DE2344779C3 - N-Cyan-N'-methyl-N''-${2-[(5-methyl-imidazol-4-yl)-methylthio]-äthyl}-guanidin, seine Salze mit Säuren und seine Verwendung als Histamin-H↓2↓-Receptor-Antagonist - Google Patents
N-Cyan-N'-methyl-N''-${2-[(5-methyl-imidazol-4-yl)-methylthio]-äthyl}-guanidin, seine Salze mit Säuren und seine Verwendung als Histamin-H↓2↓-Receptor-AntagonistInfo
- Publication number
- DE2344779C3 DE2344779C3 DE2344779A DE2344779A DE2344779C3 DE 2344779 C3 DE2344779 C3 DE 2344779C3 DE 2344779 A DE2344779 A DE 2344779A DE 2344779 A DE2344779 A DE 2344779A DE 2344779 C3 DE2344779 C3 DE 2344779C3
- Authority
- DE
- Germany
- Prior art keywords
- methyl
- histamine
- cyano
- methylthio
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/32—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/26—Radicals substituted by sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
Aus den am 24. August 1972 ausgelegten Unterlagen ts
der BE-PS 7 79 775 sind Harnstoffderivate und ihre Salze mit Säuren der allgemeinen Formel
-(CH2), Y(CH2LNH-C
NHR1
20
25
bekannt, 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 AlkylresLdieTrifluormethyl-, Hydroxyl-,
Bsczyl- oder Aminogruppe oder den Rest der
allgemeinen Formel
J5
(CH2), Y(CH2)mNHC
NHR1
40
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 Sauerstoff- oder Schwefelatom oder die NH-Gruppe, E ein
Sauei stoff- oder Schwefelatom oder sofern A so beschaffen ist. daß kein Pyridinring gebildet werden
kann, eine NRj-Gruppe. Ri ein Wasserstoffatom, einen
niederen Alkylrest, niederen Acylrest oder Dialkylami- in
noalkylrest und R2 ein Wasserstoffatom, die Nitro· oder
Cyangruppe bedeutet.
Der ungesättigte heterocyclische Ring kann ein
Imidazol-. Pyridin-. Thiazol-, O-.azol-. Pyrazol-. Triazol-.
Thiadiazol-, Pyrimidin-, Pyrazin· oder Pyridazinring
sein. Unter die vorstehend angegebene allgemeine Formel fallen auch Cyanguanidin^
Antagonisten des Histamins sind seit 1937 bekannt
(vgl D Bovet und A.-M. Staub. CR. Seanc. Soc.
Biol., Bd. 124 [IS37], S. 547). Diese HistaminvAniagoni- 6n
»ten oder Antihistaminika sind in der Lage, viele Histaminwirkiingen zu blockieren, wie z. B. die bronchokonstiiktorische Wirkung, die gefäßpermeabilitätssleigernde Wirkung oder die kontrahierende Wirkung auf
das isolierte Meerschweinchenileum. Therapeutisch &5
wird diese Substanzklasse im wesentlichen dazu verwendet, das bei allergischen Reaktionen im Körper
freigesetzte oder /.. 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 B ο ν e t 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 »Hi-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 Rauenuterus.
Verbindungen, die diese Wirkungen des Histamins blockieren, werden als Histamin-H2-Receptor-Antagonisten bezeichnet (vgl. J. W. BI a c k, W. A. M. D u η -can, G. J. Durant, CR. Ganeil in 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 HrReceptor-Blocker darstellen. Beispielsweise hemmen sie selektiv die Pentagastrin- und Histamin-stimulierte Säuresekretion des
Magens, ferner die Histaminwirkungen am Meerschweinchenvorhof und am Rattenuterus.
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 (EDy)). Die Versuchsmethodik ist von
J. W. BI 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 H2-Receptor-Blockerwirkung zeigen.
Der Erfindung liegt die Aufgabe zugrunde, ein bestimmtes Cyanguanidin und seine Salze mit Säuren zu
schaffen, das als Histamin-Hj-Receplor-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
N -C N
HN N
sich durch wesentlich bessere pharmakologische Eigenschaften auszeichnet als die Bekannten Verbindungen.
Die Erfindung betriff· somit den in den Ansprüchen
gekennzeichneten Gegenstand,
Die Salze leiten sich von anorganischen oder organischen Säuren ab. wie Chlorwasserstoffsäure.
