AU614283B2

AU614283B2 - New derivatives of 1,2,5,6-tetrahydropyridine, the process for preparing them, their use as medicaments and the compositions containing them

Info

Publication number: AU614283B2
Application number: AU15111/88A
Authority: AU
Inventors: Fernando Barzaghi; Carla Bonetti; Giulio Galliani; Emilio Toja
Original assignee: Roussel Uclaf SA
Current assignee: Aventis Pharma SA
Priority date: 1987-04-24
Filing date: 1988-04-22
Publication date: 1991-08-29
Anticipated expiration: 2008-04-22
Also published as: FI93211C; KR890016009A; NZ224357A; DK167758B1; HU199795B; CA1340986C; FI881892A0; ZA882595B; SU1678203A3; ATE80387T1; DE3874396D1; MX11201A; AU1511188A; OA08835A; JPS63284160A; DK216388A; IE881207L; ES2043863T3; EP0288394A3; GR3005647T3

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

Australia PATENTS ACT 1952 ,3 Form COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Thie: Int. CI: e Application Number: Lodged: Complete Specification-Lodged: ,.0.00 Accepted: S" Lapsed: Published: S Priority: ated Art: 0 Belated Art: Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: TO BE COMPLETED BY APPLICANT

ROUSSEL-UCLAF

35, Boulevard des Invalides, 75007 Paris, France.

GIULIO GALLIANI, FERNANDO BARZAGHI, CARLA BONETTI and EMILIO TOJA.

CALLINANS Patent Attorneys, of 48-50 Bridge Road, Richmond, State of Victoria, Australia.

"NEW DERIVATIVES OF 1,2,5,6- TETRAHYDROPYRIDINE, THE PROCESS Complete Specification for the invention entitled: FOR PREPARING THE, THEIR USE AS MEDICAMENTS AND THE COMPOSITIONS CONTAINING THEM" The following statement is a full description of this invention, including the best method of performing it known to me:-' SNote: The description is to be typed in double spacing, pica type face, in an area not exceeding 250 mm in deph and 160 mm in width, on tough white paper of good quality and it is to be inserted inside this form.

*r- 1 1 z

I

1 ir la The invention is concerned with new derivatives of 1, ,5,6-tetrahydropyridine and their salts, the process for preparing them, their use as medicaments and the compositions containing them.

The subject of the invention is compounds with the formula Ri

C=NOR

2

N

a I o so a 10' in which R represents hydrogen, R 1 represents a linear, branched or cyclic, alkyl, alkenyl or alkynyl containing up to 8 carbon atoms and R 2 represents a hydrogen atom or a linear or branched, alkv) alkenyl or alkynyl containing up to 8 carbon atoms, COalk 1 radical or (CH 2 2 1,,,3lk 2 2 alk 1 and alk2 representing an alkyl containing up to 8 carbon atoms, as well as their pharmaceutically acceptable addition salts with acids.

e l a a f lll| a. a i t a a a' *I e* g -2- 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, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic, such as methane- or ethanesulphonic, arylsulphonic, such as benzene- or paratoluenesulphonic acids.

When R 1

R

2 or Z 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.

When R 1

R

2 or Z represents an unsaturated alkyl radical, it is preferred to be an ethylene radical such, for example, as an allyl or 1,1-dimethylallyl radical, or an acetylene radical such, for example, as an ethynyl or propynyl radical.

When R1 or Z represents a cyclic alkyl radical, it is preferred to be a cyclopropyl, cydobutyl, cyclopentyl or cyclohexyl radical.

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

alki and alk 2 preferably represent a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isobutyl radical.

The invention products present quite unexpected pharmacological properties in view of the American Patent No. 3,004,979, which are very interesting as are shown by the results of biological tests summarized further on in the experimental part.

The invention has particularly as its subject the compounds with the formula in which R 1 represents a linear alkyl radical containing from 1 4 carbon atoms, for example, the methyl radical.

There can also be cited the compounds with the formula in which R 2 represents a hydrogen atom, those in which R 2 represents an alkyl radical containing from 1 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 12.

