DK149952B - ANALOGY PROCEDURE FOR THE PREPARATION OF AN AMINOAL COOLING RANGE - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF AN AMINOAL COOLING RANGE Download PDFInfo
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Description
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Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af et hidtil ukendt aminoalkylfuranderivat eller salte deraf med syrer, hvilke forbindelser har selektiv virkning på histamin receptorer, hvorfor der med disse forbindelser kan fremstilles farmaceutiske 5 præparater.The present invention relates to an analogous process for the preparation of a novel aminoalkylfuran derivative or salts thereof with acids, which compounds have a selective effect on histamine receptors, and thus, with these compounds, pharmaceutical compositions can be prepared.
En underinddeling af histaminreceptorer (H-receptorer) i to grupper, der betegnes som H^- og receptorer, er blevet foreslået af Ash og Schild (Brit. J. Pharmacol. Chemother., 1966, 27, s. 427) og Black et al. (Nature, 1972, 236, s. 385). Stimulation af den bløde muskula-10 tur i bronchial- og gastrointestinal-området formidles af H.|-receptorer, og virkningen deraf kan forhindres med sædvanlige histaminantagonister såsom mepyramin. Stimulation af mavesyresekretion og hjertefrekvens formidles af receptorer; disse virkninger modificeres ikke af mepyramin, men forhindres eller ophæves af h^-antago-15 nister såsom metiamid. Histamin stimulerer H^- og l·^-receptorer.A subdivision of histamine receptors (H receptors) into two groups referred to as H 2 and receptors has been proposed by Ash and Schild (Brit. J. Pharmacol. Chemother., 1966, 27, p. 427) and Black et al. eel. (Nature, 1972, 236, p. 385). Stimulation of the soft musculature of the bronchial and gastrointestinal tract is mediated by H? Receptors and the effect thereof can be prevented by conventional histamine antagonists such as mepyramine. Stomach acid secretion and heart rate stimulation are mediated by receptors; these effects are not modified by mepyramine, but are prevented or abrogated by H 2 antagonists such as methiamide. Histamine stimulates H 1 and L 2 receptors.
Det har vist sig, at det her omhandlede, hidtil ukendte aminoalkylfuranderivat er en selektiv H2_antagonist, hvilket vil sige, at det inhiberer sekretionen af mavesyre, når denne stimuleres via histamin -H2~receptorer (Ash og Schild loc. cit.). Dets evne til at forhin-20 dre sekretion af mavesyre, når denne stimuleres via histamin-Hj-re-ceptorer, kan demonstreres på en perfuseret rottemave under anvendelse af den af Ghosh og Schild (Brit. J. Pharmacol., 1958, 13, s.It has been found that the aforementioned novel aminoalkyl furan derivative is a selective H2 antagonist, that is, it inhibits the secretion of gastric acid when stimulated via histamine-H2 receptors (Ash and Schild loc. Cit.). Its ability to inhibit gastric acid secretion when stimulated via histamine H 2 receptors can be demonstrated on a perfused rat stomach using that of Ghosh and Schild (Brit. J. Pharmacol., 1958, 13). p.
54) beskrevne metode, modificeret på den nedenfor beskrevne måde, og på vågne hunde, der er udstyret med Heidenhain-lommer under 25 anvendelse af samme metode som beskrevet af Black et al. (Nature, 1972, 236, s. 385). Den ved fremgangsmåden ifølge den foreliggende opfindelse fremstillede forbindelse modificerer ikke histamin-inducerede kontraktioner i isoleret blød muskulatur fra gastrointestinalområdet.54) described method, modified in the manner described below, and on awake dogs equipped with Heidenhain pockets using the same method as described by Black et al. (Nature, 1972, 236, p. 385). The compound prepared by the process of the present invention does not modify histamine-induced contractions in isolated soft muscle from the gastrointestinal tract.
