IL95691A - Carboxylates of tropanyl derivatives their preparation and pharamceutical compositions containing them - Google Patents
Carboxylates of tropanyl derivatives their preparation and pharamceutical compositions containing themInfo
- Publication number
- IL95691A IL95691A IL9569190A IL9569190A IL95691A IL 95691 A IL95691 A IL 95691A IL 9569190 A IL9569190 A IL 9569190A IL 9569190 A IL9569190 A IL 9569190A IL 95691 A IL95691 A IL 95691A
- Authority
- IL
- Israel
- Prior art keywords
- compounds
- thienyl
- tropanyl
- methobromide
- group
- Prior art date
Links
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 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
95691/2 .mnpii vami GJi_ r» , 3Na \? flvr w o\?bfcpianp Carboxylates of tropanyl derivatives, their preparation and pharmaceutical compositions contaning them BOEHRINGER INGELHEIM KG.
C.81584 55914.13 "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.
According to one aspect of the invention, we provide compounds of the formula (I) 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 -CH2-CH2-, -CHJ-CHJ-CHJ-, " -CH=CH-, and -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 radical; or R and R' together form a C4.6-alkylene radical ; R1 represents an optionally methyl-substituted thienyl, phenyl, furyl , , cyclopentyl or cyclohexyl radical, the groups thienyl and phenyl optionally being fluoro- or , chloro-substituted ; j represents a hydrogen atom, or an OH,. C1.4-alkoxy or C^-alkyl group; Ra rePresents hydrogen,- fluorine, chlorine or CH^; with the proviso that when A represents the 3-tropanyl radical, R1 represents a 2- or 3-thienyl radical and R2 represents OH, then Ra is not hydrogen; and quaternary derivatives thereof, wherein one equivalent of an anion. (Xe) opposes the positive charge of the N atom in the group Q'; and all diastereoisomeric, enantiomeric arid racemic forms thereof or mixtures thereof; and/or, where appropriate, acid-addition salts thereof; Compounds of the present invention which are preferred include compounds of formula' I as defined above wherein R1 represents thienyl; and all diastereoisomeric, · enantiomeric arid racemic forms thereof or mixtures thereof; and/or, where appropriate, acid-addition salts thereof.
Compounds of the present invention which are particularly preferred include compounds of formula I as defined above wherein ]¾ represents OH; and all diastereoisomeric, enantiomeric and racemic forms 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 or 6,7-dehydrotropine or the corresponding nor-compounds; however, -OA may also have the β-configuration, as in pseudotropine or pseudoscopine.
Compounds of the present invention which are especially preferred include compounds of formula I as defined above wherein A represents a group selected from: and all diastereoisomeric, enantiomeric and racemic forms thereof or mixtures thereof; and/or, where appropriate, acid-addition salts thereof.
The substituent R is preferably a lower alkyl radical, for example, CH3, C2H5 n-C^Hj, i-CjHy; R' is preferably CH3. R and R' together may represent, for example -(CH2)5-. As halogen substituents for R, fluorine or chlorine are preferred. If R denotes a halogen-substituted or hydroxy-substituted alkyl radical, it is preferably -CH2-CH2F or -CH2-CH2 H.
Accordingly, the group A represents, for example, the radicals of scopine, N-ethylnorscopine, N-isopropylnorscopine, tropine, N-isopropylnortropine, 6 , 7-dehydrotropine, N-3-fluoroethy1nortropine, N-isopropyl-6,7-dehydronortropine, N-methylgranatoline or the corresponding quaternary derivatives, wherein the anion Χθ is preferably Bre or CH3S03e.
For the acyl radical (III) particular mention must be made of the following groups; The compounds of the present invention may be prepared by the following process, which process constitutes a further feature of the present invention: an ester of formula IV R. wherein R" represents a C^-alkyl radical, preferably a methyl or ethyl radical, and R^, j and Ra have the above meanings, is preferably transesterified using an amino alcohol of the formula V wherein ra, n and Q have the above meanings, Q" represents =NR or =NH and the OH group is in the a- or /3-position, in the presence of a conventional transesterification catalyst, and the compound thereby obtained is either a) if Q" denotes =NR (R ≠ H) optionally quaternised, using a reactive mono-functionalised derivative Z-(G|-C4-alkyl) of a corresponding alkane (Z = leaving group) or b) if Q" denotes =NH, is optionally quaternised using a terminally disubstituted alkane Z-(C4-C6-alkylene) -Z, without isolation of intermediates.
The transesterification is advantageously carried out with heat in an organic solvent, for example toluene, xylene, heptane, or in a melt; strong bases such as sodium methylate, sodium ethylate, sodium hydride or metallic sodium are preferably used as catalyst. Reduced pressure may be used to remove the released lower alcohol from the equilibrium; the alcohol may optionally be distilled off azeotropically. The transesterification in general takes place at temperatures which do not exceed 95°C. Transesterification often proceeds more favourably in a melt.
If required, the free bases may be obtained by conventional techniques from the acid addition salts of the tertiary amines using suitable basic compounds.
Quaternisation may be carried out in suitable solvents, for example acetonitrile or acetonitrile/methylene chloride, preferably at room temperature; a corresponding alkyl halide, for example alkyl bromide, is preferably used in the process as a quaternising agent. Transesterification products wherein Q' represents NH are used as starting materials for those compounds in which R and R' together represent a C4_6-alkylene group. Conversion into the tertiary and then quaternary compound then takes place with the aid of suitable 1,4-dihaloalkanes, 1, 5-dihaloalkanes or 1, 6-dihaloalkanes without isolation of intermediates.
The starting materials may be obtained by methods known per se.
