DK167758B1

DK167758B1 - 1,2,5,6-TETRAHYDROPYRIDINE DERIVATIVES, PROCEDURES FOR THEIR PREPARATION, AND MEDICINAL PRODUCTS CONTAINING THEREOF

Info

Publication number: DK167758B1
Application number: DK216388A
Authority: DK
Inventors: Fernando Barzaghi; Carla Bonetti; Giulio Galliani; Emilio Toja
Original assignee: Roussel Uclaf
Priority date: 1987-04-24
Filing date: 1988-04-21
Publication date: 1993-12-13
Also published as: IT8720260A0; DE3874396T2; ES2043863T3; IT1203971B; JP2727192B2; EP0288394A2; IE881207L; PT87290B; FI881892A; DE3874396D1; IE63172B1; DK216388D0; IL86157A0; KR960012365B1; NZ224357A; KR890016009A; AU1511188A; SU1678203A3; FI881892A0; HU199795B

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

DK 167758 B1DK 167758 B1

Opfindelsen angår hidtil ukendte derivater af 1,2,5,6-tetrahydropyridin og salte heraf, en fremgangsmåde til deres fremstilling og lægemidler med indhold heraf.The invention relates to novel derivatives of 1,2,5,6-tetrahydropyridine and their salts, to a process for their preparation and to drugs containing them.

Opfindelsen angår forbindelser med formlen (I) samt deres additionssalte med syrer 5 I1 j^J-C=N0R2 (I)The invention relates to compounds of formula (I) as well as their addition salts with acids.

RR

10 hvor R betegner et hydrogenatom, en hydroxylgruppe, en lineær eller forgrenet, mættet eller umættet alkylgruppe med indtil 8 carbonatomer, eller R betegner en cykloalkylgruppe med indtil 8 carbonatomer eller en aralkylgruppe med indtil 10 carbonatomer, R-j betegner en lineær eller forgrenet, mættet eller umættet alkylgruppe med indtil 8 carbonatomer eller en cykloalkyl-15 gruppe med indtil 8 carbonatomer, og R2 betegner et hydrogenatom eller en lineær eller forgrenet, mættet eller umættet alkylgruppe med indtil 8 carbonatomer, dog må R2 ikke betegne et hydrogenatom, når R betegner en alkylgruppe.Wherein R represents a hydrogen atom, a hydroxyl group, a linear or branched, saturated or unsaturated alkyl group of up to 8 carbon atoms, or R represents a cycloalkyl group of up to 8 carbon atoms or an aralkyl group of up to 10 carbon atoms, R 2 represents a linear or branched, saturated or unsaturated alkyl group having up to 8 carbon atoms or a cycloalkyl group having up to 8 carbon atoms, and R2 represents a hydrogen atom or a linear or branched, saturated or unsaturated alkyl group having up to 8 carbon atoms, however, R2 must not represent a hydrogen atom when R represents an alkyl group .

Blandt additionssaltene med syrer kan især nævnes sådanne, som dannes med mineralsyre, 20 som f.eks. saltsyre, hydrogenbromid, svovlsyre eller phosphorsyre eller sådanne, der dannes med organiske syrer, som f.eks. myresyre, eddikesyre, propionsyre, benzoesyre, maleinsyre, fumarsyre, ravsyre, vinsyre, citronsyre, oxalsyre, glyoxylsyre, asparaginsyre, alkansulfonsyre, som f.eks. methan- eller ethansulfonsyre, arylsulfonsyre, som f.eks. benzen- eller para-toluen-sulfonsyre.In particular, among the addition salts with acids are those formed with mineral acid, such as e.g. hydrochloric acid, hydrogen bromide, sulfuric acid or phosphoric acid or those formed with organic acids such as e.g. formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkanesulfonic acid, e.g. methane or ethanesulfonic acid, arylsulfonic acid, e.g. benzene or para-toluene sulfonic acid.

25 Når R, R1 eller R2 betegner en mættet, lineær eller forgrenet alkylgruppe, drejer det sig fortrinsvis om en methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, sec.-butyl, iso-butyl-, n-pentyl-eller en n-hexylgruppe.When R, R 1 or R 2 represent a saturated, linear or branched alkyl group, it is preferably a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, iso-butyl, , n-pentyl or an n-hexyl group.

30 Når R, R-j eller R2 betegner en umættet alkylgruppe, drejer det sig fortrinsvis om en alkenyl-gruppe som f.eks. en allyl- eller en 1,1-dimethylallylgruppe, eller om en alkynylgruppe som f.eks. en ethynyl- eller propynylgruppe.When R, R 1 or R 2 represent an unsaturated alkyl group, it is preferably an alkenyl group such as e.g. an allyl or a 1,1-dimethylallyl group, or an alkynyl group such as e.g. an ethynyl or propynyl group.

Når R eller R-j betegner en cykloalkylgruppe, drejer det sig fortrinsvis om en cyklopropyl-, 35 cyklobutyl-, cyklopentyl- eller en cyklohexylgruppe.When R or R-j represents a cycloalkyl group, it is preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

Når R betegner en aralkylgruppe, drejer det sig fortrinsvis om en benzylgruppe.When R represents an aralkyl group, it is preferably a benzyl group.

Nærbeslægtede forbindelser, især 1-methyl-4-acetyi-1,2,5,6-tetrahydropyridinoxim, er forbin- bindelser, som er velkendt for deres parasympatomimetiske egenskaber (vedrørende dette emne se det amerikanske patentskrift nr. 3.004.979).Related compounds, especially 1-methyl-4-acetyl-1,2,5,6-tetrahydropyridine oxime, are compounds that are well known for their parasympathomimetic properties (for this subject see U.S. Patent No. 3,004,979).

22

UK ΙΟ//DO D IUK ΙΟ // DO D I

5 Forbindelserne ifølge opfindelsen frembyder i forhold til disse kendte forbindelser helt uventede farmakologiske egenskaber, som er meget interessante, hvilket fremgår af resultaterne af de biologiske undersøgelser, som sammenfattes nedenfor i den eksperimentelle del.The compounds of the invention, in relation to these known compounds, offer totally unexpected pharmacological properties which are very interesting, as can be seen from the results of the biological studies summarized below in the experimental part.

Opfindelsen angår især forbindelser med formlen (I), hvor R-j betegner en lineær alkylgruppe 10 med fra 1-4 carbonatomer, f.eks. en methylgruppe.The invention relates in particular to compounds of formula (I) wherein R 1 represents a linear alkyl group 10 having from 1 to 4 carbon atoms, e.g. a methyl group.

Blandt opfindelsens foretrukne forbindelser kan nævnes de forbindelser med formlen (I), såvel som deres additionssalte med syrer, hvor R betegner et hydrogenatom, og disse hvor R betegner en hydroxylgruppe, og disse hvor R betegner en lineær eller forgrenet, mættet eller umæt-15 tet alkylgruppe med fra 1-4 carbonatomer som f.eks. en methyl-, ethyl-, propyl- eller allyl-gruppe.Among the preferred compounds of the invention are those compounds of formula (I), as well as their addition salts with acids wherein R represents a hydrogen atom and those wherein R represents a hydroxyl group and those wherein R represents a linear or branched, saturated or unsaturated group. a alkyl group having from 1 to 4 carbon atoms, e.g. a methyl, ethyl, propyl or allyl group.

Man kan yderligere nævne de forbindelser med formlen (I), hvor R2 betegner et hydrogenatom samt forbindelser, hvor R2 betegner en alkylgruppe med fra 1-4 carbonatomer og især en 20 methylgruppe.One may further mention those compounds of formula (I) wherein R 2 represents a hydrogen atom as well as compounds wherein R 2 represents an alkyl group having from 1-4 carbon atoms and especially a methyl group.

Opfindelsen angår naturligvis i særdeleshed de forbindelser, hvis fremstilling anvises nedenfor i den eksperimentelle del, og ganske særligt forbindelserne i eksempel 2,3 og 12.Of course, the invention relates in particular to the compounds of which the preparation is set forth below in the experimental part, and in particular to the compounds of Examples 2,3 and 12.

25 Forbindelserne ifølge opfindelsen udviser ved oral indgift en vigtig cholinomimetisk aktivitet med en lang virkningstid.The compounds of the invention exhibit an important cholinomimetic activity with a long duration of action upon oral administration.

Forbindelserne udviser endvidere en kraftig adskillelse mellem den centrale og den perifere aktivitet, hvilket fremgår af resultaterne i de nedenfor beskrevne undersøgelser.Furthermore, the compounds exhibit a strong separation between the central and the peripheral activity, as evidenced by the results of the studies described below.

3030

Testen med ileum isoleret fra marsvin viser den perifere cholinergiske aktivitet, mens testen med den hypotermiske effekt viser den centrale cholinergiske aktivitet.The test with ileum isolated from guinea pigs shows the peripheral cholinergic activity, while the hypothermic effect test shows the central cholinergic activity.

Gyldigheden af den cholinergiske hypotese ved behandlingen af Alzheimers syge er velkendt, 35 se f.eks. R.T. Bartus et al i Science, 217, 208,1982 og E. Hollander et al i Brit. Med. Bull., 42, 97,1986.The validity of the cholinergic hypothesis in the treatment of Alzheimer's disease is well known, see e.g. R.T. Bartus et al in Science, 217, 208, 1982 and E. Hollander et al in Brit. With. Bull., 42, 97, 1986.

DK 167758 B1 3DK 167758 B1 3

Opfindelsen angår altså forbindelser, som er nyttige især i behandlingen af Alzheimers syge eller senildemens og ligeledes i behandlingen af hukommelsessvigt.The invention thus relates to compounds which are useful especially in the treatment of Alzheimer's disease or senile dementia and also in the treatment of memory failure.

Det er velkendt, at indlærings- og hukommelsesproblemer hos ældre mennesker især skyldes 5 en svigten i det centrale cholinergiske system, i særdeleshed hvad angår senildemens og Alzheimers syge.It is well known that learning and memory problems in older people are mainly caused by a failure of the central cholinergic system, especially with regard to senile dementia and Alzheimer's disease.

Det er således indlysende, at forbindelser med en central cholinergisk virkning kan anvendes i den terapeutiske behandling af disse sygdomme (Bartus, R.I., Science, 217,408,1982).Thus, it is obvious that compounds with a central cholinergic effect can be used in the therapeutic treatment of these diseases (Bartus, R.I., Science, 217,408, 1982).

1010

Det er vist, at arecolin indgivet ad intravenøs vej har en positiv effekt på patienter med hukommelsessvigt (Sitaram, N. et al, Science, 201, 274, 1978; Christie, JLE. et al, Brit. J. Psychiatry, 138, 46,1981).Arecoline administered intravenously has been shown to have a positive effect on patients with memory impairment (Sitaram, N. et al., Science, 201, 274, 1978; Christie, JLE. Et al, Brit. J. Psychiatry, 138, 46 , 1981).

