NO162071B - PROCEDURE TE FOR PREPARATION OF 6- (1-HYDROXY-2-DMINOMETHYL-ALLYL) -FURO- (3,4-C) -PYRIDINE DERIVATES. - Google Patents

PROCEDURE TE FOR PREPARATION OF 6- (1-HYDROXY-2-DMINOMETHYL-ALLYL) -FURO- (3,4-C) -PYRIDINE DERIVATES. Download PDF

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NO162071B
NO162071B NO853418A NO853418A NO162071B NO 162071 B NO162071 B NO 162071B NO 853418 A NO853418 A NO 853418A NO 853418 A NO853418 A NO 853418A NO 162071 B NO162071 B NO 162071B
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Andre Esanu
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Scras
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description

Denne oppfinnelse angår en ny fremgangsmåte for fremstilling av 6-(l-hydroksy-2-dimetylaminometyl-allyl)-furo-[3,4-c]-pyridin-derivater. This invention relates to a new process for the production of 6-(1-hydroxy-2-dimethylaminomethyl-allyl)-furo-[3,4-c]-pyridine derivatives.

Oppfinnelsen angår mer spesielt en ny fremgangsmåte for fremstilling av l,3-dihydro-6-(l-hydroksy-2-dimetylaminometyl-allyl)-7-hydroksy-furo-[3,4-c]-pyridin-derivater med den generelle formel: The invention relates more particularly to a new process for the preparation of 1,3-dihydro-6-(1-hydroxy-2-dimethylaminomethyl-allyl)-7-hydroxy-furo-[3,4-c]-pyridine derivatives with the general formula:

hvor Ax er aikyl med fra 1 til 5 karbonatomer; cykloheksyl,furyl fenyl eventuelt substituert med 1 til 2 halogenatomer, alkyl med 1 til 4 karbonatomer, alkoksy med fra 1 til 5 karbonatomer, trifluormetyl, dietylaminometoksy eller pyrolidinyletoksy, og A2 er hydrogen; fenyl eventuelt substituert med trifluormetyl, alkoksy med 1 til 5 karbonatomer, halogen eller tiometyl; furyl eller tienyl. wherein Ax is alkyl having from 1 to 5 carbon atoms; cyclohexyl, furyl phenyl optionally substituted with 1 to 2 halogen atoms, alkyl with 1 to 4 carbon atoms, alkoxy with from 1 to 5 carbon atoms, trifluoromethyl, diethylaminomethoxy or pyrrolidinylethoxy, and A 2 is hydrogen; phenyl optionally substituted with trifluoromethyl, alkoxy of 1 to 5 carbon atoms, halogen or thiomethyl; furyl or thienyl.

Forbindelsene som fremstilles ifølge oppfinnelsen, er av interesse på grunn av sin terapeutiske aktivitet, særlig på området diurese, reduksjon av blodtrykk, nyrebeskyttelse og også som antihistaminmidler. The compounds produced according to the invention are of interest due to their therapeutic activity, particularly in the area of diuresis, reduction of blood pressure, kidney protection and also as antihistamines.

Det er overraskende funnet at ved fremgangsmåten beskrevet i vår tidligere patentansøkning 85 0399, kan blokkeringstrinnet for OH-gruppen i 7-stilling utelates, og allikevel kan produktet fremstilles med et bedre utbytte. It has surprisingly been found that by the method described in our previous patent application 85 0399, the blocking step for the OH group in the 7-position can be omitted, and still the product can be prepared with a better yield.

Fremgangsmåten ifølge foreliggende oppfinnelse består således i at et 6-formyl-7-hydroksy-furo-[3,4-c]-pyridin-derivat med den generelle formel II The method according to the present invention thus consists in that a 6-formyl-7-hydroxy-furo-[3,4-c]-pyridine derivative of the general formula II

hvor og A2 har de ovenfor angitte betydninger, omsettes med et lite overskudd av 1-dimetyl-aminometyl-vinylmagnesiumbromid ved koketemperatur, i et ikke-polart oppløsningsmiddel såsom tetrahydrofuran. 6-formyl-7-hydroksy-furo-[3,4-c]-pyridin-derivater II kan oppnås fra de tilsvarende 6-metyl-7-hydroksy-derivater med den generelle formel III hvor A^ og A_ har de ovenfor angitte betydninger, ved det følgende reaksjonsforløp: where and A2 have the above meanings, is reacted with a small excess of 1-dimethyl-aminomethyl-vinylmagnesium bromide at boiling temperature, in a non-polar solvent such as tetrahydrofuran. 6-formyl-7-hydroxy-furo-[3,4-c]-pyridine derivatives II can be obtained from the corresponding 6-methyl-7-hydroxy derivatives of the general formula III where A^ and A_ have the above indicated meanings, by the following course of reactions:

Forbindelsene med formel III er beskrevet i våre patentansøkninger 82.0253 og 84.1322. The compounds of formula III are described in our patent applications 82.0253 and 84.1322.

Det er i henhold til foreliggende oppfinnelse overraskende funnet at den reaktive 7-OH-gruppe ikke medfører noen ulemper under omsetningen. Dette fremgår av den følgende tabell hvor det er foretatt en sammenligning med vår tidligere ansøkning 85.0399 hvor eksemplene angår fremstilling av de samme forbindelser som foreliggende oppfinnelse. Den tidligere ansøkning ble gjort ålment tilgjengelig efter foreliggende ansøknings prioritetsdato. According to the present invention, it has surprisingly been found that the reactive 7-OH group does not cause any disadvantages during the reaction. This is evident from the following table where a comparison has been made with our previous application 85.0399 where the examples relate to the production of the same compounds as the present invention. The previous application was made generally available after the priority date of the present application.

