DD283395A5 - PROCESS FOR PREPARING TETRAHYDROPYRIDINES - Google Patents

Abstract

The invention relates to a process for the preparation of novel tetrahydrofuro and of the general formula I, wherein the substituents have the meaning given in the description. The new compounds can be used as active ingredients in drugs with cholinomimetic properties. Formula I {Tetrahydropyridines, Manufacturing Processes, Pharmaceuticals, Cholinomimetic Properties}

Description

26339 5

Process for the preparation of tetrahydropyridines

Field of application of the invention

The invention relates to a process for the preparation of tetrahydrofuran and thieno (2,3-c) pyridines and their acid addition salts. These partially novel compounds can be used as drugs, especially as cholinomimetics.

Characteristic of the known state of the art

Already P. Mertens et al. 0. Org. Chem. 33, 133 (1968) have made futile attempts at synthesis, the unknown tetrahydrofuro (2,3-c) pyridines of the type

by a ring closure reaction of suitable substituted furans, such as. B. N- (5-Mei: hyl-2-furfuryl) -N-methylglycinethylester represent.

Compounds of general formula I are known in part. Thus, DE-OS 26 28 045 tetrahydro-thienopyridine, which are substituted exclusively in the 6- and 7-position as compounds with anti-inflammatory properties, anti-arrhythmic properties as well

20339 5Γ

an inhibition of platelet aggregation.

In contrast to the tetrahydro-thienopyridines, it has hitherto not been known of the corresponding tetrahydro-furopyridines of the general formula I to use these as medicaments.

Object of the invention

The aim of the invention is to make accessible by a suitable method for the first time the above-mentioned tetrahydro (2,3-c) pyridines as well as their acid addition salts.

Explanation of the essence of the invention

The invention has for its object to produce tetrahydrofuro (2,3-c) pyridines with valuable pharmacological properties.

It has been found that compounds of the general formula I

- hydrogen, branched or unbranched alkyl having 1 to 6 carbon atoms, in which optionally a CH, may be replaced by C = O, branched or unbranched

8339

branched hydroxyalkyl having 1 to 4 carbon atoms, branched or unbranched alkoxy having 1 to 4 carbon atoms, halogen, cyano, COOR 'wherein R ^{1 represents} a branched or unbranched alkyl group having 1 to 4 carbon atoms;

R _{2 is} hydrogen, halogen or branched or unbranched alkyl having 1 to 4 Kohler.stoff atoms;

R, hydrogen or branched or unbranched alkyl having 1 to 4 carbon atoms;

R. hydrogen or branched or unbranched alkyl having 1 to 4 carbon atoms;

Rc is hydrogen or branched or unbranched alkyl of 1 to 4 carbon atoms;

R _{6 is} hydrogen or methyl;

and X oxygen or sulfur means grains

and optionally their pharmacologically acceptable acid addition salts or their quaternary compounds can be used as drugs having cholinomimetic properties.

For the purposes of this invention are considered alkyl groups - optionally also as part of other functional groups - methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl as well as their isomers considered.

- 3a - 2 8 3 3 9

Preference is given to compounds of the general formula I in which R _{1 is} a branched or unbranched alkyl group having 1 to 8, more preferably 1 to 4, carbon atoms, R ₂ , R and / or R _{5 is} hydrogen, R is hydrogen and R _{4 is} a branched or may mean unbranched alkyl group having 1 to 4 carbon · atoms.

Preferred alkyl groups, also as part of other substituents, are methyl, ethyl, n-propyl, iso-propyl, η-butyl, sec-butyl, iso-butyl and tert-butyl. Halogen means one of the atoms from the group fluorine, chlorine, bromine or ood.

Particularly preferred compounds of the general formula I, wherein X is an oxygen atom, R ₁ and R ₄ , the

may be the same or different, an alkyl radical having 1 to 4 carbon atoms, preferably R in the

Meaning methyl, ethyl, n-propyl or η-butyl and R

Methyl, and R, R, R and R are hydrogen 2 3 5 6

mean.

