NZ237285A - 1-hydroxy(and esterified carboxy)-1,2,5,6 tetra hydro pyridine-3-acyl oxime derivatives; preparatory processes and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £37285 237 2 8 Pnorttv • • • ■^r""-^7 ! compos Specification Fiied: «■■■•■ S 29jAN1«2 \ P'jisracstsorc n r> .*.rt»?TSat.

Unfeter—TTfS 'provisions of Reg lation 23 (1) the Specification has been ante-dated to 3&...Q&{a.L 19 Initials Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION OXIME COMPOUNDS ,f£5"T ' v. ^ >'v / r i/'X WE, ROUSSEL-UCLAF, a French body corporate of 35 Boulevard des Invalides, Paris 7eme, France, hereby declare the invention, for which We pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to new derivatives of 1,2,5,6-tetrahvdropyridine and their salts, the production of these compounds, their use as medicaments and compositions containing thera.

Accordingly, the invention provides a compound which is an oxirae of formula (I): n I R CI) or a salt thereof, in which R represents a hydrogen atom; a hydroxyl radical; 10 a- linear;—branched or-cyclic—oaturatcd or unoatugafced,' alkyl radieal eenfeainiag up tea 8 carbon atoms and ■ ■oftfcionally cubottitiutiod by a-frao or octorifiod carboxy radical! an- aralltyl radical containing'up to 10 carbon-■ Qtomo»- or a radical -C00Z in which Z represents a 15 linear, branched or cyclic, saturated or unsaturated, alkyl radical containing up to S carbon atoms or an aralkyl radical containing from 7 to 10 carbon atoms; R^ represents a linear, branched or cyclic, saturated or unsaturated, alkyl radical containing up to 20 8 carbon atoms; and R2 represents a hydrogen atom; a linear or branched, saturated or unsaturated, alkyl radical containing up to 8 carbon atoms; or a COalk^ or (CF^-jiVCalk?)? radical, alkj- and alk£ representing a 25 saturated alkyl radical containing up to 8 carbon atoms; with the proviso that if R represents a linear or branched, saturated, alkyl radical R2 does not represent a hydrogen atom.

The oximes of formula (I) form addition salts with acids. Among such salts there can be mentioned those formed with mineral acids, such as hydrochloric, hydrobromic, sulphuric, or phosphoric, acids, or with organic acids, such as formic, acetic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic such as methane- or ethanesulphonic, or arylsulphonic such as benzene- or paratoluene-sulphonic, acids.

When-fty* ftp ^2 or ^ rePresents a saturated, linear or branched, alkyl radical, it is preferred to be a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isotutyl, n-pentyl or n-hexyl radical.

When -ft;- R-^, R2 or Z represents an unsaturated alkyl radical, it can be an ethylenically unsaturated radical such, for example, as an allyl or 1,1-dimethylallyl radical, or an acetylenically unsaturated radical such, for example, as an ethynyl or propynyl radical.

When-ftr or Z represents a cyclic alkyl radical, it is preferred to be a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical.

When II oc Z represents an aralkyl radical, it is preferred to be a benzyl radical.

Preferably, alkj and alk2 represents a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isobutyl radical. corresponding to The oximes -©^/formula (I) in which R represents an alkyl radical and R2 a hydrogen atom, notably 1-methyl-4-acetyl-l,2,5,6-tetrahydropyridin-oxime, are known for their parasympathomimetic properties (see on this subject the American Patent N°. 3,004,979).

The compounds of the present invention, however, present quite unexpected pharmacological properties in view of the American Patent, which are very interesting as are shown by the results of the biological tests D • described further on in the Examples.

In the present compounds, Rj represents particularly a linear alkyl radical containing from 1-4 carbon atoms, for example the methyl radical.

Among the preferred compounds of the invention, there can be mentioned the oximes of formula (I) in which R roprooonto-Q hydrogen aton, as well aa thoae in which R represents a hydroxyl radical/ and ehooe in whieh R reprcacnta a linear of branched,—aaturated or— CD 10 unsaturated, alkyl radical containing from 1 to 4 carbon afcoinfl't—ouch, far example, aa a-methyl, ethyl, propyl or allyl radical^ as well as their addition salts with acids.

There can also be mentioned the compounds in which 15 &2 represents a hydrogen atom, and those in which R£ represents an alkyl radical containing from 1 to 4 carbon atoms, notably a methyl radical.

The invention provides specifically the compounds whose production is described further on in the 10-12, Examples / and especially the product of Example: 2, 3» and- 12.

The present compounds present especially an important cholinomimetic activity of long duration of activity, by the oral route.

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

Accordingly, the present compounds are indicated 30 for use as medicaments, in particular in the treatment of Alzheimer's disease or of senile dementia and equally in the treatment of memory disorders.

It is well known that disorders of learning and of memory in old people are connected above all with a 35 deficiency in the central cholinergic system, particularly in senile dementia and Alzheimer's disease.

