SE462218B - PROCEDURES FOR PREPARATION OF 6-SUBSTITUTED FURO- (3,4, -C) -PYRIDINE DERIVATIVES - Google Patents
PROCEDURES FOR PREPARATION OF 6-SUBSTITUTED FURO- (3,4, -C) -PYRIDINE DERIVATIVESInfo
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- SE462218B SE462218B SE8503869A SE8503869A SE462218B SE 462218 B SE462218 B SE 462218B SE 8503869 A SE8503869 A SE 8503869A SE 8503869 A SE8503869 A SE 8503869A SE 462218 B SE462218 B SE 462218B
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- hydroxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D491/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Description
462 218 intresse på grund av sin terapeutiska aktivitet, speciellt inom diuresområdet, området för sänkning av blodtryck, området för njurskydd och även som antihistaminmedel. 462 218 interest due to its therapeutic activity, especially in the field of diuresis, the field of lowering blood pressure, the field of kidney protection and also as an antihistamine.
Det har förvånansvärt visat sig att i det förfarande, som beskrives i vår tidigare svenska patentansökan 8500460-4 kan blockeringssteget för OH-gruppen i 7-ställning utelämnas, och icke desto mindre kan produkten framställas med ett bättre utbyte.It has surprisingly been found that in the process described in our earlier Swedish patent application 8500460-4 the blocking step for the OH group in the 7-position can be omitted, and nevertheless the product can be produced with a better yield.
Det nya förfarandet enligt uppfinningen består följaktligen i att omsätta ett 6-formyl-7-hydroxi-furo-(3,4-c)-pyridinderivat med den allmänna formeln II II OHC vari A1 och A2 har de ovan angivna betydelserna, med ett litet överskott av 1-dimetyl-aminometyl-vinylmagnesiumbromid vid kokpunkten i ett icke polärt lösningsmedel såsom tetra- hydrofuran. 6-formyl-7-hydroxi-furo-(3,4-c)-pyridinderivaten II kan erhål- las från motsvarande 6-metyl-7-hydroxi-derívat med den all- männa formeln III III vari Al och A2 har de ovan angivna betydelserna, genom följande reaktionssekvens: 3 _ 462 218 m-kloro-peroxibensoesyra 3' (CF3 CO)2 O MnO OHC Föreningarna III beskrives i våra patentansökningar 8200744-4 Och 8401841-5.Accordingly, the novel process of the invention consists in reacting a 6-formyl-7-hydroxy-furo- (3,4-c) -pyridine derivative of the general formula II II OHC wherein A1 and A2 have the meanings given above, with a small excess 1-dimethylaminomethyl-vinylmagnesium bromide at the boiling point of a non-polar solvent such as tetrahydrofuran. The 6-formyl-7-hydroxy-furo- (3,4-c) -pyridine derivatives II can be obtained from the corresponding 6-methyl-7-hydroxy-derivative of the general formula III III wherein A1 and A2 have the above the meanings indicated, by the following reaction sequence: 3 - 462 218 m-chloroperoxybenzoic acid 3 '(CF 3 CO) 2 O MnO OHC Compounds III are described in our patent applications 8200744-4 and 8401841-5.
Framställningen av endast en av utgångsföreníngarna, 1,3-dí- hydro-3-p-klorofenyl-6-formyl-7-hydroxí-furo-(3.4-c)-pyrídín 462 218 beskrives nu i detalj. Andra utgångsmaterial kan erhållas på samma sätt. a) I en 1 1 reaktor försedd med omrörare, uppvärmning och kyl- anordníng. behandlas 22.3 9 av l,3-dihydrox-3-p-klorofenyl-6- -formyl-7-hydroxi-furo-(3.4-c)-pyridin vid 0°C i närvaro av 300 ml metylenklorid med 18.2 g m-peroxibensoesyra, som till- sättes sakta. Efter omrörning över natt vid rumstemperatur tillsattes 150 ml 10%-ig natriumsulfatlösníng. Efter omrörning och dekantering tvättades metylendikloridfasen med samma mängd natriumsulfatlösning, två gånger med 150 ml natriumbikarbonat- lösning och tre gånger med 100 ml vatten och torkades över vattenfritt natriumsulfat. Genom indunstning till torrhet erhölls en beige fällníng. som tvättades med petroleumeter. filtrerades och torkades. Utbyte 22,9 g (96%) av 1,3-díhydro- -3-p-klorofenyl-6-metyl-7-hydroxi-furo-(3.4-c)-pyridín-N-oxid. b) I samma reaktor som ovan behandlades 22.9 g av den före- ning. som erhölls i det föregående steget. vid 0-5°C i närvaro av 175 ml metylendikloríd, med 4.3 ml trifluoroättiksyraan- hydrid, tillsatt droppvis under omrörning. Blandníngen omrör- des över natt vid rumstemperatur och kyldes sedan och behand- lades droppvis med 95 ml metanol. Efter indunstning till torr- het togs återstoden upp i 300 ml kloroform. tvättades två gånger med 75 ml 10%-ig natriumbikarbonatlösning och tre gånger med 100 ml vatten och torkades på vattenfri natriumsul- fat. Kloroformen avdrevs. och återstoden tvättades med dietyl- eter och torkades under sänkt tryck. Utbyte 21.3 g (93%) av 1.3-dihydro-3-p-klorofenyl-6-hydroxímetyl-7-hydroxi-furo-(3.4-c) -pyridin. c) 21.3 g av den förening, som erhölls i det föregående steget. behandlades i en 2 1 reaktor med 27 g mangandioxid i närvaro av 0,9 l kloroform vid 28-30°C under omrörning 3 timmar. Efter separation. filtrering, tvätt med kloroform och sedan med etylacetat indunstades lösningen till torrhet. och pastan behandlades med ísopropyloxid. sedan med pentan. Man erhöll sålunda 20.1 9 (95%) av 1,3-dihydro-3-p-klorofenyl-6- 462 218 -formyl-7-hydroxi-furo-(3.4-c)-pyridin.The preparation of only one of the starting compounds, 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine 462 218, is now described in detail. Other starting materials can be obtained in the same way. a) In a 1 L reactor equipped with stirrer, heating and cooling device. 22.39 of 1,3-dihydrox-3-p-chlorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine is treated at 0 ° C in the presence of 300 ml of methylene chloride with 18.2 g of m-peroxybenzoic acid , which is added slowly. After stirring overnight at room temperature, 150 ml of 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 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 that compound were treated. obtained in the previous step. at 0-5 ° C in the presence of 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 sulphate. 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 of the compound obtained in the previous step. was treated in a 2 L reactor with 27 g of manganese dioxide in the presence of 0.9 L of 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. then with pentane. There was thus obtained 20.19 (95%) of 1,3-dihydro-3-p-chlorophenyl-6,462,218-formyl-7-hydroxy-furo- (3,4-c) -pyridine.
