DE2344833C2 - 5-Methylimidazol-4-ylmethylthioethylguanidines and their use as histamine H 2-receptor antagonists - Google Patents

5-Methylimidazol-4-ylmethylthioethylguanidines and their use as histamine H 2-receptor antagonists

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DE2344833C2
DE2344833C2 DE2344833A DE2344833A DE2344833C2 DE 2344833 C2 DE2344833 C2 DE 2344833C2 DE 2344833 A DE2344833 A DE 2344833A DE 2344833 A DE2344833 A DE 2344833A DE 2344833 C2 DE2344833 C2 DE 2344833C2
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methyl
ethanol
histamine
acid
hours
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DE2344833A1 (en
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Graham John Welwyn Garden City Hertfordshire Durant
John Colin Codicote Hertfordshire Emmett
Charon Robin Welwyn Garden City Hertfordshire Ganellin
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Smith Kline and French Laboratories Ltd
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Description

1515th

in der X die Gruppe CONH2 oder SO2R bedeutet, wobei R eine Propyl-, Trifluormethyl-, Amino-, Phenyl-, 4-Chlorphenyl-, 3,4-Dichlorphenyl-, 4-Methylphenyl- oder 4-Aminophenylgruppe darstellt, sowie N-(2-[(4-Methyl-5-imidazolyI)-methylthio]-äthyl}-N'-sulfamylguanidin und ihre Salze mit Säuren. in which X is the group CONH 2 or SO 2 R, where R is a propyl, trifluoromethyl, amino, phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-methylphenyl or 4-aminophenyl group, as well as N- (2 - [(4-methyl-5-imidazoly) -methylthio] -ethyl} -N'-sulfamylguanidine and their salts with acids.

2. Verwendung der Verbindungen gemäß Anspruch 1 als Histamin-H2-Receptor-Antagonisten.2. Use of the compounds according to claim 1 as histamine H 2 receptor antagonists.

Aus den am 24. August 1972 ausgelegten Unterlagen der BE-PS 7 79 775 sind Harnstoffderivate und ihre Salze mit Säuren der allgemeinen FormelFrom the documents of BE-PS 7 79 775 laid out on August 24, 1972 are urea derivatives and their Salts with acids of the general formula

3030th

3535

C—(CH2), Y(CH2),„NH — CC- (CH 2), Y (CH 2), "NH - C

NHRiNHRi

4040

bekannt,known,

in der A mit dem C-Ringatom einen fünf- oder sechsgliedrigen ungesättigten, heterocyclischen Ring bildet, der mindestens ein Stickstoffatom und gegebenenfalls weitere Heteroatome, wie ein Schwefel- oder Sauerstoffatom, enthält, Xi und X2, die gleich oder verschieden sind, ein Wasserstoff- oder Halogenatom, einen niederen Alkylrest, die Trifluormethyl-, Hydroxyl-, Benzyl- oder Aminogruppe oder den Rest der allgemeinen Formelin which A and the C ring atom form a five- or six-membered unsaturated, heterocyclic ring which contains at least one nitrogen atom and optionally further heteroatoms, such as a sulfur or oxygen atom, Xi and X 2 , which are identical or different, are hydrogen - Or halogen atom, a lower alkyl radical, the trifluoromethyl, hydroxyl, benzyl or amino group or the radical of the general formula

(CHJ1Y(CH2)^NHC'(CHJ 1 Y (CH 2 ) ^ NHC '

4545

5050

5555

NHR1 NHR 1

bedeuten oder Xi mit X2 und mindestens zwei Atomen des Ringes A einen weiteren Ring bildet, /und m ganze Zahlen mit einem Wert von 0 bis 4 sind, wobei die Summe von / und m 3 oder 4 beträgt, Y ein Sauerstoffoder Schwefelatom oder die NH-Gruppe, E ein Sauerstoff- oder Schwefelatom oder sofern A so beschaffen ist, daß kein Pyridinring gebildet werden kann, eine NR2-Gruppe, Ri ein Wasserstoffatom, einen niederen Alkylrest, niederen Acylrest oder Dialkylaminoalkylrest und R2 ein Wasserstoffatom die Nitro- oder Cyangruppe bedeutet.or Xi with X 2 and at least two atoms of ring A forms another ring, / and m are integers with a value from 0 to 4, the sum of / and m being 3 or 4, Y an oxygen or sulfur atom or the NH group, E is an oxygen or sulfur atom or, if A is such that a pyridine ring cannot be formed, an NR2 group, Ri is a hydrogen atom, a lower alkyl radical, lower acyl radical or dialkylaminoalkyl radical and R 2 is a hydrogen atom, the nitro or Cyano group means.