D 237285 lo iS'l 1 J 31 It is evident therefore that products having a central cholinergic action might 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 route has a positive effect on patients having a memory defect (Sitaram N. et al., Science 201, 274, 1978), (Christie J.S. et al. Brit. J. 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 the oral route and a short duration of action.

The present compounds, after administration by the oral route, have shown a central cholinomimetic activity much superior to that of arecoline and with a longer duration of action.

The usual posology is variable according to the affection concerned, the suject treated and the 20 administration route; it can be between 50 mg and 300 mg per day, for example between 15 and 150 mg per day, in one or more doses for the product of Example 3, administered by the oral route.

Thus, the invention provides a pharmaceutical 25 composition comprising a pharmaceutically acceptable excipient together with a compound which is the present oxime or a pharmaceutically acceptable salt thereof. The invention provides also the compound or composition for use in a method of treatment of the human or animal 30 body by therapy.

The pharmaceutical compositions contain as active principle at least one oxime of formula (I) or pharmaceutically acceptable salt thereof. The compositions can be solid or liquid and can be presented 35 in the pharmaceutical forms currently used in human medicine such as plain or sugar-coated compressed 237285 a tablets, capsules, granules, suppositories or injectable preparations. The pharmaceutical forms can be prepared by the usual methods.

The active principle is usually employed in 5 admixture with a pharmaceutically acceptable excipient, which may be an excipient known for use in the formulation of pharmaceutical compositions. Such excipients may be solid or liquid as appropriate to the pharmaceutical form chosen, and may include a wide range of organic and 10 inorganic solids, and aqueous and non-aqueous liquids; examples include talc, gum arabic, starch, lactose, magnesium stearate or fatty substances of animal or vegetable origin such as cocoa butter, paraffin derivatives or glycols. The active principle may be 15 compounded with one or more wetting, dispersing or emulsifying agents and/or one or more preservatives.

The invention provides a process for preparing the present compounds wherein R represents other than a hydroxyl radical, which process comprises submitting a 20 halide of formula (VI): (VI) in which Rj is as defined above; R^ represents a hydrogen atom; or a linear or branched, saturated or unsaturated, alkyl radical containing up to 8 carbon atoms; R' represents a linear, branched or cyclic, 25 saturated or unsaturated, alkyl radical containing up to 8 carbon atoms and optionally substituted by a free or esterified carboxy radical; or an aralkyl radical containing up to 10 carbon atoms; and Hal represents a t 237285 halogen atom, to the action of a hydrogenation agent, in order to obtain an oxime of formula (Ip: = N0R' in which R', Rj and R'2 are as defined above, which,-rf-roquirodt—i-o oithc? oalifiod! ort ■ if R^ represents a hydrogen atom, is submitted to the action of a reactant of formula: R"2-Hal in which Hal represents a halogen atom and R"2 represents a-COalk^ or -(CH2)2N(alk2)2 radical, alkj and alk2 being as defined above, in order to obtain the corresponding oxime of formula (Ig): Crc fi =nor"2 N I R* in which R^, R* and R"2 are as defined above, which, ■*£-roquirod| io oalified, ei1, if R' represents an aralkyl radical, the oxime of formula (I^) or (Ig )/ -if d a. J ii11 d , is submitted to the action of a cleavage agent, in order to obtain an oxime of formula (Ic): 237285 | ' l^>r-c=NOf^ (IC> i H in which R-^ and R^ are as defined above, whieh, if ■ - required, ia aalificd, • and the oxime of formula or* (Ig) if R1 represents an aralkyl radical or (Iq), -££-d'ooirodi ■ is submitted to the action of an alkyl or 5 aralkyl haloformate in order to obtain an oxime of formula (Ip): in which Rj, R2 and 2 are as defined above, which, if required, is salified.

The halide of formula (VI) is preferably prepared 10 by submitting a pyridine oxime of formula (IV): n cooz (Id) r (IV) in which Rj and R'2 are as defined above, to the action of an alkyl halide of formula (V): R'-Hal r r- L O 237285 in which R* and Hal are as defined above.

The pyridine oxime of formula (IV) is preferably prepared by submitting a pyridine ketone of formula (II): O 0" en) © in which Rj is as defined above, to the action of a hydroxylamine of formula (III): NH20R'2 (III) or a salt thereof, in which R'2 is as defined above.

In a preferred aspect, therefore, the present compounds wherein R represents other than a hydroxyl 10 radical are prepared from the pyridine ketone of formula (II) by the sequence of steps set out above.

Preferably: - the hydroxylamine of formula (III) is used in the form of its hydrochloride, - Hal (in the alkyl halide of formula R'-Hal or the reactant of formula R"2-Hal) represents a bromine or iodine atom, - the hydrogenation agent is sodium borohydride, - the cleavage agent is alpha-chloroethoxycarbonyl 20 choride, - the haloformate which is used is a chloroformate, for example of ethyl or of benzyl.