Följande exempel belyser uppfinningen.The following examples illustrate the invention.
Exempel l lg3-díhydro-3-metyl-6-(1-hydroxí-2-dimetylaminometyl-a1lvl)-7- -hydroxí-furo-(3.4-c)-Pyridin a) Framställning av organomagnesiumreagenset I en 2 l reaktor försedd med värmnings-, kylnings- och omrör- ningsanordníngar hälldes under kvävecirkulering 19,4 g (0,8 mol) magnesium och 100 ml tetrahvdrofuran, som tidigare destillerats på litiumaluminíumhydrid. Blandningen återlopps- kokades.Example 11g3-Dihydro-3-methyl-6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo- (3,4-c) -Pyridine a) Preparation of the organomagnesium reagent In a 2 L reactor equipped with heating, cooling and stirring devices were poured under nitrogen circulation 19.4 g (0.8 mol) of magnesium and 100 ml of tetrahydrofuran, previously distilled on lithium aluminum hydride. The mixture was refluxed.
Man tillsatte därefter sakta 132 g (0,8 mol) 3-dimetylamino-2- -bromo-l-propylen. Ingen extern värmning anbríngades, varvid âterloppet upprätthölls och kontrollerades genom tillsatsen av denna förening. Vid slutet av tillsatsen tillsattes 1 1 destíllerad tetrahydrofuran. Blandningen âterloppskokades 2 timmar och kyldes sedan till 10°C. b> Till reaktionsblandníngen från det föregående steget sattes långsamt under omröring 89 g (0,5 mol) l.3-dihydro-3-metyl-6- -formyl-7-hydroxi-furo-(3,4-c)-pyridín. Temperaturen nådde ca °C vid slutet av tillsatsen. Omrörníng upprätthölls över natt vid rumstemperatur. Blandningen kyldes sedan till 0°C och 250 ml vatten mättad med ammoniumklorid och 250 ml dietyleter sattes därtill. Efter omrörning under 15 minuter vid rums- temperatur erhölls en tvåfasblandning med en oljeövervätska.132 g (0.8 mol) of 3-dimethylamino-2-bromo-1-propylene were then slowly added. No external heating was applied, the reflux being maintained and controlled by the addition of this compound. At the end of the addition, 1 l of distilled tetrahydrofuran was added. The mixture was refluxed for 2 hours and then cooled to 10 ° C. To the reaction mixture from the previous step was slowly 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 about ° C at the end of the addition. Stirring was maintained 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 thereto. After stirring for 15 minutes at room temperature, a two-phase mixture with an oil supernatant was obtained.
Blandningen separerades, och vattenfasen extraherades två gånger med 250 ml volymer av dietyleter. Extrakten sattes till oljefasen, som hade tvättats med vatten tre gånger. Den oljiga fasen torkades sedan på magnesiumsulfat, torkades med kol- *30 462 218 5 svart. koncentrerades till torrhet och extraherades två gånger med 250 ml diisopropyleter. Extrakten filtrerades, koncentre- rades (reduktion till 1/4 av den ursprungliga volymen) och kyldes över natt, vilket ledde till en fällning. som separera- des och tvättades med díisopropyleter. Utbyte 105 g (80%).The mixture was separated, and the aqueous phase was extracted twice with 250 ml volumes of diethyl ether. The extracts were added to the oil phase, which had been washed with water three times. The oily phase was then dried over magnesium sulphate, dried over carbon black. concentrated to dryness and extracted twice with 250 ml of diisopropyl ether. The extracts were filtered, concentrated (reducing to 1/4 of the original volume) and cooled overnight, leading to a precipitate. which was separated and washed with diisopropyl ether. Yield 105 g (80%).
Framställningen av de andra föreningarna enligt uppfinningen följer samma förlopp förutom att i steg (b) utgångsmaterialet är annorlunda. Följande exempel kommer följaktligen att refe- rera till exempel 1 och endast ange det nya utgångsmaterialet, det totala utbytet och egenskaperna hos den erhållna förening- en.The preparation of the other compounds according to the invention follows the same process except that in step (b) the starting material is different. The following examples will therefore refer to Example 1 and indicate only the new starting material, the total yield and the properties of the obtained compound.