Examples of preparations of starting materials methyl di- (2-thienyl) glycolate from dimethyl oxalate and 2-thienyl magnesium bromide; ethyl di- (2-thienyl) glycolate from (2-thienyl)glyoxylic 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.
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 quaternary derivatives are particularly suitable for therapeutic application, whereas the tertiary compounds are important not only as active ingredients but also as intermediate products. 95691/2 - 9 - The compounds of the present invention have strong anti-cholinergic activity and have a prolonged action. Action lasting at least 24 hours is achieved at inhaled dosages in the range. In addition, the toxicity is in the same range as the commercial product Ipratropium bromide, while at the same time the therapeutic effect is stronger.
The compounds of the present invention are, therefore, suitable, in accordance with their anti-cholinergic nature, for the treatment of, for example, chronic obstructive bronchitis and (slight to moderately severe) asthma, and also for the treatment of vagally induced sinus bradycardia.
Whereas application of the compounds of the present invention (in particular the quaternary derivatives) by inhalation is mainly recommended for respiratory tract diseases, as a result of which side-effects are largely eliminated, the application for sinus bradycardia is preferably carried out intravenously or orally. It has thus proved to be advantageous that the compounds leave the gastro/intestinal motility largely unaffected.
For administration the compounds of the present invention are processed using known auxiliaries and/or excipients to give conventional galenic preparations, for example inhalation solutions, suspensions in liquified propellants, preparations containing liposomes or proliposomes, injection solutions, tablets, tablets, capsules, inhalation powders for use conventional inhalation apparatus.
Thus, according to a yet further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula I or a quaternised derivative thereof, as hereinbefore defined, in the form of a single enantiomer or diastereoisomer or mixtures thereof and/or a physiologically acceptable acid-addition salt thereof in association with one or more pharmaceutically acceptable carriers, diluents or excipients.
Pharmacological characteristics The advantageous properties of the compounds of the present invention are shown, for example, in the inhibition of broncholysis in the rabbit (acetylcholine spasms intravenously) .
After intravenous administration of the novel active ingredients (dosage 3 Mg/kg intravenously) , the maximum effect occurred after 10 to 40 minutes. After 5 hours the inhibiting effect had still not been reduced to half; the half effect time is more, in some cases considerably more, than 5 hours, as shown by the residual effects after 5 hours listed below: Compound Residual effect in % A 76 B 76 C 81 D 61 E 68 F 73 G 69 The data above relate to the following compounds formula I: Compounds of the formula Compound 2-thienyl B 3-thienyl 2-thienyl 3-thienyl cyclopentyl -O— / CH3-IN/®-CH2-CH2F cyclopentyl Compound C For the compounds A to G above:- i) the compounds in which R1 does not represent 2-thienyl are racemates. ii) the compounds are 3α-compounds in each case.
The following examples serve to illustrate the present invention without limiting it.
Example 1 Scopine di-f2-thienyl) glycolate 50.87 g (0.2 mole) of methyl di- (2-thienyl) glycolate and 31.04 g (0.2 mole) of scopine are dissolved in 100 ml of absolute toluene and reacted at a bath temperature of 90°C with addition of 1.65 g (0.071 gram atom) of sodium in several portions. The resulting methanol is distilled off at a reaction mixture temperature of 78 - 90°C under a pressure of 500 mbar. After a reaction time of about 5 hours, the reaction mixture is stirred into a mixture of ice and hydrochloric acid. The acid phase is separated off, rendered alkaline using sodium carbonate and the free base is extracted using methylene chloride. After drying over sodium sulphate, the methylene chloride is distilled off under reduced pressure and the residue is recrystallised from acetonitrile; beige-coloured crystals (from acetonitrile) , m.p. 149 - 50°C, Yield: 33.79 g (44.7 % of theoretical).
Example 2 Scopine di- (2-thienyl) 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 100 ml of water and 100 ml of methylene chloride while monitoring the temperature, and the methylene chloride phase is extracted several times using water. The methylene chloride phase is extracted using the corresponding amount of dilute hydrochloric acid. The scopine di- (2-thienyl) glycolate is extracted from the combined aqueous phases using methylene chloride after adding the corresponding amount of sodium carbonate and dried over sodium sulphate. The hydrochloride is prepared from the dried methylene chloride solution in a conventional manner. The crystals are filtered off under suction, washed using acetone and dried under reduced pressure at 35°C. Pale yellow crystals (from methanol) , m.p. 238 - 41°C (decomposition) ; Yield: 10.99 g (53.1 % of theoretical).
The hydrochloride may be converted to the base in a conventional manner.
Example 3 Scopine di- (2-thienyl) alveolate 38.15 g (0.15 mole) of methyl di-(2-thienyl)glycolate and 23.28 g (0.15 mole) of scopine are mixed, 0.34 g (0.015 gram atom) of sodium is added and the mixture is melted in a heating bath at 90°C under a water jet vacuum. The reaction lasts 2.5 hours. 100 ml of absolute toluene are then added and the mixture is stirred at a heating bath temperature of 90°C until a solution is produced. The reaction solution is cooled to room temperature and stirred into a mixture of ice and hydrochloric acid cooled using ice. The hydrochloride of the basic ester crystallising out is filtered off under suction and washed using a small amount of water and a large amount of diethyl ether. The filtrate phases are separated off and the aqueous phase is extracted using diethyl ether. The hydrochloride filtered off under suction is suspended in the (acid) aqueous phase and converted to the base while monitoring the temperature and adding the corresponding amount of sodium carbonate; the base is extracted using methylene chloride. The combined methylene chloride phases are dried over sodium sulphate. After distilling off the methylene chloride, crystals remain which are purified over active charcoal and recrystallised from acetonitrile. Pale yellow crystals (from acetonitrile) , m.p. 148 - 49°C; Yield: 39.71 g (70.1 % of theoretical).
