DE1445538C - 2 (2,6 dibromophenyl) amino 1,3 diazacyclopentene (2), its acid addition salts and processes for their preparation - Google Patents
2 (2,6 dibromophenyl) amino 1,3 diazacyclopentene (2), its acid addition salts and processes for their preparationInfo
- Publication number
- DE1445538C DE1445538C DE1445538C DE 1445538 C DE1445538 C DE 1445538C DE 1445538 C DE1445538 C DE 1445538C
- Authority
- DE
- Germany
- Prior art keywords
- amino
- dibromophenyl
- diazacyclopentene
- acid addition
- acid
- 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
- 239000002253 acid Substances 0.000 title claims description 10
- 150000003839 salts Chemical class 0.000 title claims description 7
- 239000011780 sodium chloride Substances 0.000 title claims description 7
- 238000000034 method Methods 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title claims description 3
- JUEMQEWCEFMUAA-UHFFFAOYSA-N BrC1=C(C(=CC=C1)Br)N1C(=NCC1)N Chemical compound BrC1=C(C(=CC=C1)Br)N1C(=NCC1)N JUEMQEWCEFMUAA-UHFFFAOYSA-N 0.000 title 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- UMGDCJDMYOKAJW-UHFFFAOYSA-O hydron;thiourea Chemical class NC(N)=[SH+] UMGDCJDMYOKAJW-UHFFFAOYSA-O 0.000 claims description 3
- 230000003472 neutralizing Effects 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- ACGDKVXYNVEAGU-UHFFFAOYSA-N Guanethidine Chemical compound NC(N)=NCCN1CCCCCCC1 ACGDKVXYNVEAGU-UHFFFAOYSA-N 0.000 description 5
- 229960003602 Guanethidine Drugs 0.000 description 5
- -1 ammonium thioureas Chemical class 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229960000583 Acetic Acid Drugs 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 230000003276 anti-hypertensive Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000001624 sedative Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 210000001715 Carotid Arteries Anatomy 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N Dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 229960002598 Fumaric acid Drugs 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229940074355 Nitric Acid Drugs 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229940116315 Oxalic Acid Drugs 0.000 description 1
- 229940095574 Propionic acid Drugs 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 230000001077 hypotensive Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
Description
i 445i 445
Es wurde gefunden, daß 2-(2',6'-Dibromphenyl)-amino-l,3-diazacyclopenten-(2) sowie dessen Salze wertvolle pharmazeutische Eigenschaften aufweisen.It has been found that 2- (2 ', 6'-dibromophenyl) -amino-l, 3-diazacyclopentene- (2) and its salts have valuable pharmaceutical properties.
Nach der Erfindung kann die Verbindung z. B. durch Umsetzung eines Isothiuroniumsalzes der FormelAccording to the invention, the connection can, for. B. by reacting an isothiuronium salt formula
BrBr
-NH--NH-
BrBr
NH ...
-C' -HX
SRNH ...
-C '-HX
SR
IIII
worin R einen niederen Alkylrest und X einen Säurerest bedeutet, mit Äthylendiamin hergestellt werden. Die Umsetzung wird vorzugsweise ohne Verwendung eines Lösungsmittels durch einfaches Erhitzen der Reaktionskomponenten auf etwa 100 bis 200°Cdurchgeführt. Diese Methode führt in kurzer Zeit zu befriedigenden Ausbeuten an dem gewünschten Endprodukt. Prinzipiell kann die Reaktion auch bei niedrigeren Temperaturen (60 bis 1400C) unter Zusatz eines geeigneten Lösungsmittels, das vorzugsweise polare Gruppen enthält, wie Wasser oder niedere Alkohole, ablaufen; es wurde jedoch festgestellt, daß hierbei lange Reaktionszeiten in Kauf genommen werden müssen, wenn man gute Ausbeuten erzielen will.where R is a lower alkyl radical and X is an acid radical, are prepared with ethylenediamine. The reaction is preferably carried out without using a solvent by simply heating the reaction components to about 100 to 200 ° C. This method leads to satisfactory yields of the desired end product in a short time. In principle, the reaction can also take place at lower temperatures (60 to 140 ° C.) with the addition of a suitable solvent, which preferably contains polar groups, such as water or lower alcohols; however, it has been found that long reaction times have to be accepted if good yields are to be achieved.
