DK155368B

DK155368B - Oxadiazolylpiperidine compounds, and pharmaceutical preparation comprising such compounds

Info

Publication number: DK155368B
Application number: DK444087A
Authority: DK
Inventors: Per Sauerberg; Frank Waetjen; Leif Helth Jensen; Jens William Kindtler
Original assignee: Ferrosan As
Priority date: 1986-09-08
Filing date: 1987-08-26
Publication date: 1989-04-03
Also published as: DK444087A; DK155368C; DK444087D0

Description

iin

DK 155368 BDK 155368 B

Oxadiazolylpiperidinforbindelser, og farmaceutisk præparat indeholdende sådanne forbindelser 5 Opfindelsen angår hidtil ukendte terapeutisk aktive piperi-dinforbindelser og farmaceutiske præparater omfattende forbindelserne, som er egnet til brug ved stimulering af de cognitive funktioner af forhjerne og hippocampus hos pattedyr, inklusiv mennesker, og i behandling af Alzheimers syg-10 dom. De nye forbindelser ifølge opfindelsen er nyttige som stimulanter af den cognitive funktion af forhjernen og hippocampus i pattedyr og i særdeleshed i behandlingen af Alzheimers sygdom.The invention relates to novel therapeutically active piperidine compounds and pharmaceutical compositions comprising the compounds suitable for use in stimulating the cognitive functions of the brain and mammalian hippocampus, including in humans, and in the treatment of Alzheimer's, and in the treatment of Alzheimer's. illness. The novel compounds of the invention are useful as stimulants of the cognitive function of the forebrain and hippocampus in mammals and in particular in the treatment of Alzheimer's disease.

15 På grund af den generelt forøgede folkesundhed i den vestlige verden, er aldersoms-lignende sygdomme betydelig mere almindelige nu end før i tiden og vil sandsynligvis være endnu mere almindelige fremover.15 Due to the generally increased public health of the western world, age-like diseases are now much more common now than in the past and are likely to be even more common in the future.

20 Et af de alderdoms-relaterede symptomer er en reduktion af de cognitive funktioner. Dette symptom er specielt udpræget i den patofysiologiske sygdom Alzheimers sygdom. Denne sygdom er ledsaget af, og sandsynligvis også forårsaget af, en optil 90% degeneration af de muscarine cholinerge neuroner 25 i nucleus basalis, som er en del af substantia innominata. Disse neuroner projekterer til den prefrontale cortex og hippocampus og har en generelt stimulerende effekt på de cognitive funktioner i forhjernen såvel som i hippocampus, nemlig indlæring, association, konsolidering og genkaldel-30 se.20 One of the age-related symptoms is a reduction in cognitive functions. This symptom is especially pronounced in the pathophysiological disease of Alzheimer's disease. This disease is accompanied by, and probably also caused by, up to 90% degeneration of the muscarinic cholinergic neurons 25 in the nucleus basalis, which is part of the substantia innominata. These neurons project to the prefrontal cortex and hippocampus and have a general stimulatory effect on the cognitive functions of the forebrain as well as in the hippocampus, namely learning, association, consolidation and recall.

Det er karakteristisk for Alzheimers sygdom, at skønt de cholinerge neuroner degenererer, eksisterer de postsynap-tiske muscarine receptorer i forhjernen og hippocampus sta-35 dig. Derfor er muscarine cholinerge agonister nyttige i behandlingen af Alzheimers sygdom og til at øge de cognitive funktioner hos ældre.It is characteristic of Alzheimer's disease that although the cholinergic neurons degenerate, the postsynaptic muscarinic receptors exist in the forebrain and hippocampus steadily. Therefore, muscarinic cholinergic agonists are useful in the treatment of Alzheimer's disease and in increasing the cognitive functions of the elderly.

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Det er velkendt, at arecolin (methyl l-methyl-l,2,5,6-tetra-hydropiperidin-3-carboxylat) er en sådan cholinerg agonist.It is well known that arecoline (methyl 1-methyl-1,2,5,6-tetrahydropiperidine-3-carboxylate) is such a cholinergic agonist.

Arecolin har imidlertid en meget kort biologisk halverings-5 tid og en lille separation mellem centrale og perifere muscarine effekter. Endvidere er arecolin en temmelig toksisk forbindelse.However, arecoline has a very short biological half-life and a small separation between central and peripheral muscarinic effects. Furthermore, arecoline is a rather toxic compound.

Fra US patentskrift nr. 3,996,748 kendes 1-substituerede 10 piperidinderivater, der i piperidinringens 4-stilling kan være substitueret med en 5-cyclopropyl-l,2,4-oxadiazol-3-yl gruppe. Disse forbindelser angives at have anti-psykotiske, neurologiske og analgesiske egenskaber.U.S. Patent No. 3,996,748 discloses 1-substituted 10 piperidine derivatives which, in the 4-position of the piperidine ring, may be substituted by a 5-cyclopropyl-1,2,4-oxadiazol-3-yl group. These compounds are said to have anti-psychotic, neurological and analgesic properties.

15 Det er et formål med herværende opfindelse at finde nye muscarine cholinerge forbindelser med forbedret virkning i forhold til arecolin.It is an object of the present invention to find new muscarinic cholinergic compounds with improved efficacy over arecoline.

De nye forbindelser ifølge opfindelsen, er piperidinforbin-20 delser med den almene formel 1 hvori 30 mindst en af R3, R4, og R5 er jJL*· eller og den anden eller de andre uafhængigt er H eller C^_g-alkyl, hvori R' er C^g-alkyl, phenyl, thienyl, cyclopropyl eller 35 C1_2~alkoxymethyl ; og R1 og R6 uafhængigt er H eller C1_g-alkyl og 3The novel compounds of the invention are piperidine compounds of general formula 1 wherein at least one of R3, R4, and R5 is jJL * or and the other or others is independently H or C1-6 alkyl, wherein R 'is C 1-6 alkyl, phenyl, thienyl, cyclopropyl or C 1-10 alkoxymethyl; and R 1 and R 6 are independently H or C 1-6 alkyl and 3

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WW er 'ch^ch7 e^er te' ' \ / \ / \ og salte deraf med en farmaceutisk acceptabel syre.WW is 'ch ^ ch7 e ^ is tea' \ / \ / \ and its salts with a pharmaceutically acceptable acid.

55

Eksempler på sådanne salte inkluderer uorganiske og organiske syre additions salte såsom hydrochloridet, hydrobro-midet, sulfatet, fosfatet, acetatet, fumaratet, maleatet, citratet, laktatet, tartratet, oxalatet, eller lignende 10 farmaceutisk acceptable uorganiske eller organiske syre additions salte.Examples of such salts include inorganic and organic acid addition salts such as the hydrochloride, hydrobromide, sulfate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts.

Forbindelserne ifølge opfindelsen fremstilles ved en fremgangsmåde der omfatter 15The compounds of the invention are prepared by a process comprising 15

a) omsætning af et reaktivt derivat af en forbindelse med den almene formel IIa) reacting a reactive derivative of a compound of general formula II

’ & - 25 hvori r\ r®, og har de ovennævnte betydninger og'& - 25 wherein r \ r®, and has the above meanings and

hvori mindst en af R3', R4' og R5' er C02H eller et reak-30 tivt derivat deraf, såsom en ester, og de andre uafhængigt er H eller C^g- alkyl, med en forbindelse med den almene formel IIIwherein at least one of R 3 ', R 4' and R 5 'is CO 2 H or a reactive derivative thereof, such as an ester, and the others are independently H or C 1-6 alkyl, with a compound of the general formula III

R'-C(=N0H)NH2 IIIR'-C (= NOH) NH2 III

35 435 4

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hvori R' har den ovennævnte betydning til dannelse af en 3 forbindelse med den almene formel I, hvori mindst en af R , 4 5 R , og R er 5 P-η -ζ,Μ·wherein R 'is as defined above to form a 3 compound of general formula I wherein at least one of R, 45 is R, and R is 5 P-η -ζ, Μ ·

MM

hvori R' har den ovennævnte betydning,wherein R 'is as defined above,

10 b) omsætning af en forbindelse med den almene formel IIB) reacting a compound of general formula II

if .if.

i’ 20 hvori r\ R^, og >—( har de ovennævnte betydninger og 3« λ* 5» hvori mindst en af R , R , og R er CN og de andre uafhængigt er H eller C. fi-alkyl, med NHL OH til dannelse af en x~o z 2 f forbindelse med den almene formel II hvori mindst en af R , 4' 5' 25 R , og R er C(=N0H)NH2 og de andre uafhængigt er H eller C1_g- alkyl, og omsætning af denne forbindelse med R'-COCl eller (R'-C0)90 til dannelse af en forbindelse med den al- z 3 4 5 mene formel I, hvori mindst en af R ,R , og R erin '20 wherein r \ R 1, and> - (have the above meanings and 3' λ * 5 'wherein at least one of R, R, and R is CN and the others are independently H or C 1-6 alkyl, with NHL OH to form an x ~ oz 2 f compound of general formula II wherein at least one of R, 4 '5' 25 R, and R is C (= NOH) NH 2 and the others are independently H or C 1-6 alkyl, and reacting this compound with R'-COCl or (R'-CO) 90 to form a compound of the general formula I wherein at least one of R, R, and R is

30 r-P30 r-P

-Q-« hvori R’ har den ovennævnte betydning.-Q- 'wherein R' has the above meaning.