Bromwasserstoffsäure. Jodwpsserstoffsäure, Schwefelsäure. Salpetersäure, Pikrinsäure. Maleinsäure, Citronensäure. Apfelsäure, Bernsteinsäure. Weinsäure, Essigsäure. Propionsäure und Oxalsäure.
Die Verbindung der Erfindung kann nach üblichen Methoden hergestellt werden.
Als wirksamste Histamin-Ha-Receptor-Antagonisten
waren am Prioritätstag der vorliegenden Anmeldung (5. September 1972) das klinisch untersuchte Burirnamide (vgl. Black und Mitarb, Nature, a. a. Ο.) und Metiamide (vgl Beispiel 2 der BE-PS 7 79 775 bekannt. In
der nachstehenden Tabelle wird die Wirksamkeit von Burimamide, Metiamide und Cimetidine (Verbindung
der Erfindung) verglichen. Dabei sind folgende Werte angegeben:
Dieser Wert bezieht sich auf den Magensäuresekretionstest bei Ratten gemäß Black und Mitarb, Nature, a. a. O.
Kg:
10
Intravenöse Verabfolgung an Ratten.
Wirkung als Antagonist der durch Histamin induzierten Reizung des rechten Vorhofs von
Meerschweinchenherzen. Die Dissoziationskonstante Ka wird aus der Gleithung
K0= B/(x- 1)
berechnet, wobei χ das Verhältnis der Konzentrationen von Histamin ist, das zur Erzeugung
halbmaximaler Reaktionen in Gegenwart oder Abwesenheit unterschiedlicher Konzentrationen (B) des Antagonisten notwendig ist.
!5
Tabelle
R
il
Y
HN N
ED50
μ Mol/kg
LDi0
μ Mol/kg
χ Ό Ί
(vgl. Black und Mitarb.,
Nature, a.a.O.)
Metiamide
(vgl. Beispiel 2
der BE-PS 7 79 775)
Cimetidine
(erfindungsgemäß)
H CH2 S 6,4
(2,7-19,2)
Me S S 1,6
(1,2-2,2)
Me S NCN 1,37
(1,02-1,90)
1590 7,8
(1410-1780) (6,4-9,6)
Me = Methyl.
580
(500-650)
422
(398-488)
0,92
(0,74-1,15)
0,79
(0,68-0,92)
Aus den vorstehenden Werten geht die Überlegenheit von Cimetidine gegenüber Burimamide klar hervor.
Cimetidine wirkt auch besser als Metiamide. jedoch ist der Unterschied in der EDw relativ gering. Es hat sich
aber herausgestellt, daß Cimetidine gegenüber Metiamide bei der Therapie wesentliche Vorteile mit sich
bringt, da1 es wesentlich geringere Nebenwirkungen
aufweist. Bei akuten Toxmtätsuntersuchungen an Hunden ergab es sich nämlich, daß einige Tiere nach Metiamide-Dosen von mehr als 50 mg/kg an Lungenödemen
und pleuralen Effusionen eingingen, was bei entsprechenden Untersuchungen mit Cimetidine nicht der Fall
war. Außerdem hat sich bei einer anhaltenden, subakulen Toxizitätsuntersuchung an Ratten ergeben, daß
nach 9Otägiger oder längerer Verabfolgung von 366 mg/kg Metiamide pro Tag Störungen in den proximalen Nierentubuli auftreten. Bei entsprechenden subikuien Versuchen mil Cimetidine ließen sich auch nach
zweijähriger Verabfolgung von 950 mg/kg keine entsprechenden Feststellungen machen. Bei einer dreimonatigen Untersuchung an Hunden riefen tägliche
Metiamide-Dosen von 162 mg/kg Nekrosen an den Nierentubuli und zentrilobuläre Lebernekrosen hervor.
Ferner ergab sich bei diesen Hunden gelegentlich Granulozytopenie. Bei einer entsprechenden einjährigen Untersuchung mit Cimetidine-Dosen von 504 mg/kg
pro Tag ließen sich keine derartigen Feststellungen machen. Bezüglich der erwähnten toxikologischen Unter-
suchungen mit Metiamide wird auf Brimblecombe und Mitarb., Gastroenterology. Bd. 74 (1978), S. 339 bis 347,
insbesondere 346, verwiesen.