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

r 1 -3- The products 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.

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.

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.

S1& It is therefore evident that products having a central cholinergic action could be employed in the therapeutic treatment of these diseases (Bartus, R.L, Science 217, 408, 1982).

S It has been demonstrated that arecoline injected by intravenous route has A a positive effect on patients having a memory defect (Sitaram N. et al., Science 201, 274, 1978), (Christie J.E. 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 oral route and a 4 44.4I -T 1 I ia

I

4 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 that 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 mg 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 active principle at least one product with S* the formula The pharmaceutical compositions of the invention can **oo be solid or liquid and can be presented In the pharmaceutical forms 15 currently used in human medecine, such, for example, as plain or sugar- S coated tablets, 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, 20 gum arabic, 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 in which R, and R 2 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 (11) 0

(II)

in which R 1 retains the same lignificance as previously, is submitted to the action of a compound with ihe formula (17)

NII

2 0R' 2 (i) r e 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)

C_=NOR,2(V 2 which is submitted to the action of an alkyl halide with the formula (v) 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 carboxy radical or R' represents an aralkyl radical containing p to jcarbon atoms, in order to obtain the compound with the formula (VT) I

(VI

0 i,-I rcNORI 2

(T

R' Hal(l which is submitted to the action of a hydrogenation agent, in order to obtain the compound with the formula

(IA)

1 N C NOR 2 is either sallfied, or, if R' represents a hydrogein atom, is submitted 2 to the action of a compound with the formula

R"

2 -1Hal in which t1al represents a halogen atom and R" 2 represents a radical COalk 1 or a radical -(CH 2 2 N(AIk 2 2 alk, and alk 2 being defined as previously, in order to obtain the corresponding compound with the 6 fot 1mu11a (I R1 CJ=~bNOR'0 2 it) which RIP, R' and R" 2 are defined as previously which, if irequiired, is salified, or if RI represents an aralkyl radical, compound of formula (IA)or (B)is submitted to the action of a cleavage agent, in order to obtain the compound with the formula(I L0 Rl =N OR 2 N (TC)

H

in which R, and R2are defiLned as previously, which, :If required, is salified, and products with the formulae (Id) Or (i13) In which R' represents an aralky). radical or (IC) which, if desired, are subitted to thle action of an alkyl or arilkyl halogenoformate in order ,to obtain a compound with the formula D) 0 00

ID)

In which R 1

R

2 and Z are defined as previously, which, if required, 1i5 salified.

in a preferred mode of real! ing the process of thle Invention -the compound with the formula (III) is used in the form of tile hydrochloride, Hal (in thle compound with thle formlulae R'-Hial or R" 2 -hlal) represents a bromine or Iodine atom, -the hydrogenation agent Is sodium borohydride, -the cleavage agent is alphia-cioroetoxycarbonyl chloride, the hialogenoformate which is used Is a chlloroformate, for example, of ethyl or of benzyl.

The invention also has as its Subject a variant of thle preceding process -haracterized i~n that a compound with thle formula (I'dA)

R

C=NI

011

,A)

in which R" represents an aralkyl radical containing up to 10 carbon atoms and R I retains its previous significance is submitted to the action of a silylation agent, in order to obtain the comp.und with the formula (VII) C NO Si( alk N

(VII)

0 H" 3 15 in which alk 3 represents an alkyl radical containing from 1 to 8 carbon atoms, which is submitted to the action of a cleavage agent, in o order to obtain the compound with the formula (IE)

RI

"-NOH

S0, 20

H

in which R I is defined as previously, which, if required, is salified.

25 In a preferred way of realizing this process R" represents a benzyl radical, the silylation agent is trimethylsilyl chloride, the cleavage agent is alp(ia-chloroethoxycarbonyl chloride.

The invention also has as subject a process for preparing the products with the formula in which Ri and R 2 have the previously tidicated significance and R represents a hydroxyl radical, chqracterized in that a compound with the formula (VII)

N

r ^"¢NORg (viII) 0

PAN

8 is submitted to the action of a reducing agent in order to obtain a compound with the formula (IF):

R.

in which R and R 2 are defined as previously, which, if required, is salified.

