FI93211B - Process for the preparation of novel therapeutically useful 1,2,5,6-tetrahydropyridine derivatives - Google Patents

Abstract

New compounds (I): <IMAGE> in which R denotes a hydrogen, a hydroxyl or an alkyl containing up to 8 C, optionally substituted by a carboxy or R denotes an aralkyl containing up to 10 C or -COOZ, Z being an alkyl containing up to 8 C or an aralkyl containing from 7 to 10 C, R1 denotes an alkyl containing up to 8 C, R2 denotes a hydrogen or an alkyl containing up to 8 C, -COalk1 or (CH2)2N(alk2)2, alk1 and alk2 denoting an alkyl containing up to 8 C, it being understood that if R denotes an alkyl, R2 does not denote a hydrogen, and their addition salts with acids.

Description

93211

Process for the preparation of new therapeutically useful 1,2,5,6-tetrahydropyridine derivatives

The invention relates to a process for the preparation of therapeutically useful 1,2,5,6-tetrahydropyridine derivatives of the formula (I) and their acid addition salts:

Rx 10 -C = NOrn

U

R

Wherein R represents a hydrogen atom, a hydroxyl radical, a linear, branched or cyclic, saturated or unsaturated alkyl radical having up to 4 carbon atoms, R2 represents a linear, branched or cyclic, saturated or unsaturated, saturated or unsaturated, up to 8 carbon atoms or an unsaturated alkyl radical having up to 6 carbon atoms, provided that R cannot be methyl.

As the acid addition salts, mention may be made of salts of mineral acids, such as hydrochloric, hydrobromic, sulfuric or phosphoric acids, or of organic acids, such as formic, acetic, propionic, benzoic, malic, fumaric, succinic and , salts of tartaric, citric, oxalic, glyoxalic, aspartic acids, salts of alkanesulfonic acids such as methanesulfonic and ethanesulfonic acids, salts of arylsulfonic acids such as benzene or paratoluenesulfonic acids.

The closest prior art is represented by FI patent application 875 363, Journal of Pharmaceutical Sciences vol. 56, 35 No. 9, 1967, pp. 1190-1192, Chemical Abstracts, vol. 90 (1979), 168416x and FR Patent 1,258,847.

2 93211

In formula (I), the saturated, linear or branched alkyl radical is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl, or n- hexyl radical.

The unsaturated alkyl radical is preferably an ethylene radical, for example an allyl radical or a 1,1-dimethylallyl radical, or an acetylene radical, such as an ethynyl or propynyl radical.

The cyclic alkyl radical is preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical.

Compounds of formula (I) in which R represents an alkyl radical and R 2 represents a hydrogen atom, in particular 1-methyl-4-acetyl-1,2,5,6-tetrahydropyridine oxime, are known for their parasympathomimetic properties (see U.S. Pat. 3,004,979).

The compounds prepared by the process of the invention have completely unexpected pharmacological properties for the purposes of this U.S. patent, which are of great interest, as shown by the results of the biological experiments presented later in the experimental section.

The invention relates in particular to a process for the preparation of compounds of formula (I) in which R 2 represents a linear alkyl radical having 1 to 4 carbon atoms, for example a methyl radical.

Among the compounds of formula (I), those compounds in which R 2 represents an alkyl radical having 1 to 4 carbon atoms and in particular a methyl radical can also be mentioned.

The invention naturally relates most particularly to a process for the preparation of the compounds whose preparation is described later in the experimental section, and in particular to the compounds of Examples 3 and 9.

The compounds obtained by the process of the invention have significant cholinomimetic properties and a long duration of action when administered orally.

il 3 93211

In addition, the compounds have a strongly distributed central and peripheral effect, as shown by the results of subsequent experiments.

Thus, the compounds of the invention prepared by the process of the invention, as well as their pharmaceutically acceptable acid addition salts, can be used as medicaments, in particular for the treatment of Alzheimer's disease or dementia in old age, as well as for the treatment of memory disorders.

It is well known that problems with learning and memory 10 in the elderly are particularly associated with disorders of the cholinergic system of the central nervous system, particularly dementia in old age and Alzheimer's disease.

Thus, it is clear that compounds with cholinergic activity of the central nervous system can be used for the therapeutic treatment of these diseases (Bartus, R.I. Science 217, 408, 1982).

Arecoline injected intravenously has been shown to have a positive effect on patients suffering from memory disorders (Sitaram N. et al. Science 201, 20 274, 1978), (Christie J.E. et al. Brit. J. Psychiatry 138, 46, 1981).

One limitation of the therapeutic use of arecoline is that this compound has a very weak effect when administered orally, as well as a short duration of action.

