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

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USRE39820E1
USRE39820E1 US11254213 US25421305A USRE39820E US RE39820 E1 USRE39820 E1 US RE39820E1 US 11254213 US11254213 US 11254213 US 25421305 A US25421305 A US 25421305A US RE39820 E USRE39820 E US RE39820E
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thienyl
tropanyl
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methobromide
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Rolf Banholzer
Rudolf Bauer
Richard Reichl
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Boehringer Ingelheim Pharma GmbH and Co KG
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D451/00Heterocyclic 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
    • C07D451/14Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D451/00Heterocyclic 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
    • C07D451/02Heterocyclic 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
    • C07D451/04Heterocyclic 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
    • C07D451/06Oxygen atoms
    • C07D451/10Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

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)

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.
US11254213 1989-09-16 2005-10-18 Esters of thienyl carboxylic acids and amino alcohols and their quaternization products Expired - Lifetime USRE39820E1 (en)

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US83872492 true 1992-03-13 1992-03-13
US10082293 true 1993-08-02 1993-08-02
US25432494 true 1994-06-06 1994-06-06
US08405111 US5610163A (en) 1989-09-16 1995-03-16 Esters of thienyl carboxylic acids and amino alcohols and their quaternization products
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Cited By (26)

* 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

Families Citing this family (107)