In a preferred way of realizing the invention .process: p, the reducing agent is sodium borohydride.

The eventual salification of the products with the formula is carried out according to the usual methods, by making a mineral or organic acid react in sensibly stoichiometric proportions on the said pro- *ducts with the formula (E The compounds with the formula (II) are products known in a general way, which can be prepared tfS according to the process described in the American patent 3,004,979.

The compounds with the formula (VIII) are i products described or obtained according to the process described in J. Het. Chem., 16, 1459, 1979.

The following examples illustrate the invention without, however, limiting it.

Example 1 3-acetyl-l,2,5,6-tetrahydropyridine-oxime and its hydrochloride.

Stage A l-benzyl-3-acetyl-pyridine-oxime bromide.

7.4 g of 3-acetylpyridine oxime is dissolved in 80 cm 3 of ethanol, 8 cm 3 of benzyl bromide is added to it, with heating at reflux for 6 hours. The solvent is eliminated followed by crystallization from an ether/ 9 methanol mixture. 14.21 g of the expected product is obtained. m.p. 200-201 0

C.

Analysis Calculated C% 54.74 H% 4.92 N% 9.12 Found 54.56 4.98 9.07 Stage B l-benzyl-3-acetyl-l,2,5,6-tetrahydropyridineoxime.

13.76 g of the product obtained at stage A in solution in 100 cm of methanol is cooled to 0CC, 2.54 g of sodium hydroboride is added, the whole is allowed to return to ambient temperature and agitated for 45 minutes. After concentrating under reduced t pressure, water is added and extraction is done with chloroform. The organic phase is dried, the solvent is eliminated, and the residue is chromatographed on silica (eluent ethyl acetate toluene After crystallization of the residue fr(oi ethyl acetate, 7.8 g of the expected product is obtained. m.p, 103-105 0

C.

Analysis Calculated C% 73.01 H% 7.88 N% 12,16 I Found 72.74 7.81 12.04 SStage C l-benzyl-3-acetyl-l,2,5,6-tetrahydropyridinetrimethylsilyl oxime.

3.6 g of the product obtained at stage B is S2'9 dissolv .d in 60 cm 3 of benzene and 1.86 g of 1,4i diazabicyo octane, and over 5 minutes, under an inert atmosphere, 2.07 cm of trimethylchlorosilane i! 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.

150'C, under 0.05 mbar) Analysis Cal-4lated C% 67.50 H% 8.66 N% 9.26 Found 67.33 8.59 9.19 I- MEW--~ 4 4 44i404 4 li ii 9a Stage D 3 -acetyl-l,2,5,6-tetrahydropyridine-oxime and its hydrochloride.

Under an inert atmosphere, 20 g of the product obtained as at stage C in solution in 20 cm 3 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, 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 0 C (with decomposition).

Analysis C 7

H

2

N

2 0, HC1 Calculated C% 47.59 H% 7.4. N% 15.86 Found 47.74 7.38 15.78 6,85 g of methoxylamine hydrochloride is added to 10 g 3-acetyl pridne n 5 cm of tnethanoZ aind the whole is heated to eflux for hours. The scolvent is eliminatW~ under reduced pressu the residue is taken up in vrter, alkalized with potassium carbo te and extracted with ethyl acetate. After evaporating, i1 g of th expected product is recovered. 115-118%G under 18 mm Hg). b g f t h e pec t ed P r B :i-methyl 3-acetvl-pyridine-0-pethyl xime chloride.

020.5 g of methyl iodide is added to 11 g of the product obtain~ed 1, at stage A in 110 cm~ of ethyl acetate, Lhe whole is heated to reflux for 3 hours. After cooling, fi tering and crystallizing the 0 product from ethanol, 19.3 g of the xpeizted product is obtained.

15 m.p. 155-157*C.

Stage C :l-methyl-3-acetyl-1, ,5,6-tetraliydropyridine-0-methyloxime and its hydrochloride.

