IE881207L

IE881207L - New derivatives of 1,2,5,6-tetrahydropyridine, the process¹for preparing them, their use as medicaments and the¹compositions containing them

Info

Publication number: IE881207L
Application number: IE881207A
Authority: IE
Inventors: Giulio Galliani; Fernando Barzaghi; Carla Bonetti; Emilio Toja
Original assignee: Bs & B Safety Systems Inc
Priority date: 1987-04-24
Filing date: 1988-04-22
Publication date: 1988-10-24
Also published as: FI93211B; AU614283B2; AU1511188A; OA08835A; CA1340986C; JPS63284160A; IT1203971B; IT8720260A0; DE3874396D1; FI881892A; MX11201A; EP0288394B1; KR890016009A; DK216388A; ATE80387T1; IE63172B1; FI93211C; IL86157A; PH25574A; JP2727192B2

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

6 -1 7 9 W 1 f V — 1 I20J-/SS- 4 New derivatives of 1,2,5 ,6-tetrahydropyridine, the process for preparing them, their use as medicaments and the compositions containing them.

A**************************** Company named : ROUSSEL UCLAF ***************************** The invention is concerned with new derivatives of 1,2,5,6-tetra-hydropyridine and their salts, the process for preparing them, their use as medicaments and the compositions containing them.

The subject of the invention is the compounds with the formula (I) : 5 i1 0-c=nor2 (i) "l R 10 in which R represents a hydrogen atom, a hydroxyl radical, a linear, branched or cyclic, saturated or unsaturated, alkyl radical, containing up to 8 carbon atoms, or R represents an aralkyl radical containing up to 10 15 carbon atoms, R.j represents a linear, branched or cyclic, saturated or unsaturated, alkyl radical containing up to 8 carbon atoms and R2 20 represents a hydrogen atom or a linear or branched, saturated or unsaturated alkyl radical containing up to 8 carbon atoms, a COalk^ r -• -i n o < ~J J i i . .. 2 radical or a (CH2)2N(ail<2)2 radical, alk^ and alk2 representing an alkyl radical containing up to 8 carbon atoms, as well as their addition salts with acids, with the condition that if R represents an alkyl radical R2 does not represent a hydrogen atom. 5 Among the addition salts with acids, there can be cited those formed with mineral acids, such as hydrochloric, hydrobromic, sulphuric or phosphoric acids, or with organic acids, such as formic, acetic, propionic, benzoic, raaleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic, such as methane- or 10 ethanesulphonic, arylsulphonic, such as benzene- or paratoluene— sulphonic acids.

Vfhen R, RpOr represents a saturated, linear or branched alkyl radical, it is preferred to be a methyl, ethyl, n-propyl, isopropyl, n-butyl sec-butyl, isobutyl, n-pentyl or n-hexyl radical. 15 When R, R^, or R£ represents an unsaturated alkyl radical, it is preferred to be an ethylene radical such, for example, as an allyl or 1,1-dimeChylallyl radical, or an acetylene radical such, for example, as an ethynyl or propynyl radical.

When R or R-j represents a cyclic alkyl radical, it is 20 preferred to be a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical.

When R represents an aralkyl radical, it is preferred to be a benzyl radical. alk^ and alk£ preferably represent a methyl, ethyl, n-propyl, 25 isopropyl, n-butyl, sec-butyl or isobutyl radical.

The products with the formula (I) in which R represents an alkyl radical and R2 a hydrogen atom, notably l-methyl-A-acetyl-1,2,5,6--tetrahydropyridin-oxime, are products known for their parasympathomimetic properties (see on this subject the U.S. Patent 30 N°. 3,004,979 .

The invention products present quite unexpected pharmacological properties in view of the U.S. Patent, which are very interesting as are shown by the results of biological tests summarized further on in the experimental part. 35 The invention has particularly as its subject the compounds with the formula (I) in which R^ represents a linear alkyl radical containing from 1-4 carbon atoms, for example, the methyl radical. 3 Among the preferred compounds of the invention, there can be cited the compounds with the formula (I) in which R represents a hydrogen atom, as well as those in which R represents a hydroxyl radical and those in which R represents a linear or branched, saturated or 5 unsaturated alkyl radical, containing from 1 to A carbon atoms , such, T for example, as a methyl, ethyl, propyl or allyl radical, as well as their addition salts with acids.

There can also be cited the compounds with the formula (I) in which R£ represents a hydrogen atom, those in which R0 represents 10 an alkyl radical containing from I to 4 carbon atoms and notably a methyl radical.

Naturally, the invention has more particularly as subject the . compounds of which the preparation is given further on in the experimental part and quite specially the products of examples 2, 3 and 15 12.

The Invention products notably present an important cholinomimetic activity of long duration of activity, by oral route.

The products further present a strong dissociation between the central activity and the peripheral activity, as is shown by the 20 results of the tests set out further on.

Therefore, a subject of the invention is the invention products as medicaments, useful in particular in the treatment of Alzheimer's disease or of senile dementia and equally in the treatment of memory disorders . 25 It is well known that disorders of learning and of memory in aged persons are connected above all with a deficiency in the central cholinergic system, particularly in senile dementia and Alzheimer's disease.

It is therefore evident that products having a central cholinergic 30 action could be employed in the therapeutic treatment of these diseases (Bartus, R.I., Science 217, 408, 1982).

It has been demonstrated that arecoline injected by intravenous I route has a positive effect on patients having a memory defect (Sitaram N. et al., Science 201, 274, 1978), (Christie J.E. et al. Brit. J. 35 Psychiatry, 138, 46, 1981).

A limitation to the therapeutic use of arecoline Is bound up with the fact that this product has a very weak activity by oral route and a short duration of action.