35 *****35 *****

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55

De farmakologiske egenskaber af forbindelserne ifølge opfindelsen kan illustreres ved at bestemme deres evne til at 3 3 hæmme den specifikke binding af H-QNB ( H-quinuclidinyl benzilat) med 50%. Den hæmmende effekt af en substans af 3 5 H-QNB bindingen til hjernemembraner afspejler affiniteten af forbindelsen for de muscarine acetylcholin receptorer. (Yamamura, H.I. og Snyder, S.H., Proc. Natl. Acad. Sci. 71, 1725-29 (1979)). Testen udføres som følger: 10 Frisk hel forhjerne fra han Wistar rotter (200-250 g) homogeniseres i en Ultra-Turrax homogenisator (5-10 s) i volumener af 0,32 M sucrose. Homogenatet centrifugeres ved 4,300 x g i 5 min. Bundfaldet kasseres og supernatanten centrifugeres ved 40,000 x g i 15 min. Det endelige bundfald rehomo-15 geniseres i 50 mM K^PO^, pH 7.1 (1000 ml per g oprindeligt væv) og dette rå membranpræparat benyttes til bindings assay'ene. Til 2,5 ml vævssuspension tilsættes 25 μΐ test- 3 opløsning1 og 25 μΐ H-QNB (1 nM slutkoncentration). Prøverne blandes grundigt og inkuberes ved 37°C i 20 min. Efter 20 inkubering, bliver prøverne hældt direkte på GF/C glasfiberfiltre med sug og vaskes straks 2 gange med 10 ml buffer ved 0°C. Non-specifik binding dobbeltbestemmes ved at anvende atropin (1 pg/ml, slutkoncentration) som testsubstans. Radioaktiviteten i filtrene bestemmes på sædvanlig vis ved 25 flydende scintilationstælling. Specifik binding er total binding minus non-specifik binding.The pharmacological properties of the compounds of the invention can be illustrated by determining their ability to inhibit the specific binding of H-QNB (H-quinuclidinyl benzilate) by 50%. The inhibitory effect of a substance of the 35 H-QNB binding to brain membranes reflects the affinity of the compound for the muscarinic acetylcholine receptors. (Yamamura, H.I. and Snyder, S.H., Proc. Natl. Acad. Sci. 71, 1725-29 (1979)). The test is performed as follows: 10 Fresh whole brain from Wistar rats (200-250 g) is homogenized in an Ultra-Turrax homogenizer (5-10 s) in volumes of 0.32 M sucrose. The homogenate is centrifuged at 4,300 x g for 5 min. The precipitate is discarded and the supernatant is centrifuged at 40,000 x g for 15 min. The final precipitate rehomo-15 is generated in 50 mM K 2 PO 2, pH 7.1 (1000 ml per g of original tissue) and this crude membrane preparation is used for the binding assays. To 2.5 ml of tissue suspension are added 25 μΐ of test 3 solution1 and 25 μΐ of H-QNB (1 nM final concentration). The samples are thoroughly mixed and incubated at 37 ° C for 20 min. After 20 incubation, the samples are poured directly onto GF / C glass fiber filters with suction and washed immediately 2 times with 10 ml buffer at 0 ° C. Non-specific binding is double-determined using atropine (1 µg / ml, final concentration) as the test substance. The radioactivity in the filters is usually determined by 25 scintillation liquid counts. Specific binding is total binding minus non-specific binding.

Testforbindelsen opløses i 10 ml 96% ethanol (hvis nødvendigt, tilsættes 25 μΐ IN HC1 og der varmes på et dampbad i 30 mindre end 5 minutter) til en koncentration på 0,22 mg/ml.Dissolve the test compound in 10 ml of 96% ethanol (if necessary, add 25 μΐ IN HCl and heat on a steam bath for less than 5 minutes) to a concentration of 0.22 mg / ml.

Tre fortyndinger fremstilles i 48% ethanol (1.1 pg/ml, 11 pg/ml og 110 pg/ml). Koncentrationer af 10, 100 og 1000 ng/ml (slutkoncentration) tilsættes til dublerede assays. 25-75% hæmning af specifik binding skal opnås før beregning 35 af IC50.Three dilutions are made in 48% ethanol (1.1 pg / ml, 11 pg / ml and 110 pg / ml). Concentrations of 10, 100 and 1000 ng / ml (final concentration) are added to duplicate assays. 25-75% inhibition of specific binding must be achieved before calculation of IC50.

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Testværdien vil blive givet som IC^q (koncentration/pg/ml) af testforbindelsen som hæmmer den specifikke binding af 3H-QNB med 50%.The test value will be given as IC ^ q (concentration / µg / ml) of the test compound which inhibits the specific binding of 3 H-QNB by 50%.

5 IC(-q= (anvendt testsubstans koncentration) x - pg/kg \-5 IC (-q = (concentration of test substance used) x - pg / kg

Cx 10 hvor Co er den specifikke binding i kontrol assays og Cx er den specifikke binding i test assay*et (beregningen forudsætter normal masseaktion interaktion).Cx 10 where Co is the specific binding in control assays and Cx is the specific binding in the test assay * (the calculation assumes normal mass-action interaction).

Testresultater opnået ved at teste nogle af forbindelserne 15 ifølge opfindelsen vil fremgå af følgende tabel 1.Test results obtained by testing some of the compounds of the invention will be shown in the following Table 1.

TABEL 1 & Hæmning m " vitro R1 r3 r4 r5 r6 0^^ \ / (¾ Η Η H fe—cv 3.5 25 0—N \ / 0¾ Η Η H /C—C\ 2.0 N-O \ / (3¾ Η Η H f—\ 3.2 30 Qij· Η Η H 4.9 H Η Η H 4.7 / \ ™3 _?'£___ Η H (¾ V=c' 3.3 35 H 0-N H OL Η V—rf 7.5 ΛΛ' * / ~' *) 0¾ OO^ Η Η H --..0 * ) arecolin kendt sammenligningsfarbindelseTABLE 1 & Inhibition with vitro R1 r3 r4 r5 r6 0 ^^ \ / (¾ Η Η H fe — cv 3.5 25 0 — N \ / 0¾ Η Η H / C — C \ 2.0 NO \ / (3¾ Η Η H f— \ 3.2 30 Qij · Η Η H 4.9 H Η Η H 4.7 / \ ™ 3 _? '£ ___ Η H (¾ V = c' 3.3 35 H 0-NH OL Η V — rf 7.5 ΛΛ '* / ~ '*) 0¾ OO ^ Η Η H - .. 0 *) arecoline known comparative compound

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Forbindelsen ifølge opfindelsen kan sammen med et traditionelt adjuvans, en bærer eller et fortyndingsmiddel, og hvis ønsket i form af et farmaceutisk acceptabelt syre additions salt deraf, formgives til farmaceutiske sammensætninger, og 5 enhedsdoser heraf, og kan i sådan form anvendes som faste materialer, såsom tabletter eller fyldte kapsler, eller som væsker, såsom opløsninger, suspensioner, emulsioner, eliksirer, eller kapsler fyldt med samme, alle beregnet på oral anvendelse, eller de kan fremstilles til suppositorier til 10 rectal indgivelse eller i form af sterile, injicerbare opløsninger til parenteral (inklusiv subkutane anvendelser). Sådanne farmaceutiske præparationer og enhedsdosisformer heraf kan omfatte traditionelle bestanddele i traditionelle mængder, med eller uden yderligere aktive forbindelser eller 15 principper, og sådanne enheddosisformer kan indeholde en hvilken som helst hensigtsmæssig effektiv muscarin choli-nerg agonistisk mængde af den aktive forbindelse svarende til den daglige dosis, det er hensigten at anvende. Tabletter indeholdende ti (10) milligram af den aktive forbin-20 delse eller, mere bredt, ti (10) til hundrede (100) milligram per tablet, repræsenterer hensigtsmæssige repræsentative enhedsdosisformer.The compound of the invention, together with a conventional adjuvant, carrier or diluent, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof, can be formed into pharmaceutical compositions and unit doses thereof, and in such form can be used as solid materials. such as tablets or filled capsules, or as liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all intended for oral use, or may be prepared for suppositories for rectal administration or in the form of sterile injectable solutions for parenteral (including subcutaneous applications). Such pharmaceutical preparations and unit dosage forms thereof may comprise conventional constituents in traditional amounts, with or without additional active compounds or principles, and such unit dosage forms may contain any conveniently effective muscarinic cholinergic agonist amount of the active compound corresponding to the daily dose. , it is intended to apply. Tablets containing ten (10) milligrams of the active compound or, more broadly, ten (10) to one hundred (100) milligrams per tablet, represent appropriate representative unit dosage forms.

Forbindelserne ifølge opfindelsen kan således anvendes til 25 formulering af farmaceutiske præparater, f.eks. til oral eller parenteral indgivelse til pattedyr, inklusiv mennesker, ved fremgangsmåder som er velkendt indenfor galénisk farmaci.Thus, the compounds of the invention may be used to formulate pharmaceutical compositions, e.g. for oral or parenteral administration to mammals, including humans, by methods well known in the art of Galenic Pharmacy.

30 De farmaceutiske præparater ifølge opfindelsen er ejendommelige ved det i krav 3’s kendetegnede del angivne.The pharmaceutical compositions of the invention are peculiar to the feature of claim 3.