1.7 g of sodium hydr oride is added to a solution of 10 g of che b 9 3 9 product obtained at sta e B in 100 Cm of methanol and the whole is go 20 cooled to fter agitating for 1 hour at ambient temperature, the solvent is eli nated under reduced pressure, and the residue is tknup nwt xrce ihehlehr n vprtdt dryness. Th~ ai stknu ihehlehr itrdo I' ctvaedc rcol ndsaifedwit gseuhyrocloicacd.Th %*25 salt is ndfo itr fiorpnladehlehr and 2 g ofthe xetdpouti band Ip 6-7C Ama ss C 9

H

6

I~

2 afta0 C cdaed C 5280 11% .37 N 1.6 ed .4 3atae. Th is hextated t ex fot8hour, thnd evaoraed and f iredan the sid obaie ir crsalzdfo0ta 46ynesof the expctdu prodkucwth ety obthenrd filpre 199on neh/$ 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-tetrahydrcpyridine-0methyl-oxime.

g of the product prepared at stage A in 3 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 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.

"415 128-130°C. under 0.4 mbar) S. .Analysis Calculated C% 73.74 H% 8.25 N% 11.47 Found 73.56 8.21 11.52 S' Stage C 1-alpha-chloroethoxycarbonyl-3-acetyl-l,2,5,6- 2 0 tetrahydropyridine-0-methyl-oxime.

7.2 g of the product obtained at stage B in 3 solution in 100 cm 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 evaporated off, and 8.44 g of product is obtained which is utilized as it is for the following stage. 210°C under 0.06 mbar).

Analysis Calculated C% 50.68 H% 6.57 N% 10.75 Found 50.86 6.46 10.59 Stage D 3 -acetyl-l,2,5,6-tetrahydropyridine-0-methyloxime and its hydrochloride.

_1 r 12 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 0 C. Using the process of example 2 the expected hydrochloride is obtained.

Analysis Calculated C% 50.39 H% 7.93 N% 14.69 Found 50.31 7.84 14.55 Eample '1 I-methyl-3 -acetyl-l, 2,5 6-ttrahdropyr-in- "0 0-ethyl-oxime and its hydrochloride.

Stage A 3 e3 4.8 cm of 3-acetyl pyridine is dissolved in 50 cm of methanol, to this 4.27 g of orthoet 1 Shydroxylamine hydrochloride is added and the w le is taken to reflux for 3 hours, then cooled and/evaporated to dryness under reduced pressure. The re idue is taken up with water, neutralized with sodium carbonate and Sdextracted with ethyl acetate. The ex acts are dried and concentrated to dryness under r duced pressure.

6.9 g of the expected product, is i tained, utilisable I k for the following stage, m.p. 60-162 0 C, crystallized from an ether-isopropanol mi ure in the form of the I hydrochloride.

23 Stage B l-methyl-3-ace yl-pyridine-0-ethyl-oxime iodide.

A mixture of/5.3 g of the product obtained at 3 stage A and 4.1 cm f methyl iodide is agitated for 8 hours at reflux i 80 cm 3 of ethanol, then distilled to dryness. 9. g of the expected product is obtained.

m.p. 95C, c stallized from an ether-isopropanol mixture.

Stage C methyl-3-acetyl-l,2,5,6-tetrahydropyridine-0ethyl-ox' e and its hydrochloride.

1.7 g of boron and sodium hydride is added to solution of 9.1 g of the product obtained at stage B/n 90 cm 3 of methanol, maintained at 5°C, After 4 1ours at ambient tempcraturc, thic is ovpraed- to r

-Q

13 ness under roducod prczzur. The rciduc taken- upj with water, extracted with ethyl acetate, and con ntrated to dryness under reduced pressure. The resi is taken up with water, extracted with ethyl acet e, and the extracts are concentrated to dryness nder reduced pressure. The residue is chroma graphed on silica gel (eluent chloroform-methano The 3.5 g of oil obtained is dissolved i ether and salified with gaseous hydrochloric acid. /fter evaporating to dryness, 3.7 g of the expecte roduct is obtained. m.p. 186-188 0

C,

recrystall ed from an isopropanol-ether mixture.

