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-Antagonist

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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
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methyl
histamine
cyano
methylthio
ethyl
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DE2344779B2 (de
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John Colin Codicote Hertfordshire Emmett
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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

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
CH, CH2SCH2C H2NHC NHCH,
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
CH1XCH2CHjNHCNHCH1
il Y
HN N
Verbindung
ED50 μ Mol/kg
LDi0 μ Mol/kg
χ Ό Ί
Burimamide
(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.
Die in Klammern angegebenen Werte geben die 95%igen Vertrauensgrenzen an.
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.
Beispiel
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)

  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
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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Families Citing this family (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4287198A (en) * 1971-03-09 1981-09-01 Smith Kline & French Laboratories Limited Pharmacologically active guanidine compounds
US4024271A (en) * 1971-03-09 1977-05-17 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
IE47044B1 (en) 1977-04-20 1983-12-14 Ici Ltd Guanidine 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
JPS54132566A (en) 1978-01-18 1979-10-15 Ici Ltd Guanidine derivative*its manufacture and secretion controlling pharmaceutical composition containing it
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
EP0006679B1 (de) 1978-05-24 1982-07-21 Imperial Chemical Industries Plc Anti-Sekretion Thiadiazol-Derivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
YU40716B (en) * 1978-07-19 1986-04-30 Pliva Pharm & Chem Works Process for obtaining n-cyano-n'-methyl-n'-û2-|5-metylimidazole4-yl)-methyl¨-thioethylù guanidine
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
NL8000869A (nl) * 1979-02-16 1980-08-19 Eisai Co Ltd Cyanoguanidine-derivaten en werkwijze voor de bereiding daarvan.
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
IE960442L (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
EP2488544B1 (de) * 2009-10-15 2015-03-18 Monash University Affinitätsliganden und verfahren zur proteinreinigung
US20230349922A1 (en) 2020-08-11 2023-11-02 Université De Strasbourg H2 Blockers Targeting Liver Macrophages for the Prevention and Treatment of Liver Disease and Cancer

Family Cites Families (9)

* Cited by examiner, † Cited by third party
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
GB1338169A (en) * 1971-03-09 1973-11-21 Smith Kline French Lab Ureas thioureas and guanidines
IE36050B1 (en) * 1971-03-09 1976-08-04 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

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CA1045142A (en) 1978-12-26
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FR2199467A2 (de) 1974-04-12
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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
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