It has been found that the compounds prepared by the method of the invention have a significantly greater central nervous system cholinomimetic effect than arecoline when administered orally, as well as a longer duration of action.

The usual posology will vary according to the reason for the treatment, the subject to be treated and the route of administration, it may be between 50 mg and 300 mg / day, e.g.

The compounds prepared by the process of the invention, as well as their pharmaceutically acceptable salts, can thus be used as an active ingredient in the preparation of pharmaceutical compositions containing them.

The pharmaceutical compositions may be solid or liquid, and may be presented in conventional pharmaceutical forms such as compressed or granular, capsule, granular, suppository, injectable preparations; which are prepared by conventional methods. The active ingredient (s) may be combined with carriers conventionally used in pharmaceutical compositions, such as talc, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous media, animal or vegetable fats, paraffin derivatives, glycols with dispersing or emulsifying agents or preservatives.

The process of the invention is characterized in that a) for the preparation of compounds of formula (I) wherein Rx and R2 are as defined above and R20 is as defined above except for hydroxyl, a compound of formula (II) is obtained:

O

LM (II) wherein Rx is as defined above, to react with a compound of formula 30 (III): nh2or'2 (III) or a salt thereof, wherein R'z is linear, saturated or unsaturated, up to 6 carbon

II

9321 1 alkyl atom containing 5 liatoms to give a compound of formula (IV): 5 ^ 1 - C = NOR '·, I * Γ <IV) 10 which is reacted with an alkyl halide of formula (V): R'-Hal ( V) wherein Hal represents a halogen atom and R 'represents a linear, branched or cyclic, saturated or unsaturated alkyl radical having up to 4 carbon atoms, to give a compound of formula (VI): 20 μl N = C = NOR'2 (VI) R ®Hal® 25 which is reacted with a hydrogenating compound such as sodium borohydride to give a compound of formula (IA): 30 μl -C = NOR'9 L Γ u *)

OF

R '6 9321 1 wherein R', Rx and R'2 are as defined above, which is optionally converted into a salt, or b) for the preparation of compounds of formula (I) wherein Rx and R2 are as defined above and R is a hydroxyl radical , reacting a compound of formula (VIII): R 1 aC = NOR 2 (Vili) 10 with a reducing agent such as sodium borohydride to give a compound of formula (IF): T 1 -C = NOR-j

U

20 I

OH

wherein Rx and R2 are as defined above, which is optionally converted to a salt.

In a preferred embodiment of the process according to the invention: the compound of formula (III) is in the form of the hydrochloride,

Hal (in the formula R'-Hal) means a bromine or iodine atom, and the hydrogenating compound is sodium borohydride.

In a preferred embodiment of the process according to the invention, the reducing agent is sodium borohydride.

The compounds of formula (I) are converted into a salt by conventional methods, by reacting the compounds of formula (I) with mineral or organic acids in stoichiometric proportions.

7 93211

The compounds of formula (II) are well known and can be prepared according to the method disclosed in U.S. Patent No. 3,004,979.

Compounds of formula (VIII) are disclosed or may be prepared according to J. Het. Chem., 16, 1459, (1979).

The following examples illustrate the invention without limiting it in any way.

Example 1 (not a compound of the invention) 3-Acetyl-1,2,5,6-tetrahydropyridine oxime hydrochloride

Step A; 1-Benzyl-3-acetyl-1,2,5,6-tetrahydropyridine oxime bromide 7.4 g of 3-acetylpyridine oxime are dissolved in 80 cm3 of ethanol, 8 cm3 of benzyl bromide are added and the mixture is refluxed for 6 hours. The solvent is removed and crystallized from a mixture of ether and methanol. 14.21 g of the expected compound are obtained. Sp. * 200-201 ° C.

Analysis: Calculated: C% 54.74 H% 4.92 N% 9.12

Found: 54.56 4.98 9.07

Step B: 1-Benzyl-3-acetyl-1,2,5,6-tetrahydropyridine oxime.

13.76 g of the compound obtained in step A in 100 cm3 of methanol are cooled to 0 [deg.] C., 2.54 g of sodium borohydride are added, the mixture is allowed to return to ambient temperature and stirred for 45 minutes. I drive. The solution is concentrated under reduced pressure, water is added and extracted with chloroform. The organic phase is dried, the solvent is removed, the residue is purified by silica gel chromatography (eluent: ethyl acetate-toluene 8-2) and, after crystallization of the residue from ethyl acetate, 7.8 g of the expected product are obtained. Sp. = 103-105 ° C.

Analysis: 35 Calculated: C% 73.01 H% 7.88 N% 12.16

Found: 72.74 7.81 12.04 8 93211

Lie C: 1-Benzyl-3-acetyl-1,2,5,6-tetrahydropyridine trimethylsilyloxime.