■The ifwewfeion alao provides a proceao for ■proporing the 'preoent compound which io an- oximo of' 25 formula (Ig) ? -31 o to -M - 237285 ■ R" represents a bcneyl radical.-—the ailylotion agent io trimethylailyl chloridet— the cleavage agent ia alpha ehloroethoxyearbonyl chloride^— The invention also provides a process for preparing the present compound wherein R represents a hydroxyl radical, which process comprises submitting an N-oxide of formula (VIII): r OC*N0R2 (VIII) 1 in which Rj and R2 are as defined above, to the action of a reducing agent in order to obtain an oxime of formula (Ip): • . /5N-C=M0R2 j Y / (lp) oh in which Rj and R2 are as defined above, which, if required, 10 is salified.

In a preferred way of realizing this process: - the reducing agent is sodium borohydride.

The invention provides alae a proceoo fog preparingo^ ■ compound which is an oxime of formula (1^) as deJjjtetT'above or 1 5 a salt thereof, which process compriseg^soWnitting an oxime of formula (1^) or (Ig) as defin^d-^Sove in which R' represents an aralkyl radical toj^wfaction of a cleavage agent, preferably alpha-ch^£M»oSfIioxycarbonyl chloride, in order to obtain the wefat) of formula (I(j), whieh, if required, ia salLCied.

The optional salification of the oximes of formula (I) can be carried out by the usual methods, in particular by reacting a mineral or organic acid in substantially stoichiometric proportions with the oxime of formula (I). — The pyridine ketones of formula (II) are known in a — general way; they can be prepared by the process ^ ~ y <391 . V, ***"' ' ' V ' '' • • \ ", r\ t' o 11 - 42- - described in American patent 3,004,979.

The N-oxides of formula (VIII) are described, or can be obtained by the process described, in J.Het.Chem., 16, 1459, 1979.

The invention is illustrated by the following Examples. In these examples only Examples 10 to 12 result in compounds of the invention. The remaining Examples are included to illustrate the processes of the invention and the pharmaceutical compositions.

Example 1 : 3-acetyi-1.2.5,6-tetrahvdroprridine-oxime and its hydrochloride.

Stage A : l-benzyl-3-acetyl-pyridine-oxime bromide. 7.4 g of 3-acetylpyridine oxime is dissolved in 80 3 3 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 crystallization 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 NZ 9.12 Found : 54.56 4.98 9.07 Stage B : l-benzyl-3-acetyl-i,2,5,6-tetrahydropyridine— 20 oxime. 13.76 g of the product obtained at stage A in solution in 100 cm of methanol is cooled to 0°C, 2.54 g of sodium hydroboride ?37285 12* - - is added, the whole is allowed co return to ambienc temperature and agitated for 45 minutes. After concentrating under reduced pressure, water is added and extraction is done with chloroform. The organic phase is dried, the solvent is eliminated, and the residue is 5 chromatographed on silica (eluent : ethyl acetate - toluene 3-2).

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

Analysis : Calculated : C Z 73.01 HZ 7.88 N Z 12.16 10 Found : 72.74 7.81 12.04 Stage C : l-benzyl-3-acetyl-l,2,5,6-tetrahydropyridine-trimethyl-silyl oxime. 3.6 g of the product obtained at stage 3 is dissolved in 60 cm"' of benzene and 1.86 g of I,4-diazabicyclo [2.2.2.] octane, and over 5 15 minutes, under an inert atmosphere, 2.07 cra^ 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. (b.p. 150"c, under 0.05 mbar) Analysis : Calculated : C Z 67.50 H 2 8.66 N Z 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 O 0 stage C in solution in 20 cm 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).

Analysis : CjHj^J^O, HC1 Calculated : C Z 47.59 H Z 7.42 N Z 15.86 Found : 47 .74 7 .38 15.78 /3> _ - 237285 Example 2 : l-aethyl-3-acetyl-l, 2,5 ,6-tetrahydropyridlne-Q-methyl- oxime .ind its hydrochloride.

Stage A : 3-acetyl-pyridine-Q-raethyl-oxirae. 6.85 g of methoxylamine hydrochloride Ls added to 10 g of 3-acetyi 5 pyridine in 50 era 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 ls recovered, (b.p. : 115-118°C under 18 ram Hg) .

Stage B : 1-methyl 3-acety1-pyridioe-O-methyl oxime chloride. .5 g of methyl iodide is added to 11 g of the product obtained at stage A in 110 cmJ of ethyl acetate, and the whole is heated to reflux foe 3 hours. After cooling, filtering and crystallizing the product from ethanol, 19.3 g of the expected product is obtained. 15 ra.p. 155-L57°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 *1 product obtained at stage B in 100 cm of methanol and the whole is 20 cooled to +5/+l0°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, in.p. 169-l7l°C.