Preferred bases whose pharmacologically acceptable acid addition salts and quaternary compounds are:

2,6-dimethyl-4,5,6,7-tetrahydro-furo [2,3-c] pyridin2,6-dimethyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridin6-methy1 -4,5,6,7-tetrahydro-thieno [2,3-c] pyridin6-methyl-4,5,6,7-tetrahydro-furo [2,3-c] pyridin2-methyl-4,5, 6,7-tetrahydro-furo [2,3-c] pyridin2-ethyl-6-methyl-4,5,6,7-tetrahydro-furo [2,3-c] pyridin6-methyl-2-n-propyl- 4,5,6,7-tetrahydro-furof2.3-c] pyridine-6-methyl-2-n-butyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine 6-methyl-2 -iso-butyl-4,5,6,7, -te /cahydro-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-c] pyridine 6-ethyl-2-methyl-4,5,6,7-tetrahydrothieno [2, 3-c] pyridine 2-chloro-6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine 2-methyl-6,6-dimethyl-4,5,6,7 -tetrahydrothienc [2,3-c] -pyridiniumjodid

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

2-acetyl-6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridin2-bromo-6-methyl-4,5,6,7-tetrahydro-thieno [2, 3-c] pyridin3,6-dimethyl-4,5,6,7-tetrahydro-furo [2,3-c] pyridin2-ethyl-6-methyl-4,5,6,7-tetrahydro-furo [2, 3-c] pyridin2-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

" ⁵ " 2 8339

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 _L 6-dimethyl-4,5,6,6-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-tetrahydrofuro (2,3-c) pyridine

The compounds of the general formula I show muscarinic agonistic properties and are thus suitable for the therapy of diseases with a subfunction of the cholinergic system.

The tertiary amines of the general formula I according to the invention show affinities for muscarinic receptors in the CNS and in animal experiments muscarinic agonistic properties in the CNS.

For example, the 2,6-dimethyl-4 _# 5,6 _t 7-tetrahydrofuro (2,3-c) pyridine hydrochloride in the EEG (electroencephalogram) of the awake rabbit at an application of 3 mg / kg po (1 mg / kg iv) a typical arousal reaction for cholinomimetics.

In haloperidol-sensitized monkeys, compounds of the invention, e.g. the 2, 6-dimethyl-4,5,7,7-tetrahydro-thieno [2,3-c] pyridine hydrochloride (dose <1 mg / kg im) causes dyskinesias caused by haloperidol, or dissolve dyskinesias together with subliminal doses out. Furthermore, the compounds of the invention show in vitro studies muscarinic binding properties, or muscarinic agonistic GTP shifts (guanosine triphosphate). Birdsall, N.I.M., E.C. Hulme and J.M. Stockton 1984 in T.I.P.S. Supplement, Proc. Boarding school, symposium on subtypes of Muscarinic Receptors, Ed. Hirschowitz, Hammer, Giacchetti, Keirns, Levine; Elsevier p. 4-8.

Receptor binding studies in the muscarinic cholinergic system were performed on the three receptor subtypes according to the literature references below

(Watson, M., H.I. Yamamura and J. Aoeske 1983, Life Sci. 32, 3001-3011;

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

Hammer, R., E. Giraldo, G.B. Schiavi, E. Monferini and H. Ladinsky 1986, Life Sei. 38, 1653-1662;).

The results are summarized in Table I.