The products which are the subject of the invention, after administration by oral route, have shown a central cholinomimetic activity much superior to chat of arecoline and with a longer duration of action.

The usual posology is variable according to the affection concerned, the subject treated and the administration route; it can be between 50 mg and 300 mg per day, for example, between 15 and 150 rag per day in one or more doses for the product of example 3, administered by oral route.

The present invention also has as its subject the pharmaceutical compositions containing as accive principle at least one product with the formula (I). The pharmaceutical compositions of Che invention can be solid or liquid and can be presented in the pharmaceutical forms currently used in human medecine, such, for example, as plain or sugar-coated tablecs, capsules, granules, suppositories, injectable preparations : they are prepared according to the usual methods. The active principle or principles can be incorporated in them with the excipients usually employed in these pharmaceutical compositions, such as talc, gum arable, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, the various wetting, dispersing or emulsifying agents, and preservatives.

The invention also has as its subject a process for the preparation of the products with the formula (I) in which and R2 have the significance previously indicated and R has the significance previously indicated with the exception of the hydroxyl value, characterized In that a compound with the formula (II) : in which R^ retains the same significance as previously, Is submitted to the action of a compound with the formula (III) : 0 (II) nh2or'2 (III) 5 20 25 or one of its salts, in which R'2 represents a hydrogen atom or a linear or branched, saturated or unsaturated, alkyl radical containing up to 8 carbon atoms, in order to obtain the compound with the formula (IV) : o 1 (iv) C=N0R 2 which is submitted to the action of an alkyl halide with the formula (V) : 10 R'-Hal (V) * in which Hal represents a halogen atom and R' represents a linear, branched or cyclic alkyl radical, saturated or unsaturated, containing up to 8 carbon atoms, possibly substituted by a free or esterified 15 carboxy radical or R' represents an aralkyl radical containing up to 10 carbon atoms, in order to obtain the compound with the formula (VI) : I1 i (^>C=N0R,2 y 2 (vi) R' which is submitted to the action of a hydrogenation agent, in order to obtain the compound with the formula (1^) : I1 QC=N0R' y (IA> R in which R', R^ and R'2 are defined as previously which, if required, 30 is either salified, or, if R'^ represents a hydrogen atom, is submitted to the action of a compound with the formula : R"2~Hal 35 in which Hal represents a halogen atom and R"2 represents a radical COalk^ or a radical -(CH2)2N(Alk2)2, alk^ and alk2 being defined as previously, in order to obtain the corresponding compound with the 6 formula (tg) : R o C=N0R"2 I R' 5 in which R^, R' and R"2 are defined as previously which, if required, is salified, or if R' represents an aralkyl radical^ the compound of formula (1^) or (Ig) is submitted to the action of a cleavage agent, in order to obtain the compound with the formula (Iq) : . i H 15 in which and R2 are defined as previously, which, if appropriate is salified.

In a preferred mode of realizing the process of the Invention : - the compound with the formula (III) is used in the form of the hydrochloride, 30 - Hal (in the compound with the formulae R'-Hal or R'^-Hal) represents a bromine or iodine atom, - the hydrogenation agent is sodium borohydride, - the cleavage agent is alpha-chloroethoxycarbony1 chloride, - the halogenoforraate which is used is a chloroformate, for example, 35 of ethyl or of benzyl.

The invention also has as its subject a variant of the preceding process characterized in that a compound with Che formula (1'^) ' 10 20 25 7 I1 r^rc=N°a I R" In which R" represents an aralkyl radical containing up to 10 carbon atoms and R^ retains its previous significance is submitted to the action of a silylation agent, in order to obtain the compound with the formula (VII) : 10 Jl Cr ^C=NOSi(alk3)3 " The invention also has as subject a process for preparing the 30 products with the formula (I) in which and R2 have the previously indicated significance and R represents a hydroxy1 radical, characterized in that a compound with the formula (VIII) : ?' 35 r ^TC=N0R2 (VIII) Cr ■N" I 0 Is submitted to the action of a reducing agent in order to obtain a compound with the formula (1^) : a C=N0R2 I OH in which R^ and R2 are defined as previously, which, if required, is salified. 10 In a preferred way of realizing the invention process : - the reducing agent is sodium borohydride.

The optional salification of the products with the formula (I) is carried out according to the usual methods, by making a mineral or organic acid react in sensibly stoichiometric proportions on the said 15 products with the formula (I).

The compounds with the formula (II) are products known in a general way, which can be prepared according to the process described in the U.S. patent 3,004,979.

The compounds with the formula (VIII) are products described or 20 obtained according to the process described in J.Het.Chem., J^, 1459, 1979.

The following examples illustrate the invention without, however, n-"1"* "• WW Example 1 : 3-acetyl-l, 2,5,6-tetrahydropyridlne-oxime^hydrochloride. 25 Stage A : l-benzyl-3-acetyl-pyridine-0Xime bromide. 7.4 g of 3-acetylpyridine oxime is dissolved in 80 cm of ethanol, 8 cm of benzyl bromide is added to It, with heating at reflux for 6 hours. The solvent is eliminated followed by crystal-30 lization from an ether/methanol mixture. 14.21 g of the expected product is obtained, m.p. = 200-201°C.

Analysis : Calculated : C % 54.74 H % 4.92 N % 9.12 Found : 54.56 4.98 9.07 35 Stage B : l-benzyl-3-acetyl-l,2,5,6-tetrahydropyridine-oxime. 13.76 g of the product obtained at stage A in solution in 100 cm3 of methanol is cooled to 0°C, 2.54 g of ;sodiura hydroboride 9 is added, the whole is allowed to return to ambient temperature and agitated for 45 minutes. After concentrating under reduced pressure, water is added and extraction is done with chloroform. The organic A phase is dried, the solvent is eliminated, and the residue is 5 chromatographed on silica (eluent : ethyl acetate - toluene 8-2).