3.6 g of the compound obtained in step B are dissolved in 60 cm3 of benzene, 1.86 g of 1,4-diazabicyclo [2.2.2] -5-octane, and added for 5 min. under inert conditions 2.07 cm 3 of trimethylchlorosilane. The mixture is heated at reflux for 3 hours, cooled, filtered and concentrated to dryness. The residue is taken up in ethyl ether, filtered, the solvent is removed under reduced pressure to give 4.5 g of the desired compound, (b.p. 150 [deg.] C. at 0.05 mbar). Analysis:

Calculated: C% 67.50 H% 8.66 N% 9.26

Found: 67.33 8.59 9.19

Step D: 3-Acetyl-1,2,5,6-tetrahydropyridinoxime hydrochloride.

20 g of the compound obtained in step C in 20 cm3 of methylene chloride are cooled to 0 [deg.] C. and 21.6 g of alpha-chloroethyl chloroformate are added. The solution is heated at reflux for 2 h, cooled, filtered, the solvent removed, the residue taken up in ethyl ether, ground and filtered. The solvent is evaporated off, the residue is taken up in methanol, refluxed for 30 minutes, concentrated to dryness, the residue is taken up in methanol and ethyl ether, filtered, crystallized from ethanol and 2.1 g of the desired compound are obtained. Sp. = 237 ° C (decomposition).

Analysis:

Calculated: C% 47.59 H% 7.42 N% 15.86

Found: 47.74 7.38 15.78 Example 2 (not a compound of the invention) 1-Methyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-methyloxime and its hydrochloride Step A: 3-Acetylpyridine -O-methyloxime 6.85 g of methoxylamine hydrochloride are added to a solution of 10 g of 3-acetylpyridine in 50 cm3 of methanol. The solution is heated at reflux for 3 hours,

II

The solvent is removed under reduced pressure, the residue is taken up in water, basified with potassium carbonate and extracted with ethyl acetate. The solvent is evaporated to give 11 g of the desired compound. (Mp 115-118 ° C at 18 mm Hg.) Step B: 1-Methyl-3-acetylpyridine-O-methyloxime 20.5 g of methyl iodide are added to a solution of 11 g of the compound obtained in Step A in 110 cm 3: in ethyl acetate, and the mixture is heated at reflux for 3 hours. Cool, filter and crystallize the compound in ethanol.

Step C; 1-Methyl-3-acetyl-1,2,5,6-tetrahydro-pyridine-O-methyloxime hydrochloride 1.7 g of sodium borohydride are added to a solution of 10 g of the compound obtained in step B in 100 cm3 of methanol. , and cooled to + 5 / + 10 ° C. The solution is stirred for 1 hour at ambient temperature, the solvent is removed under reduced pressure, the residue is taken up in water, extracted with ethyl ether, evaporated to dryness, taken up in ethyl ether, filtered on activated carbon and salified with gaseous hydrochloric acid. The salt is recrystallized from a mixture of isopropanol and ethyl ether to give 2.8 g of the desired compound. Sp. = 169-171 ° C.

Analysis: Calculated: C% 52.80 H% 8.37 N% 13.68

Found: 53.06 8.44 13.57

Example 3 3-Acetyl-1,2,5,6-tetrahydropyridine-O-methyloxime and its hydrochloride Step A: 1-Benzyl-3-acetylpyridine-O-methyloxime bromide 27.8 cm 3 of benzyl bromide are added to the solution. with 23.4 g of the compound prepared in Example 2, step A in 200 cm3 of ethyl acetate. The solution is heated at reflux for 8 hours, cooled, filtered and crystallized from ethanol. 46 g of the expected compound are obtained. Sp. = 191-192 ° C.

Analysis:

Calculated: C% 56.09 H% 5.34 N% 8.72 5 Found: 56.24 5.37 8.67

Step B: 1-Benzyl-3-acetyl-1,2,5,6-tetrahydropyridine O-methyloxime 20 g of the compound obtained in Step A in 150 cm3 of methanol are cooled to 0 ° C. At this temperature, 3.6 g of sodium borohydride are added, the mixture is stirred for 1 hour at ambient temperature, the methanol is removed under reduced pressure, the residue is taken up in water, sodium carbonate is added to the saturation point, extracted with ethyl ether, the organic phase is dried and the solvent is evaporated. 10.66 g of the desired compound are obtained. (B.p. 128-130 ° C at 0.4 mbar.) Analysis:

Calculated: C% 73.74 H% 8.25 N% 11.47

Found: 73.56 8.21 11.52

Step C: 1-Alpha-chloroethoxycarbonyl-3-acetyl-1,2,5,6,6-tetrahydropyridine-O-methyloxime 7.2 g of the compound obtained in Step B in 100 cm3 of dichloroethane are cooled to 0 [deg.] C. and added 20 min. during which time 6.05 g of alpha-chloroethyl chloroformate in dichloroethane. The solution is heated at reflux for 1% hour, cooled, filtered and the solvent removed under reduced pressure. Take up the residue in ethyl ether and filter again. The solvent is removed to give 8.44 g of compound, which is used as such in the next step. (B.p. 210 ° C at 0.06 mbar.) 30 Analysis:

Calculated: C% 50.68 H% 6.57 N% 10.75

Found: 50.86 6.46 10.59

Step D: 3-Acetyl-1,2,5,6-tetrahydropyridine-O-methyloxime

35 Heat at reflux for 2 hours in step C.

the compound obtained in 70 cm3 of methanol, cooled, evaporated; 11 93211 is dried and the residue is crystallized from ethanol. 3.9 g of the expected compound are obtained. Sp. = 199 - 200 ° C. Following the procedure as in Example 2, the desired hydrochloride is obtained. Analysis: Calculated: C% 50.39 H% 7.93 N% 14.69

Found: 50.31 7.84 14.55

Example 4 (not a compound of the invention) 1-Methyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-ethyloxime and its hydrochloride Step A: 3-Acetyl-pyridine-O-ethyloxime 4.8 g of 3-acetyl-pyridine dissolved in 40 cm3 of methanol. 4.27 g of orthoethylhydroxylamine hydrochloride are added to the solution. The mixture is heated at reflux for 3 hours. The mixture is cooled and evaporated to dryness under reduced pressure. The residue is taken up in water, neutralized with sodium bicarbonate and extracted with ethyl acetate, dried and concentrated to dryness under reduced pressure. 6.9 g of the desired compound are obtained, which is used in the following step. Sp. = 160-162 ° C, crystallized from a mixture of ether and isopropanol in hydrochloride form.

Step B: Iodide of 1-methyl-3-acetylpyridine-O-ethyloxime

A mixture of 5.3 g of the compound obtained in step A and 4.1 cm3 of methyl iodide in 80 cm3 of ethanol is stirred for 8 hours at reflux. The solution is distilled to dryness. 9.3 g of the expected compound are obtained. Sp. * 95 ° C, crystallized from a mixture of ether and isopropanol.

False C: 1-methyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-ethyloxime 30 To a solution of 9.1 g of the compound obtained in step B in 90 cm3 of methanol at 5 ° C. , 1.7 g of sodium and borohydride are added. The mixture is kept at ambient temperature for 4 hours and the solution is evaporated to dryness under reduced pressure. The residue is taken up in water, extracted with ethyl acetate and concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica gel 9321 1 12 (eluent: chloroform-methanol 5-1). 3.5 g of the oil obtained are dissolved in ether and salified with gaseous hydrochloric acid. The solution is evaporated to dryness to give 3.7 g of the desired compound. Sp. * 186-188 ° C recrystallized from a mixture of isopropanol and ether. Analysis:

Calculated: C% 54.91 H% 8.76 N% 12.81

Found: 54.88 8.94 12.76

Example 5 3-Acetyl-1,2,5,6-tetrahydropyridine-O-ethyloxime and its hydrochloride

Step A: 1N-Benzyl-3-acetylpyridine-O-ethyloxime bromide 6.9 g of compound 15 obtained in Example 4, Step A are dissolved in 70 cm3 of ethanol, 6 cm3 of benzyl bromide are added, the mixture is refluxed for 6 hours, cooled and evaporated. under reduced pressure and 13.9 g of the desired compound are isolated in ether.

Step B: 1N-Benzyl-3-acetyl-1,2,5,6-tetrahydro-20-pyridine-O-ethyloxime a) To a solution of 0.8 g of sodium in 50 cm 3 of ethanol is added 3.8 g of Example 1 of the compound obtained in step B and 1.25 cm3 of bromoethane. After refluxing for 3 hours, the solution is cooled and concentrated to dryness. 2.84 g of the desired compound are isolated after chromatographic purification (eluent: ethyl acetate-toluene 3-2). (B.p. 180-190 ° C at 0.05 mbar.) B) The compound can also be prepared in 71% yield by reduction with borohydride and sodium by proceeding as in Example 1, Step B starting from the compound obtained in Example 5, Step A.