Traditionelle tilsætningsstoffer er sådanne farmaceutisk acceptable organiske eller uorganiske bærestoffer, egnet 35 til parenteral eller enteral indgivelse, og som ikke på skadelig måde reagerer med de aktive forbindelser.Conventional additives are such pharmaceutically acceptable organic or inorganic carriers, suitable for parenteral or enteral administration, and which do not adversely react with the active compounds.

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Eksempler på sådanne bærestoffer er vand, saltopløsninger, alkoholer, polyethylenglycoler, polyhydroxyethoxyleret ricinusolie, gelatine, laktose, amylose, magnesium stearat, talkum, kiselsyre, fedtsyre monoglycerider og diglycerider, 5 pentaerythritol fedtsyreestre, hydroxymethylcellulose og polyvinylpyrrolidone.Examples of such carriers are water, saline, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol polyacrylic acid esters, hydroxyl fatty acid esters, hydroxyl

De farmaceutiske præparationer kan steriliseres og blandes, hvis ønsket, med hjælpestoffer, smørende midler, salte på-10 virkende det osmotiske tryk, buffere, og/eller farvestoffer og lignende, som ikke reagerer på skadelig måde med de aktive forbindelser.The pharmaceutical preparations can be sterilized and mixed, if desired, with adjuvants, lubricants, salts acting on the osmotic pressure, buffers, and / or dyes and the like, which do not react adversely with the active compounds.

Til parenteral anvendelse er injiserbare opløsninger eller 15 suspensioner fortrinsvis vandige opløsninger af den aktive forbindelse opløst i polyhydroxyleret ricinusolie, specielt egnede.For parenteral use, injectable solutions or suspensions are preferably aqueous solutions of the active compound dissolved in polyhydroxylated castor oil, particularly suitable.

Ampuller er hensigtsmæssige enhedsdoser.Ampoules are appropriate unit doses.

2020

Tabletter, drageer, eller kapsler med talkum og/eller kulhydratbærer eller binder eller lignende, fortrinsvis laktose og/eller majsstivelse og/eller kartoffelstivelse, er specielt egnede til oral anvendelse. En sirup, eliksir eller 25 lignende kan benyttes i tilfælde hvor der bruges en sødet bærer.Tablets, dragons, or capsules with talc and / or carbohydrate carrier or binder or the like, preferably lactose and / or corn starch and / or potato starch, are particularly suitable for oral use. A syrup, elixir or the like can be used in cases where a sweetened carrier is used.

Almindeligvis dispenseres forbindelserne ifølge opfindelsen i enhedsdosisform indeholdende 1-100 mg i en farmaceutisk 30 acceptabel bærer per enhedsdosis.Generally, the compounds of the invention are dispensed in unit dosage form containing 1-100 mg in a pharmaceutically acceptable carrier per unit dose.

Dosis af forbindelserne ifølge opfindelsen er 1-100 mg/dag, fortrinsvis 10-70 mg/dag, når de indgives til patienter, d.v.s. mennesker, som et lægemiddel.The dosage of the compounds of the invention is 1-100 mg / day, preferably 10-70 mg / day, when administered to patients, i.e. people, as a drug.

En typisk tablet som kan fremstilles ved traditionelle table tterings teknikker indeholder: 35A typical tablet, which can be prepared by traditional tableting techniques, contains: 35

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99

Aktiv forbindelse 5,0 mgActive compound 5.0 mg

Laktose 67,8 mg Ph.Eur.Lactose 67.8 mg Ph.Eur.

Avicel 31,4 mg Ph.Eur.Avicel 31.4 mg Ph.Eur.

Amberlite® IRP 88 1,0 mg 5 Magnesii stearas 0,25 mg Ph.Eur.Amberlite® IRP 88 1.0 mg 5 Magnesii stearas 0.25 mg Ph.Eur.

På grund af den høje muscarine cholinerge receptor agonistiske aktivitet, er forbindelserne ifølge opfindelsen særdeles nyttige til behandling af symptomer relateret til en 10 reduktion af de cognitive funktioner i hjernen på pattedyr, når de indgives i en mængde som er effektiv til at stimulere de cognitive funktioner af forhjernen og hippocampus.Because of the high muscarinic cholinergic receptor agonistic activity, the compounds of the invention are particularly useful in treating symptoms related to a reduction in the cognitive functions of the mammalian brain when administered in an amount effective to stimulate the cognitive functions. of the forebrain and hippocampus.

Den vigtige stimulerende aktivitet af forbindelserne ifølge opfindelsen inkluderer både aktivitet mod den patofysiolo-15 giske sygdom, Alzheimer's sygdom, såvel som mod normal degeneration af hjernefunktion. Forbindelserne ifølge opfindelsen kan derfor indgives til et individ, d.v.s. en levende organisme, inkluderende et menneske, som har behov for stimulering af de cognitive funktioner af forhjernen og 20 hippocampus, og om ønsket i form af et farmaceutisk-accep-tabelt syre additions salt heraf (såsom hydrobromidet, hydrochloridet, eller sulfatet, under alle omstændigheder fremstillet på den sædvanlige eller traditionelle måde, d.v.s. ved inddampning af den frie base i opløsning med 25 syren), normalt samvirkende, samtidig, eller sammen med en farmaceutisk-acceptabel bærer eller fortynder, specielt og fortrinsvist i form en en farmaceutisk præparation heraf, enten ved oral, rektal, eller parenteral (inklusiv subcu-tan) indgivelse i en effektiv forhjerne og hippocampus sti-30 mulerende mængde, og under alle omstændigheder en mængde, som er effektiv til at øge de cognitive funktioner hos pattedyr på grund af deres muscarine cholinerge receptor agonistiske aktivitet. Passende dosisgrænser er 1-100 milligram daglig, 10-100 milligram daglig, og specielt 30-70 mi-35 lligram daglig, som sædvanlig afhængig af den eksakte måde, hvorpå indgivet, form hvorpå indgivet, den indikation hvorimod indgivelsen er rettet, individet involveret og legems-The important stimulatory activity of the compounds of the invention includes both activity against the pathophysiologic disease, Alzheimer's disease, as well as against normal degeneration of brain function. Therefore, the compounds of the invention may be administered to a subject, i.e. a living organism, including a human in need of stimulation of the cognitive functions of the forebrain and the hippocampus, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulfate, in all circumstances prepared in the usual or conventional manner, i.e. by evaporation of the free base in solution with the acid), usually cooperatively, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, in particular and preferably in the form of a pharmaceutical preparation thereof, either by oral, rectal, or parenteral (including subcutaneous) administration in an effective cerebral and hippocampal stimulating amount, and in any case an amount effective to increase the cognitive functions of mammals due to their muscarinic cholinergic receptor agonistic activity. Appropriate dose limits are 1-100 milligrams daily, 10-100 milligrams daily, and especially 30-70 milligrams daily, as usual, depending on the exact mode of administration, the form in which it is administered, the indication to which the administration is directed, the individual involved. and bodily

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xo vægten af individet involveret og preferencer og erfaringer hos de ansvarlige læger eller dyrlæger.xo the weight of the individual involved and the preferences and experiences of the responsible physicians or veterinarians.

Opfindelsen vil nu blive beskrevet nærmere med henvisning 5 til de følgende eksempler.The invention will now be described in more detail with reference to the following examples.

EKSEMPEL 1 l-methyl-3-(3-methoxymethy1-1,2,4-oxadiazol-5-yl)-1,2,5,6-10 tetrahydropyridinium oxalatExample 1 1-Methyl-3- (3-methoxymethyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Til en opløsning af natrium ethoxid (fremstillet af natrium (180 mg; 7.8 mmol)), destilleret ethanol (20 ml), molekylsi 15 (5 g)), tilsattes methoxymethylcarboxamid oxim (832 mg; 8 mmol). Blandingen omrørtes ved stuetemperatur i 10 min. hvorefter arecolin hydrobromid (1.0 g; 4.23 mmol) tilsattes. Blandingen opvarmedes til 80°C i 12 timer, filtreredes og inddampedes in vacuo. Til inddampningsresten tilsattes 20 vand (10 ml), og blandingen ekstraheredes med æter (3 x 25 ml). De sammenslåede ekstrakter tørredes (MgSO^) og inddampedes in vacuo. Efter at inddampningsresten var opløst i ethanol (99,9%; 5 ml) tilsattes en opløsning af oxalsyre (350 mg; 3,9 mmol) i ethanol (99,9%; 10 ml). Tilsætning af 25 æter gav et analytisk rent produkt i et udbytte på 500 mg (40%). Smp. 153-154°C.To a solution of sodium ethoxide (prepared from sodium (180 mg; 7.8 mmol)), distilled ethanol (20 ml), molecular sieve (5 g)) was added methoxymethylcarboxamide oxime (832 mg; 8 mmol). The mixture was stirred at room temperature for 10 min. then arecoline hydrobromide (1.0 g; 4.23 mmol) was added. The mixture was heated to 80 ° C for 12 hours, filtered and evaporated in vacuo. To the evaporation residue was added 20 water (10 ml) and the mixture extracted with ether (3 x 25 ml). The combined extracts were dried (MgSO4) and evaporated in vacuo. After the residue was dissolved in ethanol (99.9%; 5 ml), a solution of oxalic acid (350 mg; 3.9 mmol) in ethanol (99.9%; 10 ml) was added. Addition of 25 ether gave an analytically pure product in a yield of 500 mg (40%). Mp. 153-154 ° C.

