NO160143B - ANALOGUE PROCEDURE FOR PREPARING NEW, THERAPEUTIC-ACTIVE 6-AMINOMETHYL-FURO- (3,4-C) -PYRIDINE DERIVATIVES. - Google Patents

ANALOGUE PROCEDURE FOR PREPARING NEW, THERAPEUTIC-ACTIVE 6-AMINOMETHYL-FURO- (3,4-C) -PYRIDINE DERIVATIVES. Download PDF

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NO160143B
NO160143B NO853475A NO853475A NO160143B NO 160143 B NO160143 B NO 160143B NO 853475 A NO853475 A NO 853475A NO 853475 A NO853475 A NO 853475A NO 160143 B NO160143 B NO 160143B
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furo
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Andre Esanu
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Conseils Rech E Applic Scient
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    • 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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    • A—HUMAN NECESSITIES
    • 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 fremgangsmåte for fremstilling av nye 6-aminometyl-furo-[3,4-c]-pyridin-derivater. This invention relates to a process for the production of new 6-aminomethyl-furo-[3,4-c]-pyridine derivatives.

Ifølge oppfinnelsen fremstilles 1,3-dihydro-6-aminometyl-7-hydroksy-furo-[3,4-c]-pyridin-derivater med den generelle formel I According to the invention, 1,3-dihydro-6-aminomethyl-7-hydroxy-furo-[3,4-c]-pyridine derivatives of the general formula I are prepared

hvor Ai er C^- C^ alkyl, fenyl eventuelt substituert med 1-3 where Ai is C₁-C₁ alkyl, phenyl optionally substituted with 1-3

C1-C4 alkoksysubstituenter, 1-2 klor- eller fluorsubstituenter, C1-C4 alkoxy substituents, 1-2 chlorine or fluorine substituents,

en Ci-C4 alkyl-, trifluormetyl- eller dimetylaminoetoksy-substituent, eller er en vinyl-, dimetylaminopropyl-, cykloheksyl- eller furylgruppe, a C1-C4 alkyl, trifluoromethyl or dimethylaminoethoxy substituent, or is a vinyl, dimethylaminopropyl, cyclohexyl or furyl group,

A2 er hydrogen, fenyl eventuelt substituert med 1-2 klor-, A2 is hydrogen, phenyl optionally substituted with 1-2 chlorine-,

fluor- eller tiometylsubstituenter, eller A2 er en furyl-, fluoro or thiomethyl substituents, or A2 is a furyl,

tienyl- eller metoksy-N-pyrolidinylgruppe; og farmasøytisk godtagbare salter av slike forbindelser. thienyl or methoxy-N-pyrrolidinyl group; and pharmaceutically acceptable salts of such compounds.

Forbindelsene fremstilt ifølge oppfinnelsen er av interesse The compounds prepared according to the invention are of interest

på grunn av sin terapeutiske virkning, særlig på området anti-allergisk virkning. due to its therapeutic effect, particularly in the area of anti-allergic effect.

Ifølge oppfinnelsen fremstilles de ovennevnte forbindelser According to the invention, the above-mentioned compounds are produced

ved at 6-formyl-7-hydroksy-furo-[3,4-c]-pyridin-derivater med den generelle formel II in that 6-formyl-7-hydroxy-furo-[3,4-c]-pyridine derivatives of the general formula II

hvor A^ og A_ har de ovenfor angitte betydninger, omsettes med en støkiometrisk mengde av hydroksylamin eller av NaOH i vann ved romtemperatur, derefter hydrogeneres det således oppnådde oksim ved romtemperatur under normalt trykk i eddiksyre ved hjelp av hydrogen i nærvær av en Pd/C-katalysator, i henhold til følgende reaksjonsskjerna: 6-formyl-7-hydroksy-furo-[3,4-c]-pyridin-derivater II kan oppnås fra de tilsvarende 6-metyl-7-hydroksy-furo-[3,4-c]-pyridin-derivater med den generelle formel III hvor A^ og A2 har de ovenfor angitte betydninger, ved hjelp av følgende reaksjonsforløp: where A^ and A_ have the meanings given above, is reacted with a stoichiometric amount of hydroxylamine or of NaOH in water at room temperature, then the thus obtained oxime is hydrogenated at room temperature under normal pressure in acetic acid by means of hydrogen in the presence of a Pd/C -catalyst, according to the following reaction core: 6-formyl-7-hydroxy-furo-[3,4-c]-pyridine derivatives II can be obtained from the corresponding 6-methyl-7-hydroxy-furo-[3,4 -c]-pyridine derivatives of the general formula III where A^ and A2 have the meanings given above, by means of the following reaction sequence:

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.

