USRE39820E1 - Esters of thienyl carboxylic acids and amino alcohols and their quaternization products - Google Patents

Esters of thienyl carboxylic acids and amino alcohols and their quaternization products Download PDF

Info

Publication number
USRE39820E1
USRE39820E1 US11/254,213 US25421305A USRE39820E US RE39820 E1 USRE39820 E1 US RE39820E1 US 25421305 A US25421305 A US 25421305A US RE39820 E USRE39820 E US RE39820E
Authority
US
United States
Prior art keywords
thienyl
tropanyl
compound
methobromide
accordance
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime, expires
Application number
US11/254,213
Inventor
Rolf Banholzer
Rudolf Bauer
Richard Reichl
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=6389619&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=USRE39820(E1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US08/405,111 external-priority patent/US5610163A/en
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Priority to US11/254,213 priority Critical patent/USRE39820E1/en
Application granted granted Critical
Publication of USRE39820E1 publication Critical patent/USRE39820E1/en
Adjusted expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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

Definitions

  • the invention relates to novel thienylcarboxylates of amino alcohols and their quaternary products and to the preparation of the novel compounds and their use as active ingredients in medicaments.
  • R 1 preferably represents thienyl
  • R 2 preferably represents OH
  • the group —OA preferably has the ⁇ -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 ⁇ -configuration, as in pseudotropine, pseudoscopine.
  • the substituent R is preferably a lower alkyl radical, such as CH 3 , C 2 H 5 , n-C 3 H 7 , i-C 3 H 7 , R′ is preferably CH 3 .
  • R and R′ together are, for example —(CH 2 ) 5 —.
  • halogen substituents for R F or, as second choice, Cl are suitable.
  • R denotes a halogen-substituted or hydroxy-substituted alkyl radical, it is preferably —CH 2 —CH 2 F or —CH 2 —CH 2 OH.
  • 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 CH 3 SO 3 ⁇ .
  • 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.
  • novel compounds are suitable, in accordance with their anti-cholinergic nature, for example for the treatment of chronic obstructive bronchitis and (slight to moderately severe) asthma, also for the treatment of vagally induced sinus bradycardia.
  • the novel active ingredients in particular the quaternary compounds
  • 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.
  • 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.
  • 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.
  • Controlled dosage aerosol Active ingredient 0.005 Sorbitan trioleate 0.1 monofluorotrichloromethane and to 100 Difluorodichloromethane 2:3
  • the suspension is poured into a conventional aerosol container with a dosage valve. 50 ⁇ l 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 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.
  • the advantageous properties of the novel compounds are shown, for example, in the inhibition of broncholysis in the rabbit (acetylcholine spasms intravenously).
  • the maximum effect occurred after 10 to 40 minutes.
  • 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:
  • R′′ represents a C 1 -C 4 -alkyl radical, preferably a methyl or ethyl radical (R 1 , R 2 and R a have the above meanings)
  • R 1 , R 2 and R a have the above meanings
  • R 1 , R 2 and R a have the above meanings
  • Q′′ represents ⁇ NR or ⁇ NH and the OH group is in the ⁇ - or ⁇ -position, in the presence of a conventional transesterification catalyst, and the compound obtained is optionally quaternised
  • the transesterification is 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, 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 azeotropically.
  • the transesterification takes place at temperatures which in general do not exceed 95° C. Transesterification often proceeds more favourably in a melt.
  • 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, preferably at room temperature; a corresponding alkyl halide, for example alkyl bromide, is preferably used in the process as quaternising agent.
  • 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 quaternising agent.
  • Transesterification products wherein Q′ represents NH are used as starting materials for those compounds in which R and R′ together represent a C 4 -C 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 analogously to known compounds—in as much as they have not already been described.
  • 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 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);
  • the hydrochloride may be converted to the base in a conventional manner.
  • 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.;

Abstract

Compounds of the formula
Figure USRE039820-20070904-C00001
of which, in exemplary compounds, the thienyl group is attached via the 2-position and;
    • (a) A is 3α-(6β, 7β-epoxy)-tropanyl methobromide and R1 is 2-thienyl;
    • (b) A is 3α-(6, 7dehydro)-tropanyl methobromide and R1 is 2-thienyl;
    • (c) A is 3β-tropanyl methobromide and R1 is 2-thienyl; and,
    • (d) A is 3α-(N-isopropyl)-nortropanyl methobromide and R1 is cyclopentyl.
      There are anticholinergics. Administered by inhalation, they are useful for the treatment of chronic obstructive bronchitis or slight to moderately severe asthma. Administered by the intravenous or oral routes, they are useful for the treatment of vagally induced sinus bradycardia.

Description

This is a continuation of application Ser. No. 08/254,324, filed on Jun. 6, 1994, now abandoned which is a continuation of application Ser. No. 08/100,822, filed on Aug. 2, 1993, now abandoned, which is a continuation of application Ser. No. 07/838,724, filed on Mar. 13, 1992, now abandoned.
The invention relates to novel thienylcarboxylates 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
Figure USRE039820-20070904-C00002
in which
    • A represents the group
      Figure USRE039820-20070904-C00003
      wherein
    • m and n independently of one another denote 1 or 2,
    • Q represents one of the double-bonding groups
      Figure USRE039820-20070904-C00004
      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 ═NR denotes a secondary or tertiary amino group, also the acid addition salts.
In the compounds of formula I, R1 preferably represents thienyl, R2 preferably represents OH. The group —OA preferably has the α-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, pseudoscopine.
Corresponding radicals are, for example
Figure USRE039820-20070904-C00005
The substituent R is preferably a lower alkyl radical, such as CH3, C2H5, 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—CH2OH. Accordingly, the group A represents, for example the radicals of scopine, N-ethylnorscopine, N-isopropylnorscopine, tropine, N-isopropylnortropine, 6,7-dehydrotropine, N-β-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
Figure USRE039820-20070904-C00006
the following are particularly suitable:
Figure USRE039820-20070904-C00007
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 μg 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 for 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.
Formulation examples (measures in weight per cent):
1. Controlled dosage aerosol
Active ingredient according to the invention 0.005
Sorbitan trioleate 0.1
monofluorotrichloromethane and to 100
Difluorodichloromethane 2:3
The suspension is poured into a conventional aerosol container with a dosage valve. 50 μl 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.
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 μg/kg intravenously), the maximum effect occurred after 10 to 40 minutes. After 5 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 %
A 76
B 76
C 81
D 61
E 68
F 73
G 69
Compounds of the formula
Figure USRE039820-20070904-C00008
Com-
pound A R1
A
Figure USRE039820-20070904-C00009
 		2- thienyl
B
Figure USRE039820-20070904-C00010
 		3- thienyl
D
Figure USRE039820-20070904-C00011
 		2- thienyl
E
Figure USRE039820-20070904-C00012
 		3- thienyl
F
Figure USRE039820-20070904-C00013
 		cyclo- pentyl
G
Figure USRE039820-20070904-C00014
 		cyclo- pentyl
Compound C
Figure USRE039820-20070904-C00015
Notes:
1. The compounds in which R1 is not 2-thienyl are racemates.
2. The compounds are 3α-compounds in each case.

