CA2066248C - Esters of thienyl carboxylic acids and amino alcohols, their quaternization products, and manufacture and use of said compounds - Google Patents
Esters of thienyl carboxylic acids and amino alcohols, their quaternization products, and manufacture and use of said compoundsInfo
- Publication number
- CA2066248C CA2066248C CA002066248A CA2066248A CA2066248C CA 2066248 C CA2066248 C CA 2066248C CA 002066248 A CA002066248 A CA 002066248A CA 2066248 A CA2066248 A CA 2066248A CA 2066248 C CA2066248 C CA 2066248C
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- Prior art keywords
- thienyl
- formula
- compound
- tropanyl
- compounds according
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Classifications
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- 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
Abstract
The novel compounds of the formula (see fig. I) , (A, R1, Ra and R2 are defined in the description) may be prepared in accordance with processes known per se and used as active ingredients for medicaments.
Description
- - 206~248 NEW ESTERS OF THIENYL CARBOXYLIC ACIDS AND AMINO ALCOHOLS, THEIR QUATERNIZATION PRODUCTS, AND MANUFACTURE AND USE OF
SAID COMPOUNDS
The invention relates to novel thienyicarboxylates of amino alcohols and their quaternary products and to the preparation of the novel compounds and their use as active ingredients in medicaments.
The novel compounds correspond to the formula =, Ra S
+/
T (I), ~ 2 in which A represents the group (CH2)m~CH ~
-CHQ~ Q (II) J
'~ ( CH2 ) n~
wherein m and n independently of one another denote 1 or 2, Q represents one of the double-bonding groups -CH2-CH2-~ -C~2-cH2-cH2-~ -CH=CH-, -CII C~-~_ 0/
SAID COMPOUNDS
The invention relates to novel thienyicarboxylates of amino alcohols and their quaternary products and to the preparation of the novel compounds and their use as active ingredients in medicaments.
The novel compounds correspond to the formula =, Ra S
+/
T (I), ~ 2 in which A represents the group (CH2)m~CH ~
-CHQ~ Q (II) J
'~ ( CH2 ) n~
wherein m and n independently of one another denote 1 or 2, Q represents one of the double-bonding groups -CH2-CH2-~ -C~2-cH2-cH2-~ -CH=CH-, -CII C~-~_ 0/
- 2 - 2066~48 and Q' represents the group =NR or the group =NRR', whereln R
denotes H or an optionally halogen-substituted or hydroxy-substltuted Cl-C4-alkyl radlcal, R' denotes a Cl-C4-alkyl radlcal and R and R' together may also form a C4-C6-alkylene radlcal, and whereln, ln the case of quaternary compounds, one equlvalent of an anlon (X~) opposes the posltlve charge of the N atom, Rl represents a thlenyl, phenyl, furyl, cyclopentyl or cyclohexyl radical, whereln these radlcals may also be methyl-substltuted, thlenyl and phenyl may also be fluoro-substltuted or chloro-substltuted, R2 represents hydrogen, OH, Cl-C4-alkoxy or Cl-C4-alkyl Ra represents H, F, Cl or CH3 and, lf =NR denotes a secondary or tertlary amlno group, also the acld addltlon salt thereof, provlded that lf A represents 3-tropanol Rl represents 2-thlenyl or 3-thlenyl and R2 represents OH then Ra does not represent hydrogen.
In the compounds of formula I, Rl preferably represents thlenyl, R2 preferably represents OH. The group -OA preferably has the a-conflguratlon and ls derlved from, for example scoplne, troplne, granatollne or 6,7-dehydrotroplne or the correspondlng nor-compounds; however, -OA may also have the ~-conflguratlon, as ln pseudotroplne, pseudoscoplne.
Correspondlng radlcals are, for example - 2a -2066248 --0~ R- I --0<R- I -R' ~3 --0~ R- I / --O~R- I -R' / X~
A 21~00137 . 206~4~
-O ~ R-N , -O- / R-N~-~' Xe \
-O ~ R-N ) , -O ~ R-l -R' > Xe -O < ~N ~ Xe ~
The substituent R is preferably a lower alkyl radical, such as CH3~ C2Hs~ n-C3H7, i-C3H7, R' is preferably CH3. R
and R' together are, for example -(CH2)5-. As halogen substituents for R, F or, as second choice, Cl are suitable.
If R denotes a halogen-substituted or hydroxy-substituted alkyl radical, it is preferably -CH2-CH2F or -CH2-CH20H.' Accordingly, the group A
represents, for example the radicals of scopine, N-ethylnorscopine, N-isopropylnorscopine, tropine, N-isopropylnortropine, 6,7-dehydrotropine, N-~-fluoroethylnortropine, N-isopropyl-6,7-dehydronortropine, N-methylgranatoline or the corresponding quaternary compounds, wherein the anion is preferably Br or CH3SO3-.
As the acid radical R = S
I /
Rl-C-CO- (III) ' 20662~8 the following are particularly suitable:
~S ~ ~
=/ ~ ~
_ HO-C-CO- Ho- -CO- ~Or-;-CO-=~ =\S
\=/ .
~s 9s =\s HO-C-Co- ~ O- H3C-C-Co-~\ S ~
~ F=~ --\
=~S ~S e~S
HO-C-CO- HO-C-CO- HO-C-CO-~ ~f ~
The quaternary compounds are particularly suitable for therapeutic application, whereas the tertiary compounds are important not only as active ingredients but also as intermediate products.
The compounds of the invention are strong anti-cholinergic agents and have prolonged action.
Action lasting at least 24 hours is achieved at inhaled dosages in the ~g 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 novel compounds are suitable, in accordance with their anti-cholinergic nature, for example ~or the treatment of chronic obstructive bronchitis and (slight to moderately severe) asthma, also for the treatment of vagally induced sinus bradycardia.
Whereas application of the novel active ingredients (in particular the quaternary compounds) 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 novel compounds leave the gastro/intestinal motility largely unaffected.
For administration the compounds of the 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 or proliposomes, injection solutions, tablets, coated tablets, capsules, inhalation powders for use in conventional inhalation apparatus.
206624~
- 5a -The lnventlon extends to a commerclal package contalnlng a compound of the general formula (I) or a pharmaceutlcally acceptable salt thereof, together wlth instructlon for the treatment of the aforementloned allments.
A 27400-1~7 -Formulation examples (measures in weight per cent):
1. Controlled dosaqe 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 ~1 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.
_ 7 _ ~ 06~2 48 The advantageous properties of the novel compounds 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 ~g/kg intravenously), the maximum effect occurred after 10 to 40 minutes. After S hours the inhibiting effect had still not been reduced to half, that is to say the half effect time is more, in some cases considerably more, than 5 hours, as made clear by the residual effects after 5 hours listed below:
( Compound Residual effect in %
~ 61 (. .
: 206~2~8 Compounds of the formula HO-CI-CO-A
Compound A R
B ~
A j ¦ \ 2-thienyl (; -0 ~ CH3- ~ -CH3 0 B ~
._o ~ CH3- ~-CH3 ~ 3-thienyl B~ .
D -O ~ CH3- ~ -CH3 2-thienyl B ~
E -O ~ CH3-~-CH3 3-th~enyl B r~3 -O ~ CH3- ~-CH(CH3)2 F \ I cyclopentyl Bf~
--O _ ~ CH3--1~--CH2--CH2F
G \ ¦ cyclopentyl - - 20662~
g Compound C
/ Br~
HO-C-CO-O- < CH3- ~-CH
~3 Notes:
1. The compounds in which Rl is not 2-thienyl are racemates.
2. The compounds are 3~-compounds in each case.
Processes known per se are used to prepare the novel compounds.
An ester of the formula a _ ~
Rl-~-CO-OR~ (IV), wherein R" represents a Cl-C4-alkyl radical, preferably a methyl or ethyl radical (Rl, R2 and Ra have the above meanings), is preferably transesterified using an amino alcohol of the formula (CH2)m CH\
HO-CH Q" Q ( V ) (CH2)n CH
wherein m, n and Q have the above meanings, Q" represents =NR
or =NH and the OH group is in the ~- or ~-position, in the presence of a suitable transesterification catalyst, and the compound obtained is optionally quaternised a) if Q" denotes =NR (R ~ H), using a reactive mono-functionalised derivative Z-(C1-C4-alkyl) of a corresponding alkane (Z = leaving group) or is optionally quaternised b) if Q" denotes =NH, using a terminally disubstituted alkane Z-(C4-C6-alkylene)-Z without isolation of intermediates.
The transesterification is carried out with heat in an organic solvent, for example toluene, xylene, heptane, or iIl a melt, strong bases such as sodium methylate, sodium ethylate, sodium hydride, metallic sodium, being used as catalyst. Reduced pressure is used to remove the released lower alcohol from the equilibrium, the alcohol is optionally distilled off lOa azeotropically. The transesterification takes place at temperatures which in general do not exceed 95~C.
Transesterification often proceeds more favourably in a melt.
If required, the free bases may be obtained in a manner known per se from acid addition salts of the tertiary amines using suitable basic compounds. Quaternisation is carried out in suitable solvents, for example acetonitrile or acetonitrile/
methylene chloride, ~13SÇ~24~
preferably at room temperature; a corresponding alkyl halide, for example alkyl bromide, is preferably used in the process as 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-C6-alkylene group. Conversion into the tertiary and then quaternary compound then taXes 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 analogously to known compounds - in as much as they have not already been described.
Examples:
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).
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.
20662~
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 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 following examples illustrate the invention without limiting it.
Example 1 ~06624~
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 lO0 ml of absolute toluene and reacted at a bath temperature of 9o~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 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-rZ-thienYl)qlycolate 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 lO0 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 20~2~8 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).