In den Beispielen 46 und 47 der BE-PS 7 79 775 sind
Verbindungen mit einer Guanidingruppierung beschrie
ben. Die Verbindung von Beispiel 46. nämlich 2-[(4-lmid-
azolyl-methylthio]-äthylguanidin-sulfat, weist einen ED«, Wert von 60 und die Verbindung von Beispiel 47.
nämlich N-(2-[(4-Methyl-5-imidazolyl)methylthio]-äthyl-N'-nitroguanidin. einen Wert von 21 auf. Diese
Verbindungen, die der beanspruchten Verbindung strukturmäßig am nächsten kommen, zeigen also eine erheblich geringere Aktivität als Cimetidine.
m
N-Cyan-N7-me(hyl-N"-|2-[(5-methylimidazol-
4-yl)-methylthio]-äthyl|-guanidin
(a) Eine Lösung von 17 g 5-Methyl-4-[(2-aminoäthyl)-thiomethyl]-imidazol und 11,2 g N-Cyan-N'.S-dimethylf>5 isothioharnstoff in 500 ml Acetonitril wird 24 Stunden
unter Rückfluß erhitzt. Nach dem Einengen und anschließendem Chromatographieren des Rückstandes
an Kieselgel mit Acetonitril als Elutionsmittel erhält
man die Titelverbindung, die aus Acetonitril/Äther
umkristallisiert wird; F. 141 bis 142°C.
(b) Eine Lösung von 2,44 g N-Methyl-N'-[2-(5-methylirnidazol-4-yl)-methylthio)-äthyl]-thioharnstoff
in 50 ml Acetonitril wird mit 3 g Bleicyanamid versetzt. Nach
Zugabe von 20 ml Dimethylformamid wird die Suspension
24 Stunden unter Rückfluß erhitzt und gerührt. Nach aem Abfiltrieren und Eindampfen unter vermindertem
Dr'ck wird die erhaltene Verbindung an Kieselgel mit Acetonitril als Elutionsmittel chromatographisch
gereinigt und umkristallisiert. Man erhält die Tittlverbindung vom F. 139 bis 1410C.
(c) (i) Eine Lösung von 23,4 g 5-Methyl-4-[(2-aminoäthyl)-thiomethyl]-imiüazol
in Äthanol wird bei Raumtemperatur langsam unter 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-methylimidazol-4-yl)-methylthio]-äthyl}-S-methylisothioharnstoff
vom F. 148 bis 1500C erhalten. Das Filtrai wird unier
vermindertem Druck eingeengt, der RPtrkstand mit kaltem Wasser digeriert und der erhaltene Niederschlag
abfiltriert und zweimal aus Isopropa.iolMther unikristallisiert.
Es werden weitere 27 g Produkt vom F. 148 bis 150° C erhalten.
(ii) 75 ml 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 2Vj Stunden stehengelassen. Nach dem Eindampfen
unter vermindertem Druck wird der Rückstand zweimal aus Isopropanol/Petroläther umkristailisiert.
Ausbeute 8,6 g der Titelverbindung vom F. 141 bis 143° C.
(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 mit 22 ml einer 33prozentigen Methylaminlösung
in Äthanol versetzt und 4 Stunden stehengelassen. Nach dem Eindämmen und Umkristallisieren
aus Isopropanol/Äther werften 2 g der Titelverbindung
vom F. 139 bis 1400C erhalten.