Processes known per se are used to prepare the novel compounds.
An ester of the formula
Figure USRE039820-20070904-C00016
wherein R″ represents a C1-C4-alkyl radical, preferably a methyl or ethyl radical (R1, R2 and Ra have the above meanings), is preferably transesterified using an amino alcohol of the formula
Figure USRE039820-20070904-C00017
wherein m, n and Q have the above meanings, Q″ represents ═NR or ═NH and the OH group is in the α- or β-position, in the presence of a conventional transesterification catalyst, and the compound obtained is optionally quaternised
    • a) if Q″ denotes ═NR (R≢H), using a reactive monofunctionalised 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 in 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 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, 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 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 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.
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 EXAMPLE 1 Scopine di-(2-thienyl)glycolate
50.87 g (0.2 mole) of methyl di-(2-thienyl)glycolate and 31.04 g (0.2 mole) of scopine are dissolved in 100 ml of absolute toluene and reacted at a bath temperature of 90° C. with addition of 1.65 g (0.071 gram atom) of sodium in several portions. The resulting methanol is distilled off at a reaction mixture temperature of 78°-90° C. under a pressure of 500 mbar. After a reaction time of about 5 hours, the reaction mixture is stirred into a mixture of ice and hydrochloric acid. The acid phase is separated off, rendered alkaline using sodium carbonate and the free base is extracted using methylene chloride. After drying over sodium sulphate, the methylene chloride is distilled off under reduced pressure and the residue is recrystallised from acetonitrile; beige-coloured crystals (from acetonitrile).
m.p. 149°-50° C.
Yield: 33.79 g (44.7% of theoretical).
EXAMPLE 2 Scopine di-(2-thienyl)glycolate
12.72 g (0.05 mole) of methyl di-(2-thienyl)glycolate and 7.76 g (0.05 mole) of scopine are melted in a heating bath at 70° C. under a water jet vacuum. 2.70 g (0.05 mole) of sodium methylate are introduced into this melt and heated for 1 hour in a heating bath at 70° C. under a water jet vacuum and subsequently for a further hour in a heating bath at 90° C. The solidified melt is taken up in a mixture of 100 ml of water and 100 ml of methylene chloride while monitoring the temperature, and the methylene chloride phase is extracted several times using water. The methylene chloride phase is extracted using the corresponding amount of dilute hydrochloric acid. The scopine di-(2-thienyl)glycolate is extracted from the combined aqueous phases using methylene chloride after adding the corresponding amount of sodium carbonate and dried over sodium sulphate. The hydrochloride is prepared from the dried methylene chloride solution in a conventional manner. The crystals are filtered off under suction, washed using acetone and dried under reduced pressure at 35° C. Pale yellow crystals (from methanol), m.p. 238°-41° C. (decomposition);
Yield: 10.99 g (53.1% of theoretical).
The hydrochloride may be converted to the base in a conventional manner.
EXAMPLE 3 Scopine di-(2-thienyl)glycolate
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).
TABLE I
Compounds of the formula
Figure USRE039820-20070904-C00018
M.p. [° C.]
Hydro-
No. A R1 Base chloride
1 3α-(6β,7β-epoxy)-tropanyl 2-thienyl 149-50 238-41
2 3α-tropanyl 2-thienyl 167-8  253
3 3α-(6,7-dehydro)-tropanyl 2-thienyl 164-5 
4 3α-(N-β-fluoroethyl)- 2-thienyl 236
nortropanyl
5 3α-(N-isopropyl)- 2-thienyl 232
granatanyl
6 3α-(N-isopropyl)- 2-thienyl 256
nortropanyl
7 3α-(6β,7β-epoxy)-N- 2-thienyl 206
isopropyl-nortropanyl
8 3α-(6β,7β-epoxy)-N-ethyl 2-thienyl 212-3
nortropanyl
9 3α-(N-ethyl)-nortropanyl 2-thienyl 256-7
10 3α-(N-N-methyl)- 2-thienyl 241
granatanyl
11 3α-(6β,7β-epoxy)-N-β 2-thienyl 188-90
fluoroethylnortropanyl
12 3α-(6β,7β-epoxy)-N-n 2-thienyl 104-6
propylnortropanyl
13 3α-(6β,7β-epoxy)-N-n 2-thienyl 225-7
butylnortropanyl
14 3α-(6β,7β-epoxy)-tropanyl phenyl 246-7
15 3α-tropanyl phenyl 243-4
16 3α-(N-β-fluoroethyl)- phenyl 219-20
nortropanyl
17 3α-(6,7-dehydro)-tropanyl phenyl 181-3
18 3α-(N-ethyl)-nortropanyl phenyl 231-2
19 3α-(N-isopropyl)- phenyl 246-7
nortropanyl
20 3α-tropanyl cyclo- 260
hexyl
21 3α-(N-β-fluoroethyl)- cyclo- 203-4
nortropanyl hexyl
22 3α-(6β,7β-epoxy)-tropanyl cyclo- 237
pentyl
23 3α-tropanyl cyclo- 260
pentyl
24 3α-(N-β-fluoroethyl)- cyclo- 182-3
nortropanyl pentyl
25 3α-(N-ethyl)-nortropanyl cyclo- 227-8
pentyl
26 3α-(N-isopropyl)- cyclo- 174-5
nortropanyl pentyl
27 3α-(6β,7β-epoxy)-tropanyl 2-thienyl 240-2
28 3β-tropanyl 2-thienyl 217-9
29 3β-(6,7-dehydro)-tropanyl 2-thienyl 233-5
30 3α-(6,7-dehydro)-trapanyl 3-thienyl 247-8
31 3α-(6β,7β-epoxy)-tropanyl 3-thienyl 242-3
32 3α-(6β,7β-epoxy)-tropanyl 2-furyl
33 3α-(6,7-dehydro)-tropanyl 2-furyl
34 3α-tropanyl 2-furyl
35 3α-tropanyl 2-pyridyl
36 3α-(6β,7β-epoxy)-tropanyl 2-pyridyl
37 3α-(6,7-dehydro)-tropanyl 2-pyridyl
38 3α-tropanyl 3-thienyl
39 3α-(6,7-dehydro)-tropanyl cyclo-
pentyl
40 3α-(6β,7β-epoxy)-tropanyl cyclo-
hexyl
41 3α-(6,7-dehydro)-tropanyl cyclo-
hexyl
Note:
All hydrochlorides melt with decomposition.
EXAMPLE 4 Scopine di-(2-thienyl)glycolate 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.
TABLE II
Quaternary compounds of the formula
Figure USRE039820-20070904-C00019
No. A R1 M.p. [° C.]
1 3α-(6β,7β-epoxy)-tropanyl 2-thienyl 217-18
methobromide
2 3α-tropanyl methobromide 2-thienyl 263-64
3 3α-(6,7-dehydro)-tropanyl 2-thienyl 191-92
methobromide