Analysis : CgH^g^O, HC1 Calculated : C 7. 52.80 H " 8.37 N % 13.68 Found : 53.06 8-44 13.57 Example 3 : 3-acecyl-l,2,5,6-cetrahydropyridine-0-methyl-oxlne and its hydrochloride Stage A : l-benzyl-3-acetyl-pyridine-0-raethyl-oxirae bromide.

-J 27.8 cm of benzyl bromide is added to 23.4 g of the product 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. ^ g y ~; ■ : o n • • ^ W' i < 'v < I U J RFfiFIV-n 237285 O Analvsis Calculated : C Z 56.09 H 7. 5.34 N Z 8.72 Found : 56.24 5.37 8.67 Stage B : l-benzyl-3-ncetyl-l,2,5,6-tetrahydropyridine-0-methyl-5 oxime. 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 I 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: Calculated : CZ 73.74 H Z 8.25 N Z 11.47 Found : 73.56 8.21 11.52 Stage C : l-alpha-chloroethoxycarbonyl-3-acecyl-l,2,5,6-tetrahydro-pyridlne-0-raethyl-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-chloroechyl chloroforraate 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 evaporaced off, and 8.44 g of produce is obtained which is utilized as it is for the following stage, (b.p. 210°C under 0.06 mbar).

Analysis Calculated : C Z 50.68 HZ 6.57 N Z 10.75 Found : 50-86 6"*6 10-59 /hydroxhloride/ Stage D : 3-acetyl-l,2,5,6-tetrahydropyridine-O-methyl-oxime and its The product obcained 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/> Analysis /hydrochloride is obtain<Td7 Calculated : C Z 50.39 H Z 7.93 N Z 14.69 Found : 50.31 7.84 14.55 / j j'. o 'j i li IS ] eceiv:d /9 - ye - 237285 Example 4 : l-methyl-3-acetyl-l,2,5,6-tetrahydropyridlne-Q-ethyl-oxime and its hydrochloride.

Stage A : 3-acetyl-pyridine-0-ethyl-oxime. 3 1 4.8 cm of 3-acetyl pyridine is dissolved in 50 cm of methanol, to this 4.27 g of orchoethyl hydroxylamine hydrochloride is added and the whole is taken to reflux for 3 hours, then cooled and evaporated co 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 pressure. 6.9 g of the expected product is obtained, utilisable for the following stage. ra.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.

A mixture of 5.3 g of the product obtained at stage A and 4.1 cm of methyl iodide i3 agitated for 8 hours at reflux in 80 cra^ of ethanoL, then distilled to dryness. 9.3 g of the expected product is obtained, m.p. 95°C, crystallized from an ether-is.opropanol mixture.. , /and its hydrochloride Stage C : l-methyl-3-acetyl-l,2,5, 6-tetrahydropyridine-O-ethyl-oxirael 1.7 g of boron and sodium hydride is added to a solution of 9.1 g of the product obtained at stage B in 90 cnr* 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 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, recrystallized from an isopropanol-ether mixture.

Analysis Calculated : C I 54.91 H Z 8.76 N Z 12.81 Found : 54.88 8.94 12.76 /and its/ Example 5 : 3-acetyl-l,2,5,6-tetrahydropyrldlne-O-ethyl-oxime hydro-35 chloride Stage A : l-N-benzyl-3-acetyl-pyridine-O-ethyl-oxime bromide. 6.9 g of the product obtained at stage A of example 4 is /G - yr - 237285 dissolved in 70 cm^ of echanol, 6 cm^ of benzyl bromide is added, and Che whole is heated to reflux for 6 hours, Chen cooled, evaporated under reduced pressure, and 13.9 g of the expected product is isolated from the ether.

Stage B : 1-N-benzyl—3-acecyl-l,2,5,6-cetrahydropyridine-0-ethyl oxime. a) To a solution of 0.8 g of sodium in 50 ca^ of ethanol, 3.8 g of the product obtained at stage B of example 1 and 1.25 ca"' of bromo-ethane are added and the whole is taken to reflux for 3 hours, then cooled and concentrate Co dryness. 2.84 g of Che expecced product is obcained, afcer elution on a column (eluent : ethyl acetate - coluene, 3-2). (b.p. 180-190'C under 0.05 mbar). b) The product can also be obtained with a yield of 71 Z by reduction with boron and sodium hydride, operating as at stage B of example I, starting with the product obtained at stage A of example 5. /hydrochloride/ Stage C : 3-acetyl-l,2,5,6-tetrahydropyridine-0-ethyl-oxime anditsV 2.7 g of the product obtained at stage 3 is dissolved in 50 cm of dichloroethane, then, at 0°C, 1.8 g of alpha-chloroethyl-chloro-formate is added; Che whole is taken to reflux for 1 hour 30 minutes, then evaporated to dryness and'taken up with ether. The insoluble 20 macter is filtered off and evaporated to dryness under reduced •1 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 is isolated and crystallized from an ether-methanol mixture. m.p. 198-199°C (decomposition). Using Che process of example 2 Che expecced hydrochloride is obcained.