The hydrochloride may be converted to the base in a conventional manner.
Exam~le 3 ScoPine di-(2-thienyl)~lycolate 38.15 g (o.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;
20~6248 ~ - 15 -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).
,_ .
( 2~6248 Table I
Compounds of the formula HO-C-CO-OA
M.p.t-C]
No. A R1 Base Hydro-chloride 3~-(6,~,7,~1-epoxy)-tropanyl 2-thienyl 149-50 238-41 2 3~-tropanyl 2-thienyl 167-8 253 3 3~-(6,7-dehydro)-tropanyl 2-thienyl 164-5 4 3cr-(N-~-fluoroethyl)- 2-thienyl nortropanyl ' 236 3~-(N-isopropyl)-granatanyl 2-thienyl 232 6 3c~-(N-isopropyl)-nortropanyl 2-thienyl 256 7 3~-(6,~,7,~-epoxy)-N-isopropyl-nortropanyl 2-thienyl 206 8 3~-(6,~,7~B-epoxy)-N-ethyl- 2-thienyl nortropanyl 212-3 9 3~-(N-ethyl)-nortropanyl 2-thienyl 256-7 3~-(N-N-methyl)-granatanyl 2-thienyl 241 11 3~-(6,~,7,~--epoxy)-N-,B- 2-thienyl fluoroethylnortropanyl 188-90 206~248 M.p.t C]
No. A R1 Base Hydro-chloride 12 3~-(6~,7~-epoxy)-N-n- 2-thienyl 104-6 propylnortropanyl 13 3~-(6~,7~-epoxy)-N-n- 2-thienyl butylnortropanyl 225-7 14 3~-(6~,7~-epoxy)-tropanyl phenyl 246-7 15 3~-tropanyl phenyl 243-4 16 3~-(N-~-fluoroethyl)- phenyl nortropanyl 219-20 17 3~-(6,7-dehydro)-tropanyl phenyl 181-3 18 3~-(N-ethyl)-nortropanyl phenyl 231-2 19 3~-(N-isopropyl)-nortropanyl phenyl 246-7 20 3~-tropanyl cyclohexyl 260 21 3~-(N-~-fluoroethyl)- cyclohexyl nortropanyl 203-4 22 3~-(6~,7~-epoxy)-tropanyl cyclopentyl 237 23 3~-tropanyl cyclopentyl 260 24 3~-(N-~-fluoroethyl)- cyclopentyl nortropanyl 182-3 2S 3~-(N-ethyl)-nortropanyl cyclopentyl 227-8 26 3~-(N-isopropyl)-nortropanyl cyclopentyl 174-5 27 3~-(6~,7~-epoxy)-tropanyl 2-thienyl 240-2 28 3~-tropanyl 2-thienyl 217-9 29 3~-(6,7-dehydro)-tropanyl 2-thienyl 233-5 30 3~-(6,7-dehydro)-tropanyl 3-thienyl 247-8 31 3~-(6~,7~-epoxy)-tropanyl 3-thienyl 242-3 32 3~-(6~,7~-epoxy)-tropanyl 2-furyl 33 3~-(6,7-dehydro)-tropanyl 2-furyl 34 3~-tropanyl 2-furyl 35 3~-tropanyl 2-pyridyl 36 3~-(6~,7~-epoxy)-tropanyl 2-pyridyl 206~248 M.p.[-C]
No. A Rt Base Hydro-chloride 37 3~-(6,7-dehydro)-tropanyl 2-pyridyl 38 3~-tropanyl 3-thienyl 39 3~-(6,7-dehydro)-tropanyl cyclopentyl 40 3~-(6~,7~-epoxy)-tropanyl cyclohexyl 41 3~-(6,7-dehydro)-tropanyl cyclohexyl ~ote: All hydrochlorides melt with decomposition.
Example 4 ScoPine di-(2-thienYl~ql~colate methobromide 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 12.8 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.
- 206~248 Table II
Quaternary compounds of the formula HO-C-CO-OA
R
! No. A R1 M.p.[-C~
____ ____________ 1 3~-(6~,7~-epoxy)-tropanyl methobromide 2-thienyl 217-18 2 3~-tropanyl methobromide 2-thienyl 263-64 3 3~-(6,7-dehydro)-tropanyl methobromide 2-thienyl 191-92 4 3~-(N-~-fluoroethyl)-nortropanylmethobromide 2-thienyl 242-43 5 3~-tropanyl-~-fluoroethobromide 2-thienyl 214-15 6 3~-(N-isopropyl)-granatanyl methobromide 2-thienyl 229-30 7 3~-(N-isopropyl)-nortropanylmethobromide 2-thienyl 245-46 8 3~-(6~,7~-epoxy)-N-isopropyl-nortropanyl methobromide 2-thienyl 223-24 9 3~-(6~,7~-epoxy)-N-ethylnortropanyl methobromide 2-thienyl 215-16 10 3~-(N-ethyl)-nortropanyl methobromide 2-thienyl 260-61 2~6~2~8 No. A ~ M.p.[~C]
denotes H or an optionally halogen-substituted or hydroxy-substltuted Cl-C4-alkyl radlcal, R' denotes a Cl-C4-alkyl radlcal and R and R' together may also form a C4-C6-alkylene radlcal, and whereln, ln the case of quaternary compounds, one equlvalent of an anlon (X~) opposes the posltlve charge of the N atom, Rl represents a thlenyl, phenyl, furyl, cyclopentyl or cyclohexyl radical, whereln these radlcals may also be methyl-substltuted, thlenyl and phenyl may also be fluoro-substltuted or chloro-substltuted, R2 represents hydrogen, OH, Cl-C4-alkoxy or Cl-C4-alkyl Ra represents H, F, Cl or CH3 and, lf =NR denotes a secondary or tertlary amlno group, also the acld addltlon salt thereof, provlded that lf A represents 3-tropanol Rl represents 2-thlenyl or 3-thlenyl and R2 represents OH then Ra does not represent hydrogen.
In the compounds of formula I, Rl preferably represents thlenyl, R2 preferably represents OH. The group -OA preferably has the a-conflguratlon and ls derlved from, for example scoplne, troplne, granatollne or 6,7-dehydrotroplne or the correspondlng nor-compounds; however, -OA may also have the ~-conflguratlon, as ln pseudotroplne, pseudoscoplne.
Correspondlng radlcals are, for example - 2a -2066248 --0~ R- I --0<R- I -R' ~3 --0~ R- I / --O~R- I -R' / X~
A 21~00137 . 206~4~
-O ~ R-N , -O- / R-N~-~' Xe \
-O ~ R-N ) , -O ~ R-l -R' > Xe -O < ~N ~ Xe ~
The substituent R is preferably a lower alkyl radical, such as CH3~ C2Hs~ n-C3H7, i-C3H7, R' is preferably CH3. R
and R' together are, for example -(CH2)5-. As halogen substituents for R, F or, as second choice, Cl are suitable.
If R denotes a halogen-substituted or hydroxy-substituted alkyl radical, it is preferably -CH2-CH2F or -CH2-CH20H.' Accordingly, the group A
represents, for example the radicals of scopine, N-ethylnorscopine, N-isopropylnorscopine, tropine, N-isopropylnortropine, 6,7-dehydrotropine, N-~-fluoroethylnortropine, N-isopropyl-6,7-dehydronortropine, N-methylgranatoline or the corresponding quaternary compounds, wherein the anion is preferably Br or CH3SO3-.
As the acid radical R = S
I /
Rl-C-CO- (III) ' 20662~8 the following are particularly suitable:
~S ~ ~
=/ ~ ~
_ HO-C-CO- Ho- -CO- ~Or-;-CO-=~ =\S
\=/ .
~s 9s =\s HO-C-Co- ~ O- H3C-C-Co-~\ S ~
~ F=~ --\
=~S ~S e~S
HO-C-CO- HO-C-CO- HO-C-CO-~ ~f ~
The quaternary compounds are particularly suitable for therapeutic application, whereas the tertiary compounds are important not only as active ingredients but also as intermediate products.
The compounds of the invention are strong anti-cholinergic agents and have prolonged action.
Action lasting at least 24 hours is achieved at inhaled dosages in the ~g 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 novel compounds are suitable, in accordance with their anti-cholinergic nature, for example ~or the treatment of chronic obstructive bronchitis and (slight to moderately severe) asthma, also for the treatment of vagally induced sinus bradycardia.
Whereas application of the novel active ingredients (in particular the quaternary compounds) 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 novel compounds leave the gastro/intestinal motility largely unaffected.
For administration the compounds of the 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 or proliposomes, injection solutions, tablets, coated tablets, capsules, inhalation powders for use in conventional inhalation apparatus.
206624~
- 5a -The lnventlon extends to a commerclal package contalnlng a compound of the general formula (I) or a pharmaceutlcally acceptable salt thereof, together wlth instructlon for the treatment of the aforementloned allments.
A 27400-1~7 -Formulation examples (measures in weight per cent):
1. Controlled dosaqe 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 ~1 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.
_ 7 _ ~ 06~2 48 The advantageous properties of the novel compounds 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 ~g/kg intravenously), the maximum effect occurred after 10 to 40 minutes. After S hours the inhibiting effect had still not been reduced to half, that is to say the half effect time is more, in some cases considerably more, than 5 hours, as made clear by the residual effects after 5 hours listed below:
( Compound Residual effect in %
~ 61 (. .
: 206~2~8 Compounds of the formula HO-CI-CO-A
Compound A R
B ~
A j ¦ \ 2-thienyl (; -0 ~ CH3- ~ -CH3 0 B ~
._o ~ CH3- ~-CH3 ~ 3-thienyl B~ .
