Banholzer, Rolf (Stuttgart, DE)
Bauer, Rudolf (Ockenheim, DE)
Reichl, Richard (Gau-Algesheim, DE)

Plaque It!

11/254213

09/04/2007

10/18/2005

Images are available in PDF form when logged in. To view PDFs, Login  or  Create Account (Free!)

Click for automatic bibliography generation

Boehringer Ingelheim Pharma GmbH & Co. KG (Ingelheim, DE)

514/291

546/125, 546/18, 546/91, 514/304

A61K31/435; C07D451/12

546/91, 514/291, 514/304, 546/18, 546/77, 546/125

3673195	DERIVATIVES OF 6,6,9-TRI-LOWER ALKYL-9-AZABICYCLO(3.3.1) NONAN-3α-OR 3β-OL	June, 1972	Yoneda et al.
3808263		April, 1974	Yoneda
4353922	Anticholinergic bronchodilators	October, 1982	Pfister	514/339
4855422	Process for the preparation of azoniaspironortropanol esters	August, 1989	Grimminger

DE1166787	April, 1964
EP0418716	April, 1994			Thienylcarboxylic acid ester of aminoalcohols, their quaternary products, their preparation and use of the compounds.
GB845056	August, 1960
GB955535	April, 1964
GB1350928	April, 1974

CAS Accession No. 1983:34827 (Pfister et al.).
CAS Accession No. 1992:20937 (Banholzer et al.).
Wilhelm, The Chemistry of Polycyclic Psycho-active Drugs: Serendipity or Systematic Investigation?, Pharm. J., 214:414-416 (1975).
Frank & Maclaren, The Use of an Anticholinergic Drug in the treatment of Asthma, ANN. Allergy, 15(3):261-9 (1957).
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).
The Merck Index, 11th ed (1989) Merck and Co. Inc. p. 242 and 802-803.
Banholzer et al. “preparation of tropanyl . . . ” CA 119:28006 (1993).
Nyberg et al., “Investigations of Diethienylglycolic Esters,” Acta Chem. Scand., 24 (1970) No. 5, pp. 1590-1596.
Atkinson et al., J. Med. Chem. 1977, vol. 20, No. 12, 1612-17.
Sterling Drug, Inc., Chem. Abstracts, vol. 61, No. 1839f (1964).
N-Butylscopolammonium Bromide (Buscopan), Merck Index, 10th Edition, pp. 219-220 (1983).
N-Butylscopolammonium Bromide (Buscopan), Merck Index, 11th Edition, p. 242 (1989).
Valpin, Goodman & Gilman, The Pharmacological Basis of Therapeutics, 6th Edition, p. 130 (MacMillan 1980).
Ipratropium Bromide (Atrovent), Merck Index, 10th Edition, p. 733 (1983).
Ipratropium Bromide (Atrovent), Merck Index, 10th Edition, pp. 802-803 (1989).
Foster et al., “Further New Tropine Derivatives,” Journal of the Chemical Society, p. 3575-3578 (1957).
Jun. 2, 1992 Examination Report from European Patent Application No. 90117554.7 (EP 418716) and English translation.
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.
Apr. 23, 1993 Reply to Examination Report from European Patent Application No. 90117554.7 (EP 418716) and English translation.
International Search Report mailed Jan. 10, 1991 from PCT/EP90/01517 (WO 91/04252).

Chang, Celia

Morris, Michael P.
Witkowski X, Timothy
Petka, Wendy A.

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.

We claim:

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 CH₃SO₃₋.

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.

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,
  • R_a 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
	monofluorotrichl oromethane 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	65.0 0
	Potato starch	28.00
	Polyvinylpyrrolid one	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 R_a 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).

