NO884835L - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE TETRAHYDRO-FURO-AND-TIENO (2,3.-C) PYRIDINES. - Google Patents

Description

The invention relates to the use of tetrahydro-furo- and -thieno[2,3-c]pyridines and their acid addition salts as pharmaceuticals, especially as cholinomimetics. The compounds are partly new.

It has now been found that compounds with the general formula

IN

where

R1 means hydrogen, branched or unbranched alkyl with 1-8

carbon atoms, in which optionally a CH2 can be replaced by C=0, branched or unbranched hydroxyalkyl with 1-4 carbon atoms, branched or unbranched alkoxy with 1-4 carbon atoms, halogen, cyano, COOR', in which R' is a

branched or unbranched alkyl group of 1-4 carbon atoms; R 2 is hydrogen, halogen or branched or unbranched

alkyl of 1-4 carbon atoms;

R 3 is hydrogen or branched or unbranched alkyl of 1-4

carbon atoms;

R 4 is hydrogen or branched or unbranched alkyl of 1-4

carbon atoms;

R 5 is hydrogen or branched or unbranched alkyl of 1-4

carbon atoms;

R 6 is hydrogen or methyl;

and X can mean oxygen or sulphur,

as well as possibly their pharmacologically acceptable acid addition salts and their quaternary compounds, have been shown to be able to be used as drugs with cholinomimetic properties.

In this context, alkyl groups are, possibly also as part

of other functional groups: methyl, ethyl, propyl, butyl,

pentyl, hexyl, heptyl and octyl and their isomers.

Preferred are compounds of the general formula I, where Rx can mean a branched or unbranched alkyl group with 1-8, especially 1-4, carbon atoms, R2, R3 and/or R5 can mean hydrogen, R6hydrogen and R4 a branched or unbranched alkyl group with 1-4 carbon atoms.

Preferred alkyl groups, also as parts of other substituents, are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. Halogen means one of the atoms within the group of fluorine, chlorine, bromine or iodine.

Particularly preferred are compounds of the general formula I, where X means an oxygen atom, R1 and R4, which can be the same or different, is an alkyl residue with 1-4 carbon atoms, Rx preferably having the meaning methyl, ethyl, n-propyl or n-butyl and R4 stands for methyl, and R2, R3, R5 and R6 represent hydrogen.

Preferred bases, pharmacologically acceptable acid addition salts and quaternary compounds thereof, are: 2,6-dimethyl-4,5,6,7-tetrahydro-furo[2,3-c]pyridine, 2,6-dimethyl-4,5,6, 7-tetrahydro-thieno[2,3-c]pyridine, 6-methyl-4,5,6,7-tetrahydro-thieno-[2,3-c]pyridine, 6-methyl-4,5,6,7 -tetrahydro-furo[2,3-c]pyridine, 2-methyl-4,5,6,7-tetrahydro-furo[2,3-c]pyridine, 2-ethyl-6-methyl-4,5,6 ,7-tetrahydro-furo[2,3-c]pyridine, 6-methyl-2-n-propyl-4,5,6,7-tetrahydro-furo[2,3-c]pyridine, 6-methyl-2 -n-butyl-4,5,6,7-tetrahydro-furo[2,3-c]pyridine, 6-methyl-2-isobutyl-4,5,6,7-tetrahydro-furo[2,3-c ]pyridine, 2-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine, 2,3,6-trimethyl-4,5,6,7-tetrahydro-thieno[2,3 -b]pyridine, 6-ethyl-2-methyl-4,5,6,7-tetrahydro-thieno[2,3-b]pyridine, 2-chloro-6-methyl-4,5,6,7-tetrahydro -thieno[2,3-c]pyridine, 2-methyl-6,6-dimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridinium iodide,

2-methyl-6,6-dimethyl-4,5,6,7-tetrahydro-furo[2,3-c]pyridinium iodide,

2-acetyl-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine, 2-bromo-6-methyl-4,5,6,7-tetrahydro-thieno[2, 3-c]pyridine, 3,6-dimethyl-4,5,6,7-tetrahydro-furo[2,3-cjpyridine, 2-ethyl-6-methyl-4,5,6,7-tetrahydro-furo[ 2,3-c]pyridine,