Exempel 2 1,3-dihydro-3-Dropyl-6-(1-hvdroxi-2-dimetylaminometyl-allyl)-7- -hydroxi-furo-(3.4-c)-pyridin Förfarandet enligt exempel 1 upprepades men man startade med 83 g (0,4 mol) 1,3-dihydro-3-propyl-6-formyl-7-hydroxi-furo- -(3,4-c)-pyrídin. Utbyte 89 g (66%) av en produkt. som smälter vid 187-l94°C (Tottoli) med sönderfall, vars analys visade god överensstämmelse med formeln C H N 0 2HCl. 16 24 2 3' Exempel 3 1,3-dihydro-3-cyklohegy1-6-(l-hydroxi-2-dimetylaminometyl- -allyl)-7-hydroxi-furo-(3.4-c)-Dyridin Förfarandet enligt exempel 1 upprepades men utgående ifrån 99 g (0,4 mol) l.3-dihydro-3-cyklohexyl-6-formyl-7-hydroxi-furo- -(3,4-c)-pyridin. Utbyte 92 g (59%) av en produkt, som smälter vid 180-l84°C (Tottoli) under sönderfall. vars analys visade en god överensstämmelse med formeln Cl9H28N2°3' ZHCI' Exempel 4 1,3-dihydro-3-fenyl-6-(l-hydroxi-g-dimetylaminometyl-allyl)-7- -hydroxi-furo-(3.4-c)-Dyridín Förfarandet enligt exempel l upprepades men utgående ifrån 99 462 218 g (0,4 mol) 1,3-dihydro-3-feny1-6-formyl-7-hydroxi-furo-(3.4- -c)-pyrídín. Utbyte 77 g (47%) av en produkt. som smälter vid 210-2l5°C (Tottoli) under sönderfall, vars analys visade en god överensstämmelse med formeln C H N O 2HCl. 19 22 2 3' Exempel 5 1,3-dihydro-3-p-klorofenvl-6-(l-hydroxi-2-dimetylaminometyl- -allyl)-7-hydroxi-furo-(3.4-c)-pyrídin Förfarandet enligt exempel 1 upprepades men utgående från 110 g (0,4 mol) 1,3-dínydro-3-p-klorofenyl-6-formyl-7-hydroxi- -furo-(3,4-c)-pyrídin. Utbyte 95 g (57%) av en produkt, som smälter vid 195-200°C (Tottoli) under sönderfall. vars analys visade en god överensstämmelse med formeln CIQHZICINZO3, 2HC1.Example 2 1,3-Dihydro-3-Dropyl-6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo- (3,4-c) -pyridine The procedure of 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 89 g (66%) of a product. melting at 187-194 ° C (Tottoli) with decomposition, the analysis of which showed good agreement with the formula C H N 0 2HCl. Example 3 1,3-Dihydro-3-cyclohegyl-6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo- (3,4-c) -Dyridine The procedure of Example 1 was repeated. but starting from 99 g (0.4 mol) of 1,3-dihydro-3-cyclohexyl-6-formyl-7-hydroxy-furo- - (3,4-c) -pyridine. Yield 92 g (59%) of a product, melting at 180 DEG-184 DEG C. (Tottoli) during decomposition. whose analysis showed a good agreement with the formula C 19 H 28 N 2 O 3 'ZHCl' Example 4 1,3-Dihydro-3-phenyl-6- (1-hydroxy-g-dimethylaminomethyl-allyl) -7- -hydroxy-furo- (3,4- c) -Dyridine The procedure of Example 1 was repeated but starting from 99,462,218 g (0.4 mol) of 1,3-dihydro-3-phenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine . Yield 77 g (47%) of a product. melting at 210-215 ° C (Tottoli) during decomposition, the analysis of which showed a good agreement with the formula C H N O 2HCl. 19 22 2 3 'Example 5 1,3-Dihydro-3-p-chlorophenyl-6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo- (3,4-c) -pyridine The procedure of Example 1 was repeated but starting from 110 g (0.4 mol) of 1,3-dinydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine. Yield 95 g (57%) of a product, melting at 195-200 ° C (Tottoli) during decomposition. whose analysis showed a good agreement with the formula CIQHZICINZO3, 2HC1.
Exempel 6 1,3-dihydro-3-(2.3-diklorofenyl)-6-(1-hydroxí-2-dimetylamino- metyl-allyl)-7-hydroxi-furo-(3.4-c)-Dyridin Förfarandet enligt exempel 1 upprepades men utgående från 124 g (0,4 mol) 1,3-díhydro-3-(2,3-díkloro-fenyl)-6-formyl-7- -hydroxí-furo-(3,4-c)-pyridín. Utbyte 82 g (62%) av en pro- dukt. som smälter vid 180-l84°C (Tottolí). med sönderfall, vars analys visade god överensstämmelse med formeln CIQHZOCIZNZO3. 2HCl.Example 6 1,3-Dihydro-3- (2,3-dichlorophenyl) -6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo- (3,4-c) -Dyridine The procedure of Example 1 was repeated. but starting from 124 g (0.4 mol) of 1,3-dihydro-3- (2,3-dichloro-phenyl) -6-formyl-7-hydroxy-furo- (3,4-c) -pyridine. Yield 82 g (62%) of a product. melting at 180-184 ° C (Tottoli). with decomposition, the analysis of which showed good agreement with the formula CIQHZOCIZNZO3. 2HCl.
Exempel 7 1.3-dihydro-3-p-f1uorofeny1-6-(1-nydroxi-2-dimetylaminometyl- -a11y1)-7-hydroxí-furo-(3.4-0)-pyrídín Förfarandet i exempel 1 upprepades men utgående ifrån 104 g (0,4 mol) l,3-dihydro-3-p-fluorofenyl-6-formyl-7-hydroxi-furo- -(3,4-c)-pyrídín. Utbyte 85 g (62%) av en produkt. som smälter vid l98°C (Tottolí). under sönderfall. vars analys visade god överensstämmelse med formeln CIQHZIFNZO3. 2HCll 462 218 8 Exempel 8 1,3-dihydro-3-p-to1uYl-6-(1-hvdroxí-2-dimetylamínometvl-allyl)- -7-hydroxi-furo-(3.4-5)-Dyridín Förfarandet í exempel 1 upprepades men utgående från 103 g (0,4 mol) 1.3-díhydro-3-p-toluyl-6-formyl-7-nydroxí-furo-(3,4- -c)-pyridin. Utbyte 81 g (66%) av en produkt, som smälter vid 203-207°C (Tottolí) med sönderfall, vars analys visade god overenss ammelse med formeln C20H24N2O3 2HCl 1 tu ' _ Exempel 9 1,3-díhydro-3-p-metoxifenyl-6-(1-hvdroxí-2-dimetylaminometyl- -allyl)-7-hvdroxi-furo-(3.4_a)-Dvridín Förfarandet i exempel 1 upprepades men utgående ifrån 110 g (0,4 mol) 1.3-dihydro-3-p-metoxifenyl-6-formyl-7-hydroxi-furo- -(3,4-c)-pyridín. Utbyte 86 g (63%) av en produkt som smälter vid 169-170°C (Tottoli). vars analys visade en god överens- stammelse med formeln C2oH24N204.2HCl.Example 7 1,3-Dihydro-3-p-fluorophenyl- 6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo- (3.4-O) -pyridine The procedure of Example 1 was repeated starting from 104 g (0.4 mol) 1,3-dihydro-3-p-fluorophenyl-6-formyl-7-hydroxy-furo- - (3,4-c) -pyridine. Yield 85 g (62%) of a product. melting at 98 ° C (Tottoli). during decay. whose analysis showed good agreement with the formula CIQHZIFNZO3. 2HCl 462 218 Example 8 1,3-Dihydro-3-p-toluyl-6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo- (3.4-5) -Dyridine The procedure of Example 1 was repeated but starting from 103 g (0.4 mol) of 1,3-dihydro-3-p-toluyl-6-formyl-7-hydroxy-furo- (3,4--c) -pyridine. Yield 81 g (66%) of a product melting at 203 DEG-207 DEG C. (Tottoli) with decomposition, the analysis of which showed a good agreement with the formula C20 H24 N2 O3 2 HCl 1 tu '_ Example 9 1,3-Dihydro-3-p -Methoxyphenyl-6- (1-hydroxy-2-dimethylaminomethyl--allyl) -7-hydroxy-furo- (3.4_a) -Dyridine The procedure of Example 1 was repeated but starting from 110 g (0.4 mol) of 1,3-dihydro- 3-p-methoxyphenyl-6-formyl-7-hydroxy-furo- - (3,4-c) -pyridine. Yield 86 g (63%) of a product melting at 169-170 ° C (Tottoli). whose analysis showed a good agreement with the formula C20H24N2O4.2HCl.