Example 4 Scopine di- (2-thienyl) alveolate 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 .
According to the invention, the compounds listed in the following Tables may also be obtained.
Table I Compounds of the formula M.p. [ °C] Base Hydrochloride 3a- (6/3 , 7/9-epoxy) -tropanyl 2-thienyl 149-50 238-41 3a-tropanyl 2-thienyl 167-8 253 3a- (6 , 7-dehydro) -tropanyl 2-thienyl 164-5 3a- (N-/3-fluoroethyl) - 2-thienyl nortropanyl 236 3a- (N-isopropyl) - granatanyl 2-thienyl 232 3a- (N-isopropyl) - nortropanyl 2-thienyl 256 3a- ( 6β , 73-epoxy) -N- isopropyl-nortropanyl 2-thienyl 206 3a- (6/3 , 7j3-epoxy) -N-ethyl- 2-thienyl nortropanyl 212-3 3a- (N-ethyl) -nortropanyl 2-thienyl 256-7 3a- (N-N-methyl) -granatanyl 2-thienyl 241 3a- (6/3, 7/3-epoxy) -N-/3- 2-thienyl fluoroethylnortropanyl 188-90 M.p. [ °C Base Hydrochloride 12 3a-(6j8,7/3-epoxy) -N-n- 2-thienyl 104-6 propylnortropanyl 13 3a-(69,7jB-epoxy) -N-n- 2-thienyl butylnortropanyl 225-7 14 3a- (6/3, 73-epoxy) -tropany 1 phenyl 246-7 15 3ot-tropanyl phenyl 243-4 16 3a-(N-0-fluoroethyl) - phenyl nortropanyl 219-2 17 3a- (6, 7-dehydro) -tropany 1 phenyl 181- 3 18 3 a- (N-ethyl) -nortropanyl phenyl 231-2 19 3a- (N-isopropyl) - nortropanyl phenyl 246- 7 20 3a-tropanyl cyclohexyl 260 21 3a-(N-/3-fluoroethyl)- cyclohexyl nortropanyl 203-4 22 3a-(63,7/3-epoxy) -tropany 1 cyclopentyl 237 23 3a-tropanyl cyclopentyl 260 24 3a-(N-j3-fluoroethyl)- cyclopentyl nortropanyl 182- 3 25 3a- (N-ethyl) -nortropanyl cyclopentyl 227-8 26 3a- (N-isopropyl) nortropanyl cyclopentyl 174-5 27 3jS-(60,7/3-epoxy) -tropanyl 2-thienyl 240-2 28 33-tropanyl 2-thienyl 217-9 29 3β- (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-fury 1 33 3a- (6, 7-dehydro) -tropanyl 2-fury 1 34 3a-tropanyl 2-fury 1 35 3a-tropanyl 2-pyridyl 36 3a- (6/3, 73-epoxy) -tropanyl 2-pyridyl M.p.fC] No. A R, Base Hydrochloride 37 3ot- (6, 7-dehydro) -tropanyl 2-pyridyl 38 3a-tropanyl 3-thienyl 39 3a- (6 , 7-dehydro) -tropanyl cyclopentyl 40 3a- (6/3, 73-epoxy) -tropanyl cyclohexyl 41 3a- (6, 7-dehydro) -tropanyl cyclohexyl Note: All hydrochlorides melt with decomposition.
Table II Quaternary compounds of the formula HO-C-CO-OA No. R, M.p. [ °C] 3a- (6/3 , 7/8-epoxy) -tropanyl methobromide 217-18 3a-tropanyl methobromide 263-64 3a- ( 6 , 7-dehydro) -tropanyl methobromide 191-92 3a- (N-/3-fluoroethyl) - nortropanylmethobromide 242-43 3a-tropanyl-3- fluoroethobromide 214-15 3a- (N-isopropyl) - granatanyl methobromide 229-30 3a- (N-isopropyl) - nortropanylmethobromide 245-46 3a- ( 6/3 , 7/3-epoxy) -N- isopropyl-nortropanyl methobromide 223-24 3a- (6/3, 7/3-epoxy) -N- ethylnortropariyl methobromide 215-16 3a-(N-ethyl) -nortropanyl methobromide 260-61 NO. M.p. [ °C] 11 3a-(N-methyl) -granatanyl- methobromide 2-thienyl 246-47 12 3a-(6j9,7/3-epoxy)-N- -fluoroethyl- nortropanyl methobromide 2-thienyl 182-83 13 3a-(6/8,7/3-epoxy)-N-n- propylnortropanyl methobromide 2-thienyl 209-10 14 3a-tropanyl-3- hydroxyethobromide 2-thienyl 231-32 15 3a-(6/3,7/3-epoxy) -tropanyl methobromide phenyl 217-18 16 3a-tropanyl methobromide phenyl 273-74 17 3a- (N-/9-fluoroethyl) - nortropanylmethobromide phenyl 215 18 3a- (6, 7-dehydro) -tropanyl methobromide phenyl 170-71 19 3a- (N-ethyl) -nortropanyl methobromide phenyl 249-50 20 3a-(N-isopropyl) - nortropanyl methobromide phenyl 259-60 21 3a-tropanyl ethobromide phenyl 248-49 22 3a- (N-ethyl) -nortropanyl ethobromide phenyl 244-45 23 3a- (60,7/3-epoxy) -tropanyl ethobroraide phenyl 226 24 3a-tropanyl-3- fluoroethobromide phenyl 241 25 3a-tropanyl methobromide cyclohexyl 278 26 3a-(N-0-fluoroethyl)- nortropanyl methobromide cyclohexyl 198 27 3a-tropanyl-3- fluoroethobromide cyclohexyl 233-34 M.p. [ °C] 3a-tropanyl methobromide cyclopentyl 260 3a-tropanyl ethobromide cyclopentyl 235-36 3a- (N-ethyl) -nortropany1 methobromide cyclopentyl 251-52 3a- (N-isopropyl) -nortropanyl-methobromide cyclopentyl 244-45 3a-tropanyl-/8-fluoroethobromide cyclopentyl 189-90 3a- (N-jS-fluoroethyl) -nortropany1-methobromide cyclopentyl 226-27 3a- (6 , 7-dehydro) -tropany1 metho-methanesulphonate 2-thienyl 225-6 3/3- ( 6/3 , 7/3-epoxy) -tropanyl methobromide 2-thienyl 218-20 3/3-tropanyl methobromide 2-thienyl 243-4 3β- (6 , 7-dehydro) -tropanyl methobromide 2-thienyl 211-4 3a- ( 6 , 7-dehydro) -tropanyl methobromide 3-thienyl 182-3* 3α- (6/3 , 73-epoxy) -tropanyl methobromide 3-thienyl 217-8 (+) enantiomer of No. 1 (-) enantiomer of No. 1 3a- (6β , 73-epoxy) -tropanyl methobromide 2-furyl 3a- ( 6 , 7-dehydro) -tropanyl methobromide 2-furyl 3a-tropanyl methobromide 2-furyl 3a- (6/3, 7/3-epoxy) -tropanyl methobromide 2-pyridyl 3a- (6, 7-dehydro) -tropanyl methobromide 2-pyridyl 3a-tropanyl methobromide 2-pyridyl 3a-tropanyl methobromide 3-thienyl NO. M.p. [ °C] 49 3a- (6 , 7-dehydro) -tropanyl methobromide cyclopentyl 50 3a- (6/3, 73-epoxy) -tropanyl methobromide cyclohexyl 51 3a- (6, 7-dehydro) -tropanyl methobromide cyclohexyl 52 3a- (63, 73-epoxy) -tropanyl methobromide cyclopentyl * contains crystalline methanol Note: All compounds in the table melt with decomposition.
Table III Compounds of the formula NO. M.p. [ °C] Hydrochloride 1 3a- (6/3 , 73-epoxy) -tropanyl phenyl 246-7 2 3a- (6 , 7-dehydro) -tropanyl phenyl .261-2 3 3a- ( 6β , 73-epoxy) -tropanyl 3-thienyl 4 3a- (6, 7-dehydro) -tropanyl 3-thienyl 5 3a-tropanyl 3-thienyl 6 3a- (N-methyl) -granatanyl 3-thienyl Table IV Compounds of the formula No. A R2 M.p.[°C] Hydrochloride 1 3a-(6j8,7/9-epoxy) -tropanyl H 2 3a- (6,7-dehydro) -tropanyl H 3 3a- (6/3, 7/9-epoxy) -tropanyl methyl 4 3a- (6,7-dehydro) -tropanyl methyl 210-2.5 5 3α- (6β , 7β-epoxy) -tropanyl methoxy 6 3a- (6 , 7-dehydro) -tropanyl methoxy Table V Compounds of the formula No. A R1 Ra 1 3a-■(6/3f7i8-epoxy) -tropanyl 2-thienyl 5--methyl 2 3a-■(6,7-dehydro) -tropanyl 2-thienyl 5· -methyl 3 3a-■tropanyl 2-thienyl 5--methyl 4 3a-■(6/3, 73-epoxy) -tropanyl 2-(5-methyl)- thienyl 5--methyl 5 3a-■(6,7-dehydro) -tropanyl 2-(5-methyl)- thienyl 5· -methyl 6 3a-■tropanyl 2-(5-methyl)- thienyl 5--methyl 7 3a-■(6/8, 7/3-epoxy) -tropanyl 2-thienyl 5--fluoro 8 3a- (6,7-dehydro) -tropanyl 2-thienyl 5--fluoro 9 3a-■tropanyl 2-thienyl 5· -fluoro 10 3a-•(6/9, 7/3-epoxy) -tropanyl 2-(5-fluoro)- thienyl 5· -fluoro 11 3a- (6,7-dehydro) -tropanyl 2- (5-fluoro) - thienyl 5--fluoro 12 3a-•tropanyl 2- (5-fluoro) - thienyl 5--fluoro Table VI Compounds of the formula No. 3a- (6/9 , 73-epoxy) -tropanyl 2-thienyl 5-methyl methobromide 3a- (6 , 7-dehydro) -tropanyl 2-thienyl 5-methyl methobromide 3 3a-tropanyl-methobromide 2-thienyl 5-methyl 4 3a- (6/3 , 7j8-epoxy) -tropanyl 2-(5-methyl) methobromide thienyl 5-methyl 5 3a- ( 6 , 7-dehydro) -tropanyl 2-(5-methyl)- methobromide thienyl 5-methyl 6 3a-tropanyl methobromide 2-(5-methyl)- thienyl 5-methyl 7 3a- (6/3, 7/3-epoxy) -tropanyl 2-thienyl 5-fluoro methobromide 8 3a- (6 , 7-dehydro) -tropanyl 2-thienyl 5-fluoro methobromide 9 3a-tropanyl methobromide 2-thienyl 5-fluoro 10 3a- (6/8, 7j8-epoxy) -tropanyl 2-(5-fluoro) - methobromide thienyl 5-fluoro 11 3a- (6, 7-dehydro) -tropanyl 2-(5-fluoro)- methobromide thienyl 5-fluoro 12 3a-tropanyl methobromide 2-(5-fluoro) - thienyl 5-fluoro Table VII Compounds of the formula HO-C-CO-OA No. M.p. [ °C] 3a- ( 6/3 , 70-epoxy) -tropanyl 211-2 methobromide 3a- (6 , 7-dehydro) -tropanyl 158-60* methobromide 3a- (6β , 70-epoxy) -tropanyl methobromide 3a- (6 , 7-dehydro) -tropanyl methobromide 5 3a-tropanyl methobromide 6 3a- (N-methyl) -granatanyl methobromide * (with crystalline methanol) Table VIII Quaternary compounds of the formula No. .p. [ °C] 3a- (6/3 , 7/9-epoxy) -tropanyl H methobromide 3a- ( 6 , 7-dehydro) -tropanyl H methobromide 3a- (6β , 7/8-epoxy) -tropanyl methyl methobromide 3a- (6, 7-dehydro) -tropanyl methyl methobromide 5 3a-tropanyl methobromide methoxy 6 3a- (N-methyl) -tropanyl methobromide methoxy The following preparation examples serve to further illustrate the present invention without, however, limiting it (measures are given in weight per cent):- 1. Controlled dosage aerosol Active ingredient according to the invention 0.005 Sorbitan trioleate 0.1 Monofluorotrichloromethane and Difluorodichloromethane 2 : 3 to 100 The suspension is poured into a conventional aerosol container with a dosage valve. 50 μΐ of suspension are preferably dispensed per actuation. The active ingredient may also be metered in a higher amount if required (for example 0.02 wt.%).