2-ethoxycarbonyl-6-methyl-4,5,6,7-tetrahydro-furo[2,3-c]pyridine, 2-acetyl-3,6-dimethyl-4,5,6,7-tetrahydro-furo[ 2,3-c]pyridine, 2-ethyl-3,6-dimethyl-4,5,6,7-tetrahydro-furo[2,3-c]pyridine, 2-bromo-3,6-dimethyl-4, 5,6,7-tetrahydro-furo[2,3-c]pyridine, 2-chloro-3,6-dimethyl-4,5,6,7-tetrahydro-furo[2,3-c]pyridine, 2- cyano-6-methyl-4,5,6,7-tetrahydro-furo[2,3-c]pyridine, 2-hydroxymethyl-6-methyl-4,5,6,7-tetrahydro-furo[2,3- c]pyridine.

Compounds of the general formula I are partly known. Thus, it appears from DE-OS 26 28 045 that tetrahydro-thienopyridines which are exclusively substituted in the 6- and 7-position are compounds with anti-inflammatory properties, antiarrhythmic properties, and which also have an inhibitory effect on platelet aggregation.

In contrast to tetrahydro-thienopyridines, it has so far not been known to use the corresponding tetrahydro-furopyridines with the general formula I as a medicine.

The compounds of the general formula I have muscarinic agonistic properties and are thus suitable for therapeutic use in diseases with an underfunction of the cholinergic system.

The tertiary amines of general formula I exhibit affinity for muscarinic receptors in the central nervous system (CNS) and, in animal experiments, muscarinic agonistic properties in the CNS.

Thus, for example, 2,6-dimethyl-4,5,6,7-tetrahydro-furo[2,3-c]pyridine hydrochloride shows in the EEG (electroencephalogram) upon administration of 3 mg/kg p.o. (1 mg/kg i.v.) to conscious rabbits, an arousal reaction typical of cholinomimetics.

In monkeys sensitized to haloperidol, the novel compounds, e.g. 2,6-dimethyl-4,5,6,7-tetrahydro-thieno [2, 3-c]pyridine hydrochloride (dose <1 mg/kg i.m.) dyskinesias caused by haloperidol, resp. triggers dyskinesias in case of underdosing. In addition, the compounds show muscarinic binding properties in in vitro studies, resp. muscarinic-agonistic GTP-Shifts (guanosine triphosphate). Birdsall, N.I.M., E.C. Hulme & J.M. Stockton 1984 in T.I.P.S. Supplement, Proe. Boarding school. Symposium on Subtypes of Muscarinic Receptors, Ed. Hirschowitz, Hammer, Giachetti, Keirns, Levine; Elsevier p. 4-8.

The receptor binding studies in the muscarinic-cholinergic system were carried out on the three receptor subtypes according to the references given below: (Watson, M., H.I. Yamamura & W.R. Roeske 1983, Life Sei., 32, 3001-3011);

Hammer. R., CP. Berrie, N.I.M. Birdsall, A.S.V. Burgen & E.C. Hulme 1980, Nature, 283, 90-92;

Hammer, R., E. Giraldo, G.B. Schiavi, E. Monferini & H. Ladinsky 1986, Life Sci., 38, 1653-1662).

The results are summarized in Table I.

The compounds produced according to the invention displace the muscarinic agonists with high affinity from the agonistic binding sites. The binding studies of [<3>H]cis-methyl-dioxolane were carried out according to A. Closs et al., Naunyn Schmiedeberg's Arch. Pharmacol. 335, 372-377 (1987). The results are compiled in Table Ia.

According to pharmacological findings, the compounds are suitable for the treatment of the following diseases: Alzheimer's disease, senile dementia and cognitive disorders, and the compounds can also be used to improve memory.

Quaternary compounds of the general formula I are particularly suitable for peripheral applications, e.g. for glaucoma treatment. The invention also relates to new compounds of the general formula I

where

Ri means hydrogen, branched or unbranched alkyl of 1-8

carbon atoms, in which optionally a CH2 can be replaced by a C=0, branched or unbranched hydroxyalkyl with 1-4 carbon atoms, a branched or unbranched alkoxy group with 1-4 carbon atoms, halogen, cyano, COOR', in which R' stands for a branched or unbranched alkyl group with 1-4

carbon atoms;

R 2 is hydrogen, halogen or branched or unbranched

alkyl of 1-4 carbon atoms;

R 3 is hydrogen or branched or unbranched alkyl of 1-4

carbon atoms;