I tabellen er det i første spalte angitt utbyttet for de forskjellige forbindelser beskrevet i de 20 eksempler, mens det i annen spalte er angitt de samme tall multiplisert med 0,9, og i tredje spalte er angitt verdiene for de samme eksempler i foreliggende ansøkning. Eksemplene i de to ansøkninger angår fremstilling av de samme forbindelser. In the table, the yield for the various compounds described in the 20 examples is given in the first column, while the same numbers multiplied by 0.9 are given in the second column, and the values for the same examples in the present application are given in the third column. The examples in the two applications relate to the preparation of the same compounds.

I den tidligere ansøkning 85.0399 er de angitte utbytter basert på 7-benzyloksy-derivatet som utgangsmateriale, og dette er selvsagt oppnådd fra ,7-hydroksy-derivatet ved en omsetning hvor utbyttet aldri er så høyt som 100%. Under de beste betingelser er omdannelsen av 7-hydroksy-derivatet til 7-benzyloksy-derivatet foretatt med et utbytte på 90%, og dette er bakgrunnen for annen spalte i den følgende tabell. Det korrigerte utbyttet i spalte 2 kan sammenlignes airekte med utbyttet i spalte 3 eftersom utgangsmaterialet er nøyaktig det samme. In the previous application 85.0399, the stated yields are based on the 7-benzyloxy derivative as starting material, and this is of course obtained from the ,7-hydroxy derivative in a reaction where the yield is never as high as 100%. Under the best conditions, the conversion of the 7-hydroxy derivative to the 7-benzyloxy derivative is carried out with a yield of 90%, and this is the background for the second column in the following table. The corrected yield in column 2 can be directly compared to the yield in column 3 since the starting material is exactly the same.

Når det gjelder de verdier som er angitt i tabellen, er de utbytter som er oppnådd ved fremgangsmåten ifølge foreliggende oppfinnelse, i alle tilfeller bedre enn i henhold-til den tidligere ansøkning (minst 15% bedre og ofte ca. 50% bedre). Forskjellen er langt høyere enn hva man med rimelighet kunne vente. As regards the values indicated in the table, the yields obtained by the method according to the present invention are in all cases better than according to the previous application (at least 15% better and often about 50% better). The difference is far higher than what one could reasonably expect.

Fremstillingen av én av utgangsforbindeIsene, 1,3-dihydro-3-p-klorfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, skal i det følgende beskrives i detalj, idet andre utgangsmaterialer kan fremstilles på samme måte. a) I en 1-liter reaktor utstyrt med røre-, oppvarmnings- og avkjølings-innretninger, ble 22,3 g 1,3-dihydro-3-p-klorfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin behandlet ved 0°C, i nærvær av 300 ml metylendiklorid, med 18,2 g m-peroksybenzosyre som ble langsomt tilsatt. Efter omrøring natten over ved romtemperatur ble det tilsatt 150 ml av en 10% natriumsulfat-oppløsning. Efter omrøring og dekantering ble metylendiklorid-fasen vasket med den samme mengde av natriumsulfatoppløsning, to,ganger med 150 ml natriumbikarbonatoppløsning og tre ganger med 100 ml vann og derefter tørket over vannfritt natriumsulfat. Ved inndampning til tørrhet fikk man et beige bunnfall som ble vasket med petroleter, filtrert og tørket. Utbytte: 22,9 g (96%) av 1,3-dihydro-3-p-klorfenyl-6-metyl-7-hydroksy-furo-[3,4-c]-pyridin-N-oksyd. b) I den samme reaktor som ovenfor ble 22,9 g av forbindelsen oppnådd i foregående trinn behandlet ved 0-5°C, i nærvær av The production of one of the starting compounds, 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, will be described in detail below, as other starting materials can produced in the same way. a) In a 1-liter reactor equipped with stirring, heating and cooling devices, 22.3 g of 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo-[3, 4-c]-pyridine treated at 0°C, in the presence of 300 ml of methylene dichloride, with 18.2 g of m-peroxybenzoic acid which was added slowly. After stirring overnight at room temperature, 150 ml of a 10% sodium sulfate solution was added. After stirring and decanting, the methylene dichloride phase was washed with the same amount of sodium sulfate solution, twice with 150 ml of sodium bicarbonate solution and three times with 100 ml of water and then dried over anhydrous sodium sulfate. Evaporation to dryness gave a beige precipitate which was washed with petroleum ether, filtered and dried. Yield: 22.9 g (96%) of 1,3-dihydro-3-p-chlorophenyl-6-methyl-7-hydroxy-furo-[3,4-c]-pyridine-N-oxide. b) In the same reactor as above, 22.9 g of the compound obtained in the previous step was treated at 0-5°C, in the presence of

175 ml metylendiklorid, med 4,3 ml trifluoreddiksyreanhydrid som ble tilsatt dråpevis under omrøring. Blandingen ble omrørt natten over ved romtemperatur og derefter avkjølt og behandlet dråpevis med 9 5 ml metanol. Efter inndampning til tørrhet ble residuet tatt opp i 300 ml kloroform, vasket to ganger med 75 ml 10% natriumbikarbonatoppløsning og tre ganger med 100 ml vann og tørket på vannfritt natriumsulfat. Kloroformen ble avdampet, og residuet ble vasket med dietyleter og tørket under redusert trykk. Utbytte: 21,3 g (93%) av 1,3-dihydro-3-p-klorfenyl-6-hydroksymetyl-7-hydroksy-furo-[3,4-c]-pyridin. 175 ml of methylene dichloride, with 4.3 ml of trifluoroacetic anhydride added dropwise with stirring. The mixture was stirred overnight at room temperature and then cooled and treated dropwise with 95 mL of methanol. After evaporation to dryness, the residue was taken up in 300 ml of chloroform, washed twice with 75 ml of 10% sodium bicarbonate solution and three times with 100 ml of water and dried over anhydrous sodium sulfate. The chloroform was evaporated, and the residue was washed with diethyl ether and dried under reduced pressure. Yield: 21.3 g (93%) of 1,3-dihydro-3-p-chlorophenyl-6-hydroxymethyl-7-hydroxy-furo-[3,4-c]-pyridine.