Fremstilling av én av utgangsforbindelsene, 1,3-dihydro-3-p-klorfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, beskrives i detalj i det følgende, idet andre utgangsmaterialer kan fremstilles på samme måte. a) I en 1-liter reaktor utstyrt med omrørings-, 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 10% natriumsulfatoppløsning. Efter omrøring og dekantering ble metylendikloridfasen vasket med den samme mengde natriumsulfatoppløsning, to ganger med 150 ml natriumbikarbonatoppløsning og tre ganger med 100 ml vann og ble 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 Preparation of one of the starting compounds, 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, is described in detail in the following, as other starting materials can be prepared Similarly. 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 10% sodium sulphate 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 was 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 95 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) I en 2-liter reaktor ble 21,3 g av forbindelsen oppnådd i foregående trinn behandlet med 27 g mangandioksyd i nærvær av c) In a 2-liter reactor, 21.3 g of the compound obtained in the previous step was treated with 27 g of manganese dioxide in the presence of

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, og pastaen ble behandlet med isopropyloksyd og derefter med pentan. Man fikk således 20,1 g (95%) av 1,3-dihydro-3-p-klorfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin. 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 and 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 were thus obtained.

Oppfinnelsen illustreres ved de følgende eksempler. The invention is illustrated by the following examples.

Eksempel 1 Example 1

1, 3- dihydro- 3- metyl- 6- aminometyl- 7- hydroksy- furo-[ 3, 4- c]-pyridin 1, 3- dihydro- 3- methyl- 6- aminomethyl- 7- hydroxy- furo-[ 3, 4- c]-pyridine

I en 2 liter reaktor ved romtemperatur ble hellet 71,2 g (0,4 mol) l,3-dihydro-3-metyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, 270 ml IN natriumhydroksyd og derefter, dråpevis under omrøring, 27,8 g (0,4 mol) hydroksylamin-hydroklorid oppløst i 200 ml vann. Omrøring ble fortsatt i 10 timer, og reaksjonsblandingen ble filtrert for å gi, efter vasking med vann og tørking, 74 g (96%) av det tilsvarende 6-oksim-derivat. 74 g av 6-oksim-derivatet ble derefter hellet med 0,9 1 eddiksyre i en lukket reaktor utstyrt med gass-sirkulasjons-innretning. Efter sirkulering av nitrogen ble 15 g palladium-på-kull-katalysator anbrakt i reaktoren, og blandingen ble omrørt ved romtemperatur med en tilmålt hydrogentilsetning under normaltrykk i 4 timer. Into a 2 liter reactor at room temperature was poured 71.2 g (0.4 mol) 1,3-dihydro-3-methyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, 270 ml of 1N sodium hydroxide and then, dropwise with stirring, 27.8 g (0.4 mol) of hydroxylamine hydrochloride dissolved in 200 ml of water. Stirring was continued for 10 hours and the reaction mixture was filtered to give, after washing with water and drying, 74 g (96%) of the corresponding 6-oxime derivative. 74 g of the 6-oxime derivative was then poured with 0.9 L of acetic acid into a closed reactor equipped with a gas circulation device. After circulating nitrogen, 15 g of palladium-on-charcoal catalyst was placed in the reactor, and the mixture was stirred at room temperature with a measured addition of hydrogen under normal pressure for 4 hours.

Efter filtrering av reaksjonsblandingen ble den inndampet til tørrhet. Residuet ble behandlet med toluen og derefter med metanol, hvorfra det ble omkrystallisert 70 g (76%) av acetatet av 1,3-dihydro-3-metyl-6-aminometyl-7-hydroksy-furo-[3,4-c]-pyridin, et beige produkt som smelter ved 167°C (Tottoli), After filtering the reaction mixture, it was evaporated to dryness. The residue was treated with toluene and then with methanol, from which 70 g (76%) of the acetate of 1,3-dihydro-3-methyl-6-aminomethyl-7-hydroxy-furo-[3,4-c] were recrystallized -pyridine, a beige product melting at 167°C (Tottoli),

og analysen av dette viste god overensstemmelse med formelen CgH^2N2°2» <C>2H4°2' Denne forbindelse var uoppløselig i vann. and the analysis of this showed good agreement with the formula CgH^2N2°2» <C>2H4°2' This compound was insoluble in water.

Eftersom den samme metode ble anvendt for alle de synteti-serte forbindelser, er arbeidsdetaljer ikke gjentatt i de følgende eksempler. De tilsvarende baser (uten syredelen) og andre salter av nevnte baser oppnås på vanlig måte. Since the same method was used for all the synthesized compounds, working details are not repeated in the following examples. The corresponding bases (without the acid part) and other salts of said bases are obtained in the usual way.