15 En begrænsning i den terapeutiske anvendelse af arecolin skyldes, at denne forbindelse ved oral indgift har en meget svag aktivitet og en kort virkningstid.A limitation in the therapeutic use of arecoline is due to the fact that this compound on oral administration has a very weak activity and a short duration of action.

Forbindelserne ifølge opfindelsen frembyder ved oral indgift en central cholinomimetisk aktivitet, som er bedre end arecolins og med en meget længere virkningstid.The compounds of the invention present by oral administration a central cholinomimetic activity which is superior to arecolin and with a much longer duration of action.

2020

Den dosering, som skal anvendes, afhænger af den pågældende lidelse, den pågældende patient og administrationsvejen, den kan være mellem 50 mg og 300 mg/dag, f.eks. for forbindelsen i eksempel 3 indgivet ad oral vej mellem 15 og 150 mg/dag i en eller flere doser.The dosage to be used depends on the disorder in question, the patient concerned and the route of administration, it may be between 50 mg and 300 mg / day, e.g. for the compound of Example 3 administered orally between 15 and 150 mg / day in one or more doses.

25 Den foreliggende opfindelse angår ligeledes farmaceutiske præparater, der som aktivt stof indeholder mindst en af forbindelserne med formlen (I). De farmaceutiske præparater ifølge opfindelsen kan være faste eller flydende og forefindes på en i human medicin almindelig brugt form, som f.eks. tabletter med eller uden overtræk, geiatinekapsler, granulater, suppositorier eller injektionspræparater, der fremstilles ved gængse metoder. Det aktive stof eller de aktive 30 stoffer kan inkorporeres i bindemidler, som normalt anvendes i disse farmaceutiske præparater, f.eks. talkum, gummi arabicum, lactose, stivelse, magnesiumstearat, kakaosmør, med bærestoffer, der er vandige eller ikke, animalske eller vegetabilske fedtstoffer, paraffinderivater, glycoller, diverse fugtemidler, dispergeringsmidler eller emulgeringsmidler, konserveringsmidler.The present invention also relates to pharmaceutical compositions containing as active ingredient at least one of the compounds of formula (I). The pharmaceutical compositions of the invention may be solid or liquid and are in a form commonly used in human medicine, such as e.g. tablets with or without coatings, geiatin capsules, granules, suppositories or injection preparations prepared by conventional methods. The active substance (s) may be incorporated into binders normally used in these pharmaceutical compositions, e.g. talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, with aqueous or non-carrier substances, animal or vegetable fats, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

Opfindelsen angår ligeledes en fremgangsmåde til fremstilling af forbindelser med formlen (I), hvor R-j og R£ har samme betydning som tidligere nævnt, og R har samme betydning som 35 UIV I0//00 Dl 4 tidligere nævnt med undtagelse af en hydroxygruppe, hvilken fremgangsmåde er ejendommelig ved, at man laderen forbindelse med formlen (II): 0 5 r^jrc-R i (Π)The invention also relates to a process for the preparation of compounds of formula (I) wherein R 1 and R 2 have the same meaning as previously mentioned and R has the same meaning as previously mentioned except for a hydroxy group which The process is characterized in that the charger is compound of formula (II): 0 5 r ^ jrc-R in (Π)

^IT^ IT

hvor R-( betyder det samme som tidligere nævnt, reagere med en forbindelse med formlen (III): 10 NH2OR2 (III) elleret salt heraf, hvor R2 betegner det samme som tidligere nævnt, under dannelse af forbindelsen med formlen (IV): 15 - (IV) 20 som man lader reagere med et alkylhalogenid med formlen (V): R'-Hal (V) 25 hvor Hal betegner et halogenatom, og R' betegner en lineær eller forgrenet, mættet eller umættet alkylgruppe med indtil 8 carbonatomer, eller R' betegner en cykloalkylgruppe med indtil 8 carbonatomer eller en aralkylgruppe med indtil 10 carbonatomer, under dannelse af en forbindelse med formlen (VI): 30 R.j f>C=MRz y (vi) R' ©Hal© 1 som man lader reagere med et hydrogeneringsmiddel under dannelse af en forbindelse med formlen (IA): 5 DK 167758 B1 I1 |^Vc=NOR2wherein R- (means the same as previously mentioned, react with a compound of formula (III): NH 2 OR 2 (III) or the salt thereof, wherein R 2 represents the same as previously mentioned, to give the compound of formula (IV): 15 - (IV) 20 which is reacted with an alkyl halide of formula (V): R 1 -Hal (V) 25 wherein Hal represents a halogen atom and R 'represents a linear or branched, saturated or unsaturated alkyl group having up to 8 carbon atoms, or R 'represents a cycloalkyl group of up to 8 carbon atoms or an aralkyl group of up to 10 carbon atoms, to give a compound of formula (VI): 30 R f = C = MR 2 y (vi) R' © Hal © 1 to which one is reacted with a hydrogenating agent to give a compound of formula (IA): 5 V 16 = NOR2

s J <Ws J <W

R· 10 hvor R', R-j og R 2 er defineret som tidligere, som man, om ønsket, omdanner ti! et salt.R · 10 where R 1, R 1 and R 2 are defined as before, which, if desired, converts ten! a salt.

Opfindelsen foretrækkes udført på følgende måde: - forbindelsen med formlen (III) bruges I form af sit hydrochlorid, - Hal (i forbindelsen med formlen R'-Hal) betegner et brom eller iodatom, 15 - hydrogeneringsmidlet er natriumborhydrid,The invention is preferably carried out as follows: - the compound of formula (III) is used in the form of its hydrochloride, - Hal (in the compound of formula R'-Hal) represents a bromine or iodine atom, - the hydrogenating agent is sodium borohydride,

Opfindelsen angår ligeledes en variant af den tidligere beskrevne fremgangsmåde, som er ejendommelig ved, at man lader en forbindelse med formlen (TA): 20 (fV=N0H (ΓΑ> R" 25 hvor R" betegner en aralkylgruppe med indtil 10 carbonatomer, og R-j har samme betydning som hidtil, reagere med et silyleringsmiddel under dannelse af en forbindelse med formlen (VII): I1 OC=N0SKalc313 (VII) R" hvor alC3 betegner en alkylgruppe med fra 1-8 carbonatomer, som man lader reagere med et 35 spaltningsmiddel under dannelse af en forbindelse med formlen (IE):The invention also relates to a variant of the previously described process which is characterized by leaving a compound of formula (TA): 20 (fV = NOH (ΓΑ> R "25 where R" represents an aralkyl group having up to 10 carbon atoms) and R 1 has the same meaning as heretofore, reacting with a silylating agent to give a compound of formula (VII): 11 OC = NOScalc313 (VII) R "where alC3 represents an alkyl group having from 1-8 carbon atoms which is reacted with a cleaving agent to form a compound of formula (IU):

L/IY ΙΌ// 90 D IL / IY ΙΌ // 90 D I

6 I16 I1

OrN0H σΕ>OrN0H σΕ>

XNTXNT

5 H5 H

hvor R-j har samme betydning som tidligere, som man, om ønsket, omdanner til et salt.wherein R-j has the same meaning as before, which, if desired, is converted to a salt.

I en foretrukken udførelsesform en 10 - R" en benzylgruppe, - silyleringsmidlet trimethylsilylchlorid, - spaltningsmidlet a-chlorethoxycarbonylchlorid.In a preferred embodiment, a 10 - R "a benzyl group, - the silylating agent trimethylsilyl chloride, - the decomposing agent α-chloroethoxycarbonyl chloride.

Opfindelsen angår ligeledes en fremgangsmåde til fremstilling af forbindelser med formlen (I), 15 hvor R-j og R2 har samme betydning som tidligere, og R betegner en hydroxygruppe, hvilken fremgangsmåde er ejendommelig ved, at man lader en forbindelse med formlen (VIII): I1 f^J-C=NOR2 20 (VIII)The invention also relates to a process for the preparation of compounds of formula (I), wherein R 1 and R 2 have the same meaning as before, and R represents a hydroxy group which is characterized by leaving a compound of formula (VIII): I 1 f JC = NOR2 (VIII)

OISLAND

hvor Ri og R2 har samme betydning som tidligere nævnt, reagere med et reduktionsmiddel 25 under dannelse af en forbindelse med formlen (lp): I1 r^Tc=N0R2 dF)wherein R 1 and R 2 have the same meaning as previously mentioned, react with a reducing agent 25 to give a compound of formula (Ip):

NrNo

30 °H30 ° H

hvor Ri og R2 har samme betydning som tidligere, som man, om ønsket, omdanner til et salt.wherein R 1 and R 2 have the same meaning as before, which, if desired, is converted to a salt.

I en foretrukken udførelse af fremgangsmåden ifølge opfindelsen er reduktionsmidlet natrium-35 borhydrid.In a preferred embodiment of the process according to the invention, the reducing agent is sodium borohydride.

7 DK 167758 B17 DK 167758 B1

Den eventuelle omdannelse til et salt af forbindelsen med formlen (I) udføres på sædvanlig vis, idet man lader en mineralsk eller organisk syre reagere med den pågældende forbindelse med formlen (I) i støkiometriske mængder.The optional conversion to a salt of the compound of formula (I) is carried out in the usual manner by reacting a mineral or organic acid with the compound of formula (I) in stoichiometric amounts.

5 Forbindelserne med formlen (II) er velkendte forbindelser, som kan fremstilles ved den fremgangsmåde, som er beskrevet i det amerikanske patentskrift nr. 3.004.979.The compounds of formula (II) are well known compounds which can be prepared by the process described in U.S. Patent No. 3,004,979.

Forbindelserne med formlen (VIII) er forbindelser, som fremstilles ved en metode, som er beskrevet i J. Het. Chem., 16,1459, (1979).The compounds of formula (VIII) are compounds prepared by a method described in J. Het. Chem., 16.1459, (1979).

1010

Eksempel 1:3-acetyl-1,2,5,6-tetrahydropyridinoxim og hydrochloridet herafExample 1: 3-Acetyl-1,2,5,6-tetrahydropyridine oxime and its hydrochloride

Trin A: l-benzyl-3-acetylpyridinoximbromidStep A: 1-Benzyl-3-acetylpyridinoxime bromide

Man opløser 7,4 g 3-acetylpyridinoxim i 80 ml ethanol, tilsætter 8 ml benzylbromid og opvarmer med tilbagesvaling i 6 timer. Opløsningsmidlet fjernes, og der udkrystalliseres i en ether-15 methanol-blanding. Man får 14,21 g af den ventede forbindelse. Smp. = 200-201 °C.7.4 g of 3-acetylpyridine oxime are dissolved in 80 ml of ethanol, 8 ml of benzyl bromide is added and refluxed for 6 hours. The solvent is removed and crystallized in an ether-methanol mixture. 14.21 g of the expected compound are obtained. Mp. = 200-201 ° C.