En forbindelse med histamin-H2_blokerende virkning kan anvendes til 30 behandling af tilstande, hvor der er hypersekretion af mavesyre, fx ved gastrisk og peptisk ulceration, og til behandling af allergiske tilstande, hvor histamin er en kendt mediator. Forbindelsen kan anvendes enten alene eller i kombination med andre aktive stoffer til behandling af allergiske og inflammatoriske tilstande, fx urticaria.A compound with histamine H2-blocking effect can be used to treat conditions in which there is hypersecretion of gastric acid, for example by gastric and peptic ulceration, and to treat allergic conditions in which histamine is a known mediator. The compound can be used either alone or in combination with other active substances to treat allergic and inflammatory conditions, eg urticaria.
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Den foreliggende opfindelse bygger på denne erkendelse og angår en analogifremgangsmåde til fremstilling af N-[2-[[[5-(dimethylamino)me-thyl-2-furanyl]methyi]thio] ethyl]-N'-methyl-2-nitro-1,1-ethendiamin med formlen IThe present invention is based on this disclosure and relates to an analogous process for the preparation of N- [2 - [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro -1,1-Ethenediamine of Formula I
CH3 \ f/-^ HCN°2 5 N_CH2 -CH2S (CH2} 2NH<2NHCH3 'CH3 \ f / - ^ HCN ° 2 N_CH2 -CH2S (CH2} 2NH <2NHCH3 '
eller fysiologisk tolerable salte deraf, hvilken fremgangsmåde er ejendommelig ved, at en forbindelse med den almene formel IVor physiologically tolerable salts thereof, characterized in that a compound of the general formula IV
CH3\ ri 7 —ch2or' iv ca3 0CH3 \ ri 7 —ch2or 'iv ca3 0
hvor betegner hydrogen eller acyl, omsættes med thiolen med form-10 len Vwherein hydrogen or acyl is reacted with the thiol of formula V
HS(CH,).NHCNHCH.HS (CH,). NHCNHCH.
\\ VV
hcno2 hvorefter, til fremstilling af fysiologisk tolerable salte, forbindelsen med formlen I behandles med en fysiologisk tolerabel uorganisk eller organisk syre, eller et vundet salt omdannes til et andet salt deraf 15 med en fysiologisk tolerabel syre.hcno2, then, for the production of physiologically tolerable salts, the compound of formula I is treated with a physiologically tolerable inorganic or organic acid, or a won salt is converted to another salt thereof with a physiologically tolerable acid.
Forbindelsen med formlen I har den fordel, at den let kan fremstilles ud fra let tilgængelige udgangsmaterialer.The compound of formula I has the advantage that it can be readily prepared from readily available starting materials.
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Forbindelsen med formlen I kan udvise tautomeri, og formlen skal dække alle de tautomere.The compound of formula I may exhibit tautomerism and the formula should cover all the tautomers.
Forbindelsen med formlen I danner let fysiologisk tolerable salte.The compound of formula I readily forms physiologically tolerable salts.
Sådanne salte omfatter salte med uorganiske og organiske syrer såsom 5 hydrochlorider, hydrobromider og sulfater. Særlig værdifulde salte af organiske syrer dannes med aliphatiske mono- eller di-carboxylsyrer.Such salts include salts with inorganic and organic acids such as hydrochlorides, hydrobromides and sulfates. Particularly valuable salts of organic acids are formed with aliphatic mono- or di-carboxylic acids.
Eksempler på sådanne salte er acetater, maleater og fumarater.Examples of such salts are acetates, maleate and fumarates.
Forbindelsen med formlen I administreres oralt, topisk eller parente-ralt eller som suppositorier, og den foretrukne administrationsvej er 10 den orale. Den kan anvendes i form af basen eller som fysiologisk tolerabelt salt. Forbindelsen blandes sædvanligvis med et farmaceutisk tolerabelt bærestof eller en diluent til dannelse af et farmaceutisk præparat.The compound of formula I is administered orally, topically or parenterally or as suppositories, and the preferred route of administration is the oral. It can be used in the form of the base or as physiologically tolerable salt. The compound is usually mixed with a pharmaceutically tolerable carrier or diluent to form a pharmaceutical composition.