D -O ~ CH3- ~ -CH3 2-thienyl B ~
E -O ~ CH3-~-CH3 3-th~enyl B r~3 -O ~ CH3- ~-CH(CH3)2 F \ I cyclopentyl Bf~
--O _ ~ CH3--1~--CH2--CH2F
G \ ¦ cyclopentyl - - 20662~
g Compound C
/ Br~
HO-C-CO-O- < CH3- ~-CH
~3 Notes:
1. The compounds in which Rl is not 2-thienyl are racemates.
2. The compounds are 3~-compounds in each case.
Processes known per se are used to prepare the novel compounds.
An ester of the formula a _ ~
Rl-~-CO-OR~ (IV), wherein R" represents a Cl-C4-alkyl radical, preferably a methyl or ethyl radical (Rl, R2 and Ra have the above meanings), is preferably transesterified using an amino alcohol of the formula (CH2)m CH\
HO-CH Q" Q ( V ) (CH2)n CH
wherein m, n and Q have the above meanings, Q" represents =NR
or =NH and the OH group is in the ~- or ~-position, in the presence of a suitable transesterification catalyst, and the compound obtained is optionally quaternised a) if Q" denotes =NR (R ~ H), using a reactive mono-functionalised derivative Z-(C1-C4-alkyl) of a corresponding alkane (Z = leaving group) or is optionally quaternised b) if Q" denotes =NH, using a terminally disubstituted alkane Z-(C4-C6-alkylene)-Z without isolation of intermediates.
The transesterification is carried out with heat in an organic solvent, for example toluene, xylene, heptane, or iIl a melt, strong bases such as sodium methylate, sodium ethylate, sodium hydride, metallic sodium, being used as catalyst. Reduced pressure is used to remove the released lower alcohol from the equilibrium, the alcohol is optionally distilled off lOa azeotropically. The transesterification takes place at temperatures which in general do not exceed 95~C.
Transesterification often proceeds more favourably in a melt.
If required, the free bases may be obtained in a manner known per se from acid addition salts of the tertiary amines using suitable basic compounds. Quaternisation is carried out in suitable solvents, for example acetonitrile or acetonitrile/
methylene chloride, ~13SÇ~24~
preferably at room temperature; a corresponding alkyl halide, for example alkyl bromide, is preferably used in the process as 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-C6-alkylene group. Conversion into the tertiary and then quaternary compound then taXes 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 analogously to known compounds - in as much as they have not already been described.
Examples:
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).
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.
20662~
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 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 following examples illustrate the invention without limiting it.
Example 1 ~06624~
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 lO0 ml of absolute toluene and reacted at a bath temperature of 9o~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 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-rZ-thienYl)qlycolate 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 lO0 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 20~2~8 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).
The hydrochloride may be converted to the base in a conventional manner.
Exam~le 3 ScoPine di-(2-thienyl)~lycolate 38.15 g (o.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;
20~6248 ~ - 15 -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).
,_ .
( 2~6248 Table I
Compounds of the formula HO-C-CO-OA
M.p.t-C]
No. A R1 Base Hydro-chloride 3~-(6,~,7,~1-epoxy)-tropanyl 2-thienyl 149-50 238-41 2 3~-tropanyl 2-thienyl 167-8 253 3 3~-(6,7-dehydro)-tropanyl 2-thienyl 164-5 4 3cr-(N-~-fluoroethyl)- 2-thienyl nortropanyl ' 236 3~-(N-isopropyl)-granatanyl 2-thienyl 232 6 3c~-(N-isopropyl)-nortropanyl 2-thienyl 256 7 3~-(6,~,7,~-epoxy)-N-isopropyl-nortropanyl 2-thienyl 206 8 3~-(6,~,7~B-epoxy)-N-ethyl- 2-thienyl nortropanyl 212-3 9 3~-(N-ethyl)-nortropanyl 2-thienyl 256-7 3~-(N-N-methyl)-granatanyl 2-thienyl 241 11 3~-(6,~,7,~--epoxy)-N-,B- 2-thienyl fluoroethylnortropanyl 188-90 206~248 M.p.t C]
No. A R1 Base Hydro-chloride 12 3~-(6~,7~-epoxy)-N-n- 2-thienyl 104-6 propylnortropanyl 13 3~-(6~,7~-epoxy)-N-n- 2-thienyl butylnortropanyl 225-7 14 3~-(6~,7~-epoxy)-tropanyl phenyl 246-7 15 3~-tropanyl phenyl 243-4 16 3~-(N-~-fluoroethyl)- phenyl nortropanyl 219-20 17 3~-(6,7-dehydro)-tropanyl phenyl 181-3 18 3~-(N-ethyl)-nortropanyl phenyl 231-2 19 3~-(N-isopropyl)-nortropanyl phenyl 246-7 20 3~-tropanyl cyclohexyl 260 21 3~-(N-~-fluoroethyl)- cyclohexyl nortropanyl 203-4 22 3~-(6~,7~-epoxy)-tropanyl cyclopentyl 237 23 3~-tropanyl cyclopentyl 260 24 3~-(N-~-fluoroethyl)- cyclopentyl nortropanyl 182-3 2S 3~-(N-ethyl)-nortropanyl cyclopentyl 227-8 26 3~-(N-isopropyl)-nortropanyl cyclopentyl 174-5 27 3~-(6~,7~-epoxy)-tropanyl 2-thienyl 240-2 28 3~-tropanyl 2-thienyl 217-9 29 3~-(6,7-dehydro)-tropanyl 2-thienyl 233-5 30 3~-(6,7-dehydro)-tropanyl 3-thienyl 247-8 31 3~-(6~,7~-epoxy)-tropanyl 3-thienyl 242-3 32 3~-(6~,7~-epoxy)-tropanyl 2-furyl 33 3~-(6,7-dehydro)-tropanyl 2-furyl 34 3~-tropanyl 2-furyl 35 3~-tropanyl 2-pyridyl 36 3~-(6~,7~-epoxy)-tropanyl 2-pyridyl 206~248 M.p.[-C]
No. A Rt Base Hydro-chloride 37 3~-(6,7-dehydro)-tropanyl 2-pyridyl 38 3~-tropanyl 3-thienyl 39 3~-(6,7-dehydro)-tropanyl cyclopentyl 40 3~-(6~,7~-epoxy)-tropanyl cyclohexyl 41 3~-(6,7-dehydro)-tropanyl cyclohexyl ~ote: All hydrochlorides melt with decomposition.
Example 4 ScoPine di-(2-thienYl~ql~colate methobromide 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 12.8 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.
- 206~248 Table II
Quaternary compounds of the formula HO-C-CO-OA
R
! No. A R1 M.p.[-C~
____ ____________ 1 3~-(6~,7~-epoxy)-tropanyl methobromide 2-thienyl 217-18 2 3~-tropanyl methobromide 2-thienyl 263-64 3 3~-(6,7-dehydro)-tropanyl methobromide 2-thienyl 191-92 4 3~-(N-~-fluoroethyl)-nortropanylmethobromide 2-thienyl 242-43 5 3~-tropanyl-~-fluoroethobromide 2-thienyl 214-15 6 3~-(N-isopropyl)-granatanyl methobromide 2-thienyl 229-30 7 3~-(N-isopropyl)-nortropanylmethobromide 2-thienyl 245-46 8 3~-(6~,7~-epoxy)-N-isopropyl-nortropanyl methobromide 2-thienyl 223-24 9 3~-(6~,7~-epoxy)-N-ethylnortropanyl methobromide 2-thienyl 215-16 10 3~-(N-ethyl)-nortropanyl methobromide 2-thienyl 260-61 2~6~2~8 No. A ~ M.p.[~C]
11 3a-(N-methyl)-granatanyl-methobromide 2-thienyl 246-47 12 3~-(6~,7~-epoxy)-N--fluoroethyl-nortropanyl methobromide 2-thienyl 182-83 13 3~-(6~,7~-epoxy)-N-n-propylnortropanyl methobromide 2-thienyl 209-10 14 3~-tropanyl-~-hydroxyethobromide 2-thienyl 231-32 15 3~-(6~7~-epoxy)-tropanyl methobromide phenyl 217-18 16 3~-tropanyl methobromide phenyl 273-74 17 3~-(N-~-fluoroethyl)-nortropanylmethobromide phenyl 215 18 3a-(6,7-dehydro)-tropanyl methobromide phenyl 170-71 19 3~-(N-ethyl)-nortropanyl methobromide phenyl 249-S0 20 3~-(N-isopropyl)-nortropanyl methobromide phenyl 2S9-60 21 3~-tropanyl ethobromide phenyl 248-49 22 3~-(N-ethyl)-nortropanyl ethobromide phenyl 244-45 23 3~-(6~,7~-epoxy)-tropanyl ethobromide phenyl 226 24 3~-tropanyl-~-fluoroethobromide phenyl 241 25 3~-tropanyl methobromide cyclohexyl 278 26 3~-(N-~-fluoroethyl)-nortropanyl methobromide cyclohexyl 198 27 3~-tropanyl-~- -fluoroethobromide cyclohexyl 233-34 20662~8 No. A Rl M.p.[-C]
28 3~-tropanyl methobromide cyclopentyl 260 29 3~-tropanyl ethobromide cyclopentyl 235-36 30 3~-(N-ethyl)-nortropanyl methobromide cyclopentyl 251-52 31 3~-(N-isopropyl)-nortropanyl-methobromide cyclopentyl 244-45 32 3~-tropanyl-~-fluoroethobromide cyclopentyl 189-90 33 3~-(N-~-fluoroethyl)-nortropanyl-methobromide cyclopentyl 226-27 t 34 3~-(6,7-dehydro)-tropanyl metho-methanesulphonate 2-thienyl 225-6 35 3~-(6~,7~-epoxy)-tropanyl methobromide 2-thienyl 218-20 36 3~-tropanyl methobromide 2-thienyl 243-4 37 3~-(6,7-dehydro)-tropanyl methobromide 2-thienyl 211-4 38 3~-(6,7-dehydro)-tropanyl methobromide 3-thienyl 182-3*
39 3~-(6~,7~-epoxy)-tropanyl methobromide 3-thienyl 217-8 40 (+) enantiomer of No. 1 41 (-) enantiomer of No. 1 f. 42 3~-(6~,7~-epoxy)-tropanyl methobromide 2-furyl 43 3~-(6,7-dehydro)-tropanyl methobromide 2-furyl 44 3~-tropanyl methobromide 2-furyl 3~-(6~,7~-epoxy)-tropanyl methobromide 2-pyridyl 46 3~-(6,7-dehydro)-tropanyl methobromide 2-pyridyl 47 3~-tropanyl methobromide 2-pyridyl 48 3~-tropanyl methobromide 3-thienyl - 2'D~6248 ~o. A Rl M.p.r~C3 ~9 3~-(6,7-dehydro)-tropanyl methobromide cyclopentyl 3~-(6~,7~-epoxy)-tropanyl methobromide cyclohexyl 51 3~-(6,7-dehydro)-tropanyl methobromide cyclohexyl 52 3~-(6~,7~-epoxy)-tropanyl methobromide cyclopentyl . _ * contains crystalline methanol Note: All compounds in the table melt with decomposition.