Exmepel 10 lpg-dihvdro-3-m-trífluorometylfenyl-6-(1-hvdroxi-2-dimetv1amino- metyl-allyl)-7-hvdroxi-furo-(3,4-c)-Dyrídin Förfarandet enligt exempel 1 upprepades men utgående från 124 g (0,4 mol) 1,3-díhydro-3-m-trífluorometylfenyl-6-formyl-7- -hydroxi-furo-(3.4-c)-pyrídín. Utbyte 102 g (58%) av en produkt. som smälter vid 217-223°C (Tottolí) med sönderfall, vars analys visade en god överensstämmelse med formeln C20H2lF3N2O3.2HC1.Example 10 1pg-Dihydro-3-m-trifluoromethylphenyl-6- (1-hydroxy-2-dimethylamino-methyl-allyl) -7-hydroxy-furo- (3,4-c) -Dyridine The procedure of Example 1 was repeated but starting from 124 g (0.4 mol) of 1,3-dihydro-3-m-trifluoromethylphenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine. Yield 102 g (58%) of a product. melting at 217-223 ° C (Tottolí) with decomposition, the analysis of which showed a good agreement with the formula C20H21F3N2O3.2HCl.
Exempel ll 1,3-dihvdro-3-p-(díetylaminoetoxi-fenyl)-6-(1-hvdroxi-2-dimety1- aminometyl-allyl)-7-hYdroxí-§g;9-(3,4-0)-Dyríåín Förfarandet enligt exempel 1 upprepades men utgående från 142 g (0,4 mol) 1,3-dihydro-3-p-(díetylamínoetoxífenyl)-6-formy1- -7-hydroxi-furo-(3,4-c)-pyrídín. Utbyte 76 g (51%) av en pro- 9 462 218 dukt. som smälter vid 158-l60°C (Tottolí), vars analys visade d " t" 1 . . en go overenss amme se med formeln C25H35N3O4 2HC1 Exempel 12 1,3-dihydro-3-p-(pyrrolidínyletoxí-fenyl)-6-(1-hydroxi-2-dí- metylamínometyl-allyl)-7-hydroxí-furo-(3,4-c)-pyrídin Förfarandet i exempel 1 upprepades men utgående från 142 g (0,4 mol) 1,3-dihydro-3-p-(pyrrolídinyletoxi-fenyl)-6-formyl- -7-hydroxí-furo-(3,4-c)-pyridin. Utbyte 70 g (53%) av en produkt. som smälter vid l73°C (Tottoli) vars analys visade en d N 0 go overensstammelse med formeln C25H33N304.2HCl.Example 11 1,3-Dihydro-3-p- (diethylaminoethoxy-phenyl) -6- (1-hydroxy-2-dimethyl-aminomethyl-allyl) -7-hydroxy-phenyl; 9- (3,4-0) The procedure of Example 1 was repeated but starting from 142 g (0.4 mol) of 1,3-dihydro-3-p- (diethylaminoethoxyphenyl) -6-formyl- -7-hydroxy-furo- (3,4-c) -pyridine. Yield 76 g (51%) of a product. melting at 158-160 ° C (Tottolí), the analysis of which showed d "t" 1. . a good compound of the formula C25H35N3O4 2HCl Example 12 1,3-dihydro-3-p- (pyrrolidinylethoxy-phenyl) -6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo- ( 3,4-c) -pyridine The procedure of Example 1 was repeated but starting from 142 g (0.4 mol) of 1,3-dihydro-3-p- (pyrrolidinylethoxy-phenyl) -6-formyl--7-hydroxy-furo - (3,4-c) -pyridine. Yield 70 g (53%) of a product. melting at 73 ° C (Tottoli) whose analysis showed a d N 0 go agreement with the formula C25H33N304.2HCl.
Exempel 13 l.3-díhydro-3-metyl-3-n-pentyl-6-(l-hydroxi-2-dimetylamino- metyl~a1lyl)-7-hydroxí-furo-(3,4-c)-pyridín Förfarandet í exempel 1 upprepades men utgående från 99 g (0,4 mol) av 1,3-díhydro-3-metyl-3-n-pentyl~6-formy1-7-hydroxi- -furo-(3,4-c)-pyridin. Utbyte 94 g (59%) av en produkt. som smälter vid 187-l9l°C (Tottoli) med sönderfall, vars analys visade god överensstämmelse med formeln C19H30N203.2HC1.Example 13 1,3-Dihydro-3-methyl-3-n-pentyl-6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo- (3,4-c) -pyridine in Example 1 was repeated but starting from 99 g (0.4 mol) of 1,3-dihydro-3-methyl-3-n-pentyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine. Yield 94 g (59%) of a product. melting at 187-119 ° C (Tottoli) with decomposition, the analysis of which showed good agreement with the formula C19H30N2O3.2HCl.