Forbindelsen med formlen I kan administreres i kombination med andre 15 aktive bestanddele, om nødvendigt fx sædvanlige antihistaminer. Til oral administration kan det farmaceutiske præparat være i form af kapsler eller tabletter, der kan være tabletter med langsom frigivelse.The compound of formula I may be administered in combination with other active ingredients, if necessary, for example, conventional antihistamines. For oral administration, the pharmaceutical composition may be in the form of capsules or tablets which may be slow release tablets.
Præparatet kan også have form af en dragée eller kan være i sirupform. Egnede topiske præparater omfatter salver, lotioner, cremer, 20 pulvere og spraymidler.The preparation may also be in the form of a dragee or may be in syrup form. Suitable topical compositions include ointments, lotions, creams, powders and sprays.
En bekvem daglig dosis til oral administration ligger i området mellem 100 mg og 1,2 g/dag i form af dosisenheder indeholdende mellem 20 og 200 mg pr. dosisenhed. En bekvem kur i tilfælde af anvendelse af tabletter med langsom frigivelse kan være administration to eller tre 25 gange daglig.A convenient daily dose for oral administration is in the range of 100 mg to 1.2 g / day in the form of dosage units containing between 20 and 200 mg per day. dosage unit. A convenient cure in case of slow release tablets may be administration two or three 25 times daily.
Parenteral administration kan udføres ved injektioner med mellemrum eller som kontinuerlig infusion. Injektionsopløsninger kan indeholde 10-100 mg/ml aktivstof.Parenteral administration can be performed by intermittent injections or by continuous infusion. Injection solutions may contain 10-100 mg / ml of active substance.
Til topisk applikation kan anvendes en spray, salve, creme eller 30 lotion. Disse præparater kan indeholde en virksom mængde af den aktive bestanddel, fx i størrelsesordenen 1 1/2 - 2 vægtprocent af det totale præparat.For topical application a spray, ointment, cream or 30 lotion can be used. These compositions may contain an effective amount of the active ingredient, e.g., on the order of 1 1/2 - 2% by weight of the total composition.
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Ved fremgangsmåden fremstilles forbindelsen ud fra et udgangsmateriale med den almene formel IVIn the process, the compound is prepared from a starting material of general formula IV
“3\ J L 7“3 \ J L 7
N-CH2——CHjOR IVN-CH2 —— CH2OR IV
æ3 ° hvor R^ er hydrogen eller acyl såsom acetyl eller p-nitrobenzoyl.is hydrogen or acyl such as acetyl or p-nitrobenzoyl.
5 De ovenfor anførte forbindelser IV omsættes med thiolen med formlen VThe above-mentioned compounds IV are reacted with the thiol of formula V
HS(CH-)-NHCNHCH, 2 2 II 3 v hcno2HS (CH -) - NHCNHCH, 2 2 II 3 v hcno2
Reaktionen udføres fortrinsvis ved 0°C i koncentreret saltsyre.The reaction is preferably carried out at 0 ° C in concentrated hydrochloric acid.