2~662~
Table III
Compounds of the formula HO-C-CO-OA
No. A R1M.p.~-C]
. ~ydrochloride __________ ___________ 1 3~-(6~,7~-epoxy)-t~opanyl phenyl246-7 2 3~-(6,7-dehydro)-tropanyl phenyl261-2 - 3 3~-(6~,7~-epoxy)-tropanyl 3-thienyl ( 4 3~-(6,7-dehydro)-tropanyl 3-thienyl 3~-tropanyl 3-thienyl 6 3~-(N-methyl)-granatanyl 3-thienyl Table IV
Compounds of the formula S
No. A R~M.p.t-C]
Hydrochloride _____ ________________ 13~-(6~,7~-epoxy)-tropanyl H
23a-(6,7-dehydro)-tropanyl H
33~-(6~,7~-epoxy)-tropanyl methyl 43~-(6,7-dehydro)-tropanyl methyl 210-2.5 ._ 53a-(6~,7~-epoxy)-tropanyl methoxy ( 63a-(6,7-dehydro)-tropanyl methoxy Table V 2066248 Compounds of the formula R S
a ~
~o - f -CO-OA
Rl No. A R Ra M.p.~ C~
__________ 1 3~-(6~,7~-epoxy)-tropanyl 2-thienyl 5-methyl 2 3~-(6,7-dehydro)-tropanyl 2-thienyl 5-methyl 3 3~-tropanyl 2-thienyl 5-methyl 4 3~-(6~,7~-epoxy)-tropanyl 2-(5-methyl)-thienyl 5-methyl 3~-t6,7- ehydro)-tropanyl 2-(5-methyl)-thienyl 5-methyl 6 3~-tropanyl 2-(5-methyl)-thienyl 5-methyl 7 3a-(6~,7~-epaxy)-tropanyl 2-thi_nyl 5-fluoro 8 3~-(6,7-dehydro)-tropanyl 2-thienyl 5-fluoro 9 3~-tropanyl 2-thienyl 5-fluoro 3~-(6~,7~-epoxy)-tropanyl 2-(5-fluoro)-thienyl 5-fluoro 11 3~-(6,7-dehydro)-tropanyl 2-(5-fluoro)-thienyl 5-fluoro 12 3~-tropanyl 2-(5-fluoro)-thienyl 5-fluoro ~- 27400-137 A
Ta~le VI
Compounds of the formula Ra , S
HO-~-CO-OA
Rl No. A R1Ra M.p-[ C]
_______ ___ 1 3¢-(6~,7~-epoxy)-tropanyl 2-thienyl 5-methyl methobromide 2 3~-(6,7-dehydro)-t~opanyl ~-thienyl 5-metnyl metho~romide 3 3~-tropanyl-methobromide 2-thienyl 5-methyl 4 3~-(6~,7~-epGxy)-t.opanyl 2-(5-methyl)-methobromide thienyl5-methyl 3~-(6,7-denydro)-tropanyl 2-(5-methyl)-methobromide thienyl5-methyl 6 3¢-tropznyl methobromide 2-(5-methyl)-thienyl5-methyl 3~-(6~,7~-epoxy)-tropanyl 2-thienyl 5-fluoro methobromide 8 3~-(6,7-dehydro)-t-opanyl 2-thienyl 5-flucrs ~ethobromide 9 3~-tropanyl methobromide 2-thienyl 5-fluoro 10 3¢-(6~7~-epoxy)-trop~nyl 2-(5-fluoro)-methObromide thienyl 5-fluoro 11 3¢-(6,7-dehydro)-trop2nYl 2-(5-fluoro)-methobroml~e thienyl 5-fluoro 12 3~-tropanyl metho~romide 2-(5-fluoro)-thienyl 5-fluoro Table VII
Compounds of the formula HO-C-CO-OA
Rl No. A Rl M.p.t-C]
_______________________ 1 3a-(6~,7~-epoxy)-tropanyl phenyl 211-2 methobromide 2 3a-(6,7-dehydro)-tropanyl phenyl 158-60*
methobromide 3 3a-(6~,7~-epoxy)-tropanyl 3-thienyl methobromide ~ 4 3a-(6,7-dehydro)-tropanyl 3-thienyl ( methobromide 5 3a-tropanyl methobromide 3-thienyl 6 3a-(N-methyl)-granatanyl 3-thienyl methobromide * (with crystalline methanol) ~ - 28 -Table VIII
Quaternary compounds of the formula R2-c-co-oA
No. A ~ M.p.~-C]
____ _ ___________________ 1 3~-(6~,7~-epoxy)-tropanyl H
methobromide 2 3~-(6,7-dehydro)-tropanyl H
~ methobromide (- . 3 3~-(6~,7~-epoxy)-tropanyl methyl methobromide 4 3~-(6,7-dehydro)-tropanyl methyl 206-8 methobromide 5 3~-tropanyl methobromide methoxy 6 3~-(N-methyl)-tropanyl methobromide methoxy
39 3~-(6~,7~-epoxy)-tropanyl methobromide 3-thienyl 217-8 40 (+) enantiomer of No. 1 41 (-) enantiomer of No. 1 f. 42 3~-(6~,7~-epoxy)-tropanyl methobromide 2-furyl 43 3~-(6,7-dehydro)-tropanyl methobromide 2-furyl 44 3~-tropanyl methobromide 2-furyl 3~-(6~,7~-epoxy)-tropanyl methobromide 2-pyridyl 46 3~-(6,7-dehydro)-tropanyl methobromide 2-pyridyl 47 3~-tropanyl methobromide 2-pyridyl 48 3~-tropanyl methobromide 3-thienyl - 2'D~6248 ~o. A Rl M.p.r~C3 ~9 3~-(6,7-dehydro)-tropanyl methobromide cyclopentyl 3~-(6~,7~-epoxy)-tropanyl methobromide cyclohexyl 51 3~-(6,7-dehydro)-tropanyl methobromide cyclohexyl 52 3~-(6~,7~-epoxy)-tropanyl methobromide cyclopentyl . _ * contains crystalline methanol Note: All compounds in the table melt with decomposition.