4 3α-(N-β-fluoroethyl)- 2-thienyl 242-43
nortropanylmethobromide
5 3α-tropanyl-β- 2-thienyl 214-15
fluoroethobromide
6 3α-(N-isopropyl)- 2-thienyl 229-30
granatanyl methobromide
7 3α-(N-isopropyl)- 2-thienyl 245-46
nortropanylmethobromide
8 3α-(6β,7β-epoxy)-N- 2-thienyl 223-24
isopropyl-nortropanyl
methobromide
9 3α-(6β,7β-epoxy)-N- 2-thienyl 215-16
ethylnortropanyl
methobromide
10 3α-(N-ethyl)-nortropanyl 2-thienyl 260-61
methobromide
11 3α-(N-methyl)-granatanyl 2-thienyl 246-47
methobromide
12 3α-(6β,7β-epoxy)-N- 2-thienyl 182-83
fluoroethyl-
nortropanyl methobromide
13 3α-(6β,7β-epoxy)-N-n- 2-thienyl 209-10
propylnortropanyl
methobromide
14 3α-tropanyl-β- 2-thienyl 231-32
hydroxyethobromide
15 3α-(6β,7β-epoxy)-tropanyl phenyl 217-18
ethobromide
16 3α-tropanyl methobromide phenyl 273-74
17 3α-(N-β-fluoroethyl)- phenyl
nortrapanylmethobromide
18 3α-(6,7-dehydro)-tropanyl phenyl 110-71
methobromide
19 3α-(N-ethyl)-nortropanyl phenyl 249-50
methobromide
20 3α-(N-isopropyl)- phenyl 259-60
nortropanyl methobromide
21 3α-tropanyl ethobromide phenyl 248-49
22 3α-(N-ethyl)-nortropanyl phenyl 244-45
ethobromide
23 3α-(6β,7β-epoxy)-tropanyl phenyl 226
ethobromide
24 3α-tropanyl-β- phenyl 241
fluoroethobromide
25 3α-tropanyl methobromide cyclohexyl 278
26 3α-(N-β-fluoroethyl)- cyclohexyl 198
nortropanyl methobromide
27 3α-tropanyl-β- cyclohexyl 233-34
fluoroethobromide
28 3α-tropanyl methobromide cyclopentyl 260
29 3α-tropanyl ethobromide cyclopentyl 235-36
30 3α-(N-ethyl)-nortropanyl cyclopentyl 251-52
methobromide
31 3α-(N-isopropyl)- cyclopentyl 244-45
nortropanyl-methobromide
32 3α-tropanyl-β- cyclopentyl 189-90
fluoroethobromide
33 3α-(N-β-fluoroethyl)- cyclopentyl 226-27
nortropanyl-methobromide
34 3α-(6,7-dehydro)-tropanyl 2-thienyl 225-6 
metho-methanesulphonate
35 3α-(6β,7β-epoxy)-tropanyl 2-thienyl 218-20
methobromide
36 3α-tropanyl methobromide 2-thienyl 243-4 
37 3α-(6,7-dehydro)-tropanyl 2-thienyl 211-4 
methobromide
38 3α-(6,7-dehydro)-tropanyl 3-thienyl 182-3*
methobromide
39 3α-(6β,7β-epoxy)-tropanyl 3-thienyl 217-8
methobromide
40 (+) enantiomer of No. 1
41 (−) enantiomer of No. 1
42 3α-(6β,7β-epoxy)-tropanyl 2-furyl
methobromide
43 3α-(6,7-dehydro)-tropanyl 2-furyl
methobromide
44 3α-tropanyl methobromide 2-furyl
45 3α-(6β,7β-epoxy)-tropanyl 2-pyridyl
methobromide
46 3α-(6,7-dehydro)-tropanyl 2-pyridyl
methobromide
47 3α-tropanyl methobromide 2-pyridyl
48 3α-tropanyl methobromide 3-thienyl
49 3α-(6,7-dehydro)-tropanyl cyclopentyl
methobromide
50 3α-(6β,7β-epoxy)-tropanyl cyclohexyl
methobromide
51 3α-(6,7-dehydro)-tropanyl cyclohexyl
methobromide
52 3α-(6β,7β-epoxy)-tropanyl cyclohexyl
methobromide
*contains crystalline methanol
Note:
All compounds in the table melt with decomposition.
TABLE III
Compounds of the formula
Figure USRE039820-20070904-C00020
M.p. [° C.]
No. A R1 Hydrochloride
1 3α-(6β,7β-epoxy)-tropanyl phenyl 246-7
2 3α-(6,7-dehydro)-tropanyl phenyl 261-2
3 3α-(6β,7β-epoxy)-tropanyl 3-thienyl
4 3α-(6,7-dehydro)-tropanyl 3-thienyl
5 3α-tropanyl 3-thienyl
6 3α-(N-methyl)-granatanyl 3-thienyl
TABLE IV
Compounds of the formula
Figure USRE039820-20070904-C00021
M.p. [° C.]
No. A R2 Hydrochloride
1 3α-(6β,7β-epoxy)-tropanyl H
2 3α-(6,7-dehydro)-tropanyl H
3 3α-(6β,7β-epoxy)-tropanyl methyl
4 3α-(6,7-dehydro)-tropanyl methyl 210-2.5
5 3α-(6β,7β-epoxy)-tropanyl methoxy
6 3α-(6,7-dehydro)-tropanyl methoxy
TABLE V
Compounds of the formula
Figure USRE039820-20070904-C00022
M.p.
No. A R2 Ra [° C.]
1 3α-(6β,7β-epoxy)- 2-thienyl 5-methyl
tropanyl
2 3α-(6,7-dehydro)- 2-thienyl 5-methyl
tropanyl
3 3α-tropanyl 2-thienyl 5-methyl
4 3α-(6β,7β-epoxy)- 2-(5-methyl)- 5-methyl
tropanyl thienyl
5 3α-(6,7-dehydro)- 2-(5-methyl)- 5-methyl
tropanyl thienyl
6 3α-tropanyl 2-(5-methyl)- 5-methyl
thienyl
7 3α-(6β,7β-epoxy)- 2-thienyl 5-fluoro
tropanyl
8 3α-(6,7-dehydro)- 2-thienyl 5-fluoro
tropanyl
9 3α-tropanyl 2-thienyl 5-fluoro
10 3α-(6β,7β-epoxy)- 2-(5-fluoro)- 5-fluoro
tropanyl thienyl
11 3α-(6,7-dehydro)- 2-(5-fluoro)- 5-fluoro
tropanyl thienyl
12 3α-tropanyl 2-(5-fluoro)- 5-fluoro
thienyl
TABLE VI
Compounds of the formula
Figure USRE039820-20070904-C00023
M.p.
No. A R1 Ra [° C.]
1 3α-(6β,7β-epoxy)-tropanyl 2-thienyl 5-methyl
methobromide
2 3α-(6,7-dehydro)-tropanyl 2-thienyl 5-methyl
methobromide
3 3α-tropanyl-methobromide 2-thienyl 5-methyl
4 3α-(6β,7β-epoxy)-tropanyl 2-(5-methyl)- 5-methyl
methobromide thienyl
5 3α-(6,7-dehydro)-tropanyl 2-(5-methyl)- 5-methyl
methobromide thienyl
6 3α-tropanyl methobromide 2-(5-methyl)- 5-methyl
thienyl
7 3α-(6β,7β-epoxy)-tropanyl 2-thienyl 5-fluoro
methobromide
8 a-(6,7-dehydro)-tropanyl 2-thienyl 5-fluoro
methobromide
9 3α-tropanyl methobromide 2-thienyl 5-fluoro
10 3α-(6β,7β-epoxy)-tropanyl 2-(5-fluoro)- 5-fluoro
methobromide thienyl
11 3α-(6,7-dehydro)-tropanyl 2-(5-fluoro)- 5-fluoro
methobromide thienyl
12 3α-tropanyl methobromide 2-(5-fluoro)- 5-fluoro
thienyl
TABLE VII
Compounds of the formula
Figure USRE039820-20070904-C00024
No. A R1 M.p. [° C.]
1 3α-(6β,7β-epoxy)-tropanyl phenyl 211-2 
methobromide
2 3α-(6,7-dehydro)-tropanyl phenyl 158-60*
methobromide
3 3α-(6β,7β-epoxy)-tropanyl 3-thienyl
methobromide
4 3α-(6,7-dehydro)-tropanyl 3-thienyl
methobromide
5 3α-tropanyl methobromide 3-thienyl
6 3α-(N-methyl)-granatanyl 3-thienyl
methobromide
*(with crystalline methanol)
TABLE VIII
Quaternary compounds of the formula
Figure USRE039820-20070904-C00025
No. A R2 M.p. [° C.]
1 3α-(6β,7β-epoxy)-tropanyl H
methobromide
2 3α-(6,7-dehydro)-tropanyl H
methobromide
3 3α-(6β,7β-epoxy)-tropanyl methyl
methobromide
4 3α-(6,7-dehydro)-tropanyl methyl 206-8
methobromide
5 3α-tropanyl methobromide methoxy
6 3α-(N-methyl)-tropanyl methoxy
methobromide