chloride< td/>14< td>phenyl< tr>< td>3α-tropanyl< td>37

TABLE I
Compounds of the formula
				M.p. [° C.]
				Hydro-
No.	A	R1	Base
1	3α-(6β,7β-epoxy)-tropanyl< /td>	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-methy l)-	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
3α-(6β,7β-epoxy)-tropanyl	phenyl		246-7
15	3α-tropanyl	phenyl		243-4
16	3 α-(N-β-fluoroethyl)-	phenyl		219-20
	nortropanyl
17	3α-(6,7-dehydro)-tropanyl	phenyl		181-3
18	3α-(N-ethyl)-nortropanyl		231-2
19	3α -(N-isopropyl)-	phenyl		246-7
	nortropanyl
20	3α-trop anyl	cyclo-		260
		hexyl
21	3α-(N-β-fluoroethyl) -	cyclo-		203-4
	no rtropanyl	hexyl
22	3α-(6β ,7β-epoxy)-tropanyl	cyclo-		237
		pentyl
23	3α-t ropanyl	cyclo-		260
	pentyl
24	3α-(N-β-fluoroet hyl)-	cyclo-		182-3
nortropanyl	pentyl
25	3α -(N-ethyl)-nortropanyl	cyclo-		227-8
		pentyl
26	3 α-(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		2 33-5
30	3α-(6,7-dehydro)-trapanyl< /td>	3-thienyl		247-8
31	3α-(6β,7β-epoxy)-tropanyl	3-thienyl		242-3
32	3α-(6β,7β-epoxy)-t ropanyl	2-furyl
33	3α-(6,7 -dehydro)-tropanyl	2-furyl
34	2-furyl
35	3α-tropanyl	2-pyridyl
36	3 α-(6β,7β-epoxy)-tropanyl	2-pyridyl
3α-(6,7-dehydro)-tropanyl	2-pyridyl
38	3α-tropanyl	3-thienyl
39	3α-(6,7-dehydro)-tropanyl	cyclo-
		pentyl
4 0	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.

< td>3< /tr>< tr>< td>3α-(N-isopropyl)-< tr>< td>19829< td>3α-tropanyl methobromide< tr>< td/>

TABLE II
Quaternary compounds of the formula
No.	A	R1	M.p. [° C.]
1	3α-(6β,7β-epoxy)-tropanyl< /td>	2-thienyl	217-18
	metho bromide
2	3α-tropanyl methobromide	2-thienyl	263-64
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< /td>	214-15
	fluoroethobromide
6	3α-(N-isopropyl)-	2-thienyl	229-30
	granatanyl methobromide
7	3α-(N-isopropyl)-	2-thienyl	245-46
	nortro panylmethobromide
8	3α-(6β,7β-ep oxy)-N-	2-thienyl	223-24
< td>isopropyl-nortropanyl
	methobromide< /td>
9	3α-(6β,7β-epoxy)-N-	2- thienyl	215-16
	ethylnortropany l
	methobromide
10	3α-(N-ethyl)-nortropanyl	2-thienyl	260 -61
	methobromide
11	3α-(N-methyl)-granatanyl	2-thienyl	2 46-47
	methobromide
12	3α-(6β,7β-epoxy)-N-	2-thienyl	18 2-83
	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	ph enyl	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< /td>
	methobromide
20	phenyl	259-60
	nortropanyl methobromide
21	3α-tropanyl ethobromide	phenyl	248-49
2 2	3α-(N-ethyl)-nortropanyl	phenyl	2 44-45
	ethobromide
23< /td>	3α-(6β,7β-epoxy)-tropanyl	phenyl	226
	ethobromide
24	3α-tropanyl-β-	phenyl	241
	fluoroethobromide
25	3� �-tropanyl methobromide	cyclohexyl	278
26	3α-(N-β-fluoroethyl)-	cyclohexyl
	nortropanyl methobromide
27	3α-tropanyl-β-	cyclohexyl	233-34
	fluoro ethobromide
28	3α-tropanyl methobromide	cyclopentyl	260
3α-tropanyl ethobromide	cyclopentyl	235-36
30	3α-(N-ethyl)-nortropanyl	cyclopentyl	251-52
	methobromide
31	3α-(N-isopropyl)-	cyclopentyl	244-45
	nortropanyl-methobromide< /td>
32	3α-tropanyl-β-	cyclope ntyl	189-90
	fluoroethobromide< /td>
33	3α-(N-β-fluoroethyl)-	cyclopentyl	226-27
	nortropanyl -methobromide
34	3α-(6,7-dehydro)- tropanyl	2-thienyl	225-6
	metho-methanesulphonate
35	3� �-(6β,7β-epoxy)-tropanyl	2-thienyl	218-20< /td>
	methobromide
36	2-thienyl	243-4
37	3α-(6,7-dehydro)-tropanyl	2-thienyl	211-4
	methobromide
38	3α-(6,7-dehydro)-tropanyl	3-th ienyl	182-3*
	methobromide
39	3α-(6β,7β-epoxy)-tropanyl	3-thienyl	217-8
	methobromide< /td>
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-dehy dro)-tropanyl	2-pyridyl
	methob romide
47	3α-tropanyl methobromide	2-pyridyl
48	3 α-tropanyl methobromide	3-thienyl
49	3 α-(6,7-dehydro)-tropanyl	cyclopentyl
methobromide
50	3α-(6β,7� �-epoxy)-tropanyl	cyclohexyl
	m ethobromide
51	3α-(6,7-dehydro)-tr opanyl	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< /td>	phenyl	246-7
2	3α- (6,7-dehydro)-tropanyl	phenyl	261-2
3	3α-(6β,7β-epoxy)-tropanyl	3-th ienyl
4	3α-(6,7-dehydro)-tropanyl< /td>	3-thienyl
5	3α-tropanyl	3-thienyl
6	3α-(N-methyl)-gr anatanyl	3-thienyl