Eksempel 2 Example 2

1, 3- dihydro- 3- propyl- 6- aminometyl- 7- hydroksy- furo-[ 3, 4- c]-<p>yridin 1, 3- dihydro- 3- propyl- 6- aminomethyl- 7- hydroxy- furo-[ 3, 4- c]-<p>yridine

Ved å starte med 1,3-dihydro-3-propyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 77%) et lyst beige produkt som smelter ved 187°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen cn<H>i<6>N2°2" C2H4°2*Starting with 1,3-dihydro-3-propyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, a pale beige product melting at 187° was obtained (yield 77%) C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula cn<H>i<6>N2°2" C2H4°2*

Eksempel 3 Example 3

1, 3- dihydro- 3-( 3', 4', 5'- trimetoksyfenyl)- etyl- 6- aminometyl-7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3-( 3', 4', 5'- trimethoxyphenyl)- ethyl- 6- aminomethyl-7- hydroxy- furo- [ 3, 4-c]- pyridine

Ved å starte med 1,3-dihydro-3-(3',4<1>,5'-trimetoksyfenyl)-etyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 61%) et hvitt produkt som smelter ved 140-144°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C,QH_.N„Oc. C,H,0_. Starting with 1,3-dihydro-3-(3',4<1>,5'-trimethoxyphenyl)-ethyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, obtained one (yield 61%) a white product which melts at 140-144°C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula C,QH_.N„Oc. C, H, O_.

19 24 2 5 2 4 2 19 24 2 5 2 4 2

Eksempel 4 Example 4

1, 3- dihydro- 3- cykloheksyl- 6- aminometyl- 7- hydroksy- furo-[ 3, 4- c]-pyridin 1, 3- dihydro- 3- cyclohexyl- 6- aminomethyl- 7- hydroxy- furo-[ 3, 4-c]-pyridine

Ved å starte med 1,3-dihydro-3-cykloheksyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 67%) et hvitt produkt som smelter ved 173-177°C (Tottoli.) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen ci4H2o<N>2°2' C2<H>4°2" Starting with 1,3-dihydro-3-cyclohexyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, a white product melting at 173-177 was obtained (yield 67%) °C (Tottoli.) and is insoluble in water, and the analysis of this showed good agreement with the formula ci4H2o<N>2°2' C2<H>4°2"

Eksempel 5 Example 5

1, 3- dihydro- 3- g- tienyl- 6- aminometyl- 7- hydroksy- furo-[ 3, 4- c]-pyridi n 1, 3- dihydro- 3- g- thienyl- 6- aminomethyl- 7- hydroxy- furo-[ 3, 4- c]-pyridi n

Ved å starte med 1,3-dihydro-3-a-tienyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 58%) et gulaktig produkt som smelter ved 148°C (Tottoli) og er uopp-løselig i vann, og analysen av dette viste god overensstemmelse med formelen ci2<H>12<N>2°2<S>l<*><C>2<H>4°2<*>Starting with 1,3-dihydro-3-a-thienyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, a yellowish product was obtained (yield 58%) melting at 148 °C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula ci2<H>12<N>2°2<S>l<*><C>2<H>4°2 <*>

Eksempel 6 Example 6

1, 3- dihydro- 3- fenyl- 6- aminometyl- 7- hydroksy- furo- [ 3, 4- c] - pyridin 1, 3- dihydro- 3- phenyl- 6- aminomethyl- 7- hydroxy- furo- [ 3, 4- c] - pyridine

Ved å starte med 1,3-dihydro-3-fenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 82%) et lyst beige produkt som smelter ved 188°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C;L4Hi4N202' C2H4°2*Starting with 1,3-dihydro-3-phenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, a pale beige product melting at 188° was obtained (yield 82%) C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula C;L4Hi4N202' C2H4°2*

Eksempel 7 Example 7

1, 3- dihydro- 3- p- klorfenyl- 6- aminometyl- 7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- p- chlorophenyl- 6- aminomethyl- 7- hydroxy- furo-[ 3, 4- c]- pyridine

Ved å starte med 1,3-dihydro-3-p-klorfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridi.n, fikk man (utbytte 86%) et lyst beige produkt som smelter ved 204-206°C (Tottoli.) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C,.H,,ClNo0o. C_H.0o. Starting with 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, a light beige product was obtained (yield 86%) which melts at 204-206°C (Tottoli.) and is insoluble in water, and the analysis of this showed good agreement with the formula C,.H,,ClNo0o. C_H.0o.