Table I: Results of receptor binding studies:

^R i ^R 2 receptor ^R 4 ^R 5 ^M i ^M 2 ^M 3 I 24.2 ^CH 3 H subtype ^CH 3 H 53.1 CH ₃ H organ CH ₃ H HIPPO heart tears > 100 H H CH ₃ H CAMPUS gland > 100 CH ₃ H H H Piren- N-MethyIscopolamin 34.1 ^CH 3 H CH ₃ ^CH 3 zepin 11.4 ^CH 3 H et H % n-Bu H £ ³ H] ligand ^CH 3 H [ΜΜοί; % X et H ^CH 3 H 2.7 O iso-Bu H CH ₃ H 8.3 6, 5 % S ^CH 3 ^CH 3 receptor et H 7.5 14 S binding 36.3 > 100 S ^R 3 39.6 > 100 S H 5.8 8.4 S H 2.2 4.5 O H 0.5 0.7 O H 1.4 1.0 O H 0.8 2.5 O H 3.2 3.2 H H H H

R = hydrogen / bu = butyl, Et = ethyl

28339 p

The compounds of the invention displace the muscarinic agonists with high affinity from the agonist binding site. The [3H] cis-methyldioxolane binding studies are carried out analogously to A Closs et al., Naunyn Schmiedebergs Arch. Pharmacol 335, 372-377 (1987). The results are summarized in Table Ia

Table Ia:

 ι ^R ₂ ^R 3 3 [HJ ligand receptor binding cis-methyldioxolane Ki [10 " ⁹ mol / ltr X n-Bu H H ^R 4 ^R 5 O N-Pr H H CH H 39 O et H H OH H 53 O CH ₃ H H CH H 52 O n-Pr H H CH H 81 O H H 160

R = hydrogen

Et = ethyl, Pr = propyl

Due to phacmacological findings, the compounds are suitable for the treatment of the following diseases: Alzheimer's disease, senile dementia, cognitive disorders and also the compounds can 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 further relates to novel compounds of general formula I.

R is hydrogen, branched or unbranched alkyl having 1 to 8 carbon atoms, in which optionally a CH may be replaced by C = O, branched or unbranched hydroxyalkyl having 1 to 4 carbon atoms, a branched or unbranched alkoxy group having 1 to 4 carbon atoms, halogen, cyano, COOR ¹ , wherein R · represents a branched or unbranched alkyl group having 1 to 4 carbon atoms;

- 10 -

2 * 339 5 "

Rp is hydrogen, halogen or branched or unbranched alkyl of 1 to 4 carbon atoms;

R, hydrogen or branched or unbranched alkyl having 1 to 4 carbon atoms;

R _{4 is} hydrogen or branched or unbranched alkyl having 1 to 4 carbon atoms;

R _{5 is} hydrogen or branched or unbranched alkyl having 1 to 4 carbon atoms;

R _{6 is} hydrogen or methyl;

and X may signify oxygen or sulfur

and optionally their pharmacologically acceptable acid addition salts or their quaternary compounds with the proviso that in the case of the free base if

X ss oxygen and R ₁ , Rp, R ₃ , R ₅ and R _{6 are} hydrogen - R _{4 is} not methyl -;

X = sulfur - R ₁ to R _{6 are} not all hydrogen -;

X = sulfur and R 1, R ₀ , R ₁ , R _c and R are hydrogen.

JL d. ύ 3 D

- R _{4 must} not be methyl.

The compounds of the invention can be prepared by known analogy methods.

Starting from 4-hydroxy-substituted compounds of the general formula

II

wherein R ₁ to R ₆ and X have the abovementioned meaning by reduction into compounds of general formula I and then converted by known methods into their acid addition salts or quaternary salts. It is understood that when R _{1 contains} a reducible functional group - such. B. contains a hydroxy group or a carbonyl function (ketone or aldehyde), this must first be protected by a protective group. The protective group is split off again after the reduction.

1 8 3 3 9 5

The reduction is conveniently carried out in a mixture of glacial acetic acid and concentrated hydrochloric acid with tin (II) chloride at temperatures between room temperature and the boiling point of the reaction mixture, preferably at 50 to 70 ⁰ C.

In a process variant, the reaction of the corresponding alcohol with a mixture of hydriodic acid and red phosphorus in glacial acetic acid at boiling temperature.