Analys Ca ulated C% 54.91 H% 8.76 N% 12.81 54.88 8.94 12.7G i, Example 3 3-acetyl-l,2,5,6-tetrahydropyridine-0-ethyloxime and its hydrochloride.

Stage A bromide.

i 6.9 g of the product obtained at stage A of example 4 is dissolved in 70 cm of ethanol, 6 cm 3 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.

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 the product obtained at stage B of example I and 1.25 cm 3 of bromoethane are added and the whole is taken to reflux for 3 hours, then cooled and concentrated to dryness. 2.84 g of the expected product is obtained, after elution on a column (eluent ethyl acetate toluene, 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, operat- ALi

/U

13a ing as at stage B of example 1, starting with the product obtained at stage A of example Stage C 3-acetyl-l,2,5,6-tetrahydropryidine-0-ethyloxime and its hydrochloride.

2.7 g of the product obtained at stage B is dissolved in 50 cm of dichloroethane, then, at o0C, 1.8 g of alpha-chloroethyl-chloroformate is added; the whole is taken to reflux for 1 hour 30 minutes, then evaporated to dryness and taken up with ether. The insoluble matter is filtered off an'A evaporated to dryness under reduced pressure. The idual oil is taken up with 40 cm 3 o 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 "lIS expected base is isolated and crystallized from an ether- 0i methanol mixture. m.p. 198-199°C (decomposition).

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

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

Stage A l-N-benzyl-3-acetyl-l,2,5,6-tetrahydropyridine- 0-2-propynyl-oxime.

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 401C, the insoluble matter is filtered off, the solvent is evaporated, and the residue is chromatographed on silica (eluent ethyl acetate).

g of the expected product is obtained.

rT S14 Stage B 3-acetyl-1,2,5,6-tetrahydropyridine-0-2-propynyl-oxime and its hydrochloride.

g of the product obtained at stage A is dissolved in 100 cm 3 of dichloroethane. After 1 hour at reflux, the solvent is evaporated, the residue is taken up with ether, the insoluble matter Ls filtered off and the remainder Ls 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 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.

SAnalysis

S

t t Calculated C 55.94 H 7.04 N 13.05 15 Found 55.72 7.01 12.99 -prpynyl-ime and it #Vo ~hydrochloride.

9 Stage A 3-acetyl-pyridine-0-2-propynyl oxime.

g of 3-acetyl-pyridine is dissolved in 20 cm 3 of water, 3 5 g 20 of sodium bicarbonate and 4.45 g of ortho-2-propynyl-hydroxy mine hydrochloride in 30 cm 3 of water are added, and the mixt e is left for 16 hours, then heated for 3 hours at 40°C. After concetrating, it is rir; extracted with ethyl acetate, the extracts are ev orated to dryness and purified on silica gel (eluent ethyl aceta 5.7 g of the expected product is obtained. m.p. 156-157°C., recr tallized from isopropanol.

Stage B l-N-methyl-3-acetyl-pyridine- -2-propynyl-oxime iodide.

S5.6 g of product obtained at d ge A is dissolved in 60 cm of methanol and 8.6 g of methyl io de is added. After 3 hours of reflux, and evaporating to dryness, e residue is taken up with a mixture of acetone and ether and fi ered. 9.7 g is obtained, m.p. 150-151 0

C

recrystallized from iopropanol.

Stage C l-methy 3-acetyl-tetrahydropyridine-0-2-propynyl-oxime and its hydrochloride 9.7 of product obtained at stage B is dissolved in 100 cm 3 of methan and 2.35 g of boron and sodium hydride is added at 0OC.

Af r 1 hour at 0° C, then evaporating, the residue is taken up with .8ter and extracted with ethyl azctaet. The zitraets Fira dri.old and 1.1 4 C~0 0i1 'evaperated te dryness3. The residde is salified in e -h with gaseous hydrochloric acid, and 2.7 g of t'expected product is obtained. m.p. 195-l96* ecrystallized from an isopropanol-ether ure.

