DK157871B - METHOD FOR PREPARING 1,3-DIHYDRO-6- (1-HYDROXY-2-DIMETHYLAMINOMETHYL-ALLYL) -7-HYDROXY-FURO- (3,4-C) -PYRIDINE DERIVATIVES - Google Patents
METHOD FOR PREPARING 1,3-DIHYDRO-6- (1-HYDROXY-2-DIMETHYLAMINOMETHYL-ALLYL) -7-HYDROXY-FURO- (3,4-C) -PYRIDINE DERIVATIVES Download PDFInfo
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Description
DK 157871 BDK 157871 B
Den foreliggende opfindelse angår en hidtil ukendt fremgangsmåde til fremstilling af 1,3-dihydro-6-(1-hydroxy- 2-dimethylaminomethyl-allyl)-7-hydroxy-furo-(3,4-c)-py-ridinderivater.The present invention relates to a novel process for the preparation of 1,3-dihydro-6- (1-hydroxy-2-dimethylaminomethyl-allyl) -7-hydroxy-furo (3,4-c) pyridine derivatives.
5 De ved fremgangsmåden ifølge opfindelsen fremstillede pyridinderivater har den almene formel: _0 h3c ch, 'åo.-sy^y AiThe pyridine derivatives prepared by the process according to the invention have the general formula:
V 11 J IKV 11 J IK
N—CH,— C-CH—lx J 1 / 2 I ^n/N-CH 2 -C-CH-1x J 1/2
h3c OHh3c OH
hvori hver af A1 og uafhængigt betegner et hydrogenatom, en ligekædet mættet eller umættet carbonhydrid-gruppe indeholdende 1-5 carbonatomer, en heterocyclisk 10 gruppe indeholdende op til 6 ringatomer, en carbomono-cyclisk gruppe, en phenylalkylgruppe eller en phenylal-kenylgruppe, idet hver af de grupper, som er betegnet med A·^ og A2, kan være ikke-substituerede, eller de kan være substituerede med et eller flere chloratomer eller 15 fluoratomer, trifluormethylgrupper, alkylgrupper indeholdende 1-5 carbonatomer, alkoxygrupper indeholdende 1-5 carbonatomer, alkylthiogrupper indeholdende 1-5 carbonatomer, dialkylaminogrupper, hvori hver alkylgruppe indeholder 1-5 carbonatomer, dlalkylaminoalkoxygrupper, 20 hvori hver af de to alkylgrupper og alkoxygrupperne indeholder 1-5 carbonatomer, eller a- eller β-alkoxy-N-pyrrolidinylgrupper, i hvilket alkoxygruppen indeholder 1-5 carbonatomer.wherein each of A1 and independently represents a hydrogen atom, a straight chain saturated or unsaturated hydrocarbon group containing 1 to 5 carbon atoms, a heterocyclic group containing up to 6 ring atoms, a carbomycyclic group, a phenylalkyl group or a phenylalkenyl group, each of which of the groups represented by A A and A₂ may be unsubstituted or may be substituted by one or more chlorine atoms or fluorine atoms, trifluoromethyl groups, alkyl groups containing 1-5 carbon atoms, alkoxy groups containing 1-5 carbon atoms, alkylthio groups containing 1-5 carbon atoms, dialkylamino groups wherein each alkyl group contains 1-5 carbon atoms, dlalkylamino alkoxy groups, wherein each of the two alkyl groups and alkoxy groups contains 1-5 carbon atoms, or α- or β-alkoxy-N-pyrrolidinyl groups, in which alkoxy group contains 1-5 carbon atoms.
De omhandlede forbindelser er af interesse på grund af 25 deres terapeutiske aktivitet, hovedsagelige inden for området diurese, sænkning af blodtryk, beskyttelse af nyrerne og ligeledes som antihistamin-midler.The present compounds are of interest because of their therapeutic activity, mainly in the area of diuresis, lowering of blood pressure, renal protection and also as antihistamine agents.
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22
Man har nu overraskende fundet, at man ved den fremgangsmåde, som er beskrevet i den tidligere danske patentansøgning nr. 455/85, kan udelade det blokerende trin af OH-gruppen i 7-stillingen, og at man ikke desto mindre 5 kan fremstille slutproduktet med et forbedret udbytte.It has now surprisingly been found that by the method described in the earlier Danish patent application No. 455/85, the blocking step of the OH group in the 7 position can be omitted and that the final product can nevertheless be produced. with an improved yield.
Fremgangsmåden ifølge den foreliggende opfindelse består således i, at man omsætter et 6-formyl-7-hydroxy-furo-(3,4-c)-pyridinderivat med den almene formel: _0Thus, the process of the present invention consists in reacting a 6-formyl-7-hydroxy-furo (3,4-c) pyridine derivative of the general formula:
HO WHO W
x y a2 hvori A·^ og A£ har den tidligere anførte betydning, med 10 et lille overskud af 1-dimethyl-aminomethyl-vinylmagne-siumbromid under kogning i et ikke-polært opløsningsmiddel, såsom tetrahydrofuran.x y a2 in which A · and A har have the meaning previously stated, with a small excess of 1-dimethylaminomethyl-vinylmagnesium bromide while boiling in a non-polar solvent such as tetrahydrofuran.
Man kan opnå 6-formyl-7-hydroxy-furo-(3,4-c)-pyridinde-rivaterne (II) ud fra de tilsvarende 6-methyl-7-hydroxy-15 derivater med den almene formel: /Al Ηθ-^γΐ /A2 V “ hvori A^ og A2 har den tidligere anførte betydning, idet man anvender følgende sekvens af reaktioner: 3The 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: ^ γΐ / A2 V 'wherein A ^ and A2 have the meaning previously stated, using the following sequence of reactions: 3
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_O_ISLAND
\sAi H° —ji^Yl I il A rrt-chlorperoxybenzoesyre H3c Xn ' ^ _,0 A1 H (CF3 C0)2 0\ sAi H ° -ji ^ Yl I il A rrt-Chloroperoxybenzoic Acid H3c Xn '^, 0 A1 H (CF3 CO) 2 0
Aj -»Aj - »
H-.C WH-.C W
0 _o ^ A! ho —Mno? T J A2 -> ho-ch2 N' _o "Xj/0 _o ^ A! ho —Mno? T J A2 -> ho-ch2 N '_o "Xj /
OHCOHC
Forbindelserne med formel (III) er omtalt i dansk patentansøgning nr. 543/82 og i dansk patentansøgning nr. 1780/84.The compounds of formula (III) are disclosed in Danish Patent Application No. 543/82 and in Danish Patent Application No. 1780/84.
DK 157871 BDK 157871 B
4 I det følgende beskrives detaljeret fremstillingen af kun én af udgangsforbindelserne, 1,3-dihydro-3-p-chlor-phenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin, idet man kan opnå de øvrige udgangsmaterialer på tilsvarende 5 måde.4 The following describes in detail the preparation of only one of the starting compounds, 1,3-dihydro-3-p-chloro-phenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine, obtain the other starting materials in a similar manner.