Claims (1)
- Patentansprüche:l.N-Cyan-N'-methyl-N"-{2-[(5-methyI-imidazol-4-yl)-meihyIthio]-äthyl|-guanidin und seine Salze mit Säuren.Z Verwendung von N-Cyan-N'-methyl-N"-{2-[(5-methylirnidazoI-4-yl)-methylthio]-äthyI}-guanidin und seinen Salzen mit Säuren als Histamin-H2-Receptor-Antagonist
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB4116072A GB1397436A (en) | 1972-09-05 | 1972-09-05 | Heterocyclic n-cyanoguinidines |
GB615473 | 1973-02-08 |
Publications (3)
Publication Number | Publication Date |
---|---|
DE2344779A1 DE2344779A1 (de) | 1974-03-14 |
DE2344779B2 DE2344779B2 (de) | 1979-04-26 |
DE2344779C3 true DE2344779C3 (de) | 1981-05-27 |
Family
ID=26240478
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE2344779A Expired DE2344779C3 (de) | 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 |
Country Status (14)
Country | Link |
---|---|
US (2) | US3876647A (de) |
JP (1) | JPS561309B2 (de) |
AU (1) | AU472456B2 (de) |
CA (1) | CA1045142A (de) |
CY (1) | CY855A (de) |
DE (1) | DE2344779C3 (de) |
FR (1) | FR2199467B2 (de) |
GB (1) | GB1397436A (de) |
HK (1) | HK55276A (de) |
IE (1) | IE38353B1 (de) |
KE (1) | KE2626A (de) |
MY (1) | MY7600229A (de) |
NL (1) | NL187240C (de) |
SG (1) | SG28676G (de) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2928857B2 (de) | 1978-07-19 | 1981-07-23 | Pliva pharmazeutische und chemische Fabrik, Zagreb | Verfahren zur Herstellung von N-Cyano-N'-methyl-N''-[2-{[(5-methylimidazol-4-yl)-methyl]-thio}-ethyl]-guanidin |
Families Citing this family (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4024271A (en) * | 1971-03-09 | 1977-05-17 | Smith Kline & French Laboratories Limited | Pharmacologically active guanidine compounds |
US4287198A (en) * | 1971-03-09 | 1981-09-01 | Smith Kline & French Laboratories Limited | Pharmacologically active guanidine compounds |
US4221802A (en) * | 1972-02-03 | 1980-09-09 | Smith Kline & French Laboratories Limited | Pharmacologically active guanidine compounds for inhibiting H-2 histamine receptors |
US4000302A (en) * | 1972-04-20 | 1976-12-28 | Smith Kline & French Laboratories Limited | Pharmaceutical compositions and methods of inhibiting H-1 and H-2 histamine receptors |
US4104382A (en) * | 1972-04-20 | 1978-08-01 | Smith Kline & French Laboratories Limited | Pharmaceutical compositions and methods of inhibiting H-1 and H-2 histamine receptors |
GB1421999A (en) * | 1973-02-08 | 1976-01-21 | Smith Kline French Lab | Heterocyclic containing sulphoxides |
US3979398A (en) * | 1973-02-08 | 1976-09-07 | Smith Kline & French Laboratories Limited | Sulphoxides |
GB1421792A (en) * | 1973-05-17 | 1976-01-21 | Smith Kline French Lab | Heterocyclic substituted-1, 1-diamino-ethylene derivatives methods for their preparation and compositions containing them |
US4002759A (en) * | 1973-05-17 | 1977-01-11 | Smith Kline & French Laboratories Limited | Pyridylbutylamino ethylene compounds |
US4024260A (en) * | 1973-05-17 | 1977-05-17 | Smith Kline & French Laboratories Limited | Ethylene derivatives |
GB1531231A (en) * | 1974-09-02 | 1978-11-08 | Smith Kline French Lab | Process for the production of cyanoguanidine derivatives |
GB1489879A (en) * | 1974-12-20 | 1977-10-26 | Leo Pharm Prod Ltd | N'-cyano-n'-3-pyridylguanidines |
GB1554153A (en) * | 1975-05-15 | 1979-10-17 | Smith Kline French Lab | Process for making 2-amino-2-alkylthionitroethylenes |