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

Stage A : l-N-benzyl-3-acetyl-l, 2,5,6-tetrahydropyridine-0-2-propynyi—ojcime . 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 acetatep-.-. 4.5 g of the expected product is obtained. I 2 8 ;jy j 3 31 i* L n,':nm/-n .U- 237285 Stage B : 3-acetyl-l, 2 ,5 ,6-teCrahydropyridine-0-2-propynyl-oxime and its hydrochloride. 7.5 g of Che product obtained at stage A is dissolved in 100 ca^ of dichloroethane. After 1 hour at reflux, the solvent Ls evaporated, 5 the residue is taken up with ether, che insoluble matter Is filtered off and the remainder Ls evaporated to dryness. The residue Ls taken up with methanol, taken to reflux for 30 minutes, then evaporated to dryness, and the residue Ls taken up with a solution of sodium bicarbonate. This is extracted with ethyl acetate and the extracts are 10 evaporated Co dryness. The residue is taken up with ether and salified wich gaseous hydrochloric acid. 1.25 g of Che expected product is obtained, m.p. 178°C, Isolated from an ether-echanol mixture.

Analysis Calculated : C Z 55.94 H 7. 7.04 M Z 13.05 15 Found : 55.72 7.01 12.99 Example 7 : l-methyl-3-acetyl-tetrahydropyridlne-0-2-propynyl-oxlme and its hydrochloride.

Stage A : 3-acetyl-pyridine-0-2-propynyl oxime. g of 3-acetyl-pyridine is dissolved in 20 cm of water, 3.45 g 20 of sodium bicarbonate and 4.45 g of ortho-2-propynyl-hydroxylamine •1 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 acecace, the extracts are evaporated to dryness and purified on silica gel (eluent ethyl acetate). 5.7 g of the expected 25 produce is obtained, m.p. 156-157°C., recrystallized from isopropanol.

Stage B : l-N-methyl-3-acetyl-pyridine-0—2-propynyl-oxirae iodide, .6 g of product obcained at sCage A is dissolved in 60 cm of methanol and 8.6 g of methyl iodide is added. AfCer 3 hours of reflux, and evaporating Co dryness, Che residue is taken up wich a mixture of aceCone and ether and filtered. 9.7 g is obcained, ra.p. 150-151°C recrystallized from isopropanol.

Stage C : l-methyl-3-acetyl-tetrahydropyridine-O—2-propynyl-oxime and its hydrochloride. ■5 9.7 g of product obtained at stage B is dissolved in 100 cm of 55 methanol, and 2.35 g of boron and sodium hydride is added ac 0°C.

AfCer 1 hour at 0° C, then evaporating, the residue is taken up wich wacer and excracced wich ethyl acetate. The extracts are dried and 1% - 19 - 23728 evaporated to dryness. The residue Ls salified in ether with gaseous hydrochloric acid, and 2.7 g of the expected product is obtained, m.p. 195-L96°C, recrysta1lized from an Lsopropano1-echer mixture.

Analysis : HC1.

Calculated : C 2 57.76 H v. 7.49 n % 12.25 Found : 57.59 7.33 L2.ll , /and its/ Example 8 : 3-propionyl-1, 2, 5.6-tetrahydropvrldlne-oxlme^ hydrochloride. Stage A : L-N-benzyl-3-propionyl-pyridine-oxi:ne bromide.

A mixture of 17-3 g of 3-propionyl pyridine oxime (US Patent 10 3,004,979 (1961) and 13 cm^ of benzyl bromide is maintained at reflux for 7 hours 30 rainuces in 250 cm^ of ethyl acetate. After cooling and separating, 36.5 g of the expected product is obtained, ra.p. 178-180°C, recrystallized from an ethanol-ether mixture.

Stage B : l-N-benzyl-3-propionyl-l,2,5 ,6-tetrahydropyridine-oxime. 15 36.2 g of product obcained 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, Che residue is taken up with waCer, and extracced with ethyl acetate. The extracts are 20 dried and Che solvent is evaporated. The residue is purified by chromatography on a column (eluenC : echyl acecace) and 21 g of Che expected product is obtained, ra.p. lll-112°C, recryscallized from echyl acecace.

Stage C : l-N-benzyl-3-propionyl-l,2,5,6-tetrahydropyridine-O-tri-25 raechyl-silyl-oxirae. 6 g of Che producc obcained at stage B, 70 cm of benzene and 2.95 g of l,4-diazabicyclo[2.2.2. JocCane are mixed together. 3.23 cm^ of triraethylsilyl chloride is added, and the whole is Caken to reflux for 3 hours, then cooled. The insoluble matter is filtered off, the 30 solvent is evaporated, and the residue is Caken up with ether. The insoluble raacter is filtered off and Che remainder is evaporated Co dryness. 7.5 g of Che expecced product is obtained, b.p. : 250°C under 0.06 mbar).