Forbindelsen med formlen I adskiller sig strukturelt fra de i britisk 10 patentskrift nr. 1.307.539, 1.338.169, 1.397.436 og 1.421.792 beskrevne forbindelser ved at være aminoalkylfuranderivater og ikke forbindelser indeholdende en nitrogenholdig heterocyclisk ring. De kendte forbindelser, som på trods heraf må siges at være forbindelse I nærmestliggende, er beskrevet i britisk patentskrift nr. 1.338.169 15 og 1.421.792 og har den almene formel ch3 . —CH2S(CH2)2NH^ /nhch3 hn. n 9 149952 5The compound of formula I differs structurally from the compounds disclosed in British Patent Nos. 1,307,539, 1,338,169, 1,397,436 and 1,421,792 by being aminoalkylfuran derivatives and not compounds containing a nitrogen-containing heterocyclic ring. The known compounds, which, in spite of this, must be said to be compound I, are described in British Patent Nos. 1,338,169 15 and 1,421,792 and have the general formula ch3. -CH2S (CH2) 2NH2 / nhch3 hn. n 9 149952 5
Forbindelsen cimetidin (X = NCN) og det tilsvarende nitrovinylderivat deraf (X = CHNOj) har dog langt større ED^-værdier end forbindelse I, hvilket indicerer svagere virkning.However, the compound cimetidine (X = NCN) and its corresponding nitrovinyl derivative (X = CHNO 2) have far greater ED 1 values than compound I, indicating weaker efficacy.
Ved fremgangsmåden fås forbindelsen med formlen I som nævnt ved 5 omsætning af en forbindelse med formlen IV med thiolen med formlen V. Forbindelsen med formlen V kan fremstilles ud fra et thiazolidin-mellemprodukt med formlen XVIIn the process, the compound of formula I, as mentioned, is obtained by reacting a compound of formula IV with the thiol of formula V. The compound of formula V can be prepared from a thiazolidine intermediate of formula XVI
ΛΛΛΛ
S NHS NH
γ xvi :hno2γ xvi: hno2
ved omsætning med methylamin. Thiazolidinen med formlen XVI kan 10 fremstilles ud fra cysteamin og en bis-methylthioforbindelse med formlen XVIIby reaction with methylamine. The thiazolidine of formula XVI can be prepared from cysteamine and a bis-methylthio compound of formula XVII
CH-SCSCH, II 3 xvn CHN02CH-SCSCH, II 3 xvn CHNO 2
Forbindelsen med formlen I har som nævnt vist sig at inhibere mave-syresekretion, der induceres af histamin. Dette er påvist på rotter 15 under anvendelse af en modifikation af den fremgangsmåde, der er beskrevet af M.N. Ghosh og H.O. Schild i British Journal of Pharmacology, 1958, 13, s. 54.As mentioned, the compound of formula I has been shown to inhibit gastric acid secretion induced by histamine. This has been demonstrated in rats 15 using a modification of the method described by M.N. Ghosh and H.O. Shield in British Journal of Pharmacology, 1958, 13, p. 54.
Hunrotter med en vægt på ca. 150 g suites natten over og gives derefter 8% saccharose i normalt saltvand i stedet for drikkevand.Female rats weighing approx. 150 g of suites overnight and then 8% sucrose in normal saline instead of drinking water.
20 Rotterne anæstetiseres ved en enkelt intraperitoneal injektion af en 25 vægt/volumenprocents urethanopløsning (0,5 ml/100 g), og der lægges kanyler i trachea og halsvenerne.The rats are anesthetized by a single intraperitoneal injection of a 25% w / v urethane solution (0.5ml / 100g) and cannulae are inserted into the trachea and throat veins.
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Der lægges et midtlinjesnit i abdomenvæggen for at blotlægge maven, som skilles fra leveren og milten ved overskæring af bindevævet. En lille åbning laves i fundusregionen i maven, og maven vaskes med en 5%'s dextroseopløsning. Oesophagus drænes med en gummislange, og 5 oesophagus og vagi overskæres derefter over kanylen.A midline incision is made in the abdominal wall to expose the abdomen which is separated from the liver and spleen by cutting the connective tissue. A small opening is made in the fundus region of the abdomen and the abdomen is washed with a 5% dextrose solution. The esophagus is drained with a rubber tube and 5 oesophagus and vagi are then cut over the cannula.