US4154838A (en) * | 1975-07-31 | 1979-05-15 | Smith Kline & French Laboratories Limited | Alkoxy pyridine |
GB1564502A (en) | 1975-07-31 | 1980-04-10 | Smith Kline French Lab | Guanidines thioureas and 1,1-diamino-2-nitroethylene derivatives |
IN146736B (de) * | 1975-10-02 | 1979-08-25 | Smith Kline French Lab | |
US4067984A (en) * | 1975-11-05 | 1978-01-10 | Smith Kline & French Laboratories Limited | Pyridylbutylamino ethylene compounds |
GB1565966A (en) | 1976-08-04 | 1980-04-23 | Allen & Hanburys Ltd | Aminoalkyl furan derivatives |
NZ184893A (en) * | 1976-09-21 | 1980-11-28 | Smith Kline French Lab | Pure crystalline form of cimetidine a(n-methyl-n-cyano-n-(-2-(5-methyl-4imidazolyl) methylthio) ethyl)-guanidine andpharmaceutical compositions containing it |
DD129906A5 (de) * | 1976-09-21 | 1978-02-15 | Smith Kline French Lab | Verfahren zur herstellung einer kristallographisch reinen polymorphen form von cimetidin(cimetidin a) |
DE2817078C2 (de) * | 1977-04-20 | 1995-06-14 | Zeneca Ltd | Guanidinderivate |
ZA782129B (en) | 1977-04-20 | 1979-03-28 | Ici Ltd | Hertocyclic derivatives |
US4165378A (en) | 1977-04-20 | 1979-08-21 | Ici Americas Inc. | Guanidine derivatives of imidazoles and thiazoles |
GB1601459A (en) | 1977-05-17 | 1981-10-28 | Allen & Hanburys Ltd | Aminoalkyl thiophene derivatives |
NZ187376A (en) * | 1977-06-03 | 1981-05-29 | Bristol Myers Co | N-cyano-n-(2-(4-methyl-5-imidazolyl)methylthio)ethyl)-n-alkynyl guanidines intermediates pharmaceutical compositions |
DE2800148A1 (de) | 1978-01-03 | 1979-07-12 | Basf Ag | Verfahren zur herstellung von 4-methyl-5-chlormethyl-imidazol |
DE2905134A1 (de) * | 1978-02-17 | 1979-08-23 | Degussa | Neue acylierte aminoalkyl-cyanoguanidine mit einem heterocyclischen rest |
YU40332B (en) * | 1978-04-26 | 1985-12-31 | Lek Tovarna Farmacevtskih | Process for preparing n-cyano-n'-methyl-n''-((2-((4-methyl-5-imidazolyl)-methylthio)ethyl)-guanidine |
DE2963363D1 (en) | 1978-05-24 | 1982-09-09 | Ici Plc | Antisecretory thiadiazole derivatives, processes for their manufacture and pharmaceutical compositions containing them |
US4250316A (en) * | 1978-11-24 | 1981-02-10 | Bristol-Myers Company | Pyridyl guanidine anti-ulcer agents |
JPS5914460B2 (ja) * | 1978-12-27 | 1984-04-04 | 相互薬工株式会社 | H↓2受容体「きつ」抗剤シメチジンの製造法 |
EP0014057B1 (de) * | 1979-01-18 | 1985-01-02 | Imperial Chemical Industries Plc | Guanidin-Derivate, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen |
US4287346A (en) * | 1979-02-16 | 1981-09-01 | Eisai Co., Ltd. | Cyanoguanidine derivatives |
US4220654A (en) * | 1979-06-04 | 1980-09-02 | Merck & Co., Inc. | Cyclic imidazole cyanoguanidines |
DE3107599C2 (de) * | 1981-02-27 | 1982-12-16 | Ludwig Heumann & Co GmbH, 8500 Nürnberg | N-Cyan-N'-methyl-N"-{2-[(5-methylthio-imidazol-4-yl)-methylthio]-äthyl}-guanidin, Verfahren zu seiner Herstellung und diese Verbindung enthaltende Arzneimittel |
DE3213509A1 (de) * | 1982-04-10 | 1983-10-20 | Basf Ag, 6700 Ludwigshafen | N-substituierte imidazol-derivate, ihre herstellung, diese enthaltende arzneimittel und ihre verwendung |
JPS5933267A (ja) * | 1982-08-19 | 1984-02-23 | Fujimoto Seiyaku Kk | グアニジン誘導体およびその製造法 |