(a) Man behandlede i en reaktor på en liter udstyret med midler til omrøring, opvarmning og afkøling 22,3 g 1,3-dihydro-3-p-chlorphenyl-6-methyl-7-hy-droxy-furo-(3,4-c)-pyridin ved 0°C i nærvær af 300 10 ml methylendichlorid med 18,2 g m-peroxybenzoesyre, som langsomt blev tilsat. Efter omrøring natten over ved stuetemperatur tilsatte man 150 ml 10% natriumsulfatopløsning. Efter omrøring og dekantering blev methylendichloridfasen vasket med den 15 samme mængde natriumsulfatopløsning, to gange med 150 ml natriumhydrogencarbonatopløsning og tre gange med 100 ml vand, hvorpå den blev tørret over vandfrit natriumsulfat. Man opnåede ved inddamp-ning til tørhed et beigefarvet bundfald, som blev 20 vasket med petroleumether, filtreret og tørret.(a) 22.3 g of 1,3-dihydro-3-p-chlorophenyl-6-methyl-7-hydroxy-furo- (3) was treated in a reactor equipped with a stirring, heating and cooling means. , 4-c) -pyridine at 0 ° C in the presence of 300 10 ml of methylene dichloride with 18.2 g of m-peroxybenzoic acid, which was slowly added. 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 then dried over anhydrous sodium sulfate. Evaporation to dryness yielded a beige colored precipitate which was washed with petroleum ether, filtered and dried.
Udbytte: 22,9 g (96%) 1,3-dihydro-3-p-chlorphenyl-' 6-methyl-7-hydroxy-furo-(3,4-c)-pyridin-N-oxid.Yield: 22.9 g (96%) of 1,3-dihydro-3-p-chlorophenyl-6-methyl-7-hydroxy-furo (3,4-c) -pyridine N-oxide.
(b) Man behandlede i den samme reaktor som ovenfor beskrevet 22,9 g af den i det foregående syntese- 25 trin opnåede forbindelse ved 0-5°C og i nærvær af 175 ml methylendichlorid med 4,3 ml trifluoreddi-kesyreanhydrid, som blev tilsat dråbe for dråbe under omrøring. Blandingen blev omrørt natten over ved stuetemperatur og derpå afkølet og behandlet 30 ved dråbevis tilsætning af 95 ml methanol. Efter inddampning til tørhed blev inddampningsresten opløst i 300 ml chloroform, vasket to gange med 75 ml 10% natriumhydrogencarbonatopløsning og tre gange med 100 ml vand og tørret med vandfrit natriumsul-35 fat. Chloroformen blev afdampet, og inddampnings-(b) 22.9 g of the compound obtained in the previous synthesis step were treated at 0-5 ° C in the same reactor as described above and in the presence of 175 ml of methylene dichloride with 4.3 ml of trifluoroacetic anhydride which was was added drop by drop with stirring. The mixture was stirred overnight at room temperature and then cooled and treated by dropwise addition of 95 ml of methanol. After evaporation to dryness, the evaporation residue was dissolved 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 with anhydrous sodium sulfate. The chloroform was evaporated and the
DK 157871 BDK 157871 B
5 resten blev vasket med diethylether og tørret under reduceret tryk. Udbytte: 21,3 g (93%) 1,3-dihydro- 3-p-chlorphenyl-6-hydroxymethyl-7-hydroxy-furo-(3,4- c)-pyridin.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.
5 (c) Man behandlede i en reaktor på 2 liter 21,3 g af den i forudgående syntesetrin opnåede forbindelse med 27 g mangandioxid i nærvær af 0,9 liter chloroform ved 28-30°C, idet man omrørte i 3 timer. Efter separering, filtrering, vask med chloroform og derpå 10 med ethylacetat, blev opløsningen inddampet til tør hed, og den opnåede pasta blev behandlet med' isopro-pyloxid og derpå med pentan. På denne måde opnåede man 20,1 g (95%) 1,3-dihydro-3-p-chlorphenyl-6-for-myl-7-hydroxy-furo-(3,4-c)-pyridin.(C) In a reactor of 2 liters, 21.3 g of the compound obtained in the previous synthesis step were treated with 27 g of manganese dioxide in the presence of 0.9 liters of chloroform at 28-30 ° C, stirring for 3 hours. After separation, filtration, washing with chloroform and then 10 with ethyl acetate, the solution was evaporated to dryness and the obtained paste was treated with isopropyloxide and then with pentane. In this way, 20.1 g (95%) of 1,3-dihydro-3-p-chlorophenyl-6-formyl-7-hydroxy-furo- (3,4-c) -pyridine were obtained.
15 De efterfølgende eksempler belyser opfindelsen.The following examples illustrate the invention.
EKSEMPEL 1 2r^I§i]3Y^I2l^IID§y}YilfliIli}Y^£2£Xl2-dimethYlaminomethYl- allyl).-7-hYdroxY-furo;_i3i4-c)--pYridin (a) Fremstilling af organomagnesiumreagenset 20 Man hældte i en reaktor på 2 liter, som var udstyret med midler til opvarmning, til afkøling og til omrøring, under nitrogencirkulation 19,4 g (0,8 mol) magnesium og 100 ml tetrahydrofuran, som fortrinsvis var blevet destilleret over lithiumaluminiumhydrid. Blandingen blev 25 holdt under tilbagesvaling.EXAMPLE 1 2r ^ I§i] 3Y ^ I2l ^ IID§y} YilfliIli} Y ^ £ 2 £ Xl2-dimethylaminomethyl-allyl) .- 7-HydroxY-furo; (13,4-c) -pyridine (a) Preparation of the organomagnesium reagent In a 2 liter reactor equipped with heating, cooling and stirring agents, 19.4 g (0.8 mole) of magnesium and 100 ml of tetrahydrofuran, which were preferably distilled over lithium aluminum hydride, were poured into nitrogen. The mixture was refluxed.
Derpå tilsatte man langsomt 132 g (0,8 mol) 3-dimethyl-amino-2-brom-l-propylen. Man tilførte ikke nogen varme udefra, idet tilbagesvalingen blev opretholdt og reguleret gennem tilsætning af denne forbindelse. Ved af-30 slutningen af tilsætningen tilførte man 1 liter destil- 6Then 132 g (0.8 mole) of 3-dimethylamino-2-bromo-1-propylene was slowly added. No external heat was applied, the reflux being maintained and regulated through the addition of this compound. At the end of the addition, 1 liter of distillate was added
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leret tetrahydrofuran. Blandingen blev opvarmet under tilbagesvaling i 2 timer og derpå afkølet til 10°C.the clay tetrahydrofuran. The mixture was heated at reflux for 2 hours and then cooled to 10 ° C.
(b) Reaktion(b) Reaction
Man satte langsomt under omrøring til reaktionsblandin-5 gen fra det forudgående syntesetrin 89 g (0,5 mol) 1,3-dihydro-3-methyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin. Temperaturen nåede ved afslutningen af tilsætningen ca.89 g (0.5 mole) of 1,3-dihydro-3-methyl-6-formyl-7-hydroxy-furo- (3,4-c) -hydro- pyridine. At the end of the addition, the temperature reached approx.
25°C. Omrøringen blev fortsat natten over ved stuetemperatur. Blandingen blev derpå afkølet til 0°C, og man 10 tilsatte 250 ml vand mættet med ammoniumchlorid og 250 ml diethylether. Efter omrøring i 15 minutter ved stuetemperatur opnåede man en tofaset blanding, hvori olien udgj orde supernatanten.25 ° C. 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 was obtained in which the oil constituted the supernatant.
