DE2344779B2 - N-Cyan-N'-methyl-N"- {2- [(5- methyl-imidazol-4yl)-methylthio] -äthylj -guanidin, seine Salze mit Säuren und seine Verwendung als Histamin -H2 -Receptor-Antagonist - Google Patents

N-Cyan-N'-methyl-N"- {2- [(5- methyl-imidazol-4yl)-methylthio] -äthylj -guanidin, seine Salze mit Säuren und seine Verwendung als Histamin -H2 -Receptor-Antagonist

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DE2344779B2
DE2344779B2 DE2344779A DE2344779A DE2344779B2 DE 2344779 B2 DE2344779 B2 DE 2344779B2 DE 2344779 A DE2344779 A DE 2344779A DE 2344779 A DE2344779 A DE 2344779A DE 2344779 B2 DE2344779 B2 DE 2344779B2
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methyl
histamine
cyano
salts
acids
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DE2344779A1 (de
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Graham John Welwyn Garden City Durant
John Colin Codicote Emmett
Charon Robin Welwyn Garden City Ganellin
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Smith Kline and French Laboratories Ltd
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  • Pyridine Compounds (AREA)
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  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
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Description

(CH2), Y(CH2)mNHC
NHR1
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 Wasserstoffatoni, einen niederen Alkylrest, niederen Acylrest oder Dialkylaminoalkylrest und R2 ein Wasserstoffatom, die Nitro- oder Cyangruppe bedeutet.
Der ungesättigte heterocyclische Ring kann ein Imidazol-, Pyridin-, Thiazol-, Oxazol-, Pyrazol-, Triazol-, Thiadiazol-, Pyrimidin-. Pyrazin- oder Pyridazinring sein. Unter die vorstehend angegebene allgemeine Formel fallen auch Cyanguanidine. Die in dieser Patentschrift beschriebenen Verbindungen sind Antagonisten von Histamin-H2-Receptoren oder ^-Receptor-Blockern mit einer ED50, die im allgemeinen oberhalb 100 Mikromol pro Kilogramm Körpergewicht liegt.
Antagonisten des Histamins sind seit 1937 bekannt (vgl. D. Bovet und A.-M. Staub, CR. Seanc. Soc. Biol., Bd. 124 [1937], S. 547). Diese Histamin-Antagonisten oder Antihistaminika sind in der Lage, viele Histaminwirkungen zu blockieren, wie z. B. diebronchokonstriktorische Wirkung, die gefäßpermeabilitätsstei-
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, X| 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 Formel
gernde 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.
Die für die Histaminwirkungen verantwortlichen und durch die von Bovet und Staub entdeckten Antihistaminika hemmbaren Receptoren sind überwiebend in der glatten Muskulatur lokalisiert. Sie tragen nach Ash und Schild (Brit. J. Pharmac. Chemother, Bd. 27 [1966], S. 427) den Namen »H,-Receptoren«, da auch Histaminwirkungen existieren, die sich nicht durch die klassischen Antihistaminika blockieren lassen: Stimulierende Wirkung auf das Herz und die Magensekretion und hemmende Wirkung auf die elektrisch stimulierte Kontraktion des Rattenuterus.
Verbindungen, die diese Wirkungen des Histamins blockieren, werden als Histamin-HrReceptor-Antagonisten bezeichnet (vgl. J. W. Black, W. A. M. Duncan, G. J. Durant, CR. Ganellin und E. M. Parsons, Nature, Bd. 236 [1972], S. 385 bis 390). Bei der Wirkungsweise dieser Verbindungen handelt es sich um ein neues pharmakologisches Prinzip.
Die vorstehend erwähnte BE-PS 7 79 775 beschreibt Verbindungen, die wertvolle H2-Receptor-Blocker darstellen. Beispielsweise hemmen sie selektiv die Pentagastrin- und Histamin-stimulierte Säuresekretion des Magens, ferner die Histaminwirkungen am Meerschweinchenvorhof und am Rattenvorhof.
Viele der Verbindungen bewirken bei einer Dosis von weniger als 80 Mikromol pro Kilogramm Körpergewicht eine 50prozentige Hemmung der Histamin-stimulierten Säuresekretion des Magens von mit Urethan narkotisierten Ratten. Die Versuchsmethodik ist von J. W. B1 a c k u. Mitarb., Nature, Bd. 236 (1972), S. 385 bis 390, beschrieben. Für die meisten der in den Beispielen aufgeführten Verbindungen der Erfindung ist die letale Dosis mindestens lOmal höher als die Dosis, bei der die Verbindungen eine signifikante HrReceptor-Blockerwirkung zeigen.