Claims (19)

We claim:
1. A compound of the formula
Figure USRE039820-20070904-C00026
wherein
Q is a group of the formula —CH2—CH2—, —CH═CH— or
Figure USRE039820-20070904-C00027
R and R′ are each independently C1-C4-alkyl;
R1 is thienyl, phenyl, cyclopentyl or cyclohexyl; and,
X− is a physiologically acceptable anion.
2. A compound in accordance with claim 1, of the formula
Figure USRE039820-20070904-C00028
wherein
R is CH3, C2H5, n-C3H7, or i-C3H7;
R′ is CH3; and
R1, Q and X− are as defined in claim 1.
3. A compound in accordance with claim 2 wherein R1 is thienyl.
4. A compound in accordance with claim 2 wherein X− is Br− or CH3SO3 CH3 SO 3 − .
5. A compound of the formula
Figure USRE039820-20070904-C00029
wherein X− is a physiologically acceptable anion.
6. A compound of the formula
Figure USRE039820-20070904-C00030
wherein X− is a physiologically acceptable onion.
7. A compound of the formula
Figure USRE039820-20070904-C00031
8. A compound of the formula
Figure USRE039820-20070904-C00032
wherein R1 is 2-thienyl and A is 3α-(6,7-dehydro)-tropanyl methobromide.
9. A compound of the formula
Figure USRE039820-20070904-C00033
wherein R1 is 2-thienyl and A is 3β-tropanyl methobromide.
10. A compound of the formula
Figure USRE039820-20070904-C00034
wherein R1 is cyclopentyl and A is 3α-(N-isopropyl)-nortropanyl methobromide.
11. A method for treating chronic obstructive bronchitis which comprises administering, by inhalation, to a subject suffering from the same, a therapeutic amount of a compound in accordance with claims 1, 2, 3, 4, 6, 7, or 8, 9, 10 .
12. A method for treating slight to moderately severe asthma which comprises administering, by inhalation, to a subject suffering from the same, a therapeutic amount of a compound in accordance with claims 1, 2, 3, 4, 6, 7, 8, 9, 10.
13. A method for treating vagally induced sinus bradycardia which comprises administering, by the intravenous or oral routes, to a subject suffering from the same, a therapeutic amount of a compound in accordance with claims 1, 2, 3, 4, 6, 7, or 8, 9, 10 .
14. A pharmaceutical composition, for administration by inhalation, suitable for the treatment of chronic obstructive bronchitis or slight to moderately severe asthma , which comprises a compound in accordance with claims 1, 2, 3, 4, 6, 7, or 8, 9, 10 .
15. A pharmaceutical composition for oral administration, suitable for the treatment of vagally induced sinus bradycardia, which comprises a compound in accordance with claims 1, 2, 3, 4, 6, 7, or 8, 9, 10 .
16. A pharmaceutical composition, for intravenous administration, suitable for the treatment of vagally induced sinus bradycardia, which comprises a compound in accordance with claims 1, 2, 3, 4, 6, 7, or 8, 9, 10 .
17. A method for treating chronic obstructive bronchitis which comprises administering, by inhalation, to a subject suffering from the same, a therapeutic amount of a compound in accordance with claim 5.
18. A pharmaceutical composition, for administration by inhalation, suitable for the treatment of chronic obstructive bronchitis, which comprises a compound in accordance with claim 5.
19. A pharmaceutical composition, for administration by inhalation, suitable for the treatment of chronic obstructive bronchitis, comprising an inhalation powder comprising a compound in accordance with claim 5.
US11/254,213 1989-09-16 2005-10-18 Esters of thienyl carboxylic acids and amino alcohols and their quaternization products Expired - Lifetime USRE39820E1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/254,213 USRE39820E1 (en) 1989-09-16 2005-10-18 Esters of thienyl carboxylic acids and amino alcohols and their quaternization products

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
DE3931041.8 1989-09-16
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
EPPCT/EP90/01517 1990-09-08
PCT/EP1990/001517 WO1991004252A1 (en) 1989-09-16 1990-09-08 New esters of thienyl carboxylic acids and amino alcohols, their quaternization products, and manufacture and use of said compounds
US83872492A 1992-03-13 1992-03-13
US10082293A 1993-08-02 1993-08-02
US25432494A 1994-06-06 1994-06-06
US08/405,111 US5610163A (en) 1989-09-16 1995-03-16 Esters of thienyl carboxylic acids and amino alcohols and their quaternization products
US11/254,213 USRE39820E1 (en) 1989-09-16 2005-10-18 Esters of thienyl carboxylic acids and amino alcohols and their quaternization products

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US08/405,111 Reissue US5610163A (en) 1989-09-16 1995-03-16 Esters of thienyl carboxylic acids and amino alcohols and their quaternization products

Publications (1)

Publication Number Publication Date
USRE39820E1 true USRE39820E1 (en) 2007-09-04

Family

ID=6389619

Family Applications (1)

Application Number Title Priority Date Filing Date
US11/254,213 Expired - Lifetime USRE39820E1 (en) 1989-09-16 2005-10-18 Esters of thienyl carboxylic acids and amino alcohols and their quaternization products

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) SK279453B6 (en)
UA (1) UA41272C2 (en)
WO (1) WO1991004252A1 (en)
YU (1) YU47800B (en)
ZA (1) ZA907338B (en)

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050143410A1 (en) * 2003-11-03 2005-06-30 Boehringer Ingelheim International Gmbh Novel crystalline anhydrate with anticholinergic efficacy
US20060154951A1 (en) * 2003-01-16 2006-07-13 Wood Ronald W Quaternary antimuscarinic compounds for the treatment of bladder diseases
US20070015785A1 (en) * 2002-03-20 2007-01-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Crystalline Micronisate, Process for the Manufacture Thereof and Use Thereof for the Preparation of a Medicament
US20070155773A1 (en) * 2006-01-04 2007-07-05 Michael Engel Use of Tiotropium Salts in the Treatment of Moderate Persistent Asthma
US20090134655A1 (en) * 2007-10-29 2009-05-28 Carl Paluszkiewicz Motorcycle wind deflector accessory support
US20090299042A1 (en) * 2006-07-21 2009-12-03 Nuria Busquets Baque Process for manufacturing 3(r)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide
WO2010101538A2 (en) 2009-03-06 2010-09-10 Bilgic Mahmut New crystal forms
WO2010138868A2 (en) 2009-05-29 2010-12-02 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting b2 adrenergic receptor agonists and associated methods and systems
US20110020454A1 (en) * 2008-03-13 2011-01-27 Rosa Lamarca Casado Novel dosage and formulation
US8088127B2 (en) 2008-05-09 2012-01-03 Innovative Pulmonary Solutions, Inc. Systems, assemblies, and methods for treating a bronchial tree
US8172827B2 (en) 2003-05-13 2012-05-08 Innovative Pulmonary Solutions, Inc. Apparatus for treating asthma using neurotoxin
US8324266B2 (en) 2009-05-29 2012-12-04 Pearl Therapeutics, Inc. Compositions, methods and systems for respiratory delivery of two or more active agents
US20130030182A1 (en) * 2010-04-01 2013-01-31 Mahmut Bilgic Methods for the synthesis of tiotropium bromide
US8483831B1 (en) 2008-02-15 2013-07-09 Holaira, Inc. System and method for bronchial dilation
US8513279B2 (en) 1999-07-14 2013-08-20 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US8680297B2 (en) 2011-10-06 2014-03-25 Drug Process Licensing Assoc., LLC Manufacturing process for tiotropium bromide
US8740895B2 (en) 2009-10-27 2014-06-03 Holaira, Inc. Delivery devices with coolable energy emitting assemblies
WO2014165303A1 (en) 2013-04-01 2014-10-09 Pulmatrix, Inc. Tiotropium dry powders
US8911439B2 (en) 2009-11-11 2014-12-16 Holaira, Inc. Non-invasive and minimally invasive denervation methods and systems for performing the same
US9149328B2 (en) 2009-11-11 2015-10-06 Holaira, Inc. Systems, apparatuses, and methods for treating tissue and controlling stenosis
US9398933B2 (en) 2012-12-27 2016-07-26 Holaira, Inc. Methods for improving drug efficacy including a combination of drug administration and nerve modulation
WO2016185282A1 (en) 2015-05-18 2016-11-24 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
WO2017138896A1 (en) 2016-02-11 2017-08-17 Sima Patent Ve Lisanslama Hizmetleri Ltd. Şti Crystalline form of tiotropium bromide anhydrate
US9737520B2 (en) 2011-04-15 2017-08-22 Almirall, S.A. Aclidinium for use in improving the quality of sleep in respiratory patients
WO2018069887A1 (en) 2016-10-14 2018-04-19 Glenmark Specialty S.A. Nebulizable compositions of tiotropium and formoterol
US9987260B2 (en) 2015-05-18 2018-06-05 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
US10085974B2 (en) 2008-03-13 2018-10-02 Almirall, S.A. Dosage and formulation
US10653683B2 (en) 2015-05-18 2020-05-19 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
WO2020141472A1 (en) 2019-01-03 2020-07-09 Glenmark Specialty S.A. Nebulization composition comprising tiotropium and indacaterol
US11471468B2 (en) 2013-03-15 2022-10-18 Pearl Therapeutics, Inc. Methods and systems for conditioning of particulate crystalline materials
WO2023283441A1 (en) 2021-07-09 2023-01-12 Astrazeneca Pharmaceuticals Lp Compositions, methods and systems for aerosol drug delivery
WO2023119093A1 (en) 2021-12-20 2023-06-29 Astrazeneca Ab Compositions, methods and systems for aerosol drug delivery