Step C: 3-Acetyl-1,2,5,6-tetrahydropyridine-O-ethyloxime hydrochloride 2.7 g of the compound obtained in Step B are dissolved in 35 to 50 cm3 of dichloroethane. 1.8 g of alpha-chloroethyl chloroformate are added at 0 ° C. 1 hour and 30 min. after refluxing, the solution is evaporated to dryness, the residue is taken up in ether, the insoluble matter is filtered off and evaporated to dryness under reduced pressure. The remaining oily residue is taken up in 40 cm3 of methanol. 1 hour and 30 min. after refluxing the ref-5, the solution is evaporated to dryness, the residue is taken up in ether, filtered and 4.2 g of the desired compound are obtained, which is crystallized from a mixture of ether and methanol. Sp. = 198 - 199 ° C (decomposition). Following the procedure as in Example 2, the desired hydrochloride is obtained.

10 Analysis:

Calculated: C% 52.81 H% 8.37 N% 13.69

Found: 52.59 8.25 13.48

Example 6 3-Acetyl-1,2,5,6-tetrahydropyridine-O-2-propynyloxy oxime and its hydrochloride

False A: 1-N-Benzyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-2-propynyloxime

To a solution of 1.1 g of sodium in 50 cm3 of ethanol is added 5 g of the compound obtained in Example 1, step B. 3.95 g of propargyl bromide are added to the solution at 0 ° C. The solution is heated at 40 [deg.] C. for 3 hours, the insoluble matter is filtered off, the solvent is evaporated off and purified by chromatography on silica gel (eluent: ethyl acetate). 4.5 g of the desired compound are obtained.

Step B: 3-Acetyl-1,2,5,6-tetrahydropyridine-O-2-propynyloxime hydrochloride.

7.5 g of the compound obtained in formula A are dissolved in 100 cm3 of dichloroethane. The mixture is refluxed for 1 hour, the solvent is evaporated off, the residue is taken up in ether, the insoluble matter is filtered off and evaporated to dryness. The residue is taken up in methanol, refluxed for 30 minutes, evaporated to dryness, taken up in sodium bicarbonate, extracted with ethyl acetate and evaporated to dryness. The residue taken up in ether is converted into a salt with gaseous hydrogen chloride-35. 1.25 g of the desired compound are obtained. Sp. = 178 ° C, isolated with a mixture of ether and ethanol with hydrochloric acid.

93211 14

Analysis:

Calculated: C% 55.94 H% 7.04 N% 13.05

Found: 55.72 7.01 12.99

Example 7 (not a compound of the invention) 3-Propionyl-1,2,5,6-tetrahydropyridinoxyl and its hydrochloride

Step A: 1-N-Benzyl-3-propionylpyridioxine bromide

A mixture of 17.8 g of 3-propionylpyridine ok-10 mesh (U.S. Patent 3,004,979 (1961)) and 18 cm 3 of benzyl bromide in 250 cm 3 of ethyl acetate is refluxed for 7 hours and 30 min. The mixture is cooled, the precipitate is separated to give 36.5 g of the desired compound. Sp. = 178-180 ° C, crystallized from a mixture of ethanol and ether.

False B: 1N-Benzyl-3-propionyl-1,2,5,6-tetrahydropyridine oxime 36.2 g of the compound obtained in step A are dissolved in 250 cm3 of methanol and the temperature is maintained at 10 [deg.] C. with the gradual addition of 6 , 4 g of borohydride and sodium. Stir for 3 to 20 hours, evaporate under reduced pressure, take up the residue in water, extract with ethyl acetate, dry and evaporate the solvent. Purify by silica gel column chromatography (eluent: ethyl acetate) to give 21 g of the desired compound. Sp. = 111-112 ° C crystallized from ethyl acetate.

Step C: 1N-Benzyl-3-propionyl-1,2,5,6-tetrahydropyridine-O-trimethylsilyloxime Dissolve 6 g of the compound obtained in Step B in 70 cm3 of benzene and add 2.95 g of 1,4-diazabicyclo -30 lo [2.2.2. ] Octane. 3.25 cm3 of trimethylsilyl chloride are added, the mixture is refluxed for 3 hours, cooled, the insoluble matter is filtered off, the solvent is evaporated off, the residue is taken up in ether, the insoluble matter is filtered off and evaporated to dryness. 7.5 g of the desired compound are obtained. (B.p. 250 ° C 35 at 0.06 mbar.) Li: 15 93211

False D: 3-Propionyl-1,2,5,6-tetrahydropyridinium oxime hydrochloride 16 g of the compound obtained in step C are dissolved in 150 cm3 of dichloroethane. Cool to 0 ° C and adjust 16.2 g of alpha-chloroethyl chloroformate. The solution is heated at reflux for 3 hours, after which the solvent is evaporated, the residue is taken up in ether, filtered and concentrated to dryness. The residue is taken up in 100 cm3 of methanol and refluxed for 6 hours. The methanol is evaporated, after which the residue is purified by passing it through aluminum (eluent: chloroform-methanol 7-3, then methanol only). Evaporate to dryness, take up the residue in ethanol, filter with charcoal and mix by adding hexane. After filtration and purification with ethanol-hexane, 1.3 g of the desired compound are obtained. Sp. = 205 - 206 ° C. Following the procedure as in Example 2, the desired hydrochloride is obtained.