After crystallization of the residue from ethyl acetate, 7.8 g of the expected product is obtained, m.p. 103-105°C.

Analysis : Calculated : C % 73.01 H % 7.88 N % 12.16 10 Found : 72.7^ 7.81 12.04 Stage C : l-benzyl-3-acetyl-l,2,5,6-tetrahydropyridine-triraethyl-silyl oxime. •5 3.6 g of the product obtained at stage B is dissolved in 60 cm of benzene and 1.86 g of 1,4-diazabicyclo [2.2.2.] octane, and over 5 15 minutes, under an inert atmosphere, 2.07 cm of trimethylchlorosilane is added. The suspension is heated to reflux for 3 hours, then cooled, filtered and concentrated to dryness. The residue is taken up in ethyl ether, filtered, the solvent is eliminated under reduced pressure, and 4.5 g of the expected product is obtained. 20 (b.p. 150°c, under 0.05 mbar) Analysis : Calculated : C % 67.50 H % 8.66 N % 9.26 Found : 67.33 8.59 9.19 , . . , /and its/ Stage D : 3-acetyl-l ,2,5 ,6-tetrahydropyridine-oxime''hydrochloride. 25 Under an inert atmosphere, 20 g of the product obtained as at stage C in solution in 20 cm3 of methylene chloride is cooled to 0°C, 21.6 g of alpha-chloroethyl chloroformate is added, followed by heating to reflux for two-and-a-half hours. After cooling, filtering and eliminating the solvent, the residue is taken up in ethyl ether, 30 triturated and filtered. The solvent is evaporated off, the residue is taken up in methanol, heated to reflux for 30 minutes, then concentrated to dryness. The residue is taken up in methanol and ethyl ether, * filtered, crystallized from ethanol, and 2.1 g of the expected product is collected, m.p. 237°C (with decomposition). 35 Analysis : CyHj^^O, HCl Calculated : C % 47.59 H % 7.42 N % 15.86 Found : 47.74 7.3 8 15.78 10 Example 2 : l-methyl-3-acetyl-l,2,5,6-tetrahydropyridine-O-methyl- oxime and its hydrochloride.

Stage A : 3-acetyl-pyridine-0-methyl-oxirae. 6.85 g of raethoxylamine hydrochloride is added to 10 g of 3-acetyl * 5 pyridine in 50 cm of methanol and the whole is heated to reflux for 3 hours. The solvent is eliminated under reduced pressure, the residue « is taken up in water, alkalized with potassium carbonate and extracted with ethyl acetate. After evaporating, 11 g of the expected product is recovered, (b.p. : 115-118°C under 18 mm Hg). 10 Stage B : 1—methyl 3-acetvl»pyridine-0-methyl oxime chloride. 20.5 g of methyl iodide is added to 11 g of the product obtained at stage A in 110 cm of ethyl acetate, and the whole is heated to reflux for 3 hours. After cooling, filtering and crystallizing the product from ethanol, 19.3 g of the expected product is obtained. 15 m.p. 155-157°C.

Stage C : l-methyl-3-acetyl-l,2,5,6-tetrahydropyridine-0-methyl-oxime and its hydrochloride. 1.7 g of sodium hydroboride is added to a solution of 10 g of the product obtained at stage B in 100 cm of methanol and the whole is 20 cooled to +5/+10°C. After agitating for 1 hour at ambient temperature, the solvent is eliminated under reduced pressure, and the residue is taken up in water, extracted with ethyl ether, and evaporated to dryness. The residue is taken up with ethyl ether, filtered on activated charcoal and salified with gaseous hydrochloric acid. The 25 salt is recrystallized from a mixture of isopropanol and ethyl ether, and 2.8 g of the expected product is obtained, m.p. 169-171°C.

Analysis : C^H^^O, HC1 Calculated : C Z 52.80 H % 8.37 N % 13.68 Found : 53.06 8.44 13.57 30 Example 3 : 3-acetyl-l,2,5,6-tetrahydropyridine-O-methyl-oxime and its hydrochloride Stage A : l-benzyl-3-acetyl-pyridine-0-methyl-oxime bromide. 27.8 cm^ of benzyl bromide is added to 23.4 g of the product • 3 prepared at stage A of example 2 in solution in 200 cm of ethyl 35 acetate. This is heated to reflux for 8 hours, then cooled and filtered, and the solid obtained is crystallized from ethanol. 46 g of the expected product is obtained, m.p. 191-192°C. 11 Analysis : Calculated : C % 56.09 H % 5.34 N % 8.72 Found : 56.24 5.37 8.67 Stage B : l-benzyl-3-acetyl-l,2,5,6-tetrahydropyridine-0-methyl-oxime. o 3 0 g of the product prepared at stage A in solution in 150 cm of methanol is cooled to 0°C. At this temperature 3.6 g of sodium borohydride is added, with agitation for 1 hour at ambient temperature. The methanol is eliminated under reduced pressure, the residue is taken 10 up with water, sodium carbonate is added until saturated, and extraction is done with ethyl ether. The organic phase is dried and the solvent is evaporated. 10.66 g of the expected product is obtained, (b.p. 128-130°C. under 0.4 mbar).

Analysis: 15 Calculated : C % 73.74 H % 8.25 N % 11.47 Found : 73.56 8.21. 11.52 Stage C : l-alpha-chloroethoxycarbonyl-3-acetyl-l,2,5,6-tetrahydro-pyridine-0-methyl-oxime. 7.2 g of the product obtained at stage B in solution in 100 cm 20 of dichloroethane is cooled to 0°C and, over 20 minutes, 6.05 g of alpha-chloroethyl chloroformate is added, dissolved in dichloroethane.