2~662~
Table III
Compounds of the formula HO-C-CO-OA
No. A R1M.p.~-C]
. ~ydrochloride __________ ___________ 1 3~-(6~,7~-epoxy)-t~opanyl phenyl246-7 2 3~-(6,7-dehydro)-tropanyl phenyl261-2 - 3 3~-(6~,7~-epoxy)-tropanyl 3-thienyl ( 4 3~-(6,7-dehydro)-tropanyl 3-thienyl 3~-tropanyl 3-thienyl 6 3~-(N-methyl)-granatanyl 3-thienyl Table IV
Compounds of the formula S
No. A R~M.p.t-C]
Hydrochloride _____ ________________ 13~-(6~,7~-epoxy)-tropanyl H
23a-(6,7-dehydro)-tropanyl H
33~-(6~,7~-epoxy)-tropanyl methyl 43~-(6,7-dehydro)-tropanyl methyl 210-2.5 ._ 53a-(6~,7~-epoxy)-tropanyl methoxy ( 63a-(6,7-dehydro)-tropanyl methoxy Table V 2066248 Compounds of the formula R S
a ~
~o - f -CO-OA
Rl No. A R Ra M.p.~ C~
__________ 1 3~-(6~,7~-epoxy)-tropanyl 2-thienyl 5-methyl 2 3~-(6,7-dehydro)-tropanyl 2-thienyl 5-methyl 3 3~-tropanyl 2-thienyl 5-methyl 4 3~-(6~,7~-epoxy)-tropanyl 2-(5-methyl)-thienyl 5-methyl 3~-t6,7- ehydro)-tropanyl 2-(5-methyl)-thienyl 5-methyl 6 3~-tropanyl 2-(5-methyl)-thienyl 5-methyl 7 3a-(6~,7~-epaxy)-tropanyl 2-thi_nyl 5-fluoro 8 3~-(6,7-dehydro)-tropanyl 2-thienyl 5-fluoro 9 3~-tropanyl 2-thienyl 5-fluoro 3~-(6~,7~-epoxy)-tropanyl 2-(5-fluoro)-thienyl 5-fluoro 11 3~-(6,7-dehydro)-tropanyl 2-(5-fluoro)-thienyl 5-fluoro 12 3~-tropanyl 2-(5-fluoro)-thienyl 5-fluoro ~- 27400-137 A
Ta~le VI
Compounds of the formula Ra , S
HO-~-CO-OA
Rl No. A R1Ra M.p-[ C]
_______ ___ 1 3¢-(6~,7~-epoxy)-tropanyl 2-thienyl 5-methyl methobromide 2 3~-(6,7-dehydro)-t~opanyl ~-thienyl 5-metnyl metho~romide 3 3~-tropanyl-methobromide 2-thienyl 5-methyl 4 3~-(6~,7~-epGxy)-t.opanyl 2-(5-methyl)-methobromide thienyl5-methyl 3~-(6,7-denydro)-tropanyl 2-(5-methyl)-methobromide thienyl5-methyl 6 3¢-tropznyl methobromide 2-(5-methyl)-thienyl5-methyl 3~-(6~,7~-epoxy)-tropanyl 2-thienyl 5-fluoro methobromide 8 3~-(6,7-dehydro)-t-opanyl 2-thienyl 5-flucrs ~ethobromide 9 3~-tropanyl methobromide 2-thienyl 5-fluoro 10 3¢-(6~7~-epoxy)-trop~nyl 2-(5-fluoro)-methObromide thienyl 5-fluoro 11 3¢-(6,7-dehydro)-trop2nYl 2-(5-fluoro)-methobroml~e thienyl 5-fluoro 12 3~-tropanyl metho~romide 2-(5-fluoro)-thienyl 5-fluoro Table VII
Compounds of the formula HO-C-CO-OA
Rl No. A Rl M.p.t-C]
_______________________ 1 3a-(6~,7~-epoxy)-tropanyl phenyl 211-2 methobromide 2 3a-(6,7-dehydro)-tropanyl phenyl 158-60*
methobromide 3 3a-(6~,7~-epoxy)-tropanyl 3-thienyl methobromide ~ 4 3a-(6,7-dehydro)-tropanyl 3-thienyl ( methobromide 5 3a-tropanyl methobromide 3-thienyl 6 3a-(N-methyl)-granatanyl 3-thienyl methobromide * (with crystalline methanol) ~ - 28 -Table VIII
Quaternary compounds of the formula R2-c-co-oA
No. A ~ M.p.~-C]
____ _ ___________________ 1 3~-(6~,7~-epoxy)-tropanyl H
methobromide 2 3~-(6,7-dehydro)-tropanyl H
~ methobromide (- . 3 3~-(6~,7~-epoxy)-tropanyl methyl methobromide 4 3~-(6,7-dehydro)-tropanyl methyl 206-8 methobromide 5 3~-tropanyl methobromide methoxy 6 3~-(N-methyl)-tropanyl methobromide methoxy
Claims (33)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Compound of the formula , in which A represents the group wherein m and n independently of one another denote 1 or 2, Q represents one of the double-bonding groups -CH-CH2-, -CH2-CH2-CH2-, -CH=CH, .
and Q' represents the group =NR or the group =NRR', wherein R
denotes H or an optionally halogen-substituted or hydroxy-substituted C1-C4-alkyl radical, R' denotes a C1-C4-alkyl radical and R and R' together may also form a C4-C6-alkylene radical, and wherein, in the case of quaternary compounds, one equivalent of an anion (X-) opposes the positive charge of the N atom, R1 represents a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl radical, wherein these radicals may also be methyl-substituted, thienyl and phenyl may also be fluoro-substituted or chloro-substituted, R2 represents hydrogen, OH, C1-C4-alkoxy or C1-C4-alkyl, Ra represents H, F, Cl, or CH3 and, if Q denotes =NR a secondary or tertiary amino group, also an acid addition salt thereof, provided that if A represents 3-tropanol, R1 represents 2- or 3-thienyl and R2 represents OH, then Ra does not represent hydrogen.
and Q' represents the group =NR or the group =NRR', wherein R
denotes H or an optionally halogen-substituted or hydroxy-substituted C1-C4-alkyl radical, R' denotes a C1-C4-alkyl radical and R and R' together may also form a C4-C6-alkylene radical, and wherein, in the case of quaternary compounds, one equivalent of an anion (X-) opposes the positive charge of the N atom, R1 represents a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl radical, wherein these radicals may also be methyl-substituted, thienyl and phenyl may also be fluoro-substituted or chloro-substituted, R2 represents hydrogen, OH, C1-C4-alkoxy or C1-C4-alkyl, Ra represents H, F, Cl, or CH3 and, if Q denotes =NR a secondary or tertiary amino group, also an acid addition salt thereof, provided that if A represents 3-tropanol, R1 represents 2- or 3-thienyl and R2 represents OH, then Ra does not represent hydrogen.
2. Compounds according to claim 1, wherein R1 represents 2-thienyl.
3. Compounds according to claim 1, wherein R2 represents OH.
4. Compounds according to claim 2, wherein R2 represents OH.
5. Compounds according to any one of claims 1 to 4 wherein A represents wherein R and Xe have the above meaning.
6. Compounds according to claim 5 wherein the group is attached to the 2-position of the thienyl group of formula I.
7. Compounds according to claim 5 wherein the group is attached to the 3-position of the thienyl group of formula I.
8. Compounds according to any one of claims 1 to 4, 6 and 7 wherein Ra is hydrogen, or a methyl group in the 5-position of the thienyl ring or fluorine atom in the 5-position of the thienyl ring.
9. Compounds according to claim 5 wherein Ra is hydrogen, or a methyl group in the 5-position of the thienyl ring or fluorine atom in the 5-position of the thienyl ring.
10. Compounds according to any one of claims 1 to 4, 6 and 7 wherein R is methyl, ethyl, .beta.-fluoroethyl, .beta.-hydroxyethyl, n-propyl, isopropyl or n-butyl and R1 is methyl.
11. Compounds according to claim 5 wherein R is methyl, ethyl, .beta.-fluoroethyl, .beta.-hydroxyethyl, n-propyl, isopropyl or n-butyl and R1 is methyl.
12. Compounds according to any one of claims 1 to 4, in which R1 denotes 2-thienyl and A represents the radical in the 3.alpha.-form, wherein Xe is one equivalent of an anion.
13. Compounds according to claim 12 wherein Xe is Bre or CH3 SO3e.
14. Compounds according to claim 13 wherein the group is attached to the 2-position of the thienyl ring of formula I.
15. Compounds according to claim 13 wherein the group is attached to the 3-position of the thienyl ring of formula I.
16. A compound of the formula in the 3.alpha.-form, or an acid addition salt or the methobromide or the methomethanesulphonate salt thereof.
17. A compound of the formula in the 3.alpha.-form, or an acid addition salt or the methohromide or methomethanesulphonate salt thereof.
18. A compound of the formula wherein X- is a physiologically acceptable anion.
19. A compound of the formula wherein X- is a physiologically acceptable anion.
20. A compound of the formula wherein R1 is 2-thienyl and A is 3.alpha.-(6.beta., 7.beta.-epoxy)-tropanyl methobromide.
21. A compound of the formula wherein R1 is 2-thienyl and A is 3.beta.-tropanyl methobromide.
22. A compound of the formula wherein R1 is 2-thienyl and A is 3.alpha.-(6,7-dehydro)-tropanyl methobromide.
23. A compound of the formula wherein R1 is cyclopentyl and A is 3.alpha.-(N-isopropyl)-nortropanyl methobromide.
24. Process for the preparation of compounds according to any one of claims 1 to 4, 6, 7, 9, 11 and 13 to 23, characterised in that an ester of the formula , wherein R" represents a C1-C4-alkyl radical and R1, R2 and Ra have the meaning given in any one of claims 1 to 4, 6, 7, 9, 11 and 13 to 23, is transesterified using an amino alcohol of the formula wherein m, n and Q have the meanings given in any one of claims 1 to 4, 6, 7, 9, 11 and 13 to 23 and Q" represents =NR
or =NH, in an inert organic solvent or in a melt, in the presence of a transesterification catalyst, and the compound obtained is, if required, quaternised a) if Q" denotes =NR and R is other than hydrogen, using a reactive mono-functionalised derivative Z-(C1-C4-alkyl) of an alkane (wherein Z is a leaving group) or, if required, substituted and quaternised b) if Q" denotes =NH, using a terminally disubstituted alkane Z-(C4-C6-alkylene)-Z without isolation of intermediates, or if required a compound of formula I in which Q' is =NH or =NR
is converted to an acid addition salt.
or =NH, in an inert organic solvent or in a melt, in the presence of a transesterification catalyst, and the compound obtained is, if required, quaternised a) if Q" denotes =NR and R is other than hydrogen, using a reactive mono-functionalised derivative Z-(C1-C4-alkyl) of an alkane (wherein Z is a leaving group) or, if required, substituted and quaternised b) if Q" denotes =NH, using a terminally disubstituted alkane Z-(C4-C6-alkylene)-Z without isolation of intermediates, or if required a compound of formula I in which Q' is =NH or =NR
is converted to an acid addition salt.
25. A process for the quaternisation of a compound of the formula I as defined in any one of claims 1 to 4, 6, 7, 9, 11 and 13 to 23, wherein a compound of the formula I in which Q' is =NR is reacted with a compound of the general formula Z-(C1-C4-alkyl) or Z-(C4-C6)-Z, wherein Z is a suitable leaving group.