Tablets Active ingredient according to the invention Colloidal silicic acid 0.95 Lactose 65.00 Potato starch 28.00 Polyvinylpyrrolidone 3.00 Na cellulose glycolate 2.00 Magnesium stearate 1.00 The constituents are processed in conventional manner to give tablets of 200 mg.
Claims (15)
1. Compounds of formula I in which A represents the group wherein m and n independently of one another denote 1 Q represents one of the double-bonding groups -CH2-CH2-, -CH2-CH2-CH2- , -CH=CH-, and -CH CH- ; - 32 - 95691/4 Q ' represents the group >NR or the group >NRR ' , 14. IX.90 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 ' together form a C4_0-alkylene radical ; R1 represents an "Optionally methyl-substituted thienyl, phenyl, furyl, cyclopentyl or cyclohexyl radical, the 14. IX.90 groups thienyl and phenyl optionally being fluoro- or . chloro-substituted; Rj represents a hydrogen atom, or an OH, C^-alkoxy or C^-alkyl group; Ra represents hydrogen, fluorine, chlorine or CH^; with the proviso that when A represents the 3-tropanyl radical, R]_ represents a 2- or 3-thienyl radical and R2 represents OH, then Ra is not hydrogen; and quaternary derivatives thereof, wherein one equivalent of an anion (Χθ) opposes the positive charge of the N atom in the group Q' ; and all diastereoisoraeric, enantiomeric and racemic 14. IX.90 forms thereof or mixtures thereof; and/or, where appropriate, acid-addition salts thereof.
2. Compounds as claimed in claim 1, wherein R, represents a 2-thienyl group.
3. Compounds as claimed in claim 1 or claim 2, wherein R-, represents OH.
4. Compounds as claimed in any one of claims 1, 2 or 3, wherein A represents a group selected from wherein R and Χθ are as defined in claim 1 and R' is defined in claim 1 with the exception of hydrogen.
5. Compounds as claimed in any one of claims 1 to 4, wherein R, represents 2-thienyl and A represents the radical or in the 3a-form, wherein Χθ is one equivalent of an anion.
6. Compounds as claimed in claim 5 wherein Χθ represents Bre or CH3S03e.
7. Compounds as claimed in any one of claims selected from: in the 3a form and their acid addition salts and their methobromides or methomethanesulphonates .
8. Compounds as claimed in claim 1 as herein specifically disclosed in any of the Examples.
9. A process for the preparation of compounds as claimed in claim 1 wherein an ester of the formula IV wherein R" represents a C1.4-alkyl radical and ,, and Ra are as defined in claim 1, is transesterified using an amino alcohol of the formula V wherein m, n and Q are as defined in claim 1 and Q" represents =NR or =NH, in an inert organic solvent or in a melt, in the presence of a transesterification catalyst; the compound thereby obtained is either a) if Q" denotes =NR (R * H) optionally quaternised, using a reactive mono-functionalised derivative Z- (C^-alkyl) of an alkane (Z = leaving group) or b) if Q" denotes =NH is optionally substituted and quaternised, using a terminally disubstituted alkane Z-(C, 6-alkylene)-Z, without isolation of intermediates; and, if desired, the compounds thereby obtained are converted into acid-addition salts thereof using conventional techniques. 95691 /2 - 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 or a quaternised derivative thereof, as defined in claim 1, in the form of a single enantiomer or diastereoisomer or mixtures thereof and/or a physiologically acceptable acid-addition salt thereof in association with one or more pharmaceutically acceptable carriers, diluents or excipients.
13. Compositions as claimed in claim 12 substantially as herein described.
14. Compounds of general formula I as claimed in claim 1 and physiologically acceptable acid addition salts for use in therapy.
15. The use of a compound as claimed in any one of claims 1 to 8 or 11 or a physiologically acceptable acid addition salt thereof for the preparation of a medicament for use in the treatment of diseases or disorders in which anti-cholinergic therapy is required substantially as described in the specification.