Blandingen blev separeret, og den vandige fase blev eks-15 traheret to gange med 250 ml aliquote dele diethylether. Ekstrakterne blev sat til oliefasen, som var blevet vasket tre gange med vand. Oliefasen blev derpå tørret over magnesiumsulfat, behandlet med carbonblack, opkon-centreret til tørhed og ekstraheret to gange med 250 ml 20 diisopropylether. Ekstrakterne blev filtreret, opkoncen-treret (reduktion til en fjerdedel af det oprindelige rumfang) og afkølet natten over, hvilket førte til et bundfald, som blev frasepareret og vasket med diisopropylether. Udbytte: 105 g (80%).The mixture was separated and the aqueous phase was extracted twice with 250 ml aliquot of diethyl ether. The extracts were added to the oil phase, which had been washed three times with water. The oil phase was then dried over magnesium sulfate, treated with carbon black, concentrated to dryness and extracted twice with 250 ml of diisopropyl ether. The extracts were filtered, concentrated (reduced to a quarter of the original volume) and cooled overnight, resulting in a precipitate which was separated and washed with diisopropyl ether. Yield: 105 g (80%).
25 Fremstillingen af de øvrige omhandlede forbindelser følger den samme fremgangsmåde med undtagelse af, at udgangsmaterialet i trin (b) er forskelligt; de i det følgende viste eksempler vil derfor henvise til eksempel 1 og udelukkende nævne det nye udgangsmateriale, det samlede ud-30 bytte samt karakteristika for de således opnåede forbindelser.The preparation of the other compounds of this invention follows the same procedure except that the starting material of step (b) is different; The examples shown below will therefore refer to Example 1 and mention only the new starting material, the overall yield and the characteristics of the compounds thus obtained.
DK 157871 BDK 157871 B
EKSEMPEL 2 7EXAMPLE 2 7
Ii^I§ii}Y^£2l^lE£2EYll§l!ill}Zåi22Yl2idimethYlaminomethYl-allYl)_-7-hYdr2XY-furo-_(3_, 4-c)_-gYridinIi ^ I§ii} Y ^ £ 2l ^ IE £ 2EYll§l} Zåi22Yl2idimethYlaminomethyl-allYl) -7-hydroxy2YY-furo -_ (3_, 4-c) _-gYridine
Man gentog fremgangsmåden fra eksempel 1, idet man dog 5 gik ud fra 83 g (0,4 mol) l,3-dihydro-3-propyl-6-formyl- 7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 66% af et re aktionsprodukt, som smeltede ved 187-194°C (Tottoli) under dekomponering, og hvis elementæranalyse viste god overensstemmelse med formlen , 2HC1.The procedure of Example 1 was repeated, however, starting from 83 g (0.4 mol) of 1,3-dihydro-3-propyl-6-formyl-7-hydroxy-furo- (3,4-c) - pyridine. Yield: 66% of a reaction product which melted at 187-194 ° C (Tottoli) during decomposition and whose elemental analysis showed good conformity to the formula, 2HCl.
10 EKSEMPEL 3 ii^I^i^YÉE2l^l2Y2i2i}§iXil£liili}Z£E2£Xl2Ydimethylamin2"EXAMPLE 3 ii ^ I ^ i ^ YÉE2l ^ l2Y2i2i} §iXil £ liili} Z £ E2 £ Xl2Ydimethylamine2 "
5)§^Yiz§iiYii”ZliiY^E25YlfliY2li3ril2ilEYE^:§iD5) § ^ Yiz§iiYii "ZliiY ^ ^ E25YlfliY2li3ril2ilEYE: §iD
Man gentog fremgangsmåden i eksempel 1, idet man dog gik ud fra 99 g (0,4 mol) 1,3-dihydro-3-cyclohexyl-6-formyl-15 7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 59% af et re aktionsprodukt, som smeltede ved 180-184°C (Tottoli) under dekomponering, og hvis elementæranalyse viste god overensstemmelse med formlen C^I^g^Og^HCl.The procedure of Example 1 was repeated, however, starting from 99 g (0.4 mole) of 1,3-dihydro-3-cyclohexyl-6-formyl-7-hydroxy-furo- (3,4-c) - pyridine. Yield: 59% of a reaction product which melted at 180-184 ° C (Tottoli) under decomposition and whose elemental analysis showed good agreement with the formula C
EKSEMPEL 4 20 liZ^dihydro-SYphenYl-e^^l-hydroxy^g-dimethylaminometh-yl-allYl2-7Yhydroxy-furoM3£4-c|3PYridinEXAMPLE 4 LiZ 2 dihydro-SYphenyl-e 2'1-hydroxy-g-dimethylaminomethyl-yl-allyl 2 -7Yhydroxy-furoM 3 £ 4-c | 3-pyridine
Man gentog fremgangsmåden i eksempel 1, idet man dog gik ud fra 99 g (0,4 mol) 1,3-dihydro-3-phenyl-6-formyl-7-hy-droxy-furo-(3,4-c)-pyridin. Udbytte: 49% af et reakti- 25 onsprodukt, som smeltede ved 210-215°C (Tottoli) under dekomponering, og hvis elementæranalyse viste god overensstemmelse med formlen C^H^^O^^HCl.The procedure of Example 1 was repeated, however, starting from 99 g (0.4 mole) of 1,3-dihydro-3-phenyl-6-formyl-7-hydroxy-furo- (3,4-c) pyridine. Yield: 49% of a reaction product which melted at 210-215 ° C (Tottoli) during decomposition and whose elemental analysis showed good agreement with the formula C
DK 157871 BDK 157871 B
EKSEMPEL 5 8 ix3-dihYdro-3-g-chlor2henYl-5-j[l-h2droxY-2-dimethYlami- nomethYl^allYl^-V-hYdroxY-furo-^S^^-c^-gYridinEXAMPLE 5 8x3-Dihydro-3-g-chloro 2 -henyl-5-j [1- (2-hydroxy-2-dimethylamino-methyl) -alyl] -N-hydroxy-furo-3 S-4-c-gyridine
Man gentog fremgangsmåden i eksempel 1, idet man dog gik 5 ud fra 110 g (0,4 mol) 1,S-dihydro-S-p-chlorphenyl-e- formyl^-hydroxy-furo- (3,4-c)-pyridin. Udbytte: 57% af et reaktionsprodukt, som smeltede ved 195-200°C (Totto-li) under dekomponering, og hvis elementæranalyse viste god overensstemmelse med formlen C^I^Cl^O^, 2HC1.The procedure of Example 1 was repeated, however, starting from 110 g (0.4 mole) of 1, 5-dihydro-Sp-chlorophenyl-e-formyl β-hydroxy-furo- (3,4-c) -pyridine . Yield: 57% of a reaction product which melted at 195-200 ° C (Totto-li) during decomposition, and whose elemental analysis showed good agreement with the formula C ^ I ^Cl₂O₂, 2HCl.
