-cholinergic activity and have a prolonged action. Action lasting at least 24 hours is achieved at inhaled dosages in the jig 5 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 and 3-tropanyl 10 di(2-or 3-thienyl)glycolate 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 15 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 20 treatment is required which comprises administering to said subject an effective amount of a compound of formula I as hereinbefore defined or 3-tropanyl di(2-or 3-thienyl)glycolate or a physiologically acceptable acid addition thereof. 25 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 30 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. 35 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 -9 FEB 1993 none iveq - 10 - 23 5306 or proliposomes, injection solutions, tablets, coated tablets, capsules, inhalation powders for use in conventional inhalation apparatus. 5 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 3-tropanyl di(2-or 3-thienyl)glycolate or a quatemised derivative thereof, as hereinbefore defined, 10 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 pharmaceutical^ acceptable carriers, diluents or excipients. 15 U.Z.. PJVVfir?}" 0FFK3J -9 FEB 1993 235 306 - n - Pharmacological characteristics Tfra advantageous properties of the compounds of the prer.«mt invention are shown, for example, in the 5 inhibition of broncholysis in the rabbit (acetylcholine spasms intravenously). After intravenous administration of the novel active ingredients (dosage 3 /ug/kg intravenously), the maximum effect occurred after 10 to 40 minutes. After 5 hours xO 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: 15 Compound Residual effect in % A 76 B 76 C 81 20 D 61 E 68 F 73 G 69 25 The data above relate to the following compounds of formula I: - 12 - Compounds of the formula r\ /s —T ho-<j:-co-a R1 Compound 235 30 10 15 L, • K -O—/ CH3-I<®-CH3 O Bl@ / 2-thienyl b 20 -o—v ch3-1u-ch3 Bx@ -O—< CH3-E-CH3 Br© 3-thienyl 2-thienyl 25 E -o—/ CH3—rfcp—CH3 -J®-< Bi® 3-thienyl 30 BxP -O—/ CH3-I^-CI (CH3) 2 cyclopentyl 35 -o _/ ch3 -^-ch2-ch2f Bl® cyclopentyl 5 10 15 20 25 30 235306 - 13 - <?pffip<?mva c For the compounds A to G above: - i) the compounds in which R, 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 Sg<?Rine di-(2-thienyl)qlycplate 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 235306 10 - 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-thienvl1alveolate 15 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 20 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 25 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 30 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 tinder reduced pressure at 35°C. Pale yellow 35 crystals (from methanol), m.p. 238 - 41°C (decomposition); Yield: 10.99 g (53.1 % of theoretical). 235 306 5 - 15 - The hydrochloride nay be converted to the base in a conventional nanner. Example 3 ggoplna di-r a-thitnyl)qlycQlatq 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 10 (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 15 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 20 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 25 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 30 and recrystallised from acetonitrile. Pale yellow crystals (from acetonitrile), m.p. 148 - 49°C; Yield: 39.71 g (70.1 % of theoretical). 35 235 306 - 16 - Example 4 Scopine dl- ( 2-thlanvl1 glvoolata mathobromlda 5 10.0 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.B g (0.1325 mole) of methyl bromide (as 50 % strength solution in anhydrous acetonitrile), 10 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. 15 White crystals (from methanol/acetone), m.p. 217 - 8°C (decomposition) after drying at lll°c under reduced pressure. According to the invention, the compounds listed in the 20 following Tables may also be obtained. - 17 - Table X £3 5 34* Compounds of the formula 10 HO-C-CO-OA 15 No. M.p.