After heating to reflux for one-and-a-half hours, cooling and filtering, the solvent is eliminated under reduced pressure. The residue is taken up in ethyl ether and filtered again. The solvent is 25 evaporated off, and 8.44 g of product is obtained which is utilized as it is for the following stage, (b.p. 210°C under 0.06 mbar).

Analysis Calculated : C % 50.68 H % 6.57 N % 10.75 Found : 50.86 6.46 10.59 /hydroxhloride/ 30 Stage D : 3-acetyl-l,2,5,6-tetrahydropyridine-0-methyl-oxime and its is* ■i The product obtained at stage C in 70 cm of methanol is heated to reflux for 2 hours, then cooled, evaporated to dryness, and the residue is crystallized from ethanol. 3.9 g of the expected product is obtained, m.p. 199-200°C. Using the process of example 2 the expected/\ 35 Analysis /hydrochloride is obtained/ Calculated : C % 50.39 H % 7.93 N % 14.69 Found : 50.31 7.84 14.55 12 Example 4 : l-methyl-3-acetyl-l,2,5,6-tetrahydropyridine-O-ethyl- oxlme and its hydrochloride.

Stage A : 3-acetyl-pyridine-0-ethyl-oxime. "5 3 4.8 cm of 3-acetyl pyridine is dissolved in 50 cm of methanol, 5 to this 4.27 g of orthoethyl hydroxylamine hydrochloride is added and the whole is taken to reflux for 3 hours, then cooled and evaporated to dryness under reduced pressure. The residue is taken up with water, neutralized with sodium bicarbonate and extracted with ethyl acetate. The extracts are dried and concentrated to dryness under reduced 10 pressure. 6.9 g of the expected product is obtained, utilisable for the following stage. m.p. 160-162°C, crystallized from an ether-isopropanol mixture in the form of the hydrochloride.

Stage B : l-methyl-3-acetyl-pyridine-0-ethyl-oxime iodide. 3 A mixture of 5.3 g of the product obtained at stage A and 4.1 cm 3 15 of methyl iodide is agitated for 8 hours at reflux in 80 cm of ethanol, then distilled to dryness. 9.3 g of the expected product is obtained, m.p. 95°C, crystallized from an ether-isopropanol mixture.. /and its hydrochloride/ Stage C : l-methyl-3-acetyl-l,2,5,6-tetrahydropyridine-0-ethyl-oximeV 1.7 g of boron and sodium hydride is added to a solution of 9.1 g 20 of the product obtained at stage B in 90 cm of methanol, maintained at 5°C. After 4 hours at ambient temperature, this is evaporated to dryness under reduced pressure. The residue is taken up with water, extracted with ethyl acetate, and concentrated to dryness under reduced pressure. The residue is taken up with water, extracted with ethyl 25 acetate, and the extracts are concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel (eluent : chloroform-methanol 5-1). The 3.5 g of oil obtained is dissolved in ether and salified with gaseous hydrochloric acid. After evaporating to dryness, 3.7 g of the expected product is obtained, m.p. 186-188°C, 30 recrystallized from an isopropanol-ether mixture.

Analysis Calculated : C % 54.91 H % 8.76 N % 12.81 Found : 54.88 8.94 12.76 /and its/ —v— Example 5 : 3-acetyl-l,2,5,6-tetrahydropyridine-O-ethyl-oxime hydro-35 chloride Stage A : l-N-benzyl-3-acetyl-pyridine-0-ethyl-oxime bromide. 6.9 g of the product obtained at stage A of example 4 is 13 1 O dissolved in 70 cm of ethanol, 6 cm of benzyl bromide is added, and the whole is heated to reflux for 6 hours, then cooled, evaporated under reduced pressure, and 13.9 g of the expected product is isolated from the ether. 5 Stage B : l-N-benzyl-3-acetyl-l,2,5,6-tetrahydropyridine-0-ethyl oxime. a) To a solution of 0.8 g of sodium in 50 cm of ethanol, 3.8 g of •i the product obtained at stage B of example 1 and 1.25 cm of bromo-ethane are added and the whole is taken to reflux for 3 hours, then cooled and concentrate to dryness. 2.84 g of the expected product is 10 obtained, after elution on a column (eluent : ethyl acetate - toluene, 3-2). (b.p. 180-190°C under 0.05 mbar). b) The product can also be obtained with a yield of 71 % by reduction with boron and sodium hydride, operating as at stage B of example 1, starting with the product obtained at stage A of example 5. /hydrochloride/ 15 Stage C : 3-acetyl-l,2,5,6-tetrahydropyridine-0-ethyl-oxime and itsl^ 3 2.7 g of the product obtained at stage B is dissolved in 50 cm of dichloroethane, then, at 0°C, 1.8 g of alpha-chloroethyl-chloro- formate is added; the whole is taken to reflux for 1 hour 30 minutes, then evaporated to dryness and taken up with ether. The insoluble 20 matter is filtered off and evaporated to dryness under reduced pressure. The residual oil is taken up with 40 cm of methanol, taken to reflux for 1 hour 30 minutes, then evaporated to dryness. The residue is taken up with ether, filtered, and 4.2 g of the expected base j[S isolated and crystallized from an ether-methanol mixture. 25 m.p. 198-199°C (decomposition). Using the process of example 2 the expected hydrochloride is obtained.

Analysis Calculated : C % 52.81 H % 8.37 N % 13.69 Found : 52.59 8.25 13.48 Example 6 : 3-acetyl-lt2,5,6-tetrahydropyridlne-0-2-propynyl-oxime and its 30 hydrochloride.