Stage D : 3-propionyl-l ,2,5,6-tecrahydropyridine oxime and its hydrochloride. 16 g of the product obtained at stage C is dissolved in 150 cm of dichloroethane, and afcer cooling co 0°C, 16.2 g of alpha-chloro-ethyl chlorofonnate is added and the whole is maintained at reflux for 3*S 23/28b O o 3 hours, then the solvent is evaporated off. The residue ts taken up with ether, filtered, and concentrated to dryness. The residue is taken up with LOO cm^ of methanol, and taken to reflux for 6 hours. The methanol is evaporated nt'f, and the remainder Ls purified by passage 5 through alumina (eiuent : 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 ethano1-hexane mixture, L.3 g of the expected product Ls obtained, m.p. 205-206°C.

Using the process of example 2, the expected hydrochloride is obtained.

Analysis : HCJ-- Calculated : C % 50.39 H % 7.93 N 7. 14.69 Found : 50.08 7.87 14.48 Example 9 : 3-proplonyl-l,2,5,6-tetrahydropyridine-Q-methyl-oxime and its hydrochloride.

Stage A : l-N-benzyl-3-propionyl-l,2,5,6-tetrahydropyridine-0-raethyl-oxime. 6.11 g of the product obtained at stage B of example 8 is added 1 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 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 ts chromatographed (eluent : ethyl acetate - toluene 6-4), so obtaining 2.5 g of the expected product, (m.p. 170°C at 0.05 mbar).

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 ctn^ 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 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 ts re-crystallized from a mixture of ethanol and ether, and 1.17 g of the expected product is obtained, ra.p. 210-212°C.

Using the process of example 2, the expected hydrochloride is obtained.

Analysis : CgH^gNnO, HC1.

Calculated : C Z 52.53 H Z 8.26 M Z 13-56 Found : 52.80 8.37 13-68 3 1391 zo - y - Example 10 : l-N-carboxyethyl-3-acecyl-l,2,5,6-Cetrahydropyridine-O-methyl-oxine. 1-8 g of the producc obcained ac example 3 is dissolved in 30 cm"* of benzene ac 5°C, Chen 1.63 era'' of triethylamine and 1.12 cra^ of 5 ethyl chloroformate are added. AfCer agitating for 30 minutes at ambienc Ceraperacure, washing with water, evaporating to dryness and rectifying, 2.56 g of Che expecced produce is obcained. (b.p. 155°C under 0.07 mbar).

Analysis Calculated : C 7. 58.39 H Z 8.02 N Z 12.38 Found : ,58.41 , 7.88 12.29 /car boxy/ Example 11 : l-N-^enzyl-3-acetyl-l, 2,5,6-tetrahydropyridine-Q-Tnethy 1-oxine. 2.5 g of produce obcained aC sCage B of example 3 is dissolved in 15 40 cm of anhydrous benzene, 2.7 era of benzyl chlorofortnate is added; the mixture is caken Co reflux for 1 hour, Chen cooled, washed •7 wich 10 cm of 5 Z hydrochloric acid and dried, and Che solvenc is evaporated. The benzyl chloride formed is eliminated, and 2.3 g of Che expecced produce is obcained, re-crysCallized from cyclohexane. m.p. 20 90°C.

Analysis Calculated : C Z 65.68 H Z 6.61 N Z 10.21 Found : 65.81 6,58 10.17 Example 12 : l-N-hydroxyl-3-acetyl-l,2,5,6-tetrahydropyridlne-0-aethyl-25 oxime. 3.5 g of 3-acetyl-pyridine-0-meChyl-oxime-N-oxide [J. Hecerocyclic Chem. 1459, (1979)]is dissolved in 50 cm of methanol and cooled to -10°C. 2.4 g of boron and sodium hydride is added, wich agiCaeion for 2 hours ac ambienc CemperaCure followed by evaporaCion Co dryness. 30 The residue is caken up with waCer and excracced wich echyl acetate. The extracts are dried, evaporated Co dryness, and purified by chroma cography on silica gel, (eluenC : ethyl acetate). 2.85 g of Che expected product is obtained, ra.p. 94-96°C, afcer crystallizing from hexane.

Analysis Calculated : C Z 56.45 H Z 8.29 N Z 16.46 Found : 56.28 8.32 16.31 —— 29 NOV 1991 2\ - 2? - 237285 Example 13 : l-methy1-3-cyclopropylcarbonyl-1,2,5,6-tetrahydropyrldine- -O-methyl-oxlaie and its benzene sulphonace.