c) 21,3 g av forbindelsen oppnådd i foregående trinn ble behandlet i en 2-liter reaktor med 27 g mangandioksyd i nærvær c) 21.3 g of the compound obtained in the previous step was treated in a 2-liter reactor with 27 g of manganese dioxide in the presence

av 0,9 1 kloroform ved 28-30°C under omrøring i 3 timer. Efter separering, filtrering, vasking med kloroform og derefter med etylacetat, ble oppløsningen inndampet til tørrhet, bg pastaen ble behandlet med isopropyloksyd og derefter med pentan. Man fikk således 20,1 g (95%) 1,3-dihydro-3-p-klorfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyri din. of 0.9 1 chloroform at 28-30°C with stirring for 3 hours. After separation, filtration, washing with chloroform and then with ethyl acetate, the solution was evaporated to dryness, bg the paste was treated with isopropyl oxide and then with pentane. 20.1 g (95%) of 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine was thus obtained.

De følgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.

Eksempel 1 Example 1

1, 3- dihydro- 3- metyl- 6-( l- hydroksy- 2- dimetylaminometyl- allyl)-7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- methyl- 6-( l- hydroxy- 2- dimethylaminomethyl- allyl)-7- hydroxy- furo- [ 3, 4- c]- pyridine

a) Fremstilling av organomagnesiumreagenset a) Preparation of the organomagnesium reagent

I en 2-liter reaktor utstyrt med oppyarmnings-, avkjølings-og omrørings-anordninger ble hellet under nitrogensirkulering, 19,4 g (0,8 mol) magnesium og 100 ml tetrahydrofuran, fortrinns-vis destillert på litiumaluminiumhydrid. Blandingen ble tilbakeløpsbehandlet. In a 2-liter reactor equipped with enrichment, cooling and stirring devices, 19.4 g (0.8 mol) magnesium and 100 ml tetrahydrofuran, preferably distilled on lithium aluminum hydride, were poured under nitrogen circulation. The mixture was refluxed.

Det ble langsomt tilsatt 132 g (0,8 mol) 3-dimetylamino-2-brom-l-propylen. Ingen ytre oppvarmning ble tilført, idet tilbakeløp ble opprettholdt og regulert ved tilsetning av denne forbindelse. Ved slutten av tilsetningen ble 1 liter destillert tetrahydrofuran tilsatt. Blandingen ble tilbakeløpsbehandlet i 2 timer og derefter avkjølt til 10°C. 132 g (0.8 mol) of 3-dimethylamino-2-bromo-1-propylene were added slowly. No external heating was added, as reflux was maintained and regulated by the addition of this compound. At the end of the addition, 1 liter of distilled tetrahydrofuran was added. The mixture was refluxed for 2 hours and then cooled to 10°C.

b) Reaksjon b) Reaction

Til reaksjonsblandingen fra foregående trinn ble langsomt Until the reaction mixture from the previous step became slow

tilsatt, under omrøring, 89 g (0,5 mol) 1,3-dihydro-3-metyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Temperaturen nådde ca. 25°C ved slutten av tilsetningen. Omrøring ble fortsatt natten over ved romtemperatur. Blandingen ble derefter avkjølt til 0°C, og 250 ml vann mettet med ammoniumklorid og 250 ml dietyleter ble tilsatt. Efter omrøring i 15 minutter ved romtemperatur ble det oppnådd en to-fase-blanding med en olje på toppen. added, with stirring, 89 g (0.5 mol) of 1,3-dihydro-3-methyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine. The temperature reached approx. 25°C at the end of the addition. Stirring was continued overnight at room temperature. The mixture was then cooled to 0°C, and 250 ml of water saturated with ammonium chloride and 250 ml of diethyl ether were added. After stirring for 15 minutes at room temperature, a two-phase mixture with an oil on top was obtained.

Blandingen ble separert, og den vandige fase ble ekstrahert to ganger med 250 ml porsjoner av dietyleter. Ekstraktene ble derefter satt til den oljeaktige fase som var vasket med vann tre ganger. Den oljeaktige fase ble derefter tørket på magnesiumsulfat, behandlet med kjønrøk, konsentrert til tørrhet og ekstrahert to ganger med 250 ml di isopropyleter. Ekstraktene ble filtrert, konsentrert (reduksjon til 1/4 av opprinnelig volum) og avkjølt natten over, hvilket førte til et bunnfall som ble separert og vasket med diisopropyleter. Utbytte: 105 g (80%). The mixture was separated and the aqueous phase was extracted twice with 250 ml portions of diethyl ether. The extracts were then added to the oily phase which had been washed with water three times. The oily phase was then dried over magnesium sulfate, treated with carbon black, concentrated to dryness and extracted twice with 250 ml of di isopropyl ether. The extracts were filtered, concentrated (reduction to 1/4 of original volume) and cooled overnight, giving a precipitate which was separated and washed with diisopropyl ether. Yield: 105 g (80%).

Fremstillingen av de andre forbindelser med formel I skjer efter samme fremgangsmåte, bortsett fra at i. trinn (b) The preparation of the other compounds of formula I takes place according to the same procedure, except that in step (b)

er utgangsmaterialet forskjellig. De følgende eksempler vil derfor referere til eksempel 1 og bare nevne det nye utgangs-materi alet, det totale utbytte og de karakteristiske data for den fremstilte forbindelse. is the starting material different. The following examples will therefore refer to example 1 and only mention the new starting material, the total yield and the characteristic data for the compound produced.