Analyse:Analysis:

Beregnet: C% 54,74 H% 4,92 N% 9,12Calculated: C% 54.74 H% 4.92 N% 9.12

Fundet: 54,56 4,98 9,07 20 Trin B: 1-benzyl-3-acetyl-1,2,5,6-tetrahydropyridinoxim.Found: 54.56 4.98 9.07 Step B: 1-Benzyl-3-acetyl-1,2,5,6-tetrahydropyridine oxime.

13,76 g af den i trin A opnåede forbindelse opløst i 100 ml methanol afkølestil 0 °C, der tilsættes 2,54 g natriumborhydrid, man lader temperaturen stige til stuetemperatur og omrører i 45 min. Man opkoncentrerer ved formindsket tryk, tilsætter vand og ekstraherer med chloroform. Den organiske fase tørres, opløsningsmidlet fjernes, det resterende stof chromatografe-25 res på silica (elueringsmiddel: ethylacetat-toluen: 8-2), og man får efter udkrystallisering af det resterende stof i ethylacetat 7,8 g af den ventede forbindelse. Smp. = 103-105 eC.13.76 g of the compound obtained in step A dissolved in 100 ml of methanol cool to 0 ° C, add 2.54 g of sodium borohydride, allow the temperature to rise to room temperature and stir for 45 minutes. Concentrate at reduced pressure, add water and extract with chloroform. The organic phase is dried, the solvent is removed, the residue is chromatographed on silica (eluent: ethyl acetate-toluene: 8-2) and after crystallization of the residue in ethyl acetate 7.8 g of the expected compound are obtained. Mp. = 103-105 AD.

Analyse:Analysis:

Beregnet: C% 73,01 H% 7,88 N% 12,16Calculated: C% 73.01 H% 7.88 N% 12.16

Fundet: 72,74 7,81 12,04 30Found: 72.74 7.81 12.04 30

Trin C: 1-benzyl-3-acetyl-1,2,5,6-tetrahydropyridintrimethylsilyloxim.Step C: 1-Benzyl-3-acetyl-1,2,5,6-tetrahydropyridine trimethylsilyloxime.

Der opløses 3,6 g af den i trin B fremstillede forbindelse og 1,86 g af 1,4 diazabicyklo-(2.2.2)-octan i 60 ml benzen, og der tilsættes i løbet af 5 min. under inert atmosfære 2,07 ml trimethyl-chlorsilan. Opslemningen opvarmes med tilbagesvaling i tre timer, afkøles, filtreres og ind-35 dampes til tørhed. Det resterende stof genopløses i diethylether, filtreres, opløsningsmidlet fjernes under reduceret tryk, og man får 4,5 g af den ventede forbindelse. Kp.: 150 eC/0,05 mbar).3.6 g of the compound prepared in step B is dissolved and 1.86 g of 1.4 diazabicyclo- (2.2.2) -octane in 60 ml of benzene and added over 5 minutes. under inert atmosphere 2.07 ml of trimethyl chlorosilane. The slurry is heated at reflux for three hours, cooled, filtered and evaporated to dryness. The residue is redissolved in diethyl ether, filtered, the solvent is removed under reduced pressure to give 4.5 g of the expected compound. Bp: 150 eC / 0.05 mbar).

UK I O//08 D IUK I O // 08 D I

88

Analyse:Analysis:

Beregnet: C% 67,50 H% 8,66 N% 9,26Calculated: C% 67.50 H% 8.66 N% 9.26

Fundet: 67,33 8,59 9,19 5 Trin D: hydrochloridet af 3-acety!-1,2,5,6-tetrahydropyridinoxim.Found: 67.33 8.59 9.19 Step D: The hydrochloride of 3-acetyl-1,2,5,6-tetrahydropyridine oxime.

Under inert atmosfære afkøles 20 g af den i trin C opnåede forbindelse opløst i 20 ml methy-lenchlorid, og der tilsættes 21,6 g α-chlorethylchlorformiat. Der opvarmes under tilbagesvaling i 2.5 time, afkøles, filtreres, opløsningsmidlet fjernes, det resterende stof genopløses i diethyl-ether, formales og filtreres. Opløsningsmidlet afdampes, det resterende stof genopløses i me- 10 thanol, opvarmes under tilbagesvaling i 30 min., inddampes til tørhed, det resterende stof gen opløses i methanol og diethylether, filtreres, udkrystralliseres i ethanol, og man får 2,1 g af den ventede forbindelse. Smp. = 237 °C (dekomponering).Under inert atmosphere, 20 g of the compound obtained in step C is dissolved in 20 ml of methylene chloride and 21.6 g of α-chloroethyl chloroformate is added. It is heated under reflux for 2.5 hours, cooled, filtered, the solvent removed, the residue redissolved in diethyl ether, ground and filtered. The solvent is evaporated, the residue is redissolved in methanol, heated under reflux for 30 minutes, evaporated to dryness, the residue dissolved in methanol and diethyl ether, filtered, crystallized in ethanol to give 2.1 g of it. expected connection. Mp. = 237 ° C (decomposition).

Analyse: Oy H^^O, HOIAnalysis: Oy H ^^ O, HOI

Beregnet: C% 47,59 H% 7,42 N% 15,86 15 Fundet: 47,74 7,38 15,78Calculated: C% 47.59 H% 7.42 N% 15.86 Found: 47.74 7.38 15.78

Eksempel 2:1-methyl-3-acetyl-1,2,5,6-tetrahydropyridin-0-methyloxim og hydrochloridet herafExample 2: 1-methyl-3-acetyl-1,2,5,6-tetrahydropyridine-0-methyloxime and its hydrochloride

Trin A: 3-acetylpyridin-O-methyloxim 20 Der tilsættes 6,85 g methoxylaminhydrochlorid til 10 g 3-acetylpyridin i 50 ml methanol. Der opvarmes under tilbagesvaling i 3 timer, opløsningsmidlet fjernes under formindsket tryk, det resterende stof genopløses i vand, som er gjort alkalisk med kaliumcarbonat, og der ekstrahe-res med ethylacetat. Der afdampes, og man får 11 g af den ventede forbindelse. (Kp.: 115-118 eC/18 mm Hg) 25Step A: 3-acetylpyridine-O-methyloxime 20.85 g of methoxylamine hydrochloride is added to 10 g of 3-acetylpyridine in 50 ml of methanol. The mixture is heated under reflux for 3 hours, the solvent is removed under reduced pressure, the residue is redissolved in water made alkaline with potassium carbonate and extracted with ethyl acetate. Evaporate and give 11 g of the expected compound. (Bp: 115-118 eC / 18 mm Hg) 25

Trin B: 1-methyl-3-acetylpyridin-0-methyloximiodid.Step B: 1-methyl-3-acetylpyridine-O-methyloxime iodide.

20.5 g methyiiodid sættes til 11 g af den forbindelse, der er opnået i trin A, opløst i 110 ml ethylacetat, og der opvarmes 3 timer med tilbagesvaling. Der afkøles, filtreres, og forbindelsen udkrystalliseres i ethanol. Man får 10,3 g af den ventede forbindelse. Smp. = 155-157 °C.20.5 g of methyl iodide are added to 11 g of the compound obtained in step A, dissolved in 110 ml of ethyl acetate, and refluxed for 3 hours. It is cooled, filtered and the compound is crystallized in ethanol. 10.3 g of the expected compound are obtained. Mp. = 155-157 ° C.

3030

Trin C: Hydrochloridet af 1-methyl-3-acetyl-1,2,5,6-tetrahydropyridin-O-methyloxim.Step C: The hydrochloride of 1-methyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-methyloxime.

Til en opløsning af 10 g af den i trin B opnåede forbindelse opløst i 100 ml methanol sættes 1,7 g natriumborhydrid, der afkøles til +5 - +10 °C. Der omrøres i 1 time ved stuetemperatur, opløsningsmidlet fjernes under formindsket tryk, det resterende stof genopløses i vand, ekstra-35 heres med diethylether, filtreres på aktivt kul, og forbindelsen omdannes til sit salt ved hjælp af gasformig saltsyre. Saltet omkrystalliseres i en blanding af isopropanol og diethylether, og man får 2,8 g af den ventede forbindelse. Smp. = 169-171 °C.To a solution of 10 g of the compound obtained in step B dissolved in 100 ml of methanol is added 1.7 g of sodium borohydride which is cooled to +5 - +10 ° C. The mixture is stirred for 1 hour at room temperature, the solvent is removed under reduced pressure, the residue is redissolved in water, extracted with diethyl ether, filtered on activated carbon and the compound converted to its salt by gaseous hydrochloric acid. The salt is recrystallized in a mixture of isopropanol and diethyl ether to give 2.8 g of the expected compound. Mp. = 169-171 ° C.

9 “DK 167758 B19 “DK 167758 B1

Analyse: C9 H16N20, HCIAnalysis: C9 H16N2O, HCl

Beregnet: C% 52,80 H% 8,37 N% 13,68Calculated: C% 52.80 H% 8.37 N% 13.68

Fundet: 53,06 8,44 13,57 5 Eksempel 3:3-acetyl-1,2,5,6-tetrahydropyridin-0-methyloxim og hydrochloridet herafFound: 53.06 8.44 13.57 Example 3: 3-Acetyl-1,2,5,6-tetrahydropyridine-0-methyloxime and its hydrochloride

Trin A: 1 -benzyl-3-acetylpyridin-O-methyloximbromidStep A: 1-Benzyl-3-acetylpyridine-O-methyloxime bromide

Til 23,4 g af den i eksempel 2 trin A fremstillede forbindelse opløst i 200 ml ethylacetat tilsættes 27,8 ml benzyibromid. Der opvarmes under tilbagesvaling i 8 timer, afkøles, filtreres, og den faste forbindelse udkrystalliseres i ethanol. Man får 46 g af den ventede forbindelse.To 23.4 g of the compound prepared in Example 2 Step A dissolved in 200 ml of ethyl acetate is added 27.8 ml of benzybromide. It is refluxed for 8 hours, cooled, filtered and the solid is crystallized in ethanol. 46 g of the expected compound are obtained.

10 Smp. = 191-192 °C.M.p. = 191-192 ° C.

Analyse:Analysis:

Beregnet: C% 56,09 H% 5,34 N% 8,72Calculated: C% 56.09 H% 5.34 N% 8.72

Fundet: 56,24 5,37 8,67 15 Trin B: 1-benzyl-3-acetyl-1,2,5,6-tetrahydropyridin-0-methyloxim.Found: 56.24 5.37 8.67 Step B: 1-Benzyl-3-acetyl-1,2,5,6-tetrahydropyridine-0-methyloxime.