* 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 Thienylcarbonsäuren with aminoalcohols, their quaternization products, processes for their preparation and pharmaceutical compositions containing them
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
DE4108393A1 (en) * 1991-03-15 1992-09-17 Boehringer Ingelheim Kg New ester bi- and tricyclic amino alcohols, their production and their use in medicinal products
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
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
GB0009583D0 (en) * 2000-04-18 2000-06-07 Glaxo Group Ltd Respiratory formulations
GB0009605D0 (en) * 2000-04-18 2000-06-07 Glaxo Group Ltd Medicaments
US6858596B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivative
US6750210B2 (en) 2000-08-05 2004-06-15 Smithkline Beecham Corporation Formulation containing novel anti-inflammatory androstane derivative
US6777399B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
CN1315867C (en) 2000-08-05 2007-05-16 葛兰素集团有限公司 17.beta.-carbothioate 17.alpha.-arylcarbonyloxyloxy androstane derivative as anti-inflammatory agents
US6858593B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
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
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
US6908928B2 (en) 2000-10-12 2005-06-21 Bi Pharma Kg. Crystalline tiotropium bromide monohydrate, processes for the preparation thereof, and pharmaceutical compositions
CN1221549C (en) * 2000-10-12 2005-10-05 贝林格尔英格海姆法玛两合公司 Crystalline monohydrate, method for producing the same and the use thereof in the production of medicament
CA2395653C (en) 2000-10-12 2006-05-09 Boehringer Ingelheim Pharma Kg New inhalable powder containing tiotropium
US6506900B1 (en) 2001-01-31 2003-01-14 Boehringer Ingelheim Pharma Ag Process for preparing a scopine ester intermediate
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
RU2282629C2 (en) 2000-12-28 2006-08-27 Альмиралль Продесфарма Аг Derivatives of quinuclidine, method for their preparing and pharmaceutical composition based on thereof
GB0108800D0 (en) 2001-04-07 2001-05-30 Glaxo Group Ltd Novel compounds
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
JP2005504015A (en) * 2001-06-22 2005-02-10 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト Anticholinergics, their use for the production of their preparation and pharmaceutical compositions
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 Sprinkling method for preparation of powder formulations
DE60230546D1 (en) 2001-10-26 2009-02-05 Pharmacia & Upjohn Co Llc quaternary ammonium compounds and their use as active ingredients antimuscarinic
DE10200943A1 (en) * 2002-01-12 2003-07-24 Boehringer Ingelheim Pharma A process for preparing Scopinestern
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 anticholinergic, processes for their preparation and their use as medicaments
GB0202635D0 (en) * 2002-02-05 2002-03-20 Glaxo Wellcome Mfg Pte Ltd Formulation containing novel anti-inflammatory androstane derivative
WO2003068233A1 (en) * 2002-02-11 2003-08-21 Pfizer Limited Nicotinamide derivatives and a tiotropium salt in combination for the treatment of e.g. inflammatory, allergic and respiratory diseases
GB0203193D0 (en) * 2002-02-11 2002-03-27 Pfizer Ltd Nicotinamide derivatives useful as pde4 inhibitors
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
DE10214264A1 (en) * 2002-03-28 2003-10-16 Boehringer Ingelheim Pharma HFA suspension formulations of an anhydrate
CN101574552B (en) 2002-04-09 2011-12-07 贝林格尔英格海姆法玛两合公司 Tiotropium containing inhalation powder inhalation kit
DE10216036A1 (en) 2002-04-11 2003-10-23 Boehringer Ingelheim Pharma An aerosol formulation for inhalation containing a tiotropium salt
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
US7358244B2 (en) 2003-05-28 2008-04-15 Theravance, Inc. Azabicycloalkane compounds
KR20060117334A (en) * 2003-11-03 2006-11-16 베링거 인겔하임 인터내셔날 게엠베하 Method for producing tiotropium salts, tiotropium salts and pharmaceutical formulations, containing the same
CA2544357A1 (en) * 2003-11-03 2005-05-12 Boehringer Ingelheim International Gmbh Tiotropium salts, methods for the production thereof, and pharmaceutical formulations containing the same
KR101313904B1 (en) * 2003-11-03 2013-09-30 베링거 인겔하임 인터내셔날 게엠베하 Novel crystalline anhydrate with anticholinergic effect
US20080027094A1 (en) * 2004-08-30 2008-01-31 Ono Pharmaceutical Co., Ltd. Tropane Compounds and Pharmaceutical Compositions Comprising the Same as an Active Ingredient
JP2008540367A (en) * 2005-05-02 2008-11-20 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 crystalline tiotropium bromide
CN101166738B (en) 2005-05-02 2011-06-01 贝林格尔·英格海姆国际有限公司 Novel crystalline forms of tiotropium bromide
DE102005035112A1 (en) 2005-07-27 2007-02-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg New process for the preparation of tiotropium salts, using organic solvent-soluble N-Methylscopiniumsalzen
RU2442771C2 (en) 2005-08-08 2012-02-20 Арджента Дискавери Лтд Derivants of bicyclo[2, 2, 1] hept-7-ylamine and their applications
DE102005059602A1 (en) * 2005-12-14 2007-06-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg Methods of micronising
US20070167480A1 (en) * 2005-12-19 2007-07-19 Sicor Inc. Pure and stable tiotropium bromide
ES2396978T5 (en) * 2005-12-19 2015-12-04 Sicor, Inc. novel crystalline form of tiotropium bromide and method for preparation thereof