Eksempel 2 Example 2

1, 3- dihydro- 3- propyl- 6-( l- hydroksy- 2- dimetylaminometyl- allyl)-7- hydroksy- furo-[ 3, 4- c]- pyri din 1, 3- dihydro- 3- propyl- 6-(1- hydroxy- 2- dimethylaminomethyl- allyl)-7- hydroxy- furo-[ 3, 4- c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men ved å starte med 83 g (0,4 mol) 1,3-dihydro-3-propyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 66% av et produkt som smeltet ved 187-194°C (Tottoli), med dekomponering, og analysen av dette viste en god overensstemmelse med formelen <C>16<H>24<N>2°3' <2>HC1*The procedure according to example 1 was repeated, but starting with 83 g (0.4 mol) of 1,3-dihydro-3-propyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine. Yield: 66% of a product melting at 187-194°C (Tottoli), with decomposition, the analysis of which showed a good agreement with the formula <C>16<H>24<N>2°3' <2> HC1*

Eksempel 3 Example 3

1, 3- di hydro- 3- cykloheksyl- 6-( l- hydroksy- 2- dimetylaminoetyl-allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- cyclohexyl- 6-( l- hydroxy- 2- dimethylaminoethyl-allyl)- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 99 g (0,4 mol) 1,3-dihydro-3-cykloheksyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 59% av et produkt som smeltet ved 180-184°C (Tottoli), med dekomponering, og analysen av dette viste god overensstemmelse med formelen C19H28N2°3' 2HC1- The procedure according to example 1 was repeated, but starting with 99 g (0.4 mol) of 1,3-dihydro-3-cyclohexyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine. Yield: 59% of a product melting at 180-184°C (Tottoli), with decomposition, the analysis of which showed good agreement with the formula C19H28N2°3' 2HC1-

Eksempel 4 Example 4

1, 3- dihydro- 3- fenyl- 6-( l- hydroksy- 2- di metylaminometyl- ally1)-7- hydroksy- furo-[ 3, 4- c]- pyri di n 1, 3- dihydro- 3- phenyl- 6-(l- hydroxy- 2- dimethylaminomethyl- ally1)-7- hydroxy- furo-[ 3, 4- c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 99 g (0,4 mol) 1,3-dihydro-3-fenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 49% av et produkt som smeltet ved 210-215°C (Tottoli), med dekomponering, og analysen av dette produkt viste god overensstemmelse med formelen C19H22N2°3* 2HC1-The procedure according to example 1 was repeated, but starting with 99 g (0.4 mol) of 1,3-dihydro-3-phenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine. Yield: 49% of a product which melted at 210-215°C (Tottoli), with decomposition, and the analysis of this product showed good agreement with the formula C19H22N2°3* 2HC1-

Eksempel 5 Example 5

l, 3- dihydro- 3- p- klorfenyl- 6-( l- hydroksy- 2- dimetylaminometyl-allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyridin l, 3- dihydro- 3- p- chlorophenyl- 6-( l- hydroxy- 2- dimethylaminomethyl-allyl)- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 110 g (0,4 mol) 1,3-dihydro-3-p-klorfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 57% av et produkt som smeltet ved 195-200°C (Tottoli), med dekomponering, og analysen av dette produkt viste god overensstemmelse med formelen C19H21C1N203. 2HC1. The procedure according to example 1 was repeated, but starting with 110 g (0.4 mol) of 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine . Yield: 57% of a product which melted at 195-200°C (Tottoli), with decomposition, and the analysis of this product showed good agreement with the formula C19H21C1N203. 2HC1.

Eksempel 6 Example 6

1, 3- dihydro- 3- ( 2 , 3- diklorfenyl) - 6- ( l- hydroksy- 2- di. metylaminometyl- allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3-( 2 , 3- dichlorophenyl)- 6-( 1- hydroxy- 2- di. methylaminomethyl- allyl)- 7- hydroxy- furo- [ 3, 4-c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 124 g (0,4 mol) 1,3-dihydro-3-(2,3-diklorfenyl)-6- formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 62% av et produkt som smeltet ved 180-184°C (Tottoli), med dekomponering, og analysen av dette produkt viste god overensstemmelse med formelen ci9H2oC12N2°3' 2HC1-The procedure according to example 1 was repeated, but starting with 124 g (0.4 mol) of 1,3-dihydro-3-(2,3-dichlorophenyl)-6-formyl-7-hydroxy-furo-[3,4- c]-pyridine. Yield: 62% of a product which melted at 180-184°C (Tottoli), with decomposition, and the analysis of this product showed good agreement with the formula ci9H2oC12N2°3' 2HC1-

Eksempel 7 Example 7

1, 3- dihydro- 3- p- fluorfenyl- 6-( l- hydroksy- 2- dimetylaminometyl-allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- p- fluorophenyl- 6-( l- hydroxy- 2- dimethylaminomethyl-allyl)- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 104 g (0,4 mol) 1,3-dihydro-3-p-fluorfenyl-6-formyl-7- hydroksy-furo-[3,4-c]-pyridin. Utbytte: 62% av et produkt som smeltet ved 198°C (Tottoli), med dekomponering, og analysen av dette produkt viste god overensstemmelse med formelen <C>19H21FN203.2HC1. The procedure according to example 1 was repeated, but starting with 104 g (0.4 mol) of 1,3-dihydro-3-p-fluorophenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine . Yield: 62% of a product which melted at 198°C (Tottoli), with decomposition, and the analysis of this product showed good agreement with the formula <C>19H21FN203.2HC1.