Exempel 14 1,3-dihydro-3-metyl-3-fenyl-6-(1-hydroxi-2-dimetylaminometyl- -ally1)-7-hydroxi-furo-(3,4-c)-Dyridin Förfarandet enligt exempel l upprepades men utgående från 103 g (0,4 mol) 1,3-díhydro-3-metyl-3-fenyl-6-formyl-7-hydroxí- -furo-(3,4-c)-pyridin. Utbyte 104 g (69%) av en produkt, som smälter vid 178-179°C (Tottolí), vars analys visade en god överensstämmelse med formeln C2oH24N2O3.2HCl.Example 14 1,3-Dihydro-3-methyl-3-phenyl-6- (1-hydroxy-2-dimethylaminomethyl--allyl) -7-hydroxy-furo- (3,4-c) -Dyridine The procedure of Example 1 was repeated but starting from 103 g (0.4 mol) of 1,3-dihydro-3-methyl-3-phenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine. Yield 104 g (69%) of a product melting at 178-179 ° C (Tottolí), the analysis of which showed a good agreement with the formula C20H24N2O3.2HCl.
Exempel 15 1,3-dihydro-3-metyl-3-CÅ-tienyl-6-(1-hydroxí-2-dimetylamino- metyl-allyl)-7-hydroxi-furo-(3.4-C)-Dyrídífl Förfarandet enligt exempel l upprepades men utgående från 67 g ' C H 462 218 10 (0,4 mol) 1.3-díhydro~3-metyl-3-(K-tienyl-6-formyl-7-hydroxi- -furo-(3,4-c)-pyridin. Utbyte 77 g (67%) av en produkt, som smälter vid 169-l75°C (Tottoli) under sönderfall, vars analys visade en god överensstämmelse med formeln Cl8H22SN2O3.2HC1.Example 15 1,3-Dihydro-3-methyl-3-CO-thienyl-6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo- (3,4-C) -Dyridine The procedure of Example 1 was repeated but starting from 67 g of CH 462 218 (0.4 mol) of 1,3-dihydro-3-methyl-3- (K-thienyl-6-formyl-7-hydroxy-furo- (3,4-c Yield 77 g (67%) of a product, melting at 169 DEG-175 DEG C. (Tottoli) during decomposition, the analysis of which showed a good agreement with the formula C18 H22 SN2 O3.2HCl.
Exempel 16 1,3-dihydro-3-etyl-3-m-trif1uorometylfenyl-6-(l-hydroxi-2- -dimetylaminometyl-allvl)-7-hydroxi-furo-(3,4-c)-pyridin Förfarandet enligt exempel l upprepades men utgående från 136 g (0,4 mol) 1.3-dihydro~3-etyl-3-m-trífluorometyl-fenyl-6- -formyl-7-hydroxi-furo-(3.4-c)-pyridin. Utbyte 117 g (72%) av en produkt. som smälter vid l85°C (Tottoli), vars analys visar en god överensstämmelse med formeln 22 25F3N2O3.2HCl.Example 16 1,3-Dihydro-3-ethyl-3-m-trifluoromethylphenyl-6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo- (3,4-c) -pyridine Example 1 was repeated but starting from 136 g (0.4 mol) of 1,3-dihydro-3-ethyl-3-m-trifluoromethyl-phenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine. Yield 117 g (72%) of a product. melting at 185 ° C (Tottoli), the analysis of which shows a good agreement with the formula 22 25F3N2O3.2HCl.
Exemgel 17 1,3-dihydro-3-etyl-3-CX-furyl-6-(1-hvdroxi-2-dímetylamino- metyl-allyl)-7-hvdroxi-furo-(3,4-c)-Dvridin Förfarandet enligt exempel 1 upprepades men utgående från 104 g (0,4 mol) l.3-dihydro-3-etyl-3-(Å-furyl-6-formyl-7-hydroxi- -furo-(3,4-c)-pyridin. Utbyte 68 g (58%) av en produkt. som smälter vid 164-l69°C (Tottoli), med sönderfall, vars analys visade en god överensstämmelse med formeln Cl9H24N2O4.2HCl.Example Gel 17 1,3-Dihydro-3-ethyl-3-CX-furyl-6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo- (3,4-c) -Dyridine Process according to Example 1 was repeated but starting from 104 g (0.4 mol) of 1,3-dihydro-3-ethyl-3- (α-furyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine Yield 68 g (58%) of a product melting at 164 DEG-169 DEG C. (Tottoli), with decomposition, the analysis of which showed a good agreement with the formula C19H24N2O4.2HCl.
Exemgel 18 1,3-dihydro-3-fenyl-3-p-etoxifeny1-6-(l-hydroxi-2-dímetYl- aminometyl-allyl)-7-hydroxí-furo-(3.4-0)-Dyrídín Förfarandet enligt exempel l upprepades men utgående från 144 g (0,4 mol) 1,3-dihydro-3-fenyl-3-p-etoxifenyl-6-formyl-7- _nydroxi-furo-(3,4-c)-pyridín. Utbyte 99 g (64%) av en pro- auxz, som smälter vid 148-149°c (Totto1í>. vara analys viaafla en god överensstämmelse med formeln C27H30N204.2HC1. 462 218 Exempel 19 1,3-díhydro-3,3-di-p-fluorofeny1-6-(1-hydroxi-2-dimetylamíno- metyl-allyl)-7-hydroxi-furo-(3,4-c)-pyrídín Förfarandet i exempel 1 upprepades men utgående ifrån 142 g (0,4 mol) 1,3-dihydro-3.3-di-p-fluorofenyl-6-formyl-7- -hydroxi-furo-(3,4-c)-pyridin. Utbyte 115 g (70%) av en pro- dukt, som smälter vid 175°C (Tottoli). vars analys visade en d l l go overensstammelse med formeln C25H24F2N203.2HCl.Example Gel 18 1,3-Dihydro-3-phenyl-3-p-ethoxyphenyl- 6- (1-hydroxy-2-dimethyl-aminomethyl-allyl) -7-hydroxy-furo- (3,4-O) -Dyridine The procedure of Example 1 was repeated but starting from 144 g (0.4 mol) of 1,3-dihydro-3-phenyl-3-p-ethoxyphenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine. Yield 99 g (64%) of a pro-auxz, melting at 148-149 ° C (Totto1>> be analysis via a good agreement with the formula C27H30N2O4.2HCl. 462 218 Example 19 1,3-dihydro-3,3 -di-p-fluorophenyl- 6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo- (3,4-c) -pyridine The procedure of Example 1 was repeated but starting from 142 g (0 4 mol) 1,3-dihydro-3,3-di-p-fluorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine Yield 115 g (70%) of a pro- melting at 175 ° C (Tottoli), the analysis of which showed a dll good agreement with the formula C25H24F2N2O3.2HCl.