Stage A : l-N-benzyl-3-acetyl-l,2,5,6-tetrahydropyridine-0-2-propynyl oxime. 5 g of the product obtained at stage B of example 1 is added to a solution of 1.1 g of sodium in 50 cm of ethanol, then, at 0°C, 3.95 g of propargyl bromide is added. After heating for 3 hours to 40°C, the 35 insoluble matter is filtered off, the solvent is evaporated, and the residue is chromatographed on silica (eluent : ethyl acetate). 4.5 g of the expected product is obtained. 14 Stage B : 3-acetyl-l,2,5,6-tetrahydropyridine-0-2-propynyl-oxime and its hydrochloride. 7.5 g of the product obtained at stage A is dissolved in 100 cm of dichloroethane. After 1 hour at reflux, the solvent is evaporated, 5 the residue is taken up with ether, the insoluble matter Is filtered off and the remainder is evaporated to dryness. The residue is taken up with methanol, taken to reflux for 30 minutes, then evaporated to dryness, and the residue is taken up with a solution of sodium bicarbonate. This is extracted with ethyl acetate and the extracts are 10 evaporated to dryness. The residue is taken up with ether and salified with gaseous hydrochloric acid. 1.25 g of the expected product is obtained, m.p. 178°C, isolated from an ether-ethanol mixture.

Analysis Calculated : C X 55.94 H % 7.04 N % 13.05 15 Found : 55.72 7.01 12.99 Example 7 : l-methyl-3-acetyl-tetrahydropyridine-0-2-propynyl-oxlme and i.ts hydrochloride.

Stage A : 3-acetyl-pyridine-0-2-propynyl oxime. 5 g of 3-acetyl-pyridine is dissolved in 20 cnr of water, 3.45 g 20 of sodium bicarbonate and 4.45 g of ortho-2-propynyl-hydroxylamine hydrochloride in 30 cm of water are added, and the mixture is left for 16 hours, then heated for 3 hours at 40°C. After concentrating, it is extracted with ethyl acetate, the extracts are evaporated to dryness and purified on silica gel (eluent ethyl acetate). 5.7 g of the expected 25 product is obtained, m.p. 156-157°C., recrystallized from isopropanol.

Stage B : l-N-methyl-3-acetyl-pyridine-0-2-propynyl-oxime iodide. 3 5.6 g of product obtained at stage A is dissolved in 60 cm of methanol and 8.6 g of methyl iodide is added. After 3 hours of reflux, and evaporating to dryness, the residue is taken up with a mixture of 30 acetone and ether and filtered. 9.7 g is obtained, m.p. 150-151°C recrystallized from isopropanol.

Stage C : l-methyl-3-acetyl-tetrahydropyridine-0-2-propynyl-oxime and its hydrochloride. o 9.7 g of product obtained at stage B is dissolved in 100 cm of 35 methanol, and 2.35 g of boron and sodium hydride is added at 0°C.

After 1 hour at 0° C, then evaporating, the residue is taken up with water and extracted with ethyl acetate. The extracts are dried and 15 evaporated to dryness. The residue is salified in ether with gaseous hydrochloric acid, and 2.7 g of the expected product is obtained, m.p. 195-196°C, recrystallized from an isopropanol-ether mixture.

Analysis : C^H^N^O, HC1. 5 Calculated : C Z 57.76 H % 7.49 N % 12.25 Found : 57.59 7.38 12.11 , , . , /and its/ Example 8 : 3-propionyl-l,2,5 >6-tetrahydropyridine-oximev hydrochloride. Stage A : l-N-benzyl-3-propionyl-pyridine-oxime bromide.

A mixture of 17.8 g of 3-propionyl pyridine oxime [US Patent 10 3,004,979 (1961) and 18 cm3 of benzyl bromide is maintained at reflux for 7 hours 30 minutes in 250 cm of ethyl acetate. After cooling and separating, 36.5 g of the expected product is obtained, m.p. 178-180°C, recrystallized from an ethanol-ether mixture.

Stage B : "l-N-benzyl-3-propionyl-l,2,5,6-tetrahydropyridine-oxime. o 15 36.2 g of product obtained at stage A is dissolved in 250 cm of methanol, and the temperature is maintained at 10°C while 6.4 g of boron and sodium hydride is added in portions, with agitation for 3 hours. After evaporating under reduced pressure, the residue is taken up with water, and extracted with ethyl acetate. The extracts are 20 dried and the solvent is evaporated. The residue is purified by chromatography on a column (eluent : ethyl acetate) and 21 g of the expected product is obtained, m.p. 111-112°C, recrystallized from ethyl acetate.

Stage C : l-N-benzyl-3-propionyl-l,2,5,6-tetrahydropyridine-0-tri-25 methyl-silyl-oxime. "1 6 g of the product obtained at stage B, 70 cm of benzene and 2.95 g of 1,4-diazabicyclo[2.2.2.Joctane are mixed together. 3.23 cm of trimethylsilyl chloride is added, and the whole is taken to reflux for 3 hours, then cooled. The insoluble matter is filtered off, the 30 solvent is evaporated, and the residue is taken up with ether. The insoluble matter is filtered off and the remainder is evaporated to dryness. 7.5 g of the expected product is obtained, b.p. : 250°C under 0.06 mbar).

Stage D : 3-propionyl-l,2,5,6-tetrahydropyridine oxime and its hydrochloride. rt 35 16 g of the product obtained at stage C is dissolved in 150 cmJ of dichloroethane, and after cooling to 0°C, 16.2 g of alpha-chloro-ethyl chloroformate is added and the whole is maintained at reflux for 16 3 hours, then the solvent is evaporated off. The residue is taken up with ether, filtered, and concentrated to dryness. The residue is taken up with 100 cm of methanol, and taken to reflux for 6 hours. The methanol is evaporated off, and the remainder is purified by passage 5 through alumina (eluent : chloroform-methanol 7-3, then methanol alone). After evaporating to dryness, the residue is taken up with ethanol, filtered on charcoal and precipitated by adding hexane. The precipitate is filtered and, after purification in an ethanol-hexane mixture, 1.3 g of the expected product is obtained, m.p. 205-206°C.