Eksempel 8 Example 8

1, 3- dihydro- 3- p- toluyl- 6-( l- hydroksy- 2- dimetylaminometyl-allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- p- toluyl- 6-( l- hydroxy- 2- dimethylaminomethyl-allyl)- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 103 g (0,4 mol) 1,3-dihydro-3-p-toluyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 66% av et produkt som smeltet ved 203-207°C (Tottoli), med dekomponering, og analysen av dette produkt viste god overensstemmelse med formelen <C>20<H>24<N>2°3'<2HC1>' The procedure according to example 1 was repeated, but starting with 103 g (0.4 mol) of 1,3-dihydro-3-p-toluyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine . Yield: 66% of a product melting at 203-207°C (Tottoli), with decomposition, and the analysis of this product showed good agreement with the formula <C>20<H>24<N>2°3'<2HC1> '

1 .L 1.L

Eksempel 9 Example 9

1, 3- dihydro- 3- p- metoksyfenyl- 6-( l- hydroksy- 2- dimetylaminometyl- allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyri di n 1, 3- dihydro- 3- p- methoxyphenyl- 6-( l- hydroxy- 2- dimethylaminomethyl- allyl)- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 110 g (0,4 mol) 1,3-dihydro-3-p-metoksyfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 63% av et produkt som smeltet ved 169-170°C (Tottoli), og analysen av dette produkt viste god overensstemmelse med formelen C20H24N2°4- 2HC1- The procedure according to example 1 was repeated, but starting with 110 g (0.4 mol) of 1,3-dihydro-3-p-methoxyphenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine . Yield: 63% of a product which melted at 169-170°C (Tottoli), and the analysis of this product showed good agreement with the formula C20H24N2°4- 2HC1-

Eksempel 10 Example 10

1, 3- dihydro- 3- m- tri fluormetylfenyl- 6-( l- hydroksy- 2- dimetyl-aminometyl- allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyri din 1, 3- dihydro- 3- m- trifluoromethylphenyl- 6-( l- hydroxy- 2- dimethyl- aminomethyl- allyl)- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 124 g (0,4 mol) 1,3-dihydro-3-m-trifluormetylfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 58% av et produkt som smeltet ved 217-223°C (Tottoli), med dekomponering, og analysen av dette produkt viste god overensstemmelse med formelen C20<H>21F3N2°3* 2HC1- The procedure according to example 1 was repeated, but starting with 124 g (0.4 mol) of 1,3-dihydro-3-m-trifluoromethylphenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine . Yield: 58% of a product melting at 217-223°C (Tottoli), with decomposition, and the analysis of this product showed good agreement with the formula C20<H>21F3N2°3* 2HC1-

Eksempel 11 Example 11

1, 3- di hydro- 3- p-( di etylaminoetoksyfenyl)- 6-( l- hydroksy- 2-dimetylaminometyl- allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyridi n 1, 3- dihydro- 3- p-(diethylaminoethoxyphenyl)- 6-( l- hydroxy- 2-dimethylaminomethyl- allyl)- 7- hydroxy- furo-[ 3, 4- c]- pyridi n

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 142 g (0,4 mol) 1,3-dihydro-3-p-(dietylaminoetoksy-fenyl)-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 51% av et produkt som smeltet ved 158-160°C (Tottoli), og analysen av dette produkt viste god overensstemmelse med formelen <C>25<H>35<N>3°4' <2>HC1-The procedure according to example 1 was repeated, but starting with 142 g (0.4 mol) of 1,3-dihydro-3-p-(diethylaminoethoxy-phenyl)-6-formyl-7-hydroxy-furo-[3,4- c]-pyridine. Yield: 51% of a product which melted at 158-160°C (Tottoli), and the analysis of this product showed good agreement with the formula <C>25<H>35<N>3°4' <2>HC1-

Eksempel 12 Example 12

1, 3- dihydro- 3- p-( pyrrolidinyletoksy- fenyl)- 6-( l- hydroksy- 2-dimetylaminometyl - allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyri din 1, 3- dihydro- 3- p-( pyrrolidinylethoxy- phenyl)- 6-( l- hydroxy- 2-dimethylaminomethyl - allyl)- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 142 g (0,4 mol) 1,3-dihydro-3-p-(pyrrolidinyletoksy-fenyl) -6-formyl-7-hydroksy-furo- [3 , 4-c] -pyridin. Utbytte: 53% av et produkt som smeltet ved 173°C (Tottoli), og analysen av dette produkt viste god overensstemmelse med formelen C25H33N3°4- 2HC1- The procedure according to example 1 was repeated, but starting with 142 g (0.4 mol) of 1,3-dihydro-3-p-(pyrrolidinylethoxy-phenyl)-6-formyl-7-hydroxy-furo-[3 , 4- c]-pyridine. Yield: 53% of a product which melted at 173°C (Tottoli), and the analysis of this product showed good agreement with the formula C25H33N3°4- 2HC1-

Eksempel 13 Example 13

1, 3- dihydro- metyl- 3- n- pentyl- 6-( l- hydroksy- 2- dimetylaminometyl- allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- methyl- 3- n- pentyl- 6-( l- hydroxy- 2- dimethylaminomethyl- allyl)- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 99 g (0,4 mol) 1,3-dihydro-3-metyl-3-n-pentyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 59% av et produkt som smeltet ved 187-191°C (Tottoli), med dekomponering, og analysen av dette produkt viste god overensstemmelse med formelen Ci9<H>30N2°3- 2HC1. The procedure according to example 1 was repeated, but starting with 99 g (0.4 mol) of 1,3-dihydro-3-methyl-3-n-pentyl-6-formyl-7-hydroxy-furo-[3,4- c]-pyridine. Yield: 59% of a product which melted at 187-191°C (Tottoli), with decomposition, and the analysis of this product showed good agreement with the formula Ci9<H>30N2°3- 2HC1.