['C] Base Hydrochloride 1 3a- (6/3, 7j0-epoxy) -tropanyl 2-thienyl 149-50 238-41 20 25 30 3 3a-(6,7-dehydro)-tropanyl 4 3a- (N-jS-f luoroethyl) - nortropanyl 5 3a-(N-isopropyl)-granatanyl 6 3a-(N-isopropyl)-nortropanyl 7 3a-(60,7jS-epoxy)-N-isopropyl-nortropanyl 2-thienyl 164-5 2-thienyl 2-thienyl 2-thienyl 2-thienyl 236 232 256 206 35 8 3a-(6/3,70-epoxy)-N-athyl- 2-thienyl nortropanyl 9- 3a-(N-ethyl)-nortropanyl 2-thienyl 10 3a-(N-N-raethyl)-granatanyl 2-thienyl 11 3a-(6/0,7/3-epoxy) -N-j8- ' 2-thienyl fluoroethylnortropanyl 212-3 256-7 241 188-90 -3 FEB '3^6 235306 - 18 - e No. A R, Base M.p.[«C] Hydrochloride 12 3a- (6/3, 7/3-epoxy) -N-n- 2-thienyl 104-6 propylnortropanyl 13 3a- (6/3,7/3-epoxy) -N-n- 2-thienyl butylnortropanyl 225-7 10 14 3 a- (6/3, 7j3-epoxy) -tropanyl phenyl 246-7 15 3a-tropanyl phenyl 243-4 16 3a- (N-/3-f luoroethyl) - phenyl nortropanyl 219-2( 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-jS-f luoroethyl) - cyclohexyl 20 nortropanyl - 203-4 22 3a- (6)3,7/3-epoxy) -tropanyl cyclopentyl 237 23 3a-tropanyl cyclopentyl 260 24 3a- (N-/3-f luoroethyl) - cyclopentyl nortropanyl 182-3 25 25 3a-(N-ethyl)-nortropanyl cyclopentyl 227-8 26 3a-(N-isopropyl)- nortropanyl cyclopentyl 174-5 27 3/3- (6/3,7/3-epoxy) -tropanyl 2-thienyl 240-2 30 29 3/3- (6,7-dehydro) -tropanyl 2-thienyl 233-5 30 3a-(6,7-dehydro)-tropanyl 3-thienyl 247-8 31 3a- (6/3,7/3-epoxy) -tropanyl 3-thienyl 242-3 32 3a- (6/3,7/3-epoxy) -tropanyl 2-furyl 33 3a-(6,7-dehydro)-tropanyl 2-furyl 35 34 3a-tropanyl 2-furyl 35 3a-tropanyl 2-pyridy1 36 3a- (6/3,7/3-epoxy) -tropanyl 2-pyridyl > ^ 235 3 - 19 - M.p.[*C] No. A R1 Base Hydro chloride 37 3a-(6,7-dehydro) 38 3a-tropanyl 39 3a-(6,7-dehydro) 40 3a-(6/9,7/9-epoxy) 41 3a-(6,7-dehydro) -tropanyl 2-pyridyl 3-thienyl -tropanyl cyclopentyl -tropanyl cyclohexyl -tropanyl cyclohexyl Note: All hydrochlorides melt with decomposition. - 20 - Table II Quaternary compounds of the formula 235 10 H0-C-C0-0A K No. M.p.fC] 15 1 3a- (6/8,7/3-epoxy) -tropanyl methobromide 2-thienyl 2 3a-tropanyl methobromide 2-thienyl 20 3 3a-(6,7-dehydro)-tropanyl methobromide 2-thienyl 4 3a- (N-/3-f luoroethyl) - •> nortropanylmethobromide 2-thienyl 5 3a-tropanyl-/9- 25 fluoroethobromide 2-thienyl 6 3a-(N-isopropyl)- granatanyl methobromide 2-thienyl 7 3a-(N-isopropyl)-nortropanylmethobromide 2-thienyl 30 8 3a- (6/8,7/8-epoxy) -N- isopropyl-nortropanyl methobromide 2-thienyl 9 3a-(6/3,7/3-epoxy )-N-ethylnortropanyl 35 methobromide 2-thienyl 10 3a-(N-ethyl)-nortropanyl methobromide 2-thienyl 217-18 263-64 191-92 242-43 214-15 229-30 245-46 223-24 215-16 260-61 - 21 - 235 305 No. M.p.[*C] 5 ll 3a-(N-methyl)-granatanyl-methobromide 12 3a- ( 60,7/9-epoxy) -N--fluoroethyl-nortropanyl methobromide 10 13 3a- (6/9,7/9-epoxy) -N-n-propylnortropanyl methobromide 14 3a-tropanyl-)3- hydroxyethobromide 15 15 3a-(6/9,7/8-epoxy)-tropanyl methobromide 16 3a-tropanyl methobromide 17 3 a- (N-/9-f luoroethyl) -nortropanylmethobromide 20 18 3a-(6,7-dehydro)-tropanyl methobromide 19 3a-(N-ethyl)-nortropanyl methobromide 20 3a-(N-isopropyl)- 25 nortropanyl methobromide 21 3a-tropanyl ethobromide 22 3a-(N-ethyl)-nortropanyl ethobromide 23 3a- ( 6/9,7/9-epoxy) -tropanyl 30 ethobromide 24 3a-tropanyl-0-fluoroethobromide 25 3a-tropanyl methobromide 26 3a-(N-^-fluoroethyl)- 35 nortropanyl methobromide 27 3a-tropanyl-0-fluoroethobromide 2-thienyl 2-thienyl 2-thienyl 2-thienyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl cyclohexyl cyclohexyl cyclohexyl 246-47 182-83 209-10 231-32 217-18 273-74 215 170-71 249-50 259-60 248-49 244-45 226 241 278 198 233-34 No, 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 235 3 06 - 22 - M.p.