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Publication numberUSRE39820 E1
Publication typeGrant
Application numberUS 11/254,213
Publication dateSep 4, 2007
Filing dateOct 18, 2005
Priority dateSep 16, 1989
Fee statusPaid
Also published asCA2066248A1, CA2066248C, DE3931041A1, DE3931041C2, DE10299026I1, DE10299026I2, DE59005250D1, EP0418716A1, EP0418716B1, WO1991004252A1
Publication number11254213, 254213, US RE39820 E1, US RE39820E1, US-E1-RE39820, USRE39820 E1, USRE39820E1
InventorsRolf Banholzer, Rudolf Bauer, Richard Reichl
Original AssigneeBoehringer Ingelheim Pharma Gmbh & Co. Kg
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Esters of thienyl carboxylic acids and amino alcohols and their quaternization products
US RE39820 E1
Abstract
Compounds of the formula
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.
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Claims(19)
1. A compound of the formula
wherein
Q is a group of the formula —CH2—CH2—, —CH═CH— or
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
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
wherein X is a physiologically acceptable anion.
6. A compound of the formula
wherein X is a physiologically acceptable onion.
7. A compound of the formula
8. A compound of the formula
wherein R1 is 2-thienyl and A is 3α-(6,7-dehydro)-tropanyl methobromide.
9. A compound of the formula
wherein R1 is 2-thienyl and A is 3β-tropanyl methobromide.
10. A compound of the formula
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.
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


in which

    • A represents the group
      wherein
    • m and n independently of one another denote 1 or 2,
    • Q represents one of the double-bonding groups
      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

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


the following are particularly suitable:

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
Com-
pound A R1
A 2- thienyl
B 3- thienyl
D 2- thienyl
E 3- thienyl
F cyclo- pentyl
G cyclo- pentyl
Compound C
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


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
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
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
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
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
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
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
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
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
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