Analysis: C H -1 HCI.

Calcua C 57.76 H% 7.49 N% 12.25 onund 5 7.59 7.30 i2.11 Examplo :5 3-propionyl-1,2,5,6-tetrahydropyridine-oxime and its hydrochloride.

0Stage A 1-N-benzyl-3-propionyl-pyridine-oxime bromide.

A mixture of 17.8 g of 3-propionyl pyridine 4; oxime [US Patent 3,004,979 (1961)] and 18 cm"- of benzyl bromide is maintained at reflux for 7 hours 30 minutes in 250 cm 3 of ethyl acetate. After cooling and separating, 36.5 g of the expected product is obtained. m.p.

178-180 0 C, recrystallized from an ethanoJ.-ether mixture.

Stage B 1-N-benzyl-3-propionyl-1,2,5,,6-tetrahydropyridine-oxime.

000 36.2 g of product obtained at stage A is .0.0 dissolved in 250 cm of methanol, and the tempe.--.ture is maintained at 10 0 C while 6.4 g of boron and sodium 06.* 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.

2 The extracts are dried and the solvent i.s 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 0 C, recrystallized from ethyl acetate.

3 G, StagyeC 1-N-benzyl-3-propionyl1,2,5,6-tetrahydropyridine-0-trimethyl-silyl-oxime.

6 g of the product obtained at stage B, cm 3 of benzene aad 2.95 g of 1,4-diazabiqyclo[2.2.2.] octane are mixed -together. 3.23 cm 3 of trimethylsilyl chloride is added., and the whole is taken to reflux for 3 hours, then cooled. The insoluble matter is T

I/

filtered off, the 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. 250°C under 0.06 mbar).

Stage D 3-propionyl-l,2,5,6-tetrahydropyridine oxime and its hydrochloride.

16 g of the product obtained at stage C is dissolved in 150 cm of dichloroethane, and after cooling to 0°C, 16.2 g of alpha-chloroethyl chloroformate is added and the whole is maintained at reflux for 4I 0 S 4 SI 4 I #4 4 i i l I 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 3 of methanol, and taken to reflux for 6 hours. The methanol is evaporated off, and the remainder is purified by passage 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 0

C.

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

10 Analysis CH 14

N

2 0, HC1.

,Calculated C 50.39 H 7.93 N 14.69 Found 50.08 7.87 14.48 Example 6; 3-propionyl-1,2,5,6-tetrahydropyridine-0-methyl-oxime and its hydrochloride.

15 Stage A l-N-benzyl-3-propionyl-l,2,5,6-tetrahydropyridine-0-methyloxime.

6.11 g of the product obtained at stage B of example 8 is added to a solution of 1.2 g of sodium in 80 cm of ethanol. 1.58 cm of aoo 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 is chromatographed (eluent ethyl acetate toluene so obtaining 2.5 g of the expected product. 170°C at 0.05 mbar).

Stage B 3-propionyl-1,2,5,6-tetrahydropyridine-0-methyl-oxime and its hydrochloride.

g of product from stage A is dissolved in 50 cm 3 of chloroethane, and at 0 0 C, 2.04 g of alpha-chloroethyl chloroformate is added. After 3 hours at reflux, the -ilvent is evaporated off, the residue is taken up with ether, filtered and evaporated to dryness.

The residue is taken up with 30 cm 3 of methanol and taken to reflux for 30 minutes, than evaporated to dryness. The residue is recrystallized from a mixture of ethanol and ether, and 1.17 g of the expected pi:oduct is obtained. m.p. 210-2120C.

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

Analysis C 9 1 6

N

2 0, HC1.