US9108962B2 (en) 2005-12-19 2015-08-18 Sicor, Inc. Forms of tiotropium bromide and processes 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
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
EP2172190A1 (en) 2008-10-02 2010-04-07 Laboratorios Liconsa, S.A. Inhalable particles comprising tiotropium
WO2011015883A1 (en) 2009-08-07 2011-02-10 Generics [Uk] Limited Dichloromethane solvate of tiotropium bromide and its use
WO2011015882A3 (en) 2009-08-07 2011-09-01 Generics [Uk] Limited Anhydrate of triotropium bromide
WO2011015884A1 (en) 2009-08-07 2011-02-10 Generics [Uk] Limited Process to prepare scopine esters
EP2480287A2 (en) 2009-09-23 2012-08-01 Mahmut Bilgic Dry powder combination of tiotropium
WO2011037549A3 (en) 2009-09-23 2011-06-09 Bilgic Mahmut Dry powder formulation of tiotropium carried in blister strip
EP2515847A1 (en) 2009-12-25 2012-10-31 Mahmut Bilgic Combination of tiotropium, mometasone and a cromoglicic acid derivative in dry powder form
EP2515846B1 (en) 2009-12-25 2015-10-28 Mahmut Bilgic Dry powder combination of tiotropium, budesonide and a cromoglicic acid derivative
EP2515845B1 (en) 2009-12-25 2014-04-30 Mahmut Bilgic Dry powder combination of tiotropium, formoterol and a cromoglicic acid derivative
WO2011078818A1 (en) 2009-12-25 2011-06-30 Bilgic Mahmut Dry powder combination of tiotropium, a corticosteroid and a cromoglicic acid derivative
US8834931B2 (en) 2009-12-25 2014-09-16 Mahmut Bilgic Dry powder formulation containing tiotropium for inhalation
WO2011078824A1 (en) 2009-12-25 2011-06-30 Mahmut Bilgic Dry powder formulation containing tiotropium for inhalation
WO2011093810A3 (en) 2010-01-28 2012-02-23 Mahmut Bilgic Dry powder pharmaceutical composition comprising tiotropium and mometasone
WO2011093812A3 (en) 2010-01-28 2012-02-02 Mahmut Bilgic Pharmaceutical formulation comprising tiotropium and budesonide in dry powder form
WO2011093809A3 (en) 2010-01-28 2012-02-23 Mahmut Bilgic Dry powder pharmaceutical composition comprising tiotropium and ciclesonide
EP2528600B1 (en) 2010-01-28 2016-06-29 Mahmut Bilgic Dry powder pharmaceutical composition comprising tiotropium and fluticasone
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WO2011093816A1 (en) * 2010-01-29 2011-08-04 Mahmut Bilgic Dry powder formulation comprising a pharmaceutical combination of tiotropium bromide, formoterol fumarate and mometasone furoate
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EP2552911B1 (en) 2010-04-01 2016-07-20 Bilgic Mahmut Tiotropium bromide preparation process
WO2012026906A1 (en) 2010-08-25 2012-03-01 Mahmut Bilgic New tiotropium bromide crystal and its production method
WO2012118460A1 (en) 2011-02-28 2012-09-07 Mahmut Bilgic Crystalline compound comprising tiotropium bromide
EP2681212A1 (en) 2011-03-03 2014-01-08 Bilgic, Mahmut Crystalline compound comprising tiotropium bromide
WO2012118462A1 (en) 2011-03-03 2012-09-07 Mahmut Bilgic Anhydrous crystalline form of tiotropium bromide
WO2013046138A1 (en) 2011-09-27 2013-04-04 Lusochimica S.P.A. Process for the preparation of scopine esters
WO2013079040A1 (en) 2011-11-28 2013-06-06 Zentiva K.S. Mixed solvate of tiotropium bromide and a method of its preparation
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EP2825535B1 (en) 2012-03-16 2016-04-27 Zentiva, K.S. A method of preparing the scopine ester of di-(2-thienyl)glycolic acid, an intermediate in the synthesis of tiotropium bromide, and its new form
ES2570979T3 (en) 2012-03-30 2016-05-23 Zentiva K S A method of preparing scopine ester of di- (2-thienyl) glycolic acid, an intermediate in the synthesis of tiotropium bromide
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US20150157567A1 (en) 2012-07-05 2015-06-11 Arven Ilac Sanayi Ve Ticaret A.S. Inhalation compositions comprising muscarinic receptor antagonist
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EP2913332A1 (en) 2014-02-27 2015-09-02 Euticals S.P.A. Crystalline form of tiotropium bromide with lactose
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WO2017068119A1 (en) 2015-10-23 2017-04-27 Arven Ilac Sanayi Ve Ticaret A.S. Blister for tiotropium bromide inhalable formulation
EP3159277A1 (en) 2015-10-23 2017-04-26 Arven Ilac Sanayi Ve Ticaret A.S. Blister for inhalable formulation of tiotropium bromide
CN106467535A (en) * 2016-08-28 2017-03-01 杭州百诚医药科技股份有限公司 Purification process for preparation of 2,2-bis(2-thienyl)glycolic acid scopoletin

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 A process for the preparation of novel Granatanol- (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 A process for the preparation of novel Granatanol- (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 (22)

* 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).
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, 11<SUP>th </SUP>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). *
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. *
Valpin, Goodman & Gilman, The Pharmacological Basis of Therapeutics, 6<SUP>th </SUP>Edition, p. 130 (MacMillan 1980).
Wilhelm, The Chemistry of Polycyclic Psycho-active Drugs: Serendipity or Systematic Investigation?, Pharm. J., 214:414-416 (1975). *

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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
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
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