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3673195May 25, 1970Jun 27, 1972Tanabe Seiyaku CoDerivatives of 6,6,9-tri-lower alkyl-9-azabicyclo(3.3.1) nonan-3{60 -or 3{62 -ol
US3808263Apr 28, 1971Apr 30, 1974Tanabe Seiyaku Co6,6-dimethyl-9-alkyl-9-azabicyclo(3.3.1)nonan-3-ols
US4353922 *Mar 13, 1981Oct 12, 1982Syntex (U.S.A.) Inc.Anticholinergic bronchodilators
US4855422Dec 23, 1986Aug 8, 1989Madaus Gmbh & Co.Process for the preparation of azoniaspironortropanol esters
DE1166787BJul 9, 1960Apr 2, 1964Boehringer & Soehne GmbhVerfahren zur Herstellung von neuen Granatanol-(3‰)-estern und ihren Hydrohalogeniden
EP0418716A1Sep 12, 1990Mar 27, 1991Boehringer Ingelheim KgThienylcarboxylic acid ester of aminoalcohols, their quaternary products, their preparation and use of the compounds
GB845056A Title not available
GB955535A Title not available
GB1350928A Title not available
Non-Patent Citations
Reference
1Apr. 23, 1993 Reply to Examination Report from European Patent Application No. 90117554.7 (EP 418716) and English translation.
2Atkinson et al., J. Med. Chem. 1977, vol. 20, No. 12, 1612-17.
3 *Banholzer et al. "preparation of tropanyl . . . " CA 119:28006 (1993).
4 *CAS Accession No. 1983:34827 (Pfister et al.).
5 *CAS Accession No. 1992:20937 (Banholzer et al.).
6Dec. 1, 1992 Reply to Examination Report from European Patent Application No. 90117554.7 (EP 418716) and English translation.
7Feb. 5, 1993 Examination Report from European Patent Application No. 90117554.7 (EP 418716) and English translation.
8Foster et al., "Further New Tropine Derivatives," Journal of the Chemical Society, p. 3575-3578 (1957).
9 *Frank & Maclaren, The Use of an Anticholinergic Drug in the treatment of Asthma, ANN. Allergy, 15(3):261-9 (1957).
10International Search Report mailed Jan. 10, 1991 from PCT/EP90/01517 (WO 91/04252).
11Ipratropium Bromide (Atrovent), Merck Index, 10<SUP>th </SUP>Edition, p. 733 (1983).
12Ipratropium Bromide (Atrovent), Merck Index, 10<SUP>th </SUP>Edition, pp. 802-803 (1989).
13Jun. 2, 1992 Examination Report from European Patent Application No. 90117554.7 (EP 418716) and English translation.
14N-Butylscopolammonium Bromide (Buscopan), Merck Index, 10<SUP>th </SUP>Edition, pp. 219-220 (1983).
15N-Butylscopolammonium Bromide (Buscopan), Merck Index, 11<SUP>th </SUP>Edition, p. 242 (1989).
16Nyberg et al., "Investigations of Diethienylglycolic Esters," Acta Chem. Scand., 24 (1970) No. 5, pp. 1590-1596.
17 *Nyberg et al., Investigations of Dithienylglycolic Esters, Acta Chem. Scan. 24:1590-1596 (1970).
18 *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).
19Sterling Drug, Inc., Chem. Abstracts, vol. 61, No. 1839f (1964).
20 *The Merck Index, 11<SUP>th </SUP>ed (1989) Merck and Co. Inc. p. 242 and 802-803.
21Valpin, Goodman & Gilman, The Pharmacological Basis of Therapeutics, 6<SUP>th </SUP>Edition, p. 130 (MacMillan 1980).
22 *Wilhelm, The Chemistry of Polycyclic Psycho-active Drugs: Serendipity or Systematic Investigation?, Pharm. J., 214:414-416 (1975).
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US8044205Jul 16, 2007Oct 25, 2011Laboratorios 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
US8088127May 8, 2009Jan 3, 2012Innovative Pulmonary Solutions, Inc.Systems, assemblies, and methods for treating a bronchial tree
US8172827May 8, 2012Innovative Pulmonary Solutions, Inc.Apparatus for treating asthma using neurotoxin
US8226638Jul 24, 2012Innovative Pulmonary Solutions, Inc.Systems, assemblies, and methods for treating a bronchial tree
US8324266Dec 4, 2012Pearl Therapeutics, Inc.Compositions, methods and systems for respiratory delivery of two or more active agents
US8481518Jan 15, 2004Jul 9, 2013University Of RochesterQuaternary antimuscarinic compounds for the treatment of bladder diseases
US8483831Feb 17, 2009Jul 9, 2013Holaira, Inc.System and method for bronchial dilation
US8489192Jun 14, 2012Jul 16, 2013Holaira, Inc.System and method for bronchial dilation
US8513279Jan 20, 2012Aug 20, 2013Almirall, S.A.Quinuclidine derivatives and medicinal compositions containing the same
US8680297Oct 6, 2011Mar 25, 2014Drug Process Licensing Assoc., LLCManufacturing process for tiotropium bromide
US8703806Dec 3, 2012Apr 22, 2014Pearl Therapeutics, Inc.Compositions, methods and propellant-based systems for respiratory delivery of glycopyrrolate and one or more active agents
US8731672Jun 18, 2013May 20, 2014Holaira, Inc.System and method for bronchial dilation
US8740895Jun 28, 2013Jun 3, 2014Holaira, Inc.Delivery devices with coolable energy emitting assemblies
US8777943Jun 28, 2013Jul 15, 2014Holaira, Inc.Delivery devices with coolable energy emitting assemblies
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US8808280Apr 20, 2012Aug 19, 2014Holaira, Inc.Systems, assemblies, and methods for treating a bronchial tree
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US8821489Apr 20, 2012Sep 2, 2014Holaira, Inc.Systems, assemblies, and methods for treating a bronchial tree
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US8957209 *Oct 1, 2012Feb 17, 2015Mahmut BilgicMethods for the synthesis of tiotropium bromide
US8961507Apr 20, 2012Feb 24, 2015Holaira, Inc.Systems, assemblies, and methods for treating a bronchial tree
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US9149328Nov 11, 2010Oct 6, 2015Holaira, Inc.Systems, apparatuses, and methods for treating tissue and controlling stenosis
US9242979 *Jan 26, 2015Jan 26, 2016Mahmut BilgicMethods for the synthesis of tiotropium bromide
US9254262Nov 9, 2012Feb 9, 2016Almirall, S.A.Dosage and formulation
US9333195May 14, 2015May 10, 2016Almirall, S.A.Quinuclidine derivatives and medicinal compositions containing the same
US9339618Nov 5, 2012May 17, 2016Holaira, Inc.Method and apparatus for controlling narrowing of at least one airway
US20050143410 *Oct 29, 2004Jun 30, 2005Boehringer Ingelheim International GmbhNovel crystalline anhydrate with anticholinergic efficacy
US20060154951 *Jan 15, 2004Jul 13, 2006Wood Ronald WQuaternary antimuscarinic compounds for the treatment of bladder diseases
US20070015785 *Sep 18, 2006Jan 18, 2007Boehringer Ingelheim Pharma Gmbh & Co. KgCrystalline Micronisate, Process for the Manufacture Thereof and Use Thereof for the Preparation of a Medicament
US20070155773 *Dec 28, 2006Jul 5, 2007Michael EngelUse of Tiotropium Salts in the Treatment of Moderate Persistent Asthma
US20090134655 *Jul 30, 2008May 28, 2009Carl PaluszkiewiczMotorcycle wind deflector accessory support
US20090299042 *Jul 16, 2007Dec 3, 2009Nuria Busquets BaqueProcess for manufacturing 3(r)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide
US20110020454 *Mar 13, 2009Jan 27, 2011Rosa Lamarca CasadoNovel dosage and formulation
US20110023876 *Feb 3, 2011Pearl Therapeutics, Inc.Compositions for pulmonary delivery of long-acting muscarinic antagonists and associated methods and systems
US20110132356 *Jun 9, 2011Pearl Therapeutics, Inc.Compositions for pulmonary delivery of long-acting b2 adrenergic receptor agonists and associated methods and systems
US20110132357 *Jun 9, 2011Pearl Therapeutics, Inc.Compositions, methods & systems for respiratory delivery of two or more active agents
US20110135737 *May 28, 2010Jun 9, 2011Pearl Therapeutics, Inc.Compositions for respiratory delivery of active agents and associated methods and systems
US20130030182 *Jan 31, 2013Mahmut BilgicMethods for the synthesis of tiotropium bromide
US20150148540 *Jan 26, 2015May 28, 2015Mahmut BilgicMethods for the synthesis of tiotropium bromide
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Classifications
U.S. Classification514/291, 546/18, 546/125, 546/91, 514/304
International ClassificationC07D451/14, A61P9/06, C07D451/02, A61K31/445, C07D451/10, A61K31/381, A61K31/46, A61P11/06, A61P25/02, C07D333/04, A61P11/00, A61K31/435, C07D451/12
Cooperative ClassificationC07D451/10, C07D451/14
European ClassificationC07D451/14, C07D451/10
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