Der ungesättigte heterocyclische Ring kann ein Imidazol-, Pyridin-, Thiazol-, Oxazol-, Pyrazol-, Triazoj-, Thiadiazol-, Pyrimidin-, Pyrazin- oder Pyridazinring sein. Die in Beispiel 46 und 47 der BE-PS beschriebenen Guanidinverbindungen sind Histamin-H2-Receptor-Antagonisten, die bei einer Dosis von oberhalb 21 μΜοΙ pro Kilogramm Körpergewicht eine 50prozentige Hemmung der Histamin-stimulierten Säuresekretion des Magens von mit Urethan narkotisierten Ratten bewirken. Die Versuchsmethodik ist von J. W. Black u. Mitarb., Nature, Bd. 236 (1972), S. 385 bis 390, beschrieben. Aus der DE-OS 20 53 179 sind Guanidin-Verbindungen bekannt (vgl. Beispiele 32 bis 52, 63, 64 und 66), deren EDs0 in diesem Test in der Regel etwa 63 bis 128 μΜοΙ pro Kilogramm Körpergewicht beträgt.The unsaturated heterocyclic ring can be an imidazole, pyridine, thiazole, oxazole, pyrazole, triazo, thiadiazole, pyrimidine, pyrazine or pyridazine ring. The guanidine compounds described in Examples 46 and 47 of the BE-PS are histamine H 2 receptor antagonists which, at a dose of above 21 μΜοΙ per kilogram of body weight, cause a 50 percent inhibition of the histamine-stimulated acid secretion of the stomach in rats anesthetized with urethane. The experimental method is described by JW Black et al., Nature, Vol. 236 (1972), pp. 385 to 390. From DE-OS 20 53 179 guanidine compounds are known (see. Examples 32 to 52, 63, 64 and 66) whose EDs 0 in this test is usually about 63 to 128 μΜοΙ per kilogram of body weight.

Antagonisten des Histamins sind seit 1937 bekannt (vgl. D. Bovet und A.-M. Staub, C. R. Seanc. Soc. Biol. Bd. 124 [1937], S. 547). Diese Histamin-Antagonisten oder Antihistaminika sind in der Lage, viele Histaminwirkungen zu blockieren, wie z. B. die bronchokonstriktorische Wirkung, die gefäßpermeabilitätssteigemde Wirkung oder die kontrahierende Wirkung auf das isolierte Meerschweinchenileum. Therapeutisch wird diese Substanzklasse im wesentlichen dazu verwendet, das bei allergischen Reaktionen im Körper freigesetzte oder z. B. durch Brennessel- und Insektenstiche in den Körper gelangte Histamin in seiner Wirkung abzuschwächen. Im Einzelfall können auch nicht durch Histamin-Blockade bedingte Wirkungen (z. B. bei der Reisekrankheit) therapeutisch ausgenutzt werden.Histamine antagonists have been known since 1937 (cf. D. Bovet and A.-M. Staub, C. R. Seanc. Soc. Biol. Vol. 124 [1937], p. 547). These histamine antagonists or antihistamines are capable of many histamine effects to block such. B. the bronchoconstrictor Effect, the effect of increasing the vascular permeability or the contracting effect on the isolated Guinea pig ileum. Therapeutically, this class of substances is essentially used to treat allergic reactions released in the body or z. B. by nettle and insect bites in the Body managed to weaken histamine in its effects. In individual cases, they cannot get through either Effects caused by histamine blockade (e.g. in the case of motion sickness) can be used therapeutically.

Die für die Histaminwirkungen verantwortlichen und durch die von Bovet und Staub entdeckten Antihistaminika hemmbaren Receptoren sind überwiegend in der glatten Muskulatur lokalisiert. Sie tragen nach Ash und Schild (Brit. J. Pharmac. Chemother., Bd. 27 [1966], S. 427) den Namen »Hi-Receptoren«, da auch Histaminwirkungen existieren, die sich nicht durch die klassischen Antihistaminika blockieren lassen:The antihistamines that are responsible for the effects of histamine and that were discovered by Bovet and Staub inhibitable receptors are predominantly located in the smooth muscles. They carry to Ash and Schild (Brit. J. Pharmac. Chemother., Vol. 27 [1966], P. 427) the name "Hi-Receptors", since there are also histamine effects that are not differentiated from the classical Blocking antihistamines:

Stimulierende Wirkung auf das Herz und die Magensekretion und hemmende Wirkung auf die elektrisch stimulierte Kontraktion des Rattenuterus.Stimulating effect on the heart and gastric secretion and inhibiting effect on the electrically stimulated contraction of the rat uterus.