R 4 is hydrogen or branched or unbranched alkyl of 1-4

carbon atoms;

R 5 is hydrogen or branched or unbranched alkyl of 1-4

carbon atoms;

R 6 is hydrogen or methyl;

and X can mean oxygen or sulphur,

as well as possibly their pharmacologically acceptable acid addition salts or their quaternary compounds, with the reservation that the free bases and

X = oxygen and R1; R2, R3, R5 and R6 means hydrogen, that R4 does not

may be methyl;

X = sulfur, R 1 to R 6 may not all be hydrogen;

X = sulfur and R1#R2, R3, R5 and R6 means hydrogen, that R4 cannot be methyl.

Already P. Mertens et al., J. Org.Chem., 33, 133 (1986) have attempted in vain to synthesize the unknown tetrahydro-furo[2,3-c]pyridines of the type

by a ring closure reaction of suitable substituted furans, such as e.g. N-(5-methyl-2-furfuryl)-N-methyl-glycine ethyl ester. For the first time, according to the invention, tetrahydro-furo[2,3-c]pyridines with the above-mentioned structure, as well as acid addition salts thereof, can now be obtained.

The new compounds can be prepared according to known analogue methods.

By starting from 4-hydroxy-substituted compounds with the general formula

where R 1 to R 6 and X have the previously mentioned meanings, can be transferred by reduction in compounds of the general formula I and then by known methods transferred in their acid addition salts or quaternary salts. It is obvious that when R1 contains a reducible functional group, such as e.g. a hydroxy group or a carbonyl function (ketone or

aldehyde), these must first be protected with a protecting group. After reduction, the protection group is split off again.

The reduction conveniently takes place in a mixture of glacial acetic acid and concentrated hydrochloric acid with stannous chloride at temperatures between room temperature and the boiling point of the reaction mixture, preferably at 50-70°C.

Following a variant of the procedure, the turnover takes place

the corresponding alcohol with a mixture of hydroiodic acid and red phosphorus in glacial acetic acid at the boiling point.

Other reduction methods and reagents are described in a review article "Modern methods for the radical deoxygenation of alcohols" by W. Hartwig in Tetrahedron 8_3; Vol. 39 (16) pp. 2609 to 2645 and iTetrahedron Letters, 82, Vol. 23 (19), pp. 2019.

Compounds of the general formula I wherein R 5 is

hydrogen and R1= an acyl residue, can be obtained directly from compounds of the general formula

where Rx to R4 and X have the above-mentioned meanings.

This deoxygenation is carried out, for example, according to the Wolf-Kishner method with hydrazine hydrate or according to the Huang-Minlon variant of this.

Compounds of the general formula I, where R4= alkyl, are obtained by N-alkylation of compounds of the general formula I, where R4 is hydrogen, according to known methods or by reaction with carbonyl compounds under reductive conditions, such as e.g. by the Leukart-Wallach reaction.

Compounds of the general formula I, wherein Rx and/or

R2 means hydrogen, can be transferred in the corresponding alkyl or acyl derivatives by electrophilic aromatic substitution. If both Rx and R2 are hydrogen, the substitution takes place preferably in the 2-position of the molecule.

The aromatic ring is also accessible to nucleophilic aromatic substitution reactions. Compounds with the general formula I where R1= halogen, such as e.g. chlorine or bromine, can be transferred in the corresponding alkyl or alkoxy compounds. The reaction conditions for the aromatic substitution are known and need no further explanation. By reaction with copper (I) cyanide, the corresponding nitriles are obtained, for example.

N-allyl-thiophene derivatives of the general formula

where Rx to R5 independently of each other mean hydrogen or alkyl with the previously indicated meaning, can be cyclized in the presence of Lewis acids, such as e.g. aluminum chloride, in inert organic solvents, such as e.g. halogenated hydrocarbons, e.g. dichloromethane, to compounds of the general formula I.

The quaternary compounds of the general formula I

is obtained by usual methods from corresponding tertiary amines by reaction with a suitable agent for the formation of quaternary compounds, such as e.g. methyl iodide, p-toluene sulfonic acid methyl ester, in polar solvents, such as e.g. nitro-methane, acetonitrile or alcohols.