EKSEMPEL 2 30 l-Methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydropyridinium oxalatExample 2 1-Methyl-3- (3-methyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Denne forbindelse blev syntetiseret som beskrevet i eksem-35 pel 1 ved anvendelse af acetamid oxim i stedet for methoxymethylcarboxamid oxim. Krystallisation gav titelforbindelsen i 44% udbytte. Smp. 159-160°C.This compound was synthesized as described in Example 1 using acetamide oxime instead of methoxymethylcarboxamide oxime. Crystallization gave the title compound in 44% yield. Mp. 159-160 ° C.

(RS)-l-Methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl) piperidinium oxalat 5 -— 11 EKSEMPEL 3(RS) -1-Methyl-3- (3-methyl-1,2,4-oxadiazol-5-yl) piperidinium oxalate 5- 11 EXAMPLE 3

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Denne forbindelse blev syntetiseret som beskrevet ovenfor i eksempel 2 ved anvendelse af dihydroarecolin hydrobromid (Gloge et al., Br. J. Pharmac. Chemother. 27, 185 (1966)) 10 istedet for arecolin hydrobromid. Krystallisation gav titelforbindelsen i 44% udbytte. Smp. 132-133°C.This compound was synthesized as described above in Example 2 using dihydroarecoline hydrobromide (Gloge et al., Br. J. Pharmac. Chemother. 27, 185 (1966)) instead of arecoline hydrobromide. Crystallization gave the title compound in 44% yield. Mp. 132-133 ° C.

EKSEMPEL 4 15 (RS)-l-Methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl) piperidinium oxalatExample 4 (RS) -1-Methyl-3- (3-ethyl-1,2,4-oxadiazol-5-yl) piperidinium oxalate

Denne forbindelse syntetiseredes som beskrevet ovenfor i 20 eksempel 3 ved anvendelse af propionamid oxim i stedet for acetamid oxim. Krystallisation gav analytisk ren titelforbindelse i 33% udbytte. Smp. 145-146°C.This compound was synthesized as described above in Example 3 using propionamide oxime instead of acetamide oxime. Crystallization afforded analytically pure title compound in 33% yield. Mp. 145-146 ° C.

EKSEMPEL 5 25 (RS)-1-Methyl-3-(3-cyclopropyl-1,2,4-oxadiazol-5-y1) piperidinium oxalat 1 35EXAMPLE 5 (RS) -1-Methyl-3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) piperidinium oxalate

Denne forbindelse syntetiseredes som beskrevet ovenfor i eksempel 3 ved anvendelse af cyclopropylcarboxamid oxim i stedet for acetamid oxim. Krystallisation gav titelforbindelsen i 42% udbytte. Smp. 108-109°C.This compound was synthesized as described above in Example 3 using cyclopropylcarboxamide oxime instead of acetamide oxime. Crystallization gave the title compound in 42% yield. Mp. 108-109 ° C.

l-Methyl-4-(3-cyclopropyl-l;2,4-oxadiazol-5-yl) piperidinium oxalat 5 - 12 EKSEMPEL 61-Methyl-4- (3-cyclopropyl-1; 2,4-oxadiazol-5-yl) piperidinium oxalate 5-12 EXAMPLE 6

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Denne forbindelse syntetiseredes som beskrevet ovenfor i eksempel 5 ved anvendelse af 1-methyl-4-ethoxycarbonyl-piperidinium chloride (Lambrecht and Mutschler, Arzneimit-10 tel Forsoh. (Drug Res.) 23, 1427 (1973)) i stedet for dihy-droarecolin. Krystallisation gav titelforbindelsen i 50% udbytte. Smp. 168-169°C.This compound was synthesized as described above in Example 5 using 1-methyl-4-ethoxycarbonyl-piperidinium chloride (Lambrecht and Mutschler, Arzneimit-10 Forsoh. (Drug Res.) 23, 1427 (1973)) droarecolin. Crystallization gave the title compound in 50% yield. Mp. 168-169 ° C.

EKSEMPEL 7 15 l-Methyl-4-(3-methyl-l,2,4-oxadiazol-5-yl) piperidinium oxalat 20 Denne forbindelse syntetiseredes som beskrevet ovenfor i eksempel 6 ved anvendelse af acetamid oxime i stedet for cyclopropylcarboxamid oxi'm. Krystallisation gav titel forbindelsen i 53% udbytte. Smp. 173-174°C.EXAMPLE 7 1-Methyl-4- (3-methyl-1,2,4-oxadiazol-5-yl) piperidinium oxalate This compound was synthesized as described above in Example 6 using acetamide oxime instead of cyclopropylcarboxamide oxime. . Crystallization gave the title compound in 53% yield. Mp. 173-174 ° C.

25 EKSEMPEL 8 l-Methyl-4-(3-propyl-l,2,4-oxadiazol-5-yl) piperidinium oxalat 1 35EXAMPLE 8 1-Methyl-4- (3-propyl-1,2,4-oxadiazol-5-yl) piperidinium oxalate

Denne forbindelse blev syntetiseret som beskrevet ovenfor i eksempel 6 ved anvendelse af butanamid oxim. Krystallisation gav titelforbindelsen i 33% udbytte. Smp. 117-118°C.This compound was synthesized as described above in Example 6 using butanamide oxime. Crystallization gave the title compound in 33% yield. Mp. 117-118 ° C.

EKSEMPEL 9 l-Methyl-3-(3-propyl-l,2,4-oxadiazol-5-yl)-1,2,5,6- tetrahydropyridinium oxalat 5 - 13EXAMPLE 9 1-Methyl-3- (3-propyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate 5-13

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Denne forbindelse syntetiseredes som beskrevet ovenfor i eksempel 1 ved anvendelse af butanamid oxim i stedet for methoxymethylcarboxamid oxime. Krystallisation gav titel-10 forbindelsen i 32% udbytte. Smp. 153-154°C.This compound was synthesized as described above in Example 1 using butanamide oxime instead of methoxymethylcarboxamide oxime. Crystallization gave the title-10 compound in 32% yield. Mp. 153-154 ° C.

EKSEMPEL 10 l-Methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-1,2,5,6-15 tetrahydropyridinium oxalatEXAMPLE 10 1-Methyl-3- (3-ethyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Denne forbindelse blev syntetiseret som beskrevet i eksempel 1 ved anvendelse af propionamid oxim i stedet for me-20 thoxymethylcarboxamid oxime. Krystallisation gav titelforbindelsen i 25% udbytte. Smp. 168-169°C.This compound was synthesized as described in Example 1 using propionamide oxime instead of methoxymethylcarboxamide oxime. Crystallization gave the title compound in 25% yield. Mp. 168-169 ° C.

EKSEMPEL 11 25 l-Methyl-3-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydropyridinium oxalatEXAMPLE 11 1-Methyl-3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Denne forbindelse blev syntetiseret som beskrevet ovenfor i 30 eksempel 1 Ved anvendelse af cyclopropyl-carboxamid oxime i stedet for methoxymethylcarboxamid oxime. Krystallisation gav titelforbindelsen i 34% udbytte. Smp. 169-172°C.This compound was synthesized as described above in Example 1, using cyclopropyl-carboxamide oxime instead of methoxymethylcarboxamide oxime. Crystallization gave the title compound in 34% yield. Mp. 169-172 ° C.

35 1-Methyl-3-(3-phenyl-l,2,4-oxadiazol-5-yl)-1,2,5,6- tetrahydropyridinium oxalat 5 ----- 14 EKSEMPEL 121-Methyl-3- (3-phenyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate 5 ----- Example 12

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Denne forbindelse blev syntetiseret som beskrevet ovenfor i eksempel 1 ved anvendelse af benzamid oxim i stedet for me-thoxymethylcarboxamid oxim. Krystallisation gav titelfor-10 bindeisen i 16% udbytte. Smp. 185-186°C.This compound was synthesized as described above in Example 1 using benzamide oxime instead of methoxymethylcarboxamide oxime. Crystallization gave the title compound 10 ice in 16% yield. Mp. 185-186 ° C.

EKSEMPEL 13 a. 1-Methyl-l,2,5,6-tetrahydropyridin-3-carboxamid oxim 15 — — ---EXAMPLE 13 a. 1-Methyl-1,2,5,6-tetrahydropyridine-3-carboxamide oxime 15 - - ---

Til en opløsning af natrium methoxid, fremstillet af natrium (575 mg; 25 mmol) i methanol (30 ml), tilsattes hy-droxylamonium chloride (1,74 g; 25 mmol). Denne blanding 20 omrørtes ved stuetemperatur i 30 min. og filtreredes. En opløsning af 1-methyl-3-cyano-1,2,5,6-tetrahydropyridin (Liberatore et al., Tetrahedron Letters 46, 4735 (1968) (1,65 g; 13,5 mmol) i methanol (20 ml) tilsattes til dette filtrat. Reaktionsblandingen blev omrørt ved stuetemperatur 25 i 20 timer og inddampedes. Inddampningsresten extraheredes med ethanol (50 ml), filtreredes og inddampedes til den rene titelforbindelsen; 25% udbytte.To a solution of sodium methoxide prepared from sodium (575 mg; 25 mmol) in methanol (30 ml) was added hydroxylamonium chloride (1.74 g; 25 mmol). This mixture was stirred at room temperature for 30 min. and filtered. A solution of 1-methyl-3-cyano-1,2,5,6-tetrahydropyridine (Liberatore et al., Tetrahedron Letters 46, 4735 (1968) (1.65 g; 13.5 mmol) in methanol (20 ml The reaction mixture was stirred at room temperature 25 for 20 hours and evaporated The residue was extracted with ethanol (50 ml), filtered and evaporated to give the pure title compound; 25% yield.