Exempel 20 lL3-dihydro-3-0(-furyl-3-p-tiometylfenyl-6-(l-hydroxi-2-di- metylaminometyl-allyl)-7-hydroxi-furo-(3,4-c)-Dyridin Förfarandet enligt exempel 1 upprepades men utgående från 141 g (0,4 mol) 1,3-dihydro-3-cá-furyl-3-p-tiometylfenyl-6-formyl- -7-hydroxi-furo-(3.4-c)-pyridin. Utbyte 82 g (48%) av en pro- dukt, som smälter vid 143-15l°C (Tottoli). med sönderfall. vars analys visade en god överensstämmelse med formeln C24H26SN2O4.2HC1.Example 20 11-Dihydro-3-O (-furyl-3-p-thiomethylphenyl-6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo- (3,4-c) -Dyridine The procedure of Example 1 was repeated but starting from 141 g (0.4 mol) of 1,3-dihydro-3-cá-furyl-3-p-thiomethylphenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine Yield 82 g (48%) of a product, melting at 143 DEG-151 DEG C. (Tottoli), with decomposition, the analysis of which showed a good agreement with the formula C24H26SN2O4.2HCl.
Toxicítet Ingen av de framställda föreningarna uppvisade någon väsentlig toxicitet per os: LDSO uppgick till mellan 0.8 och 1.2 g/kg hos råttor och till mellan 0.7 och l g/kg hos möss.Toxicity None of the compounds produced showed any significant oral toxicity: the LDSO was between 0.8 and 1.2 g / kg in rats and between 0.7 and 1 g / kg in mice.
Farmakologi Aktiviteten för föreningarna enligt uppfinningen har påvisats medelst olika test av vilka tre återges nedan mera i detalj.Pharmacology The activity of the compounds of the invention has been demonstrated by various tests, three of which are set forth in more detail below.
I. Letalitet, framkallad av Yohimbine Hcl hos möss.I. Lethality, induced by Yohimbine Hcl in mice.
Detta test utfördes med grupper om 10 CD-l (Charles River) möss av hankön. Varje behandlad mus erhöll 0.25 ml/20 g av en suspension, innehållande den testade dosen förening. En timme efter administreringen injicerades mössen subkutant 30 mg/kg .20 4620 218 12 Yohimbine HCI. Procentuell avdödníng (L) bestämdes 18 timmar efter ínjektionen. En Yohimbine HCl-kontrollgrupp användes för varje förening. Resultaten återges i tabell I.This test was performed with groups of 10 male CD-1 (Charles River) mice. Each treated mouse received 0.25 ml / 20 g of a suspension containing the tested dose of compound. One hour after administration, mice were injected subcutaneously at 30 mg / kg .20 4620 218 12 Yohimbine HCl. Percent kill (L) was determined 18 hours after injection. A Yohimbine HCl control group was used for each compound. The results are given in Table I.
II. Antagonísm mot katalepsi. åstadkommen medelst haloperidol.II. Antagonism against catalepsy. achieved by haloperidol.
Detta experiment utfördes i jämförelse med två referensföre- níngar. Imipramine och 5-hydroxitryptofan. på Histar-råttor av hankön. 140/170 9. i grupper om 6 råttor i varje grupp.This experiment was performed in comparison with two reference compounds. Imipramine and 5-hydroxytryptophan. on male Histar rats. 140/170 9. in groups of 6 rats in each group.
Intraperitoneal administrering av haloperidol med 5 mg/kg índucerar katalepsi. Ytterligare oral administrering av de testade föreningarna en timme efter haloperidol-injektion har en motsatt verkan mot katalepsi. Åtta av föreningarna enligt uppfinningen testades med olika doser (en sats för varje dos av varje förening). Verkan på katalepsi uppskattades l.2.3.4 och 5 timmar efter administre- ringen av de testade föreningarna genom att man placerade råttornas bakfot på en metallstav belägen på ett avstånd av 10 cm ovanför bordsnivån (testet utfördes i ett ljudisolerat rum vid 22°C). Om råttan uppvisade förmåga att kvarstanna under 20 sekunder bedömdes provet med en l. För 40 sekunder var bedöm- ningen 2 och fortsättningsvis uppåt till 100 sekunder som mot- svarade bedömningen 5. Medelvärden beräknades för varje grupp tillsammans med motsvarande procentuell antagonism.Intraperitoneal administration of haloperidol at 5 mg / kg induces catalepsy. Further oral administration of the tested compounds one hour after haloperidol injection has the opposite effect against catalepsy. Eight of the compounds of the invention were tested at different doses (one batch for each dose of each compound). The effect on catalepsy was estimated on 1.2.3.4 and 5 hours after the administration of the tested compounds by placing the hind legs of the rats on a metal rod 10 cm above the table level (the test was performed in a soundproof room at 22 ° C). . If the rat showed the ability to remain for 20 seconds, the test was assessed with a l. For 40 seconds, the assessment was 2 and continued up to 100 seconds, which corresponded to the assessment 5. Mean values were calculated for each group together with the corresponding percentage antagonism.
Resultaten återges i tabell II.The results are given in Table II.
III. Test avseende misströstan eller slöhet hos möss.III. Test for malaise or lethargy in mice.
Detta experiment utfördes med CD-l (Charles River)-möss av hankön i grupper om 10 möss i varje grupp. i jämförelse med Maprotiline som referensförening. En timme före testet erhöll 'mössen en dos av 0.4 ml/20 g suspension. den lämpliga dosen i mg/kg av de testade föreningarna.This experiment was performed with male CD-1 (Charles River) mice in groups of 10 mice in each group. in comparison with Maprotiline as a reference compound. One hour before the test, the mice received a dose of 0.4 ml / 20 g of suspension. the appropriate dose in mg / kg of the tested compounds.