10 EKSEMPEL 6 li^-dihydro-S-^^S-dichlorphenyll-e-^l-hydroxy-^-di-ii!-§tiiZi§iSiS2S§£^Yil§iiYiil2liiY^£25Yliil£2li31£14-c)_-pyridin Man gentog fremgangsmåden i eksempel 1, idet man dog gik ud fra 124 g (0,4 mol) 1,3-dihydro-3-(2,3-dichlorphenyl)-15 6-formyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 62% af et reaktionsprodukt, som smeltede ved 180-184°C (Tot-toli) under dekomponering, og hvis elementæranalyse viste god overensstemmelse med formlen ci9H20C12N2O3'2HC1' EKSEMPEL 7 2 0 liS-dihYdTO-S-p-fl^rphenYl-S-^l-hyd^XY-^-dimethyl- §®iS2n)§t^Yiz§ilZiizZzhydr2xy-fur2-X3i4-c)_-pYridinEXAMPLE 6 li-dihydro-S - ^^ S-dichlorophenyl-e- ^ l-hydroxy - ^ - di-ii -§tiiZi§iSiS2S§ £ ^ Yil§iiYiil2liiY ^ £ 25Yliil £ 2li31 £ 14-c) The procedure of Example 1 was repeated, but starting from 124 g (0.4 mole) of 1,3-dihydro-3- (2,3-dichlorophenyl) -6 6-formyl-7-hydroxy-furo - (3,4-c) -pyridine. Yield: 62% of a reaction product which melted at 180-184 ° C (Tot-toli) under decomposition and whose elemental analysis showed good agreement with the formula ci9H20C12N2O3'2HC1 EXAMPLE 7 20S-dihYdTO-Sp-flphenyl S- ^ l -hyd ^ XY - ^ - dimethyl- §®iS2n) §t ^ Yiz§ilZiizZzhydr2xy-fur2-X3i4-c) -pyridine
Man gentog fremgangsmåden i eksempel 1, idet man dog gik ud fra 104 g (0,4 mol) 1,3-dihydro-3-p-fluorphenyl- 6-formyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 62% 25 af et reaktionsprodukt, som smeltede ved 198°C (Tottoli) under dekomponering, og hvis elementæranalyse viste god overensstemmelse med formlen c^H2iFN2°3,2HC1·The procedure of Example 1 was repeated, however, starting from 104 g (0.4 mole) of 1,3-dihydro-3-p-fluorophenyl-6-formyl-7-hydroxy-furo (3,4-c) pyridine. Yield: 62% 25 of a reaction product which melted at 198 ° C (Tottoli) during decomposition and whose elemental analysis showed good conformity to the formula c2H2FN2 ° 3.2HC1 ·
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EKSEMPEL 8 9 ii3-dihYdro-3-£-toluYl-6;Ml-hYdroxY-2-dimethYlaminometh-Yl-allyl)_-7-hYdroxY-furo-jB^-c^-pyridinEXAMPLE 8 9 (3-dihydro-3β-toluyl-6; M1-hydroxy-2-dimethylaminometh-yl-allyl) -7-hydroxy-furo-β-β-pyridine
Man gentog fremgangsmåden i eksempel 1, idet man dog gik 5 ud fra 103 g (0,4 mol) 1,3-dihydro-3-p-toluyl-6-formyl- 7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 66% af et re aktionsprodukt, som smeltede ved 203-207°C (Tottoli) under dekomponering, og hvis elementæranalyse viste god overensstemmelse med formlen C20H24N2°3'2HCl' 10 EKSEMPEL 9 !i3-dihYdro-3-g-methoxYphenyl-6;;_{l-hydroxY-2-dimethYl- aminomethYl-allyl^-T-hYdroxY-furg-^^-cO-gYridinThe procedure of Example 1 was repeated, however, starting from 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 reaction product which melted at 203-207 ° C (Tottoli) under decomposition, and whose elemental analysis showed good agreement with the formula C20H24N2 ° 3'2HCl 'EXAMPLE 9 11-Dihydro-3-g-methoxylphenyl -6; - {1-hydroxy-2-dimethyl-aminomethyl-allyl ^ -T-hydroxy-furg - ^ - c0 -gyridine
Man gentog fremgangsmåden i eksempel 1, idet man dog gik ud fra 110 g (0,4 mol) l,3-dihydro-3-p-methoxyphenyl-6-15 formyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 63% af et reaktionsprodukt, som smeltede ved 169-170°C (Tottoli), og hvis elementæranalyse viste god overensstemmelse med formlen C2()H24N204,2HC1.The procedure of Example 1 was repeated, however, starting from 110 g (0.4 mol) of 1,3-dihydro-3-p-methoxyphenyl-6-15-formyl-7-hydroxy-furo- (3,4-c ) -pyridine. Yield: 63% of a reaction product which melted at 169-170 ° C (Tottoli) and whose elemental analysis showed good agreement with formula C2 () H24N2O4.2HCl.
EKSEMPEL 10 20 li3-dihydro-3-m-trifluormethYlghenYl-6-^l-hYdroxY-2-di-^§thYlaminomethYl-allYl)_-7-hYdrgxY-furo3_(3_, 4-c]_-pyridinEXAMPLE 10 11β-dihydro-3-m-trifluoromethylghenyl-6- [1-hydroxy-2-di-β-thylaminomethyl-allyl] -7-hydroxy-furo3- (3_, 4-c] pyridine
Man gentog fremgangsmåden i eksempel 1, idet man dog gik ud fra 124 g (0,4 mol) 1,3-dihydro-3-m-trifluormethyl-phenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte:The procedure of Example 1 was repeated, however, starting from 124 g (0.4 mole) of 1,3-dihydro-3-m-trifluoromethyl-phenyl-6-formyl-7-hydroxy-furo- c) -pyridine. Yield:
25 58% af et reaktionsprodukt, som smeltede ved 217-223°C25% of a reaction product which melted at 217-223 ° C
(Tottoli) under dekomponering, og hvis elementæranalyse viste god overensstemmelse med formlen C20H21F3N2°3'2HC1*(Tottoli) during decomposition and whose elemental analysis showed good agreement of formula C20H21F3N2 ° 3'2HC1 *
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EKSEMPEL 11 10 ii3-dihYdro-3-g-_(diethYlaminoethoxY32ii§SZiil§lilzhZ^E2XZ“ ^I^i^thylaminomethYl-allyl^-V-hYdroxY^furoMS^-c^-gYri- dln 5 Man gentog fremgangsmåden i eksempel 1, idet man dog gik ud fra 142 g (0,4 mol) 1,3-dihydro-3-p-(diethylaminoeth-oxy-phenyl)-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 51% af et reaktionsprodukt, som smeltede ved 158- 160°C (Tottoli), og hvis elementæranalyse viste god over-10 ensstemmelse med formlen C^H^N^O^,2HC1.EXAMPLE 11 II3-Dihydro-3-g -_ (diethylaminoethoxY32ii§SZiil§lilzhZ ^ E2XZ “^ I ^ i ^ thylaminomethyl-allyl ^ -V-HydroxY ^ furoMS ^ -c ^ -gYri-dln The procedure was repeated in Example 5 1, however, starting from 142 g (0.4 mol) of 1,3-dihydro-3-β- (diethylaminoethoxy-phenyl) -6-formyl-7-hydroxy-furo- (3,4-c Yield: 51% of a reaction product which melted at 158 DEG-160 DEG C. (Tottoli) and whose elemental analysis showed good agreement with the formula C1 H2 N3 O2, 2HCl.