20 g af den i trin A fremstillede forbindelse opløst i 150 ml methanol afkøles til 0 °C. Ved denne temperatur tilsættes 3,6 g natriumbortiydrid, der omrøres 1 time ved stuetemperatur, methano-len fjernes under formindsket tryk, det resterende stof genopløses i vand, man tilsætter natri-umcarbonat til mætning, ekstraherer med diethylether, tørrer den organiske fase og afdamper 20 opløsningsmidlet. Man får 10,66 g af den ventede forbindelsé. (Kp.: 128-130 eC / 0,4 mbar).20 g of the compound prepared in step A dissolved in 150 ml of methanol are cooled to 0 ° C. At this temperature, 3.6 g of sodium borohydride which is stirred for 1 hour at room temperature is added, the methanol is removed under reduced pressure, the residue is redissolved in water, sodium carbonate is added to saturate, extract with diethyl ether, dry the organic phase and evaporate. 20 of the solvent. 10.66 g of the expected compound are obtained. (Bp: 128-130 eC / 0.4 mbar).

Analyse:Analysis:

Beregnet: C% 73,74 H% 8,25 N% 11,47Calculated: C% 73.74 H% 8.25 N% 11.47

Fundet: 73,56 8,21 11,52 25 Trin C: 1-a-chlorethoxycarbonyl-3-acetyl-1,2,5,6-tetrahydropyridin-O-methyloxim.Found: 73.56 8.21 11.52 Step C: 1- alpha-chloroethoxycarbonyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-methyloxime.

7,2 g af den i trin B opnåede forbindelse opløst i 100 ml dichlorethan afkøles til 0 °C, og der tilsættes i løbet af 20 min. 6,05 g α-chlorethylchlorformiat opløst i dichlorethan. Der opvarmes under tilbagesvaling i 1,5 time, afkøles, filtreres, og opløsningsmidlet fjernes underformindsket tryk. Det resterende stof genopløses i diethylether og filtreres igen. Man afdamper opløs-30 ningsmidiet og får 8,44 g af en forbindelse, som bruges uforandret i det følgende trin. (Kp.: 210 °C/0,06 mbar)7.2 g of the compound obtained in step B dissolved in 100 ml of dichloroethane are cooled to 0 ° C and added over 20 minutes. 6.05 g of α-chloroethyl chloroformate dissolved in dichloroethane. It is refluxed for 1.5 hours, cooled, filtered and the solvent removed under reduced pressure. The residue is redissolved in diethyl ether and filtered again. The solvent is evaporated to give 8.44 g of a compound which is used unchanged in the following step. (Bp: 210 ° C / 0.06 mbar)

Analyse:Analysis:

Beregnet: C% 50,68 H% 6,57 N% 10,75Calculated: C% 50.68 H% 6.57 N% 10.75

Fundet: 50,86 6,46 10,59 35 10Found: 50.86 6.46 10.59 35 10

UKlb//D»BIUKlb // D 'BI

Trin D: 3-acetyl-1,2,5,6-tetrahydropyridin-O-methyloxim.Step D: 3-acetyl-1,2,5,6-tetrahydropyridine-O-methyloxime.

Forbindelsen fra trin C opløst i 70 ml methanol opvanmes under tilbagesvaling i to timer, der afkøles, inddampes til tørhed, og det resterende stof udkrystalliseres i ethanol. Man får 3,9 g af den ventede forbindelse. Smp. = 199-200 eC.The compound of step C dissolved in 70 ml of methanol is heated under reflux for two hours, which is cooled, evaporated to dryness and the residue is crystallized in ethanol. 3.9 g of the expected compound are obtained. Mp. = 199-200 eC.

5 Ved en fremgangsmåde som i eksempel 2 fås det ventede hydrochlorid.5 By a method such as in Example 2, the expected hydrochloride is obtained.

Analyse:Analysis:

Beregnet: C% 50,39 H% 7,93 N% 14,69Calculated: C% 50.39 H% 7.93 N% 14.69

Fundet: 50,31 7,84 14,55 10 Eksempel 4: 1 -methyl-3-acetyl-1,2,5,6-tetrahydropyridin-O-ethyloxim og hydrochloridet herafFound: 50.31 7.84 14.55 Example 4: 1-Methyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-ethyloxime and its hydrochloride

Trin A: 3-acetylpyridin-O-ethyloxim 4.8 ml 3-acetylpyridin opløses i 50 ml methanol. Der tilsættes 4,27 g ortoethylhydroxylaminhy-drochlorid. Opløsningen bringes til tilbagesvaling i tre timer. Der afkøles og inddampes til tør- 15 hed under formindsket tryk. Der genopslemmes i vand, neutraliseres med natriumbicarbonat og ekstraheres med ethylacetat, tørres og inddampes til tørhed under formindsket tryk. Man får 6.9 g af den ventede forbindelse, som anvendes i følgende trin. Smp. = 160-162 °C for den forbindelse, der udkrystalliseres af ether-isopropanolblandingen i form af hydrochloridet.Step A: 3-Acetylpyridine-O-Ethyloxime Dissolve 4.8 ml of 3-acetylpyridine in 50 ml of methanol. 4.27 g of orthoethyl hydroxylamine hydrochloride are added. The solution is refluxed for three hours. It is cooled and evaporated to dryness under reduced pressure. It is resuspended in water, neutralized with sodium bicarbonate and extracted with ethyl acetate, dried and evaporated to dryness under reduced pressure. 6.9 g of the expected compound are obtained which are used in the following steps. Mp. = 160-162 ° C for the compound crystallized by the ether-isopropanol mixture in the form of the hydrochloride.

20 Trin B: 1-methyl-3-acetylpyridin-0-ethyloximiodid.Step B: 1-methyl-3-acetylpyridine-O-ethyloxime iodide.

En blanding af 5,3 g af den i trin A fremstillede forbindelse og 4,1 ml methyliodid i 80 ml ethanol omrøres i 8 timer. Der inddampes til tørhed. Man får 9,3 g af den ventede forbindelse.A mixture of 5.3 g of the compound prepared in step A and 4.1 ml of methyl iodide in 80 ml of ethanol is stirred for 8 hours. Evaporate to dryness. 9.3 g of the expected compound are obtained.

Smp. = 95 °C for den forbindelse, der udkrystalliseres af ether-isopropanolblandingen.Mp. = 95 ° C for the compound crystallized by the ether-isopropanol mixture.

25 Trin C: 1-methyl-3-acetyl-1,2,5,6-tetrahydropyridin-0-ethyloxim, hydrochlorid.Step C: 1-methyl-3-acetyl-1,2,5,6-tetrahydropyridine-0-ethyloxime hydrochloride.

Til en opløsning af 9,1 g af den i trin B fremstillede forbindelse opløst i 90 ml methanol, som holdes ved 5 °C, tilsættes 1,7 g natriumborhydrid. Efter 4 timer ved stuetemperatur inddampes til tørhed under formindsket tryk. Det resterende stof genopløses i vand, ekstraheres med ethylacetat og inddampes til tørhed under reduceret tryk. Det resterende stof chromatograferes 30 på silicagel (elueringsmiddel: chloroform - methanol: 5 -1). De 3,5 g af den opnåede olie opløses i ether og omdannes til et salt med gasformig saltsyre. Der inddampes til tørhed, og man får 3,7 g af den ventede forbindelse. Smp. = 186-188 °C for den forbindelse, som omkrystalliseres i en blanding af isopropanol-ether.To a solution of 9.1 g of the compound prepared in step B dissolved in 90 ml of methanol kept at 5 ° C is added 1.7 g of sodium borohydride. After 4 hours at room temperature, evaporate to dryness under reduced pressure. The residue is redissolved in water, extracted with ethyl acetate and evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel (eluent: chloroform - methanol: 5 -1). The 3.5 g of the oil obtained is dissolved in ether and converted into a salt with gaseous hydrochloric acid. Evaporate to dryness to give 3.7 g of the expected compound. Mp. = 186-188 ° C for the compound which is recrystallized from a mixture of isopropanol ether.

Analyse: 35 Beregnet: C% 54,91 H% 8,76 N% 12,81Calculated: C% 54.91 H% 8.76 N% 12.81

Fundet: 54,88 8,94 12,76 DK 167758 B1 11Found: 54.88 8.94 12.76 DK 167758 B1 11

Eksempel 5: 3-acetyl-1,2,5,6-tetrahydropyridin-0-ethyloxim og hydrochloridet herafExample 5: 3-Acetyl-1,2,5,6-tetrahydropyridine-0-ethyloxime and its hydrochloride

Trin A: l-N-benzyl-3-acetylpyridin-O-ethyloximbromid 6,9 g af den i eksempel 4 trin A fremstillede forbindelse opløses i 70 ml ethanol, der tilsættes 6 ml benzylbromid, opvarmes under tilbagesvaling i 6 timer, afkøles, opløsningsmidlet afdam-5 pes under formindsket tryk, og man isolerer fra ether 13,9 g af den ventede forbindelse.Step A: 1N-Benzyl-3-acetylpyridine-O-ethyloxime bromide 6.9 g of the compound prepared in Example 4 Step A are dissolved in 70 ml of ethanol, added to 6 ml of benzyl bromide, refluxed for 6 hours, cooled, the solvent evaporated -5 d under reduced pressure and 13.9 g of the expected compound are isolated from ether.

Trin B: 1-N-benzyl-3-acetyl-1,2,5,6-tetrahydropyridin-O-ethyloxim.Step B: 1-N-benzyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-ethyloxime.

a) Til en opløsning af 0,8 g natrium i 50 ml ethanol sættes 3,8 g af den i eksempel 1 trin B fremstillede forbindelse og 1,25 ml ethylbromid. Efter 3 timer med tilbagesvaling afkøler man 10 og inddamper til tørhed. Man får 2,84 g af den ventede forbindelse efter eluering på en kolonne (elueringsmiddel: ethylacetat - toluen: 3 - 2). (Kp.: 180-190 °C / 0,05 mbar).a) To a solution of 0.8 g of sodium in 50 ml of ethanol is added 3.8 g of the compound prepared in Example 1 Step B and 1.25 ml of ethyl bromide. After 3 hours of reflux, cool 10 and evaporate to dryness. 2.84 g of the expected compound is obtained after elution on a column (eluent: ethyl acetate-toluene: 3 - 2). (Bp: 180-190 ° C / 0.05 mbar).

b) Forbindelsen kan også fås med et udbytte på 71% ved reduktion med natriumborhydrid, idet man går frem som i eksempel 1 trin B med den i eksempel 5 trin A fremstillede forbindelse.b) The compound can also be obtained with a 71% yield by reduction with sodium borohydride, proceeding as in Example 1 Step B with the compound of Example 5 Step A.