Another method of making compounds

with the general formula I is the N-alkylation of furo- or thieno[2,3-c]pyridines of the general formula

where X and R1 to R6 have the previously mentioned meanings as well as the subsequent reduction of the pyridine ring. In this method, for example, the reaction conditions used by Shiotoni et al. in J. Heterocyclic Chem., 23, 233 (1986) in the synthesis of 6-methyl-4,5,6,7-tetrahydro-furo-[2,3-c]pyridine, is used.

The alcohols of the general formula II are also available by known methods or analogous methods, e.g. by reduction of the corresponding ketones with complex hydrides, e.g. lithium aluminum hydride, in inert organic solvents, such as e.g. diethyl ether, tetrahydrofuran, etc.

A further method for producing thieno derivatives consists in reacting the corresponding formyl derivatives with the general formula or their acetals, in protic reaction media, such as e.g. in semi-concentrated hydrochloric acid at room temperature and subsequent reduction to I.

Tetrahydro-furo- resp. -thieno[3,2-c]pyridines of the general formula I can be converted into their physiologically acceptable acid addition salts in the usual way.

Suitable acids for salt formation are, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valerian acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, 8-chlorotheophylline and the like.

Preferred acid addition salts are hydrochlorides and hydrobromides.

According to the described methods, for example, the following compounds of general formula I can be obtained:

The compounds of the general formula I can be used

alone or in combination with other active substances produced according to the invention, possibly also in combination with other pharmacologically active active substances, e.g. additional cerebroactivators. Suitable forms of application are, for example

tablets, capsules, suppositories, solutions, syrups, emulsions or dispersible powders. Tablets can, for example, be obtained by mixing the active substance(s) with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, smoothing agents such as magnesium stearate or talc and/or agents to achieve a depot effect, such as e.g. carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.

In accordance with this, coatings can be produced by making cores in a similar way to the tablets and coating them with agents that are usually used for coating, for example collidon or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to prevent incompatibility, the cores can also consist of several layers. Likewise, the coating can also consist of several layers to achieve a depot effect, under which the excipients mentioned in connection with the tablets can be used.

Syrups of the active substance or the combinations produced according to the invention may also contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, as well as a taste-enhancing agent, e.g. flavoring agent such as vanillin or orange extract. They may also contain suspending aids or thickeners, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective substances such as p-hydroxybenzoate.

Injection solutions are prepared in the usual way, e.g. by the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali salts of ethylenediaminetetraacetic acid, and bottled in injection bottles or ampoules.

Capsules containing one or more active substances or combinations of active substances can, for example, be prepared by mixing the active substance with inert carriers, such as milk sugar or sorbitol, and encapsulating in gelatin capsules.

Suitable suppositories can, for example, be prepared by mixing with suitable carriers, such as neutral fat or polyethylene glycol or derivatives thereof.

Pharmaceutical formulation examples

Finely ground active ingredient, milk sugar and part of the corn starch are mixed together. The mixture is sieved, after which it is moistened with a solution of polyvinylpyrrolidone in water, crushed, granulated in a moist state and dried. The granulate, the rest of the cornstarch and the magnesium stearate are sieved and mixed together. The mixture is then pressed into tablets of the desired shape and size.

The finely ground active substance, part of the cornstarch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, after which the mixture is sieved and processed with the rest of the cornstarch and water into a granule, which is dried and sieved. Sodium carboxymethyl starch and the magnesium stearate are then mixed in, after which the mixture is pressed

tablets of suitable size.

Manufacturing

The active substance and sodium chloride are dissolved in double-distilled water and the solution is sterilely poured into ampoules.

Manufacturing

Active ingredient and preservative are dissolved in demineralized water and the solution is filtered and bottled in 100 ml bottles.

Example 1

2,6-dimethyl-4,5,6,7-tetrahydro-furo[2,3-c]pyridine

10 g (49 mmol) 2,6-dimethyl-4-hydroxy-4,5,6,7-tetrahydro-furo[2,3-c]pyridine (prepared according to J. Chem. Soc, Perkin Trans I 1986, p 877, respectively DOS 3315157) is dissolved in a mixture of 120 ml glacial acetic acid and 60 ml conc. hydrochloric acid and 19.1 g (99 mmol) tin(II) chloride are added and stirred for 2.5 hours at 65°C. The reaction mixture is then evaporated, the residue taken up in water, made alkaline with conc. ammonia under ice cooling and extracted several times with ethyl acetate. After drying and evaporation of the solvent, purification is carried out by chromatography (silica gel, eluent = ethyl acetate:methanol:ammonia = 10:1:0.5). The purified base is transferred into the hydrochloride and recrystallized from ethanol.