Families Citing this family (116)

* Cited by examiner, † Cited by third party
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
GB0009583D0 (en) * 2000-04-18 2000-06-07 Glaxo Group Ltd Respiratory formulations
GB0009592D0 (en) * 2000-04-18 2000-06-07 Glaxo Group Ltd Respiratory combinations
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
US6750210B2 (en) 2000-08-05 2004-06-15 Smithkline Beecham Corporation Formulation containing novel anti-inflammatory androstane derivative
AU2001276497B2 (en) 2000-08-05 2005-04-07 Glaxo Group Limited 17.beta.-carbothioate 17.alpha.-arylcarbonyloxyloxy androstane derivative as anti-inflammatory agents
US6777400B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6787532B2 (en) 2000-08-05 2004-09-07 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivatives
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
GB0019172D0 (en) 2000-08-05 2000-09-27 Glaxo Group Ltd Novel compounds
US6759398B2 (en) 2000-08-05 2004-07-06 Smithkline Beecham Corporation Anti-inflammatory androstane derivative
US6777399B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
KR100488644B1 (en) 2000-10-12 2005-05-11 베링거 잉겔하임 파르마 게엠베하 운트 코 카게 Novel tiotropium-containing inhalation powder
US6908928B2 (en) 2000-10-12 2005-06-21 Bi Pharma Kg. Crystalline tiotropium bromide monohydrate, processes for the preparation thereof, and pharmaceutical compositions
AU2002214996B2 (en) * 2000-10-12 2007-03-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Crystalline monohydrate, method for producing the same and the use thereof in the production of a medicament
EP1333819B1 (en) * 2000-10-31 2007-09-19 BOEHRINGER INGELHEIM PHARMA GMBH &amp; CO. KG 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
EP1353919B1 (en) 2000-12-28 2006-07-26 Almirall Prodesfarma AG 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
KR100831534B1 (en) 2001-04-30 2008-05-22 글락소 그룹 리미티드 Anti-inflammatory 17.beta.-carbothioate ester derivatives of androstane with a cyclic ester group in position 17.alpha
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
EE05316B1 (en) * 2001-06-22 2010-08-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Crystalline anticholinergic, a process for its preparation and its use in the manufacture of a medicament
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
BR0206207A (en) 2001-10-26 2003-12-23 Pharmacia & Up John Company Quaternary 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
US7244415B2 (en) 2002-03-28 2007-07-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg HFA suspension formulations of an anhydrate
DE10214264A1 (en) * 2002-03-28 2003-10-16 Boehringer Ingelheim Pharma 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
WO2004106333A1 (en) 2003-05-28 2004-12-09 Theravance, Inc. Azabicycloalkane compounds as muscarinic receptor antagonists
EP1682542B1 (en) * 2003-11-03 2009-12-30 Boehringer Ingelheim International GmbH Novel crystalline anhydride with anticholinergic effect
EP2083007B1 (en) 2003-11-03 2013-04-24 Boehringer Ingelheim International Gmbh Tiotropium salts, method for creating same and medicinal formulations containing same
SG137859A1 (en) * 2003-11-03 2007-12-28 Boehringer Ingelheim Int Method for producing tiotropium salts, tiotropium salts and pharmaceutical formulations, containing the same
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
RU2007144531A (en) * 2005-05-02 2009-06-10 БЕРИНГЕР ИНГЕЛЬХАЙМ ИНТЕРНАЦИОНАЛЬ ГмбХ (DE) NEW CRYSTAL FORMS OF THIOTROPYBROMIDE
EP2085396A3 (en) 2005-05-02 2009-11-25 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
BRPI0614290A2 (en) 2005-08-08 2011-03-22 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
US9108962B2 (en) 2005-12-19 2015-08-18 Sicor, Inc. Forms of tiotropium bromide and processes for preparation thereof
US20070167480A1 (en) * 2005-12-19 2007-07-19 Sicor Inc. Pure and stable tiotropium bromide
EP1869035B2 (en) * 2005-12-19 2015-08-12 Sicor, Inc. Novel crystalline form of tiotropium bromide and process for preparation thereof
US8003663B2 (en) 2006-08-01 2011-08-23 Glaxo Group Limited 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
AU2009203579B2 (en) * 2008-01-10 2013-07-25 Generics [Uk] Limited Novel process for the preparation of scopine esters
EP2172190A1 (en) 2008-10-02 2010-04-07 Laboratorios Liconsa, S.A. Inhalable particles comprising tiotropium
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
TR200907236A2 (en) 2009-09-23 2011-04-21 Bi̇lgi̇ç Mahmut Transport of Tiotropium dry powder formulation in blister pack.
TR200907237A2 (en) 2009-09-23 2011-04-21 Bi̇lgi̇ç Mahmut Tiotropium dry powder combination
TR200909789A2 (en) 2009-12-25 2011-07-21 Bi̇lgi̇ç Mahmut Dry powder combination containing tiotropium, budesonide and a chromoglycic acid derivative combination
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
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.
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.
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
WO2011093810A2 (en) 2010-01-28 2011-08-04 Bilgic Mahmut Dry powder pharmaceutical composition comprising tiotropium and mometasone
WO2011093809A2 (en) 2010-01-28 2011-08-04 Mahmut Bilgic Dry powder pharmaceutical composition comprising tiotropium and ciclesonide
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.
US8834931B2 (en) 2009-12-25 2014-09-16 Mahmut Bilgic Dry powder formulation containing tiotropium for inhalation
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.
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
TR201102068A2 (en) 2011-03-03 2012-09-21 Bi̇lgi̇ç Mahmut Crystalline substances containing tiotropium bromide
TR201111589A2 (en) 2011-03-03 2012-09-21 Bi̇lgi̇ç Mahmut Tiotropium bromide anhydrous crystal form.
ITRM20110508A1 (en) 2011-09-27 2013-03-28 Lusochimica Spa PROCESS FOR THE PREPARATION OF SCOPINA'S ESTERS.
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
PL2607351T3 (en) * 2011-12-22 2017-08-31 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
US20150165038A1 (en) 2012-02-10 2015-06-18 Arven llac Sanayi Ve Ticaret A.S. Compositions comprising muscarinic receptor antagonist and sorbitol
PT106142B (en) 2012-02-10 2014-07-18 Hovione Farmaci Ncia S A PROCESS FOR THE PREPARATION OF TIOTROPE BROMIDE
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
US10105316B2 (en) 2012-07-05 2018-10-23 Arven llac Sanayi Ve Ticaret A.S. Inhalation compositions comprising muscarinic receptor antagonist
EP2705838A1 (en) 2012-09-06 2014-03-12 Xspray Microparticles Ab Tiotropium preparations
PL2914593T3 (en) 2012-11-05 2017-07-31 Zentiva, K.S. Stabilization of tiotropium solvates
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
KR101748796B1 (en) 2015-09-30 2017-06-19 한미약품 주식회사 Inhalation capsule with enhanced delivery rate of active ingredients
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
EP3159278A1 (en) 2015-10-23 2017-04-26 Arven Ilac Sanayi Ve Ticaret A.S. Blister for tiotropium bromide inhalable formulation
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
CN114213408B (en) * 2021-12-15 2023-03-31 台州仙琚药业有限公司 Preparation method of tiotropium bromide