Verbindungen, die diese Wirkungen des Histamins blockieren, werden als Histamin-^-Receptor-Antagonisten bezeichnet (vgl. J. W. Black, W. A. M. Duncan, G. J. Durant, C. R. Ganellin und E. M. Parsons, Nature, Bd. 236 [1972], S. 385 bis 390). Bei der Wirkungsweise dieser Verbindungen handelt es sich um ein neues phamakologisches Prinzip.Compounds that block these effects of histamine are called histamine - ^ - receptor antagonists (cf. J. W. Black, W. A. M. Duncan, G. J. Durant, C. R. Ganellin and E. M. Parsons, Nature, Vol. 236 [1972], pp. 385 to 390). In the way this works Connections is a new phamacological principle.

Der Erfindung liegt die Aufgabe zugrunde, bestimmte Guanidine und ihre Salze mit Säuren zu schaffen, die als Histamin-H2-Receptor-Antagonisten eingesetzt werden können.The invention is based on the object of creating certain guanidines and their salts with acids which can be used as histamine H 2 receptor antagonists.

Die Erfindung betrifft somit den in den Ansprüchen gekennzeichneten Gegenstand.The invention thus relates to the subject matter characterized in the claims.

Die Verbindungen gemäß Anspruch 1 der Erfindung haben in dem vorstehend zitierten Test eine ED50 von weniger als 18 μΜοΙ Kilogramm. Für die meisten der Verbindungen der Erfindung sowie der vorstehend genannten Vergleichsverbindungen ist die lethale Dosis mindestens lOmal höher als die Dosis, bei der die Verbindungen eine signifikante H^-Receptor-Blockerwirkung zeigen.The compounds according to claim 1 of the invention have an ED50 of in the test cited above less than 18 μΜοΙ kilograms. For most of the Compounds of the invention and the aforementioned comparative compounds is the lethal dose at least 10 times higher than the dose at which the Compounds have a significant H ^ receptor blocker effect demonstrate.

Die Salze leiten sich von anorganischen oder organischen Säuren ab, wie Chlorwasserstoffsäure, Bromwasserstoffsäure, Jodwasserstoffsäure, Schwefelsäure, Salpetersäure, Picrinsäure, Maleinsäure, Citronensäure, Apfelsäure, Bernsteinsäure, Weinsäure, Essigsäure, Propionsäure und Oxalsäure.The salts are derived from inorganic or organic acids, such as hydrochloric acid, Hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, picric acid, maleic acid, citric acid, Malic acid, succinic acid, tartaric acid, acetic acid, propionic acid and oxalic acid.

Die Verbindungen der Erfindung können nach üblichen Verfahren hergestellt werden.The compounds of the invention can be prepared by conventional methods.

Zur therapeutischen Anwendung werden die erfindungsgemäßen Guanidine zu üblichen Darreichungsformen, wie Tabletten, Kapseln, Injektionslö: jngen oder Cremes, konfektioniert.For therapeutic use, the guanidines according to the invention are converted into customary dosage forms, such as tablets, capsules, injection solutions or creams, packaged.

Die Beispiele erläutern die Erfindung.The examples illustrate the invention.

Beispiel 1example 1

N-Methyl-N'-[2-((4-methyl-5-imidazolyI)-methylthio)-äthyl]-M"-trifluormethansulfonylguanidin N-methyl-N '- [2 - ((4-methyl-5-imidazolyI) -methylthio) -ethyl] -M "-trifluoromethanesulfonylguanidine

(a) Ein Gemisch von 4,2 g Trifluormethylsulfonamid und 7,6 g Bis-(methylthio)N-methylformimin wird 4 Stunden auf 1200C erhitzt Nach dem Abkühlen und anschließender Zugabe von Hexan werden 5 g(a) A mixture of 4.2 g Trifluormethylsulfonamid and 7.6 g of bis (methylthio) N-methylformimin is 4 hours at 120 0 C heated After cooling and subsequent addition of hexane, 5 g of

N.S-Dimethyl-N'-trifluormethansulfonylisothioharnstoff vom F. 88 bis 89° C erhalten.N.S-Dimethyl-N'-trifluoromethanesulfonylisothiourea obtained from m.p. 88 to 89 ° C.