Der laves derefter en lille åbning i pylorusregionen. Der anbringes en stor perspex-kanyle via åbningen i fundusregionen på en sådan måde, at indgangsenden af kanylen går ud af maven gennem åbningen i pylorusområdet. Kanylen er af en sådan form, at den reducerer det 10 effektive rumfang i maven, og at der fremkaldes en turbulent strøm i perfusionsvæsken hen over slimhindeoverfladen. Der indlægges derefter en drænkanyle gennem åbningen i fundusregionen i maven. Begge kanyler holdes på plads af ligaturer rundt om maven anbragt således, at hovedblodårerne undgås. Der stikkes huller i væggen, og kanyler-15 ne stikkes igennem. Maven perfuseres gennem oesophagus- og pylo-rus-kanylerne med 5%’s dextroseopløsning ved 39°C med en hastighed på 1,5 ml/minut i hver kanyle. Effluenten ledes igennem en microflow pH-elektrode og måles via et pH-meter og en "flat-bed"-recorder.A small opening is then made in the pylorus region. A large perspex cannula is placed via the opening in the fundus region in such a way that the entrance end of the cannula exits the stomach through the opening in the pylorus region. The cannula is of such a shape that it reduces the effective volume of the stomach and causes a turbulent flow in the perfusion fluid over the mucosal surface. A drain cannula is then inserted through the opening in the fundus region of the abdomen. Both needles are held in place by ligatures around the abdomen so as to avoid the head blood vessels. Holes are inserted into the wall and the needles are pierced. The stomach is perfused through the oesophagus and pylo-rus cannula with 5% dextrose solution at 39 ° C at a rate of 1.5 ml / min in each cannula. The effluent is passed through a microflow pH electrode and measured via a pH meter and a flat-bed recorder.
Den basale mængde syresekretion fra maven bestemmes ved måling af 20 pH-værdien i perfusionseffluenten, og derefter induceres forøget syresekretion ved fortsat intravenøs infusion af en submaksimal histamindosis; dette fremkalder et stabilt højt niveau af syresekretion, og pH-værdien i perfusionseffluenten bestemmes, når denne tilstand er nået.The basal amount of gastric acid secretion is determined by measuring the pH of 20 in the perfusion effluent, and then increased acid secretion is induced by continued intravenous infusion of a submaximal dose of histamine; this produces a stable high level of acid secretion and the pH of the perfusion effluent is determined when this state is reached.
25 Forsøgsforbindelsen administreres derefter til rotten ved intravenøs injektion, og ændringen i "mavesyre"-sekretion bestemmes ved måling af ændringen i pH-værdien i perfusionseffluenten.The test compound is then administered to the rat by intravenous injection and the change in "gastric acid" secretion is determined by measuring the change in the pH of the perfusion effluent.
Ud fra ændringen i pH-værdien i perfusionseffluenten beregnes forskellen i syresekretion imellem den basale mængde og det histaminsti-30 mulerede niveau som hydrogen ion koncentration i mol/L. Reduktionen af syresekretion fremkaldt ved administration af forsøgsforbindelsen beregnes også som ændringen i hydrogenionkoncentration i mol/L ud fra forskellen i pH-værdien i perfusionseffluenten. Den procentvise 149952 7 reduktion af syresekretion, der fremkaldes ved administration af forsøgsforbindelsen, kan derefter beregnes ud fra de to vundne værdier.From the change in the pH of the perfusion effluent, the difference in acid secretion between the basal amount and the histamine-stimulated level is calculated as hydrogen ion concentration in mol / L. The reduction of acid secretion induced by administration of the test compound is also calculated as the change in hydrogen ion concentration in mol / L based on the difference in the pH of the perfusion effluent. The percentage reduction in acid secretion induced by administration of the test compound can then be calculated from the two values obtained.