Further reduction methods and reagents are described in a review article "Modern Methods for the Radical Deoxygenation of Alcohols" by W. Hartwig in Tetrahedron 83; Vol. 39 (16) pp. 2609 to 2645 and in Tetrahedron Letters 8.2, ^v ° l-23 (19), p. 2019.

Compounds of the general formula i in which R is hydrogen and R = an acyl radical can be obtained directly from compounds of the general formula

.2 0

Il

III

13 _Λ "

28339 p

wherein R, to R "and X are the

1 4

have the aforementioned meaning.

This deoxygenation takes place, for example, according to the Wolf-Kishner method with hydrazine hydrate or according to their Huang-Minlon variant.

Compounds of the general formula I where R = alkyl

is obtained by N-alkylation of compounds of general formula I with R-hydrogen by known methods, or reaction with carbonyl compounds under reductive conditions, such as. at the Leukart Wallach reaction.

Compounds of the general formula I in which R and / or R are hydrogen may be obtained by

it

electrophilic aromatic substitution are converted into the corresponding alkyl or acyl derivatives. When R and R are both hydrogen, the substitution is preferably in the 2-positions of the molecule.

The aromatic ring is also accessible to nucleophilic aromatic substitution reactions. Compounds of the general formula I where R = halogen, e.g. Chlorine or bromine can be converted to the corresponding alkyl or alkoxy compounds. The reaction conditions of the aromatic substitution are known and need not be explained in more detail. By reaction with copper (I) cyanide, for example, the corresponding nitriles are obtained.

- 14 - 2 8 33 ^ 5

H-Ally 1-1'hiophenderiva te the general formula

wherein IL through R independently of one another are hydrogen or alkyl as defined above, in the presence of Lewis acids such as 2i.B. Aluminum chloride, in inert organic solvents, e.g. halogenated hydrocarbons, e.g. Dichloromethane, to compounds of general formula I cyclized v / erden.

The quaternary compounds of the general formula I are obtained by customary processes from the corresponding tertiary amines by reaction with a suitable quaternization

* medium, such as Methyl iodide, p-toluene-sulphonic acid methyl ester, in polar solvents, e.g. Nitromethane, acetonitrile or alcohols.

A more general method for the preparation of compounds of general formula I is the II-alkylation of Euro-bzv /. Thieno ß>, 3-c_7pyridines of the general formula

^R 1

wherein X and R to R have the abovementioned meaning

1 6

and the subsequent reduction of the pyridine ring. For example, reaction conditions such as those described by Shiotoni et al. in J. Heterocyclic Chem. 23, 233 (1986) in the synthesis of 6-methyl-4,5,6,7-tetrhydro-furo- [2,3-c] pyridines.

The alcohols of general formula II can also be prepared by known processes or analogy processes, e.g. by reduction of the corresponding ketones with complex hydrides, e.g. Lithium aluminum hydride, in inert organic solvents, e.g. Diethyl ether, tetrahydrofuran, etc.

A further preparation process for the thieno derivatives consists in the reaction of the corresponding formyl derivatives of the general formula or their acetals,

in protic reaction media, e.g. in half-concentrated hydrochloric acid at room temperature and subsequent reduction to I.

The tetrahydro-furo- or -thieno [3,2-c] pyridines of the general formula I according to the invention can be converted into their physiologically tolerated acid addition salts in the customary manner.

¹⁶ IS 3 39 F

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

Preferred acid addition salts are the hydrochlorides and hydrobromides.

By the methods described, for example, the compounds of the general formula I can be obtained