[*C] 3a-tropanyl methobromide 3a-tropanyl ethobromide 3a-(N-ethyl)-nortropanyl methobromide 3a-(N-isopropyl)-nortropanyl-methobromide 3a-tropanyl-/9-fluoroethobromide 3a- (N-j9-f luoroethyl) -nortropanyl-methobromide 3a-(6,7-dehydro)-tropanyl metho-methanesulphonate 3)8— ( 6/3,7/3-epoxy) -tropanyl methobromide 3/9-tropanyl methobromide 3/8- ( 6,7-dehydro) -tropanyl methobromide 3a-( 6,7-dehydro)-tropanyl methobromide 3a- ( 6/8,70-epoxy) -tropanyl methobromide (+) enantiomer of No. 1 (-) enantiomer of No. 1 3a- ( 6/9,7/3-epoxy) -tropanyl methobromide 3a-(6,7-dehydro)-tropanyl methobromide 3a-tropanyl methobromide 3a- ( 6/8,7/8-epoxy) -tropanyl methobromide 3a-(6,7-dehydro)-tropanyl methobromide 3a-tropanyl methobromide 3a-tropanyl methobromide cyclopentyl cyclopentyl cyclopentyl cyclopentyl cyclopentyl cyclopentyl 2-thienyl 2-thienyl 2-thienyl 2-thienyl 3-thienyl 3-thienyl 2-furyl 2-furyl 2-furyl 2-pyridyl 2-pyridyl 2-pyridyl 3-thienyl 260 235-36 251-52 244-45 189-90 226-27 225-6 218-20 243-4 211-4 182-3* 217-8 235 3 0 S - 23 - NO. A IL M.p. [ *C] 49 3a-(6,7-dehydro)-tropanyl 5 methobromide cyclopentyl 50 3a- ( 6/8,7/9-epoxy) -tropanyl methobromide cyclohexyl 51 3a-(6,7-dehydro)-tropanyl methobromide cyclohexyl 10 52 3a- (6/9,7/9-epoxy) -tropanyl methobromide cyclopentyl * contains crystalline methanol 15 Note: All compounds in the table melt with decomposition. 20 £5 5 50$ - 24 - Table XXI Compounds of the formula 10 HO-C-CO-OA 15 20 No. M.p.[°C] . Hydrochloride 25 1 3a-(6/?, 7/9-epoxy)-tropanyl 2 3a-(6,7-dehydro)-tropanyl 3 3a- (6(3,70-epoxy) -tropanyl 4 3a-(6,7-dehydro)-tropanyl phenyl phenyl 3-thienyl 3-thienyl 246-7 261-2 30 3a-(N-methyl)-granatanyl 3-thienyl N.Z, P/.T£if7 OPFKSi -9 FEB 1993 235 306 - 25 - Table IV compounds of the formula R.-C-CO-O-A No. A Rj M.p. [ *C] Hydrochloride 1 3a- (6 ft, 7/3-epoxy) -tropanyl H 2 3a-(6,7-dehydro)-tropanyl H «> 3 3a-(6/3,7/8-epoxy)-tropanyl methyl 4 3a-(6,7-dehydro)-tropanyl methyl 210-2.5 5 3a-(6/9,7/3-epoxy)-tropanyl methoxy 6 3a-(6,7-dehydro)-tropanyl methoxy 235305 - 26 - Table V Compounds of the formula No. 1 3a- (6fi,7/3-epoxy) -tropanyl 2 3a-(6,7-dehydro)-tropanyl 3 3a-tropanyl 4 3a- (6 ft, 7/3-epoxy) -tropanyl 5 3a-(6,7-dehydro)-tropanyl 6 3a-tropanyl 7 3a- (6 fi f 7/3-epoxy) -tropanyl 8 3a-(6,7-dehydro)-tropanyl 9 3a-tropanyl 10 3a- (6/3,70-epoxy) -tropanyl 11 3a-(6,7-dehydro)-tropanyl 12 3a-tropanyl 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-fluoro 5-fluoro 5-fluoro 5-fluoro 5-fluoro 5-fluoro 235 306 - 27 - Compounds of the formula 10 a HO-^-CO-OA R, No. 15 20 3 4 3a- (6/9,7/3-epoxy) -tropanyl methobromide 3a-(6,7-dehydro)-tropanyl methobromide 3 a—tropanyl—methobromide 3 a- (6/9,7)3-epoxy) -tropanyl methobromide 2-thienyl 2-thienyl 5-methyl 5-methyl 2-thienyl 5-methyl 2-(5-methyl)-thienyl 5-methyl 25 30 35 9 10 11 12 3a-(6,7-dehydro)-tropanyl methobromide 3a-tropanyl methobromide 3a- ( 6/9,70-epoxy) -tropanyl methobromide 3a-(6,7-dehydro)-tropanyl methobromide 3a-tropanyl methobromide 3a- (6)9,7/3-epoxy) -tropanyl methobromide 3a-(6,7-dehydro)-tropanyl methobromide 3a-tropanyl methobromide 2-(5-methyl)-thienyl 5-methyl 2-(5-methyl)-thienyl 5-methyl 2-thienyl 5-f >oro 2-thienyl 5-fluoro 2-thienyl 5-fluoro 2-(5-fluoro)-thienyl 5-fluoro 2-(5-fluoro)-thienyl 5-fluoro 2-(5-fluoro)-thienyl 5-fluoro / 15 - 28 - Table VII Compounds of the formula 235 30ff 10 HO-C-CO-OA No. M.p.fC] 20 25 5 6 3a- ( 6/8,7/3-epoxy) -tropanyl methobromide 3a—(6,7-dehydro)-tropanyl methobromide 3 a- (6/8,70-epoxy) -tropanyl methobromide 3a-(6,7-dehydro)-tropanyl methobromide 3a-tropanyl methobromide 3 a- (N-methyl) -granatanyl methobromide phenyl phenyl 3-thienyl 3-thienyl 3-thienyl 3-thienyl 211-2 158-60* 30 * (with crystalline methanol) 10 15 - 29 -Tflbls VIII Quaternary compounds of the formula ■ s r2-c-co-oa £ 235 306 20 No. 25 30 5 6 3a- ( 6/3,7/3-epoxy) -tropanyl methobromide 3a-(6,7-dehydro)-tropanyl methobromide 3a- (6/9,7/3-epoxy) -tropanyl methobromide 3a-(6,7-dehydro)-tropanyl methobromide 3a-tropanyl methobromide 3a-(N-methyl)-tropanyl methobromide *2 H H methyl methyl methoxy methoxy M.p.['C] 206-8 35 </div>