EDsQ-Værdier for inhibering af syresekretion bestemmes ved at admi-5 nistrere én dosis af forsøgsforbindelsen til én rotte og gentage dette på mindst 4 rotter for hvert af tre eller flere dosisniveauer. De vundne resultater anvendes derefter til at beregne ED^-værdien ved de mindste kvadraters metode, som anvendes for hver dosis-responslinje.EDsQ values for inhibition of acid secretion are determined by administering one dose of the test compound to one rat and repeating this in at least 4 rats for each of three or more dose levels. The results obtained are then used to calculate the ED ^ value by the least squares method used for each dose-response line.
10 Under anvendelse af den ovenfor beskrevne teknik er der opnået en EDjjQ-værdi på 0,18 mg/kg.Using the technique described above, an ED₂ ED value of 0.18 mg / kg has been obtained.
Under de samme forsøgsbetingelser er der for den i britisk patentskrift nr. 1.338.169 nævnte forbindelse cimetidin opnået en ED^g-værdi på 1,12 mg/kg, og for det tilsvarende nitrovinylderivat, som 15 falder inden for omfanget af britisk patentskrift nr. 1.421.792, er der opnået en ED^g-værdi på 1,75 mg/kg. Da en lav ED^g-værdi angiver et mere aktivt produkt, er den ifølge opfindelsen fremstillede forbindelse virkningsmæssigt de tidligere beskrevne forbindelser overlegen.Under the same test conditions, for the compound cited in British Patent No. 1,338,169, cimetidine has been obtained an ED ^g value of 1.12 mg / kg and for the corresponding nitrovinyl derivative which falls within the scope of British Patent 1,421,792, an ED ED g value of 1.75 mg / kg has been obtained. Since a low ED ^g value indicates a more active product, the compound of the invention is effectively superior to the previously described compounds.
Fremgangsmåden ifølge opfindelsen belyses nærmere i nedenstående 20 eksempel 2 og 3, og fremstillingen af mellemprodukter belyses i eksempel 1.The process of the invention is elucidated in Examples 2 and 3 below, and the preparation of intermediates is illustrated in Example 1.
EKSEMPEL 1 2-Nitromethylen-thiazolidinEXAMPLE 1 2-Nitromethylene-thiazolidine
En blanding af 11,36 g cysteamin-hydrochlorid, 5,61 g kaliumhydroxid 25 og 16,52 g 1,1-bis(methylthio)-2-nitroethen i 30 ml vand og 100 ml ethanol opvarmes til kogning under tilbagesvaling i 1 time. Suspensionen inddampes til tørhed, remanensen suspenderes i vand og filtreres, og remanensen krystalliseres af methanol, hvorved der fås 9,2 g 2-nitromethylen-thiazolidin, smeltepunkt 141-142°C.A mixture of 11.36 g of cysteamine hydrochloride, 5.61 g of potassium hydroxide 25 and 16.52 g of 1,1-bis (methylthio) -2-nitroethene in 30 ml of water and 100 ml of ethanol is heated to reflux for 1 hour. . The suspension is evaporated to dryness, the residue is suspended in water and filtered, and the residue is crystallized by methanol to give 9.2 g of 2-nitromethylene-thiazolidine, mp 141-142 ° C.
149952 8149952 8
Analyse:Analysis:
Beregnet for C4HgN202S: C 32,87 H 4,14 N 19,17Calcd for C 4 H 9 N 2 O 2 S: C 32.87 H 4.14 N 19.17
Fundet: C 32,91 H 4,13 N 19,10.Found: C, 32.91; H, 4.13; N, 19.10.