2 6339 5

Table II

Invention compounds of general formula I with R, = hydrogen

VarB. X O ^R i "J ^R ₂ H 3 H H ^R 4 H ^R ₅ H Fp ⁰ C No. O ^CH 3 ^CH 3 H ^CH 3 H the O ^CH 3 CH H H H Hydro O «J CH 3 CH H H CH H chlorides 1 O O CH ^CH 3 H H H ^CH 3 C H H H 256-258 Cl H • J Dec. 2 S H H H ^CH 3 H 226 3 S H H H % j H H 201-202 4 S H ^CH 3 H H ^CH 3 CH 200-202 5 S ° 2 ^H 5 H H H ^C 2 ^H 5 H 210-211 6 S H H Ct J CH H 247-248 7 O nc H ₇ H H ^CH 3 H 265-266 8th O ^CH 3 H CH ₃ H 9 10 O O n-c H H H H CH. j H H 263 256 11 O N3 CH-CH S 7 H H CH ₃ H 215 12 O r Ct ^CH 3 (I. H H Oil (base) 13 O H H H H 174-175 14 O ^CH 3 H CH H 116-117 15 O CH H H H 170-172 16 H 198-199 17 129-130 18 260-261 19 235-236 20 184-185

$ 2 319S

The compounds of general formula I may be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with further Dharmakologically active substances, for example. further cerebro-activators are used. Suitable forms of application are, for example, tablets, capsules, suppositories, solutions. Juices, emulsions or disperse powders. Corresponding tablets may be prepared, for example, by mixing the active substance (s) with known excipients, including inert diluents such as Calc-KC carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or means for achieving depot function, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Coated tablets can accordingly be prepared by coating cores produced analogously to the tablets with agents normally used in tablet coatings, for example collidone or shellac, gum arabic, talc titania or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Likewise, the dragee wrapper to achieve üepoteffelctas may consist of several layers wherein the above-mentioned in the tablets Hilfestoffe can be used.

Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a taste-improving agent, e.g. Flavorings such as vanillin or orange extract.

They may additionally contain suspending aids or picking agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

Injection solutions are prepared in a conventional manner, e.g. prepared with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid and filled into injection bottles or ampoules.

The capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.

Appropriate suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.

The following examples illustrate the present invention without, however, limiting its scope:

Pharmaceutical Formulation Example A) Tablets

Active ingredient milk sugar corn starch polyvinyl pyrrolidone magnesium stearate

per tablet mg 100 mg 140 mg 240 mg 15 mq 5

500 mg

20

2833 ^ 5

The finely ground active substance, lactose and part of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together. The mixture is compressed into tablets of suitable shape and size.

B) Tab.let.ten

active substance

corn starch lactose Microcrystalline cellulose polyvinylpyrrolidone Sodium carboxymethyIstärke magnesium stearate

B. ^r .P_Tablett: e mg 80 mg 190 mg 55 mg 35 mg 15 mg 23 mg 2

400 mg

The finely ground active ingredient, a portion of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are blended together, the mixture is sieved and processed with the remainder of the corn starch and water to a granulate which is dried and sieved. To this is added the sodium carboxymethyl starch and the magnesium stearate, and the mixture is compressed into tablets of suitable size.

C) Ampu

Active ingredient 50 mg Sodium chloride 10 mg

bidistilled water ς.β. ad 1.0 ml

production:

The active ingredient and the sodium chloride are dissolved in bidistilled water and the solution bottled sterile in ampoules.

D) Tropf

Active ingredient 5.0 g

p-hydroxybenzoic acid methyl ester 0.1 g

propyl p-hydroxybenzoate 0.1 g

demineralised water q.s. ad 100.0 ml

He r st el1u na: The active ingredient and the preservatives are

dissolved in demineralized water and the solution

filtered and bottled to 100 ml.

²² 2 $ 339

example 1

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

10 g (49 mmol) of 2,6-dimethyl-4-hydroxy-4,5,6,7-tetrahydrofuro [2,3-c] pyridine (prepared according to J. Chem. Soc. Perkin Trans I 1986, page 877 ff or DOS 3315157) are in a mixture of 120 ml of glacial acetic acid and 60 ml of conc. Dissolved hydrochloric acid and treated with 19.1 g (99 mmol) of tin (II) chloride. Then it is stirred for 2.5 hours at 65 ⁰ C then concentrated the reaction mixture, the residue is taken up in water, with concentrated. Ammonia under ice cooling alkaline and then extracted several times with ethyl acetate. After drying and concentration of the solvent, it is purified by chromatography (silica gel, eluant = ethyl acetate: methanol: ammonia = 10: 1: 0.5). The thus purified base is converted into the hydrochloride and recrystallized from ethanol

Yield: 2.6 g (28% of the title compound as hydrochloride, mp. 256-258 C (decomp.)