Mössen placerades i en plexiglascylinder (höjd 25 cm. diameter 13 462 218 cm), innehållande vatten med en te »eratur av 22°C. Märk- ningen av imobilitetsperíoden gjordes mellan andra och sjätte minuten. Det fanns en kontrollgrupp för varje förening och en grupp per testad dosering.The mice were placed in a plexiglass cylinder (height 25 cm. Diameter 13,462,218 cm), containing water with a temperature of 22 ° C. The immobility period was marked between the second and sixth minutes. There was one control group for each compound and one group per dose tested.
Resultaten återges i tabell III. där A betecknar medel- imobilitetsperioden och B betecknar procentuell variation i jämförelse med kontrollen.The results are given in Table III. where A denotes the mean immobility period and B denotes percentage variation in comparison with the control.
Presentation-posologi Mera vanligen använda former i humanterapi omfattar tabletter eller gelatínkapslar, innehållande 0.1 g aktiv beståndsdel per doseríngsenhet, eller små flaskor, innehållande samma mängd i löst eller suspenderad form för intravaskulär injektion.Presentation Posology More commonly used forms in human therapy include tablets or gelatin capsules, containing 0.1 g of active ingredient per dosage unit, or vials, containing the same amount in dissolved or suspended form for intravascular injection.
Vanlig posologi är upp till 0.5 g/dag under minst två veckor, för orala former upp till 0.2 g/dag under minst en vecka för den injiserbara formen. varvid denna behandling efterföljes av minst en vecka med oral administrering. 14 462 218 Tabell I Produkter Dos L Yohimbine HCl 30 mg/kg SC 20 % Ex. l 30 mg/kg P0 40 100 mg/kg PO 50 g Yohimbíne HCl 30 mg/kg SC 20 EX- -4 30 Ing/kg P0 so z 60 mg/kg PO 50 g Yohimbine HCl 30 mg/kg SC 20 g Ex. 5 10 mg/kg P0 50 g mg/kg PO 50 % Yohimbíne HCl 30 mg/kg SC 20 g Ex. 7 3 mg/kg P0 50 % mg/kg P0 50 % Yohimbíne HCl 30 mg/kg SC 20 % Ex. ll 30 mg/kg PO 30 % 100 mg/kg PO 90 % Yohimbine HCl 30 mg/kg SC 20 % Ex. 12 30 m9/RQ P0 40 60 mg/kg PO 50 % Yohimbine HCl 30 mg/kg SC 20 % Ex_ 17 30 mg/kg PO 80 % ' loo :ng/kg po so a Yonimbine Hclo ao mg/kg SC 2U % Ex. 20 30 mq/ke P0 50 % 100 mg/kg PO 60 % n äs Tabell II Dos Antagonísm i % efter : (timmar) Exempel mg/kg per os 1 h 2 h 3 h 4 h 5 h Imipramine 15 100 52.3 42.3 48.2 50 60 68.7 76.1 42.3 31 33.3 HTP' 30 53.3 42.6 20.6 13.6 16.6 100 33.3 46.4 31 13.8 16.6 Ex. 1 30 60 63.6 44 35.7 25 100 100 50 54.5 46.4 40 Ex. 4 58.3 70 50 33.7 16.6 100 75 80 56.6 50 Ex. 5 10 100 100 78 78 64 37 75 46 50 47 Ex. 7 3 o 56.3 60.7 41.4 48.2 28.5 79.1 78.6 79.3 72.4 Ex, 11 10 50 100 60 53.3 53.3 100 80.7 62.9 55.1 41.4 Ex_ 12 10 30.4 37 43.3 46.6 30.4 40.7 46.6 40 Ex 17 3 1oo 54.5 49.3 24.1 26.6 100 59 51.7 24.1 40 Ex 20 10 93.3 76 70 60.7 55.1 1oo 68 50 54.5 51.7 462 218 Tabell III Exemnel D05 A 3 Kontroll _ 204 Maprotiline 10 mg/kg P0 156.3 23_4 NS mg/kg P0 143.3 29 7 , 100 mg/kg PO 86.5 57_5 xxx Kontroll _ 203-3 Ex. 1 l mg/kg P0 157.4 25 X 3 m9/kg P0 133.1 34,7 xx PÛ xxx Kontroll - 193,3 Ex. 4 10 mg/kg PO 136.4 31,2 x ms/kg P0 135.6 31,6", 100 mg/kg P0 138.3 30.3 x Kontroll ' 207-1 EX- 5 10 mg/kg P0 145.4 29.8 x ms/kg P0 124.4 39,9 xx 100 me/kg P0 86.1 58.1 xx: Kontroll - 189.9 EX- 7 3 mg/kg P0 137 27.9 x mg/kg PO 135.2 28.8 x mg/kg PO 101.1 46.6 xx Kontroll ' 20°°3 Ex. 11 10 mg/kg P0 144.6 27.8 x mg/kg PO 136.6 31.8 xx 100 mg/kg PO 118.1 41.4 xx Kontroll - 148.5 Ex, 12 30 mg/kg PO 106.1 28.6 x 100 mg/kg P0 99.0 33.3 x 300 mg/kg PO 77.4 47.9 xx Kontroll “ 200' Ex. 17 10 mg/kg P0 175.2 12.4 NS mg/kg PO 142.7 28.6 xx 100 mg/kg PO 155.4 22.3 NS Kontroll - 213-5 Ex_ 20 10 mg/kg PO 183.4 14.1 NS mg/kg PO 86.3 59.6 xx 50 mg/kg P0 97.2 54.5 xxCommon posology is up to 0.5 g / day for at least two weeks, for oral forms up to 0.2 g / day for at least one week for the injectable form. this treatment being followed by at least one week of oral administration. 14 462 218 Table I Products Dose L Yohimbine HCl 30 mg / kg SC 20% Ex. l 30 mg / kg P0 40 100 mg / kg PO 50 g Yohimbine HCl 30 mg / kg SC 20 EX- -4 30 Ing / kg P0 so z 60 mg / kg PO 50 g Yohimbine HCl 30 mg / kg SC 20 g Ex . 