26. A process according to claim 25, wherein ZCH3 is used for quaternisation, wherein Z is a suitable leaving group.
27. Use of compounds of the formula I as defined in any one of claims 1 to 4, 16 and 17 wherein Q' denotes =NR, and their salts as intermediate products for the preparation of the corresponding quaternary compounds of the formula I as defined in any one of claims 1 to 4, 6, 7, 9, 11 and 13 to 23.
28. A medicament characterised in that it contains a compound according to any one of claims 1 to 4, 6, 7, 9, 11 and 13 to 23 or a pharmaceutically acceptable salt thereof together with a suitable auxiliary or excipient.
29. Use of a compound according to any one of claims 1 to 4, 6, 7, 9, 11 and 13 to 23 or a pharmaceutically acceptable salt thereof in the preparation of anti-cholinergic medicaments.
30. Use of a compound according to any one of claims 1 to 4, 6, 7, 9, 11 and 13 to 23 or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the treatment of respiratory tract diseases and sinus bradycardia.
31. Use of a compound according to any one of claims 1 to 4, 6, 7, 9, 11 and 13 to 23 or a pharmaceutically acceptable salt thereof as an anti-cholinergic.
32. Use of a compound according to any one of claims 1 to 4, 6, 7, 9, 11 and 13 to 23 or a pharmaceutically acceptable salt thereof in the treatment of respiratory tract diseases and sinus bradycardia.
33. A commercial package containing a compound of the formula I as defined in any one of claims 1 to 4, 6, 7, 9, 11 and 13 to 23 or a pharmaceutically acceptable salt thereof, together with instructions for its use as an anti-cholinergic or its use for the treatment of respiratory tract diseases and sinus bradycardia.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3931041A DE3931041C2 (en) | 1989-09-16 | 1989-09-16 | Esters of thienyl carboxylic acids with amino alcohols, their quaternization products, processes for their preparation and medicaments containing them |
| DEP3931041.8 | 1989-09-16 |
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| CA2066248A1 CA2066248A1 (en) | 1991-03-17 |
| CA2066248C true CA2066248C (en) | 1998-08-04 |
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| CA002066248A Expired - Lifetime CA2066248C (en) | 1989-09-16 | 1990-09-08 | Esters of thienyl carboxylic acids and amino alcohols, their quaternization products, and manufacture and use of said compounds |
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| US (1) | USRE39820E1 (en) |
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| BG (1) | BG61295B2 (en) |
| CA (1) | CA2066248C (en) |
| CZ (1) | CZ284589B6 (en) |
| DD (1) | DD297647A5 (en) |
| DE (3) | DE3931041C2 (en) |
| DK (1) | DK0418716T3 (en) |
| ES (1) | ES2052125T3 (en) |
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Families Citing this family (148)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3931041C2 (en) | 1989-09-16 | 2000-04-06 | Boehringer Ingelheim Kg | Esters of thienyl carboxylic acids with amino alcohols, their quaternization products, processes for their preparation and medicaments containing them |
| DE4108393A1 (en) * | 1991-03-15 | 1992-09-17 | Boehringer Ingelheim Kg | NEW ESTERS BI-AND TRICYCLIC AMINO ALCOHOLS, THEIR PREPARATION AND THEIR USE IN MEDICINAL PRODUCTS |
| US5770738A (en) * | 1992-03-05 | 1998-06-23 | Boehringer Ingelheim Kg | Esters of bi- and tricyclic amino alcohols, their preparation and their use in pharmaceutical compositions |
| DE19921693A1 (en) | 1999-05-12 | 2000-11-16 | Boehringer Ingelheim Pharma | Pharmaceutical composition for treating respiratory disorders, e.g. asthma, comprises combination of anticholinergic and beta-mimetic agents having synergistic bronchospasmolytic activity and reduced side-effects |
| ES2165768B1 (en) | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | NEW DERIVATIVES OF QUINUCLIDINE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
| US7214687B2 (en) | 1999-07-14 | 2007-05-08 | Almirall Ag | Quinuclidine derivatives and medicinal compositions containing the same |
| GB0009583D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Respiratory formulations |
| GB0009606D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Therapeutic combinations |
| GB0009605D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Medicaments |
| GB0009592D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Respiratory combinations |
| US6759398B2 (en) | 2000-08-05 | 2004-07-06 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative |
| US6787532B2 (en) | 2000-08-05 | 2004-09-07 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivatives |
| US6777400B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| ES2523930T3 (en) | 2000-08-05 | 2014-12-02 | Glaxo Group Limited | 6-alpha, 9-alpha-difluoro-17-alpha - [(2-furanylcarbonyl) oxy] -11-beta-hydroxy-16-alpha-methyl-3-oxo-androst-1,4-acid s-fluoromethyl ester -dien-17-carbothioic as an anti-inflammatory agent |
| GB0019172D0 (en) | 2000-08-05 | 2000-09-27 | Glaxo Group Ltd | Novel compounds |
| US6858593B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6750210B2 (en) | 2000-08-05 | 2004-06-15 | Smithkline Beecham Corporation | Formulation containing novel anti-inflammatory androstane derivative |
| US6858596B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivative |
| US6777399B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6908928B2 (en) | 2000-10-12 | 2005-06-21 | Bi Pharma Kg. | Crystalline tiotropium bromide monohydrate, processes for the preparation thereof, and pharmaceutical compositions |
| EP1430887A1 (en) | 2000-10-12 | 2004-06-23 | Boehringer Ingelheim Pharma GmbH & Co.KG | Powder for inhalation containing Tiotropium |
| ME00243B (en) * | 2000-10-12 | 2011-05-10 | Boehringer Ingelheim Pharma | Crystalline monohydrate of tiotropiumbromide, method for producing the same and the use thereof in the production of a medicament |
| BRPI0115076B8 (en) * | 2000-10-31 | 2021-05-25 | Boehringer Ingelheim Pharma | pharmaceutical preparation, its pharmaceutical application, as well as the process for its preparation |
| DE10064816A1 (en) * | 2000-12-22 | 2002-06-27 | Boehringer Ingelheim Pharma | Production of tiotropium bromide useful as an anticholinergic comprises oxidation of di-(2-thienyl)-glycolic acid tropenol ester and subsequent quaternisation |
| KR100869721B1 (en) | 2000-12-28 | 2008-11-21 | 알미랄 에이쥐 | Novel quinuclidine derivatives and medicinal compositions containing the same |
| US6506900B1 (en) | 2001-01-31 | 2003-01-14 | Boehringer Ingelheim Pharma Ag | Process for preparing a scopine ester intermediate |
| UA77656C2 (en) | 2001-04-07 | 2007-01-15 | Glaxo Group Ltd | S-fluoromethyl ester of 6-alpha, 9-alpha-difluoro-17-alpha-[(2-furanylcarbonyl)oxy]-11-beta-hydroxy-16- alpha-methyl-3-oxoandrosta-1,4-dien-17-beta-carbothioacid as anti-inflammatory agent |
| DE60229372D1 (en) | 2001-04-30 | 2008-11-27 | Glaxo Group Ltd | ANTIPHLOGISTIC 7.BETA.-CARBOTHIOATES ESTER DERIVATIVES OF ANDROSTAN WITH A 17.ALPHA CYCLIC ESTER GROUP |
| DE10126924A1 (en) * | 2001-06-01 | 2002-12-05 | Boehringer Ingelheim Pharma | Inhalation capsule contains powdered mixture of tiotropium and auxiliary, for treating asthma or chronic obstructive pulmonary disease, having capsule material of low moisture content to improve stability |
| US6608055B2 (en) | 2001-06-22 | 2003-08-19 | Boehringer Ingelheim Pharma Kg | Crystalline anticholinergic, processes for preparing it and its use for preparing a pharmaceutical composition |
| PL208137B1 (en) * | 2001-06-22 | 2011-03-31 | Boehringer Ingelheim Pharma | Crystalline anticholinergic, method for its production, and use thereof in the production of a drug |
| US6610849B2 (en) * | 2001-06-28 | 2003-08-26 | Boehringer Ingelheim Pharma Kg | Process for the manufacture of tropenol |
| DE10141377A1 (en) | 2001-08-23 | 2003-03-13 | Boehringer Ingelheim Pharma | Scattering process for the production of powder formulations |
| ES2315425T3 (en) | 2001-10-26 | 2009-04-01 | PHARMACIA & UPJOHN COMPANY LLC | QUATERNARY AMMONIUM COMPOUNDS AND ITS USE AS ANTIMUSCARINIC AGENTS. |
| DE10200943A1 (en) * | 2002-01-12 | 2003-07-24 | Boehringer Ingelheim Pharma | Process for the preparation of scopine esters |
| DE10203749A1 (en) * | 2002-01-31 | 2003-08-14 | Boehringer Ingelheim Pharma | New anticholinergics, process for their preparation and their use as medicines |