(b) Eine Lösung von 3,54 g 5-[(2-Aminoäthyl)-thiomethyl]-4-methyIimidazol und 4,9 g N,S-Dimethyl-N'-trifluormethansulfonylisothioharnstoff in 50 ml Äthanol wird 24 Stunden unter Rückfluß erhitzt. Nach dem Eindampfen und chromatographischer Reinigung an Kieselgel mit Äthylacetat/Äthanol (4:1) als Elutionsmittel werden 2,8 g der Titelverbindung in Form eines Glases erhalten. Die Analyse bestätigt die Summenformel (b) A solution of 3.54 g of 5 - [(2-aminoethyl) thiomethyl] -4-methylimidazole and 4.9 g of N, S-dimethyl-N'-trifluoromethanesulfonylisothiourea in 50 ml of ethanol is refluxed for 24 hours. After evaporation and chromatographic purification on Silica gel with ethyl acetate / ethanol (4: 1) as the eluent gives 2.8 g of the title compound in the form of a Preserved glass. The analysis confirms the empirical formula

C10H16F^N5O2S2.C 10 H 16 F 1 N 5 O 2 S 2 .

Beispiel 2Example 2

N-(4-Chlorbenzolsulfonyl)-N'-methyl-N- (4-chlorobenzenesulfonyl) -N'-methyl-

N"-[2-((4-methyl-5-imidazoIy])-methylthio)-N "- [2 - ((4-methyl-5-imidazoIy]) - methylthio) -

äthyl]-guanidinethyl] guanidine

(a) Ein Gemisch von 6 g 4-Chlorbenzolsulfonamid und 8,5 g Bis-(methylthio)N-methylformimin wird 4 Stunden auf 120 bis 125° C erhitzt. Ausbeute 5,8 g N-(4-Chlorbenzolsulfonyl)-N',S-dimethylisothioharnstoff vom F. 121 bis 123° C.(a) A mixture of 6 g of 4-chlorobenzenesulfonamide and 8.5 g of bis (methylthio) N-methylformimine are heated to 120 to 125 ° C. for 4 hours. Yield 5.8 g of N- (4-chlorobenzenesulfonyl) -N ', S-dimethylisothiourea from 121 to 123 ° C.

(b) Eine Lösung von 3,33 g 5-[(2-Aminoäthyl)-thiomethyl]-methyl-imidazol und 5,4 g N-(4-ChlorbenzolsulfonyI)-N',S-dimethylisothioharnstoff in Acetonitril wird 24 Stunden unter Rückfluß gekocht. Nach dem Eindampfen und Umkristallisieren aus wäßrigem Äthanol werden 4,6 g der Titelverbindung vom F. 153 bis 154° C erhalten.(b) A solution of 3.33 g of 5 - [(2-aminoethyl) thiomethyl] methyl imidazole and 5.4 g of N- (4-chlorobenzenesulfonyl) -N ', S-dimethylisothiourea in acetonitrile Boiled under reflux for 24 hours. After evaporation and recrystallization from aqueous Ethanol, 4.6 g of the title compound of F. 153 up to 154 ° C.

Beispiel 3Example 3

N-(3,4-Dichlorbenzolsulfonyl)-N'-methyl-N- (3,4-dichlorobenzenesulfonyl) -N'-methyl-

N"-[2-((4-methyl-5-imidazolyl)-methylthio)-N "- [2 - ((4-methyl-5-imidazolyl) -methylthio) -

äthyl]-guanidinethyl] guanidine

(a) Ein Gemisch von 6,5 g 3,4-Dichlorbenzolsulfonämid und 8,0 g Bis(-methylthio-)N-methylformimin wird 4 Stunden auf 120°C erhitzt. Nach Umkristallisation aus Methanol werden 7,3 g N-(3,4-Dichlorbenzolsulfonyl)-N',S-dimethylisothioharnstoff vom F. 158 bis 159° C erhalten.(a) A mixture of 6.5 grams of 3,4-dichlorobenzenesulfonemide and 8.0 g of bis (-methylthio-) N-methylformimine is heated to 120 ° C. for 4 hours. After recrystallization from Methanol is 7.3 g of N- (3,4-dichlorobenzenesulfonyl) -N ', S-dimethylisothiourea obtained from m.p. 158 to 159 ° C.