< /tr>

TABLE IV
Compounds of the formula
			M.p. [° C.]
No.	A	R2	Hydrochloride
1	3α-(6β,7β-epoxy)-tropanyl< /td>	H
2	3α-(6,7-dehydro)- tropanyl	H
3	3α-(6β,7β-e poxy)-tropanyl	methyl
4	3α -(6,7-dehydro)-tropanyl	methyl	210-2.5
5	3α-(6β,7β-epoxy)-tropanyl	m ethoxy
6	3α-(6,7-dehydro)-tropanyl	methoxy

< td>No.< tr>< tr>

TABLE V
Compounds of the formula
				M.p.
A	R2	Ra	[° C.]
1	3α-(6β,7β-epoxy)-	2-thienyl	5-methyl
	tropanyl
2	3α-(6,7-dehydro)-	2-thieny l	5-methyl
	tropanyl
3	3α-tropanyl	2-thienyl	5-me thyl
4	3α-(6β,7β-epoxy)-	2-(5-methyl)-	5-methyl
	tropan yl	thienyl
5	3α-(6,7-dehyd ro)-	2-(5-methyl)-	5-methyl
	tropanyl	thienyl
6	3� �-tropanyl	2-(5-methyl)-	5-methyl
	thienyl
7	3α-(6β,7β- epoxy)-	2-thienyl	5-fluoro
	tropanyl
8	3α-(6,7-dehydro)-< /td>	2-thienyl	5-fluoro
	tro panyl
9	3α-tropanyl	2-thie nyl	5-fluoro
10	3α-(6β,7� �-epoxy)-	2-(5-fluoro)-	5-fluoro
	tropanyl	thienyl
11	3α-(6,7-dehydro)-	2-(5-fluoro)-	5-fluor o
	tropanyl	thienyl
12	3α-tropanyl	2-(5-fluoro)-	5-fluoro
		thienyl

< td>No.3α-tropanyl methobromide

TABLE VI
Compounds of the formula
				M.p.
A	R1	Ra	[° C.]
1	3α-(6β,7β-epoxy)-tropanyl< /td>	2-thienyl	5-methyl
	met hobromide
2	3α-(6,7-dehydro)-tropa nyl	2-thienyl	5-methyl
	methobromide
3	3α-tropanyl-methob romide	2-thienyl	5-methyl
4	3α-(6β,7β-epoxy)-tropanyl	2-(5-methyl)-< /td>	5-methyl
	methobromide	thienyl
5	3α-(6,7-dehydro)-tropany l	2-(5-methyl)-	5-methyl
< td>methobromide	thienyl
6	3 α-tropanyl methobromide	2-(5-methyl)-	5-methyl
		thienyl
7	3α-(6 β,7β-epoxy)-tropanyl	2-thienyl	5-fluoro
	methobromide
8	a-(6,7-dehydro)-tropanyl	2-thienyl	5-fluoro< /td>
	methobromide
9	2-thienyl	5-fluoro
10	3α-(6β,7β-epoxy)-tropanyl	2-(5-fl uoro)-	5-fluoro
	methobromide	thienyl
11	3α-(6,7-dehydro) -tropanyl	2-(5-fluoro)-	5-fluoro
	methobromide	thienyl
12< /td>	3α-tropanyl methobromide	2-(5-fluoro)-	5-fluoro
		thienyl

< td>3α-(6,7-dehydro)-tropanyl< td>3α-(6β,7β-epoxy)-tropanyl< tr>

TABLE VII
Compounds of the formula
No.	A	R1	M.p. [° C.]
1	3α-(6β,7β-epoxy)-tropanyl< /td>	phenyl	211-2
	methobromide
2	phenyl	158-60*
	methobromide
3	3-thienyl
	methobromide
4	3α-(6,7 -dehydro)-tropanyl	3-thienyl
	m ethobromide
5	3α-tropanyl methobromide	3-thienyl
6	3� �-(N-methyl)-granatanyl	3-thienyl
	methobromide
*(with crystalline methanol)

< tr>

TABLE VIII
Quaternary compounds of the formula
No.	A	R2	M.p. [° C.]
1	3α-(6β,7β-epoxy)-tropanyl< /td>	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
	me thobromide