Der Erfindung liegt die Aufgabe zugrunde, ein bestimmtes Cyanguanidin und seine Salze mit Säuren zu schaffen, das als Histamin-H2-Receptor-Antagonist eingesetzt werden kann.
Überraschenderweise wurde gefunden, daß das
N-Cyan-N'-methyl-N"-|2-[(5-methylimidazol-4-yl)-methylthio]-äthyl)-guanidin
(nachstehend kurz mit Cimetidine bezeichnet) der Formel
CH3 CH2SCH2Ch2NHCNHCH3
HN N
sich durch eine wesentlich bessere Wirksamkeit auszeichnet als die bekannten Verbindungen.
Die Erfindung betrifft somit den in den Ansprüchen gekennzeichneten Gegenstand.
Die Salze leiten sich von anorganischen oder organischen Säuren ab, wie Chlorwasserstoffsäure, Bromwasserstoffsäure, Jodwasserstoffsäure, Schwefel-
säure. Salpetersäure, Pikrinsäure, Maleinsäure, Citronensäure, Äpfelsäure, Bernsteinsäure, Weinsäure, Essigsäure, Propionsäure und Oxalsäure.
Die Verbindung der Erfindung kann nach üblichen Methoden hergestellt werden.
In der nachstehenden Tabelle ist die Wirkung verschiedener S-MethylimidazoM-yl-methylthioverbindungen als Antagonisten der durch Histamin bewirkten Reizung des rechten Vorhofes von Meerschweinchenherzen zusammengestellt. Die Dissoziationskonstante Kb wird nach der Gleichung Kb = B/(x— 1) berechnet, wobei χ das Verhältnis der Konzentrationen von Histamin ist, das zur Erzeugung halbmaxiinaler Reaktionen in Gegenwart oder Abwesenheit unterschiedlicher Konzentrationen (B) des Antagonisten notwendig ist.
Tabelle
CH3 CH2SCh2CH2NHCNHCH3
HN N
Verbindung
Antagonistische Aktivität
KB (95-%-Vertrau-
ensgrenze)
χ10~6 M
Metamide
(Bsp. 2 der BE-PS
7 79 775)
Cimetidine
(erfindungsgemäß)
N · CN 0,79 (0,68-0,92)
Die akute Toxizität beider Verbindungen ist mindestens lOmal höher als die Dosis, bei der die Verbindung eine signifikante H2-Receptor-Blockerwirkung zeigt.
Beispiel
N-Cyan-N'-methyI-N"-{2-[(5-methylimidazol-4-yl)-methylthio]-äthyllguanidin
(a) Eine Lösung von 17 g 5-Methyl-4-[(2-aminoäthyl)-thiomethyl]-imidazol und 11,2g N-Cyan-N'.S-dimethylisothioharnstoff in 500 ml Acetonitril wird 24 Stunden unter Rückfluß erhitzt. Nach dem Einengen und anschließendem Chromatographieren des Rückstandes an Kieselgel mit Acetonitril als Elutinnsmittel erhält man die Titelverbindung, die aus Acetonitril/Äther umkrisiallisiertwird;F. 141 bis 142°C.
(b) Eine Lösung von 2,44 g N-Methyl-N'-[2-(5-methyI-imidazol-4-yI)-methylthio)-äthyl]-thioharnstoff in 50 ml Acetonitril wird mit 3 g Bleicyanamid versetzt Nach
ίο Zugabe von 20 ml Dimethylformamid wird die Suspension 24 Stunden unter Rückfluß erhitzt und gerührt. Nach dem Abfiltrieren und Eindampfen unter vermindertem Druck wird die erhaltene Verbindung an Kieselgel mit Acetonitril als Elutionsmittel chromatographisch gereinigt und umkristallisierL Man erhält die Titelverbindung vom F. 139 bis 141°C.
(c) (i) Eine Lösung von 23,4 g 5-Methyl-4-[(2-aminoäthyl)-thiomethyl]-imidazol in Äthanol wird bei Raumtemperatur langsam untei Rühren zu einer Lösung von 20 g Dimethylcyandithioimidocarbonat in Äthanol gegeben. Das Gemisch wird 15 bis 18 Stunden bei Raumtemperatur stehengelassen. Nach dem Abfiltrieren werden 10,0 g N-Cyan-N'-|2-[(5-methylimidazoI-4-yl)-methylthio]-äthyl)-S-methylisothioharnstoff vom F.
148 bis 1500C ei halten. Das Filtrat wird unter vermindertem Druck eingeengt, der Rückstand mit kaltem Wasser digeriert und der erhaltene Niederschlag abfiltriert und zweimal aus Isopropanol/Äther umkristallisiert. Es werden weitere 27 g Produkt vom F. 148 bis 150°C erhalten.
(ii) 75 m! einer 33prozentigen Methylaminlösung in Äthanol werden zu einer Lösung von 10,1 g des erhaltenen Methylisothioharnstoffes in 30 ml Äthanol gegeben. Das Reaktionsgemisch wird bei Raumtemperatur 2'/2 Stunden stehengelassen. Nach dem Eindampfen unter vermindertem Druck wird der Rückstand zweimal aus Isopropanol/Petroläther umkristallisiert. Ausbeute 8,6 g der Titelverbindung vom F. 141 bis 1430C.
(d) Eine Lösung von 1,93 g 5-Methyl-4-[(2-aminoäthyl)-thiomethyl]-imidazol und 1,65 g Dimethylcyandithioimidocarbonat in 33 ml Äthanol wird 15 bis 18 Stunden bei Raumtemperatur stehengelassen. Die Lösung wird niit 22 ml einer 33prozentigen Methyl-
aminlösung in Äthanol versetzt und 4 Stunden stehengelassen. Nach dem Eindampfen und Umkristallisieren aus Isopropanol/Äther werden 2 g der Titelverbindung vom F. 139 bis 1400C erhalten.