14 13 2 2 2 4 2 14 13 2 2 2 4 2

Eksempel 8 Example 8

1, 3- dihydro- 3- ( 2 ' , 3 ' - diklorf enyl) - 6- ami. nometyl- 7- hydroksy-furo-[ 3, 4- c]- pyridin 1,3-dihydro-3-(2',3'-dichlorophenyl)-6-ami. nomethyl-7-hydroxy-furo-[3,4-c]-pyridine

Ved å starte med 1,3-di.hydro-3-(2 ' , 3'-diklorfenyl)-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 72%) et lysegult produkt som smelter ved 193-196°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C,.H,_C1_N_0_. C-H.O_. By starting with 1,3-dihydro-3-(2',3'-dichlorophenyl)-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, one obtained (yield 72% ) a pale yellow product which melts at 193-196°C (Tottoli) and is insoluble in water, the analysis of which showed good agreement with the formula C,.H,_C1_N_0_. C-H.O_.

14 12 2 2 2 2 4 2 14 12 2 2 2 2 4 2

Eksempel 9 Example 9

1, 3- di. hydro- 3- p- f luorfenyl- 6- aminometyl- 7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- di. hydro- 3- p- fluorophenyl- 6- aminomethyl- 7- hydroxy- furo-[ 3, 4- c]- pyridine

Ved å starte med 1,3-dihydro-3-p-fluorfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 69%) et lyst beige produkt som smelter ved 183-187°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C,.H,oFNo0_. C-H.O,,. Starting with 1,3-dihydro-3-p-fluorophenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, one obtained (yield 69%) a pale beige product melting at 183-187°C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula C,.H,oFNo0_. C-H.O,,.

14 13 2 2 2 4 2 14 13 2 2 2 4 2

Eksempel 10 Example 10

1, 3- dihydro- 3- p- toluyl- 6- aminometyl- 7- hydroksy- furo-[ 3,4-c]-pyri di n 1, 3- dihydro- 3- p-toluyl- 6- aminomethyl- 7- hydroxy- furo-[ 3,4-c]-pyridine

Ved å starte med 1,3-dihydro-3-p-toluyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 78%) et lyst beige produkt som smelter ved 158-160°C (Tottoli.) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C, cH,,No0_. C-.H.O-. Starting with 1,3-dihydro-3-p-toluyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, one obtained (yield 78%) a pale beige product melting at 158-160°C (Tottoli.) and is insoluble in water, and the analysis of this showed good agreement with the formula C, cH,,No0_. C-.H.O-.

15 16 2 2 2 4 2 15 16 2 2 2 4 2

Eksempel 11 Example 11

1, 3- dihydro- 3- p- metoksyfenyl- 6- amonometyl- 7- hydroksy- furo-[ 3, 4- c3- pyridin 1, 3- dihydro- 3- p- methoxyphenyl- 6- amonomethyl- 7- hydroxy- furo- [ 3, 4- c3- pyridine

Ved å starte med 1,3-dihydro-3-p-metoksyfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 62%) et lyst beige produkt som smelter ved 144-149°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen CinH,c<N>o<0>,. Co<H>.<0_>.Starting with 1,3-dihydro-3-p-methoxyphenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, one obtained (yield 62%) a pale beige product melting at 144-149°C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula CinH,c<N>o<0>,. Co<H>.<0_>.

15 16 2 3 2 4 2 15 16 2 3 2 4 2

Eksempel 12 Example 12

1, 3- dihydro- 3-( 3', 4', 5'- trimetoksy)- fenyl- 6- aminometyl- 7-hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3-( 3', 4', 5'- trimethoxy)- phenyl- 6- aminomethyl- 7- hydroxy- furo- [ 3, 4-c]- pyridine

Ved å starte med 1,3-dihydro-3-(3',4',5'-trimetoksy)-fenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 49%) et hvitaktig produkt som smelter ved 137-141°C (Tottoli.) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C^H^r^Ot-. C2H402. Starting with 1,3-dihydro-3-(3',4',5'-trimethoxy)-phenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, one obtained ( yield 49%) a whitish product which melts at 137-141°C (Tottoli.) and is insoluble in water, the analysis of which showed good agreement with the formula C^H^r^Ot-. C 2 H 4 O 2 .

Eksempel 13 Example 13

1, 3- di hydro- 3- m- trifluormetylfenyl- 6- aminometyl- 7- hydroksy-furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- m- trifluoromethylphenyl- 6- aminomethyl- 7- hydroxy- furo-[ 3, 4- c]- pyridine

Ved å starte med 1,3-dihydro-3-m-trifluormetylfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 84%) et hvitt produkt som smelter ved 197-203°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C, CH, -,FoN_0_ . C-H.O-. Starting with 1,3-dihydro-3-m-trifluoromethylphenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, a white product was obtained (yield 84%) melting at 197 -203°C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula C, CH, -,FoN_0_ . C-H.O-.