EKSEMPEL 12 li.^I^i^YÉiOl^-p^^pyrrolidinylethoxy-phenyl^-S-^l-hYdroxy- ^“dimethYlaminomethYl-allYl^-y-hYdroxY-furoHS^-c^-pyri- dinEXAMPLE 12 µl ^ i ^ YÉiOl ^ -p ^^ pyrrolidinylethoxy-phenyl ^ -S- ^ l -hydroxy- ^ 'dimethylamino-methyl-allYl ^ -y-hydroxy-furoHS ^ -c ^ -pyridine
15 Man gentog fremgangsmåden i eksempel 1, idet man dog gik ud fra 142 g (0,4 mol) 1,3-dihydro-3-p-(pyrrolidinyleth-oxy-phenyl)-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 53% af et reaktionsprodukt, som smeltede ved 173'°CThe procedure of Example 1 was repeated, however, starting from 142 g (0.4 mole) of 1,3-dihydro-3-p- (pyrrolidinylethoxy-phenyl) -6-formyl-7-hydroxy-fururo. (3,4-c) -pyridine. Yield: 53% of a reaction product which melted at 173 ° C
(Tottoli), og hvis elementæranalyse viste god overens-20 stemmelse med formlen C25H33N3°4,2HC1.(Tottoli), and whose elemental analysis showed good agreement of formula C25H33N3 ° 4.2HCl.
EKSEMPEL 13 ii^I^iliY^i2l5li&§tiiYil2lSzE§StYli6iilihydroxy-2-dimethYl-§iDiS2i?2£^Yiz§iiYiizZzi}Y^E22Yzf2£2li3i.43c)_z2yridin Man gentog fremgangsmåden i eksempel 1, idet man dog gik 25 ud fra 99 g (0,4 mol) 1,3-dihydro-3-methyl-3-n-pentyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 59% af et reaktionsprodukt, som smeltede ved 187-191°C (Tottoli) under dekomponering, og hvis elementæranalyse viste god overensstemmelse med formlen C^gH3QN2C>2,2HCl.EXAMPLE 13 ii ^ I ^ iliY ^ i2l5li & §tiiYil2lSzE§StYli6iilihydroxy-2-dimethYl-§iDiS2i? 2 £ ^ Yiz§iiYiizZzi} Y ^ E22Yzf2 £ 2li3i.43c) Exceeded the procedure in Example 1. 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: 59% of a reaction product which melted at 187-191 ° C (Tottoli) under decomposition, and whose elemental analysis showed good agreement with the formula C ^HHHNN₂C> 2.2HCl.
EKSEMPEL 14EXAMPLE 14
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11 §ί?ϊ22ί?2ί]ϊγ1-§11γ1)_ζΖ—γάΓθχγζ—ϊ2ζ1“4-α).-ργΓϊάϊη11 §ί? Ϊ22ί? 2ί] ϊγ1-§11γ1) _ζΖ — γάΓθχγζ — ϊ2ζ1 “4-α) .- ργΓϊάϊη
Man gentog fremgangsmåden i eksempel 1, idet man dog 5 gik ud fra 103 g (0,4 mol) 1,3-dihydro-3-methyl-3-phen-yl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 69% af et reaktionsprodukt, som smeltede ved 178-179°C (Tottoli), og hvis elementæranalyse viste god overensstemmelse med formlen C20H24N2°3'^H^* 10 EKSEMPEL 15 1_, 3 zdihydro—3—methyl—3—u—thienyl—6—_(1—hydroxy—2—dimethyl 1 ami n om ethy1 ~ a_l_lj_l_) -1- hydroxyjf uro-J 3_, 4 - cj -py r i d i nThe procedure of Example 1 was repeated, however, starting from 103 g (0.4 mole) of 1,3-dihydro-3-methyl-3-phenyl-6-formyl-7-hydroxy-furo- (3 , 4-c) -pyridine. Yield: 69% of a reaction product which melted at 178-179 ° C (Tottoli) and whose elemental analysis showed good conformity with the formula C20H24N2 ° 3 + H + 10 EXAMPLE 15 1, 3 zdihydro-3-methyl-3 u-thienyl-6-_ (1-hydroxy-2-dimethyl-1-amine on ethyl 1-a_l_lj_l_) -1-hydroxyph-uro-J 3,4,4-cy-pyridine
Man gentog fremgangsmåden i eksempel 1, idet man dog gik ud fra 103 g (0,4 mol) 1,3-dihydro-3-methyl-3-a-thienyl-15 6-formyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 67% af et reaktionsprodukt, som smeltede ved 169-175°C (Tottoli) under dekomponering, og hvis elementæranalyse viste god overensstemmelse med formlen C]_gH22^N203,2HC1.The procedure of Example 1 was repeated, however, starting from 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 reaction product which melted at 169-175 ° C (Tottoli) under decomposition, and whose elemental analysis showed good agreement with the formula CggH₂₂O N N₂O,2.2HCl.
EKSEMPEL 16 20 ZrZz^ii}Y^i2z2z2ti}Yiz2z2ziEiii22Ei?®£-&YiE^22Yiz^ziizi}Y“ §I2iYZ2Z^iii?§ti}Yi§i?iD2i?§ti)Yil§liYZizZz^Y§E22YzfEE2zi2i4- 2izEYEi^inEXAMPLE 16 ^ in
Man gentog fremgangsmåden i eksempel 1, idet man dog gik ud fra 136 g (0,4 mol) 1,3-dihydro-3-ethyl-3-m-trifluor-25 methylphenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin.The procedure of Example 1 was repeated, however, starting from 136 g (0.4 mole) of 1,3-dihydro-3-ethyl-3-m-trifluoro-methylphenyl-6-formyl-7-hydroxy-fururo. (3,4-c) -pyridine.
Udbytte: 72% af et reaktionsprodukt, som smeltede ved 185°C (Tottoli), og hvis elementæranalyse viste god overensstemmelse med formlen C22H25F3N2°3'^HC1‘ EKSEMPEL· 17 12Yield: 72% of a reaction product which melted at 185 ° C (Tottoli) and whose elemental analysis showed good conformity to formula C22H25F3N2 ° 3 + HCl EXAMPLE 17
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ii3idihYdro-3-ethYl-3-a2furyl-6-_(l-hYdroxY32-dirnethYl-2Si225)2i]lYiz§iiYiizZz]lY£E22Yz£H:E2zl3jLii2iiEYEi5|in Man gentog fremgangsmåden i eksempel 1, idet man dog gik 5 ud fra 104 g (0,4 mol) 1,3-dihydro-3-ethyl-3-a-furyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 58% af et reaktionsprodukt, som smeltede ved 164-169°C (Tottoli) under dekomponering, og hvis elementæranalyse viste god overensstemmelse med formlen ^9^24^2^4' 2HC1.ii3idihYdro-3-ethyl-3-a2furyl-6-((1-hydroxyY32-dirnethyl-2Si225) 2i] lYiz§iiYiizZz] lY £ E22Yz £ H: E2zl3jLii2iiEYEi5 | in The procedure of Example 1 was repeated, from 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 reaction product which melted at 164-169 ° C (Tottoli) under decomposition and whose elemental analysis showed good agreement with the formula ^ 9 ^ 24 ^ 2 ^ 4 '2HCl.