Using the process of example 2, the expected hydrochloride is obtained. 10 Analysis : CgH^^O, HC1.

Calculated : C Z 50.39 H Z 7.93 N Z 14.69 Found : 50.08 7.87 14.48 Example 9 : 3-propionyl-l,2,5,6-tetrahydropyridine-O-methyl-oxime and its hydrochloride. 15 Stage A : l-N-benzyl-3-propionyl-l,2,5,6-tetrahydropyridine-0-methyl-oxime. 6.11 g of the product obtained at stage B of example 8 is added 3 3 to a solution of 1.2 g of sodium in 80 cm of ethanol. 1.58 cm of methyl iodide is added, the whole is taken to reflux for 6 hours, then 20 cooled and concentrated to dryness under reduced pressure. The residue is taken up with water and extracted with ethyl acetate. The extracts are dried, evaporated to dryness, and the residue is chromatographed (eluent : ethyl acetate - toluene 6-4), so obtaining 2.5 g of the expected product, (m.p. 170°C at 0.05 mbar). 25 Stage B : 3-propionyl-l,2,5,6-tetrahydropyridine-0-methyl-oxime and its hydrochloride. 3.5 g of product from stage A is dissolved in 50 cm of chloroethane, and at 0°C, 2.04 g of alpha-chloroethyl chloroformate is added. After 3 hours at reflux, the solvent is evaporated off, the 30 residue is taken up with ether, filtered and evaporated to dryness. The residue is taken up with 30 cm of methanol and taken to reflux for 30 minutes, then evaporated to dryness. The residue is recrystallized from a mixture of ethanol and ether, and 1.17 g of the expected product is obtained, m.p. 210-212°C.

Using the process of example 2, the expected hydrochloride is obtained. 35 Analysis : CgH^g^O, HC1.

Calculated : C % 52.53 H % 8.26 N % 13.56 Found : 52.80 8.37 13.68 17 Example 10 : l-N-carboxyethyl-3-acetyl-l ,2,5,6-tetrahydropyridine-O-methyl-oxlme. 1.8 g of the product obtained at example 3 is dissolved in 30 cm"' of benzene at 5°C, then 1.63 cm3 of triethylamine and 1.12 cm3 of j 5 ethyl chloroformate are added. After agitating for 30 minutes at ambient temperature, washing with water, evaporating to dryness and J rectifying, 2.56 g of the expected product is obtained, (b.p. 155°C under 0.07 mbar).

Analysis 10 Calculated : C % 58.39 H % 8.02 N % 12.38 Found : 58.41 7.88 12.29 Example li : l-N-carboxy-benzyl-3-acetyl-1,2,5,6-tetrahvdroovridine-0-methyl-oxime. 2.5 g of product obtained at stage B of example 3 is dissolved in 3 3 15 40 cm of anhydrous benzene, 2.7 cm of benzyl chloroformate is added; the mixture is taken to reflux for 1 hour, then cooled, washed with 10 cm of 5 % hydrochloric acid and dried, and the solvent is evaporated. The benzyl chloride formed is eliminated, and 2.3 g of the expected product is obtained, re-crystallized from cyclohexane. m.p. 20 90° C.

Analysis Calculated : C % 65.68 H % 6.61 N % 10.21 Found : 65.81 6,58 10.17 Example 12 : l-N-hydroxyl-3-acetyl-l,2,5,6-tetrahydropyridine-O-methyl-25 oxime. 3.5 g of 3-acetyl-pyridine-0-methyl-oxime-N-oxide [J. Heterocyclic 3 Chera. 1459, (1979)]is dissolved in 50 cm of methanol and cooled to -10°C. 2.4 g of boron and sodium hydride is added, with agitation for 2 hours at ambient temperature followed by evaporation to dryness. 30 The residue is taken up with water and extracted with ethyl acetate. The extracts are dried, evaporated to dryness, and purified by chromatography on silica gel, (eluent : ethyl acetate). . 2.85 g of the expected product is obtained, m.p. 94-96°C, after crystallizing from * hexane. 35 Analysis Calculated : C % 56.45 H % 8.29 N % 16.46 Found : 56.28 8.32 16.31 13 Example 13 : 1-methyl-3-cyclopropylcarbonyl-1,2,5,6-tetrahydropyridine- -O-methyl-oxlme and its benzene sulphonate.

Stage A : 3-pyridyl-cyclopropylcetone-0-methyl-oxime. 2.03 g of methoxylaraine hydrochloride is added to a solution of *1 5 3.5 g of 3-pyridyl-cyclopropylcetone in 50 cm of methanol. After heating to reflux for 4 hours, the solvent is evaporated off and the remainder is taken up with an aqueous solution of sodium bicarbonate. This is extracted with methylene chloride, the extracts are dried then evaporated, and 4.1 g of the expected product is obtained. 10 Stage B : l-methyl-3-cyclopropylcarbonyl-pyridine-0-methyl oxime iodide. 4 g of the product obtained at stage A is added to a solution of 5.3 g of methyl iodide in 50 cm of methanol, and taken to reflux for 3 hours. After evaporating to dryness, the residue is triturated in a 15 mixture of ethanol and ether, then filtered, and 6.6 g of the expected product is obtained, recrystallized from isopropanol. m.p. 133°C, (decomposes).

Analysis : CnH15IN20 Calculated : C % 41.52 H % 4.75 N % 8.80 20 Found : 41.17 4.66 8.76 Stage C : l-methyl-3-cyclopropylcarbonyl-l,2,5,6-tetrahydropyridine--0-methyl-oxime and its benzene sulphonate.