15 Trin C: 3-acetyl-1,2,5,6-tetrahydropyridin-0-ethyloxim, hydrochlorid.Step C: 3-acetyl-1,2,5,6-tetrahydropyridine-0-ethyloxime hydrochloride.

Man opløser 2,7 g af den i trin B fremstillede forbindelse i 50 ml dichlorethan. Der tilsættes 1,8 g a-chlorethylformiat ved 0 °C. Efter tilbagesvaling i halvanden time inddamper man til tørhed, genopslemmer i ether, frafiltrerer det uopløselige stof og inddamper til tørhed under formindsket tryk. Den resterende olie genopslemmes i 40 ml methanol. Efter tilbagesvaling i 20 halvanden time inddamper man til tørhed, genopslemmer det resterende stof i ether, filtrerer og får således 4,2 g af den ventede forbindelse udkrystalliseret af en blanding af ether og methanol. Smp. = 198-199 °C (dekomponering). Ved en fremgangsmåde som i eksempel 2 fås det ventede hydrochlorid.2.7 g of the compound of step B is dissolved in 50 ml of dichloroethane. Add 1.8 g of α-chloroethyl formate at 0 ° C. After refluxing for an hour and a half, evaporate to dryness, resuspend in ether, filter out the insoluble matter and evaporate to dryness under reduced pressure. The remaining oil is resuspended in 40 ml of methanol. After refluxing for 20 and a half hours, it is evaporated to dryness, resuspended in ether, filtered and thus 4.2 g of the expected compound is crystallized out of a mixture of ether and methanol. Mp. = 198-199 ° C (decomposition). By a method as in Example 2, the expected hydrochloride is obtained.

Analyse: 25 Beregnet: C% 52,81 H% 8,37 N% 13,69Calculated: C% 52.81 H% 8.37 N% 13.69

Fundet: 52,59 8,25 13,48Found: 52.59 8.25 13.48

Eksempel 6: 3-acetyl-1,2,5,6-tetrahydropyridin-0-2-propynyloxim og hydrochloridet heraf 30 Trin A: 1 -N-benzyl-3-acetyl-1,2,5,6-tetrahydropyridin-0-2-propynyloximExample 6: 3-Acetyl-1,2,5,6-tetrahydropyridine-0-2-propynyloxime and its hydrochloride Step A: 1- N -benzyl-3-acetyl-1,2,5,6-tetrahydropyridine-0 -2-propynyl oxime

Til en opløsning af 1,1 g natrium i 50 ml ethanol sættes 5 g af den i eksempel 1 trin B fremstillede forbindelse. Man tilsætter ved 0 °C 3,95 g propargylbromid. Der opvarmes 3 timer ved 40 °C, det uopløselige stof frafiltreres, opløsningsmidlet afdampes, og man chromatograferer på silicagel (elueringsmiddel: Ethylacetat). Man får 4,5 g af den ventede forbindelse.To a solution of 1.1 g of sodium in 50 ml of ethanol is added 5 g of the compound of Example 1 Step B. 3.95 g of propargyl bromide is added at 0 ° C. Heat for 3 hours at 40 ° C, filter out the insoluble matter, evaporate the solvent and chromatograph on silica gel (eluent: ethyl acetate). 4.5 g of the expected compound are obtained.

Trin B: 3-acetyl-1,2,5,6-tetrahydropyridin-0-2-propynyloxim, hydrochlorid.Step B: 3-acetyl-1,2,5,6-tetrahydropyridine-0-2-propynyloxime hydrochloride.

7,5 g af den i trin A fremstillede forbindelse opløses i 100 ml dichlorethan. Efter en time under tilbagesvaling afdampes opløsningsmidlet, man genopslemmer i ether, frafiltrerer det uopløse- 35 127.5 g of the compound of step A is dissolved in 100 ml of dichloroethane. After an hour at reflux, the solvent, which is resuspended in ether, is evaporated to filter out the insoluble 12

Ulv ΙΌ//90 Dl lige stof, inddamper til tørhed. Det resterende stof genopslemmes i methanol, bringes til tilbagesvaling i 30 min., man inddamper til tørhed, genopslemmer det resterende stof med en na-triumbicarbonatopløsning, ekstraherer med ethylacetat og inddamper til tørhed. Det resterende stof genopløst i ether omdannes til sit salt med gasformig saltsyre. Man får 1,25 g af den ven-5 tede forbindelse. Smp. = 178 eC for den forbindelse, der isoleres fra en blanding af ether og ethanol.Wolf 90 // 90 Dl straight fabric, evaporates to dryness. The residue is resuspended in methanol, refluxed for 30 minutes, evaporated to dryness, resuspended with a sodium bicarbonate solution, extracted with ethyl acetate and evaporated to dryness. The remaining substance redissolved in ether is converted to its salt with gaseous hydrochloric acid. 1.25 g of the expected compound are obtained. Mp. = 178 eC for the compound isolated from a mixture of ether and ethanol.

Analyse:Analysis:

Beregnet: C% 55,94 H% 7,04 N% 13,05Calculated: C% 55.94 H% 7.04 N% 13.05

Fundet: 55,72 7,01 12,99 10Found: 55.72 7.01 12.99 10

Eksempel 7: 1-methyl-3-acetyItetrahydropyridin-0-2-propynyloxim og hydrochloridet herafExample 7: 1-methyl-3-acetyltetrahydropyridine-0-2-propynyloxime and its hydrochloride

Trin A: 3-acetylpyridin-0-2-propynyloxim 5 g 3-acetylpyridin opløses i 20 ml vand, man tilsætter 3,45 g natriumbicarbonat og 4,45 g orto-15 2-propynylhydoxylaminhydrochlorid i 30 ml vand. Blandingen henstår 16 timer, hvorefter der opvarmes i 3 timer ved 40 °C. Man opkoncentrerer, ekstraherer med ethylacetat, inddamper til tørhed og renser på silicagel (elueringsmiddel: Ethylacetat). Man får 5,7 g af den ventede forbindelse. Smp. = 156-157 “C for den forbindelse, der udkrystalliseres af isopropanol.Step A: 3-Acetylpyridine-0-2-propynyloxime Dissolve 5 g of 3-acetylpyridine in 20 ml of water, add 3.45 g of sodium bicarbonate and 4.45 g of ortho-2-propynylhydoxylamine hydrochloride in 30 ml of water. The mixture is allowed to stand for 16 hours, then heated for 3 hours at 40 ° C. Concentrate, extract with ethyl acetate, evaporate to dryness and purify on silica gel (eluent: ethyl acetate). 5.7 g of the expected compound are obtained. Mp. = 156-157 ° C for the compound crystallized from isopropanol.

20 Trin B: 1-N-methyl-3-acetylpyridin-0-2-propynyloximiodid.Step B: 1-N-methyl-3-acetylpyridine-0-2-propynyloxime iodide.

Man opløser 5,6 g af den i trin A fremstillede forbindelse i 60 ml methanol og tilsætter 8,6 g methyliodid. Efter 3 timer under tilbagesvaling inddampes til tørhed, der genopløses i en ace-tone-etherblanding og filtreres. Man får 9,7 g. Smp. = 150-151 °C for den forbindelse, som udkrystalliseres af isopropanol.5.6 g of the compound of step A are dissolved in 60 ml of methanol and 8.6 g of methyl iodide are added. After 3 hours under reflux, evaporate to dryness which is redissolved in an ace-tone ether mixture and filtered. 9.7 g are obtained. = 150-151 ° C for the compound crystallized from isopropanol.

2525

Trin C: 1-methyl-3-acetyltetrahydropyridin-0-2-propynyloxim, hydrochloridet.Step C: 1-methyl-3-acetyltetrahydropyridine-0-2-propynyloxime, the hydrochloride.

Man opløser 9,7 g af den i trin B fremstillede forbindelse i 100 ml methanol, tilsætter 2,35 g natriumborhydrid ved 0 °C. Efter en time ved 0 °C inddampes, det resterende stof genopslemmes i vand, der ekstraheres med ethylacetat, tønres og inddampes til tørhed. Det resterende 30 stof opløst i ether omdannes til et salt med gasformig saltsyre, og man får 2,7 g af den ventede forbindelse, Smp. = 195-196 “C for den forbindelse, som udkrystalliseres af en isopropanol-etherblanding.9.7 g of the compound prepared in step B are dissolved in 100 ml of methanol, 2.35 g of sodium borohydride is added at 0 ° C. After one hour at 0 ° C, evaporate, the remaining substance is resuspended in water extracted with ethyl acetate, dried and evaporated to dryness. The residual substance dissolved in ether is converted to a salt with gaseous hydrochloric acid to give 2.7 g of the expected compound, m.p. = 195-196 ° C for the compound crystallized by an isopropanol-ether mixture.

Analyse: On H16N20, HCIAnalysis: On H16N2O, HCl

Beregnet: C% 57,76 H% 7,49 N% 12,25 35 Fundet: 57,59 7,38 12,11 DK 167758 B1 13Calculated: C% 57.76 H% 7.49 N% 12.25 Found: 57.59 7.38 12.11 DK 167758 B1 13

Eksempel 8: 3-propionyl-1,2,5,6-tetrahydropyridinoxim og hydrochloridet herafExample 8: 3-Propionyl-1,2,5,6-tetrahydropyridine oxime and its hydrochloride

Trin A: 1-N-benzyl-3-propionylpyridinoximbromidStep A: 1-N-benzyl-3-propionylpyridinoxime bromide

En blanding af 17,8 g 3-propionylpyridinoxim (US patentskrift nr. 3.004.979 (1961)) og 18 ml benzylbromid i 250 ml ethylacetat holdes under tilbagesvaling i 7 timer og 30 min. Man afkøler, 5 centrifugerer og får 36,5 g af den ventede forbindelse. Smp. = 178-180 °C for den forbindelse, som udkrystalliseres af en ethanol-etherblanding.A mixture of 17.8 g of 3-propionylpyridine oxime (U.S. Patent No. 3,004,979 (1961)) and 18 ml of benzyl bromide in 250 ml of ethyl acetate is refluxed for 7 hours and 30 minutes. It is cooled, 5 centrifuged and 36.5 g of the expected compound are obtained. Mp. = 178-180 ° C for the compound crystallized by an ethanol-ether mixture.

Trin B: 1-N-benzyl-3-propionyl-1,2,5,6-tetrahydropyridinoxim.Step B: 1-N-benzyl-3-propionyl-1,2,5,6-tetrahydropyridine oxime.