Claims (2)

  1. Patentansprüche:
    l.N-Cyan-N'-methyl-N"-[2-[(5-methyI-imidaj:ol-4-yl)-meihylthio]-äthyl|-guanidin
    und seine Salze mit Säuren.
  2. 2. Verwendung von N-Cyan-N'-methyl-N"-l2-[(5-methylimidazol-4-yl)-methylthio]-äthyl)-guanidin und seinen Salzen mit Säuren als Histamin-H2-Receptor-Antagonist.
    Aus den am 24. August 1972 ausgelegten Unterlagen der BE-PS 7 79 775 sind Harnstoffderivate und ihre Salze mit Säuren der allgemeinen Formel
    C—(CH2), Y(CH2)mNH—C
    NHR1
DE2344779A 1972-09-05 1973-09-05 N-Cyan-N'-methyl-N''-${2-[(5-methyl-imidazol-4-yl)-methylthio]-äthyl}-guanidin, seine Salze mit Säuren und seine Verwendung als Histamin-H↓2↓-Receptor-Antagonist Expired DE2344779C3 (de)

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GB4116072A GB1397436A (en) 1972-09-05 1972-09-05 Heterocyclic n-cyanoguinidines
GB615473 1973-02-08

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DE2344779B2 true DE2344779B2 (de) 1979-04-26
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DE (1) DE2344779C3 (de)
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GB (1) GB1397436A (de)
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EP0213571A3 (de) * 1985-09-04 1988-10-19 BASF Aktiengesellschaft 3-Aminomethylpyrrol-1-yl-alkylamine und diese Verbindungen enthaltende therapeutische Mittel

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EP0213571A3 (de) * 1985-09-04 1988-10-19 BASF Aktiengesellschaft 3-Aminomethylpyrrol-1-yl-alkylamine und diese Verbindungen enthaltende therapeutische Mittel

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SG28676G (en) 1987-04-03
MY7600229A (en) 1976-12-31
US3897444A (en) 1975-07-29
US3876647A (en) 1975-04-08
HK55276A (en) 1976-09-17
CA1045142A (en) 1978-12-26
FR2199467A2 (de) 1974-04-12
NL187240C (nl) 1991-07-16
JPS4975574A (de) 1974-07-20
NL7312198A (de) 1974-03-07
KE2626A (en) 1976-05-28
CY855A (en) 1976-09-10
GB1397436A (en) 1975-06-11
IE38353L (en) 1974-03-05
DE2344779A1 (de) 1974-03-14
FR2199467B2 (de) 1977-01-28
AU5890373A (en) 1975-02-06
DE2344779C3 (de) 1981-05-27
AU472456B2 (en) 1976-05-27
IE38353B1 (en) 1978-03-01
JPS561309B2 (de) 1981-01-13

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