5 10 mg / kg P0 50 g mg / kg PO 50% Yohimbine HCl 30 mg / kg SC 20 g Ex. 7 3 mg / kg P0 50% mg / kg P0 50% Yohimbine HCl 30 mg / kg SC 20% Ex. ll 30 mg / kg PO 30% 100 mg / kg PO 90% Yohimbine HCl 30 mg / kg SC 20% Ex. 12 30 m9 / RQ P0 40 60 mg / kg PO 50% Yohimbine HCl 30 mg / kg SC 20% Ex_ 17 30 mg / kg PO 80% 'loo: ng / kg po so a Yonimbine Hclo ao mg / kg SC 2U% Ex. 30 mq / ke P0 50% 100 mg / kg PO 60% n äs Table II Dose Antagonism in% after: (hours) Example mg / kg per os 1 h 2 h 3 h 4 h 5 h Imipramine 15 100 52.3 42.3 48.2 50 60 68.7 76.1 42.3 31 33.3 HTP '30 53.3 42.6 20.6 13.6 16.6 100 33.3 46.4 31 13.8 16.6 Ex. 1 30 60 63.6 44 35.7 25 100 100 50 54.5 46.4 40 Ex. 4 58.3 70 50 33.7 16.6 100 75 80 56.6 50 Ex. 5 10 100 100 78 78 64 37 75 46 50 47 Ex. 7 3 o 56.3 60.7 41.4 48.2 28.5 79.1 78.6 79.3 72.4 Ex, 11 10 50 100 60 53.3 53.3 100 80.7 62.9 55.1 41.4 Ex_ 12 10 30.4 37 43.3 46.6 30.4 40.7 46.6 40 Ex 17 3 1oo 54.5 49.3 24.1 26.6 100 59 51.7 24.1 40 Ex 20 10 93.3 76 70 60.7 55.1 1oo 68 50 54.5 51.7 462 218 Table III Example D05 A 3 Control _ 204 Maprotiline 10 mg / kg P0 156.3 23_4 NS mg / kg P0 143.3 29 7, 100 mg / kg PO 86.5 57_5 xxx Control _ 203-3 Ex. 1 l mg / kg P0 157.4 25 X 3 m9 / kg P0 133.1 34.7 xx PÛ xxx Control - 193.3 Ex. 4 10 mg / kg PO 136.4 31.2 x ms / kg P0 135.6 31.6 ", 100 mg / kg P0 138.3 30.3 x Control '207-1 EX- 5 10 mg / kg P0 145.4 29.8 x ms / kg P0 124.4 39.9 xx 100 me / kg P0 86.1 58.1 xx: Control - 189.9 EX- 7 3 mg / kg P0 137 27.9 x mg / kg PO 135.2 28.8 x mg / kg PO 101.1 46.6 xx Control '20 °° 3 Ex. 11 10 mg / kg P0 144.6 27.8 x mg / kg PO 136.6 31.8 xx 100 mg / kg PO 118.1 41.4 xx Control - 148.5 Ex .12 30 mg / kg PO 106.1 28.6 x 100 mg / kg P0 99.0 33.3 x 300 mg / kg PO 77.4 47.9 xx Control “200 'Ex. 17 10 mg / kg P0 175.2 12.4 NS mg / kg PO 142.7 28.6 xx 100 mg / kg PO 155.4 22.3 NS Control - 213-5 Ex_ 20 10 mg / kg PO 183.4 14.1 NS mg / kg PO 86.3 59.6 xx 50 mg / kg P0 97.2 54.5 xx
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB848422029A GB8422029D0 (en) | 1984-08-31 | 1984-08-31 | 6-substituted-furo-(3 4-c)-pyridine derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| SE8503869D0 SE8503869D0 (en) | 1985-08-19 |
| SE8503869L SE8503869L (en) | 1986-03-01 |
| SE462218B true SE462218B (en) | 1990-05-21 |
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| Application Number | Title | Priority Date | Filing Date |
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| SE8503869A SE462218B (en) | 1984-08-31 | 1985-08-19 | PROCEDURES FOR PREPARATION OF 6-SUBSTITUTED FURO- (3,4, -C) -PYRIDINE DERIVATIVES |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS6160688A (en) |
| AR (1) | AR241455A1 (en) |
| AT (1) | AT396590B (en) |
| BE (1) | BE903122A (en) |
| CA (1) | CA1300149C (en) |
| CH (1) | CH666688A5 (en) |
| DE (1) | DE3531004A1 (en) |
| DK (1) | DK157871C (en) |
| ES (1) | ES8604967A1 (en) |
| FI (1) | FI82468C (en) |
| FR (1) | FR2569698B1 (en) |
| GB (2) | GB8422029D0 (en) |
| HK (1) | HK6189A (en) |
| IE (1) | IE58522B1 (en) |
| IT (1) | IT1201459B (en) |
| LU (1) | LU86052A1 (en) |
| NL (1) | NL8502324A (en) |
| NO (1) | NO162071C (en) |
| OA (1) | OA08088A (en) |
| PT (1) | PT81054B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB8427218D0 (en) * | 1984-10-27 | 1984-12-05 | Scras | Pyridine derivatives |
| 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 |
-
1984
- 1984-08-31 GB GB848422029A patent/GB8422029D0/en active Pending
-
1985
- 1985-08-12 ZA ZA856088A patent/ZA856088B/en unknown
- 1985-08-12 GB GB08520169A patent/GB2163744B/en not_active Expired
- 1985-08-19 SE SE8503869A patent/SE462218B/en not_active IP Right Cessation
- 1985-08-20 AR AR85301339A patent/AR241455A1/en active
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- 1985-08-29 AT AT0252985A patent/AT396590B/en not_active IP Right Cessation
- 1985-08-30 FR FR8512917A patent/FR2569698B1/en not_active Expired
- 1985-08-30 DE DE19853531004 patent/DE3531004A1/en active Granted
- 1985-08-30 IT IT22035/85A patent/IT1201459B/en active
- 1985-08-30 JP JP60190033A patent/JPS6160688A/en active Granted
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- 1985-08-30 DK DK396085A patent/DK157871C/en not_active IP Right Cessation
- 1985-08-30 IE IE214385A patent/IE58522B1/en not_active IP Right Cessation
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1989
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