b. l-Methyl-3-(5-methyl-l,2,4-oxadiazol-3-yl)-1,2,5,6- 30 tetrahydropyridinium oxalatb. 1-Methyl-3- (5-methyl-1,2,4-oxadiazol-3-yl) -1,2,5,6-tetrahydropyridinium oxalate

En opløsning af l-methyl-1,2,5,6-tetrahydropyridin-3-carbox-amid oxim (200 mg; 1,29 mmol) i eddikesyreanhydrid (5 ml) 35 blev opvarmet til 80°C i 24 timer. Efter inddampning in vacuo opløstes inddampningsresten i 4N NaOH (5 ml) og eks-traheredes med æter (3 x 25 ml). Æterfasen blev tørretA solution of 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxamide oxime (200 mg; 1.29 mmol) in acetic anhydride (5 ml) was heated to 80 ° C for 24 hours. After evaporation in vacuo, the residue was dissolved in 4N NaOH (5 mL) and extracted with ether (3 x 25 mL). The ether phase was dried

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15 (MgS04), filtreret og inddampet in vacuo. Inddampningsres-ten opløstes i ethanol (99,9%; 5 ml) og tilsattes en opløsning af oxalsyre (150 mg; 1,1 mmol) i ethanol (99,9%; 5 ml). Tilsætning af æter gav titelforbindelsen i et udbytte på 5 52%. Smp. 173-174°C.15 (MgSO 4), filtered and evaporated in vacuo. The residue was dissolved in ethanol (99.9%; 5 ml) and a solution of oxalic acid (150 mg; 1.1 mmol) in ethanol (99.9%; 5 ml) was added. Addition of ether gave the title compound in a yield of 5 52%. Mp. 173-174 ° C.

EKSEMPEL 14 l-Methyl-3-(3-ethyl-l,2,4-oxadiazol~3-yl)-l,2,5-6-10 tetrahydropyridinium oxalatExample 14 1-Methyl-3- (3-ethyl-1,2,4-oxadiazol-3-yl) -1, 2,5-6-10 tetrahydropyridinium oxalate

Denne forbindelse syntetiseredes som beskrevet ovenfor i eksempel 13b ved anvendelse af propion anhydrid i stedet 15 for eddikesyreanhydrid. Krystallisation gav titel forbindelsen i 38% udbytte. Smp. 181-182°C.This compound was synthesized as described above in Example 13b using propionic anhydride instead of acetic anhydride. Crystallization gave the title compound in 38% yield. Mp. 181-182 ° C.

EKSEMPEL 15 20 1-Methyl-3-(5-propyl-l,2,4-oxadiazol-3-yl)-1,2,5,6- tetrahydropyridinium oxalatEXAMPLE 15 1-Methyl-3- (5-propyl-1,2,4-oxadiazol-3-yl) -1,2,5,6-tetrahydropyridinium oxalate

Denne forbindelse syntetiseredes som beskrevet ovenfor i 25 eksempel 13b ved anvendelse af butansyreanhydrid i stedet for eddikesyreanhydrid. Krystallisation gav titelforbindelsen i 65% udbytte. Smp. 170-171°C.This compound was synthesized as described above in Example 13b using butanoic anhydride instead of acetic anhydride. Crystallization gave the title compound in 65% yield. Mp. 170-171 ° C.

EKSEMPEL 16 30 a. l-Methyl-4-carbamoyl-l,2,5,6-tetrahydropyridinium chlorid 35 Til en opløsning af ammoniak i vand (25%; 50 ml) tilsattes l-methyl-4-ethoxycarbonyl-l,2,5,6-tetrahydropyridinium chlorid (Lambrecht og Mutschler, Arzneimittel Porsch. (Drug 16EXAMPLE 16 a. 1-Methyl-4-carbamoyl-1,2,5,6-tetrahydropyridinium chloride 35 To a solution of ammonia in water (25%; 50 ml) was added 1-methyl-4-ethoxycarbonyl-1,2 , 5,6-tetrahydropyridinium chloride (Lambrecht and Mutschler, Arzneimittel Porsch. (Drug 16

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Res.) 23, 1427 (1973)) (4,5 g; 21,9 mmol) og blandingen om-rørtes ved stuetemperatur i 20 timer. Efter inddampning in vacuo, rekrystalliseredes inddampningsresten fra methanol og æter. Smp. 191-192°C.Res. (23, 1427 (1973)) (4.5 g; 21.9 mmol) and the mixture was stirred at room temperature for 20 hours. After evaporation in vacuo, the residue was recrystallized from methanol and ether. Mp. 191-192 ° C.

5 b. l-Methyl-4-cyano-l,2,5,6-tetrahydropyridinB. 1-Methyl-4-cyano-1,2,5,6-tetrahydropyridine

En opløsning af l-methyl-4-carbamoyl-l,2,5,6-tetrahydropyri-10 dinium chloride (3,6 g; 20,4 mmol) i natriumhydroxid (4N; 30 ml) ekstraheredes med methylenchlorid (3 x 50 ml). De kombinerede ekstrakter tørredes, filtreredes og inddampedes til 50 ml. Til ekstraktet tilsattes en opløsning af triphe-nylphosphin (15,7 g; 60 mmol), brom (3,3 ml; 65 mmol) og 15 triethylamin (11 ml) i 150 ml methylenchlorid. Reaktionsblandingen omrørtes ved stuetemperatur i 20 timer og inddampedes in vacuo. Inddampningsresten opløstes i vand (50 ml) og vaskedes med methylenchlorid (3 x 75 ml). Til vandfasen tilsattes natriumhydroxyd (4N; 30 ml) og blandingen 20 ekstraheredes med methylenchlorid. De kombinerede ekstrakter tørredes, filtreredes og inddampedes in vacuo til titelforbindelsen.A solution of 1-methyl-4-carbamoyl-1,2,5,6-tetrahydropyridinium chloride (3.6 g; 20.4 mmol) in sodium hydroxide (4N; 30 ml) was extracted with methylene chloride (3 x 50 mL). The combined extracts were dried, filtered and evaporated to 50 ml. To the extract was added a solution of triphenylphosphine (15.7 g; 60 mmol), bromine (3.3 ml; 65 mmol) and 15 triethylamine (11 ml) in 150 ml of methylene chloride. The reaction mixture was stirred at room temperature for 20 hours and evaporated in vacuo. The residue was dissolved in water (50 ml) and washed with methylene chloride (3 x 75 ml). To the aqueous phase was added sodium hydroxide (4N; 30 ml) and the mixture was extracted with methylene chloride. The combined extracts were dried, filtered and evaporated in vacuo to give the title compound.

c. 1-Methyl-l,2,5,6-tetrahydropyridin-4-carboxamid oxim 25--c. 1-Methyl-1,2,5,6-tetrahydropyridine-4-carboxamide oxime 25 -

Denne forbindelse syntetiseredes som beskrevet i eksempel 13a ved anvendelse af l-methyl-4-cyano-l,2,5,6-tetrahydro-pyridin i stedet for 1-methyl-3-cyano-1,2,5,6-tetrahydro-30 pyridin.This compound was synthesized as described in Example 13a using 1-methyl-4-cyano-1,2,5,6-tetrahydro-pyridine instead of 1-methyl-3-cyano-1,2,5,6-tetrahydro -30 pyridine.

d. l-Methyl-4-(5-methyl-l,2,4-oxadiazol-3-yl)-1,2,5,6-tetrahydropyridinium oxalatd. 1-Methyl-4- (5-methyl-1,2,4-oxadiazol-3-yl) -1,2,5,6-tetrahydropyridinium oxalate

Denne forbindelse syntetiseredes som beskrevet i eksempel 13b ved anvendelse af 1-methyl-l,2,5,6-tetrahydropyridin- 35 17This compound was synthesized as described in Example 13b using 1-methyl-1,2,5,6-tetrahydropyridine-17

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4-carboxamid oxim i stedet for 1-methyl-l,2,5,6-tetrahydro-pyridin-3-carboxamid oxim. Krystalliastion gav titelforbindelsen i 13% udbytte. Snip. 204-205°C.4-carboxamide oxime instead of 1-methyl-1,2,5,6-tetrahydro-pyridine-3-carboxamide oxime. Crystallization gave the title compound in 13% yield. Snip. 204-205 ° C.