| US6696462B2 (en) | 2002-01-31 | 2004-02-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Anticholinergics, processes for the preparation thereof, and pharmaceutical compositions |
| GB0202635D0 (en) * | 2002-02-05 | 2002-03-20 | Glaxo Wellcome Mfg Pte Ltd | Formulation containing novel anti-inflammatory androstane derivative |
| GB0203193D0 (en) * | 2002-02-11 | 2002-03-27 | Pfizer Ltd | Nicotinamide derivatives useful as pde4 inhibitors |
| AU2003201745A1 (en) * | 2002-02-11 | 2003-09-04 | Pfizer Limited | Nicotinamide derivatives and a tiotropium salt in combination for the treatment of e.g. inflammatory, allergic and respiratory diseases |
| DE10212264A1 (en) | 2002-03-20 | 2003-10-02 | Boehringer Ingelheim Pharma | Crystalline micronisate, process for its preparation and its use for the manufacture of a medicament |
| US7309707B2 (en) * | 2002-03-20 | 2007-12-18 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Crystalline micronisate, process for the manufacture thereof and use thereof for the preparation of a medicament |
| DE10214264A1 (en) * | 2002-03-28 | 2003-10-16 | Boehringer Ingelheim Pharma | HFA suspension formulations of an anhydrate |
| US7244415B2 (en) | 2002-03-28 | 2007-07-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | HFA suspension formulations of an anhydrate |
| UA80123C2 (en) | 2002-04-09 | 2007-08-27 | Boehringer Ingelheim Pharma | Inhalation kit comprising inhalable powder of tiotropium |
| DE10216036A1 (en) | 2002-04-11 | 2003-10-23 | Boehringer Ingelheim Pharma | Aerosol formulation for inhalation containing a tiotropium salt |
| DE10224091A1 (en) * | 2002-05-31 | 2003-12-11 | Boehringer Ingelheim Pharma | Technical process for the production of tropenol |
| GB2389530B (en) | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
| US7763280B2 (en) | 2002-11-28 | 2010-07-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Tiotropium containing powder formulation for inhalation |
| EP1589968A4 (en) * | 2003-01-16 | 2009-05-06 | Univ Rochester | Quaternary antimuscarinic compounds for the treatment of bladder diseases |
| US20040226556A1 (en) | 2003-05-13 | 2004-11-18 | Deem Mark E. | Apparatus for treating asthma using neurotoxin |
| ATE435862T1 (en) | 2003-05-28 | 2009-07-15 | Theravance Inc | AZABICYCLOALKAN COMPOUNDS AS MUSCARINE RECEPTOR ANTAGONISTS |
| PL1682542T3 (en) * | 2003-11-03 | 2010-06-30 | Boehringer Ingelheim Int | Novel crystalline anhydride with anticholinergic effect |
| ATE460414T1 (en) | 2003-11-03 | 2010-03-15 | Boehringer Ingelheim Int | METHOD FOR PRODUCING TIOTROPIUM SALTS |
| EP2322522A1 (en) | 2003-11-03 | 2011-05-18 | Boehringer Ingelheim International Gmbh | New tiotropium salts, processes for their preparation and drug formulations containing them |
| US7968717B2 (en) | 2003-11-03 | 2011-06-28 | Boehringer Ingelhein International Gmbh | Crystalline anhydrate with anticholinergic efficacy |
| SE0303570L (en) | 2003-12-03 | 2005-06-04 | Microdrug Ag | Moisture-sensitive medical product |
| US20080027094A1 (en) * | 2004-08-30 | 2008-01-31 | Ono Pharmaceutical Co., Ltd. | Tropane Compounds and Pharmaceutical Compositions Comprising the Same as an Active Ingredient |
| AU2006243238B2 (en) | 2005-05-02 | 2012-05-24 | Boehringer Ingelheim International Gmbh | Novel crystalline forms of tiotropium bromide |
| RU2007144531A (en) * | 2005-05-02 | 2009-06-10 | БЕРИНГЕР ИНГЕЛЬХАЙМ ИНТЕРНАЦИОНАЛЬ ГмбХ (DE) | NEW CRYSTAL FORMS OF THIOTROPYBROMIDE |
| DE102005035112A1 (en) | 2005-07-27 | 2007-02-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | A new process for the preparation of tiotropium salts using N-methylscopinium salts soluble in organic solvents |
| US7994211B2 (en) | 2005-08-08 | 2011-08-09 | Argenta Discovery Limited | Bicyclo[2.2.1]hept-7-ylamine derivatives and their uses |
| US20070088030A1 (en) | 2005-10-10 | 2007-04-19 | Barbara Niklaus-Humke | Aerosol formulations for the inhalation of beta-agonists |
| DE102005059602A1 (en) * | 2005-12-14 | 2007-06-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Micronization process |
| US20070167480A1 (en) * | 2005-12-19 | 2007-07-19 | Sicor Inc. | Pure and stable tiotropium bromide |
| US9108962B2 (en) | 2005-12-19 | 2015-08-18 | Sicor, Inc. | Forms of tiotropium bromide and processes for preparation thereof |
| CN102731494A (en) * | 2005-12-19 | 2012-10-17 | 西科尔公司 | Novel forms of tiotropium bromide and processes for preparation thereof |
| AU2006334367B2 (en) * | 2006-01-04 | 2012-11-08 | Boehringer Ingelheim International Gmbh | Use of tiotropium salts in the treatment of moderate persistent asthma |
| ES2298049B1 (en) | 2006-07-21 | 2009-10-20 | Laboratorios Almirall S.A. | PROCEDURE FOR MANUFACTURING BROMIDE OF 3 (R) - (2-HIDROXI-2,2-DITIEN-2-ILACETOXI) -1- (3-PHENOXIPROPIL) -1-AZONIABICICLO (2.2.2) OCTANO. |
| JP2009545579A (en) | 2006-08-01 | 2009-12-24 | グラクソ グループ リミテッド | Pyrazolo [3,4-B] pyridine compounds and their use as PDE4 inhibitors |
| EP1923393A1 (en) * | 2006-11-17 | 2008-05-21 | Boehringer Ingelheim Pharma GmbH & Co. KG | Crystalline form of tiotropium bromide and urea |
| EP1925295A1 (en) * | 2006-11-22 | 2008-05-28 | Boehringer Ingelheim Pharma GmbH & Co. KG | Stable powder formulation containing a new antichinolinergic agent |
| GB0716026D0 (en) | 2007-08-16 | 2007-09-26 | Norton Healthcare Ltd | An inhalable medicament |
| CA2608561A1 (en) * | 2007-10-29 | 2009-04-29 | Carl Paluszkiewicz | Motorcycle wind deflector accessory support |
| CN101918401A (en) * | 2008-01-10 | 2010-12-15 | 基因里克斯(英国)有限公司 | Novel process for the preparation of scopine esters |
| US8483831B1 (en) | 2008-02-15 | 2013-07-09 | Holaira, Inc. | System and method for bronchial dilation |
| EP2100599A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
| EP2100598A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
| CA2723806C (en) | 2008-05-09 | 2022-05-31 | Innovative Pulmonary Solutions, Inc. | Systems, assemblies, and methods for treating a bronchial tree |
| EP2172190A1 (en) | 2008-10-02 | 2010-04-07 | Laboratorios Liconsa, S.A. | Inhalable particles comprising tiotropium |
| WO2010101538A2 (en) | 2009-03-06 | 2010-09-10 | Bilgic Mahmut | New crystal forms |
| US8815258B2 (en) | 2009-05-29 | 2014-08-26 | Pearl Therapeutics, Inc. | Compositions, methods and systems for respiratory delivery of two or more active agents |
| EP2435023B1 (en) * | 2009-05-29 | 2016-07-06 | Pearl Therapeutics, Inc. | Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting beta 2 adrenergic receptor agonists and associated methods and systems |
| JP5822831B2 (en) * | 2009-08-07 | 2015-11-24 | ジェネリクス・［ユーケー］・リミテッド | Tiotropium bromide anhydride |
| WO2011015884A1 (en) | 2009-08-07 | 2011-02-10 | Generics [Uk] Limited | Process to prepare scopine esters |
| WO2011015883A1 (en) | 2009-08-07 | 2011-02-10 | Generics [Uk] Limited | Dichloromethane solvate of tiotropium bromide and its use |
| TR200907237A2 (en) | 2009-09-23 | 2011-04-21 | Bi̇lgi̇ç Mahmut | Tiotropium dry powder combination |
| TR200907236A2 (en) | 2009-09-23 | 2011-04-21 | Bi̇lgi̇ç Mahmut | Transport of Tiotropium dry powder formulation in blister pack. |
| JP5843777B2 (en) | 2009-10-27 | 2016-01-13 | ホライラ， インコーポレイテッド | Delivery device having a coolable energy release assembly |
| AU2010319477A1 (en) | 2009-11-11 | 2012-05-24 | Holaira, Inc. | Systems, apparatuses, and methods for treating tissue and controlling stenosis |
| US8911439B2 (en) | 2009-11-11 | 2014-12-16 | Holaira, Inc. | Non-invasive and minimally invasive denervation methods and systems for performing the same |
| TR201000679A2 (en) * | 2010-01-29 | 2011-08-22 | B�Lg�� Mahmut | Dry powder formulations containing a pharmaceutical combination. |
| TR200909788A2 (en) | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Dry powder formulation suitable for inhalation with tiotropium |
| US8834931B2 (en) | 2009-12-25 | 2014-09-16 | Mahmut Bilgic | Dry powder formulation containing tiotropium for inhalation |
| WO2011093810A2 (en) | 2010-01-28 | 2011-08-04 | Bilgic Mahmut | Dry powder pharmaceutical composition comprising tiotropium and mometasone |
| TR200909789A2 (en) | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Dry powder combination containing tiotropium, budesonide and a chromoglycic acid derivative combination |