Yield: 2.6 g (28% of the title compound as hydrochloride with m.p. 256-258°C (decomp.)

Calculated: C, 57.59; H, 7.51; N, 7.46; Cl, 18.89

Found: C, 57.31; H, 7.56; N, 7.65; Cl, 18.65

Example 2

2,6-dimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine 2.1

63.5 g (0.45 mol) of 2-(N-methylaminomethyl)-5-methylthiophene, 47.5 g of sodium carbonate, 0.5 g of potassium iodide and 76.3 g (0.5 mol) of chloroacetaldehyde-diethyl acetal are stirred at 250 ml of anhydrous dimethylformamide for 5.5 hours at 130°C. The suspension is filtered off, the filtrate is evaporated and the residue is distilled in vacuum.

64.7 g (56%) 5-methyl-2-(N-methyl-N-2,2-diethoxyethylaminomethyl)-thiophene, b.p. (14 torr) 150-155°C.

2.2

The amine prepared in 2.1 is boiled under reflux in 210 ml of 6N hydrochloric acid for 3 hours, after which the mixture is cooled and then poured onto ice, made alkaline with ammonia and extracted several times with ethyl acetate. After the usual work-up and purification, the base thus obtained is transferred into the hydrochloride, which is recrystallized from isopropyl ether.

22.3 g (49% of the theoretical) of 2,6-dimethyl-4-hydroxy-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine hydrochloride with m.p. 156°C.

2.3

Starting from 9.4 g (51 mmol) of 2,6-dimethyl-4-hydroxy-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine hydrochloride, analogously to Example 1: 7.3 g (70%) of the title compound as hydrochloride with m.p. 226°C

C9H13NS x HC1 (203.73)

Calculated: C, 53.06; H, 6.93; N, 6.88; Cl, 17.40

Found: C, 52.85; H, 6.98; N, 6.81; Cl, 17,21

Example 3

2,4,6-trimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine

14.1 g (78 mmol) of 5-methyl-2-(N-allyl-N-methylaminomethyl)thiophene are dissolved in 220 ml of dichloroethane and 22.6 g of aluminum chloride are added while cooling. The reaction mixture is then allowed to slowly warm to room temperature. It is stirred for a further 24 hours, after which the reaction mixture is poured onto ice and made alkaline, after which the organic phase is separated. The aqueous phase is extracted twice more with 200 ml portions of dichloromethane. After drying and evaporation of the combined organic phases, chromatography is carried out on silica gel with dichloromethane/methanol (97:3), after which the uniform fractions, after evaporation of the solvent, are added to ethanolic hydrochloric acid and precipitated by the addition of ether. The crystals obtained are recrystallized from ethanol/ether.

0.6 g of the title compound is thus obtained in the form of the hydrochloride with m.p. 200-202°C.

Example 4

6-ethyl-2-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine

The hydrochloride of 2-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine with m.p. 201-202°C, prepared analogously to Example 2, is alkylated in the following way: 2.5 g (13 mmol) of the hydrochloride is dissolved in 100 ml anhydrous dimethylformamide and 2.8 g (18 mmol) ethyl iodide, 1.2 g potassium iodide are added and 4.2 g of sodium carbonate and stirred for 3 hours at 100°C. The mixture is evaporated, taken up in water and dichloromethane, after which the aqueous phase is made alkaline and processed further in the usual way. The resulting residue is chromatographed on silica gel with dichloromethane/methanol (97:3) as eluent. The isolated base is transferred into the hydrochloride which is recrystallized from ethanol.

Yield: 1.2 g (43%, mp: 210-211°C).

Example 5

2-chloro-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine

2.7 g (14 mmol) of 6-methyl-4,5,6,7-tetrahydro-thieno-[2,3-pyridine hydrochloride with m.p. 226-228°C (prepared according to Example 2) is dissolved in 90 ml of glacial acetic acid and 2.2 g (16 mmol) of sulfuryl chloride are added dropwise at 15°C. The mixture is stirred for 48 hours at room temperature, poured onto ice, made alkaline and extracted several times with dichloromethane. The crude product obtained from the organic phase by drying and evaporation is chromatographed on silica gel with dichloromethane/methanol. Uniform fractions are evaporated and transferred into the hydrochloride.