5 EKSEMPEL 17 l-Methyl-3-(3-isopropyl-l,2,4-oxadiazol-5-yl)-l,2,5,6-tetrahydropyridinium oxalat 10 816 mg (8.0 mmol) isopropylcarboxamidoxim tilsattes til en opløsning af natriumethoxid (7.8 mmol) i 20 ml destilleret ethanol og 5 g molekylsi. Blandingen rørtes ved stuetemperatur i 10 min. hvorefter 1.0 g(4.23 mmol) arecolin,HBr til-15 sattes. Blandingen varmedes til 80°C i 12 timer, hvorefter den filtreredes og inddampedes in vacuo. 10 ml vand tilsattes til inddampnlngsresten og blandingen ekstraheredes med æter (3 x 5 ml). De kombinerede ekstrakter blev tørret med MgSO^ og inddampedes in vacuo. Inddampningsresten opløstes 20 i 5 ml 99.9% ethanol og en opløsning af 380 mg (4.23 mmol) oxalsyre i 10 ml 99.9% ethanol tilsattes. Krystallisation fra æter gav titelforbindelsen i 37% udbytte. Smp. 133-134°C.EXAMPLE 17 1-Methyl-3- (3-isopropyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate 8166 mg (8.0 mmol) of isopropylcarboxamidoxime was added to a solution of sodium ethoxide (7.8 mmol) in 20 ml of distilled ethanol and 5 g of molecular sieve. The mixture was stirred at room temperature for 10 min. then 1.0 g (4.23 mmol) of arecoline, HBr was added. The mixture was warmed to 80 ° C for 12 hours, then filtered and evaporated in vacuo. 10 ml of water was added to the evaporation residue and the mixture was extracted with ether (3 x 5 ml). The combined extracts were dried over MgSO 4 and evaporated in vacuo. The residue was dissolved in 5 ml of 99.9% ethanol and a solution of 380 mg (4.23 mmol) of oxalic acid in 10 ml of 99.9% ethanol was added. Crystallization from ether gave the title compound in 37% yield. Mp. 133-134 ° C.

25 EKSEMPEL 18 1-Methyl-3-(3-butyl-l,2,4-oxadiazol-5-yl)-1,2,5,6-tetra-hydropyridinium oxalat 1 35EXAMPLE 18 1-Methyl-3- (3-butyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate 1

Forbindelse blev syntetiseret som beskrevet ovenfor i eksempel 17 ved anvendelse af pentanamidoxim i stedet for isopropylcarboxamidoxim. Smp. 121-123°C.Compound was synthesized as described above in Example 17 using pentanamidoxime instead of isopropylcarboxamidoxime. Mp. 121-123 ° C.

EKSEMPEL 19 18EXAMPLE 19 18

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3-(3-Ethyl-l,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydropyri-dinium oxalat 5 ---3- (3-Ethyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate 5 ---

Forbindelsen blev syntetiseret som beskrevet i eksempel 17 ved anvendelse af norarecoline,HCl og propionamidoxim iste-det for arecolin, HBr og isopropylcarboxamidoxim respektivt.The compound was synthesized as described in Example 17 using norarecoline, HCl and propionamidoximate for arecoline, HBr and isopropylcarboxamidoxime, respectively.

10 Smp. 161-163°C.M.p. 161-163 ° C.

De følgende forbindelser blev syntetiseret på nøjagtig samme måde ved anvendelse af butanamidoxim, pentanamidoxim, cyclopropylcarboxamidoxim og methoxymethylcarboxamidoxim 15 respektivt.The following compounds were synthesized in exactly the same manner using butanamidoxime, pentanamidoxime, cyclopropylcarboxamidoxime and methoxymethylcarboxamidoxime 15, respectively.

3-(3-Propyl-l,2,4-oxadiazol-5-yl)-l,2,5,6-tetrahydropyri-dinium oxalat. Smp. 162-163°C.3- (3-Propyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate. Mp. 162-163 ° C.

20 3-(3-Butyl-l,2,4-oxadiazol-5-yl)-l,2,5,6- tetrahydropyri- dinium oxalat. Smp. 207-208°C.3- (3-Butyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate. Mp. 207-208 ° C.

3-(3-Cyclopropyl-l,2,4-oxadiazol-5-yl)-l,2,5,6-tetrahydro-pyridinium oxalat. Smp. 169-171°C.3- (3-Cyclopropyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydro-pyridinium oxalate. Mp. 169-171 ° C.

25 3-(3-Methoxymethyl-l,2,4-oxadiazol-5-yl)-1,2,5,6- tetrahydro-pyridinium oxalat. Smp. 188-190°C.3- (3-Methoxymethyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydro-pyridinium oxalate. Mp. 188-190 ° C.

EKSEMPEL 20 30 a. 1-Ethyl-3-methoxycarbonyl-1,2,5,6-tetrahydro-pyridinium chlorid 35 0.509 ml (6.2mmol) ethyliodid blev tilsat til en blanding af 1.0 g(5.6 mmol) norarecolin og 2.1 g kaliumkarbonat i 20 ml acetone. Reaktionsblandingen refluksedes i 16 timer,EXAMPLE 20 a. 1-Ethyl-3-methoxycarbonyl-1,2,5,6-tetrahydro-pyridinium chloride 0.509 ml (6.2 mmol) of ethyl iodide was added to a mixture of 1.0 g (5.6 mmol) of norarecoline and 2.1 g of potassium carbonate. in 20 ml of acetone. The reaction mixture was refluxed for 16 hours,

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19 filtreredes og inddampedes in vacuo. Inddampningsresten opløstes dernæst i 10ml vandig 4N natriumhydroxid og ekstra-heredes dernæst med æter (3 x 50 ml). De kombinerede æterfaser blev tørret med MgS04, filtreret og inddampet in 5 vacuo. Inddampningsresten opløstes i methanol og 10 ml 2.3 N hydrogenchlorid i æter tilsattes. Krystallisation med æter gav titelforbindelsen.19 was filtered and evaporated in vacuo. The evaporation residue was then dissolved in 10 ml of aqueous 4N sodium hydroxide and then extracted with ether (3 x 50 ml). The combined ether phases were dried over MgSO 4, filtered and evaporated in vacuo. The residue was dissolved in methanol and 10 ml of 2.3 N hydrogen chloride in ether was added. Crystallization with ether gave the title compound.

b. l-Ethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-1,2,5,6-tetra-10 hydropyridinium oxalatb. 1-Ethyl-3- (3-ethyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Titelforbindelsen blev syntetiseret som beskrevet i eksempel 17 ved anvendelse af l-ethyl-3-methoxycarbonyl-l,2,5,6-15 tetrahydropyridinium chlorid og propionamidoxim istedet for arecolin, HBr og isopropylcarboxamidoxim respektivt. Smp.The title compound was synthesized as described in Example 17 using 1-ethyl-3-methoxycarbonyl-1, 2,5,6-15 tetrahydropyridinium chloride and propionamidoxime instead of arecoline, HBr and isopropylcarboxamidoxime, respectively. Mp.

150-151°C.150-151 ° C.

EKSEMPEL 21 20 l-Ethyl-3-(3-butyl-l,2,4-oxadiazol-5-yl)-l,2,5,6-tetrahydro-pyridinium oxalat 25 Forbindelsen blev syntetiseret som beskrevet ovenfor i eksempel 20b ved anvendelse af pentanamidoxim istedet for propionamidoxim. Smp. 102-104°C.EXAMPLE 21 1-Ethyl-3- (3-butyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate The compound was synthesized as described above in Example 20b by use of pentanamidoxime instead of propionamidoxime. Mp. 102-104 ° C.

EKSEMPEL 22 30 a. l-Propyl-3-methoxycarbonyl-l,2,5,6-tetrahydro-pyridinium chlorid 35 Forbindelsen blev syntetiseret som beskrevet i eksembel 20a ved anvendelse af propylbromid istedet for ethyliodid. Smp. 173-174°C.EXAMPLE 22 a. 1-Propyl-3-methoxycarbonyl-1,2,5,6-tetrahydro-pyridinium chloride The compound was synthesized as described in Example 20a using propyl bromide instead of ethyl iodide. Mp. 173-174 ° C.

b. l-Propyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)-1,2,5,6-tetra- hydropyridinium oxalatb. 1-Propyl-3- (3-methyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

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20 5 Forbindelsen blev syntetiseret som beskrevet i eksempel 17 ved anvendelse af l-propyl-3-methoxycarbonyl-l,2,5,6-tetra-hydropyridinium chlorid og acetamidoxim istedet for areco-lin, HBr og isopropylcarboxamidoxim respektivt. Smp. 64-66°C.The compound was synthesized as described in Example 17 using 1-propyl-3-methoxycarbonyl-1,2,5,6-tetrahydropyridinium chloride and acetamidoxime instead of arecoline, HBr and isopropylcarboxamidoxime, respectively. Mp. 64-66 ° C.

10 EKSEMPEL 23 l-Propyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-1,2,5,6-tetra-hydropyridinium oxalat 15 -EXAMPLE 23 1-Propyl-3- (3-ethyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Forbindelsen blev syntetiseret som beskrevet ovenfor i eksempel 22 ved anvendelse af propionamidoxim istedet for acetamidoxim. Smp. 71-78°C.The compound was synthesized as described above in Example 22 using propionamidoxime instead of acetamidoxime. Mp. 71-78 ° C.

20 EKSEMPEL 24 a. (RS)-3-Methoxycarbonyl-5-methyl-l,2,5,6-tetrahydro-pyridinium oxalat 25--EXAMPLE 24 a. (RS) -3-Methoxycarbonyl-5-methyl-1,2,5,6-tetrahydro-pyridinium oxalate 25-

En opløsning af (RS)-3-carboxy-5-methyl-l,2,5,6-tetrahydro-pyridinium bromid (Krogsgaard-Larsen et al.. Acta chem.A solution of (RS) -3-carboxy-5-methyl-1,2,5,6-tetrahydro-pyridinium bromide (Krogsgaard-Larsen et al. Acta chem.