(b) Eine Lösung von 3,49 g 5-((2-Aminoäthyl)-thiomethyl)-4-methyl-imidazol und 6,20 g N-(3,4-Dichlorbenzolsulfonyl)-N',S-dimethylisothioharnstoff in 250 ml Acetonitril wird 48 Stunden unter Rückfluß erhitzt. Nach dem Eindampfen und anschließender chromatographischer Reinigung an Aluminiumoxid und Eluieren mit Benzol/Äthylacetat (1 :4) und hierauf mit Benzol/(b) A solution of 3.49 g of 5 - ((2-aminoethyl) thiomethyl) -4-methyl-imidazole and 6.20 g of N- (3,4-dichlorobenzenesulfonyl) -N ', S-dimethylisothiourea in 250 ml Acetonitrile is refluxed for 48 hours. After evaporation and subsequent chromatographic Purification on aluminum oxide and elution with benzene / ethyl acetate (1: 4) and then with benzene /

Äthanol (1:4) werden 1,7 g der Titelverbindung in Form eines Glases erhalten. Die Analyse bestätigt die SummenformelEthanol (1: 4) 1.7 g of the title compound are obtained in the form of a glass. The analysis confirms that Molecular formula

Ci5H19N5Cl2O2S2.Ci 5 H 19 N 5 Cl 2 O 2 S 2 .

Beispiel 4Example 4

N-Benzolsulfonyl-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)-methylthio)äthyl]-guanidin N-benzenesulfonyl-N'-methyl-N "- [2 - ((4-methyl-5-imidazolyl) -methylthio) ethyl] -guanidine

Eine Lösung von 13 g N-Benzolsulfonyliminodithiocarbonsäuredimethylester und 8,5 g 5-[(2-Aminoäthyl)-thiomethyl]-4-methyl-imidazol in 100 ml Äthanol wird 4 Stunden bei Raumtemperatur gerührt, dann mit einer Lösung von Methylamin in Äthanol im Überschuß versetzt und weitere 2 Stunden bei Raumtemperatur gerührt. Nach dem Eindampfen wird der Rückstand in Äthanol/Äther (1:1) gelöst. Nach dem Abkühlen werden 15,0 g der Titelverbindung erhalten, die aus Wasser umkristallisiert wird; F. 156,5 bis 157,5° C.A solution of 13 g of dimethyl N-benzenesulfonyliminodithiocarboxylate and 8.5 g of 5 - [(2-aminoethyl) thiomethyl] -4-methyl-imidazole in 100 ml of ethanol is 4 Stirred for hours at room temperature, then with a solution of methylamine in ethanol in excess added and stirred for a further 2 hours at room temperature. After evaporation, the residue is in Ethanol / ether (1: 1) dissolved. After cooling, 15.0 g of the title compound are obtained Water is recrystallized; F. 156.5 to 157.5 ° C.

Beispiel 5Example 5

N-MethyI-N'-[2-((4-methyl-5-imidazolyl)-methylthio)-äthyl]-N"-n-propansulfonylguanidin N-Methyl-N '- [2 - ((4-methyl-5-imidazolyl) -methylthio) -ethyl] -N "-n-propanesulfonylguanidine

(a) Eine Lösung von 13,5 g n-Propansulionamid in 75 ml Dimethylformamid wird bei 4°C mit 3,6 ml Schwefelkohlenstoff und einer Lösung von 4,45 g Natriumhydroxid in 6 ml Wasser versetzt und 10 Minuten bei 5° C gerührt. Hierauf werden weitere 2,2 g Natriumhydroxid in 3 ml Wasser und 1,5 ml Schwefelkohlenstoff zugegeben, und das Gemisch wird 10 Minuten gerührt. Die letzte Zugabe von Natriumhydroxid und Schwefelkohlenstoff wird wiederholt, und nach weiteren 10 Minuten werden bei 5° C 42,6 g Methyljodid ohne äußere Kühlung hinzugefügt. Das Gemisch wird 2 Stunden gerührt, in 750 ml Wasser eingegossen und mit Äther extrahiert. Nach dem Eindampfen wird vorher N-n-Propansulfonyliminodiihiocarbonsäuredimethylester erhalten, der aus Äthanol/Hexan umkristallisiert wird; F. 73 bis 74°C.(a) A solution of 13.5 g of n-propanesulionamide in 75 ml of dimethylformamide is mixed with 3.6 ml of carbon disulfide and a solution of 4.45 g at 4 ° C Sodium hydroxide in 6 ml of water was added and the mixture was stirred at 5 ° C. for 10 minutes. This is followed by a further 2.2 g Sodium hydroxide in 3 ml of water and 1.5 ml of carbon disulfide are added and the mixture becomes 10 Minutes stirred. The final addition of sodium hydroxide and carbon disulfide is repeated, and gradually 42.6 g of methyl iodide are added at 5 ° C. for a further 10 minutes without external cooling. The mixture is 2 Stirred for hours, poured into 750 ml of water and extracted with ether. After evaporation is before N-n-propanesulfonyliminodiihiocarboxylic acid dimethyl ester obtained, which is recrystallized from ethanol / hexane; M.p. 73 to 74 ° C.