Id 13 3 2 2 2 4 2 ID 13 3 2 2 2 4 2

Eksempel 14 Example 14

1, 3- dihydro- 3- p7dimetylaminoetoksy f enyl- 6- ami. nometyl- 7-hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro-3- p7dimethylaminoethoxy phenyl-6-ami. nomethyl-7-hydroxy-furo-[3,4-c]-pyridine

Ved å starte med 1,3-dihydro-3-p-dimetylaminoetoksyfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 46%) et lysegult produkt som smelter ved 160-164°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen ci9H23<N>3<o>2. <C>2H4<0>2. Starting with 1,3-dihydro-3-p-dimethylaminoethoxyphenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, a pale yellow product melting at 160 was obtained (yield 46%) -164°C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula ci9H23<N>3<o>2. <C>2H4<0>2.

Eksempel 15 Example 15

1, 3- di hydro- 3- metyl- 3- a- tienyl- 6- aminometyl- 7- hydroksy-furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- methyl- 3- a- thienyl- 6- aminomethyl- 7- hydroxy-furo- [ 3, 4- c]- pyridine

Ved å starte med 1,3-dihydro-3-metyl-3-a-tienyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 66%) et hvitt produkt som smelter ved 206-208°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C,,H,„N_0oS. C_H.,0o. Starting with 1,3-dihydro-3-methyl-3-α-thienyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, a white product was obtained (yield 66%) which melts at 206-208°C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula C,,H,„N_0oS. C_H.,0o.

13 14 2 2 2 4 2 13 14 2 2 2 4 2

Eksempel 16 Example 16

1, 3- di hydro- 3- etyl- 3- fenyl- 6- aminometyl- 7- hydroksy- furo-[ 3, 4- c]- pyri din 1, 3- dihydro- 3- ethyl- 3- phenyl- 6- aminomethyl- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Ved å starte med 1,3-dihydro-3-etyl-3-fenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 80%) et hvitt produkt som smelter ved 207°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen c15<H>i<8N>2°2"<C>2<H>4°2" Starting with 1,3-dihydro-3-ethyl-3-phenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, one obtained (yield 80%) a white product which melts at 207°C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula c15<H>i<8N>2°2"<C>2<H>4°2"

Eksempel 17 Example 17

1, 3- di. hydro- 3- fenyl- 3- p- tri f luormetylfenyl- 6- aminometyl-7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- di. hydro- 3- phenyl- 3- p- trifluoromethylphenyl- 6- aminomethyl-7- hydroxy- furo-[ 3, 4- c]- pyridine

Ved å starte med 1,3-dihydro-3-fenyl-3-p-trifluormetylfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 65%) et hvitt produkt som smelter ved 221°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C2iHi7<F>3<N>2°2"<C>2H4^2"Starting with 1,3-dihydro-3-phenyl-3-p-trifluoromethylphenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, a white product was obtained (yield 65%) which melts at 221°C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula C2iHi7<F>3<N>2°2"<C>2H4^2"

Eksempel 18 Example 18

1, 3- dihydro- 3- fenyl- 3- a- metoksypyrrolidi. nyl- 6- ami. nometyl- 7-hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- phenyl- 3- a- methoxypyrrolidine. nyl- 6- ami. nomethyl-7-hydroxy-furo-[3,4-c]-pyridine

Ved å starte med 1,3-dihydro-3-fenyl-3-a-metoksypyrro-li di.nyl-6-formyl-7-hydroksy-furo-[3 ,4-c]-pyridin, fikk man (utbytte 41%) et gulaktig produkt som smelter ved 129-132°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen Ci9H22N3<")3" <"2H4°2" By starting with 1,3-dihydro-3-phenyl-3-a-methoxypyrro-lidinyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, one obtained (yield 41 %) a yellowish product melting at 129-132°C (Tottoli) and insoluble in water, the analysis of which showed good agreement with the formula Ci9H22N3<")3" <"2H4°2"

Eksempel 19 Example 19

1, 3- dihydro- 3, 3- di ,- p- fluorfenyl- 6- aminometyl- 7- hydroksy-furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3, 3- di ,- p- fluorophenyl- 6- aminomethyl- 7- hydroxy- furo-[ 3, 4- c]- pyridine

Ved å starte med 1,3-dihydro-3-3-di-p-f luorfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 81%) et lysegult produkt som smelter ved 214°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C20<H>16<F>2<N>2°2* C2H4°2"Starting with 1,3-dihydro-3-3-di-p-fluorophenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, a pale yellow product was obtained (yield 81%) which melts at 214°C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula C20<H>16<F>2<N>2°2* C2H4°2"

Eksempel 20 Example 20

1, 3- dihydro- 3- a- furyl- 3- p- ti. ometylfenyl- 6- ami. nometyl- 7-hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- a- furyl- 3- p- ti. omethylphenyl-6-ami. nomethyl-7-hydroxy-furo-[3,4-c]-pyridine

Ved å starte med 1,3-dihydro-3-a-furyl-3-p-tiometylfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 63%) et hvitaktig produkt som smelter ved 153-157°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C^H^I^C^S. C2H402. Starting with 1,3-dihydro-3-a-furyl-3-p-thiomethylphenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, one obtained (yield 63%) a whitish product which melts at 153-157°C (Tottoli) and is insoluble in water, the analysis of which showed good agreement with the formula C^H^I^C^S. C 2 H 4 O 2 .