36,2 g af den i trin A fremstillede forbindelse opløses i 250 ml methanol, opløsningen holdes 10 ved 10 °C, mens der lidt efter lidt tilsættes 6,4 g natriumborhydrid. Man omrører i 3 timer, af-damper opløsningsmidlet under formindsket tryk, genopslemmer i vand, ekstraherer med ethylacetat, tørrer og afdamper opløsningsmidlet. Der oprenses ved chromatografering på en kolonne (elueringsmiddel: ethylacetat), og man får 21 g af den ventede forbindelse.Dissolve 36.2 g of the compound of step A in 250 ml of methanol, keep the solution 10 at 10 ° C while gradually add 6.4 g of sodium borohydride. The mixture is stirred for 3 hours, evaporated under reduced pressure, resuspended in water, extracted with ethyl acetate, dried and evaporated. Purify by chromatography on a column (eluent: ethyl acetate) to give 21 g of the expected compound.

Smp. - 111-112 °C for den forbindelse, som udkrystalliseres af ethylacetat.Mp. - 111-112 ° C for the compound crystallized from ethyl acetate.

1515

Trin C: 1 -N-benzyl-3-propionyl-1,2,5,6-tetrahydropyridin-O-trimethylsilyloxim.Step C: 1- N -benzyl-3-propionyl-1,2,5,6-tetrahydropyridine-O-trimethylsilyloxime.

Man blander 6 g af den i trin B fremstillede forbindelse, 70 ml benzen og 2,95 g 1,4-diazabicy-klo-(2.2.2)-octan. Der tilsættes 3,25 ml trimethylsilylchlorid, bringes til tilbagesvaling i 3 timer, afkøles, uopløseligt stof frafiltreres, opløsningsmidlet afdampes, det resterende stof genoplø-20 ses i ether, uopløseligt stof frafiltreres, og der inddampes til tørhed. Man får 7,5 g af den ventede forbindelse. Kp.: 250 °C / 0,06 mbar.Mix 6 g of the compound prepared in step B, 70 ml of benzene and 2.95 g of 1,4-diazabicylo- (2.2.2) -octane. Trimethylsilyl chloride (3.25 ml) is added, refluxed for 3 hours, cooled, the insoluble matter is filtered off, the solvent is evaporated, the residue is redissolved in ether, the insoluble matter is filtered off and the product is evaporated to dryness. 7.5 g of the expected compound are obtained. Bp: 250 ° C / 0.06 mbar.

Trin D: 3-propionyl-1,2,5,6-tetrahydropyridinoxim, hydrochlorid.Step D: 3-propionyl-1,2,5,6-tetrahydropyridine oxime, hydrochloride.

Man opløser 16 g af den i trin C fremstillede forbindelse i 150 ml dichlorethan. Man afkøler til 25 0 °C og tilsætter 16,2 g α-chlorethylchlorformiat. Opløsningen holdes under tilbagesvaling i 3 timer, hvorefter opløsningsmidlet afdampes, der genopslemmes i ether, filtreres og inddampes til tørhed. Det resterende stof genopslemmes i 100 ml methanol og bringes til tilbagesvaling i 6 timer. Methanolen afdampes, hvorefter der oprenses ved passage af aluminiumoxid (elueringsmiddel: Chloroform-methanol, 7-3, derefter rent methanol). Der inddampes til tørhed, 30 genopslemmes i ethanol, kulfiltreres og bundfældes ved tilsætning af hexan. Der filtreres, og man får efter oprensning i en ethanol-hexanblanding 1,3 g af den ventede forbindelse.16 g of the compound prepared in step C are dissolved in 150 ml of dichloroethane. It is cooled to 25 ° C and 16.2 g of α-chloroethyl chloroformate is added. The solution is refluxed for 3 hours, after which the solvent is evaporated, resuspended in ether, filtered and evaporated to dryness. The residue is resuspended in 100 ml of methanol and refluxed for 6 hours. The methanol is evaporated and then purified by passing alumina (eluent: Chloroform-methanol, 7-3, then pure methanol). It is evaporated to dryness, resuspended in ethanol, carbon filtered and precipitated by the addition of hexane. Filter and purify in the ethanol-hexane mixture 1.3 g of the expected compound.

Smp. = 205-206 °C. Ved en fremgangsmåde som i eksempel 2 fås det ventede hydrochlorid.Mp. = 205-206 ° C. By a method as in Example 2, the expected hydrochloride is obtained.

Analyse: Cg H^I^O, HCIAnalysis: Cg H 2 O, HCl

Beregnet: C% 50,39 H% 7,93 N% 14,69 35 Fundet: 50,08 7,87 14,48 DK 167758 Bl 14Calculated: C% 50.39 H% 7.93 N% 14.69 Found: 50.08 7.87 14.48 DK 167758 Bl 14

Eksempel 9: 3-propionyl-1,2,5,6-tetrahydropyridin-0-methyloxim og hydrochloridet heraf Trin A: 1 -N-benzyl-3-propionyl-1,2,5,6-tetrahydropyridin-O-methyloxim Til en opløsning af 1,2 g natrium i 80 mi ethanoi sættes 6,11 g af den i eksempel 8 trin B fremstillede forbindelse. Der tilsættes yderligere 1,58 ml methyliodid, bringes til tilbagesvaling i 5 6 timer, afkøles, inddampes til tørhed under formindsket tryk og genopslemmes i vand. Der ekstraheres med ethylacetat, tørres, inddampes til tørhed, og det resterende stof chromatogra-feres (elueringsmiddel: ethylacetat-toluen: 6-4), og man får 2,5 g af den ventede forbindelse.Example 9: 3-propionyl-1,2,5,6-tetrahydropyridine-O-methyloxime and its hydrochloride Step A: 1-N-benzyl-3-propionyl-1,2,5,6-tetrahydropyridine-O-methyloxime to a solution of 1.2 g of sodium in 80 ml of ethanol is added 6.11 g of the compound of Example 8, step B. An additional 1.58 ml of methyl iodide is added, refluxed for 6 hours, cooled, evaporated to dryness under reduced pressure and resuspended in water. Extract with ethyl acetate, dry, evaporate to dryness and chromatograph the residue (eluent: ethyl acetate-toluene: 6-4) to give 2.5 g of the expected compound.

Kp.: 170 °C / 0,05 mbar.Bp: 170 ° C / 0.05 mbar.

10 Trin B: 3-propionyl-1,2,5,6-tetrahydropyridin-0-methyloxim, hydrochlorid.Step B: 3-propionyl-1,2,5,6-tetrahydropyridine-0-methyloxime hydrochloride.

3,5 g af forbindelsen fra trin A opløses i 50 mi dichlorethan. Der tilsættes ved 0 °C 2,04 g a-chlorethylchlorformiat. Efter tilbagesvaling i 3 timer afdampes opløsningsmidlet, det resterende stof genopslemmes i ether, man filtrerer og inddamper til tørhed. Man genopslemmer i 30 ml ethanol og bringer til tilbagesvaling i 30 min. Man inddamper til tørhed, udkrystalliserer med en 15 ethanol-etherblanding og får 1,17 g af den ventede forbindelse. Smp. = 210-212 °C. Ved en fremgangsmåde som i eksempel 2 fås det ventede hydrochlorid.3.5 g of the compound of step A is dissolved in 50 ml of dichloroethane. Add 2.04 g of a-chloroethyl chloroformate at 0 ° C. After refluxing for 3 hours, the solvent is evaporated, the residue resuspended in ether, filtered and evaporated to dryness. It is resuspended in 30 ml of ethanol and refluxed for 30 min. Evaporate to dryness, crystallize with an ethanol-ether mixture and give 1.17 g of the expected compound. Mp. = 210-212 ° C. By a method as in Example 2, the expected hydrochloride is obtained.

Analyse: C9H16N20, HCIAnalysis: C9H16N2O, HCl

Beregnet: C% 52,53 H% 8,26 N% 13,56Calculated: C% 52.53 H% 8.26 N% 13.56

Fundet: 52,80 8,37 13,68 20Found: 52.80 8.37 13.68 20

Eksempel 10:1 -N-carbonyioxyethyl-3-acetyl-1,2,5,6-tetrahydropyridin-O-methyloximExample 10: 1-N-Carbonyioxyethyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-methyloxime

Man opløser 1,8 g af den i eksempel 3 fremstillede forbindelse i 30 ml benzen ved 5 °C, hvorefter der tilsættes 1,63 ml triethyiamin og 1,12 ml ethylchlorformiat. Der omrøres 30 min. ved stuetemperatur, vaskes med vand, inddampes til tørhed og rektificeres. Man får 2,56 g af den 25 ventede forbindelse. Kp.: 155 °C / 0,07 mbar.Dissolve 1.8 g of the compound of Example 3 in 30 ml of benzene at 5 ° C, then add 1.63 ml of triethylamine and 1.12 ml of ethyl chloroformate. Stir for 30 minutes. at room temperature, wash with water, evaporate to dryness and rectify. 2.56 g of the 25 expected compound are obtained. Bp: 155 ° C / 0.07 mbar.

Analyse:Analysis:

Beregnet: C% 58,39 H% 8,02 N% 12,38Calculated: C% 58.39 H% 8.02 N% 12.38

Fundet: 58,41 7,88 12,29 30 Eksempel 11:1 -N-carbonyloxybenzyl-3-acetyl-1,2,5,6-tetrahydropyridin-O-methyloximFound: 58.41 7.88 12.29 Example 11: 1-N-Carbonyloxybenzyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-methyloxime

Man opløser 2,5 g af den i eksempel 3 trin B fremstillede forbindelse i 40 ml vandfri benzen, tilsætter 2,7 ml benzylchlorformiat, bringer til tilbagesvaling i 1 time, afkøler, vasker med 10 ml 5% saltsyre, tørrer og afdamper opløsningsmidlet. Det dannede benzylchlorid fjernes under formindsket tryk, og man får 2,3 g af den ventede forbindelse udkrystalliseret fra cyklohexan.Dissolve 2.5 g of the compound of Example 3 in B in 40 ml of anhydrous benzene, add 2.7 ml of benzyl chloroformate, reflux for 1 hour, cool, wash with 10 ml of 5% hydrochloric acid, dry and evaporate the solvent. The benzyl chloride formed is removed under reduced pressure to give 2.3 g of the expected compound crystallized from cyclohexane.