Scand. B32, 327-334 (1978) i mættet methanolisk saltsyre 30 rørtes i 17- timer ved RT og inddampedes dernæst in vacuo. Inddampningsresten opløstes i vandig natriumhydroxid (4N) og ekstraheredes med æter. De kombinerede organiske faser tørredes med MgSO^, filtreredes og inddampedes in vacuo. Inddampningsresten opløstes i ethanol og en opløsning af 35 oxalsyre i ethanol tilsattes. Krystallisation fra æter gav titelforbindelsen. Smp. 184-185°C.Scand. B32, 327-334 (1978) in saturated methanolic hydrochloric acid was stirred for 17 hours at RT and then evaporated in vacuo. The residue was dissolved in aqueous sodium hydroxide (4N) and extracted with ether. The combined organic phases were dried over MgSO 4, filtered and evaporated in vacuo. The residue was dissolved in ethanol and a solution of oxalic acid in ethanol was added. Crystallization from ether gave the title compound. Mp. 184-185 ° C.

b. (RS)-5-Methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-1,2,5,6- tetrahydropyridinium oxalat 21b. (RS) -5-Methyl-3- (3-ethyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate 21

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5 Forbindelsen syntetiseredes som beskrevet i eksempel 17 ved anvendelse af (RS)-3-methoxycarbonyl-5-methyl-l,2,5,6-tetra-hydropyridinium oxalat og propionamidoxim istedet for areco-lin, HBr og isopropylcarboxamidoxim respektivt. Smp. 188-189°C.The compound was synthesized as described in Example 17 using (RS) -3-methoxycarbonyl-5-methyl-1,2,5,6-tetrahydropyridinium oxalate and propionamidoxime instead of arecoline, HBr and isopropylcarboxamidoxime respectively. Mp. 188-189 ° C.

10 EKSEMPEL 25 (RS)-5-Methyl-3-(3-buty1-1,2,4-oxadi azol-5-y1)-1,2,5,6-tetrahydropyridinium oxalat 15 -EXAMPLE 25 (RS) -5-Methyl-3- (3-butyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Forbindelsen syntetiseredes som beskrevet i eksempel 24b ved anvendelse af pentanamidoxim istedet for propionamidoxim. Smp. 189-191°C.The compound was synthesized as described in Example 24b using pentanamidoxime instead of propionamidoxime. Mp. 189-191 ° C.

20 EKSEMPEL 26 (RS)-1,6-Dimethyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydropyridinium oxalat 25 -EXAMPLE 26 (RS) -1,6-Dimethyl-3- (3-methyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Forbindelsen syntetiseredes som beskrevet i eksempel 17 ved anvendelse af 1,6-dimethyl-3-ethoxycarbonyl-l,2,5,6-tetra-hydropyridinium oxalat (Bishop, Z. Naturforsch. 25b, 1249-30 1251 (1970)) og acetamidoxim istedet for arecolin, HBr og isopropylcarboxamidoxim respektivt. Smp. 115-117°C.The compound was synthesized as described in Example 17 using 1,6-dimethyl-3-ethoxycarbonyl-1,2,5,6-tetrahydropyridinium oxalate (Bishop, Z. Naturforsch. 25b, 1249-30 1251 (1970)) and acetamidoxime instead of arecoline, HBr and isopropylcarboxamidoxime, respectively. Mp. 115-117 ° C.

De følgende forbindelser blev syntetiseret på nøjagtig samme måde ved anvendelse af propionamidoxim og pentanamidoxim 35 respektivt.The following compounds were synthesized in exactly the same manner using propionamidoxime and pentanamidoxime 35, respectively.

(RS)-1,6-Dimethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-1,2,5,6- tetrahydropyridinium oxalat- Smp. 148-149°C.(RS) -1,6-Dimethyl-3- (3-ethyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate M.p. 148-149 ° C.

2222

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(RS)-1,6-Dimethyl-3-(3-butyl-l,2,4-oxadiazol-5-yl)-1,2,5,6-5 tetrahydropyridinium oxalat. Smp. 141-142°C.(RS) -1,6-Dimethyl-3- (3-butyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate. Mp. 141-142 ° C.

EKSEMPEL 27 l-Methyl-3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-l,2,5,6-10 tetrahydropyridinium oxalat 0.182 ml (2.0 mmol) cyclopropylcarboxylsyrechlorid tilsattes til en opløsning af 200 mg (1.29 mmol) 1-methyl-l,2,5,6-15 tetrahydropyridin-3-carboxamidoxim i 8 ml DMF. Blandingen rørtes ved 55°C i 4 timer og inddampedes in vacuo. Inddamp-ningsresten refluxedes med eddikesyre i 16 timer. Efter inddampning in vacuo opløstes den resulterende inddampnings-rest i 5ml 4N vandig natriumhydroxid og ekstraheredes med 20 æter. De kombinerede æterfaser tørredes med MgSO^ og inddampedes in vacuo. Inddampningsresten indeholdt både titelforbindelsen og l-methyl-3-cyano-l,2,5,6-tetrahydropyridin. Efter kromatografisk separation krystalliseredes titelforbindelsen med oxalsyre fra ethanol og æter. Smp. 172-173 25 C.Example 27 1-Methyl-3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -1,5,6,6-tetrahydropyridinium oxalate 0.182 ml (2.0 mmol) of cyclopropylcarboxylic acid chloride was added to a solution of 200 ml. mg (1.29 mmol) of 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxamidoxime in 8 ml of DMF. The mixture was stirred at 55 ° C for 4 hours and evaporated in vacuo. The evaporation residue was refluxed with acetic acid for 16 hours. After evaporation in vacuo, the resulting evaporation residue was dissolved in 5ml of 4N aqueous sodium hydroxide and extracted with 20 ether. The combined ether phases were dried over MgSO 4 and evaporated in vacuo. The evaporation residue contained both the title compound and 1-methyl-3-cyano-1,2,5,6-tetrahydropyridine. After chromatographic separation, the title compound was crystallized with oxalic acid from ethanol and ether. Mp. 172-173 C.

EKSEMPEL 28 l-Methyl-4-(5-ethyl-l,2,4-oxadaiazol-3-yl)-l,2,5,6-tetra-30 hydropyridinium oxalatExample 28 1-Methyl-4- (5-ethyl-1,2,4-oxadiazol-3-yl) -1,2,5,6-tetrahydropyridinium oxalate

En opløsning af 1-methyl-l,2,5,6-tetrahydropyridin-4-carbox-amidoxim (200 mg; 1.0 mmol) i propionsyreanhydride (5 ml; 35 39 mmol) rørtes ved 80°C i 20 timer. Efter inddampning in vacuo opløstes inddampningsresten i vandig natriumhydroxid (4N) (5 ml) og ekstraheredes med æter (4 x 25 ml). De kom- 23A solution of 1-methyl-1,2,5,6-tetrahydropyridine-4-carboxamidoxime (200 mg; 1.0 mmol) in propionic anhydride (5 mL; 39 mmol) was stirred at 80 ° C for 20 hours. After evaporation in vacuo, the residue was dissolved in aqueous sodium hydroxide (4N) (5 ml) and extracted with ether (4 x 25 ml). They come 23

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binerede æterfaser tørredes med MgSO^, filtreredes og inddampedes in vacuo. Til en opløsning af inddampnnigsresten i ethanol (5 ml) tilsattes en opløsning af oxalsyre (90 mg; 1.0 mmol) i ethanol (5 ml). Krystallisation med æter gav 5 titelforbindelsen. Smp. 190-191°C.binary ether phases were dried over MgSO 4, filtered and evaporated in vacuo. To a solution of the evaporation residue in ethanol (5 ml) was added a solution of oxalic acid (90 mg; 1.0 mmol) in ethanol (5 ml). Crystallization with ether gave the title compound. Mp. 190-191 ° C.

EKSEMPEL 29 l-Methyl-4-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-l,2,5,6-10 tetrahydropyridinium oxalatEXAMPLE 29 1-Methyl-4- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -1,5,6,6-tetrahydropyridinium oxalate

Forbindelsen syntetiseredes som beskrevet i eksempel 27 ved anvendelse af 1-methyl-l,2,5,6-tetrahydropyridin-4-carbox-15 amidoxim istedet for 1-methyl-1,2,5,6-tetrahydropyridin-carboxamidoxim. Smp. 173-174°C.The compound was synthesized as described in Example 27 using 1-methyl-1,2,5,6-tetrahydropyridine-4-carboxamidoxime instead of 1-methyl-1,2,5,6-tetrahydropyridine carboxamidoxime. Mp. 173-174 ° C.

EKSEMPEL 30 20 (RS)-3-Methyl-5-(3-ethyl-l,2,4-oxadiazol-5-yl)-l,2,5,6-tetrahydropyridinium oxalatEXAMPLE 30 (RS) -3-Methyl-5- (3-ethyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Forbindelsen syntetiseredes som beskrevet i eksempel 17 ved 25 anvendelse af (RS,RS,RS)-4-hydroxy-5-methyl-3-methoxycarbo-nylpiperidiniumchlorid (Krogsgaard-Larsen et al., Acta Chem. Scand. B32, 327-334 (1978)) og propionamidoxim istedet for arecolin, HBr og isopropylcarboxamidoxim respektivt. Smp. 186-187°C.The compound was synthesized as described in Example 17 using (RS, RS, RS) -4-hydroxy-5-methyl-3-methoxycarbonylpiperidinium chloride (Krogsgaard-Larsen et al., Acta Chem. Scand. B32, 327-334 (1978)) and propionamidoxime instead of arecoline, HBr and isopropylcarboxamidoxime, respectively. Mp. 186-187 ° C.