Bei Verwendung von 2',6'-disubstituierten Phenylderivaten führt selbst langes Erhitzen in dem betreffenden Lösungsmittel lediglich zu einer geringfügigen Ausbeute an Reaktionsprodukt. Auch eine Variante des zuletzt angegebenen Verfahrens, der Ablauf der Reaktion unter Druck, eventuell unter Verwendung eines inerten Gases, bringt keine Steigerung der Ausbeute.When using 2 ', 6'-disubstituted phenyl derivatives, even prolonged heating results in the relevant Solvent only leads to a slight yield of the reaction product. Also one Variant of the process mentioned last, the course of the reaction under pressure, possibly under Using an inert gas does not increase the yield.
Das als Ausgangsmaterial benötigte Isothiuroniumsalz der Formel II erhält man beispielsweise durch Erhitzen eines in bekannter Weise aus 2',6'-Dibromanilin und Ammoniumrhodanid hergestellten Thioharnstoffe (s. Houben—We yl, Die Methoden der Organischen Chemie, Bd. 9, S. 887) mit einer Methylverbindung wie einem Methylhalogenid oder Dimethylsulfat in einem geeigneten Lösungsmittel, z. B. einem niederen Alkohol.The isothiuronium salt required as starting material of the formula II is obtained, for example, by heating one in a known manner from 2 ', 6'-dibromaniline and ammonium thioureas produced (see Houben-Weyl, The Methods der Organischen Chemie, Vol. 9, p. 887) with a methyl compound such as a methyl halide or Dimethyl sulfate in a suitable solvent, e.g. B. a lower alcohol.
Das 2-(.2',6'-Dibromphenyl)-amino-l,3-diazacyclopenten-(2) kann nach üblichen Methoden in die entsprechenden Säureadditionssalze mit physiologisch unbedenklichen Anionen übergeführt werden, z. B. durch Behandlung mit einer anorganischen oder organischen Säure, wie Mineralsäuren, z. B. Chlorwasserstoffsäure oder Bromwasserstoffsäure, Salpetersäure, Essigsäure, Oxalsäure, Weinsäure, Fumarsäure, Maleinsäure, Zitronensäure, Ascorbinsäure oder Propionsäure. Die Herstellung von Säureadditionssalzen ist insbesondere dann vorteilhaft, wenn wasserlösliche, für Injektionszwecke geeignete Verbindungen hergestellt werden sollen.The 2 - (. 2 ', 6'-Dibromophenyl) -amino-l, 3-diazacyclopentene- (2) can by conventional methods in the corresponding Acid addition salts are converted with physiologically harmless anions, e.g. B. by treatment with an inorganic or organic acid such as mineral acids, e.g. B. hydrochloric acid or hydrobromic acid, nitric acid, acetic acid, oxalic acid, tartaric acid, fumaric acid, Maleic acid, citric acid, ascorbic acid or propionic acid. The production of acid addition salts is particularly advantageous when preparing water-soluble compounds suitable for injection purposes should be.
Die erfindungsgemäße Verbindung besitzt wertvolle pharmazeutische, insbesondere blutdrucksenkende Eigenschaften. In der folgenden Tabelle sind die Ergebnisse der Prüfung auf blutdrucksenkende Wirkung sowie die LD50 und der therapeutische Index der erfindungsgemäßen Verbindung im Vergleich mit dem bekannten blutdrucksenkenden Mittel Guanethidin und der in der Patentschrift 1 131 687 im Beispiel 1 beschriebenen Verbindung 2-(/<-Piperidinoäthyl-amino)-imidazolin-(2) zusammengefaßt. Als Bezugssubstanz wurde Guanethidin gewählt. Als Versuchstiere dienten Kaninchen in Urethannarkose, deren Blutdruck blutig aus der Arteria carotis mit einem Quecksilbermanometer registriert wurde. Die Zufuhr der Substanzen erfolgte intravenös.The compound according to the invention has valuable pharmaceutical, in particular antihypertensive, properties. The following table shows the results of the test for antihypertensive effects, as well as the LD 50 and the therapeutic index of the compound according to the invention in comparison with the known antihypertensive agent guanethidine and the compound 2 described in patent specification 1,131,687 in example 1 - (/ <- Piperidinoethyl-amino) -imidazoline- (2) summarized. Guanethidine was chosen as the reference substance. The test animals were rabbits under urethane anesthesia, the blood pressure of which was recorded from the carotid artery with a mercury manometer. The substances were administered intravenously.