N-(2-Mercaptoethyl)-N'-methyl-2-nitro-1,1-ethendiamin 5 En opløsning af 5 g 2-nitromethylen-thiazolidin i en opløsning af 33% methylamin i 40 ml ethanol holdes ved stuetemperatur i 65 timer. Det udskilte faste stof frafiltreres, vaskes med ethanol og tørres, hvorved der fås 4,98 g N-(2-mercaptoethyl)-N’-methyl-2-nitro-1,1-ethendiamin, smeltepunkt 174-175°C, sønderdeling ved 209-211°C.N- (2-Mercaptoethyl) -N'-methyl-2-nitro-1,1-ethylenediamine 5 A solution of 5 g of 2-nitromethylene-thiazolidine in a solution of 33% methylamine in 40 ml of ethanol is kept at room temperature for 65 hours. . The precipitated solid is filtered off, washed with ethanol and dried to give 4.98 g of N- (2-mercaptoethyl) -N'-methyl-2-nitro-1,1-ethylenediamine, m.p. 174-175 ° C, dec. at 209-211 ° C.
10 Analyse:Analysis:
Beregnet for 05Η1ΊΝ3025: C 33,88 H 6,26 N 23,71Calcd for 05.13030 C: C 33.88 H 6.26 N 23.71
Fundet: C 34,05 H 5,87 N 23,85.Found: C, 34.05; H, 5.87; N, 23.85.
EKSEMPEL 2 N-[2-[[[5-(DimethyIamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-15. methy!-2-nitro-l,1-ethendiamin 125 mg N,N-dimethyl-2-furanmethanamin opløses i 1 ml iseddike, og der tilsættes 30 mg paraformaldehyd. En opløsning af 354 mg N-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1-ethendiamin i 1 ml koncentreret saltsyre og 1 ml iseddike tilsættes dråbevis, og blandingen lades 20 henstå ved stuetemperatur i 5 dage. Opløsningen fortyndes med 30 ml vand, mættes med kaliumcarbonat og ekstraheres med ethylacetat. De samlede ekstrakter renses ved præparativ tyndtlagschromatografi, hvorved der fås 89 mg af den i overskriften nævnte forbindelse. Tyndtlagschromatografi på siliciumdioxid med ethylacetat:ethanol:0,88% 25 ammoniakvand (10:1:1) giver en R^-værdi på 0,64.EXAMPLE 2 N- [2 - [[[5- (Dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-15. Methyl -2-nitro-1,1-ethanediamine 125 mg N, N-dimethyl-2-furanmethanamine is dissolved in 1 ml glacial acetic acid and 30 mg paraformaldehyde is added. A solution of 354 mg of N- (2-mercaptoethyl) -N'-methyl-2-nitro-1,1-ethylenediamine in 1 ml of concentrated hydrochloric acid and 1 ml of glacial acetic acid is added dropwise and the mixture is left at room temperature for 5 days. The solution is diluted with 30 ml of water, saturated with potassium carbonate and extracted with ethyl acetate. The combined extracts are purified by preparative thin layer chromatography to give 89 mg of the title compound. Thin layer chromatography on silica with ethyl acetate: ethanol: 0.88% ammonia water (10: 1: 1) gives an R 2 value of 0.64.