Eksempel 14 Example 14

1, 3- dihydro- 3- metyl- 3- fenyl- 6-( l- hydroksy- 2- dimetylaminometyl- allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyri din 1, 3- dihydro- 3- methyl- 3- phenyl- 6-( l- hydroxy- 2- dimethylaminomethyl- allyl)- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 103 g (0,4 mol) 1,3-dihydro-3-metyl-3-fenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 69% avet produkt som smeltet ved 178-179°C (Tottoli), og analysen av dette produkt viste god overensstemmelse med formelen ^20<H>24<N>2^3<* >2HC1. The procedure according to example 1 was repeated, but starting with 103 g (0.4 mol) of 1,3-dihydro-3-methyl-3-phenyl-6-formyl-7-hydroxy-furo-[3,4-c] -pyridine. Yield: 69% of product which melted at 178-179°C (Tottoli), and the analysis of this product showed good agreement with the formula ^20<H>24<N>2^3<* >2HC1.

Eksempel 15 Example 15

1, 3- dihydro- 3- metyl- 3- a- tienyl- 6-( l- hydroksy- 2- dimetyl-aminometyl- allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyri din 1, 3- dihydro- 3- methyl- 3- athienyl- 6-( l- hydroxy- 2- dimethyl- aminomethyl- allyl)- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 103 g (0,4 mol) 1,3-dihydro-3-metyl-3-a-tienyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 67% av et produkt som smeltet ved 169-175°C, med dekomponering, og analysen av dette produkt viste god overensstemmelse med formelen C18H22SN203. 2HC1. The procedure according to example 1 was repeated, but starting with 103 g (0.4 mol) of 1,3-dihydro-3-methyl-3-a-thienyl-6-formyl-7-hydroxy-furo-[3,4- c]-pyridine. Yield: 67% of a product which melted at 169-175°C, with decomposition, and the analysis of this product showed good agreement with the formula C18H22SN2O3. 2HC1.

Eksempel 16 Example 16

1, 3- dihydro- 3- etyl- 3- m- trifluormetylfenyl- 6-( l- hydroksy- 2-dimetylaminometyl- allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- ethyl- 3- m- trifluoromethylphenyl- 6-( l- hydroxy- 2-dimethylaminomethyl- allyl)- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Fremgangsmåten fra eksempel 1 ble gjentatt, men man startet med 136 g (0,4 mol) 1,3-dihydro-3-etyl-3-m-trifluormetylfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 72% av et produkt som smeltet ved 185°C (Tottoli), og analysen av dette produkt vi ste god overensstemmelse med formelen C22H25F3N2°3- 2HC1« The procedure from Example 1 was repeated, but starting with 136 g (0.4 mol) of 1,3-dihydro-3-ethyl-3-m-trifluoromethylphenyl-6-formyl-7-hydroxy-furo-[3,4- c]-pyridine. Yield: 72% of a product which melted at 185°C (Tottoli), and the analysis of this product showed good agreement with the formula C22H25F3N2°3-2HC1«

Eksempel 17 Example 17

1, 3- dihydro- 3- etyl- 3- a- fury1- 6-( l- hydroksy- 2- dimetylaminometyl- allyl)- 7- hydroksy-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- ethyl- 3- a- fury1- 6-( l- hydroxy- 2- dimethylaminomethyl- allyl)- 7- hydroxy-[ 3, 4- c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 104 g (0,4 mol) 1,3-dihydro-3-etyl-3-a-furyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 58% av et produkt som smeltet ved 164-169°C (Tottoli), med dekomponering, og analysen av dette produkt viste god overensstemmelse med formelen ci9<H>24N2°4- 2HC1. The procedure according to example 1 was repeated, but starting with 104 g (0.4 mol) of 1,3-dihydro-3-ethyl-3-a-furyl-6-formyl-7-hydroxy-furo-[3,4- c]-pyridine. Yield: 58% of a product which melted at 164-169°C (Tottoli), with decomposition, and the analysis of this product showed good agreement with the formula ci9<H>24N2°4- 2HC1.

Eksempel 18 Example 18

1, 3- dihydro- 3- fenyl- 3- p- etoksyfenyl- 6-( l- hydroksy- 2- dimetyl-aminometyl- allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- phenyl- 3- p- ethoxyphenyl- 6-( l- hydroxy- 2- dimethyl- aminomethyl- allyl)- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Fremgangsmåten ifølge eksempel 1 ble gjentatt, men man startet med 144 g (0,4 mol) 1,3-dihydro-3-fenyl-3-p-etoksyfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 64% av et produkt som smeltet ved 148-149°C (Tottoli), og analysen av dette produkt vi ste god overensstemmelse med formelen C27H3QN204. 2HC1. The procedure according to example 1 was repeated, but starting with 144 g (0.4 mol) of 1,3-dihydro-3-phenyl-3-p-ethoxyphenyl-6-formyl-7-hydroxy-furo-[3,4- c]-pyridine. Yield: 64% of a product which melted at 148-149°C (Tottoli), and the analysis of this product showed good agreement with the formula C27H3QN204. 2HC1.

Eksempel 19 Example 19

1, 3- dihydro- 3 , 3- di- p- f luorf eny 1- 6- ( l- hydroksy- 2- di. metylaminometyl- allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3 , 3- di- p- fluoropheny 1- 6- (l- hydroxy- 2- di. methylaminomethyl- allyl)- 7- hydroxy- furo-[ 3, 4- c]- pyridine

Fremgangsmåten fra eksempel 1 ble gjentatt, men man startet med 142 g (0,4 mol) 1,3-dihydro-3,3-di-p-fluorfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 70% av et produkt som smeltet ved 175°C (Tottoli), og analysen av dette produkt vi ste god overensstemmelse med formelen C25H24<F>2<N>2°3* 2HC1. The procedure from Example 1 was repeated, but starting with 142 g (0.4 mol) of 1,3-dihydro-3,3-di-p-fluorophenyl-6-formyl-7-hydroxy-furo-[3,4- c]-pyridine. Yield: 70% of a product which melted at 175°C (Tottoli), and the analysis of this product showed good agreement with the formula C25H24<F>2<N>2°3* 2HC1.