35 Smp. = 90 °C.M.p. = 90 ° C.

Analyse:Analysis:

Beregnet: C% 65,68 H% 6,61 N% 10,21Calculated: C% 65.68 H% 6.61 N% 10.21

Fundet: 65,81 6,58 10,17 DK 167758 B1 15Found: 65.81 6.58 10.17 DK 167758 B1 15

Eksempel 12:1 -N-hydroxyl-3-acetyl-1,2,5,6-tetrahydropyridin-O-methyloximExample 12: 1-N-hydroxyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-methyloxime

Man opløser 3,5 g 3-aætylpyridin-O-methyloxim-N-oxid (J. Het. Chem. 16, 1459, (1979)) i 50 ml methanol. Man afkøler til -10 °C og tilsætter 2,4 g natriumborhydrid. Der omrøres 2 timer 5 ved stuetemperatur. Der inddampes til tørhed, genopslemmes i vand, ekstraheres med ethyla-cetat, tørres, inddampes til tørhed. Der oprenses ved chromatografering på silicagel (elueringsmiddel: Ethylacetat). man får 2,85 g af den ventede forbindelse. Smp. = 94-96 °C for den forbindelse, som udkrystalliseres fra hexan.3.5 g of 3-ethylpyridine-O-methyloxime N-oxide (J. Het. Chem. 16, 1459, (1979)) is dissolved in 50 ml of methanol. Cool to -10 ° C and add 2.4 g of sodium borohydride. Stir for 2 hours at room temperature. It is evaporated to dryness, resuspended in water, extracted with ethyl acetate, dried, evaporated to dryness. Purify by chromatography on silica gel (eluent: ethyl acetate). 2.85 g of the expected compound are obtained. Mp. = 94-96 ° C for the compound crystallized from hexane.

Analyse: 10 Beregnet: C% 56,45 H% 8,29 N% 16,46Calculated: C% 56.45 H% 8.29 N% 16.46

Fundet: 56,28 8,32 16,31Found: 56.28 8.32 16.31

Eksempel 13: 1-methyl-3-cyklopropylcarbonyl-1,2,5,6-tetrahydropyridin-0-mefhyloxim og benzensulfonatet heraf 15 Trin A: 3-pyridylcyklopropylketon-O-methyloximExample 13: 1-Methyl-3-cyclopropylcarbonyl-1,2,5,6-tetrahydropyridine-0-mephyloxime and its benzenesulfonate Step A: 3-Pyridylcyclopropylketone-O-methyloxime

Til en opløsning af 3,5 g 3-pyridylcyklopropylketon i 50 ml methanol tilsættes 2,03 g methoxyl-aminhydrochlorid. Man opvarmer under tilbagesvaling i 4 timer, afdamper opløsningsmidlet og genopslemmer i en vandig natriumbicarbonatopløsning. Man ekstraherer med methylenchlorid, tørrer og afdamper opløsningsmidlet. Man får 4,1 g af den ventede forbindelse.To a solution of 3.5 g of 3-pyridylcyclopropyl ketone in 50 ml of methanol is added 2.03 g of methoxylamine hydrochloride. The reflux is heated for 4 hours, the solvent is evaporated and resuspended in an aqueous sodium bicarbonate solution. Extract with methylene chloride, dry and evaporate the solvent. 4.1 g of the expected compound are obtained.

2020

Trin B: 1-methyl-3-cyklopropylcarbonylpyridin-0-methyloximiodid.Step B: 1-methyl-3-cyclopropylcarbonylpyridine-0-methyloxime iodide.

Til en opløsning af 5,3 g methyliodid i 50 ml methanol sættes 4 g af den i trin A fremstillede forbindelse, og opløsningen bringes til tilbagesvaling i 3 timer. Der inddampes til tørhed, udlægges i en ethanol-etherblanding, filtreres, og man får 6,6 g af den ventede forbindelse udkry-25 stalliseret fra isopropanol. Smp. = 113 °C (dekomponering).To a solution of 5.3 g of methyl iodide in 50 ml of methanol is added 4 g of the compound prepared in step A and the solution is refluxed for 3 hours. It is evaporated to dryness, placed in an ethanol-ether mixture, filtered and 6.6 g of the expected compound are crystallized from isopropanol. Mp. = 113 ° C (decomposition).

Analvse: Gu Hi5IN20Analysis: Gu Hi5IN20

Beregnet: C% 41,52 H% 4,75 N% 8,80Calculated: C% 41.52 H% 4.75 N% 8.80

Fundet: 41,17 4,66 8,76 30 Trin C: 1-methyl-3-cyklopropylcarbonyl-1,2,5,6-tetrahydropyridin-0-methyloxim, benzensulfo-nat.Found: 41.17 4.66 8.76 Step C: 1-methyl-3-cyclopropylcarbonyl-1,2,5,6-tetrahydropyridine-0-methyloxime, benzenesulfonate.

Til en opløsning af 6,4 g af den i trin B fremstillede forbindelse i 70 ml methanol sættes ved 0 °C 1,52 g natriumborhydrid. Man lader dette reagere i halvanden time ved stuetemperatur.To a solution of 6.4 g of the compound prepared in step B in 70 ml of methanol is added 1.52 g of sodium borohydride at 0 ° C. This is allowed to react for an hour and a half at room temperature.

Man inddamper, genopslemmer i vand, ekstraherer med ethylacetat, tørrer og inddamper til 35 tørhed. Man oprenser ved eluering på aluminiumoxid (elueringsmiddel: Toluen-ethylacetat, 6- 4). Man destillerer ved 160 eC under 0,2 mm Hg. 2,45 g af den således fremstillede base genopslemmes i 100 ml benzen med 1,994 g benzensulfonsyre. Der inddampes til tørhed, udlæg- DK 167758 B1 16 ges i en smule ethylacetat, filtreres, og man får 1,7 g af den ventede forbindelse.It is evaporated, resuspended in water, extracted with ethyl acetate, dried and evaporated to dryness. Purify on alumina (eluent: toluene-ethyl acetate, 6-4). Distillate at 160 eC below 0.2 mm Hg. 2.45 g of the base thus prepared is resuspended in 100 ml of benzene with 1.994 g of benzenesulfonic acid. Evaporate to dryness, lay out in a bit of ethyl acetate, filter and give 1.7 g of the expected compound.

Smp. = 76 eC (dekomponering).Mp. = 76 eC (decomposition).

Analyse: H18N20, C6 H5S03HAnalysis: H18N2O, C6H5SO3H

Beregnet: C% 57,93 H% 6,86 N% 7,95 5 Fundet: 58,04 6,94 7,87Calculated: C% 57.93 H% 6.86 N% 7.95 Found: 58.04 6.94 7.87

Eksempler på farmaceutiske præparater a) Man fremstiller tabletter efter følgende formel:Examples of pharmaceutical compositions a) Tablets are prepared according to the following formula:

Forbindelse ifølge eksempel 3................................................................................200 mg 10 Bindemiddel til fremstilling af en tablet på..............................................................300 mg (f.eks. lactose, komstivelse, behandlet stivelse, risstivelse, magnesiumstearat, talkum).Compound of Example 3 .............................................. .................................. 200 mg 10 Binder for preparation of a tablet of ...... .................................................. ...... 300 mg (eg lactose, starch, treated starch, rice starch, magnesium stearate, talc).

b) Man fremstiller gelatinekapsler efter følgende formel:(b) Gelatin capsules are prepared according to the following formula:

Forbindelse ifølge eksempel 1................................................................................100 mg 15 Bindemiddel til fremstilling af en gelatinekapsel på................................................300 mg (f.eks. talkum, magnesiumstearat, aerosil).Compound of Example 1 .............................................. .................................. 100 mg 15 Binder for the preparation of a gelatin capsule of ...... .......................................... 300 mg (eg talc , magnesium stearate, aerosil).

c) Man fremstiller tabletter efter følgende formel:c) Tablets are prepared according to the following formula:

Forbindelse ifølge eksempel 2..................................................................................50 mg 20 Bindemiddel til fremstilling af en tablet på..............................................................300 mg (f.eks. lactose, komstivelse, behandlet stivelse, risstivelse, magnesiumstearat, talkum).Compound of Example 2 .............................................. .................................... 50 mg 20 Binder for the preparation of a tablet of ... .................................................. ........ 300 mg (eg lactose, starch, treated starch, rice starch, magnesium stearate, talc).

b) Man fremstiller tabletter efter følgende formel:b) Tablets are prepared according to the following formula:

Forbindelse ifølge eksempel 12................................................................................50 mg 25 Bindemiddel til fremstilling af en tablet på..............................................................300 mg (f.eks. lactose, komstivelse, behandlet stivelse, risstivelse, magnesiumstearat, talkum).Compound of Example 12 .............................................. .................................. 50 mg 25 Binder for preparation of a tablet of ...... .................................................. ...... 300 mg (eg lactose, starch, treated starch, rice starch, magnesium stearate, talc).

Biologisk aktivitetBiological activity

Forbindelserne anvendes i form af hydrochloridet.The compounds are used in the form of the hydrochloride.

.300.30

AkuttoxicitetAkuttoxicitet

Undersøgelsen udføres på hanmus (CD1 Charles Rivers) med en vægt på 22-24 g, som har været fastende i 16 timer. Forbindelserne indgives ad oral vej i doser på 1000, 500, 250,125, 62 og 31 mg/kg. Dødeligheden i de 7 følgende dage noteres.The study is performed on male mice (CD1 Charles Rivers) weighing 22-24 g, which has been fasting for 16 hours. The compounds are administered orally at doses of 1000, 500, 250,125, 62 and 31 mg / kg. The mortality rate for the next 7 days is noted.

35 DK 167758 B1 1735 DK 167758 B1 17

Forbindelse ifølge eksempel__DL^ i mg/kg 1 350 2 350 3 125 12 175 arecolin, HBr 600Compound of Example __DL ^ in mg / kg of 1 350 2 350 3 125 12 175 arecoline, HBr 600

Undersøgelse af ileum isoleret fra marsvinStudy of ileum isolated from guinea pigs

Man udtager ileumfragmenter fra marsvin, som er draebt ved afskæring af hovedet. Den udtagne ileum anbringes i 10 ml Tyrode-opløsning ved 37 °C og beluftes af en blanding af oxy-5 gen (95%) og carbondioxid (5%). De kontraktioner, som skyldes forbindelserne, registreres ved hjælp af en sensor, der er forbundet til en skriver. De undersøgte forbindelser tilsættes i koncentrationer mellem 1.10-3 M og 1.10-8 M.The ileum fragments are extracted from guinea pigs, which are killed by cutting off the head. The extracted ileum is placed in 10 ml of Tyrode solution at 37 ° C and aerated by a mixture of oxygen (95%) and carbon dioxide (5%). The contractions caused by the connections are recorded by a sensor connected to a printer. The compounds studied are added at concentrations between 1.10-3 M and 1.10-8 M.

De forbindelser, som har en kontraherende virkning, testes sammen med atropin og hexame-10 thonium for at undersøge, om virkningen er af "muskarinisk" eller "nikotinisk" type.The compounds having a contracting effect are tested together with atropine and hexamethonium to determine if the effect is of the "muscarinic" or "nicotinic" type.

Den agonistiske virkning udtrykkes som pD2 (den negative logaritme til den dosis, som fremkalder 50% af maximumeffekten).The agonistic effect is expressed as pD2 (the negative logarithm of the dose which produces 50% of the maximum effect).