To a solution of 6.4 g of product obtained at stage B in 70 cm of methanol, 1.52 g of boron and sodium hydride is introduced at 0°C., 25 and the mixture is allowed to react for 1 hour 30 minutes at ambient temperature, then evaporated. The residue is taken up with water, and extracted with ethyl acetate. The extracts are dried, evaporated to dryness, and purified by elution on alumina (eluent : toluene-ethyl acetate 6-4). After distilling at 160°C under 0.2 mm of mercury, 2.45 g 30 of the base obtained is taken up in 100 cm of benzene with 1.994 g of benzene sulphonic acid, evaporated to dryness, triturated in a little ethyl acetate, filtered, and 1.7 g of the expected product is obtained, m.p. 76°C (decomposes).

Analysis : CUH18N2°. C6H5S03H 35 Calculated : C % 57.93 H % 6.86 N % 7.95 Found : 58.04 6.94 7.87 19 Examples of pharmaceutical compositions a) Tablets have been prepared answering to the following formula ; - Product of example 3 200 mg 5 - Excipient q.s. for a tablet finished at 300 mg (Detail of excipient : lactose, corn starch, treated starch, rice starch, magnesium stearate, talc). b) Capsules have been prepared answering to the following formula : - Product of example 1 100 mg 10 - Excipient q.s. for a capsule terminated at 300 mg (Detail of excipient : talc, magnesium stearate, aerosil). c) Tablets have been prepared answering to the following formula ; - Product of example 2 50 mg - Excipient q.s. for a tablet finished at 300 mg 15 (Detail of excipient : lactose, corn starch, treated starch, rice starch, magnesium stearate, talc). b) Tablets have been prepared answering to the following formula : - Product of example 12 50 mg - Excipient q.s. for a capsule terminated at 300 mg 20 (Detail of excipient : lactose, corn starch, treated starch, rice starch, magnesium stearate, talc).

Biological activity The products have been utilized in the hydrochloride form.

Acute toxicity 25 The test was carried out on male mice (CD^ Charles Rivers) of 22 to 24 g, fasting for 16 hours. The products are administered by oral route at doses of 1000, 500, 250, 125, 62 and 31 mg/kg. The mortality is noted during the 7 days following the treatment.

I Product of example LD50 in mg/kg 1 I 350 1 2 350 I 3 125 1 12 175 I Arecoline HBr 600 »'' 20 Test on ileum isolated from guinea-pig Pieces of the ileum are removed from guinea-pigs killed by decapitation. The isolated ileum is placed in 10 cm'' of Tyrode's solution at 37°C and aerated with a mixture of oxygen (95 %) and carbon 5 dioxide gas (5 %). The contractions due to the products are recorded by means of a detector connected to a polygraph. The products to be tested are added at concentrations between 1.10~^M/1 and 1.10~®M/1.

The products presenting a contraction effect are tested relative to atropine and hexamethonium to establish whether the activity is of 10 the "muscarine" or "nicotine" type.

The agonist activity is expressed in pD2 (negative logarithm of the dose which produces 50 % of the maximum effect. 15 20 Example I pD2 1 I 5.25 2 I 4.85 3 I 7.50 12 I 5.39 Arecoline 1 6.48 25 Diarrhoeic activity.

The test is carried out on male mice (CD^, Charles Rivers) weighing 25 to 30 g, fasting for 6 hours. The product dissolved at 5 % in methocel is administered by oral route, by means of an oesophagic probe. 30 The control animals receive only the excipient.

After treatment, the animals are put separately in cages the base of which Is covered with blotting paper and are put under observation for 30, 60, 120 and 180 minutes.

The sheets of absorbent paper are changed after each observation. 35 The consistency of the feces is evaluated according to the method of Randall and Baruth (Arch. Int. Pharraacodyn. 220, 94, 1976) and according to the following scale of values : ;• 21 0 : firm consistency 1 : feces slightly soft with or without humid aureola. 2 : feces slightly soft with presence of a well defined humid circle. 3 : feces soft with presence of a large humid circle. 5 4 : feces without consistency with presence of a very large humid circle.

For each product, the dose was noted which caused a diarrhoea in 50 % of the animals according to the method of Miller and Tainter (Proc. Soc. Exp. Biol. Med. _57, 261, 1944). 10 15 20 Example ED^q in mg/kg 1 5 2 > 100 3 0 .85 12 1 Arecoline 35 Hypothermic activity The test is carried out on male mice (CD^ Charles Rivers), 25 weighing 25 - 30 g, fasting for 6 hours.

The temperature of the body is noted by means of a thermocouple placed in the rectum to about 1.5 cm and connected to an electric temperature recorder.

The products are administered by oral route or sub-cutaneously and 30 the temperatures are noted at the Instant 0 and 30 minutes, 1 hour, 2 hours and 2-and-a-half hours after treatment.

The degree of hypothermia is evaluated as the difference between the treated animals and the controls, and the dose necessary to reduce the body temperature by 1°C. is determined. 35 22 I Example Effective dose per os I 1 (-1°C) in mg/kg | s .c. 1 I 1 1 9 1 11 1 1 2 12 I 25 1 1 3 0.87 | 0.91 I 1 12 0.77 | 0.72 I IArecoline 194 | 1 3 1 The duration of action of the products has been evaluated by 15 using the-dose which reduces the body temperature by 1° to 1.5°C.

VARIATION OF THE BODY TEMPERATURE 20 1 I Product of Do se Admin.