Eksempel 20 Example 20

1, 3- dihydro- 3- a- furyl- 3- p- tiometylfenyl- 6-( l- hydroksy- 2-dimetylaminometyl- allyl)- 7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- a- furyl- 3- p- thiomethylphenyl- 6-( l- hydroxy- 2-dimethylaminomethyl- allyl)- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Fremgangsmåten fra eksempel 1 ble gjentatt, men man startet méd 141 g (0,4 mol) 1,3-dihydro-3-a-furyl-3-p-tiometylfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. Utbytte: 48% av et produkt som smeltet ved 143-151°C (Tottoli), med dekomponering, og analysen av dette produkt viste god overensstemmelse med formelen C-.H-cSN-O.. 2HC1. The procedure from example 1 was repeated, but starting with 141 g (0.4 mol) of 1,3-dihydro-3-a-furyl-3-p-thiomethylphenyl-6-formyl-7-hydroxy-furo-[3, 4-c]-pyridine. Yield: 48% of a product melting at 143-151°C (Tottoli), with decomposition, and the analysis of this product showed good agreement with the formula C-.H-cSN-O.. 2HC1.

24 26 2 4 24 26 2 4

Ingen av de fremstilte forbindelsene oppviste vesentlig giftighet per os. LD^g lå mellom 0,8 og 1,2 g/kg for rotter og mellom 0,7 og 1 g/kg for mus. None of the compounds produced showed significant toxicity per us. LD^g was between 0.8 and 1.2 g/kg for rats and between 0.7 and 1 g/kg for mice.

Virkningen av de nye forbindelsene er fastslått gjennom forskjellige undersøkelser, hvorav tre er beskrevet i det følgende. The effect of the new compounds has been determined through various investigations, three of which are described below.

1 - Dødelighet forårsaket av yohimbin HC1 i mus. 1 - Lethality caused by yohimbine HC1 in mice.

Undersøkelsen ble foretatt på grupper å 10 CD-1 hannmus (Charles River). Hver behandlet mus fikk 0,25 ml/20 g av en suspensjon inneholdende testforbindelsen. 1 time etter inntaket ble det subkutant injisert 30 mg/kg yohimbin HC1. Antall døds-fall uttrykt i prosent (L) ble bestemt 18 timer etter injeksjonen. For hver forbindelse ble det benyttet en kontrollgruppe som The investigation was carried out on groups of 10 CD-1 male mice (Charles River). Each treated mouse received 0.25 ml/20 g of a suspension containing the test compound. 1 hour after ingestion, 30 mg/kg yohimbine HC1 was injected subcutaneously. The number of deaths expressed as a percentage (L) was determined 18 hours after the injection. For each compound, a control group was used which

båre fikk yohimbin HC1. Resultatene er angitt i tabell nr. I. stretcher received yohimbine HC1. The results are shown in table no. I.

II - Antagonisme mot katalepsi indusert av haloperidol. II - Antagonism against catalepsy induced by haloperidol.

Forsøket ble foretatt på grupper å 6 Wistar hannrotter The experiment was carried out on groups of 6 male Wistar rats

på 140/170 g og sammenlignet med to referanseforbindelser, Imipramin og 5-hydroksytryptofan. of 140/170 g and compared to two reference compounds, Imipramine and 5-hydroxytryptophan.

Intraperdtoneal administrasjon av haloperidol i doser på Intraperdtoneal administration of haloperidol in doses of

5 mg/kg induserer katalepsi. Påfølgende'peroral administrasjon av testforbindelsene 1 time etter haloperidolinjeksjonen, har en ugunstig innvirkning på katalepsi. 5 mg/kg induces catalepsy. Subsequent oral administration of the test compounds 1 hour after the haloperidol injection has an adverse effect on catalepsy.

Åtte av forbindelsene fremstillet i henhold til oppfinnelsen, ble undersøkt på flere dosenivåer (en dyregruppe for hver dose av hver forbindelse). Virkningen på katalepsien ble fastslått 1, 2, 3, 4 og 5 timer etter administrasjon av testforbindelsen, ved å plassere rottenes forlabber på en metallstang anbrakt 10 cm over bordnivået (undersøkelsen ble foretatt ved 22 oC i et lydisolert rom). Dersom dyret var i stand til å stå i 20 sekunder ga dette 1 poeng, 40 sekunder ga 2 poeng og så videre opp til 5 poeng for 100 sekunder. Gjennomsnittsverdier og de korresponderende prosentverdier for antagonisme ble beregnet for hver gruppe. Eight of the compounds prepared according to the invention were examined at several dose levels (one group of animals for each dose of each compound). The effect on the catalepsy was determined 1, 2, 3, 4 and 5 hours after the administration of the test compound, by placing the rats' forepaws on a metal rod placed 10 cm above the table level (the examination was carried out at 22 oC in a soundproof room). If the animal was able to stand for 20 seconds this gave 1 point, 40 seconds gave 2 points and so on up to 5 points for 100 seconds. Mean values and the corresponding percentage values for antagonism were calculated for each group.

Resultatene er angitt i tabell nr. II. The results are shown in table no. II.

III - Apati-test hos mus. III - Apathy test in mice.

Eksperimentet ble utført på CD-1 hannmus (Charles River) The experiment was performed on CD-1 male mice (Charles River)

i grupper på 10 mus og med Maprotiline som referanseforbindelse. 1 time før start fikk dyrene en dose av 0,4 ml/20 g suspensjon tilsvarende passende dose i mg/kg av testforbindelsene. in groups of 10 mice and with Maprotiline as reference compound. 1 hour before the start, the animals received a dose of 0.4 ml/20 g suspension corresponding to the appropriate dose in mg/kg of the test compounds.

Musene ble anbrakt i. plexiglass sylindre (høyde 25 cm, diameter 10 cm), som inneholdt vann med 22°C. Målingen av immobilitetsperioden ble foretatt mellom det 2. og 6. minutt. En kontrollgruppe ble benyttet for hver testforbindelse og for hver dosering. The mice were placed in plexiglass cylinders (height 25 cm, diameter 10 cm), which contained water at 22°C. The measurement of the immobility period was made between the 2nd and 6th minute. A control group was used for each test compound and for each dosage.