Eksempel 21 Example 21

1, 3- dihydro- 3- 3- di- a- furyl- 6- aminometyl- 7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- 3- di- a- furyl- 6- aminomethyl- 7- hydroxy- furo- [ 3, 4- c]- pyridine

Ved å starte med 1,3-dihydro-3,3-di-a-furyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 72%) et hvitt produkt som smelter ved 178°C (Tottoli) og er uoppløselig i. vann, og analysen av dette viste god overensstemmelse med formelen ci6Hl4<N>2°4" C2<H>4°2" Starting with 1,3-dihydro-3,3-di-α-furyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, a white product was obtained (yield 72%) which melts at 178°C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula ci6Hl4<N>2°4" C2<H>4°2"

Eksempel 22 Example 22

1, 3- dihydro- 3- cykloheksyl- 3-( 2', 3',- diklor)- fenyl- 6- aminometyl- 7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- cyclohexyl- 3-( 2', 3',- dichloro)- phenyl- 6- aminomethyl- 7- hydroxy- furo-[ 3, 4- c]- pyridine

Ved å starte med 1,3-dihydro-3-cykloheksyl-3-(2',3'-diklorfenyl)-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 59%) et gult produkt som smelter ved 213°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C20H22C^2N2°2* C2H4°2" Starting with 1,3-dihydro-3-cyclohexyl-3-(2',3'-dichlorophenyl)-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, one obtained (yield 59%) a yellow product melting at 213°C (Tottoli) and insoluble in water, the analysis of which showed good agreement with the formula C20H22C^2N2°2* C2H4°2"

Eksempel 2 3 Example 2 3

1, 3- dihydro- 3- vinyl- 3- p- tiometylfenyl- 6- aminometyl- 7-hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- vinyl- 3- p- thiomethylphenyl- 6- aminomethyl- 7- hydroxy- furo-[ 3, 4- c]- pyridine

Ved å starte med 1,3-dihydro-3-vinyl-3-p-tiometylfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 66%) et beige produkt som smelter ved 155°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C^H^gt^O-jS. C2H402. Starting with 1,3-dihydro-3-vinyl-3-p-thiomethylphenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, a beige product was obtained (yield 66%) which melts at 155°C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula C^H^gt^O-jS. C 2 H 4 O 2 .

Eksempel 24 Example 24

1, 3- dihydro- 3- dimetylaminopropyl- 3- p- klorfenyl- 6- aminometyl- 7- hydroksy- furo-[ 3, 4- c]- pyridin 1, 3- dihydro- 3- dimethylaminopropyl- 3- p- chlorophenyl- 6- aminomethyl- 7- hydroxy- furo-[ 3, 4- c]- pyridine

Ved å starte med 1,3-dihydro-3-dimetylaminopropyl-3-p-klorfenyl-6-formyl-7-hydroksy-furo-[3,4-c]-pyridin, fikk man (utbytte 4 7%) et hvitt produkt som smelter ved 169°C (Tottoli) og er uoppløselig i vann, og analysen av dette viste god overensstemmelse med formelen C, nH_-ClN-,0- . C,H.O_. Starting with 1,3-dihydro-3-dimethylaminopropyl-3-p-chlorophenyl-6-formyl-7-hydroxy-furo-[3,4-c]-pyridine, one obtained (yield 4 7%) a white product which melts at 169°C (Tottoli) and is insoluble in water, and the analysis of this showed good agreement with the formula C, nH_-ClN-,0- . C, H. O_.

19 24 3 2 2 4 2 19 24 3 2 2 4 2

TOKSISITET TOXICITY

DLj-Q ble bestemt per os og IP på mus. Det ble funnet at den var mellom 0,7 til over 2,4 g/kg (per os) og 0,6 til 1,6 5 g/kg IP. DLj-Q was determined per os and IP in mice. It was found to be between 0.7 to over 2.4 g/kg (per os) and 0.6 to 1.6 5 g/kg IP.

FARMAKOLOGI PHARMACOLOGY

En fullstendig farmakologisk undersøkelse ble foretatt, og de følgende tester er beskrevet nedenfor. A full pharmacological investigation was carried out and the following tests are described below.