Analysis: C8H14N2O, HCl

Calculated: C% 50.39 H% 7.93 N% 14.69 20 Found: 50.08 7.87 14.48

Example 8 3-Propionyl-1,2,5,6-tetrahydropyridine-O-methyl-oxime and its hydrochloride

Step A: 1-N-Benzyl-3-propionyl-1,2,5,6-tetra-25-hydropyridine-O-methyloxime

To a solution of 1.2 g of sodium in 80 cm 3 of ethanol is added 6.11 g of the compound obtained in Example 8, step B. An additional 1.58 cm3 of methyl iodide are then added, the mixture is refluxed for 6 hours, cooled, concentrated to dryness under reduced pressure and the residue is taken up in water. Extract with ethyl acetate, dry, evaporate to dryness, purify the residue by chromatography (eluent: ethyl acetate-toluene 6-4) to give 2.5 g of the desired compound. (B.p. 170 ° C at 0.05 mbar.) 9321 1 16

False B; 3-Propionyl 1,2,5,6-tetrahydropyridine-O-methyloxime hydrochloride 3.5 g of the compound obtained in step A are dissolved in 50 cm3 of dichloroethane. 2.04 g of alpha-chloroethyl chloroformate are added to the mixture at 0 ° C. After refluxing for 3 hours, the solvent is evaporated off, the residue is taken up in ether, filtered and evaporated to dryness. The residue is taken up in 30 cm3 of methanol and the mixture is refluxed for 30 min. Evaporate the solvent to dryness, crystallize from a mixture of ethanol and ether to give 1.17 g of the title compound.

Sp. = 210-212 ° C. Following the procedure as in Example 2, the desired hydrochloride is obtained.

Analysis: C9H16N2O, HCl

Calculated: C% 52.53 H% 8.26 N% 13.56 15 Found: 52.80 8.37 13.68

Example 9 1-N-Hydroxyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-methyloxime 3.5 g of 3-acetylpyridine-O-methyloxime-n-oxy-20 dia [J. Heterocyclic Chem. 16, 1459, (1979)] is dissolved in 50 cm3 of methanol. The solution is cooled to -10 ° C and 2.4 g of borohydride and sodium are added. Stir for 2 hours at ambient temperature. Evaporate to dryness, take up in water, extract with ethyl acetate, dry, evaporate to dryness. The residue is purified by silica gel chromatography (eluent: ethyl acetate). 2.85 g of the desired compound are obtained. Sp. = 94-96 ° C crystallized from hexane.

Analysis: 30 Calculated: C% 56.45 H% 8.29 N% 16.46

Found: 56.28 8.32 16.31 II: 9321 1 17

Example 10 (not a compound of the invention) 1-Methyl-3-cyclopropylcarbonyl-1,2,5,6-tetrahydropyridine-O-methyloxime and its benzene sulfonate 5 Step A: 3-Pyridylcyclopropyl ketone-O-methyloxime

To a solution of 3.5 g of 3-pyridylcyclopropyl ketone in 50 cm3 of methanol is added 2.03 g of methoxylamine hydrochloride. The solution is refluxed for 4 hours, the solvent is evaporated off and the residue is taken up in aqueous sodium bicarbonate solution. Extract with methylene chloride, dry and evaporate. 4.1 g of the desired compound are obtained.

Step B: Iodide of 1-methyl-3-cyclopropylcarbonylpyridine-O-methyloxime To a solution of 5.3 g of methyl iodide in 50 cm 3 of methanol is added 4 g of the compound obtained in Step A and the mixture is refluxed for 3 hours. Evaporate to dryness, stir the residue into a mixture of ethanol and ether, filter to give 6.6 g of the desired compound crystallized from isopropanol. Sp. = 133 ° C (decomposition).

Analysis: CuH15IN20

Calculated: C% 41.52 H% 4.75 N% 8.80

Found: 41.17 4.66 8.76

Step C: 1-Methyl-3-cyclopropylcarbonyl-1,2,5,25-tetrahydropyridine-O-methyloxime and its benzene sulfonate

To a solution of 6.4 g of the compound obtained in step B in 70 cm3 of methanol are added at 0 ° C 1.52 g of borohydride and sodium. The mixture is allowed to react for 1 hour 30 and 30 min. at ambient temperature. The solvent is evaporated off, the residue is taken up in water, extracted with ethyl acetate, dried and evaporated to dryness. The residue is purified by elution in aluminum (eluent: toluene-ethyl acetate 6-4). The residue is distilled at 160 ° C under a pressure of 0.2 mm Hg. 2.45 g of the base obtained are taken up in 100 cm3 of benzene containing 1994 g of benzenesulphonic acid. Evaporate to dryness, stir in a small amount of ethyl acetate, filter to give 1.7 g of the desired compound. Sp. * 76 ° C 5 (decomposition).