(b) Eine Lösung von 4,7 g N-n-Propylsulfonyliminodithiocarbonsäuredimethylester und 3,5 g 5-[(2-Amino-(b) A solution of 4.7 g of dimethyl N-n-propylsulfonyliminodithiocarboxylate and 3.5 g of 5 - [(2-amino-

äthyl)-thiomethyl]-4-methyl-imidazol in 50 ml Äthanol wird 3 Stunden bei Raumtemperatur gerührt, dann mit einer Lösung von Methylamin in Äthanol im Überschuß versetzt und weitere 3 Stunden bei Raumtemperatur gerührt. Nach dem Eindampfen und Digerieren mit Eiswasser wird die Titelverbindung als Rohprodukt erhalten.ethyl) thiomethyl] -4-methyl-imidazole in 50 ml of ethanol is stirred for 3 hours at room temperature, then with a solution of methylamine in ethanol in excess and a further 3 hours at room temperature touched. After evaporation and digestion with ice water, the title compound is obtained as a crude product obtain.

Nach chromatographischer Reinigung an Kieselgel mit Äthylacetat/Äthanol (4:1) als Eluierungsmittel werden 5,0 g der Titelverbindung in Form eines Glases erhalten. Die Analyse bestätigt die Summenformel
C12H23N5O2S2 (+ 5 Prozent C2H5OH).After purification by chromatography on silica gel with ethyl acetate / ethanol (4: 1) as the eluent, 5.0 g of the title compound are obtained in the form of a glass. The analysis confirms the empirical formula
C 12 H 23 N 5 O 2 S 2 (+ 5 percent C 2 H 5 OH).

B e i s ρ i e I 6B e i s ρ i e I 6

N-Methyl-N'-[2-((4-methyl-5-imidazolyl)-methylthio)-äthyl]-N"-p-toluolsulfonylguanidin N-methyl-N '- [2 - ((4-methyl-5-imidazolyl) -methylthio) -ethyl] -N "-p-toluenesulfonylguanidine

Gemäß Beispiel 4 werden 10 g N-p-ToluolsuIfonyliminodithiocarbonsäuredimethylester mif 6,2 g 5-[(2-Aminoäthyl)-thiomethyl]-4-methyl-imidazol und Methylamin umgesetzt. Ausbeute 5,5 g der Titelverbindung vom F. 137,5 bis 138,5° C (Äthanol/Äther).According to Example 4, 10 g of N-p-toluene sulfonyliminodithiocarboxylic acid dimethyl ester with 6.2 g of 5 - [(2-aminoethyl) thiomethyl] -4-methyl-imidazole and methylamine implemented. Yield 5.5 g of the title compound with a melting point of 137.5 to 138.5 ° C. (ethanol / ether).

Beispiel 7Example 7

N-[2-((4-MethyI-5-imidazolyl)-methy]thio)-äthyl]-N'-sulfamylguanidin N- [2 - ((4-MethyI-5-imidazolyl) -methy] thio) -ethyl] -N'-sulfamylguanidine

(a) Eine Lösung von 19,0 g 5-[(2-aminoäthyl)-thiomethyl]-4-methyl-imidazoI und 15,1 g S-Methylisothioharnstoff-sulfat in 100 ml Wasser v.;ird 3 Stunden unter Rückfluß erhitzt Nach dem Eindampfen, Ansäuern mit Schwefelsäure und Verdünnen mit Äthanol werden 13,0 g 2-[(4-MethyI-5-imidazolyl)-rnethylthio)-äthyiiguantfin-sulfat vom F. 230 bis 235° C erhalten.(a) A solution of 19.0 g of 5 - [(2-aminoethyl) thiomethyl] -4-methyl-imidazoI and 15.1 g of S-methylisothiourea sulfate in 100 ml of water; ird for 3 hours After evaporation, acidification with sulfuric acid and dilution with ethanol 13.0 g of 2 - [(4-MethyI-5-imidazolyl) methylthio) ethyiiguantfin sulfate obtained from m.p. 230 to 235 ° C.