Citations (9)

* Cited by examiner, † Cited by third party
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
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
GB1350928A (en) 1970-01-28 1974-04-24 Boehringer Sohn Ingelheim Processes for the preparation of esters of disubstituted glycolic acids
US3808263A (en) 1970-05-12 1974-04-30 Tanabe Seiyaku Co 6,6-dimethyl-9-alkyl-9-azabicyclo(3.3.1)nonan-3-ols
US4353922A (en) * 1981-03-13 1982-10-12 Syntex (U.S.A.) Inc. Anticholinergic bronchodilators
US4855422A (en) 1985-12-27 1989-08-08 Madaus Gmbh & Co. Process for the preparation of azoniaspironortropanol esters
EP0418716A1 (en) 1989-09-16 1991-03-27 Boehringer Ingelheim Kg Thienylcarboxylic acid ester of aminoalcohols, their quaternary products, their preparation and use of the compounds

Patent Citations (9)

* Cited by examiner, † Cited by third party
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
GB1350928A (en) 1970-01-28 1974-04-24 Boehringer Sohn Ingelheim Processes for the preparation of esters of disubstituted glycolic acids
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
US4855422A (en) 1985-12-27 1989-08-08 Madaus Gmbh & Co. Process for the preparation of azoniaspironortropanol esters
EP0418716A1 (en) 1989-09-16 1991-03-27 Boehringer Ingelheim Kg Thienylcarboxylic acid ester of aminoalcohols, their quaternary products, their preparation and use of the compounds

Non-Patent Citations (29)

* Cited by examiner, † Cited by third party
Title
Apr. 23, 1993 Reply to Examination Report from European Patent Application No. 90117554.7 (EP 418716) and English translation.
Atkinson et al., J. Med. Chem. 1977, vol. 20, No. 12, 1612-17.
Banholzer et al. "preparation of tropanyl . . . " CA 119:28006 (1993). *
CAS Accession No. 1983:34827 (Pfister et al.). *
CAS Accession No. 1992:20937 (Banholzer et al.). *
Dec. 1, 1992 Reply to Examination Report from European Patent Application No. 90117554.7 (EP 418716) and English translation.
Feb. 5, 1993 Examination Report from European Patent Application No. 90117554.7 (EP 418716) and English translation.
Foster et al., "Further New Tropine Derivatives," Journal of the Chemical Society, p. 3575-3578 (1957).
Frank & Maclaren, The Use of an Anticholinergic Drug in the treatment of Asthma, ANN. Allergy, 15(3):261-9 (1957). *
International Search Report mailed Jan. 10, 1991 from PCT/EP90/01517 (WO 91/04252).
Ipratropium Bromide (Atrovent), Merck Index, 10<SUP>th </SUP>Edition, p. 733 (1983).
Ipratropium Bromide (Atrovent), Merck Index, 10<SUP>th </SUP>Edition, pp. 802-803 (1989).
Ipratropium Bromide (Atrovent), Merck Index, 10th Edition, p. 733 (1983).
Ipratropium Bromide (Atrovent), Merck Index, 10th Edition, pp. 802-803 (1989).
Jun. 2, 1992 Examination Report from European Patent Application No. 90117554.7 (EP 418716) and English translation.
N-Butylscopolammonium Bromide (Buscopan), Merck Index, 10<SUP>th </SUP>Edition, pp. 219-220 (1983).
N-Butylscopolammonium Bromide (Buscopan), Merck Index, 10th Edition, pp. 219-220 (1983).
N-Butylscopolammonium Bromide (Buscopan), Merck Index, 11<SUP>th </SUP>Edition, p. 242 (1989).
N-Butylscopolammonium Bromide (Buscopan), Merck Index, 11th Edition, p. 242 (1989).
Nyberg et al., "Investigations of Diethienylglycolic Esters," Acta Chem. Scand., 24 (1970) No. 5, pp. 1590-1596.
Nyberg et al., Investigations of Dithienylglycolic Esters, Acta Chem. Scan. 24:1590-1596 (1970). *
Rusillo & Clark, The Pharmacology of the Anticholinergic Quaternary Ammonium compound Benzomethamine [N-Diethyllaminoethyl-N′-Methyl-Benzilamide Methobromide (MC 3199)] with a Note on the Tertiary Amine Analogue (MC 3137), J. Pharmacol. Exp. Ther., 11(1):54-62 (1955). *
Rusillo & Clark, The Pharmacology of the Anticholinergic Quaternary Ammonium compound Benzomethamine [N-Diethyllaminoethyl-N'-Methyl-Benzilamide Methobromide (MC 3199)] with a Note on the Tertiary Amine Analogue (MC 3137), J. Pharmacol. Exp. Ther., 11(1):54-62 (1955). *
Sterling Drug, Inc., Chem. Abstracts, vol. 61, No. 1839f (1964).
The Merck Index, 11<SUP>th </SUP>ed (1989) Merck and Co. Inc. p. 242 and 802-803. *
The Merck Index, 11th ed (1989) Merck and Co. Inc. p. 242 and 802-803. *
Valpin, Goodman & Gilman, The Pharmacological Basis of Therapeutics, 6<SUP>th </SUP>Edition, p. 130 (MacMillan 1980).
Valpin, Goodman & Gilman, The Pharmacological Basis of Therapeutics, 6th Edition, p. 130 (MacMillan 1980).
Wilhelm, The Chemistry of Polycyclic Psycho-active Drugs: Serendipity or Systematic Investigation?, Pharm. J., 214:414-416 (1975). *