Analysis: CuH18N2O, C6H5SO3H

Calculated: C% 57.93 H% 6.86 N% 7.95

Found: 58.04 6.94 7.87

Examples of Pharmaceutical Compounds 10 a) Extrudates are prepared consisting of:

The compound of Example 3 .......................... 200 mg

Carrier to the weight of the compact ............ 300 mg (carrier: lactose, wheat starch, processed starch, rice starch, magnesium stearate, talc).

15 b) Capsules are prepared consisting of:

The compound of Example 1 .......................... 100 mg

Carrier to the weight of the compact ............ 300 mg (carrier: talc, magnesium stearate, aerosil).

c) Extrudates are prepared consisting of: 20 The compound of Example 2 .......................... 50 mg

Carrier to the weight of the compact ............ 300 mg (carrier: lactose, wheat starch, processed starch, rice starch, magnesium stearate, talc).

d) Extrudates are prepared consisting of: 25 The compound of Example 12 ......................... 50 mg

Carrier to the weight of the compact ............ 300 mg (carrier: lactose, wheat starch, processed starch, rice starch, magnesium stearate, talc). Biological Activity The compounds were used as hydrochlorides (in the following tables, the compounds of Examples 1 and 2 are not according to the invention).

Acute toxicity

The experiment was performed on male mice (0ϋχ Charles 35 Rivers) weighing 22-24 g and fasted for 16 hours. The compounds were administered orally at doses of 11,199,932,100, 500, 250, 125, 62 and 31 mg / kg. Mortality was observed within 7 days of treatment.

Example compound DL50 mg / kg 1,350 2,350 3,125 10,975

Arecoline HBr 600

Test with ileum isolated from experimental animals 15 Ileum portions were removed from decapitated experimental animals. The ileum was isolated and placed in 10 cm 3 of Tyrod's solution at 37 ° C and aerated with a mixture of oxygen (95%) and carbon dioxide (5%). The contractions caused by the compounds were recorded with a sensor connected to a plotter. Test compounds were added at concentrations of 1.10'3 to 1.10 "8 M / l.

Compounds that caused contractions were tested in combination with atropine and hexamethonium to determine if the effect was from "muscarinic" or Niko-25.

The agonist effect is expressed as pD2 (negative logarithm of the dose causing 50% of the maximal effect).

Example pD2 1 5.25 2 4.85 3 7.50 35 9 5.39

Arecoline 6.48 9321 1 20

Diarrheavaikutus

The experiment was performed on male mice (CDa Charles Rivers) weighing 25-30 g and fasted for 6 hours. The compound dissolved in 5% in the meto-5 cell was administered orally by means of a probe placed in the esophagus.

Control animals received vehicle only. After treatment, the animals were placed in separate cages with floors covered with absorbent paper and observed for 30, 60, 120, and 180 min. during.

Absorbent papers were changed after each observation.

Fecal consistency was determined according to the method of Randall et Baruth (Arch. Int. Pharmacodyn. 15 220, 94, 1976) and with the following values: 0: solid consistency, 1: lightly moist faeces, with or without a ring, 2: lightly wet faeces , present clearly detectable kos-20 tea ring, 3: moist stool, as well as a large moist ring, 4: stool without consistency, as well as a very large moist ring.

A dose was determined for each compound that caused diarrhea in 50% of animals by the method of Miller and Tainter (Proc. Soc. Exp. Biol. Med. 57, 261, 1944).

Example DE50 mg / kg 30 1 5 2> 100 3 0.85 9 1

Arecoline 35 35 --- 9321 1 21

Effect of hypothermia

The experiment was performed on male mice (CD1 Charles Rivers) weighing 25-30 g and fasted for 6 hours.

5 The body temperature was measured with a thermocouple placed in the rectum at about 1.5 cm and connected to an electronic temperature recorder.

The compounds were administered orally or subcutaneously, and temperatures were measured at 0, 30 minutes, 1 hour, 2 hours, and 2.5 hours after treatment.

The degree of hypothermia was determined as the difference between the treated and control animals, and the dose required to lower body temperature at 1 ° C was further determined.