Claims

20 235 30 - 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 10 Difluorodichloromethane 2:3 to 100 The suspension is poured into a conventional aerosol container with a dosage valve. 50 nl of suspension are 15 preferably dispensed per actuation. The active ingredient may also be metered in a higher amount if required (for example 0.02 wt.%). Tablets Active ingredient according to the invention 0.05 Colloidal silicic acid 0.95 Lactose 65.00 Potato starch 28.00 25 Polyvinylpyrrolidone 3.00 Na cellulose glycolate 2.00 Magnesium stearate 1.00 The constituents are processed in conventional manner to 30 give tablets of 200 mg. 235306 10 20 WHAT WE rr.ATiM Tq.-

1. Compounds of formula I v r^c-co-oa (i)/ K. 2 15 in which A represents the group (II) ,(ch,) -ch-z m | -ch Q • 25 (CH2)n-CH- (ii) wherein 30 m and n independently of one another denote l or 2; Q represents one of the double-bonding groups -CH2-CH2-, —CHj-CHj-CHg*" / -CH=CH-, or 35 -C0 —-CJK- ; r;.Z.°A V £ i 47 -9 FEB 1393 RECEIVED Q' 5 R1 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,.4-alkoxy or C^-alkyl group; 15 Ra represents hydrogen, fluorine, chlorine or CH3; and quaternary derivatives thereof, wherein one equivalent of an aniou (X*) 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; 25 with the exception of the compounds: 3-tropanyl di(2-thienyl)glycolate and 3-tropanyl di(3-thienyl)glycolate.