Resultatene er angitt i tabell nr. III, hvor A står for den gjennomsnittlige immobilitetsperiode og B for variasjonen 1 % i forhold til kontrollene. The results are shown in table no. III, where A stands for the average period of immobility and B for the variation of 1% in relation to the controls.

De mer vanlig benyttede preparatformer innen humanterapien utgjøres av tabletter eller gelatinkapsler med et innhold på 0,1 g virkestoff pr. doseringsenhet, eller av hetteglass som inneholder den samme mengde i en oppløst eller suspendert form beregnet for i v. injeksjon. The more commonly used forms of preparation in human therapy consist of tablets or gelatin capsules with a content of 0.1 g of active ingredient per dosage unit, or of vials containing the same amount in a dissolved or suspended form intended for intravenous injection.

Ved peroral administrasjon gis opp til 0,5 g/dag i minst For oral administration, up to 0.5 g/day is given at least

2 uker og ved injeksjon opp til 0,2 g/dag i minst 1 uke, med en påfølgende peroral behandling i minst 1 uke. 2 weeks and by injection up to 0.2 g/day for at least 1 week, with a subsequent oral treatment for at least 1 week.

Claims (1)

Fremgangsmåte for fremstilling av l,3-dihydro-6-(1-hydroksy-2-dimetylaminometyl-allyl)-7-hydroksy-furo-[3,4-c]-pyridin-derivater med den generelle formelProcess for the preparation of 1,3-dihydro-6-(1-hydroxy-2-dimethylaminomethyl-allyl)-7-hydroxy-furo-[3,4-c]-pyridine derivatives of the general formula hvor A^ er alkylmed fra 1 til 5 karbonatomer; cykloheksyl,furyl, fenyl eventuelt substituert med 1 til 2 halogenatomer, alkyl med 1 til 4 karbonatomer, alkoksy med fra 1 til 5 karbonatomer, trifluormetyl, dietylaminometoksy eller pyrolidinyletoksy, og A2 er hydrogen; fenyl eventuelt substituert med trifluormetyl, alkoksy med 1 til 5 karbonatomer, halogen eller tiometyl; furyl eller tienyl, karakterisert ved at et 6-formyl-7-hydroksy-furo-[3,4-c]-pyridin-derivat med den generelle formelwhere A 2 is alkyl with from 1 to 5 carbon atoms; cyclohexyl, furyl, phenyl optionally substituted with 1 to 2 halogen atoms, alkyl with 1 to 4 carbon atoms, alkoxy with from 1 to 5 carbon atoms, trifluoromethyl, diethylaminomethoxy or pyrrolidinylethoxy, and A 2 is hydrogen; phenyl optionally substituted with trifluoromethyl, alkoxy of 1 to 5 carbon atoms, halogen or thiomethyl; furyl or thienyl, characterized in that a 6-formyl-7-hydroxy-furo-[3,4-c]-pyridine derivative of the general formula hvor Ai og A2 har de ovenfor angitte betydninger, omsettes med et lite overskudd av 1-dimetylaminometyl-vinylmagnesium-bromid ved koketemperatur, i et ikke-polart oppløsningsmiddel såsom tetrahydrofuran.where Ai and A2 have the meanings given above, is reacted with a small excess of 1-dimethylaminomethyl-vinylmagnesium bromide at boiling temperature, in a non-polar solvent such as tetrahydrofuran.
NO853418A 1984-08-31 1985-08-30 PROCEDURE FOR PREPARING 6- (1-HYDROXY-2-DIMETHYLAMINOMETHYL-ALLYL) -FURO- (3,4-C) -PYRIDINE DERIVATIVES. NO162071C (en)

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GB8808001D0 (en) * 1988-04-06 1988-05-05 Scras Stereospecific preparative process for furol(3,4-c)pyridine derivatives
DE10323602A1 (en) * 2003-05-19 2004-12-16 Südzucker AG Mannheim/Ochsenfurt Hard caramel for human consumption, contains hard caramel base and supported food color inhomogeneously distributed within hard caramel base

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ZA786269B (en) * 1977-11-25 1979-10-31 Scras New pyridine derivative,its preparation and use
ZA842029B (en) * 1983-04-05 1984-10-31 Scras Furo-(3,4-c)-pyridine derivatives preparation thereof and therapeutic compositions containing the same
GB2153824B (en) * 1984-02-02 1987-04-01 Scras Furo-(3,4-c)-pyridine derivatives

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PT81054B (en) 1987-10-20
DK157871B (en) 1990-02-26
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CH666688A5 (en) 1988-08-15
IE852143L (en) 1986-02-28
GB8520169D0 (en) 1985-09-18
GB2163744A (en) 1986-03-05
HK6189A (en) 1989-01-27
GB8422029D0 (en) 1984-10-03
NO853418L (en) 1986-03-03
FR2569698B1 (en) 1988-12-16
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ZA856088B (en) 1986-06-25
DE3531004A1 (en) 1986-03-13
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GB2163744B (en) 1988-01-20
JPS6160688A (en) 1986-03-28
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NO162071C (en) 1989-11-01
IE58522B1 (en) 1993-10-06
LU86052A1 (en) 1986-02-18
FI82468B (en) 1990-11-30
IT8522035A0 (en) 1985-08-30
FI82468C (en) 1991-03-11
SE8503869L (en) 1986-03-01
FI853287L (en) 1986-03-01
OA08088A (en) 1987-03-31
CA1300149C (en) 1992-05-05
FR2569698A1 (en) 1986-03-07
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IT1201459B (en) 1989-02-02
ATA252985A (en) 1993-02-15
AT396590B (en) 1993-10-25
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