15 -

Example Effective dose (-1 ° C) mg / kg

V.O V.SC

1 9 11 20 2 12 25 3 0.87 0.91 9 0.77 0.72

Arecoline 194 3 25 22 93211

Variation in body temperature

Example Dose Administration- Time in minutes after treatment 5 compound method_ mg / kg 0 30 60 120 180 1 10 po 0 -0.7 -1.0 -0.2 +0.1 10 sc 0 -0.6 -0.8 -0.2 0 10 2 20 po +0.1 -1.3 -1.3 -0.9 0 40 sc +0.1 -1.0 -1.4 -1.1 -0.8 3 1 po +0.1 -1.1 -1.0 -0.1 -0.1 1 sc +0.1 -1.0 -0.8 +0.1 +0.1 9 po 0 -1.3 -1.1 0 0 15 sc -0.1 1.4 -1.3 +0.1 0

Arecoline 200 p.o + 0.1-1.1 -1.0 -0.2 -0.1 HBr 3.5 s.c -0.1 -1.5 -0.1 +0.1 +0.2 20

In order to demonstrate the inventive step of the compounds of formula (I) in relation to the closest prior art, comparative therapeutic experiments were performed in which compounds in which R is OH or H were compared with known compounds in which R is CH3.

In this case, the hypothermic effect of the compound of Example 9 of the formula <fH3 30 -ONOCH3 was studied.

OH

and, on the other hand, the compound of Example 2 of formula II 93211 23

Ch3 aC = NOCH3

ς I

5 CH3

In the hypothermia test, the effective doses were 0.77 mg / kg (former compound) and 12 mg / kg (latter compound) orally and 0.72 mg / kg and 25 mg / kg subcutaneously, respectively. Thus, compounds where R = OH are significantly more potent than compounds where R is CH3.

In addition, in the same experiment, compounds where R is H were compared with compounds where R is CH3. The results were as follows:

R

20> sC = N-OR1

Effective dose (mg / kg) 25 Product R R3 orally s.c.

Example 1 * H CH 3 0.87 0.91 *

Example 2 CH3 CH3 12 25

Example 3 H C2H5 6 4.4 *

Example 4 CH3 C2H5 14 12 30 Example 5 H CH2hCH 5.6 3.8

Example 6 CH3 CH2sCH1917 (* not a compound of the invention) 35 Based on these results, compounds where R is H are also much more potent than compounds where R is CH3.

Claims (5)

A process for the preparation of therapeutically useful 1,2,5,6-tetrahydropyridine derivatives of formula 5 (I) and acid addition salts thereof: f 1 C = N 0 R 2 represents a linear, branched or cyclic, saturated or unsaturated alkyl radical of not more than 8 carbon atoms and R 2 represents a linear, saturated or unsaturated alkyl radical of not more than 6 carbon atoms, provided that R cannot be methyl, characterized in that a) for the preparation of compounds of formula (I) wherein Rx and R2 are the same as above and R is the same as above, except hydroxyl , a compound of formula (II) is reacted: 0rLi 30. N / where Rx represents the same as above, with a compound having the formula (III): with a salt thereof, wherein R'2 represents a linear, saturated or unsaturated alkyl radicals having a maximum of 6 carbon atoms, to give a compound of formula (IV): f1 R4 N - c = nor'2 rf (lv »15 reacted with an alkyl halide having the formula (V) R * -Hai where Hai represents a halogen atom and R 'represents a linear, branched or cyclic, saturated or unsaturated alkyl radical of not more than 4 carbon atoms to give a compound of formula (VI): R1 (VI) R'Hal® reacted with a hydrogenating compound, such as sodium borohydride, to give a compound of formula (IA): VC ^ NOR'j U 5 '. R 'where R', Rx and R'2 represent the same as above, which compound, if desired, is converted to a salt, or b) to prepare compounds of formula (I) wherein R 2 and R 2 represent the same as above. and R represents a hydroxyl radical, a compound having the formula (VIII) is reacted: With a reducing agent, such as sodium borohydride, to give a compound of formula (IF): R 1, R 2 - C = NOR 2 (I, OH) where R x and R 2 denotes the same as above, which compound, if desired, is converted into a site. 2. A process according to claim 1, characterized in that as a starting material is used a compound wherein Rx represents a methyl radical. Il: 31 9321 1 3. A process according to claim 1, characterized in that, as a starting material, a compound is used, where R'2 or R2 represent a methyl radical. 4. A process according to claim 1, characterized in that a compound of formula (I) is prepared, wherein R is a hydrogen atom or a hydroxyl radical, and acid addition salts thereof. Process according to claim 1, characterized in that the following compounds of formula (I) are prepared: 3-acetyl-1, 2,5,6-tetrahydropyridine-0-methyloxime and a hydrochloride thereof, hydroxyl-3-acetyl-l, 2,5,6-tetrahydropyridine-0-methyl-oxime.