A - Passiv kutal anafylaksi A - Passive cutaneous anaphylaxis

Dette forsøk ble utført som beskrevet i Fiche Technique nr. 48 of J. Pharm., Paris 1979 10 (1) s. 69-72. This experiment was carried out as described in Fiche Technique No. 48 of J. Pharm., Paris 1979 10 (1) pp. 69-72.

Sprague-Dawley hannrotter (180-200 g) fikk to intra-dermale injeksjoner av immunserum i ryggen; 72 timer senere fikk de en iv (penis-venen) injeksjon av 1 ml av en blanding av ovalbumin (5 mg/ml) og Evans blått (2,5 mg/ml). Dette frem-kalte dannelse av blemmer rundt de steder hvor immunserum var injisert. Blemmene ble undersøkt 30 minutter efter denne dannelse, idet de ble målt og derefter inkubert i 24 timer ved 65°C i 4 ml formamid (for ekstraksjon av Evans blått). Optisk tetthet av væsken på toppen ble bestemt ved 620 nm ved hjelp av et spektrofotometer. Male Sprague-Dawley rats (180-200 g) received two intra-dermal injections of immune serum in the back; 72 hours later they received an iv (penile vein) injection of 1 ml of a mixture of ovalbumin (5 mg/ml) and Evans blue (2.5 mg/ml). This induced the formation of blisters around the sites where the immune serum had been injected. The blisters were examined 30 minutes after this formation, being measured and then incubated for 24 hours at 65°C in 4 ml of formamide (for extraction of Evans blue). Optical density of the liquid on top was determined at 620 nm using a spectrophotometer.

En første gruppe på 8 rotter ble anvendt som kontroll; A first group of 8 rats was used as control;

en annen gruppe (8) ble anvendt for behandling med en referanse-forbindelse (theofyllin, 2 5 mg/kg) og ti andre grupper (alle på 8 rotter) ble anvendt for behandling med 10 av forbindelsene fremstilt ifølge oppfinnelsen (alle 25 mg/kg) identifisert ved sitt eksempelnummer; og for disse 11 grupper ble prøve-forbindelsen administrert per os, 1 time før injiseringen av ovalbumin/Evans blått-blandingen. Den prosentvise blemme-reduksjon, i overflate og i farve ble bestemt ved sammenligning med kontrollen. Resultatene er beskrevet i venstre del av den følgende tabell. another group (8) was used for treatment with a reference compound (theophylline, 25 mg/kg) and ten other groups (all of 8 rats) were used for treatment with 10 of the compounds produced according to the invention (all 25 mg/ kg) identified by its sample number; and for these 11 groups the test compound was administered per os, 1 hour before the injection of the ovalbumin/Evans blue mixture. The percentage blister reduction, in surface and in color, was determined by comparison with the control. The results are described in the left part of the following table.

B - Anti-histaminvirkning B - Anti-histamine action

Dette forsøk ble utført som beskrevet av Doepfner W. og Cerletti A., Int. Arch. Allergy 12, 89 1958 og J. Pharmac. and exp. Ther. (1974) 191 (2) s. 300-310. This experiment was carried out as described by Doepfner W. and Cerletti A., Int. Arch. Allergy 12, 89 1958 and J. Pharmac. and exp. Ther. (1974) 191 (2) pp. 300-310.

Sprague-Dawley hannrotter (140-160 g) ble holdt vann-fastende i 18 timer før de fikk 1 ml/kg vann (som kontroll), Male Sprague-Dawley rats (140-160 g) were water-fasted for 18 hours before receiving 1 ml/kg water (as control),

og 0,2 av en vandig oppløsning eller suspensjon av prøve-forbindelsene. Volumet av den venstre bakpote ble målt ved hjelp av pletysmografi, og derefter ble 0,1 ml 5% histamin-hydroklorid injisert. Inflammasjonsreaksjonen ble bedømt ved en påfølgende volumbestemmelse 1 time senere. and 0.2 of an aqueous solution or suspension of the test compounds. The volume of the left hindpaw was measured by plethysmography, and then 0.1 ml of 5% histamine hydrochloride was injected. The inflammatory reaction was assessed by a subsequent volume determination 1 hour later.

Grupper på hver 8 dyr ble anvendt: én som kontroll, ti Groups of 8 animals each were used: one as control, ten

for de nye forbindelser (de samme som i A ovenfor) og to for referanseforbindelsene mequitazin og prometazin, alle i en dose på 25 mg/kg. Den prosentvise reduksjon av inflammatorisk reaksjon ble bestemt ved sammenligning med kontrollen. Resultatene er angitt i høyre del av den følgende tabell. for the new compounds (the same as in A above) and two for the reference compounds mequitazine and promethazine, all at a dose of 25 mg/kg. The percentage reduction of inflammatory reaction was determined by comparison with the control. The results are indicated in the right part of the following table.