Ber. C 57 , 59 H 7 , 51 N 7 , 46 Cl 18 , 89 Gef. C 57 , 31 H 7 , 56 N 7 65 Cl 18 65

Example 2

2,6-dimethyl-4,5,6,7-tetrahydrothieno [2,3-c] pycidine

63.5 g (0.45 mol) of 2- (N-methylaminomethyl) -5-methylthiophene are added together with 47.5 g of sodium carbonate, 0.5 g of potassium iodide and 76.3 g (0.5 mol) of chloroacetaldehyde diethylacetamide in 250 ml anhydrous dimethylformamide for 5.5 h at 130 C stirred. This suspension is filtered off, concentrated and the residue is distilled in vacuo.

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

That in 2.1. prepared amine is heated in 210 ml of 6N hydrochloric acid for 3 hours under reflux, cooled, then the reaction mixture on ice, made alkaline with ammonia and extracted several times with ethyl acetate. After customary work-up and purification, the base thus obtained is converted into the hydrochloride, which is recrystallized from isopropyl ether

Are isolated 22.3 g (49% d. Th.) Of 2,6-dimethyl-4-hydroxy-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine hydrochloride of mp. 156 ⁰ C ,

Starting from 9.4 g (51 mmol) of 2,6-dimethyl-4-hydroxy-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine hydrochloride is obtained analogously to Example 1: 7.3 g (70%) of the title compound as the hydrochloride, mp. 226 ⁰ C.

C H NS X HCl (203.73)

Ber .: C 53 , 06 H 6 , 93 N 6 , 88 Cl 17 40 Gef .: C 52 85 H 6 , 98 N 6 , 81 Cl 17 , 21 example 3

2,4,6-Trimethy1-4,5,6,7-tetrahydrothieno [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 treated while cooling with 22.6 g of aluminum chloride. Thereafter, the reaction mixture is allowed to warm slowly to room temperature. The mixture is stirred for a further 24 hours, the reaction mixture is poured onto ice, made alkaline and the org. Phase off. The aqueous phase is extracted twice more with 200 ml of dichloromethane. After drying and concentration of the combined organic phases, the mixture is chromatographed on silica gel with dichloromethane / methanol (97: 3) and the uniform fractions after evaporation of the solvent with ethanolic hydrochloric acid and precipitated by the addition of ether. The resulting crystals are recrystallized again from ethanol / ether.

This gives 0.6 g of the title compound as the hydrochloride of mp. 200 - 202 ⁰ C.

Example 4

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

The analogous to Example 2 hydrochloride of 2-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine, mp 201-202 ⁰ C is alkylated as follows.:

2.5 g (13 mmol) of the hydrochlorides are dissolved in 100 ml of anhydrous dimethylformamide are added 2.8 g (18 mmol) of ethyl iodide, 1.2 g of potassium iodide and 4.2 g of sodium carbonate and stirred for 3 hours at 100 ⁰ Man concentrated, takes up with water and dichloromethane, makes the aqueous phase alkaline and continues to work up as usual. The residue is chromatographed on silica gel with dichloromethane / methanol (97: 3) as the eluent. The isolated Baee is converted to the hydrochloride, which is recrystallized from ethanol.

Yield: 1.2 g (43%, mp .: 210-211 ⁰ C.

Example .5 2-Chloro-6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

2.7 g (14 mmol) of 6-methyl-4,5,7,7-thetrahydrothieno [2,3-c] pyridine hydrochloride of melting point 226-228 ° C., prepared according to Example 2), are dissolved in 90 ml of glacial acetic acid and at 15 ⁰ C, 2.2 g (16 mmol) of sulfuryl chloride are added dropwise. Then it is stirred for 48 hours at room temperature, added to ice, made alkaline and

26

2 S 2.39 5

extracted several times with dichloromethane. The crude product obtained from the organic phase by drying and concentration is chromatographed on silica gel with dichloromethane / methanol. The uniform fractions are concentrated and transferred to the hydrochloride.