Times in minutes after treatment 1 I example 1 mg/kg route 0 30 60 120 180 I 1 1 1 10 p.o. 0 -0.7 -1.0 -0.2 +0.1 1 25 1 I 10 s .c 0 -0.6 -0.8 -0.2 0 1 1 1 2 20 p.o. +0.1 -1.3 -1.3 -0.9 0 1 1 40 s .c +0.1 -1.0 -1.4 -1.1 -0.8 I 30 1 1 3 1 p.o. +0.1 -1.1 -1.0 -0.1 -0.1 1 1 1 1 s .c. +0.1 -1.0 -0.8 +0.1 +0.1 1 1 1 12 1 p.o. 0 -1.3 -1.1 0 0 1 1 1 s .c. -0.1 -1.4 -1.3 +0.1 0 1 35 1 I Arecoline 200 p.o. +0.1 -1.1 -1.0 -0.2 -0.1 1 I HBr 1 3.5 s *c • -0.1 -1.5 -0.1 +0.2 +0.2 I 23

Claims

1.- Compounds with the formula (I) : R1 Cr =N0R2 (I) in which R represents a hydrogen atom, a hydroxyl radical, a linear, branched or cyclic, saturated or unsaturated, alkyl radical, containing up to 8 carbon atoms, or R represents an aralkyl radical containing up to 10 carbon atoms, R^ represents a linear, branched or cyclic, saturated or unsaturated, alkyl radical containing up to 8 carbon atoms and R2 represents a hydrogen atom or a linear or branched, saturated or unsaturated alkyl radical containing up to 8 carbon atoms, a COalk^ radical or a (CI^^NCalk^^ radical, alk^ and alk2 representing an alkyl radical containing up to 8 carbon atoms, as well as their addition salts with acids, with the condition that if R represents an alkyl radical R2 does not represent a hydrogen atom.

2.- Compounds with the formula (I) as defined in Claim I, In which R^ represents a linear alkyl radical containing from 1 to 4 carbon atoms, as well as their addition salts with acids.

3.- Compounds with the formula (I) as defined in Claim 2, in which R^ represents a methyl radical, as well as their addition salts with acids •

4.- Compounds wich the formula (I) as defined in any one of the Claims 1 to 3 In which R represents a hydrogen atom or a hydroxyl radical as well as their addition salts with acids.

5.- Compounds with the formula (I) as defined in any one of the Claims I to 3 in which R represents a linear or branched, saturated or unsaturated alkyl radical, containing from 1 to 4 carbon atoms, as well as their addition salts wich acids.

6.- Compounds wich Che formula (I) as defined in Claim 5, in which R represents a mechyl, echyl, propyl or allyi radical as well as their addition sales wich acids.

7.- Compounds wich the formula (I) as defined in any one of the Claims I to 6 , in which R2 represents a hydrogen atom, as well as their addition salts wich acids.

8.- Compounds wich che formula (I) as defined in any one of the Claims 1 Co 6, in which R2 represents an alkyl radical concaining from I to 4 carbon acorns, and notably a methyl radical.

9.- Compounds wich Che formula (I) as defined in Claim 1, the names of which follow : - l-tnechyl-3-acetyl-l ,2 ,5 ,6-tetrahydropyridine-0-methyl-oxime and its hydrochloride, - 3-acetyi-L , 2,5 ,6-tetrahydropyridine-O-methyl-oxirae and its hydrochloride . - l-N-hydroxyl-3-acetyl-l ,2,5 ,6-tecrahydropyridine-O-mechyl-oxirae .

10.- Process for the preparation of the products with the formula (I) in which R, and R2 have Che significance previously indicated and R has the significance previously indicated with Che excepcion of the hydroxyl value, characterized in that a compound with the formula (II) CT1 (II) in which R^ retains Che same significance as previously, is submitted to the action of a compound with che formula (III) : NH2OR'2 (III) or one of its salts, in which R'2 represents a hydrogen atom or a linear or branched, saturated or unsaturated, alkyl radical containing up to 8 carbon atoms, in order to obtain the compound with Che formula (IV) : Or Ri ■1 (IV) =NOR'2 25 which is submitted to the action of an alkyl halide with the formula (V) : R'-Hal (V) 5 in which Hal represents a halogen atom and R' represents a linear, branched or cyclic alkyl radical, saturated or unsaturated, containing up to 8 carbon atoms, optionally substituted by a free or esterified carboxy radical or R' represents an aralkyl radical containing up to 10 carbon atoms, in order to obtain the compound with the formula (VI) : 10 R, I1 o ijr .(vi) R' * Hal ~ 15 which is submitted to the action of a hydrogenation agent, in order to obtain the compound with the formula (1^) : Cr R1 c-"08'2 (i.) 20 I r« in which R', R^ and R'j are defined as previously which, if appropriate, is either salified, or, if represents a hydrogen atom, is submitted to the action of a compound with the formula : 25 R"2-Hal in which Hal represents a halogen atom and R~£ represents a radical COalk^ or a radical~-(CH2)2N(A.lk2)2> alk^ and alk2 being defined as 30 previously, in order to obtain the corresponding compound with the formula (Ig) : R OC=N0R"2 Ub> I R' 35 in which R^, R' and R'*2 are defined as previously which, if appropriate, is salified, or if R' represents an aralkyl radical, the compound of formula (IA) or (Ig) is 26 submitted to the action of a cleavage agent, In order to obtain the compound wich the formula (Iq) : 1 •=NORr N- »C> J^vJ-C^NOK^ H in which R^ and are defined as previously, which, if appropriate, is salified, 10 15 20

11.- Variant of the process according to Claim 10, characterized in that a compound with the formula (I'^) J ?1 CrN0H «•*) 25 | R" in'which R" represents an aralkyl radical containing up to 10 carbon atoms and R^ retains its previous significance Is submitted to the action of a silylation agent, in order to obtain the compound with the 30 formula (VII) : I1 QC=N0Si