Claims (2)
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB32465/76A GB1565966A (en) | 1976-08-04 | 1976-08-04 | Aminoalkyl furan derivatives |
GB3246576 | 1976-08-04 | ||
GB5068576 | 1976-12-06 | ||
GB5068576 | 1976-12-06 | ||
GB2018777 | 1977-05-13 | ||
GB2018777 | 1977-05-13 | ||
KR7701808A KR810000355B1 (en) | 1977-05-13 | 1977-08-04 | Preparation for pharmacologically active compounds |
KR770001808 | 1977-08-04 |
Publications (4)
Publication Number | Publication Date |
---|---|
DK416384D0 DK416384D0 (en) | 1984-08-30 |
DK416384A DK416384A (en) | 1984-08-30 |
DK149952B true DK149952B (en) | 1986-11-03 |
DK149952C DK149952C (en) | 1987-07-06 |
Family
ID=27448487
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK337977A DK148258C (en) | 1976-08-04 | 1977-07-26 | ANALOGY PROCEDURE FOR THE PREPARATION OF AN AMINOAL COOLING RANGE |
DK416384A DK149952C (en) | 1976-08-04 | 1984-08-30 | ANALOGY PROCEDURE FOR THE PREPARATION OF AN AMINOAL COOLING RANGE |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK337977A DK148258C (en) | 1976-08-04 | 1977-07-26 | ANALOGY PROCEDURE FOR THE PREPARATION OF AN AMINOAL COOLING RANGE |
Country Status (16)
Country | Link |
---|---|
AT (1) | AT375931B (en) |
CH (2) | CH642072A5 (en) |
CY (1) | CY1077A (en) |
DE (2) | DE2760097C2 (en) |
DK (2) | DK148258C (en) |
ES (2) | ES461334A1 (en) |
FI (1) | FI72318C (en) |
HK (1) | HK55780A (en) |
IE (1) | IE45456B1 (en) |
IT (2) | IT1126759B (en) |
KE (1) | KE3080A (en) |
NZ (2) | NZ191383A (en) |
PH (1) | PH13540A (en) |
PT (1) | PT66874B (en) |
SE (3) | SE437373B (en) |
YU (2) | YU40006B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4203909A (en) * | 1978-09-26 | 1980-05-20 | Bristol-Myers Company | Furan compounds |
YU52598A (en) * | 1998-11-19 | 2001-05-28 | D.D. Zdravlje- sektor za istraživanje i razvoj | Procedure for synthesis of n-[2[[[5-[ (dialkylamino)methyl] -2-furanil]methyl]thi0]etyl]-n'-alkyl-2-nitro 1,1 alkendiamine and its hydrochloride |
-
1977
- 1977-07-22 CY CY1277A patent/CY1077A/en unknown
- 1977-07-22 FI FI772264A patent/FI72318C/en not_active IP Right Cessation
- 1977-07-25 SE SE7708521A patent/SE437373B/en not_active IP Right Cessation
- 1977-07-25 IE IE1536/77A patent/IE45456B1/en not_active IP Right Cessation
- 1977-07-26 DK DK337977A patent/DK148258C/en not_active IP Right Cessation
- 1977-07-27 NZ NZ191383A patent/NZ191383A/en unknown
- 1977-07-27 NZ NZ184759A patent/NZ184759A/en unknown
- 1977-07-28 DE DE2760097A patent/DE2760097C2/de not_active Expired
- 1977-07-28 DE DE2759959A patent/DE2759959C2/de not_active Expired
- 1977-07-29 CH CH938077A patent/CH642072A5/en not_active IP Right Cessation
- 1977-08-01 PT PT66874A patent/PT66874B/en unknown
- 1977-08-02 PH PH20057A patent/PH13540A/en unknown
- 1977-08-03 IT IT50551/77A patent/IT1126759B/en active Protection Beyond IP Right Term
- 1977-08-03 YU YU1911/77A patent/YU40006B/en unknown
- 1977-08-03 ES ES461334A patent/ES461334A1/en not_active Expired
- 1977-08-04 AT AT0574077A patent/AT375931B/en not_active IP Right Cessation
-
1978
- 1978-06-15 ES ES470836A patent/ES470836A1/en not_active Expired
-
1980
- 1980-08-30 KE KE3080A patent/KE3080A/en unknown
- 1980-10-02 HK HK557/80A patent/HK55780A/en unknown
-
1982
- 1982-08-27 CH CH509282A patent/CH641176A5/en not_active IP Right Cessation
- 1982-09-03 YU YU2000/82A patent/YU40088B/en unknown
- 1982-09-28 SE SE8205533A patent/SE454882B/en not_active IP Right Cessation
- 1982-11-17 SE SE8206556A patent/SE454883B/en not_active IP Right Cessation
-
1984
- 1984-08-30 DK DK416384A patent/DK149952C/en not_active IP Right Cessation
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1985
- 1985-08-01 IT IT48437/85A patent/IT1221058B/en active
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