| WO2011093812A2 (en) | 2010-01-28 | 2011-08-04 | Mahmut Bilgic | Pharmaceutical formulation comprising tiotropium and budesonide in dry powder form |
| TR200909792A2 (en) | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Dry powder combination containing tiotropium, corticosteroid and a combination of chromoglycic acid derivative |
| WO2011093809A2 (en) | 2010-01-28 | 2011-08-04 | Mahmut Bilgic | Dry powder pharmaceutical composition comprising tiotropium and ciclesonide |
| WO2011093813A1 (en) | 2010-01-28 | 2011-08-04 | Mahmut Bilgic | Dry powder pharmaceutical composition comprising tiotropium and fluticasone |
| TR200909793A2 (en) | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Combination of dry powder containing a combination of tiotropium, mometasone and a chromoglycic acid derivative. |
| TR201000681A2 (en) * | 2010-01-29 | 2011-08-22 | B�Lg�� Mahmut | Dry powder formulations inhaled. |
| TR200909790A2 (en) | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Combination of dry powder containing a combination of tiotropium, formoterol and a chromoglycic acid derivative. |
| TR201000733A2 (en) | 2010-02-02 | 2011-08-22 | Bi̇lgi̇ç Mahmut | Pharmaceutical compositions comprising fluticasone, tiotropium and sodium chromoglycate. |
| TR201005221A2 (en) | 2010-04-01 | 2012-01-23 | Bi̇lgi̇ç Mahmut | Improved synthesis method. |
| US8957209B2 (en) | 2010-04-01 | 2015-02-17 | Mahmut Bilgic | Methods for the synthesis of tiotropium bromide |
| TR201002520A2 (en) | 2010-04-01 | 2010-05-21 | Bi̇lgi̇ç Mahmut | Tiotropium bromide manufacturing method. |
| TR201005222A2 (en) | 2010-04-01 | 2011-10-21 | Bi̇lgi̇ç Mahmut | Tiotropium bromide synthesis method |
| TR201007108A2 (en) | 2010-08-25 | 2012-03-21 | B�Lg�� Mahmut | New tiotropium bromide crystal and production method. |
| TR201101897A2 (en) | 2011-02-28 | 2012-09-21 | Bi̇lgi̇ç Mahmut | Crystal material containing tiotropium bromide |
| TR201111589A2 (en) | 2011-03-03 | 2012-09-21 | Bi̇lgi̇ç Mahmut | Tiotropium bromide anhydrous crystal form. |
| TR201102068A2 (en) | 2011-03-03 | 2012-09-21 | Bi̇lgi̇ç Mahmut | Crystalline substances containing tiotropium bromide |
| EP2510928A1 (en) | 2011-04-15 | 2012-10-17 | Almirall, S.A. | Aclidinium for use in improving the quality of sleep in respiratory patients |
| ITRM20110508A1 (en) * | 2011-09-27 | 2013-03-28 | Lusochimica Spa | PROCESS FOR THE PREPARATION OF SCOPINA'S ESTERS. |
| US8680297B2 (en) | 2011-10-06 | 2014-03-25 | Drug Process Licensing Assoc., LLC | Manufacturing process for tiotropium bromide |
| CZ304368B6 (en) | 2011-11-28 | 2014-04-02 | Zentiva, K.S. | Tiotropium bromide mixed solvate and process for preparing thereof |
| GB201200525D0 (en) | 2011-12-19 | 2012-02-29 | Teva Branded Pharmaceutical Prod R & D Inc | An inhalable medicament |
| RS55996B1 (en) * | 2011-12-22 | 2017-09-29 | Cerbios-Pharma S A | Continuous process for the alkylation of cyclic tertiary amines |
| WO2013109213A2 (en) | 2012-01-16 | 2013-07-25 | Mahmut Bilgic | Pharmaceutical formulations comprising tiotropium |
| CZ201241A3 (en) | 2012-01-20 | 2013-07-31 | Zentiva, K.S. | Novel polymorphous forms of thiotropium iodide and process for preparing thereof |
| PT106142B (en) | 2012-02-10 | 2014-07-18 | Hovione Farmaci Ncia S A | PROCESS FOR THE PREPARATION OF TIOTROPE BROMIDE |
| WO2014007773A1 (en) | 2012-07-05 | 2014-01-09 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Compositions comprising muscarinic receptor antagonist and sorbitol |
| JP6335798B2 (en) | 2012-02-28 | 2018-05-30 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | New propellant-containing tiotropium formulation |
| CZ304808B6 (en) | 2012-03-16 | 2014-11-05 | Zentiva, K.S. | Process for preparing scopine ester of di-(2- thienyl)glycolic acid, an intermediate in the synthesis of tiotropium bromide and a new form thereof |
| CZ305012B6 (en) | 2012-03-30 | 2015-03-25 | Zentiva, K.S. | Process for preparing scopine ester of di-(2-thienyl)glycolic acid, an intermediate in the synthesis of tiotropium bromide |
| US20150174064A1 (en) | 2012-07-05 | 2015-06-25 | Arven IIac Sanayi Ve Ticaret A.S. | Compositions comprising muscarinic receptor antagonist and glucose anhydrous |
| WO2014007771A2 (en) | 2012-07-05 | 2014-01-09 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Inhalation compositions comprising muscarinic receptor antagonist |
| EP2705838A1 (en) | 2012-09-06 | 2014-03-12 | Xspray Microparticles Ab | Tiotropium preparations |
| EP2914593B1 (en) | 2012-11-05 | 2017-01-11 | Zentiva, k.s. | Stabilization of tiotropium solvates |
| US9398933B2 (en) | 2012-12-27 | 2016-07-26 | Holaira, Inc. | Methods for improving drug efficacy including a combination of drug administration and nerve modulation |
| AU2014228414B2 (en) | 2013-03-15 | 2018-09-13 | Pearl Therapeutics, Inc. | Methods and systems for conditioning of particulate crystalline materials |
| CA2907566C (en) | 2013-04-01 | 2023-08-22 | Pulmatrix, Inc. | Tiotropium dry powders |
| EP2913332A1 (en) | 2014-02-27 | 2015-09-02 | Euticals S.P.A. | Crystalline form of tiotropium bromide with lactose |
| US10034866B2 (en) | 2014-06-19 | 2018-07-31 | Teva Branded Pharmaceutical Products R&D, Inc. | Inhalable medicament comprising tiotropium |
| US9987260B2 (en) | 2015-05-18 | 2018-06-05 | Glenmark Specialty S.A. | Tiotropium inhalation solution for nebulization |
| WO2016185282A1 (en) | 2015-05-18 | 2016-11-24 | Glenmark Specialty S.A. | Tiotropium inhalation solution for nebulization |
| US10653683B2 (en) | 2015-05-18 | 2020-05-19 | Glenmark Specialty S.A. | Tiotropium inhalation solution for nebulization |
| KR101748796B1 (en) | 2015-09-30 | 2017-06-19 | 한미약품 주식회사 | Inhalation capsule with enhanced delivery rate of active ingredients |
| ES2743311T3 (en) | 2015-10-23 | 2020-02-18 | Arven Ilac Sanayi Ve Ticaret As | Ampoule for the inhalable formulation of tiotropium bromide |
| EP3159278A1 (en) | 2015-10-23 | 2017-04-26 | Arven Ilac Sanayi Ve Ticaret A.S. | Blister for tiotropium bromide inhalable formulation |
| WO2017138896A1 (en) | 2016-02-11 | 2017-08-17 | Sima Patent Ve Lisanslama Hizmetleri Ltd. Şti | Crystalline form of tiotropium bromide anhydrate |
| CN106467535A (en) * | 2016-08-28 | 2017-03-01 | 杭州百诚医药科技股份有限公司 | One kind prepares the purifying process of 2,2 pairs of (2 thienyl) glycolic Rhizoma Scopoliae Japonicae esters |
| WO2018055642A1 (en) * | 2016-09-23 | 2018-03-29 | Gbr Laboratories Pvt. Ltd. | A process for preparing tiotropium bromide and intermediates thereof |
| EA201990605A1 (en) | 2016-10-14 | 2019-10-31 | SPRAYED THIOTROPY AND FORMOTEROL COMPOSITIONS | |
| WO2020141472A1 (en) | 2019-01-03 | 2020-07-09 | Glenmark Specialty S.A. | Nebulization composition comprising tiotropium and indacaterol |
| IL309888A (en) | 2021-07-09 | 2024-03-01 | Astrazeneca Pharmaceuticals Lp | Compositions, methods and systems for aerosol drug delivery |
| CN114213408B (en) * | 2021-12-15 | 2023-03-31 | 台州仙琚药业有限公司 | Preparation method of tiotropium bromide |
| WO2023119093A1 (en) | 2021-12-20 | 2023-06-29 | Astrazeneca Ab | Compositions, methods and systems for aerosol drug delivery |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB845056A (en) | 1957-07-05 | 1960-08-17 | Egyt Gyogyszervegyeszeti Gyar | Improvements in or relating to tropane derivatives |
| DE1166787B (en) * | 1960-07-09 | 1964-04-02 | Boehringer & Soehne Gmbh | Process for the production of new garnetanol (3ª ‰) esters and their hydrohalides |
| GB955535A (en) * | 1962-10-22 | 1964-04-15 | Boehringer & Soehne Gmbh | New n-substituted norgranatanol-(3ª‰)-esters |
| DE2046659A1 (en) | 1970-01-28 | 1972-03-23 | ||
| US3808263A (en) * | 1970-05-12 | 1974-04-30 | Tanabe Seiyaku Co | 6,6-dimethyl-9-alkyl-9-azabicyclo(3.3.1)nonan-3-ols |
| US3673195A (en) * | 1970-05-25 | 1972-06-27 | Tanabe Seiyaku Co | Derivatives of 6,6,9-tri-lower alkyl-9-azabicyclo(3.3.1) nonan-3{60 -or 3{62 -ol |
| US4353922A (en) * | 1981-03-13 | 1982-10-12 | Syntex (U.S.A.) Inc. | Anticholinergic bronchodilators |
| DE3546218A1 (en) | 1985-12-27 | 1987-07-02 | Madaus & Co Dr | AZONIA SPIRONORTROPANOLESTER, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENT |
| DE3931041C2 (en) | 1989-09-16 | 2000-04-06 | Boehringer Ingelheim Kg | Esters of thienyl carboxylic acids with amino alcohols, their quaternization products, processes for their preparation and medicaments containing them |
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