(b) 10 g des erhaltenen Guanidinsulfats werden zu einer Lösung von 1,53 g Natrium in 100 ml Äthanol gegeben. Nach dem Filtrieren und Eindampfen wird die Guanidinbase erhalten, die in 20 ml Dimethylsulfoxid gelöst und langsam zu einer Lösung von 5,3 g N-Piperidylsulfamid in 10 ml Dimethylsulfoxid gegeben. Das Gemisch wird 2 Stunden auf einem Dampfbad erhitzt und dann unter vermindertem Druck eingedampft. Der Rückstand wire an KiestJgel mit Äthylacetat/Äthanol (3 :2) als ElutionsmitteJ Chromatographien. Ausbeute 2,38 g der Titelverbindung, die aus Wasser und dann aus Methanoi/Äther umkristallisiert wird; F. 130 bis 133° C.(b) 10 g of the guanidine sulfate obtained are added to a solution of 1.53 g of sodium in 100 ml of ethanol given. After filtering and evaporation, the guanidine base is obtained, which is dissolved in 20 ml of dimethyl sulfoxide dissolved and slowly added to a solution of 5.3 g of N-piperidyl sulfamide in 10 ml of dimethyl sulfoxide. The mixture is heated on a steam bath for 2 hours and then evaporated under reduced pressure. The residue wire on gravel with ethyl acetate / ethanol (3: 2) as the elution agent. Chromatographs. Yield 2.38 g of the title compound from water and then recrystallized from methanoi / ether; F. 130 to 133 ° C.

Beispiel 8Example 8

N-Methyl-N'-[2-((4-methyl-5-imidazolyl)-methyI-thio)-äthy!]-N"-sulfamylguanidin N-methyl-N '- [2 - ((4-methyl-5-imidazolyl) -methyI-thio) -ethy!] - N "-sulfamylguanidine

(a) Eine Lösung von 2,0 g N-Cyan-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)-methylthio)-äthyl]-gua nidin in 25 ml Salzsäure wird auf einem Dampfbad 2 Stunden erhitzt Nach dem Eindampfen und Umkristallisieren aus Äthanol/Äther werden 1,44 g N-Methyl-N"-[2-((4-methyI-5-imidazolyl)-methylthio)-äthy]]-guanidindihydrochlorid vom F. 204 bis 2060C erhalten.(a) A solution of 2.0 g of N-cyano-N'-methyl-N "- [2 - ((4-methyl-5-imidazolyl) methylthio) ethyl] guanidine in 25 ml of hydrochloric acid is added heated in a steam bath for 2 hours. After evaporation and recrystallization from ethanol / ether, 1.44 g of N-methyl-N "- [2 - ((4-methyI-5-imidazolyl) -methylthio) -ethy]] - guanidine dihydrochloride from F 204 to 206 0 C was obtained..

(b) 3,0 g des erhaltenen Guanidindihydrochlorids wenden zu einer Lösung von 0,46 g Natrium in 50 ml Äthanol gegeben. Das Gemisch wird 30 Minuten erwärmt und gerührt, danach gekühlt, filtriert und mit 1,64 g N-Piperidylsulfamid versetzt. Das Gemisch wird 24 Stunden unter Rückfluß gekocht und sodann eingedampft Der Rückstand wird zuerst an Kieselgel mit Äthylacetat/Äthanol {4 :1) als Elutionsmittel und dann an Aluminiumoxid mit dem gleichen Elutionsmittel chromatographiert Ausbeute i,05 g der Titelverbindung in Form eines Glases Die Analyse bestätigt die Summenformel(b) 3.0 g of the guanidine dihydrochloride obtained turn into a solution of 0.46 g of sodium in 50 ml Given ethanol. The mixture is heated and stirred for 30 minutes, then cooled, filtered and with 1.64 g of N-piperidylsulfamide are added. The mixture is refluxed for 24 hours and then The residue is first evaporated on silica gel with ethyl acetate / ethanol {4: 1) as the eluent and then chromatographed on aluminum oxide with the same eluent. Yield 1.05 g of the title compound in the form of a glass The analysis confirms the empirical formula

C9Hi8N6O2S2 ( + 3 Prozent C2H5OH).C 9 Hi 8 N 6 O 2 S 2 (+ 3 percent C 2 H 5 OH).

Beispiel SExample p

N-(4-Aminobenzolsulfonyl)-N'-methyl-N"-N- (4-aminobenzenesulfonyl) -N'-methyl-N "-

[2-(4-methyl-5-imidazolyI)-methylthio)-äthyl]-[2- (4-methyl-5-imidazolyI) -methylthio) -ethyl] -

guanidinguanidine

(a) Gemäß Beispiel 5 werden 17,2 g 4-Aminobenzolsulfonamid mit Natriumhydroxid, Schwefelkohlenstoff und Methyljodid umgesetzt. Ausbeute 9,4 g N-(4-Ami-(a) According to Example 5, 17.2 g of 4-aminobenzenesulfonamide are obtained reacted with sodium hydroxide, carbon disulfide and methyl iodide. Yield 9.4 g of N- (4-ami-

nobenzolsulfonyty-iminodithiocarbonsäuredimethylester vom F. 202 bis 2040C (Äthanol).nobenzolsulfonyty-iminodithiocarbonsäuredimethylester mp 202 to 204 0 C (ethanol).