30 EKSEMPEL 31 l-methyl-3-(3-(2-thienyl)-1,2,4-oxadiazol-5-yl)-l,2,5,6-tetrahydropyridinium oxalat 35 -EXAMPLE 31 1-Methyl-3- (3- (2-thienyl) -1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Forbindelsen syntetiseredes som beskrevet ovenfor i eksem-The compound was synthesized as described above in the Examples.

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24 pel 1 ved anvendelse af 2-thiophen carboxamidoxim istedet for methoxymethylcarboxamidoxim. Krystallisation gav titelforbindelsen i 46% udbytte. Smp. 149-150°C.24 column 1 using 2-thiophene carboxamidoxime instead of methoxymethylcarboxamidoxime. Crystallization gave the title compound in 46% yield. Mp. 149-150 ° C.

5 EKSEMPEL 32 l-methyl-3-(3-octyl-l,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahy-dropyridinium oxalat 10EXAMPLE 32 1-Methyl-3- (3-octyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate 10

Forbindelsen syntetiseredes som beskrevet ovenfor i eksempel 1 ved anvendelse af nonanamidoxim istedet for methoxymethylcarboxamidoxim. Krystallisation gav titelforbindelsen i 19% udbytte. Smp. 122-123°C.The compound was synthesized as described above in Example 1 using nonanamidoxime instead of methoxymethylcarboxamidoxime. Crystallization gave the title compound in 19% yield. Mp. 122-123 ° C.

15 EKSEMPEL 33 1-methyl-3-(3-pentyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetra-hydropyridinium oxalat 20 --EXAMPLE 33 1-Methyl-3- (3-pentyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Forbindelsen syntetiseredes som beskrevet ovenfor i eksempel 1 ved anvendelse af hexanamidoxim istedet for methoxymethylcarboxamidoxim. Krystallisation gav titelforbindelsen 25 i 40% udbytte. Smp. 149-150°C.The compound was synthesized as described above in Example 1 using hexanamidoxime instead of methoxymethylcarboxamidoxime. Crystallization gave the title compound 25 in 40% yield. Mp. 149-150 ° C.

EKSEMPEL 34 l-methyl-3-(3-heptyl-l,2,4-oxadiazol-5-yl)-l,2,5,6-tetra-30 tydropyridinium oxalatExample 34 1-Methyl-3- (3-heptyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Forbindelsen syntetiseredes som beskrevet ovenfor i eksempel 1 ved anvendelse af octanamidoxim istedet for methoxy-35 methyl carboxamidoxim. Krystallisation gav titelforbindelsen i 33% udbytte. Smp. 94-95°C.The compound was synthesized as described above in Example 1 using octanamidoxime instead of methoxymethyl carboxamidoxime. Crystallization gave the title compound in 33% yield. Mp. 94-95 ° C.

3-(3-methyl-l,2,4-oxadiazol-5-yl)-1,2, 5,6-tetrahydropyri- dinium oxalat 5 - 25 EKSEMPEL 353- (3-methyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate 5 - EXAMPLE 35

Pik' 'i K Π 7 /·; υ π ί- · ί \ 1-.).1 Ο (.> I.)Pik '' i K Π 7 / ·; υ π ί- · ί \ 1 -.). 1 Ο (.> I.)

Forbindelsen syntetiseredes som beskrevet ovenfor i eksempel 17 ved anvendelse af norarecolin, HC1 og acetamidoxim istedet for hhv. arecolin, HBr og isopropyl carboxamidoxim.The compound was synthesized as described above in Example 17 using norarecoline, HCl and acetamidoxime, respectively. arecoline, HBr and isopropyl carboxamidoxime.

10 Smp. 172-173°C.M.p. 172-173 ° C.

EKSEMPEL 36 3-(3-isopropyl-l,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydropy-15 ridinium oxalatEXAMPLE 36 3- (3-Isopropyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Forbindelsen syntetiseredes som beskrevet ovenfor i eksempel 17 ved anvendelse af norarecolin, HC1 istedet for are-20 colin, HBr. Smp. 199-200°C.The compound was synthesized as described above in Example 17 using norarecoline, HCl instead of are-20 choline, HBr. Mp. 199-200 ° C.

EKSEMPEL 37 3-(3-phenyl-l,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydropyri-25 dinium oxalatEXAMPLE 37 3- (3-Phenyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Forbindnelsen syntetiseredes som beskrevet ovenfor i eksempel 17 ved anvendelse af norarecolin, HC1 og benzamidoxim 30 istedet for hhv. arecolin, HBr og isopropyl carboxamidoxim.The compound was synthesized as described above in Example 17 using norarecoline, HCl and benzamidoxime 30 instead of respectively. arecoline, HBr and isopropyl carboxamidoxime.

Smp. 208-209°C.Mp. 208-209 ° C.

35 3-(3-(2-thienyl)-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydro- pyridinium oxalat 5 - 26 EKSEMPEL 383- (3- (2-thienyl) -1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate 5-26 EXAMPLE 38

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Forbindelsen syntetiseredes som beskrevet ovenfor i eksempel 17 ved anvendelse af norarecoline, HC1 og 2-thiophen carboxamidoxim istedet for hhv. arecolin, HBr og carbox-10 amidoxim. Smp. 199-200°C.The compound was synthesized as described above in Example 17 using norarecoline, HCl and 2-thiophene carboxamidoxime, respectively. arecoline, HBr, and carboxamido amidoxime. Mp. 199-200 ° C.

EKSEMPEL 39 1-methyl-4-(3-ethyl-l,2,4-oxadiazol-5-yl)-l,2,5,6-tetrahydro-15 pyridinium oxalatExample 39 1-Methyl-4- (3-ethyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate

Propionamidoxim (440 mg; 5.0 mmol), dicyclohexylcarbodiimide (1030 mg; 5.0 mmol) og 4-carboxy-l-methyl-l,2,5,6-tetrahy-20 dropyridinium chlorid (886 mg; 5.0 mmol) blandedes i destilleret DMF. Blandingen omrørtes ved 60°C i 1% time og ind-dampededs in vacuo. Bundfaldet tilsattes vand (50 ml) og blandingen extraheredes med toluen (3 x 75 ml). pH blev justeret til 10 ved hjælp af 4N NaOH og extraheredes med 25 toluen (3 x 100 ml). De kombinerede ekstrakter blev tørret (Na2S0^) og inddampedes in vacuo. Efter opløsning af ind-dampningsresten i ethanol (99.9%) (5 ml) blev tilsat en opløsning af oxalsyre (360 mg; 4.0 mmol) i ethanol (99.9%) (5 ml). Krystallisation gav titelforbindelsen i 15% udbytte.Propionamidoxime (440 mg; 5.0 mmol), dicyclohexylcarbodiimide (1030 mg; 5.0 mmol) and 4-carboxy-1-methyl-1,2,5,6-tetrahydropyridinium chloride (886 mg; 5.0 mmol) were mixed in distilled DMF. . The mixture was stirred at 60 ° C for 1% hour and evaporated in vacuo. The precipitate was added to water (50 ml) and the mixture extracted with toluene (3 x 75 ml). The pH was adjusted to 10 by 4N NaOH and extracted with 25 toluene (3 x 100 ml). The combined extracts were dried (Na 2 SO 4) and evaporated in vacuo. After dissolving the residue in ethanol (99.9%) (5 ml), a solution of oxalic acid (360 mg; 4.0 mmol) in ethanol (99.9%) (5 ml) was added. Crystallization gave the title compound in 15% yield.

30 Smp. 170- 171°C.M.p. 170-117 ° C.

35 EKSEMPEL 40 1-methyl-4-(3-phenyl-l,2,4-oxadiazol-5-yl)-1,2,5,6-tetra- hydropyridinium oxalat 5 -—- 27 OK 15536813EXAMPLE 40 1-Methyl-4- (3-phenyl-1,2,4-oxadiazol-5-yl) -1,2,5,6-tetrahydropyridinium oxalate 5-

Forbindelsen syntetiseredes som beskrevet ovenfor i eksempel 39 ved anvendeisse af benzamidoxim istedet for propion-amidoxim. Smp. 172-173°C.The compound was synthesized as described above in Example 39 using benzamidoxime instead of propionamidoxime. Mp. 172-173 ° C.

10 15 20 25 30 - 3510 15 20 25 30 - 35

Claims

1. Oxadiazolylpiperidine Compounds of General Formula I

Wherein R 4 is at least one of R, R, and R is or - and the other or others is independently H or C1-6 alkyl, wherein R 'is C8-6 alkyl, phenyl, thienyl , cyclopropyl or 20 C ^ g al alkoxymethyl; and R 1 and R 2 are independently H or C 1-6 alkyl and W is' -ch '' or y ~ \ 25 '' and salts thereof with a pharmaceutically acceptable acid.

2. A compound according to claim 1 characterized in that it is 1-methyl-3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -1, 2,5,6-tetrahydropyridine.

3. A pharmaceutical composition suitable for use in the stimulation of the cognitive functions of mammals and hippocampus in mammals, including humans, and in the treatment of

35 Alzheimer's disease, characterized in that it contains a compound according to claim 1 or 2, together with a pharmaceutically acceptable carrier or diluent.

Pharmaceutical composition according to claim 3, characterized in that it is in the form of an oral unit dose containing 1-100 mg of the active compound. 10 15 20 25 30 35