10 EKSEMPEL 18 ir^Z^ihYÉ£2z3iEhenYl-3-p-ethoxyphenYl-6-_[l-hydroxY22-di- 5)§iiiYi§S)i22i?§ii)Yiz§iiYiIz2z^Y§£22YzlE£2zl3x.4-cX“PYridin Man gentog fremgangsmåden i eksempel 1, idet man dog gik ud fra 144 g (0,4 mol) 1,3-dihydro-3-phenyl-3-p-ethoxy-15 phenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 64% af et reaktionsprodukt, som smeltede ved 148-149°C (Tottoli), og hvis elementæranalyse viste god overensstemmelse med formlen C27H30N2°4,2HC1· EKSEMPEL 19 20 IrJ-dihYdro-S^S-di-g-fluorphenYl-S-^l-hYdroxY-g-dimeth-Yl§2)iE2]B§£i!Yiz§iiYHzZzi)Y£E2£Yz£E:£2Z-12.£.4-c)_-gYridin Man gentog fremgangsmåden i eksempel 1, idet man dog gik ud fra 142 g (0,4 mol) 1,3-dihydro-3,3-di-p-fluorphenyl- 6-formyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 70% 25 af et reaktionsprodukt, som smeltede ved 175°C (Tottoli), og hvis elementæranalyse viste god overensstemmelse med formlen C25H24F2N2°3'EXAMPLE 18 ir ^ Z ^ ihYÉ £ 2z3iEhenYl-3-p-ethoxyphenYl-6-[[1-hydroxY22-di- 5) §iiiYi§S) i22i? §Ii) Yiz§iiYiIz2z ^ Y§ £ 22YzlE £ 2zl3x. 4-cX-Pyridine The procedure of Example 1 was repeated, but starting from 144 g (0.4 mole) of 1,3-dihydro-3-phenyl-3-p-ethoxy-15-phenyl-6-formyl-7 hydroxy-furo- (3,4-c) -pyridine. Yield: 64% of a reaction product which melted at 148-149 ° C (Tottoli) and whose elemental analysis showed good conformity to the formula C27H30N2 ° 4.2HC1 · EXAMPLE 19 IrJ-dihYdro-S ^ S-di-g-fluorophenyl -S- ^ l -HYdroxY-g-dimeth-Yl§2) iE2] B§ £ i! Yiz§iiYHzZzi) Y £ E2 £ Yz £ E: £ 2Z-12. £ .4-c) _- gYridin Man repeated the procedure of Example 1, however, starting from 142 g (0.4 mole) of 1,3-dihydro-3,3-di-p-fluorophenyl-6-formyl-7-hydroxy-furo- (3.4 c) -pyridine. Yield: 70% 25 of a reaction product which melted at 175 ° C (Tottoli) and whose elemental analysis showed good conformity to formula C25H24F2N2 ° 3 '
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EKSEMPEL 20 1^ΐ£ί!2Σ£ϊ2ΐ2ΐ£££ϋΕΣΐΐ2ΐΕΐί:ϊ}ΐ2ϊ?®ί:ίϊχ!Ε£βηγΐ26-^1-]ιγ&Γθχ^- ^I^iroethYlaminoraethYl-allYl^-V-hYdroxY-furo-jS^^-c^- PYridin 5 Man gentog fremgangsmåden i eksempel 1, idet man dog gik ud fra 141 g (0,4 mol) 1,3-dihydro-3-a-furyl-3-p-thiometh-ylphenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridin. Udbytte: 48% af et reaktionsprodukt, som smeltede ved 143- 151°C (Tottoli) under dekomponering, og hvis elementær-10 analyse viste en god overensstemmelse med formlen C24H26SN2°4'2HC1'EXAMPLE 20 1 ^ ΐ £ ί! 2Σ £ ϊ2ΐ2ΐ £££ ϋΕΣΐΐ2ΐΕΐί: ϊ} ΐ2ϊ? ®ί: ίϊχ! Ε £ βηγΐ26- ^ 1-] ιγ & Γθχ ^ - ^ I ^ iroethYlaminoraethYl-allYl ^ -V-hYdroxY pS-Pyridine 5 The procedure of Example 1 was repeated, however, starting from 141 g (0.4 mole) of 1,3-dihydro-3-a-furyl-3-p-thiomethyl-phenyl-phenyl. 6-formyl-7-hydroxy-furo- (3,4-c) -pyridine. Yield: 48% of a reaction product which melted at 143-151 ° C (Tottoli) during decomposition, and whose elemental analysis showed good agreement with the formula C24H26SN2 ° 4'2HC1 '
TOXICITETTOXICITY
Ingen af de fremstillede forbindelser udviste betydelig toxicitet per os: LD5q lå mellem 0,8 og 1,2 g/kg får 15 rotter og mellem 0,7 og 1 g/kg for musNone of the compounds produced showed significant toxicity per os: LD5q ranged from 0.8 to 1.2 g / kg in 15 rats and between 0.7 and 1 g / kg in mice
Pharmakologipharmacology
Aktiviteten af de her omhandlede forbindelser blev undersøgt ved forskellige forsøg. Tre af disse beskrives nærmere i det følgende.The activity of the compounds of this invention was investigated in various experiments. Three of these are described in more detail below.
20 I - Lethalitet_fremkaldt_af_Yohimbin_HCl_hos_mus20 I - Lethality_called_of_Yohimbin_HCl_hos_mus
Denne prøve blev gennemført på grupper af 10 hanmus, CD-I (Charles River). Hver af de behandlede mus modtog 0,25 ml/20 g af en suspension indeholdende den afprøvede dosis af en forbindelse. En time efter indgiften fik 25 musene en subcutan injektion af 30 mg/kg Yohimbin HC1.This test was conducted on groups of 10 male mice, CD-I (Charles River). Each of the treated mice received 0.25 ml / 20 g of a suspension containing the tested dose of a compound. One hour after administration, the 25 mice received a subcutaneous injection of 30 mg / kg of Yohimbin HCl.
Procenten af dødsfald (L) blev bestemt 18 timer efter denne injektion. For hver afprøvet forbindelse anvendtes en Yohimbin HCl-kontrolgruppe. Resultaterne er sammenstillet i tabel I.The percentage of deaths (L) was determined 18 hours after this injection. For each compound tested, a Yohimbine HCl control group was used. The results are summarized in Table I.
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14 II - Antagonisme_med_catalepsi_induceret_med_halogeridol14 II - Antagonism_with_catalepsia_induced_with_halogeridol
Dette forsøg blev gennemført under sammenligning med to referenceforbindelser, imipramin og 5-hydroxytrytophan, på Wistar-hanrotter på 140/170 g i grupper på seks rot-5 ter i hver gruppe.This experiment was performed in comparison with two reference compounds, imipramine and 5-hydroxytryptophan, on male Wistar rats of 140/170 g in groups of six rats in each group.
IP-indgift af 5 mg/kg haloperidol medfører catalepsi. Yderligere oral indgift af de afprøvede forbindelser 1 time efter indsprøjtning med haloperidol modvirker catalepsi.IP administration of 5 mg / kg haloperidol results in catalepsy. Further oral administration of the tested compounds 1 hour after injection with haloperidol counteracts catalepsy.