Yield: 0.5 g; m.p. 247-248°C (ethanol)

C8H10C1NS x HC1 (224.15)

Calcd: C, 42.87; H, 4.95; N, 6.25; Cl, 31.63; S, 14.31 Found: C, 42.65; H, 4.95; N, 6.07; Cl, 31.27; S, 14,38

Example 6

2-methyl-6,6-N,N-dimethyl-4,5,6,7-tetrahydro-furo[2,3-c]-pyridinium iodide

0.5 g (2.7 mmol) of 2,6-dimethyl-4,5,6,7-tetrahydro-furo[2,3-c]pyridine is dissolved in 10 ml of ethanol and 0.72 g of methyl iodide is added. After stirring for 3 hours at room temperature, the precipitated crystals are filtered off and then recrystallized from ethanol.

Yield: 0.52 g, m.p. 190-193°C

Elemental analysis: C10H16NOJ (293.15)

Calcd: C, 40.97; H, 5.50; N, 4.78; J, 43.29

Found: C, 41.00; H, 5.57; N, 4.95; J, 43.04

Example 7

2-methyl-6,6-N,N-dimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridinium iodide

Analogously to Example 6, 2.7 mmol of 2,6-dimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine dissolved in 10 ml of ethanol, 0.8 mmol of methyl iodide are added. After the work-up, the corresponding quaternary ammonium salt is obtained as white crystals with m.p. 160-161°C.

Example 8

2-acetyl-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine hydrochloride

Dissolve 3.2 g (21 mmol) of 6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine in 10 ml of dichloroethane and add 3.3 g of aluminum trichloride. 1.7 g of acetyl chloride dissolved in 20 ml of dichloroethane is added dropwise to the mixture, and stirred for 16 hours. The reaction mixture is then poured onto ice, after which it is made alkaline and the base is extracted with dichloromethane and stirred for 16 hours. The mixture is poured onto ice and made alkaline, after which the base is extracted with dichloromethane.

After usual chromatographic work-up, subsequent transfer into the hydrochloride and several times of recrystallization from ethanol, 0.5 g of the title compound is obtained with m.p. 256-257°C.

Example 9

2-(1-hydroxyethyl)-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine

4.2 g (0.018 mol) of the acetyl compound described in Example 8 in 100 ml of ethanol and 30 ml of water is added in portions to 0.4 g (0.011 mol) of sodium borohydride, during which the temperature is allowed to rise to 28°C. The mixture is stirred for 3 hours at 50°C and a further 0.4 g of sodium borohydride is added. After 2 hours, 50 ml of ice water are added to the reaction mixture and extracted with dichloromethane. After normal work-up, the residue from the organic phase is dissolved in ether/ethanol 2:1, and acidified by adding 2N ethanolic HCl. 1.7 g is obtained (40% of the theoretical)

of the desired title compound as hydrochloride with m.p. 131-132°C.

Alternatively, the reduction can be carried out in ether/THF with lithium aluminate as reducing agent.

v

Example 10

2-bromo-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine

At 0°C, a solution of 4.6 g (0.038 mol) of potassium bromide and 2.4 g (0.017 mol) of bromine, dissolved in 30 ml of water. The mixture is stirred for a further 3 hours at 10-15°C, after which the resulting crystals are filtered off and washed with ice water. They are then taken up in a dilute ammonium hydroxide solution and extracted several times with dichloromethane. After normal work-up, the residue from the organic phase is dissolved in 20 ml of methanol and acidified with 2N ethanolic HCl. 1.7 g (40% of the theoretical) of the title compound are obtained as hydrochloride in the form of colorless crystals with m.p. 260-261°C.

Example 11

3-bromo-2,6-dimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine

Analogously to Example 10, the title compound is obtained in 49% yield as light yellow crystalline hydrochloride with m.p. 300-302°C.

Example 12

3,6-dimethyl-4,5,6,7-tetrahydro-furo[2,3-c]pyridine Starting compound:

3,6-dimethyl-furo[2,3-c]pyridinium iodide

2.2 g (16.5 mmol) of 3-methyl-furo[2,3-c]pyridine is reacted with 11.7 g (82.5 mmol) of methyl iodide in 10 ml of anhydrous acetonitrile (H. Morita et al., J .HeterocyclicChem., 23, 549 (1986)).