Cited By (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9333195B2 (en) 1999-07-14 2016-05-10 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US8802699B2 (en) 1999-07-14 2014-08-12 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US8513279B2 (en) 1999-07-14 2013-08-20 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US9056100B2 (en) 1999-07-14 2015-06-16 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
USRE46417E1 (en) 1999-07-14 2017-05-30 Almirall, S.A. Quinuclidine derivatives and their use as muscarinic M3 receptor ligands
US10034867B2 (en) 1999-07-14 2018-07-31 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US9687478B2 (en) 1999-07-14 2017-06-27 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US10588895B2 (en) 1999-07-14 2020-03-17 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US20070015785A1 (en) * 2002-03-20 2007-01-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Crystalline Micronisate, Process for the Manufacture Thereof and Use Thereof for the Preparation of a Medicament
US7642268B2 (en) 2002-03-20 2010-01-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Crystalline micronisate, process for the manufacture thereof and use thereof for the preparation of a medicament
US20060154951A1 (en) * 2003-01-16 2006-07-13 Wood Ronald W Quaternary antimuscarinic compounds for the treatment of bladder diseases
US8481518B2 (en) 2003-01-16 2013-07-09 University Of Rochester Quaternary antimuscarinic compounds for the treatment of bladder diseases
US8172827B2 (en) 2003-05-13 2012-05-08 Innovative Pulmonary Solutions, Inc. Apparatus for treating asthma using neurotoxin
US9339618B2 (en) 2003-05-13 2016-05-17 Holaira, Inc. Method and apparatus for controlling narrowing of at least one airway
US10953170B2 (en) 2003-05-13 2021-03-23 Nuvaira, Inc. Apparatus for treating asthma using neurotoxin
US7968717B2 (en) 2003-11-03 2011-06-28 Boehringer Ingelhein International Gmbh Crystalline anhydrate with anticholinergic efficacy
US20050143410A1 (en) * 2003-11-03 2005-06-30 Boehringer Ingelheim International Gmbh Novel crystalline anhydrate with anticholinergic efficacy
US20070155773A1 (en) * 2006-01-04 2007-07-05 Michael Engel Use of Tiotropium Salts in the Treatment of Moderate Persistent Asthma
US8044205B2 (en) 2006-07-21 2011-10-25 Laboratorios Almirall, S.A. Process for manufacturing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide
US20090299042A1 (en) * 2006-07-21 2009-12-03 Nuria Busquets Baque Process for manufacturing 3(r)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide
US20090134655A1 (en) * 2007-10-29 2009-05-28 Carl Paluszkiewicz Motorcycle wind deflector accessory support
US9125643B2 (en) 2008-02-15 2015-09-08 Holaira, Inc. System and method for bronchial dilation
US8483831B1 (en) 2008-02-15 2013-07-09 Holaira, Inc. System and method for bronchial dilation
US8489192B1 (en) 2008-02-15 2013-07-16 Holaira, Inc. System and method for bronchial dilation
US11058879B2 (en) 2008-02-15 2021-07-13 Nuvaira, Inc. System and method for bronchial dilation
US8731672B2 (en) 2008-02-15 2014-05-20 Holaira, Inc. System and method for bronchial dilation
US10085974B2 (en) 2008-03-13 2018-10-02 Almirall, S.A. Dosage and formulation
US20110020454A1 (en) * 2008-03-13 2011-01-27 Rosa Lamarca Casado Novel dosage and formulation
US11000517B2 (en) 2008-03-13 2021-05-11 Almirall, S.A. Dosage and formulation
US9254262B2 (en) 2008-03-13 2016-02-09 Almirall, S.A. Dosage and formulation
US8088127B2 (en) 2008-05-09 2012-01-03 Innovative Pulmonary Solutions, Inc. Systems, assemblies, and methods for treating a bronchial tree
US8808280B2 (en) 2008-05-09 2014-08-19 Holaira, Inc. Systems, assemblies, and methods for treating a bronchial tree
US9668809B2 (en) 2008-05-09 2017-06-06 Holaira, Inc. Systems, assemblies, and methods for treating a bronchial tree
US8821489B2 (en) 2008-05-09 2014-09-02 Holaira, Inc. Systems, assemblies, and methods for treating a bronchial tree
US8961508B2 (en) 2008-05-09 2015-02-24 Holaira, Inc. Systems, assemblies, and methods for treating a bronchial tree
US10149714B2 (en) 2008-05-09 2018-12-11 Nuvaira, Inc. Systems, assemblies, and methods for treating a bronchial tree
US8226638B2 (en) 2008-05-09 2012-07-24 Innovative Pulmonary Solutions, Inc. Systems, assemblies, and methods for treating a bronchial tree
US11937868B2 (en) 2008-05-09 2024-03-26 Nuvaira, Inc. Systems, assemblies, and methods for treating a bronchial tree
US8961507B2 (en) 2008-05-09 2015-02-24 Holaira, Inc. Systems, assemblies, and methods for treating a bronchial tree
WO2010101538A2 (en) 2009-03-06 2010-09-10 Bilgic Mahmut New crystal forms
US9415009B2 (en) 2009-05-29 2016-08-16 Pearl Therapeutics, Inc. Compositions, methods and systems for respiratory delivery of two or more active agents
EP3111926A1 (en) 2009-05-29 2017-01-04 Pearl Therapeutics, Inc. Compositions, methods & systems for respiratory delivery of two or more active agents
US8703806B2 (en) 2009-05-29 2014-04-22 Pearl Therapeutics, Inc. Compositions, methods and propellant-based systems for respiratory delivery of glycopyrrolate and one or more active agents
US20110132356A1 (en) * 2009-05-29 2011-06-09 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting b2 adrenergic receptor agonists and associated methods and systems
US20110023876A1 (en) * 2009-05-29 2011-02-03 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists and associated methods and systems
US10716753B2 (en) 2009-05-29 2020-07-21 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists or long-acting B2 adrenergic receptor agonists and associated methods and systems
EP3111927A1 (en) 2009-05-29 2017-01-04 Pearl Therapeutics, Inc. Compositions for respiratory delivery of active agents and associated methods and systems
US20110132357A1 (en) * 2009-05-29 2011-06-09 Pearl Therapeutics, Inc. Compositions, methods & systems for respiratory delivery of two or more active agents
US8815258B2 (en) 2009-05-29 2014-08-26 Pearl Therapeutics, Inc. Compositions, methods and systems for respiratory delivery of two or more active agents
WO2010138868A2 (en) 2009-05-29 2010-12-02 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting b2 adrenergic receptor agonists and associated methods and systems
US8808713B2 (en) 2009-05-29 2014-08-19 Pearl Thereapeutics, Inc. Compositions for pulmonary delivery of long-acting β2 adrenergic receptor agonists and associated methods and systems
US20110135737A1 (en) * 2009-05-29 2011-06-09 Pearl Therapeutics, Inc. Compositions for respiratory delivery of active agents and associated methods and systems
US8324266B2 (en) 2009-05-29 2012-12-04 Pearl Therapeutics, Inc. Compositions, methods and systems for respiratory delivery of two or more active agents
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
EP3106149A1 (en) 2009-05-29 2016-12-21 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting b2 adrenergic receptor agonists and associated methods and systems
US8777943B2 (en) 2009-10-27 2014-07-15 Holaira, Inc. Delivery devices with coolable energy emitting assemblies
US9005195B2 (en) 2009-10-27 2015-04-14 Holaira, Inc. Delivery devices with coolable energy emitting assemblies
US8932289B2 (en) 2009-10-27 2015-01-13 Holaira, Inc. Delivery devices with coolable energy emitting assemblies
US9931162B2 (en) 2009-10-27 2018-04-03 Nuvaira, Inc. Delivery devices with coolable energy emitting assemblies
US9649153B2 (en) 2009-10-27 2017-05-16 Holaira, Inc. Delivery devices with coolable energy emitting assemblies
US8740895B2 (en) 2009-10-27 2014-06-03 Holaira, Inc. Delivery devices with coolable energy emitting assemblies
US9017324B2 (en) 2009-10-27 2015-04-28 Holaira, Inc. Delivery devices with coolable energy emitting assemblies
US9675412B2 (en) 2009-10-27 2017-06-13 Holaira, Inc. Delivery devices with coolable energy emitting assemblies
US9149328B2 (en) 2009-11-11 2015-10-06 Holaira, Inc. Systems, apparatuses, and methods for treating tissue and controlling stenosis
US9649154B2 (en) 2009-11-11 2017-05-16 Holaira, Inc. Non-invasive and minimally invasive denervation methods and systems for performing the same
US11712283B2 (en) 2009-11-11 2023-08-01 Nuvaira, Inc. Non-invasive and minimally invasive denervation methods and systems for performing the same
US11389233B2 (en) 2009-11-11 2022-07-19 Nuvaira, 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
US10610283B2 (en) 2009-11-11 2020-04-07 Nuvaira, Inc. Non-invasive and minimally invasive denervation methods and systems for performing the same
US8957209B2 (en) * 2010-04-01 2015-02-17 Mahmut Bilgic Methods for the synthesis of tiotropium bromide
US20130030182A1 (en) * 2010-04-01 2013-01-31 Mahmut Bilgic Methods for the synthesis of tiotropium bromide
US9242979B2 (en) * 2010-04-01 2016-01-26 Mahmut Bilgic Methods for the synthesis of tiotropium bromide
US20150148540A1 (en) * 2010-04-01 2015-05-28 Mahmut Bilgic Methods for the synthesis of tiotropium bromide
US9737520B2 (en) 2011-04-15 2017-08-22 Almirall, S.A. Aclidinium for use in improving the quality of sleep in respiratory patients
US8680297B2 (en) 2011-10-06 2014-03-25 Drug Process Licensing Assoc., LLC Manufacturing process for tiotropium bromide
US9398933B2 (en) 2012-12-27 2016-07-26 Holaira, Inc. Methods for improving drug efficacy including a combination of drug administration and nerve modulation
US11471468B2 (en) 2013-03-15 2022-10-18 Pearl Therapeutics, Inc. Methods and systems for conditioning of particulate crystalline materials
WO2014165303A1 (en) 2013-04-01 2014-10-09 Pulmatrix, Inc. Tiotropium dry powders
US10653683B2 (en) 2015-05-18 2020-05-19 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
US9757365B2 (en) 2015-05-18 2017-09-12 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
US10632108B2 (en) 2015-05-18 2020-04-28 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
US10632109B2 (en) 2015-05-18 2020-04-28 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
US9987260B2 (en) 2015-05-18 2018-06-05 Glenmark Specialty S.A. Tiotropium inhalation solution for nebulization
WO2017138896A1 (en) 2016-02-11 2017-08-17 Sima Patent Ve Lisanslama Hizmetleri Ltd. Şti Crystalline form of tiotropium bromide anhydrate
US10555903B2 (en) 2016-10-14 2020-02-11 Glenmark Specialty S.A. Nebulizable compositions of tiotropium and formoterol
WO2018069887A1 (en) 2016-10-14 2018-04-19 Glenmark Specialty S.A. Nebulizable compositions of tiotropium and formoterol
WO2020141472A1 (en) 2019-01-03 2020-07-09 Glenmark Specialty S.A. Nebulization composition comprising tiotropium and indacaterol
WO2023283441A1 (en) 2021-07-09 2023-01-12 Astrazeneca Pharmaceuticals Lp Compositions, methods and systems for aerosol drug delivery
WO2023283438A1 (en) 2021-07-09 2023-01-12 Astrazeneca Pharmaceuticals Lp Compositions, methods and systems for aerosol drug delivery
WO2023283439A1 (en) 2021-07-09 2023-01-12 Astrazeneca Pharmaceuticals Lp Compositions, methods and systems for aerosol drug delivery
EP4197528A1 (en) 2021-07-09 2023-06-21 AstraZeneca Pharmaceuticals LP Compositions, methods and systems for aerosol drug delivery
WO2023119093A1 (en) 2021-12-20 2023-06-29 Astrazeneca Ab Compositions, methods and systems for aerosol drug delivery