NL8303965A (nl) * | 1982-12-08 | 1984-07-02 | Degussa | Nieuwe etheendiamine- en guanidine-derivaten; werkwijze voor het bereiden daarvan; geneesmiddelen die ze bevatten; werkwijze voor het bereiden van dergelijke geneesmiddelen; toepassing van de verbindingen voor het bereiden van geneesmiddelen en in de geneeskunde. |
US4495193A (en) * | 1982-12-30 | 1985-01-22 | Biomeasure, Inc. | Imidazole compounds which reduce gastric acid secretion |
US4565815A (en) * | 1982-12-30 | 1986-01-21 | Biomeasure, Inc. | Pyrazolo[1,5-a]-1,3,5-triazines |
US4617311A (en) * | 1985-05-17 | 1986-10-14 | Eli Lilly And Company | Antiasthmatic method |
DE3531504A1 (de) * | 1985-09-04 | 1987-03-12 | Basf Ag | 3-aminomethylpyrrol-1-yl-alkylamine und diese verbindungen enthaltende therapeutische mittel |
IE58373B1 (en) * | 1986-06-18 | 1993-09-08 | Bloomfield Frederick Jacob | 5-Lipoxygenase pathway inhibitors |
JPH085859B2 (ja) * | 1986-07-01 | 1996-01-24 | 日本バイエルアグロケム株式会社 | 新規アルキレンジアミン類 |
IE960441L (en) * | 1988-12-27 | 1990-06-27 | Takeda Chemical Industries Ltd | Guanidine derivatives, their production and insecticides |
US5160549A (en) * | 1990-10-31 | 1992-11-03 | Foster Wheeler Energy Corporation | Tube fin trimming machine and method for use |
IT1299198B1 (it) | 1998-03-05 | 2000-02-29 | Nicox Sa | Sali nitrati di farmaci antiulcera |
WO2011044637A1 (en) * | 2009-10-15 | 2011-04-21 | Monash University | Affinity ligands and methods for protein purification |
WO2022034121A1 (en) | 2020-08-11 | 2022-02-17 | Université De Strasbourg | H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3036083A (en) * | 1959-05-15 | 1962-05-22 | Ciba Geigy Corp | Certain 2-pyridyl lower alkyl guanidines |
US3074955A (en) * | 1960-11-30 | 1963-01-22 | Us Vitamin Pharm Corp | Pyridylalkyl dicyandiamides and guanylureas |
BE758145A (fr) * | 1969-10-29 | 1971-04-28 | Smith Kline French Lab | Iso-thio-urees et derives |
BE758146A (fr) * | 1969-10-29 | 1971-04-28 | Smith Kline French Lab | Derives de l'amidine |
US3734924A (en) * | 1970-10-14 | 1973-05-22 | Smith Kline French Lab | Carboxamidines |
US3759944A (en) * | 1970-10-14 | 1973-09-18 | Smith Kline French Lab | Isothioureas and their derivatives |
IE36050B1 (en) * | 1971-03-09 | 1976-08-04 | Smith Kline French Lab | Ureas thioureas and guanidines |
GB1338169A (en) * | 1971-03-09 | 1973-11-21 | Smith Kline French Lab | Ureas thioureas and guanidines |
CA967960A (en) * | 1971-04-30 | 1975-05-20 | Sumitomo Chemical Company | Isothiourea compounds and their production and use |
-
1972
- 1972-09-05 GB GB4116072A patent/GB1397436A/en not_active Expired
-
1973
- 1973-07-26 CA CA177,408A patent/CA1045142A/en not_active Expired
- 1973-08-02 US US384993A patent/US3876647A/en not_active Expired - Lifetime
- 1973-08-02 US US385027A patent/US3897444A/en not_active Expired - Lifetime
- 1973-08-03 AU AU58903/73A patent/AU472456B2/en not_active Expired
- 1973-08-21 CY CY855A patent/CY855A/xx unknown
- 1973-08-22 IE IE1466/73A patent/IE38353B1/xx not_active IP Right Cessation
- 1973-09-04 FR FR7331885A patent/FR2199467B2/fr not_active Expired
- 1973-09-04 NL NLAANVRAGE7312198,A patent/NL187240C/xx not_active IP Right Cessation
- 1973-09-05 DE DE2344779A patent/DE2344779C3/de not_active Expired
- 1973-09-05 JP JP10012573A patent/JPS561309B2/ja not_active Expired
-
1976
- 1976-05-18 KE KE2626*UA patent/KE2626A/xx unknown
- 1976-09-08 HK HK552/76*UA patent/HK55276A/xx unknown
- 1976-12-31 MY MY1976229A patent/MY7600229A/xx unknown