På grunnlag av disse to forsøk fremgår det klart at forbindelsene fremstilt ifølge oppfinnelsen har en sterk anti-histamin virkning. On the basis of these two experiments, it is clear that the compounds produced according to the invention have a strong antihistamine effect.

TILBEREDNING - POSOLOGI PREPARATION - DOSAGE

For anvendelse til mennesker ved oral administrering foretrekkes tabletter eller gelatinkapsler inneholdende 0,20 g av en forbindelse fremstilt ifølge oppfinnelsen. For iv.-administrering anvendes ampuller inneholdende den samme mengde som injiseres ved perfusjon. Daglige doser i human-terapi er fra 0,20 ti 1 2 g per os og 0,20 til 1 g iv. For use in humans by oral administration, tablets or gelatin capsules containing 0.20 g of a compound prepared according to the invention are preferred. For IV administration, ampoules are used containing the same amount as is injected by perfusion. Daily doses in human therapy are from 0.20 to 1 2 g per os and 0.20 to 1 g iv.

Claims (1)

Analogifremgangsmåte for fremstilling av terapeutisk aktive 1,3-dihydro-6-aminometyl-7-hydroksy-furo-[3,4-c]-pyridin-derivater med den generelle formel IAnalogous process for the preparation of therapeutically active 1,3-dihydro-6-aminomethyl-7-hydroxy-furo-[3,4-c]-pyridine derivatives of the general formula I hvor Ai er 0^- 0^ alkyl, fenyl eventuelt substituert med 1-3 C-^- C^ alkoksysubstituenter, 1-2 klor- eller f luorsubstituenter, en C1-C4 alkyl-, trifluormetyl- eller dimetylaminoetoksy-substituent, eller A^ er en vinyl-, dimetylaminopropyl-, cykloheksyl- eller furylgruppe,where Ai is 0^-0^ alkyl, phenyl optionally substituted with 1-3 C-^-C^ alkoxy substituents, 1-2 chlorine or fluorine substituents, a C1-C4 alkyl, trifluoromethyl or dimethylaminoethoxy substituent, or A ^ is a vinyl, dimethylaminopropyl, cyclohexyl or furyl group, A2 er hydrogen, fenyl eventuelt substituert med 1-2 klor-, fluor- eller tiometylsubstituenter, eller A2 er en furyl-, tienyl- eller metoksy-N-pyrolidinylgruppe; og deres farmasøytisk godtagbare salter, karakterisert ved at 6-formyl-7-hydroksy-furo-[3,4-c]-pyridin-derivater med den generelle formelA2 is hydrogen, phenyl optionally substituted with 1-2 chlorine, fluorine or thiomethyl substituents, or A2 is a furyl, thienyl or methoxy-N-pyrrolidinyl group; and their pharmaceutically acceptable salts, characterized in that 6-formyl-7-hydroxy-furo-[3,4-c]-pyridine derivatives of the general formula hvor Ai og A2 har de ovenfor angitte betydninger, omsettes med en støkiometrisk mengde av hydroksylamin og av NaOH, i vann ved romtemperatur, og derefter hydrogeneres det således oppnådde oksim ved romtemperatur ved normaltrykk i eddiksyre ved hjelp av hydrogen i nærvær av en Pd/C-katalysator.where Ai and A2 have the meanings given above, is reacted with a stoichiometric amount of hydroxylamine and of NaOH, in water at room temperature, and then the thus obtained oxime is hydrogenated at room temperature at normal pressure in acetic acid with the aid of hydrogen in the presence of a Pd/C -catalyst.
NO853475A 1984-09-05 1985-09-04 ANALOGUE PROCEDURE FOR PREPARING NEW, THERAPEUTIC-ACTIVE 6-AMINOMETHYL-FURO- (3,4-C) -PYRIDINE DERIVATIVES. NO160143C (en)

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ES546702A0 (en) 1986-03-01
DK402885A (en) 1986-03-06
FR2569699A1 (en) 1986-03-07
IT1188188B (en) 1988-01-07
AT394557B (en) 1992-05-11
MY103211A (en) 1993-05-29
CA1300150C (en) 1992-05-05
FI853288L (en) 1986-03-06
IE852182L (en) 1986-03-05
FR2569562B1 (en) 1989-02-10
FI853288A0 (en) 1985-08-28
ATA260285A (en) 1991-10-15
FI82053B (en) 1990-09-28
IT8522067A0 (en) 1985-09-05
GB2164037B (en) 1988-02-17
JPS6168490A (en) 1986-04-08
FI82053C (en) 1991-01-10
SE461394B (en) 1990-02-12
DE3531747C2 (en) 1990-09-06
OA08157A (en) 1987-03-31
ES8604966A1 (en) 1986-03-01

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