After normal work-up, 4 g (88.9% of the theoretical) grey-yellow crystals with m.p. 177-178°C. Final product: 2 g (7.2 mmol) of the previously prepared iodide in 50 ml of anhydrous methanol are added at room temperature in portions to a total of 0.75 g of sodium borohydride. After hydrolytic work-up, the title compound is isolated from the organic phase (CH2C12) by adding HCl in ether, 0.9 g (66.3% of theory) as hydrochloride with m.p. 287-288°C.

Example 13

2,5,6-trimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine

10.2 g (50 mmol) of 2,5,6-trimethyl-4-hydroxy-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine are reacted with 18.9 g (100 mmol) of anhydrous stannous chloride in 60 ml anhydrous glacial acetic acid. After 6 hours, hydrolytic (NH4OH) work-up is carried out. After recrystallization from ethyl acetate/ether (8:2) 5.6 g (51% of the theoretical) of the title compound with melting point 165-166°C are obtained from the organic phase (CH2C12).

Claims (3)

1. Process for the preparation of compounds of the general formula I where R1 means hydrogen, branched or unbranched alkyl of 1-8 carbon atoms, in which a CH2 may optionally be replaced by C=0, branched or unbranched hydroxyalkyl with 1-4 carbon atoms, branched or unbranched alkoxy with 1-4 carbon atoms, halogen, cyano, COOR', in which R' is a branched or unbranched alkyl group with 1-4 carbon atoms; R 2 is hydrogen, halogen or branched or unbranched alkyl of 1-4 carbon atoms; R 3 is hydrogen or branched or unbranched alkyl with 1-4 carbon atoms; R 4 is hydrogen or branched or unbranched alkyl with 1-4 carbon atoms; R5 is hydrogen or branched or unbranched alkyl with 1-4 carbon atoms; R 6 is hydrogen or methyl; and X can mean oxygen or sulphur, as well as optionally their pharmacologically acceptable acid addition salts or their quaternary compounds, characterized by ata) a compound of the general formula II where X and R1 to R6 have the previously stated meanings and where any carbonyl and hydroxyl residues are protected with protective groups, is reduced, after which the protective groups are optionally split off, b) a pyridine derivative of the general formula where Rx to R6 have the previously indicated meanings, is reacted with an alkylating reagent of the general formula in which R4 is a branched or unbranched alkyl group with 1-4 carbon atoms and Y means a leaving group, and the obtained N-alkyl compound is then reduced, c) for the preparation of compounds of the general formula I, where R5 = hydrogen and X = sulfur, a compound of the general formula where R1 to R4 are as previously defined, cyclized in protic reaction media and then reduced, d) for the preparation of compounds of the general formula I, where X=sulphur, a compound of the general formula cyclized in the presence of Lewis acids, e) for the preparation of compounds of the general formula I, where R5 is hydrogen and Rx means an acyl residue, that a compound of the general formula III, deoxygenated according to known methods, where applicable, compounds of the general formula I, where R4 =alkyl, are obtained by N-alkylation of compounds of the general formula I, where R4 =hydrogen, or by reaction with carbonyl compounds under reductive conditions, and/or compounds with the general formula I, where R1 and/or R2 means hydrogen, are transferred in the corresponding alkyl- or acyl derivatives by electrophilic aromatic substitution, and/or compounds of the general formula I, where R^halogen, e.g. chlorine or bromine, is transferred in the corresponding alkyl or alkoxy compounds, and the prepared compounds of formula I are optionally then transferred into their pharmacologically acceptable acid addition salts or into their quaternary salts. 2. Process according to claim 1, for the production of tetrahydro-pyridines with the general formula I, where R2, R3, R5 and R6 are hydrogen, R1 is a branched or unbranched alkyl group with 1 to 4 carbon atoms, R4 is hydrogen or methyl and X can mean oxygen or sulphur, as well as their pharmacologically acceptable acid addition salts and their quaternary compounds, characterized by using corresponding starting materials. 3. Process according to claims 1-2, for the production of 2,6-dimethyl-4,5,6,7-tetrahydro-furo[2,3-c]pyridine as well as pharmacologically acceptable acid addition salts or quaternary salts of the compound, characterized by using corresponding starting materials.