Also Published As

Publication number Publication date
AU642913B2 (en) 1993-11-04
SI9011744A (en) 1997-10-31
FI921087A0 (en) 1992-03-13
NO921002D0 (en) 1992-03-13
PL286900A1 (en) 1991-12-02
KR0168432B1 (en) 1999-01-15
DE3931041A1 (en) 1991-03-28
SI9011744B (en) 1999-12-31
IE903342A1 (en) 1991-04-10
ZA907338B (en) 1992-08-26
HUT60740A (en) 1992-10-28
NO921002L (en) 1992-03-13
CA2066248A1 (en) 1991-03-17
JPH0730074B2 (en) 1995-04-05
DE10299026I2 (en) 2004-07-01
HU9200857D0 (en) 1992-05-28
YU47800B (en) 1996-01-09
NO2002009I2 (en) 2004-10-11
JPH05502438A (en) 1993-04-28
IL95691A0 (en) 1991-06-30
HRP940723B1 (en) 1999-10-31
NO301478B1 (en) 1997-11-03
DE3931041C2 (en) 2000-04-06
RU2073677C1 (en) 1997-02-20
UA41272C2 (en) 2001-09-17
LU90949I2 (en) 2002-10-30
SK452390A3 (en) 1998-11-04
EP0418716B1 (en) 1994-04-06
CA2066248C (en) 1998-08-04
HRP940723A2 (en) 1997-06-30
ATE103914T1 (en) 1994-04-15
AU6431890A (en) 1991-04-18
YU174490A (en) 1993-10-20
IE65528B1 (en) 1995-11-01
IL95691A (en) 1996-07-23
HU208823B (en) 1994-01-28
BG61295B2 (en) 1997-04-30
NZ235306A (en) 1997-06-24
CZ452390A3 (en) 1998-11-11
CZ284589B6 (en) 1999-01-13
FI114395B (en) 2004-10-15
SK279453B6 (en) 1998-11-04
PL168468B1 (en) 1996-02-29
DD297647A5 (en) 1992-01-16
EP0418716A1 (en) 1991-03-27
NL300084I1 (en) 2002-05-01
DE59005250D1 (en) 1994-05-11
HU210612A9 (en) 1995-05-29
DE10299026I1 (en) 2002-11-07
KR910006272A (en) 1991-04-29
NL300084I2 (en) 2002-08-01
PT95312A (en) 1991-05-22
PH31617A (en) 1999-01-12
PT95312B (en) 1997-06-30
MX9203150A (en) 1992-07-01
ES2052125T3 (en) 1994-07-01
DK0418716T3 (en) 1994-05-02
WO1991004252A1 (en) 1991-04-04

Similar Documents

Publication Publication Date Title
USRE39820E1 (en) Esters of thienyl carboxylic acids and amino alcohols and their quaternization products
US5610163A (en) Esters of thienyl carboxylic acids and amino alcohols and their quaternization products
US5654314A (en) Esters of bi- and tricyclic amino alcohols and their use in pharmaceutical compositions
US5770738A (en) Esters of bi- and tricyclic amino alcohols, their preparation and their use in pharmaceutical compositions
US4042700A (en) Quaternary N-β-substituted N-alkyl-nortropine benzilates
US5106843A (en) Heterocyclic compounds useful as 5-ht3 antagonists
IE83484B1 (en) New Bi- and tricyclic aminoalcohol esters, their preparation and their use in medicaments
EP0554794B1 (en) Aminobenzoic acid derivatives
US20090163541A1 (en) Quinuclidine compounds having quaternary ammonium group, its preparation method and use as blocking agents of acetylcholine
EP0112266B1 (en) Substituted tropyl and pseudotropyl benzoates and their use in migraine treatment
JPH01224361A (en) Tetrahydropyridine derivative and its production

Legal Events

Date Code Title Description
PTEF Application for a patent term extension

Free format text: PRODUCT NAME: SPIRIVA HANDIHALER (TIOTROPIUM BROMIDE INHALATION POWDER); REQUESTED FOR 1,421 DAYS

Filing date: 20040315

Expiry date: 20140311

Free format text: PRODUCT NAME: SPIRIVA HANDIHALER (TIOTROPIUM BROMIDE INHALATION POWDER); REQUESTED FOR 1,421 DAYS; ORIGINAL PATENT 5610163

Filing date: 20040315

Expiry date: 20140311

PTEG Grant of a patent term extension

Free format text: PRODUCT NAME: SPIRIVA HANDIHALER (TIOTROPIUM BROMIDE INHALATION POWDER)

Filing date: 20040315

Expiry date: 20140311

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

CC Certificate of correction
FPAY Fee payment

Year of fee payment: 12