10 Man afprøvede otte af de omhandlede forbindelser i forskellige doser (en gruppe for hver dosering med hver forbindelse). Virkningen på catalepsi blev bestemt 1, 2, 3, 4 og 5 timer efter indgiften af den afprøvede forbindelse, idet man anbragte rotternes bagpoter på en me-15 talstang 10 cm over bordniveauet (forsøget blev gennemført i et støjfrit rum ved 22°c). Hvis rotten var i stand til at blive stående i 20 sekunder, blev der tildelt 1 point, for 20 sekunder blev der tildelt 2 point osv. op til 5 point for 100 sekunder. Gennemsnitsværdi-20 erne blev, med den tilsvarende antagonisme målt i procent, beregnet for hver enkelt gruppe.Eight of the compounds in question were tested in different doses (one group for each dose with each compound). The effect on catalepsy was determined 1, 2, 3, 4 and 5 hours after administration of the tested compound, placing the rats' hind legs on a metal rod 10 cm above the table level (the experiment was conducted in a noise-free room at 22 ° C). . If the rat was able to stand for 20 seconds, 1 point was awarded, for 20 seconds, 2 points, etc., were awarded up to 5 points for 100 seconds. The average values, with the corresponding antagonism measured as a percentage, were calculated for each group.
Resultaterne er sammenstillet i tabel II.The results are summarized in Table II.
III - Fprtyivlelsesfgrsøg på musIII - Fertilization tests on mice
Dette forsøg blev gennemført på hanmus, CD-I (Charles 25 River) i grupper med 10 mus i hver gruppe under anvendelse af Maprotiline som sammenligningsforbindelse. En time før forsøget fik musene en dosering på 0,4 ml/20 kg af en suspension svarende til en passende dosis i mg/kg af de afprøvede forbindelser.This experiment was performed on male mice, CD-I (Charles 25 River) in groups of 10 mice in each group using Maprotiline as a comparison compound. One hour before the experiment, the mice received a dosage of 0.4 ml / 20 kg of a suspension corresponding to a suitable dose in mg / kg of the tested compounds.
30 Musene blev anbragt i plexiglascylindre (højde 2.5 cm, diameter 10 cm) indeholdende vand ved 22°C. ImmobiliThe mice were placed in plexiglass cylinders (height 2.5 cm, diameter 10 cm) containing water at 22 ° C. immobilisation
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15 tetsperioden blev målt mellem det andet og det sjette minut. Der anvendtes en kontrolgruppe for hver forbindelse og en kontrolgruppe pr. afprøvet dosis.The time period was measured between the second and sixth minutes. One control group was used for each compound and one control group per tested dose.
Resultaterne er sammenstillet i tabel III, hvor A bety-5 der den gennemsnitlige immobilitetsperiode, og B betyder den procentiske variation i forhold til kontrolgruppen.The results are summarized in Table III, where A means the mean immobility period and B means the percentage variation relative to the control group.
Præparatformer - posologiForms of Preparation - Posology
Mere sædvanligt anvendte former inden for human-terapien 10 er for eksempel tabletter eller gelatinekapsler indeholdende 0,1 g aktiv forbindelse pr. doseringsenhed eller ampuller indeholdende samme mængde på opløst eller suspenderet form til IV-injektion.More commonly used forms in human therapy 10 are, for example, tablets or gelatin capsules containing 0.1 g of active compound per day. dosage unit or ampoules containing the same amount of dissolved or suspended form for IV injection.
Sædvanlige doseringer er op til 0,5 g/dag i mindst to 15 uger for orale former eller op til 0,2 g/dag i mindst en uge for injektionspræparater, idet denne behandling opfølges med oral indgift i mindst 1 uge.Usual dosages are up to 0.5 g / day for at least two 15 weeks for oral forms or up to 0.2 g / day for at least one week for injections, following this treatment with oral administration for at least 1 week.
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TABEL· ITABLE · I
Produkter Doser LProducts Doses L
Yohimbin HCl 30 mg/kg SC 20 %Yohimbine HCl 30 mg / kg SC 20%
Eksempel 1 30 mg/kg PO 40 % 100 mg/kg PO 60 %Example 1 30 mg / kg PO 40% 100 mg / kg PO 60%
Yohimbin HCl 30 mg/kg SC 20 %Yohimbine HCl 30 mg / kg SC 20%
Eksempel 4 30 mg/kg PO 50 % 60 mg/kg PO 60 %Example 4 30 mg / kg PO 50% 60 mg / kg PO 60%
Yohimbin HCl 30 mg/kg SC 20 %Yohimbine HCl 30 mg / kg SC 20%
Eksempel 5 10 mg/kg PO 60 % 30 mg/kg PO 60 %Example 5 10 mg / kg PO 60% 30 mg / kg PO 60%
Yohimbin HCl 30 mg/kg SC 20 %Yohimbine HCl 30 mg / kg SC 20%
Eksempel 7 3 mg/kg PO 50 % 10 mg/kg PO 50 %Example 7 3 mg / kg PO 50% 10 mg / kg PO 50%
Yohimbin HCl 30 mg/kg SC 20 %Yohimbine HCl 30 mg / kg SC 20%
Eksempel 11 30 mg/kg PO 30 % 100 mg/kg PO 90 %Example 11 30 mg / kg PO 30% 100 mg / kg PO 90%
Yohimbin HCl 30 mg/kg SC 20 %Yohimbine HCl 30 mg / kg SC 20%
Eksempel 12 30 mg/kg PO 40 % * 60 mg/kg PO 50 %Example 12 30 mg / kg PO 40% * 60 mg / kg PO 50%
Yohimbin HCl 30 mg/kg SC 20 %Yohimbine HCl 30 mg / kg SC 20%
Eksempel 17 30 mg/kg PO 80 % 100 mg/kg PO 90 %Example 17 30 mg / kg PO 80% 100 mg / kg PO 90%
Yohimbin HCl 30 mg/kg SC 20 %Yohimbine HCl 30 mg / kg SC 20%
Eksempel 20 30 mg/kg PO 50 % 100 mg/kg PO 60 %Example 20 30 mg / kg PO 50% 100 mg / kg PO 60%
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TABEL IXTABLE IX