- 1976-12-31 SG SG286/76A patent/SG28676G/en unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2928857B2 (de) | 1978-07-19 | 1981-07-23 | Pliva pharmazeutische und chemische Fabrik, Zagreb | Verfahren zur Herstellung von N-Cyano-N'-methyl-N''-[2-{[(5-methylimidazol-4-yl)-methyl]-thio}-ethyl]-guanidin |
Also Published As
Publication number | Publication date |
---|---|
SG28676G (en) | 1987-04-03 |
CA1045142A (en) | 1978-12-26 |
DE2344779B2 (de) | 1979-04-26 |
AU472456B2 (en) | 1976-05-27 |
AU5890373A (en) | 1975-02-06 |
KE2626A (en) | 1976-05-28 |
NL7312198A (de) | 1974-03-07 |
US3876647A (en) | 1975-04-08 |
IE38353L (en) | 1974-03-05 |
IE38353B1 (en) | 1978-03-01 |
JPS4975574A (de) | 1974-07-20 |
CY855A (en) | 1976-09-10 |
NL187240C (nl) | 1991-07-16 |
MY7600229A (en) | 1976-12-31 |
FR2199467B2 (de) | 1977-01-28 |
GB1397436A (en) | 1975-06-11 |
HK55276A (en) | 1976-09-17 |
FR2199467A2 (de) | 1974-04-12 |
US3897444A (en) | 1975-07-29 |
JPS561309B2 (de) | 1981-01-13 |
DE2344779A1 (de) | 1974-03-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DE2344779C3 (de) | 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 | |
DE2211454C3 (de) | ||
DE2406166A1 (de) | Sulfoxide, ihre salze mit saeuren, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel | |
CH615669A5 (de) | ||
DE2344833C2 (de) | 5-Methylimidazol-4-ylmethylthioäthylguanidine und ihre Verwendung als Histamin-H ↓2↓-Receptor-Antagonisten | |
DD143772A5 (de) | Verfahren zur herstellung von neuen thiadiazolderivaten | |
DE3005786A1 (de) | Cyanoguanidinderivate und verfahren zu deren herstellung | |
DE2433625A1 (de) | Harnstoff-derivate, verfahren zu ihrer herstellung und arzneimittel | |
CH615916A5 (de) | ||
LU82000A1 (de) | Neue thiazolylmethylthioderivate,verfahren zu deren herstellung und arzneimittel | |
DE2604056A1 (de) | Thiocarbaminsaeure-derivate | |
DE2052692A1 (de) | Isothioharnstoffverbmdungen, ihre Salze mit Sauren, Verfahren zu ihrer Her stellung und ihre Verwendung zur Her stellung von Arzneimitteln | |
DE2510860A1 (de) | Harnstoff-derivate, verfahren zu ihrer herstellung und arzneimittel | |
CH632994A5 (en) | Process for preparing guanidine derivatives | |
DE2819874A1 (de) | Bisamidine, verfahren zu ihrer herstellung und ihre verwendung als histamin- h tief 2 - receptor-antagonisten | |
DD144916A5 (de) | Verfahren zur herstellung von pyrimidinverbindungen und ihren salzen | |
DE1545628A1 (de) | Verfahren zur Herstellung von blutdrucksenkend und sedativ wirksamen Derivaten des 2-(2-Halogenanilino)-1,3-diazacyclopentens-(2) | |
DE1445505B2 (de) | Im phenylkern substituierte 2-phenylamino-1,3-diazacyclopentene-(2) | |
DE2720111A1 (de) | Korrosionsschutzmittel fuer zweibad-stabilisatorbaeder | |
DE2131625A1 (de) | Thioharnstoffderivate,Verfahren zu ihrer Herstellung und Arzneipraeparate | |
CH641167A5 (en) | N-Cyano-N'-(2-((4-methyl-5-imidazolyl)-methylthio)ethyl)-N''-alkyny l guanidines | |
DE2733952A1 (de) | Alpha, omega-diaminoalkylenverbindungen | |
DE1934392C3 (de) | Neue 2-Pyridylthioamide und Verfahren zu ihrer Herstellung | |
DE2121694B2 (de) | Diamino-s-triazinderivate, ein verfahren zu deren herstellung und diese enthaltende therapeutische zubereitungen | |
DE2263110C3 (de) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
OI | Miscellaneous see part 1 | ||
OI | Miscellaneous see part 1 | ||
C3 | Grant after two publication steps (3rd publication) |