Applications Claiming Priority (1)
| 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL95691A0 IL95691A0 (en) | 1991-06-30 |
| IL95691A true IL95691A (en) | 1996-07-23 |
Family
ID=6389619
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL9569190A IL95691A (en) | 1989-09-16 | 1990-09-14 | Carboxylates of tropanyl derivatives their preparation and pharamceutical compositions containing them |
Country Status (33)
| Country | Link |
|---|---|
| US (1) | USRE39820E1 (en) |
| EP (1) | EP0418716B1 (en) |
| JP (1) | JPH0730074B2 (en) |
| KR (1) | KR0168432B1 (en) |
| AT (1) | ATE103914T1 (en) |
| AU (1) | AU642913B2 (en) |
| 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) |
| FI (1) | FI114395B (en) |
| HR (1) | HRP940723B1 (en) |
| HU (2) | HU208823B (en) |
| IE (1) | IE65528B1 (en) |
| IL (1) | IL95691A (en) |
| LU (1) | LU90949I2 (en) |
| MX (1) | MX9203150A (en) |
| NL (1) | NL300084I2 (en) |
| NO (2) | NO301478B1 (en) |
| NZ (1) | NZ235306A (en) |
| PH (1) | PH31617A (en) |
| PL (1) | PL168468B1 (en) |
| PT (1) | PT95312B (en) |
| RU (1) | RU2073677C1 (en) |
| SI (1) | SI9011744B (en) |
| SK (1) | SK452390A3 (en) |
| UA (1) | UA41272C2 (en) |
| WO (1) | WO1991004252A1 (en) |
| YU (1) | YU47800B (en) |
| ZA (1) | ZA907338B (en) |
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 |
| US7214687B2 (en) | 1999-07-14 | 2007-05-08 | Almirall Ag | Quinuclidine derivatives and medicinal compositions containing the same |
| ES2165768B1 (en) | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | NEW DERIVATIVES OF QUINUCLIDINE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
| 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 |
| GB0009592D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Respiratory combinations |
| GB0009605D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Medicaments |
| EP1305329B2 (en) | 2000-08-05 | 2015-03-18 | Glaxo Group Limited | 6.alpha.,9.alpha.-difluoro-17.alpha.-(2-furanylcarboxyl)oxy-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-androst-1,4-diene-17-carbothioic acid s-fluoromethyl ester as an anti-inflammatory agent |
| US6777399B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6777400B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6858593B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6858596B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivative |
| US6787532B2 (en) | 2000-08-05 | 2004-09-07 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivatives |
| US6759398B2 (en) | 2000-08-05 | 2004-07-06 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative |
| GB0019172D0 (en) | 2000-08-05 | 2000-09-27 | Glaxo Group Ltd | Novel compounds |
| US6750210B2 (en) | 2000-08-05 | 2004-06-15 | Smithkline Beecham Corporation | Formulation containing novel anti-inflammatory androstane derivative |
| US6908928B2 (en) | 2000-10-12 | 2005-06-21 | Bi Pharma Kg. | Crystalline tiotropium bromide monohydrate, processes for the preparation thereof, and pharmaceutical compositions |
| TR200402579T4 (en) * | 2000-10-12 | 2004-12-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Crystalline monohydrate, its method of manufacture and its use in the manufacture of a drug substance |
| ES2227268T3 (en) | 2000-10-12 | 2005-04-01 | BOEHRINGER INGELHEIM PHARMA GMBH & CO.KG | NEW POWDER FOR INHALATION WITH CONTENT IN TIOTROPY. |
| EA007604B1 (en) * | 2000-10-31 | 2006-12-29 | Бёрингер Ингельхайм Фарма Гмбх Унд Ко. Кг | Inhalative solution formulation containing a tiotropium salt |
| 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 |
| CN1250545C (en) | 2000-12-28 | 2006-04-12 | 阿尔米雷尔普罗迪斯制药有限公司 | Quinuclidine derivatives and their use as M3 antagonists |
| 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 |
| BR0209271A (en) | 2001-04-30 | 2004-06-15 | Glaxo Group Ltd | Compound, use of a compound pharmaceutical composition, pharmaceutical aerosol formulation, method for treating a human or animal patient with an inflammatory and / or allergic condition, and process for preparing a compound |
| 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 |
| SI1401445T1 (en) * | 2001-06-22 | 2007-02-28 | Boehringer Ingelheim Pharma | Crystalline anticholinergic, method for its production, and use thereof in the production of a drug |
| 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 |
| 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 |
| WO2003035599A1 (en) | 2001-10-26 | 2003-05-01 | Pharmacia & Upjohn Company | Quarternary ammonium compounds and their use as antimuscarinic agents |
| DE10200943A1 (en) * | 2002-01-12 | 2003-07-24 | Boehringer Ingelheim Pharma | Process for the preparation of scopine esters |
| US6696462B2 (en) | 2002-01-31 | 2004-02-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Anticholinergics, processes for the preparation thereof, and pharmaceutical compositions |
| DE10203749A1 (en) * | 2002-01-31 | 2003-08-14 | Boehringer Ingelheim Pharma | New anticholinergics, process for their preparation and their use as medicines |
| 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 |
| CA2513188A1 (en) * | 2003-01-16 | 2004-08-05 | University Of 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 |
| SI1682542T1 (en) * | 2003-11-03 | 2010-04-30 | Boehringer Ingelheim Int | Novel crystalline anhydride with anticholinergic effect |
| PT1682541E (en) | 2003-11-03 | 2010-04-14 | Boehringer Ingelheim Int | Method for producing tiotropium salts |