Yield 0.5 g; Mp. 247-248 ⁰ C (ethanol) ·

< Calc .: "8th 10 INS X HCl (224, 15) 6 25 Found .: C 42 87 H 4, 95 N 6 , 07 C 42 65 H 4, 95 N

Cl 31.63 S 14.31 Cl 31.27 S 14.38

Example. 6

2-methyl-6,6-N, N-dimethyl-4,5,6,7-tetrahydrofuro [2,3-cJ-pyridinium iodide

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

Yield 0.52 g, mp 190-193 ° C Elemental analysis: C ₁₀ H _n -NOJ (293.15)

10 16

Calc .: 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-tetrahydrothieno [2,3-c] pyridinium iodide

In analogy 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 with 0.8 methyl iodide jrsetzt. After workup erhälv you get the corresponding quaternary ammonium as white crystals of mp. 160 - 161 ° C.

Example 8

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

3.2 g (21 mmol) of 6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine are dissolved in 10 ml of dichloroethane and mixed with 3.3 g of aluminum trichloride. To the mixture is added dropwise 1.7 g of acetyl chloride dissolved in 20 ml of dichloroethane and stirred for 16 hours. Then the reaction mixture is poured onto ice, made alkaline and the base extracted with dichloromethane and stirred for 16 hours. Place on ice, make alkaline and extract the base with dichloromethane.

After usual chromatographic work-up,

subsequent conversion into the hydrochloride and

repeated recrystallization from ethanol are 0.5 g

the title compound of mp. 256 - 257 ° C won.

Example 9

2- (l-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 are introduced into 100 ml of ethanol and 30 l, l of water and added portionwise with 0.4 g (0.011 mol) of sodium borohydride, hiurbei läet the temperature to 28 ° C. increase. It is then stirred for 3 hours at 50 ⁰ C and added again 0.4 g of sodium borohydride; After 2 hours, the reaction mixture is mixed with 50 ml of ice water and extracted with dichloromethane. After conventional workup, the residue of the organic phase is dissolved in ether / ethanol 2: 1 and made acidic with the addition of 2N ethanolic HCl. This gives 1.7 g (40% of theory) of the desired title compounds as the hydrochloride of mp. 131-132 ° C.

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

Example 10 2-Bromo-6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

To a solution of 3.0 g (0.016 mol) of 6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine in 65 ml of water at 0 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, added dropwise. It is then stirred for 3 hours at 10 to 15 ° C and the resulting crystals were filtered off and washed with ice water. These are then placed in a dilute ammonium hydroxide solution

taken and extracted several times with dichloromethane. After conventional workup, the residue of the organic phase is dissolved in 20 ml of methanol and acidified with 2N ethanolic HCL. This gives 1.7 g (40% of theory) of the title compound as the hydrochloride in the form of colorless crystals of mp 260-261 ⁰ C.

Example 11

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

In analogy to Example 10, starting from 2,6-dimethyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine by bromination, the title compound is obtained as pale yellow critical tetrahydros hydrochloride in 49% yield of melting point 300 to 302 ⁰ C.

Example JL 2

3,6-Dimethy1-4,5,6,7-tetrahydrofuro [2,3-cJpyridin

Starting compound:

3,6-dimethylfuro [2,3-c] pyridinium iodide.

2.2 g (16.5 mmol) of 3-methylfuro [2,3-c] pyridine are reacted with 11.7 g (82.5 mmol) of methyl iodide in 10 ml of anhydrous acetonitrile (H. Morita et al., J. Heterocyclic Chem. 23-549 (1986)). After usual work-up, 4 g (88.9% of theory) of gray-yellow crystals of mp 177-178 ° C. are obtained.