2. Compounds as claimed in claim 1, wherein R, represents 30 a 2-thienyl -group.

3. Compounds as claimed in claim 1 or claim 2, wherein Rj represents OH. 35

4. Compounds as claimed in any one of claims l, 2 and 3, wherein A represents a group selected from 235300 - 32 - © 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 R1 denotes a C^-alkyl radical; or R and R* together form a C4.6-alkylene radical; 235306 - 33 - RNR >$ ,e 10 15 20 and / \ RNR ,€> RNR & \ 1 0 x e RNR *© ) Xs / wherein R and X* are as defined in claim 1 and R' is as defined in claim 1 with the exception of hydrogen.

5. Compounds as claimed in any one of claims 1 to 4, 25 wherein R, represents 2-thienyl and A represents the radical 30 35 or 'V " 5 AUG 1993 -■k 235 30 6 - 34 - ch3-n-®ch3 10 15 20 25 30 in the 3a-form, wherein X* is one equivalent of an anion.

6. Compounds as claimed in claim 5 wherein X* represents Br* or ch3so3*.

7. Compounds as claimed in any one of claims 1 to 6 selected from: =N s ho-c-co-o— s NCH, =/ or % HO-C-CO-O- nch. in the 3a form and their acid addition salts and their methobromides or methomethanesulphonates.

8. Compounds as claimed in claim 1 as herein 35 specifically disclosed in any of the Examples. * 235 30 6 - 35 -

9. A process for the preparation of compounds as claimed in claim 1 wherein an ester of the formula IV a R.-C-CO-OR" (IV), 10 wherein R" represents a C^-alkyl radical and R1, Rg and Ra are as defined in claim 1, is transesterified using an amino alcohol of the formula V 15 20 .<CH2>m-<fH' HO-CH Q" u (v) wherein m, n and Q are as defined in claim 1 and Qn represents »NR or «NH, in an inert organic solvent or in 25 a melt, in the presence of a transesterificatlon catalyst; the compound thereby obtained is either a) if QH denotes —NR (R # H) optionally quatemised, using a reactive mono-functionalised derivative Z- (C^-alkyl) of an alkane (Z » leaving group) 30 2t b) if Q" denotes -NH is optionally substituted and quatemised, using a terminally disubstituted alkane Z-(C4.6-alkylene)-Z, without isolation of intermediates; and, if desired, the compounds thereby obtained are 35 converted into acid-addition salts thereof using conventional techniques. 23 5306 - 36 -

10. A process as claimed in claim 9 substantially as hereinbefore described and with reference to any of the Examples.

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 10 15 ,-C-CO-OA L (i), 20 in which A represents the group (II) 25 <CH2>m-CH -CH q* (ii) 30 (ch2)n-ch- wherein 35 m and n independently of one another denote 1 or 2; Q represents one of the double-bonding groups r N.Z. PATENT Or FJGE 1 -9 FEB 1993 nseeivco 23 5306 - 37 - -CH2-CH2-, -CH2-CH2-CH2-, -CH-CH-, or -CH- -CH- ; © 5 Q * represents the group ^NR or the group =NRR', wherein R denotes a hydrogen atom or an optionally halogen-substituted or hydroxy-substituted C1.4-alkyl radical and R' denotes a C1.4-alkyl radical; or R and R' together form a C4.6-alkylene 10 radical; R1 represents an optionally methyl-substitute^ thienyl, phenyl, tv'.ryl, cyclopentyl or cyclohexyl radical, the group*- thienyl and phenyl optionally being fluoro- or 15 chlo.-o-substituted; R2 represents a hydrogen atom, or an OH, C.,_4-alkoxy or C^-alkyl group; 2 0 Ra represents hydrogen, fluorine, chlorine or CH3; and quaternary derivatives thereof, wherein one equivalent of an anion (Xe) opposes the positive charge of the N atom in the group Q'; 25 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. 30

13. Compositions as claimed in claim 12 substantially as herein described. 5 AUG 1993 7 *• ■ 0 E ' v 235306 - 38 -

14. The use of a compound as defined in any one of claims 1 to 8, 11 and 12 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.

15. The-vise as claimed in claim 14 for the treatment of chronic obstructive bronchitis, slight to moderately severe asthma and vagally induced sinus bradycardia. BOBHRIMGER IHGELHBIM INTKBWATTnwiT- ramtr END OF CLAIMS