Verbindungconnection
Blutdrucksenkung Guanethidin = I Dosis
Guanethidin = IBlood pressure reduction guanethidine = I dose
Guanethidine = I.
LD50
mg/kg Maus, s. c.LD 50
mg / kg mouse, sc
TherapeutischerMore therapeutic
Index
LD50/Spalte 3index
LD 50 / column 3
2-(2',6'-Dibromphenyl)-amino-l,3-diazacyclopenten-(2) 2- (2 ', 6'-dibromophenyl) -amino-l, 3-diazacyclopentene- (2)
Guanethidin Guanethidine
2-(//-PiperidinoäthyI-amino)-2 - (// - PiperidinoäthyI-amino) -
imidazolin-(2) imidazoline- (2)
40 I40 I.
0,09 0,025
I0.09 0.025
I.
IIII
113,5.
470113.5.
470
1165-1165-
4540
4704540
470
106106
Darüber hinaus besitzt die erfindungsgemäße Verbindung eine gute sedative Wirkung, die bei der zur Blutdrucksenkung notwendigen jeweiligen Dosierung bereits nachweisbar ist, jedoch erst in höherer Dosierung deutlich zutage tritt. Die neue Verbindung soll daher in der Medizin als Hypotensivum bzw. Sedativum Verwendung finden. Sie läßt sich zu allen für pharmazeutische Zwecke üblichen Zubereitungsformen verarbeiten. Zum Beispiel kann man daraus Pillen, Dragees, Tabletten, Suppositorien, Emulsionen, Lösungen und Injektionslösungen herstellen.In addition, the compound according to the invention has a good sedative effect, which in the for The respective dosage required to lower blood pressure can already be demonstrated, but only in higher dosage clearly emerges. The new compound should therefore be used in medicine as a hypotensive or Find sedative use. It can be processed into all forms of preparation customary for pharmaceutical purposes. For example, you can get out of it Manufacture pills, coated tablets, tablets, suppositories, emulsions, solutions and injection solutions.
6565
2-(2',6'-Dibromphenyl)-amino-l,3-diazacyclopenten-(2) 2- (2 ', 6'-dibromophenyl) -amino-l, 3-diazacyclopentene- (2)
10,4 g 2,6-Dichlorphenyl-S-methyI-isothiuroniumhydrojodid werden mit 2,3 ml Äthylendiamin (150%)10.4 g of 2,6-dichlorophenyl-S-methyl-isothiuronium hydroiodide with 2.3 ml of ethylenediamine (150%)
unter Rühren etwa 1 Stunde auf 130 bis 150°C erhitzt. Nach Beendigung der Mercaptanbildung wird das Reaktionsgemisch in heißer verdünnter Essigsäure aufgenommen und die erhaltene Lösung mit 2 n-Natronlauge alkalisiert. Die dabei ausfallende Base wird abgesaugt, mit Wasser gewaschen und getrocknet. Die Ausbeute beträgt 2,1 g = 27,4% der Theorie vom Fp. = 126 bis 1290C; Hydrochloric^ Fp. = 292 bis 2940C.heated to 130 to 150 ° C. for about 1 hour with stirring. After the formation of mercaptan has ended, the reaction mixture is taken up in hot, dilute acetic acid and the resulting solution is made alkaline with 2N sodium hydroxide solution. The base which precipitates out is filtered off with suction, washed with water and dried. The yield is 2.1 g = 27.4% of theory with a melting point of 126 to 129 ° C .; Hydrochloric ^ m.p. = 292 to 294 0 C.
Claims (2)
Family
ID=
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