Calculated C 52.53 H 8.26 N 13.56 /71 F,und 52.80 8.37 13.68 7 i

I,

4 1 17 Examples of pharmaceutical compositions a) Tablets have been prepared answering to the following Formula Product of example 3 200 mg Excipient q.s. for a tablet finished at 300 mg (Detail of excipient lacLose, 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 q S (Detail of excipient talc, magnesium stearate, aerosil).

c) Tablets have been prepared answering to the following formula Product "of example 2 50 mg .t 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 e Product of example 12 50 mg Excipient q.s. for a capsule terminated at 300 mg (Detail of excipient lactose, corn starch, treated starch, r 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 1 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.

1 1 Product of example I LD 5 0 in mg/kg

II-

1 I 2 I 1 3 12 S Arecoline HBr I

II

350 350 125 175 600 n x g 5

T

I 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 3 of Tyrode's solution at 37°C nd aerated with a mixture of oxygen (95 and carbon 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~ 3 M/1 and 1.10- 8

M/I.

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

The agonist activity is expressed in pD 2 (negative logarithm of 4 the dose which produces 50 of the maximum effect.

9 f Example pD 2 9 9 "1 I 5.25 2 I 4.85 3 I 7.50 I 12 5.39 I SArecoline 6.48 I 9I Diarrhoeic activity.

The test is carried out on male mice (CD 1 Charles Rivers) weighing 25 to 30 g, fasting for 6 hours. The product dissolved at 5 in metliocel is administered by oral route, by m, ns 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 p4,per are changed after each observation.

The consistency of the feces is evaluated according to the method of Randall and Baruth (arch. Into Pharmacodyn. 220, 94, l976, and pi/ according to the following scale of values 0-:firm consistency I1 feces slightly soft with or without humid aureola.

2 :feces slightly soft with presence of a well defined humid circle.

43 :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 dlose was noted which caused a diarrhoea in of the animals according to the method of Miller and Tainter (Proc. Soc. Exp. Biol. Med. 57, 261, 1944).

EI xample IED 0 in mg/kg I 2 I 100 I 3 0.85 9 12 I1 lArecolinel 440 004 Hypothermic activity The test is carried out on male mice (CD, Charles Rivers), 00 0 0 O 25 weighing 25 30 g, fasting for 6 hours.

The temperature of the body is noted by means of a thermocouple plhaced 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 Q and 30 minutes, I hour, 2 hours and 2-and-a-half hours after treatment.

The degree of hypothermia is evaluated as the difference betweeni the treated animals and the controls, and the dose necessary to reduce the body temperature by 1"C. is determined.

I I Example I Effective dose Ja i/kg I per os I I 9 1Li I 2 L2 I 25. 1 3 0.87 I j 12 0.77 I 0.72 lArecoline 1 194 1 3 The duration of action of the products has been evaluated by using the .dose which reduces the body temperature by 1 to VARIATION OF TIHE BODY TEMPERATURE Product of I Dose I Admin. Tines In minutes after treatment I extample ting/kg Irout'1 0 30 60 120 180 i ii I_ I_ I I II 1I 10 I plo. I 0 I -0.7 I -1.0 I -0.2 I+ +01 I i I t0 I I I -0.6 I -0.8 I -0.2 0 I I: I I I III 2 I 2 I p.o. +0 1. -1.3 I -1.3 j -0.9 I 0 I .1 I 4O I s.c I +0.1 I -1.0 I -4 1.1 -0.8 I I: I I: I I II '1 3 I i I p I +o4 I I 0 I -o.t I~t I I 1 I s.c. I I 4.o I -0.8 I+01 1 +0.1 I I I I I I II I 12 I 1, I P0 I I *:t3 I I 0 I o i I 1 I -0.1 -1.4 -1.3 0 1 I I II i Acecoline 1 200 p.co. I -1t I i .0 I -0.2 I I wr 3-5 I s c 0 I -04 1 -1.5 -0.1 1 +0.2 4 -0.2 I LJ 1_ I I "9 ,t I

Claims

1. Compounds with the formula RI J" _C=NOR2 (I) [i j, R in which R represents hydrogen, R 1 represents a linear, branched or cyclic, alkyl, alkenyl or alkynyl contabinng up to 8 carbon atoms and R 2 represents a hydrogen :atom or a linear or branched, alkyl, alkenyl or alkynyl containing up to 8 carbon atoms, COalk 1 radical or (CH 2 N(alk 2 2 alk 1 and alk 2 representing an alkyl 2 2 containing up to 8 carbon atoms, as well as their pharmaceutically acceptable addition salts with adds.