Dosis Antagonisme i % efter: (timer)Dose of Antagonism in% after: (hours)
Eksempler mg/kg - per os lh 2 h 3 h 4 h 5 hExamples mg / kg - per hour 2 h 3 h 4 h 5 h
Imipramin 15 100 52,3 42,3 48,2 50 60 68,7 76,1 42,3 31 33,3 5 HTP 30 53,3 42,8 20,6 13,8 16,6 100 33,3 46,4 31 13,8 16,6Imipramine 15 100 52.3 42.3 48.2 50 60 68.7 76.1 42.3 31 33.3 5 HTP 30 53.3 42.8 20.6 13.8 16.6 100 33.3 46 , 4 31 13.8 16.6
Eksempel 1 30 60 63,6 44 35,7 25 100 100 50 54,5 46,4 40Example 1 30 60 63.6 44 35.7 25 100 100 50 54.5 46.4 40
Eksempel 4 1 58,3 70 50 33,7 16,6 3 100 75 80 56,6 50Example 4 1 58.3 70 50 33.7 16.6 3 100 75 80 56.6 50
Eksempel 5 10 100 100 78 78 64 30 57 75 46 50 47Example 5 10 100 100 78 78 64 30 57 75 46 50 47
Eksempel 7 3 0 58,3 60,7 41,4 48,2 10 28,5 79,1 78,6 79,3 72,4Example 7 3 0 58.3 60.7 41.4 48.2 10 28.5 79.1 78.6 79.3 72.4
Eksempel 11 10 50 100 60 53,3 53,3 30 100 80,7 62,9 55,1 41,4Example 11 10 50 100 60 53.3 53.3 30 100 80.7 62.9 55.1 41.4
Eksempel 12 10 9 30,4 37 43,3 46,6 30 0 30,4 40,7 46,6 40Example 12 10 9 30.4 37 43.3 46.6 30 0 30.4 40.7 46.6 40
Eksempel 17 3 100 54,5 48,3 24,1 26,6 10 100 59 51,7 24,1 40Example 17 3 100 54.5 48.3 24.1 26.6 10 100 59 51.7 24.1 40
Eksempel 20 10 93,3 76 70 60,7 55,1 30 100 68 50 54,5 51,7Example 20 10 93.3 76 70 60.7 55.1 30 100 68 50 54.5 51.7
TABEL IIITABLE III
DK 157871 BDK 157871 B
1818
Eksempler Doser A BExamples Doses A B
Kontrol - 204Control - 204
Maprotilin 10 mg/kg PO 156,3 - 23,4 NSMaprotiline 10 mg / kg PO 156.3 - 23.4 NS
30 mg/kg PO 143,3 - 29,7 x 100 mg/kg PO 86,5 - 57,6 xxx30 mg / kg PO 143.3 - 29.7 x 100 mg / kg PO 86.5 - 57.6 xxx
Kontrol - 203,8Control - 203.8
Eksempel 1 1 mg/kg PO 157,4 - 25 x 3 mg/kg PO 133,1 - 34,7 xx 10 mg/kg PO 82,1 - 59,6 xxxExample 1 1 mg / kg PO 157.4 - 25 x 3 mg / kg PO 133.1 - 34.7 xx 10 mg / kg PO 82.1 - 59.6 xxx
Kontrol - 198,3Control - 198.3
Eksempel 4 10 mg/kg PO 136,4 - 31,2 x 30 mg/kg PO 135,6 - 31,6 x 100 mg/kg PO 138,3 - 30,3 xExample 4 10 mg / kg PO 136.4 - 31.2 x 30 mg / kg PO 135.6 - 31.6 x 100 mg / kg PO 138.3 - 30.3 x
Kontrol - 207,1Control - 207.1
Eksempel 5 10 mg/kg PO 145,4 ' - 29,8 x 30 mg/kg PO 124,4 - 39,9 xx 100 mg/kg PO 86,7 - 58,1 xxxExample 5 10 mg / kg PO 145.4 '- 29.8 x 30 mg / kg PO 124.4 - 39.9 xx 100 mg / kg PO 86.7 - 58.1 xxx
Kontrol - 189,9Control - 189.9
Eksempel 7 3 mg/kg PO 137 - 27,9 x 10 mg/kg PO 135,2 - 28,8 x 30 mg/kg PO 101,1 - 46,6 xxExample 7 3 mg / kg PO 137 - 27.9 x 10 mg / kg PO 135.2 - 28.8 x 30 mg / kg PO 101.1 - 46.6 xx
Kontrol - 200,3Control - 200.3
Eksempel 11 10 mg/kg PO 144,6 - 27,8 x 30 mg/kg PO 136,6 - 31,8 xx 100 mg/kg PO 118,1 - 41,^4 xxExample 11 10 mg / kg PO 144.6 - 27.8 x 30 mg / kg PO 136.6 - 31.8 xx 100 mg / kg PO 118.1 - 41.4 xx
Kontrol - 148,5Control - 148.5
Eksempel 12 30 mg/kg PO 106,1 - 28,6 x 100 mg/kg PO 99,0 - 33,3 x 300 mg/kg PO 77,4 - 47,9 xxExample 12 30 mg / kg PO 106.1 - 28.6 x 100 mg / kg PO 99.0 - 33.3 x 300 mg / kg PO 77.4 - 47.9 xx
Kontrol - 200Control - 200
Eksempel 17 10 mg/kg PO 175,2 - 12,4 NSExample 17 10 mg / kg PO 175.2 - 12.4 NS
30 mg/kg PO 142,7 - 28,6 xx30 mg / kg PO 142.7 - 28.6 xx
100 mg/kg PO 155,4 - 22,3 NS100 mg / kg PO 155.4 - 22.3 NS
Kontrol - 213,5Control - 213.5
Eksempel 20 10 mg/kg PO 183,4 - 14,1 NSExample 20 10 mg / kg PO 183.4 - 14.1 NS
30 mg/kg PO 86,3 -59,6xx 60 mg/kg PO 97,2 - 54,5 xx30 mg / kg PO 86.3 -59.6xx 60 mg / kg PO 97.2 - 54.5 xx
Note: NS = ikke signifikant x, xx og xxx markerer stigende grad af signifikansNote: NS = non-significant x, xx and xxx indicate increasing significance
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB848422029A GB8422029D0 (en) | 1984-08-31 | 1984-08-31 | 6-substituted-furo-(3 4-c)-pyridine derivatives |
| GB8422029 | 1984-08-31 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK396085D0 DK396085D0 (en) | 1985-08-30 |
| DK396085A DK396085A (en) | 1986-03-01 |
| DK157871B true DK157871B (en) | 1990-02-26 |
| DK157871C DK157871C (en) | 1990-07-23 |
Family
ID=10566078
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK396085A DK157871C (en) | 1984-08-31 | 1985-08-30 | PROCEDURE FOR PREPARING 1,3-DIHYDRO-6- (1-HYDROXY-2-DIMETHYLAMINOMETHYL-ALLYL) -7-HYDROXY-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) |
| SE (1) | SE462218B (en) |
| ZA (1) | ZA856088B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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
- 1985-08-22 CA CA000489219A patent/CA1300149C/en not_active Expired - Fee Related
- 1985-08-22 LU LU86052A patent/LU86052A1/en unknown
- 1985-08-23 NL NL8502324A patent/NL8502324A/en not_active Application Discontinuation
- 1985-08-23 CH CH3653/85A patent/CH666688A5/en not_active IP Right Cessation
- 1985-08-26 BE BE0/215502A patent/BE903122A/en not_active IP Right Cessation
- 1985-08-28 FI FI853287A patent/FI82468C/en not_active IP Right Cessation
- 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
- 1985-08-30 NO NO853418A patent/NO162071C/en unknown
- 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
- 1985-08-30 ES ES546590A patent/ES8604967A1/en not_active Expired
- 1985-08-30 OA OA58669A patent/OA08088A/en unknown
- 1985-08-30 PT PT81054A patent/PT81054B/en not_active IP Right Cessation
-
1989
- 1989-01-19 HK HK61/89A patent/HK6189A/en not_active IP Right Cessation
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