Stage A : 3-pyridyl-cvc lo propyLcetone-O-methyl-oxime • 2.03 g of methoxylaraine hydrochloride Ls added to a soLution of 5 3.5 3 of 3-pyridyl-cycIopropyLcecone Ln 50 cra^ of raethanoL. After heatLng to reflux for 4 hours, the solvent is evaporated off and the remainder Ls taken up with an aqueous solution of sodium bicarbonate. This Ls extracted wLth methylene chloride, the extracts are dried then evaporated, and 4.L g of the expected product Ls obtained.

Stage B : l-methyl-3-cyclopropyLcarbonyl-pyridine-O-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 cra^ 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 : C^H^l^O Calculated : C Z 41.52 H Z 4.75 N Z 8.80 20 Found : 41.17 4.66 8.76 Stage C : l-methyl-3-cyclopropylcarbonyl-i,2,5,6-tetrahydropyridine--0—raethyl-oxime and its benzene sulphonate.

To a solution of 6.4 g of product obtained at stage B in 70 of methanol, 1.52 g of boron and sodium hydride is introduced at 08C., 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 obcained Ls 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 i CgH^SO^H Calculated : C Z 57.93 H Z 6.86 N 2 7.95 Found : 58.04 6.94 7.87 22 ■33- - 237285 O Examples of pharmaceutical compositions a) Tablets have been prepared answering to the following formula ; - Product of example 3 200 rag - 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 - 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 rag (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 (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 The test was carried out on male mice (CD^ Charles Rivers) of 22 to 24 g, fasting for 16 hour3. 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.

Product of example I LD50 in mg/kg ■950- 12 Arecoline HBr -ir?5- 175 600 ? s , 10 q 1 £ n'j I i«jOi nGCEIV'ZD II _ &lr _ 237285 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 I) and carbon 5 dioxide gas (5 %). The contractions due to the products are recorded by means of n detector connected to a polygraph. The products to he 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 hexamethoniura 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 Z of the maximum effect.

D Dlarrhoeic 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 Z in methocel is administered by oral route, by means of an oesophagic probe.

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.

The consistency of the feces is evaluated according to the method of Randall and Baruth (Arch. Int. Pharmacodyn. 220, 94, 1976) and according to the following scale of values : .. i " Example 12 Arecoline pD2 .25 4.05 7.50 .39 6.48 icsi Ut- se - ?37285 0 : firm consistency L : 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. 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 7. of the animals according to the method of Miller and Tainter (Proc. Soc. Exp. Biol. Med. 57, 261 , 1944).

Example 12 Arecoline ED5q in mg/kg > 100 -6^5- 1 35 Hypothermic activity The test is carried out on male mice (CD^ Charles Rivers), 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 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 necessa^ to reduce the body temperature by 1°C. is determined. 28 KOV 1391 p rpT-'p ' o LO Exaraple 12 Arecoline 2S - -26- - Effective dose (-l°C) In mg/kg per os | s.c. +2- 0.87 0.77 194 -tir -3rS- 0.91 0.72 3 237285 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 TIIE BODY TEMPERATURE Product of example 12 Arecoline HBr Dose mg/kg -i9--te- -2Q- 40- 200 3.5 Admin. route -pro-: 1 3 . C- p.O . s le p.U, 3 «C i p .0 . s .c. p *0 . 5 -C .

Times in minutes after treatment 0 I 30 | 60 I 120 I 180 1-9-ri- 1-0.1 .1 0 -0.1 +0.1 -0.1 -QtT-- -tr3- -trG- -i-ir HrrQ- ■1.3 1.4 -I. I ■1.5 -9-rS- -H-9- -irrA- -irr0- 0.0 -1.1 -1.3 -1.0 -0.1 -Gt3- -6-r9- -br-i- .1 0 +0.1 -0.2 +0.2 -9-r8- -0ri -0-Hr 0 0 -0.1 +0.2 2 9 riOV 1031 237285 - &■ -

Claims (28)

WHAT WE CLAIM IS:

1. A compound which is an oxime of formula (I): l1 C=NCBt I R (I) or a salt thereof, in which R represents a hydroxy1 radical; or a radical -COOZ in which Z represent a linear, branched or cyclic, saturated or unsaturated, alkyl radical containing up to 8 carbon atoms or an aralkyl radical containing from 7 to 10 carbon atoms; Rj represents a linear, branched or cyclic, saturated or unsaturated, alkyl radical containing up to 8 carbon atoms; and ]?2 represents a hydrogen atom; a linear or branched, saturated or unsaturated, alkyl radical containing up to 8 carbon atoms; or a COalkj or (Cf^^NCa^^ radical, alk^ and alk2 representing a saturated alkyl radical containing up to 8 carbon atoms, ^■with the provigo that if R repreacnea a linear or-branched, saturated, alkyl radical does not represent •a hydragen atom»

2. A compound according to claim 1 wherein R2 represents a linear or branched, saturated or unsaturated, alkyl radical containing up to 8 carbon atoms; or a COalk^ or ((^2)2^(3^2)2 radical, alk^ and 29 NOV 1391 27 - # - alko representing an alkyl radical containing up to 3 carbon atoms.