30

Compound:

2 g (7.2 mmol) of the previously prepared iodine are placed in 50 ml of anhydrous methanol, then a total of 0.75 g of sodium borohydride are added in portions at room temperature. After hydrolytic work-up, 0.9 g (66.3% of theory) of the title compound are obtained from the organic phase (CHCl) as the hydrochloride of melting point 287-288 ° C. by addition of HCl in ether

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-tetrahydrothieno [2,3-c] pyridine are treated with 18.9 g (100 mmol) of anhydrous tin oxide. II-CHJ.orid reacted in 60 ml of anhydrous glacial acetic acid. After six hours, hydrolytic (NH OH) is worked up. From the organic phase (CH Cl) is obtained after the

£ * Approx

Recrystallization from ethyl acetate / ether (8: 2) 5.6 (51% of theory) of the title compound of melting point 165-166 C.

Claims (3)

claims 1. A process for the preparation of tetrahydropyridines of the general formula ϊ wherein R _{1 is} hydrogen, branched or unbranched alkyl having 1 to 8 carbon atoms, wherein optionally a CHp may be replaced by C = O, branched or unbranched hydroxyalkyl having 1 to 4 carbon atoms, a branched or unbranched alkoxy group having 1 to 4 carbon atoms, halogen, cyano 'COOR', wherein R 'represents a branched or unbranched alkyl group having 1 to 4 carbon atoms; R _{2 is} hydrogen, halogen or branched or unbranched alkyl having 1 to 4 carbon atoms; R, hydrogen or branched or unbranched alkyl having 1 to 4 carbon atoms; R _{4 is} hydrogen or branched or unbranched alkyl having 1 to 4 carbon atoms; ~ ³² ~ 2 e 33 9 5 R _{5 is} hydrogen or branched or unbranched alkyl having 1 to 4 carbon atoms; Rg is hydrogen or methyl; and X may signify oxygen or sulfur and optionally of their pharmacologically acceptable acid addition salts or their quaternary compounds with the proviso that in the case of the free base if
X = oxygen and R ", R _n , R ,, R _c and R _{e are} hydrogen 1 c. ό DO mean - R ₄ not methyl -; X = sulfur and R ₁ to R- not all hydrogen -; X = sulfur and R ₄ , R ₀ , R, R and R are hydrogen, R ₄ can not be methyl, characterized in that a) a compound of general formula II II wherein X and R ₁ to R _{ß have} the abovementioned meaning 2 θ 3 3 9 $ in which possible carbonyl and hydroxyl radicals are protected by protective groups, reduced, if appropriate, cleaved off the protective groups and then optionally converted into their pharmacologically acceptable acid addition salts or into their quaternary salts, or
b) a pyridine derivative of the general formula ^R 3 wherein R ₁ to R _{β has} the abovementioned meaning with an alkylating reagent of the general formula R ₄ - ^Y wherein R _{4 represents} a branched or unbranched alkyl group having 1 to 4 carbon atoms and Y represents a leaving group, and then reducing the resulting N-alkyl compound, or c) with the proviso that R ₅ = hydrogen and X = sulfur, a compound of the general formula wherein R ₁ to R _{4 are} as defined above, ring in protic reaction media and then reduced, or d) with the proviso that X = sulfur, a compound of the general formula D · O ^R 5 - ^R 5 cyclized in the presence of Lewis acids. 2. The method according to claim 1, characterized in that tetrahydropyridines of the general formula I are prepared, wherein Rp, R ₃ , R ₅ , and R is hydrogen, 28 33 * 5 R _{1 is} a branched or unbranched alkyl group having 1 to 4 carbon atoms, R _{4 is} hydrogen or methyl and X may be oxygen or sulfur and optionally their pharmacologically acceptable acid addition salts as well as their quaternary compounds. 3. Use of a compound of the general formula I according to claim 1 or 2, characterized in that it is used for the preparation of a medicament with cholinomimetic action.