2. Compounds with the formula as defined in Claim 1, in which R. represents a hydrogen atom, as well as pharmaceutically their addition salts with I I t I P adds,

3. Compounds with the formula as defined in Claim 1 or Claim 2, in which R 2 represents an alkyl radical containing from 1 to 4 carbon atoms, and notably a methyl radical.

4. 3-acetyl-l,2,5,6-tetrahydropyridine-O-methyl-o: ime and its hydrochloride. Compounds with the formula substantially as herein described with I reference to any one of the Examples. a -22-

6. Process for the preparation of the products with the formula in which R 1 and R 2 have the significance previously indicated and R has the significance previously indicated, characterized in that a compound with the formula (II): 0 II Q C-R 1 Ti in which R 1 retains the same significance as previously, is submitted to the action of a compound with the formula NH 2 OR' 2 (M) or one of its salts, in which R 2 represents a hydrogen atom or a linear or o branched, saturated or unsaturated, alkyl radical containing up to 8 carbon atoms, in order to obtain the compound with the formula R 1 C=NOR' 2 (IV) which is submitted to the action of an zdkyl halide with the formula 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, celiorU substituted by a free or esterified carboxy radical or R' zepresents an aralkyl radical containing up to 10 carbon atoms, in order to obtain the compound -23- with the formula (VI): SC=NOR' 2 (VI) N R' Hal" which is submitted to the action of a hydrogenation agent, in order to obtain the compound with the formula (IA): R 1 r N RC=NOR' 2 (A) salified, or, if R' represents a hydrogen atom, is submitted to the action of a compound with the formula: R"f-Hal in which Hal represents a halogen atom and R" 2 represents a radical COalk 1 or a radical )N(Alk 2 2 alk and alk being dfined as previously, in order to radical -(CH2)N(Alk2)2, alk 1 and alk 2 being defined as previously, in o):der to -24 obtain the corresponding compound with the formula (IB): RI C=NOR" (IB) I R' in which R 1 R' and R" 2 are defined as previously which, if required, is saified, or, if R' represents a aralkyl radical, compound of formula (IA) or is submitted to the action of a cleavage agent, in order to obtain the compound with the formula (Ic): C=NOR2 (Ic) N in which R 1 and R 2 are defined as previously, which, if required, is salified, and products with the formilae (IA) or (Ig) in which R' represents an aralkyl radical or (Ic) which, if desired, are submitted to the action of an alkyl or aralkyl halogenoformate in order to obtain a compound with the formula (ID): R l SC=NOR 2 (ID) N cooz in which R 1 R 2 and Z are defined as previously, which, if required, is salified. 44' 25

7. Variant of the process according to Claim 6, characterized in that a compound with the formula C=NOH (IA) in which R" represents an aralkyl radical containing up to 10 carbon atoms and R 1 retains its previous significance is submitted to the action of a silylation agent, in order to obtain the compound with the formula (VII): R SC=NOSi(alk 3 3 (VII) 0 R" in which alk 3 represents an alkyl radical containing from 1 to 8 carbon atoms, which is submitted to the action of a cleavage agent, in order to obtain the compound with the formula (IE): R, i* I C=NOH (IE) N H in which R 1 is defined as previously, which, if required, is salified.

26- 8. Process for the preparation of the products with the formula which process is substantially as herein described with reference to any one of the Examples. 9. Product whenever prepared by the process of any one of claims 6 to 8. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 9 together with a suitable carrier, adjuvant and/or diluent. 0 o DATED this 14th day of March 1991. 0 0 B CP G 00 ROUSSEL-UCLAF o By their Patent Attorneys: S°0o CALLINAN LAWRIE 0 a a a u a «a 0* O tt nr