3. A compound according to claim 1 or 2 wherein I?2 represents a saturated alkyl radical containing from 1 5 to 4 carbon atoms.

4. A compound according to claim 3 wherein J?2 represents a methyl radical.

5. A compound according to claim 1 wherein !?£ represents a hydrogen atom.

6. a compound according to any one of the preceding claims wherein R represents a hydroxyl radical.

7.. A compound according to any one of the preceding 30 claims wherein represents a linear, saturated, alkyl radical containing from 1 to 4 carbon atoms.

8. A compound according to claim 7 wherein represents a methyl radical.

9. A compound according to any one of the preceding 35 claims which is an adition salt of the oxime with acid.

10. An oxime claimed in claim 1 which is specifically named herein.

11. An addition salt with acid of the oxime claimed in claim 10.

12. l-iV-hydroxyl-3-acetyl-l,2,5,6-tetrahydropyridine 0-methyloxime.

13. A process for preparing a compound claimed in any oi the preceding claims except those compounds wherein R represents a hydroxyl radical, which process comprises submitting an oxime of formula (1^): H I (V - 59- - 237285 in which R^ and R2 are as defined above and R1 represents a hydrogen atom or an aralkyl group, which is optionally salified, to the action of an alkyl or aralkyl haloformate in order to obtain an oxime of formula (I„): E a ■—2 1=N0*: I cooz <v in which R^, R^ and z are as defined in claim 1, which, if required, is salified.

14. A process as claimed in claim 13 in which the oxime of formula (1^) where R* is hydrogen or a salt thereof, is prepared by submitting a silyl derivative of formula (VII): I1 I^^t-CsNOS i < alkj) 3 ^ N I r" (VII) in which R^ is as defined in claim 1, R" represents an aralkyl radical containing up to 10 carbon atoms and alk^ represents a saturated alkyl radical containing from 1 to 3 carbon atoms, to the action of a cleavage agent, in order to obtain the oxime of formula (I ), D which, if required, is salified.

15. A process according to claim 14 wherein the silyl derivative of formula (VII) is prepared by submitting an oxime of formula (1'^): |^j-C=N0H r" (i'a) in which R^ and R" are as defined in claim 14, to the action of a silylation agent. H.Z.PATffTCrPK 29 NOV 1991 #% 2q ™ - y$ 10 237285

16. A process for preparing a compound claimed in claim 1 wherein R represencs a hydroxyl radical, which process O comprises submitting an N-oxide of formula (VIII): ?1 OC=N0R2 (VIII) * 0 in which Rj and R£ are as defined in claim 1, to the action of a reducing agent in order to obtain an oxime of formula (Ip): I1 Cr*"082 i (ip^ OH in which R^ and R£ are as defined above, which, if required, is salified. tj- '. 237285 n n 10 15 20 25 30 35 3^ - 3Br - —■—A-process for preparing □ compound 'Which ia an, oxime of formula (Iq) as defined in claim^*6r a salt thereof, which process comprises^u-ferflfitting an oxime of formula (1^) or (Ig) asjieflned in claim in which R' represents an aj:a41<yl radical to the action of a cleava^e-Sgent in order to obtain the oxime of formula —whieht if required,—is- salified.

17. A process for preparing a compound claimed in any one of claims 1 to 12, which process is performed substantially as described herein.

18. A process for preparing a compound claimed in any one of claims 1 to 12, which process is performed substantially as described herein in any one of Examples 1 to 13.

19. A compound claimed in any one of claims 1 to 12 whenever prepared by a process claimed in any one of claims 13 to 18.

20. A pharmaceutical composition comprising a pharmaceutically acceptable excipient together with a compound which is an oxime of formula (I) or a pharmaceutically acceptable salt thereof, which compound is as claimed in any one of claims 1 to 12 and 19.

21. A composition according to claim 20 wherein the compound is an addition salt of the oxime with a pharmaceutically acceptable acid.

22. A composition according to claim 20 or 21 in the form of compressed tablets, gelatin capsules, suppositories or injectable preparations.

23. A composition according to claim .'20 or 21 which is solid.

24. A composition according to claim 20 or 21 wherein the excipient is talc, gum arabic, lactose, starch, magnesium stearate, a fatty substance of animal or vegetable origin, a paraffin derivative or a glycol.

2"5". A composition according to claim 20 or 21 which——~ - 29 KCV 1991 1- i 31 - yZ. - contains a wetting, dispersing or emulsifying agent or a preservative.

26. A composition according to claim 20 substantially as described herein.

27. A composition according to claim 2t). substantially as described herein in any one of the Examples.

28. For use in a method of treatment of the human or animal body by therapy, a compound defined in claim 20 or 21 or a composition claimed in any one of claims 20 to 27. 3h—Each and every novel compound,—composition and process aa described herein. ROUSSEL-UCLAF BALDWIN. SON & CAREY 29 NOV 1991