| PL2083007T3 (en) | 2003-11-03 | 2013-09-30 | Boehringer Ingelheim Int | Tiotropium salts, method for creating same and medicinal formulations containing same |
| 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 |
| JPWO2006025324A1 (en) * | 2004-08-30 | 2008-05-08 | 小野薬品工業株式会社 | Tropane compounds and pharmaceutical compositions containing them as active ingredients |
| CA2606552A1 (en) * | 2005-05-02 | 2006-11-09 | Boehringer Ingelheim International Gmbh | Crystalline forms of tiotropium bromide |
| EP1881980B1 (en) | 2005-05-02 | 2012-08-22 | Boehringer Ingelheim International GmbH | Novel crystalline forms of tiotropium bromide |
| 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 |
| NZ566068A (en) | 2005-08-08 | 2011-03-31 | Argenta Discovery Ltd | 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 |
| EP2123650B1 (en) * | 2005-12-19 | 2012-04-04 | Sicor, Inc. | Novel form of tiotropium bromide and process for preparation thereof |
| 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 |
| CA2634984C (en) * | 2006-01-04 | 2014-05-06 | 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 |
| 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 |
| 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 |
| 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 |
| EP2403851B1 (en) | 2009-03-06 | 2015-06-17 | Mahmut Bilgic | New crystalline forms of tiotropium bromide |
| US9463161B2 (en) | 2009-05-29 | 2016-10-11 | Pearl Therapeutics, Inc. | Compositions for pulmonary delivery of long-acting muscarinic antagonists and associated methods and systems |
| US8815258B2 (en) | 2009-05-29 | 2014-08-26 | Pearl Therapeutics, Inc. | Compositions, methods and systems for respiratory delivery of two or more active agents |
| US8697719B2 (en) | 2009-08-07 | 2014-04-15 | Generics [Uk] Limited | Anhydrate of tiotropium bromide |
| 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. |
| EP4193948A1 (en) | 2009-10-27 | 2023-06-14 | Nuvaira, Inc. | Delivery devices with coolable energy emitting assemblies |
| EP4111995A1 (en) | 2009-11-11 | 2023-01-04 | Nuvaira, Inc. | Device 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 |
| WO2011093809A2 (en) | 2010-01-28 | 2011-08-04 | Mahmut Bilgic | Dry powder pharmaceutical composition comprising tiotropium and ciclesonide |
| TR200909792A2 (en) | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Dry powder combination containing tiotropium, corticosteroid and a combination of chromoglycic acid derivative |
| TR201000679A2 (en) * | 2010-01-29 | 2011-08-22 | B�Lg�� Mahmut | Dry powder formulations containing a pharmaceutical combination. |
| US8834931B2 (en) | 2009-12-25 | 2014-09-16 | Mahmut Bilgic | Dry powder formulation containing tiotropium for inhalation |
| 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. |
| WO2011093812A2 (en) | 2010-01-28 | 2011-08-04 | Mahmut Bilgic | Pharmaceutical formulation comprising tiotropium and budesonide in dry powder form |
| WO2011093813A1 (en) | 2010-01-28 | 2011-08-04 | Mahmut Bilgic | Dry powder pharmaceutical composition comprising tiotropium and fluticasone |
| TR201000681A2 (en) * | 2010-01-29 | 2011-08-22 | B�Lg�� Mahmut | Dry powder formulations inhaled. |
| WO2011093810A2 (en) | 2010-01-28 | 2011-08-04 | Bilgic Mahmut | Dry powder pharmaceutical composition comprising tiotropium and mometasone |
| TR200909788A2 (en) | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Dry powder formulation suitable for inhalation with tiotropium |
| 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. |
| TR200909789A2 (en) | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Dry powder combination containing tiotropium, budesonide and a chromoglycic acid derivative combination |
| TR201000733A2 (en) | 2010-02-02 | 2011-08-22 | Bi̇lgi̇ç Mahmut | Pharmaceutical compositions comprising fluticasone, tiotropium and sodium chromoglycate. |
| 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 |
| 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 |
| 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 |
| EP2804591A2 (en) | 2012-01-16 | 2014-11-26 | Mahmut Bilgic | Preparation of dry powder 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 |
| WO2013127738A1 (en) | 2012-02-28 | 2013-09-06 | Boehringer Ingelheim International Gmbh | Novel propellant-gas-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 |
| US10105316B2 (en) | 2012-07-05 | 2018-10-23 | Arven llac Sanayi Ve Ticaret A.S. | Inhalation compositions comprising muscarinic receptor antagonist |
| US20150174064A1 (en) | 2012-07-05 | 2015-06-25 | Arven IIac Sanayi Ve Ticaret A.S. | Compositions comprising muscarinic receptor antagonist and glucose anhydrous |
| EP2705838A1 (en) | 2012-09-06 | 2014-03-12 | Xspray Microparticles Ab | Tiotropium preparations |
| CN104797579A (en) | 2012-11-05 | 2015-07-22 | 赞蒂瓦有限合伙公司 | 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 |
| JP6454323B2 (en) | 2013-03-15 | 2019-01-16 | パール セラピューティクス，インコーポレイテッド | Method and system for conditioning particulate crystalline materials |
| MX2015013845A (en) | 2013-04-01 | 2016-05-09 | 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 |
| CN107995861A (en) | 2015-05-18 | 2018-05-04 | 格兰马克专业公司 | The black tropine inhalation solution of Thailand for atomization |
| US9987260B2 (en) | 2015-05-18 | 2018-06-05 | 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 |
| WO2017068119A1 (en) | 2015-10-23 | 2017-04-27 | Arven Ilac Sanayi Ve Ticaret A.S. | Blister for tiotropium bromide inhalable formulation |