(b) Gemäß Beispiel 5 werden 8,9 g N-(4-Aminoben-2 <) zolsulfonylj-iminodithiocarbonsäuredimethylester mit 5,5 g 5-[(2-Arninoäthyl)-mercaptomethy]]-4-methy)-imidazol und Methylamin umgesetzt Nach chromatographischer Reinigung an Aluminiumoxid mit Äthylacetat/Äthanol (4:1) als Elutionsmittel wird die Titelverbindung in Form eines Glases erhalten. Die Analyse bestätigt die Summenformel
CH22N6O2Ss.(b) As in Example 5, 8.9 g of N- (4-aminoben-2 <) zolsulfonyl-iminodithiocarboxylic acid dimethyl ester with 5.5 g of 5 - [(2-aminoethyl) mercaptomethyl]] - 4-methy) imidazole and methylamine reacted After chromatographic purification on aluminum oxide with ethyl acetate / ethanol (4: 1) as the eluent, the title compound is obtained in the form of a glass. The analysis confirms the empirical formula
CH 22 N 6 O 2 Ss.

Beispiel 10Example 10

N-Carbamyl-N'-methyI-N"-[2-((4-methyl-5-imidazolyl)-methylthio)-äthyl]-guanidin-dihydrochlorid N-carbamyl-N'-methyl-N "- [2 - ((4-methyl-5-imidazolyl) methylthio) ethyl] guanidine dihydrochloride

Eine Lösung von 1,25 g N-Cyan-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)-methylthio)-äthyl]-guanidin in 15 ml 1 η Salzsäure wird 60 Stunden bei Raumtemperatur stehengelassen und hierauf 20 Stunden auf 40 bis 45°C erwärmt. Nach dem Eindampfen wird die Base mit Natriumäthylat in Äthanol freigesetzt und an Kieselgel mit Isopropanol als Elutionsmittel chromalographiert.A solution of 1.25 g of N-cyano-N'-methyl-N "- [2 - ((4-methyl-5-imidazolyl) -methylthio) -ethyl] -guanidine in 15 ml of 1 η hydrochloric acid is 60 hours at room temperature left to stand and then heated to 40 to 45 ° C. for 20 hours. After evaporation, the base is with Sodium ethylate is released in ethanol and chromalographed on silica gel with isopropanol as the eluent.

•40 Nach dem Ansäuern mit einer Lösung von Chlorwasserstoff in Äthanol und anschließender Umkristallisation aus Isopropanol werden 0,60 g der Titelverbindung vom F. 186 bis 187°C erhalten.• 40 After acidification with a solution of hydrogen chloride in ethanol and subsequent recrystallization from isopropanol, 0.60 g of the title compound are dated M.p. 186 to 187 ° C.

Claims (1)

Patentansprüche:Patent claims: LS-MethylimidazoM-ylmethylthioäthylguanidine der allgemeinen Formel ILS-methylimidazoM-ylmethylthioethylguanidine of the general formula I. N-XN-X CH3 CH2-S-CH2-CK2-NH-C )0 CH 3 CH 2 -S-CH 2 -CK 2 -NH-C ) 0 NH-CH3 HN NNH-CH 3 HN N (D(D
DE2344833A 1972-09-05 1973-09-05 5-Methylimidazol-4-ylmethylthioethylguanidines and their use as histamine H 2-receptor antagonists Expired DE2344833C2 (en)

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US4165378A (en) 1977-04-20 1979-08-21 Ici Americas Inc. Guanidine derivatives of imidazoles and thiazoles
NZ186965A (en) 1977-04-20 1980-02-21 Ici Ltd Guanidino derivatives and pharmaceutical compositions
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DE2835695A1 (en) 1977-08-29 1979-03-15 Yamanouchi Pharma Co Ltd NEW HETEROCYCLIC COMPOUNDS, METHODS OF MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM
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DE3108753A1 (en) * 1981-03-07 1982-09-16 Degussa Ag, 6000 Frankfurt Substituted alkylphenylsulphonylguanidines with a heterocyclic radical
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