_Eksempel___ 1 5,25 2 4,85 3 7,5 12 5,39 arecolin 6,48 15Example 5.2 1 5.25 2 4.85 3 7.5 12 5.39 arecoline 6.48 15

Det er vigtigt, at forbindelserne har en svag perifer aktivitet. Resultaterne ovenfor viser, at forbindelserne ikke er mere aktive end arecolin.It is important that the compounds have weak peripheral activity. The results above show that the compounds are no more active than arecoline.

Diarré-virkning 20 Undersøgelsen udføres på hanmus (CD! Charles Rivers) med en vægt på 25-30 g, som har været fastende i 6 timer. Forbindelsen, som er opløst i 5% Metocel, indgives ad oral vej ved hjælp af en øsofagsonde (spiserørssonde).Diarrhea effect 20 The study is performed on male mice (CD! Charles Rivers) weighing 25-30 g, which has been fasting for 6 hours. The compound, which is dissolved in 5% Metocel, is administered by oral route by means of an esophageal probe (esophageal probe).

Kontroldyr får kun bindemiddel.Control animals only get binder.

25 DK 167758 Bl 18DK 187758 Pg 18

Efter behandlingen anbringes dyrene separat i bure, hvis bund er dækket med trækpapir, og de observeres efter 30,60,120 og 180 min.After treatment, the animals are placed separately in cages, the bottom of which is covered with draft paper, and they are observed after 30,60,120 and 180 minutes.

De absorberende papirstykker skiftes efter hver observation. Fæces-konsistensen evalueres 5 efter en metode ifølge Randall og Baruth (Arch. Int. Pharmacodyn., 220, 94, 1976), idet følgende skala benyttes: 0: Fast konsistens 1: Let blød fæces med eller uden fugtige rande, 2: Let blød fæces med tilstedeværelse af en veldefineret fugtig ring, 10 3: Blød fæces med tilstedeværelse af en stor fugtig ring, 4: Fæces uden konsistens med tilstedeværelse af en meget stor fugtig ring.The absorbent pieces of paper are changed after each observation. The stool consistency is evaluated according to a method according to Randall and Baruth (Arch. Int. Pharmacodyn., 220, 94, 1976), using the following scale: 0: Solid consistency 1: Light soft stool with or without moist edges, 2: Light soft stool with the presence of a well defined moist ring, 10 3: Soft stool with the presence of a large moist ring, 4: Stool without consistency with the presence of a very large moist ring.

For hver forbindelse noteres den dosis, som fremkalder diarré hos 50% af dyrene efter en metode ifølge Miller og Tainter (Proc. Soc. Exp. Biol. Med., 57,261,1944).For each compound, the dose that causes diarrhea in 50% of the animals is noted according to a method of Miller and Tainter (Proc. Soc. Exp. Biol. Med., 57,261,1944).

1515

Eksempel _DE^i mg/kg_ 1 5 2 >100 3 0,85 12 1 arecolin 35Example _DE ^ in mg / kg_ 1 5 2> 100 3 0.85 12 1 arecoline 35

Diarré-aktiviteten er en klassisk bivirkning ved cholinomimetiske forbindelser, den må ikke være for høj.Diarrhea activity is a classic side effect of cholinomimetic compounds, it must not be too high.

20 Hvpotermisk aktivitet20 Hypothermic activity

Undersøgelsen udføres på hanmus (CD1 Charles Rivers) med en vægt på 25-30 g, som har været fastende i 6 timer.The study is performed on male mice (CD1 Charles Rivers) weighing 25-30 g, which has been fasting for 6 hours.

Kropstemperaturen registreres ved hjælp af en termoføler på ca. 1,5 cm, som er anbragt i 25 rectum og forbundet til en elektrisk temperaturregistreringsenhed.The body temperature is recorded by means of a thermal sensor of approx. 1.5 cm, which is arranged in 25 rectum and connected to an electric temperature sensing unit.

Forbindelserne indgives ad oral vej eller sub-cutant, og temperaturerne registreres til tiden 0, 30 min., 1 time, 2 timer og TA time efter behandlingen. 1The compounds are administered by oral or sub-cutant and the temperatures are recorded on time 0, 30 minutes, 1 hour, 2 hours and TA hours after treatment. 1

Graden af hypotermi evalueres som forskellen mellem de behandlede dyr og kontroldyrene og man bestemmer den dosis, som er nødvendig for at reducere kropstemperaturen med 1 °C.The degree of hypothermia is evaluated as the difference between the treated animals and the control animals and the dose needed to reduce body temperature by 1 ° C is determined.

DK 167758 B1 19DK 167758 B1 19

Den hypotermiske test viser den centrale cholinerge aktivitet og er den vigtigste test: Jo lavere værdi, desto mere effektiv forbindelse. Det er vigtigt, at forbindelserne, når de indgives peroralt og sub-cutant, er meget mere aktive end arecolin.The hypothermic test shows the central cholinergic activity and is the most important test: the lower the value, the more effective the compound. Importantly, when administered orally and sub-cutaneously, the compounds are much more active than arecoline.

Effektiv dosis (-1 °C) i mg/kg _Eksempel__peroralt__sub-cutant_ 1 9 11 2 12 25 3 0,87 0,91 12 0,77 0,72 arecolin 194 3 5Effective dose (-1 ° C) in mg / kg Example Example Percutaneous Subcutaneous 1 9 11 2 12 25 3 0.87 0.91 12 0.77 0.72 Arecoline 194 3 5

Forbindelsernes virkningstid evalueres ved brug af den dosis, som reducerer kropstemperaturen med 1-1,5 “C.The duration of action of the compounds is evaluated using the dose that reduces the body temperature by 1-1.5 ° C.

Variation i kropstemperatur 10Body temperature variation 10

Tid i min. efter behandlingenTime in min. after the treatment

Forbind- Dosis Admini- 0 30 60 120 180 else fra mg/kg strations- eksempel___vej_____;__ 1 10 p.O. 0 -0,7 -1,0 -0,2 +0,1 __10 s.c.__0__-0,6 -0,8 -0,2__0 2 20 p.o. +0,1 -1,3 -1,3 -0,9 0 __40 s.c. +0,1 -1,0 -1,4 -1,1 -0,8 3 1 p.o. +0,1 -1,1 -1,0 -0,1 -0,1 __1__S.C. +0,1 -1,0 -0,8 +0,1 +0,1 12 1 p.o. 0 -1,3 -1,1 0 0 __1__s.c. -0,1 -1,4 -1,3 +0,1__0 areco- 200 p.o. +0,1 -1,1 -1,0 -0,2 -0,1 lin, HBr 3,5 s.c. -0,1 -1,5 -0,1 +0,2 +0,2Connect Dose Admini- 0 30 60 120 180 else from mg / kg stration example ___ path _____; __ 1 10 p.O. 0 -0.7 -1.0 -0.2 + 0.1 __10 s.c .__ 0 __- 0.6 -0.8 -0.2__0 2 20 p.o. + 0.1 -1.3 -1.3 -0.9 0 __40 s.c. + 0.1 -1.0 -1.4 -1.1 -0.8 3 1 p.o. + 0.1 -1.1 -1.0 -0.1 -0.1 __1__S.C. + 0.1 -1.0 -0.8 + 0.1 + 0.1 12 1 p.o. 0 -1.3 -1.1 0 0 __1__s.c. -0.1 -1.4 -1.3 + 0.1__0 areco- 200 p.o. + 0.1 -1.1 -1.0 -0.2 -0.1 lin, HBr 3.5 s.c. -0.1 -1.5 -0.1 +0.2 +0.2

Claims

1-N-hydroxy-3-acetyl-1,2,5,6-tetrahydropyridine-O-methyl oxime.

Compounds according to claim 1, characterized in that R- | represents a linear alkyl group having from 1-4 carbon atoms.

Compounds according to claim 2, characterized in that R 1 represents a methyl group. 25

Compounds according to claims 1-3, characterized in that R represents a hydrogen atom or a hydroxyl group.

Compounds according to claims 1-3, characterized in that R represents a linear or branched, saturated or unsaturated alkyl group having from 1-4 carbon atoms.

Compounds according to claim 5, characterized in that R represents a methyl, ethyl, propyl or allyl group. 1

Compounds according to claims 1-6, characterized in that R 2 represents a hydrogen atom. DK 167758 B1

Compounds according to claims 1-6, characterized in that (¾ denotes an alkyl group having from 1-4 carbon atoms and especially a methyl group.

Compounds according to claim 1, characterized in that they are selected from 5 1-methyl-3-acetyl-1,2,5,6-tetrahydropyridine-O-methyloxime and the hydrochloride thereof, 3-acetyl-1,2,5 , 6-tetrahydropyridine-0-methyloxime and its hydrochloride,

Process for the preparation of a compound according to claim 1, characterized in that a) a compound of formula (II) is charged: 0

Wherein R 1 represents the same as in claim 1, reacting with a compound of formula NH 2 OR 2 (n 1) or a salt thereof, wherein R 2 represents the same as in claim 1, to form compound 25 of formula (IV): 1 Qpc = N ° R 2 (IV) 30 which is reacted with an alkyl halide of formula (V): R'-Hal (V) wherein Hal represents a halogen atom and R 'represents a linear or branched, saturated or unsaturated alkyl group having up to 8 carbon atoms, or R 'represents a cycloalkyl group having up to DK 167758 B1 8 carbon atoms or an aralkyl group having up to 10 carbon atoms, forming a compound of formula (VI): I1 Gr01' 5 ¥ (VI R 1 + Hal ~ which is reacted with a hydrogenating agent to give a compound of formula (IA): wherein R 1, R 1 and R 2 represent the same as mentioned above, which compound converting it into a salt, if desired, or b) leaving a compound of formula (ΓΑ): 20 I C rc = NOH «1> R" 25 where R "represents an aralkyl group of up to 10 carbon atoms and R 1 represents the same as in claim 1, reacting with a silylating agent to form a compound of formula (VII): R N o $ in <elc3> 3 ^ R "2 2 where alC3 represents an alkyl group of from 1-8 carbon atoms, which compound is reacted with a decomposing agent to form a compound of formula (IU):? In which R 1 has the same meaning as mentioned above, which compound is converted to a salt, if desired, or that a compound of formula (VIII): I (VIII) is added. 15 wherein R 1 and R 2 have the same meaning as in claim 1, reacting with a reducing agent to give a compound of formula (IF):

20. I1 rVNOR2 w T OH 25 wherein R 1 and R 2 have the same meaning as mentioned above, which compound, if desired, is converted to a salt.

Pharmaceutical compositions, characterized in that these compositions contain as at least one of the compounds according to claims 1-9. 30