| JP2019500916A (en) | 2015-10-23 | 2019-01-17 | アーヴェン イラチュ サナイ ヴェ ティヂャレット エー． エス．Ａｒｖｅｎ Ｉｌａｃ Ｓａｎａｙｉ Ｖｅ Ｔｉｃａｒｅｔ Ａ．Ｓ． | Blister for inhalation formulation of tiotropium bromide |
| 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 |
| BR112019007259A2 (en) | 2016-10-14 | 2019-07-02 | Glenmark Specialty S.A. | dual chamber container suitable for use with a nebuliser and preloaded with a nebulizable composition, kit, nebulizable composition, aqueous nebulizable solution, method for administering tiotropium and formoterol to a patient in need thereof and method for preparing a nebulizer |
| US20200215051A1 (en) | 2019-01-03 | 2020-07-09 | Glenmark Specialty S.A. | Nebulization composition comprising tiotropium and indacaterol |
| DK4197528T3 (en) | 2021-07-09 | 2024-05-06 | Astrazeneca Pharmaceuticals Lp | Aerosol drug delivery compositions, methods, and systems |
| 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 |
-
1989
- 1989-09-16 DE DE3931041A patent/DE3931041C2/en not_active Expired - Lifetime
-
1990
- 1990-09-06 DD DD90343854A patent/DD297647A5/en not_active IP Right Cessation
- 1990-09-08 AU AU64318/90A patent/AU642913B2/en not_active Expired
- 1990-09-08 HU HU9200857A patent/HU208823B/en unknown
- 1990-09-08 CA CA002066248A patent/CA2066248C/en not_active Expired - Lifetime
- 1990-09-08 WO PCT/EP1990/001517 patent/WO1991004252A1/en active IP Right Grant
- 1990-09-08 RU SU905011520A patent/RU2073677C1/en active
- 1990-09-08 JP JP2513253A patent/JPH0730074B2/en not_active Expired - Lifetime
- 1990-09-08 UA UA93060616A patent/UA41272C2/en unknown
- 1990-09-12 AT AT90117554T patent/ATE103914T1/en active
- 1990-09-12 DE DE90117554T patent/DE59005250D1/en not_active Expired - Lifetime
- 1990-09-12 DK DK90117554.7T patent/DK0418716T3/en active
- 1990-09-12 DE DE2002199026 patent/DE10299026I2/en active Active
- 1990-09-12 ES ES90117554T patent/ES2052125T3/en not_active Expired - Lifetime
- 1990-09-12 EP EP90117554A patent/EP0418716B1/en not_active Expired - Lifetime
- 1990-09-13 YU YU174490A patent/YU47800B/en unknown
- 1990-09-13 SI SI9011744A patent/SI9011744B/en unknown
- 1990-09-14 IL IL9569190A patent/IL95691A/en active Protection Beyond IP Right Term
- 1990-09-14 KR KR1019900014543A patent/KR0168432B1/en not_active IP Right Cessation
- 1990-09-14 PH PH41212A patent/PH31617A/en unknown
- 1990-09-14 ZA ZA907338A patent/ZA907338B/en unknown
- 1990-09-14 NZ NZ235306A patent/NZ235306A/en unknown
- 1990-09-14 PT PT95312A patent/PT95312B/en not_active IP Right Cessation
- 1990-09-17 SK SK4523-90A patent/SK452390A3/en not_active IP Right Cessation
- 1990-09-17 CZ CS904523A patent/CZ284589B6/en not_active IP Right Cessation
-
1992
- 1992-03-13 FI FI921087A patent/FI114395B/en active Protection Beyond IP Right Term
- 1992-03-13 IE IE334290A patent/IE65528B1/en active Protection Beyond IP Right Term
- 1992-03-13 PL PL90286900A patent/PL168468B1/en active Protection Beyond IP Right Term
- 1992-03-13 NO NO921002A patent/NO301478B1/en not_active IP Right Cessation
- 1992-06-23 MX MX9203150A patent/MX9203150A/en unknown
-
1994
- 1994-02-23 BG BG98532A patent/BG61295B2/en unknown
- 1994-10-21 HR HRP-1744/90A patent/HRP940723B1/en not_active IP Right Cessation
- 1994-12-15 HU HU94P/P00055P patent/HU210612A9/en unknown
-
2002
- 2002-02-14 NL NL300084C patent/NL300084I2/en unknown
- 2002-08-30 LU LU90949C patent/LU90949I2/en unknown
- 2002-09-17 NO NO2002009C patent/NO2002009I2/en unknown
-
2005
- 2005-10-18 US US11/254,213 patent/USRE39820E1/en not_active Expired - Lifetime
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| IL95691A (en) | Carboxylates of tropanyl derivatives their preparation and pharamceutical compositions containing them | |
| US5610163A (en) | Esters of thienyl carboxylic acids and amino alcohols and their quaternization products | |
| KR100307274B1 (en) | Esters of bicyclic and tricyclic amino alcohols, methods for their preparation and pharmaceutical compositions comprising the same | |
| US5770738A (en) | Esters of bi- and tricyclic amino alcohols, their preparation and their use in pharmaceutical compositions | |
| US4983600A (en) | Heterocyclic compounds useful as 5-HT3 antagonists | |
| IE83484B1 (en) | New Bi- and tricyclic aminoalcohol esters, their preparation and their use in medicaments | |
| JPH08502275A (en) | 5-HT 4) Heterocyclic Fused Benzoic Acid Derivatives for Receptor Antagonists | |
| IE63670B1 (en) | Esters of hexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3(4h)-one and related compounds | |
| EP0554794B1 (en) | Aminobenzoic acid derivatives | |
| US20090163541A1 (en) | Quinuclidine compounds having quaternary ammonium group, its preparation method and use as blocking agents of acetylcholine | |
| JPH0352465B2 (en) | ||
| EP0112266B1 (en) | Substituted tropyl and pseudotropyl benzoates and their use in migraine treatment | |
| AU1443092A (en) | Neuroprotectant agents | |
| JPH01207283A (en) | Aminocyclopentyl ether, its production and pharmaceutical composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FF | Patent granted | ||
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| EXTF | Application for patent extension filed | ||
| KB | Patent renewed | ||
| PEL | Intention of commissioner to extend period of protection | ||
| KB | Patent renewed | ||
| EXTG | Extension of patent term granted | ||
| EXTN | Extension order renewed | ||
| EXTN | Extension order renewed | ||
| EXTN | Extension order renewed |